A Useful Allene for the Stereoselective Synthesis of Protected Quaternary 2-Amino-2-vinyl-1,3-diols

Article abstract of DOI:10.1021/acs.joc.6b02765

Treatment of readily available allene 1 with Cy₂BH followed by addition of an aldehyde led to quaternary protected 2-amino-2-vinyl-1,3-diols in high yield and excellent stereochemical purity. The choice of benzoyl as N-protecting group is critical since the observed N- to O-Bz transfer during the process prevents later undesired isomerizations in the adducts and keeps all heteroatoms protected.

Full text of DOI:10.1021/acs.joc.6b02765

Subscriber access provided by Fudan University
Note
A Useful Allene for the Stereoselective Synthesis
of Protected Quaternary 2-Amino-2-Vinyl-1,3-diols
Aleix Rodriguez, Xavier Ariza, Miguel A. Contreras, Jordi Garcia,
Paul Lloyd-Williams, Nerea Mercadal, and Carolina Sánchez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02765 • Publication Date (Web): 13 Jan 2017
Downloaded from http://pubs.acs.org on January 13, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
A Useful Allene for the Stereoselective Synthesis of Protected
Quaternary 2-Amino-2-Vinyl-1,3-diols
7
8
9
Aleix Rodríguez,†, ‡ Xavier Ariza,*,†,‡,§ Miguel A. Contreras,† Jordi Garcia,*,†,‡,§ Paul
Lloyd-Williams, †,‡,§ Nerea Mercadal,† and Carolina Sánchez†
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
†Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Facultat de Química, Universitat de
Barcelona, Martí i Franquès 1, 08028-Barcelona, Spain
‡Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
§CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
O
O
1) Cy2BH
2) RCHO
Bz
C
O
1
N
O
HN
3
R
2
H
3) N(CH2CH2OH)3
OBz
H
1
70-90%
dr > 99:1
ABSTRACT: Treatment of readily available allene 1 with Cy2BH followed by addition
of an aldehyde led to quaternary protected 2-amino-2-vinyl-1,3-diols in high yield and
excellent stereochemical purity. The choice of benzoyl as N-protecting group is critical
since the observed N- to O-Bz transfer during the process prevents later undesired
isomerizations in the adducts and keeps all heteroatoms protected.
KEYWORDS: allene, crotylborane, hydroboration, quaternary carbon, sphingosine,
substituted serine
Quaternary a amino acids bearing adjacent hydroxyl functionalities are structural
features present in numerous metabolites of biological relevance including myriocin,1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 16
1
2
3
4
the proteasome inhibitor lactacystin,2 and the antitumor agent (–)-altemicidin (Fig. 1).3
5
6
7
Even structurally simpler a-branched serines and threonines are also important
synthetic targets.4 Furthermore, (S)-a-vinyl serine and other a-vinyl amino acids show
interesting biological activities as suicide inhibitors for enzymes of the amino acid
decarboxylase class.5
8
9
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
Figure 1. Compounds incorporating quaternary b-hydroxylated a-amino acids
Sphingolipids are a family of lipids that play essential roles as structural cell membrane
components and also in cell signalling through a complex metabolism catalyzed by
specific enzymes.6 From a structural point of view, most mammalian sphingolipids
share
a
common backbone incorporating (E)-2-amino-4-octadecen-1,3-diol
(sphingosine). Interestingly, structural analogues of sphingosine such as quaternary 2-
vinyl compound 2 might act as selective inhibitors of these enzymes.6c
ACS Paragon Plus Environment

Page 3 of 16
The Journal of Organic Chemistry
1
2
3
4
OH OH
5
6
7
8
9
NH2
Sphingosine
OH OPO3H–
OP OP"
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
3
1
2
R
R'
NHP"'
+H3N
2
Protected 2-amino-
2-vinyl-1,3-diols
Figure 2. Sphingosine, compound 2 and its possible precursor
We envisaged that both b-hydroxylated a-amino acids such as (S)-a-vinyl serine and
certain analogues of sphingolipids such as compound 2, might be generated from
protected 2-amino-2-vinyl-1,3-diols (Figure 2).7
As part of our studies aimed at the synthesis of polyhydroxylated a-amino acids,8 we
recently reported a new tandem reaction leading to protected tosylcarbamates 3 in high
yields and excellent diastereoselectivities (Scheme 1).9 This simple one-pot process was
based on the hydroboration of tosyl allene 4 with Cy2BH, followed by the addition of an
aldehyde.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 16
1
2
3
4
O
Ts
N
O
5
6
7
C
H
8
9
4
H
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) Cy2BH
2) RCHO
3) N(CH2CH2OH)3
O
O
66–95%
>95% dr
Ts
N
R
OH
non-aqueous
base
aqueous
base
3
O
Ts
Ts
NH OH
R
N
O
HO
HO
R
5
Scheme 1. Preparation of N-tosylcarbamates 3 and their hydrolysis and isomerization to
5
However, in practice this procedure was hampered by drawbacks related to the use of
the N-tosyl protecting group. This enhances the electrophilic character of the carbonyl
group in 4 favoring hydrolysis of the carbamate or its isomerization to N-
tosylcarbamates 5 in aqueous or dry basic media, respectively. Unfortunately, these
deleterious side reactions have also been observed10 occasionally during work-up and/or
chromatographic purification of compounds 3. On the other hand, removing the robust
tosyl group in the final steps of a multi-step synthetic sequence could be troublesome
limiting the synthetic utility of the methodology.
Some of these drawbacks were encountered in our approach to the synthesis of
vinylsphinganines such as 2, potential inhibitors of sphingosine-1-phosphate lyase. We
envisaged that allene 1, easily obtained from 2-butyn-1,4-diol in 61% yield (Scheme
ACS Paragon Plus Environment

Page 5 of 16
The Journal of Organic Chemistry
1
2
3
4
2)11 with the easily removable benzoyl N-protecting group, might be a better choice
5
6
7
8
since it should be bulky enough to promote high stereoselectivity in the hydroboration
step.
9
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
O
Bz
Pd2(dba)3CHCl3
(mol 1.5%)
Bz
C
O
NH
N
Bz-NCO
O
OH
O
HO
O
CH2Cl2
0 ºC
THF
rt
H
H
O
NH
Bz
1
61%
(overal yield)
Scheme 2. Synthesis of allene 1 from 2-butyn-1,4-diol
When allene 1 was hydroborated with dicyclohexylborane in CH2Cl2 followed by
addition of isobutyraldehyde and treatment with triethanolamine, carbamate 6a was
isolated in 78% yield (Scheme 3). As expected, a single diastereoisomer was obtained.
Presumably, the relative stereochemistry of 6a arises from the hydroboration of the less
hindered face of allene 1 to afford the corresponding (Z)-2-alkenylborane that is added
to the aldehyde through a six-membered transition state where 1,3-axial interactions are
minimized. Surprisingly, N to O migration of the benzoyl group in carbamate 6a had
also occurred.12 A corresponding migration was not observed when tosylated allene 4
was subjected to similar transformations. As expected, protected carbamate 6a was
stable under basic, non-nucleophilic conditions (DBU) and the ring isomerization
observed in the case of tosylcarbamates 5 did not occur with the benzoyl derivative.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 16
1
2
3
4
5
6
7
8
9
O
O
Bz
Bz
H
N
N
Cy2BH
O
O
CH2Cl2
C
BCy2
H
H
0 ºC → rt
1
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
i-PrCHO
-78 ºC → rt
O
O
Bz
O
N
i-Pr
O
N(CH2CH2OH)3
O
HN
Cy
B
H
Cy
OBz
6a
78%
Scheme 3. Addition of allene 1 to isobutyraldehyde
The reaction was repeated with a variety of aldehydes (Table 1), in order to explore its
scope. Carbamates 6 were obtained in good yields for aliphatic (entries 1 and 2),
aromatic (entry 3), a,b-alkenyl (entries 4 and 5) and a,b-alkynyl aldehydes (entry 6). In
all cases N to O migration of the benzoyl group was observed. Furthermore, a single
diastereomer13 was always obtained including in the cases of those carbamates that
might be useful in the synthesis of SPL inhibitors (entries 2, 5 and 6).
O
O
Bz
C
O
1) Cy2BH
2) RCHO
N
HN
O
R
H
H
3) N(CH2CH2OH)3
OBz
Entry
R
Product
Yield
1
2
3
4
ethyl
6b
6c
6d
6e
81%
69%
82%
84%
dodecanyl
phenyl
vinyl
ACS Paragon Plus Environment

Page 7 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
5
6
(E)-1-undecenyl
6f
74%
90%
1-heptynyl
6g
7
8
9
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
Table 1. Addition of allene 1 to aldehydes
Enantiopure carbamates were obtained when the reaction was performed with chiral
aldehydes that exhibited strong stereofacial selectivity such as those derived from (R)-
glyceraldehyde or (R)-lactaldehyde (Scheme 4). Again, only one stereoisomer of 6h and
6i were obtained in good yield with complete migration of the benzoyl group.
O
O
O
O
1) Cy2BH
OMe
1) Cy2BH
2)
OTBDPS
HN
1
HN
OMe
O
2)
OTBDPS
O
O
OBz
OHC
OBz
O
OHC
OMe
6h
85%
6i
84%
OMe
3) N(CH2CH2OH)3
3) N(CH2CH2OH)3
Scheme 4. Addition of allene 1 to enantiopure aldehydes.
Compound 6i was used to check the deprotection steps in the synthesis of sphingosine
derivatives such as myriocin (Figure 1) and we confirmed that this fully orthogonally
protected carbamate can be partially deprotected (Scheme 5). Thus, treatment of
carbamate 6i with K2CO3 in MeOH removed the benzoyl group (86% yield) with only
partial migration (10%) of the TBDPS group to the oxygen atom previously protected
by the benzoyl group. Complete removal of the TBDPS group was achieved by
treatment with TBAF and afforded carbamate 7 (78% yield). In the absence of the tosyl
group, concomitant isomerization of the carbamate, as occurred when it was present
(see Scheme 1), was minimized.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 16
1
2
3
4
5
6
7
8
O
O
O
O
OTBDPS
1) K2CO3, MeOH
HN
OH
HN
9
2) TBAF, AcOH
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
7
OBz
6i
OH
Scheme 5. Deprotection of 6i to give 7
In summary, allene 1 is a useful starting material for the synthesis of protected
quaternary 2-amino-2-vinyl-1,3-diols by hydroboration followed by aldehyde addition
since it avoids undesired migrations and affords a fully protected carbamate with
complete stereoselectivity from a range of aldehydes in one step.
Experimental Section
All reactions involving moisture- or air-sensitive reagents were performed in oven-dried
glassware under N2. Chemical shifts (d) are quoted in parts per million and in 1H NMR
13
are referenced to internal TMS (for CDCl3). C NMR are referenced to CDCl3 (d 77.0
ppm). Column chromatography was performed on silica gel (Merck 230-400 mesh).
HRMS analyses were recorded on a LC/MSD-TOF mass spectrometer. Chiral
aldehydes were prepared from D-mannitol14 and (R)-methyl lactate.15
3-Benzoyl-4-vinylideneoxazolidin-2-one (1). A solution of benzoyl isocyanate (4.20 g,
25.6 mmol) in anhydrous CH2Cl2 (20 mL) was added to 2-butyn-1,4-diol (1.00 g, 11.6
mmol) at 0 ºC under N2 atmosphere. The mixture was stirred for 5 hours at rt and the
solvent was removed. A solution of Pd2(dba)3·CHCl3 (0.055 g, 0.05 mmol) in anhydrous
THF (40 mL) and triethylamine (0.087 mL, 0.64 mmol) were added under N2
atmosphere. The mixture was stirred for 16 h at rt and filtered through a pad of Celite.
The solid was washed with EtOAc. The solvent was removed and the crude residue was
ACS Paragon Plus Environment

Page 9 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
purified by column chromatography (hexanes/EtOAc 4:1) to afford 0.595 g (61%) of
allene 1: yellow solid;mp 102-103 ºC (lit.11 101.2-103 ºC); Rf (hexanes/EtOAc 2:1) =
0.35; 1H NMR (400 MHz, CDCl3) d 7.68 (m, 2H), 7.57 (m, 1H), 7.45 (m, 2H), 5.57 (t, J
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
13
= 4.7 Hz, 2H), 5.04 (t, J = 4.7 Hz, 2H); C NMR (101 MHz, CDCl3) d 193.6, 167.3,
151.9, 132.8, 129.2, 128.1, 128.0, 103.9, 90.4, 63.9; IR (film): 1792, 1689, 1331, 1308,
1157, 1068 cm-1; HRMS (ESI+) calculated for C12H10NO3 [M+H]+ = 216.0655, found =
216.0651.
General procedure for the allene hydroboration-aldehyde addition tandem process
A solution of the allene (1.00 equiv, 1.20 mM) in anhydrous CH2Cl2 was added to a
suspension of Cy2BH (1.20 equiv, 1.40 mM) in CH2Cl2 at 0 ºC and under nitrogen
atmosphere. The resulting mixture was stirred for 10 min at 0 ºC and for 1 h at rt. The
resulting solution was then cooled to – 78 ºC, and the aldehyde (1.40 equiv) was added.
The reaction was stirred for 4 h at rt, and was then quenched by addition of
triethanolamine (2.50 equiv). The resulting mixture was stirred for 1 h at rt. Solvent
removal gave a crude that was purified by flash column cromatography yielding the
following adducts:
(RS)-2-Methyl-1-[(SR)-2-oxo-4-vinyloxazolidin-4-yl]propyl benzoate (6a), 0.221 g
(78%) from 0.210 g (0.98 mmol) of allene 1 as a colorless oil; Rf (hexanes/EtOAc 7:3) =
1
0.20; H NMR (400 MHz, CDCl3) d 8.04 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H),
7.48 (t, J = 7.6 Hz, 2H), 6.09 (dd, J = 17.3, 10.6 Hz, 1H), 5.96 (bs, 1H), 5.48 (d, J =
17.3 Hz, 1H), 5.40 (d, J = 10.6 Hz, 1H), 5.20 (d, J = 4.2 Hz, 1H), 4.53 (d, J = 8.6 Hz,
1H), 4.18 (d, J = 8.6 Hz, 1H), 2.13 (m, 1H), 1.00 (d, J = 7.4 Hz, 3H), 1.00 (d, J = 7.4
Hz, 3H); 13C NMR (101 MHz, CDCl3) d 166.1, 158.7, 136.2, 133.5, 129.7, 129.2, 128.6,
116.6, 79.5, 72.3, 65.0, 29.3, 20.8, 17.5; IR (film): 3334, 2968, 2933, 1759, 1735 cm-1;
HRMS (ESI+) calculated for C16H20NO4 [M+H]+ = 290.1387, found = 290.1386.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 16
1
2
3
4
5
6
7
8
9
(RS)-1-[(SR)-2-Oxo-4-vinyloxazolidin-4-yl]propyl benzoate (6b), 0.303 g (81%)
from 0.293 g (1.37 mmol) of allene 1 as a colorless oil; Rf (hexanes/EtOAc 7:3) = 0.20;
1H NMR (400 MHz, CDCl3) d 8.06 (t, J = 7.7 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.47
(bs, 1H), 7.45 (t, J = 7.7 Hz, 2H), 6.03 (dd, J = 17.3, 10.7 Hz, 1H), 5.46 (d, J = 17.3 Hz,
1H), 5.33 (d, J = 10.7 Hz, 1H), 5.28 (dd, J = 8.0, 2.0 Hz, 1H), 4.46 (d, J = 8.8 Hz, 1H),
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
13
4.16 (d, J = 8.8 Hz, 1H), 1.81-1.64 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); C NMR (101
MHz, CDCl3) d 166.1, 159.6, 135.6, 133.3, 129.7, 129.2, 128.5, 116.9, 77.8, 72.4, 64.8,
22.5, 10.1; IR (film): 3253, 2924, 2854, 1756, 1719, 1268, 1106 cm-1; HRMS (ESI+)
calculated for C15H18NO4 [M+H]+ = 276.1230, found = 276.1232.
(RS)-1-[(SR)-2-Oxo-4-vinyloxazolidin-4-yl]tridecyl benzoate (6c), 0.461 g (69%)
from 0.348 g (1.62 mmol) of allene 1 as a colorless oil; Rf (hexanes/EtOAc 3:2) = 0.74;
1H NMR (400 MHz, CDCl3) d 8.03-7.97 (m, 2H), 7.62-7.54 (m, 1H), 7.49-7.41 (m, 2H),
6.00 (dd, J = 17.2, 10.7 Hz, 1H), 5.83 (bs, 1H), 5.42 (d, J = 17.2 Hz, 1H), 5.35 (d, J =
10.7 Hz, 1H), 5.28 (dd, J = 8.9, 4.3 Hz, 1H), 4.45 (d, J = 8.7 Hz, 1H), 4.15 (d, J = 8.7
13
Hz, 1H), 1.70-1.58 (m, 2H), 1.37-1.16 (m, 20H), 0.86 (t, J = 6.9 Hz, 3H); C NMR
(101 MHz, CDCl3) d 166.3, 158.7, 136.2, 133.6, 129.9, 129.4, 128.7, 117.2, 76.2, 72.0,
64.8, 35.7, 32.1, 29.8, 29.7, 29.6, 29.5, 29.5, 29.4, 25.8, 25.6, 22.8, 14.3; IR (ATR):
3205, 2922, 2852, 1755, 1718, 1264, 1095, 709 cm-1; HRMS (ESI+) calculated for
C25H38NO4 [M+H]+ = 416.2795, found = 416.2789.
(RS)-[(SR)-2-Oxo-4-vinyloxazolidin-4-yl](phenyl)methyl benzoate (6d), 0.295 g
(82%) from 0.240 g (1.11 mmol) of allene 1 as a colorless solid; mp = 72-74 °C; Rf
1
(hexanes/EtOAc 7:3) = 0.18; H NMR (400 MHz, CDCl3) d 8.08 (d, J = 8.0 Hz, 2H),
7.56-7.34 (m, 9H), 6.07 (dd, J = 18.0, 9.9 Hz, 1H), 6.06 (s, 1H), 5.38 (d, J = 18.0 Hz,
13
1H), 5.35 (d, J = 9.9 Hz, 1H), 4.57 (d, J = 8.8 Hz, 1H), 4.17 (d, J = 8.8 Hz, 1H); C
NMR (101 MHz, CDCl3) d 165.1, 159.3, 135.9, 134.5, 133.4, 129.7, 129.1, 129.0,
ACS Paragon Plus Environment

Page 11 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
128.4, 127.7, 117.1, 78.2, 71.8, 65.0; IR (KBr): 3462, 3215, 1753, 1712, 1269 cm-1;
HRMS (ESI+) calculated for C19H18NO4 [M+H]+ = 324.1230, found = 324.1230.
(RS)-1-[(SR)-2-Oxo-4-vinyloxazolidin-4-yl]allyl benzoate (6e), 0.282 g (84%) from
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
0.263 g (1.22 mmol) of allene 1 as a yellow oil; Rf (hexanes/EtOAc 7:3) = 0.21; H
NMR (400 MHz, CDCl3) d 8.04 (t, J = 7.8 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.49 (t, J =
7.8 Hz, 2H), 6.41 (bs, 1H), 6.03 (dd, J = 17.3, 10.7 Hz, 1H), 5.87 (ddd, J = 17.3, 10.7,
7.0 Hz, 1H), 5.57 (d, J = 7.0 Hz, 1H), 5.56 (d, J = 0.8 Hz, 1H), 5.54 (d, J = 17.3 Hz,
1H), 5.46 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 10.7 Hz, 1H), 4.50 (d, J = 8.8 Hz, 1H), 4.17
13
(d, J = 8.8 Hz, 1H); C NMR (101 MHz, CDCl3) d 165.1, 159.4, 135.5, 133.4, 130.1,
129.7, 129.2, 128.5, 122.0, 117.4, 77.4, 71.8, 64.1; IR (film): 3250, 1756, 1721, 1266,
1070 cm-1; HRMS (ESI+) calculated for C14H16NO2 [M+H]+ = 230.1176, found =
230.1176.
(RS,E)-1-[(SR)-2-Oxo-4-vinyloxazolidin-4-yl]dodec-2-en-1-yl benzoate (6f), 0.331 g
(74%) from 0.243 g (1.13 mmol) of allene 1 as a colorless oil; Rf (hexanes/EtOAc 4:1) =
1
0.22; H NMR (400 MHz, CDCl3) d 8.04-7.98 (m, 2H), 7.59-7.53 (m, 1H), 7.46-7.41
(m, 2H), 6.30 (bs, 1H), 6.05-5.96 (m, 2H), 5.54-5.41 (m, 3H), 5.35 (d, J = 10.7 Hz, 1H),
4.46 (d, J = 8.7 Hz, 1H), 4.14 (d, J = 8.7 Hz, 1H), 2.05 (dt, J = 7.8, 4.0 Hz, =2H), 1.40-
13
1.31 (m, 2H), 1.30-1.19 (m, 12H), 0.86 (t, J = 6.9 Hz, 3H); C NMR (101 MHz, CDCl3)
d 165.4, 159.1, 140.7, 136.2, 133.5, 129.8, 129.7, 128.7, 121.8, 117.3, 77.8, 72.2, 64.3,
32.6, 32.0, 29.6, 29.5, 29.4, 29.3, 28.8, 22.8, 14.2; IR (ATR): 3240, 2923, 1755, 1707,
1263, 709 cm-1; HRMS (ESI+) calculated for C24H37N2O4 [M+NH4]+ = 417.2748, found
= 417.2747.
(RS)-1-[(SR)-2-Oxo-4-vinyloxazolidin-4-yl]oct-2-yn-1-yl benzoate (6g). 0.340 g
(90%) from 0.237 g (1.10 mmol) of allene 1 as a colorless solid; mp = 122-124 °C; Rf
1
(hexanes/EtOAc 4:1) = 0.22; H NMR (400 MHz, CDCl3) d 8.02 (m, 2H), 7.59 (m, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 16
1
2
3
4
5
6
7
8
9
7.45 (m, 2H), 6.10 (dd, J = 17.2, 10.7 Hz, 1H), 5.79 (bs, 1H), 5.65 (t, J = 2.0 Hz, 1H),
5.50 (d, J = 17.2 Hz, 1H), 5.39 (d, J = 10.7 Hz, 1H), 4.70 (d, J = 8.8 Hz, 1H), 4.20 (d, J
= 8.8 Hz, 1H), 2.21 (dt, J = 7.1, 2.0 Hz, 2H), 1.53-1.48 (m, 2H), 1.35-1.27 (m, 4H), 0.88
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
13
(t, J = 7.0 Hz, 3H); C NMR (101 MHz, CDCl3) d 165.2, 147.3, 135.2, 133.6, 130.9,
129.0, 128.5, 117.6, 89.7, 73.1, 72.0, 67.8, 64.4, 31.0, 27.8, 22.0, 18.6, 13.9; IR (KBr):
3243, 2932, 2860, 1760, 1684 cm-1; HRMS (ESI+) calculated for C20H24NO4 [M+H]+ =
342.1700, found = 342.1696.
(S)-[(2R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl][(S)-2-oxo-4-
vinyloxazolidin-4-yl]methyl benzoate (6h), 0.448 g (85%) from 0.269 g (1.25 mmol)
25
a
of allene 1 as a colorless solid; mp = 69-71 °C; Rf (hexanes/EtOAc 7:3) = 0.16; [ ]D
̶
1
81.9 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) d 7.98 (d, J = 7.9 Hz, 2H), 7.63 (d, J
= 7.9 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 6.27 (dd, J = 17.2, 10.6 Hz, 1H), 5.85 (bs, 1H),
5.59 (d, J = 17.2 Hz, 1H), 5.48 (d, J = 10.6 Hz, 1H), 5.33 (d, J = 8.7 Hz, 1H), 4.36 (d, J
= 8.7 Hz, 1H), 4.31-4.23 (m, 1H), 4.05 (d, J = 8.7 Hz, 1H), 3.73 (t, J = 11.4 Hz, 1H),
13
3.40 (dd, J = 11.4, 3.4 Hz, 1H), 3.27 (s, 3H), 3.25 (s, 3H), 1.32 (s, 3H), 1.25 (s, 3H); C
NMR (101 MHz, CDCl3) d 165.1, 158.1, 135.6, 134.1, 129.8, 128.3, 127.6, 117.2, 99.6,
98.1, 74.7, 73.7, 67.5, 63.3, 60.8, 49.2, 48.2, 17.5, 17.5; IR (KBr): 3342, 2991, 2949,
1763, 1726 cm-1; HRMS (ESI+) calculated for C21H28NO8 [M+H]+ = 422.1809, found =
422.1806.
(1S,2R)-2-[(tert-Butyldiphenylsilyl)oxy]-1-[(S)-2-oxo-4-vinyloxazolidin-4-yl]propyl
benzoate (6i), 0.673 g (84%) from 0.324 g (1.51 mmol) of allene 1 as a colorless oil; Rf
(hexanes/EtOAc 4:1) = 0.24; [ ]D +31.7 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
25
a
d 8.00 (m, 2H), 7.60-7.71 (m, 5H), 7.35-7.50 (m, 8H), 6.05 (dd, J = 17.3, 10.7 Hz, 1H),
5.59 (bs, 1H), 5.44 (d, J = 17.3 Hz, 1H), 5.39 (d, J = 10.7 Hz, 1H), 5.30 (m, 1H), 4.41
(d, J = 8.7 Hz, 1H), 4.15 (m, 1H), 4.07 (d, J = 8.7 Hz, 1H), 1.06 (s, 9H), 1.03 (d, J = 6.3
ACS Paragon Plus Environment

Page 13 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
Hz, 3H); C NMR (101 MHz, CDCl3) d 158.8, 135.9, 135.7, 135.6, 133.5, 132.7, 130.1,
129.9, 127.9, 127.7, 115.8, 78.7, 73.6, 70.7, 63.6, 27.0, 19.1, 18.9; IR (film): 3250,
3070, 2931, 2858, 1759, 1728 cm-1; HRMS (ESI+) calculated for C31H36NO5Si [M+H]+
= 530.2356, found = 530.2357.
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
(S)-4-[(1S,2R)-1,2-Dihydroxypropyl]-4-vinyloxazolidin-2-one (7). A solution of
K2CO3 (0.154 g, 1.10 mmol) in MeOH (10 mL) was added to a solution of carbamate 6i
(0.389 g, 0.735 mmol) in MeOH (10 mL) at rt under N2 atmosphere. The mixture was
stirred for 2 h. Water (10 mL) was added and the mixture was extracted with CH2Cl2 (3
x 20 mL). The combined organic phase was dried over MgSO4 and the solvent was
evaporated under vacuum. The crude residue was purified by column chromatography
(hexanes/EtOAc 3:2) to afford a mixture of debenzoylated products (0.224 g, 86%
yield). A solution of TBAF·3H2O (0.201 g, 0.62 mmol) and acetic acid (35 µL, 0.6
mmol) in anhydrous THF (10 mL) was added via cannula to the mixture of
debenzoylated products (0.175 g, 0.41 mmol) in anhydrous THF (10 mL). The solution
was stirred at rt for 5 h. Phosphate buffer solution (pH = 7, 10 mL) was added and the
aqueous layer was extracted with EtOAc (5 x 20 mL). The combined organic layer was
dried over anhydrous MgSO4, and the solvent was evaporated under vacuum. The crude
residue was purified by column chromatography (CH2Cl2/MeOH, 95:5) to afford
25
a
carbamate 7 (0.060 g, 0.32 mmol) in 78% yield: colorless oil; Rf (EtOAc) = 0.35; [ ]D
1
+31.5 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) d 6.10 (dd, J = 17.4, 10.7 Hz, 1H),
5.40 (d, J = 17.4, 1H), 5.35 (d, J = 10.7 Hz, 1H), 4.49 (d, J = 8.8 Hz, 1H), 4.14 (d, J =
13
8.8 Hz, 1H), 3.69-3.62 (m, 4H), 3.37 (d, J = 8.5 Hz, 1H), 1.25 (d, J = 6.2 Hz, 3H); C
NMR (101 MHz, CDCl3) d 135.2, 116.1, 78.4, 74.1, 69.2, 64.5, 20.9; IR (film): 3379,
2922, 1737, 1396, 933, 721 cm-1; HRMS (ESI+) calculated for C8H14NO4 [M+H]+ =
188.0916, found = 188.0917.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 16
1
2
3
4
5
6
7
8
9
ACKNOWLEDGMENT. This work was supported by the Spanish Ministerio de
Educación y Ciencia (CTQ2009-09692 and SAF2014-52223-C2-1-R), the University of
Barcelona (fellowship to A.R.) and the Generalitat de Catalunya (2009SGR1037,
2014SGR107 and fellowship to C.S.)
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
SUPPORTING INFORMATION
1H NMR spectra of the prepared starting materials allene 1 and chiral aldehydes. H
1
13
and C NMR spectra of products 6a-i, and 7. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding authors
*Fax: +34 933397878. Tel: +34 934021248. E-mail: xariza@ub.edu.
*Fax: +34 933397878. Tel: +34 934034819. E-mail: jordigarciagomez@ub.edu.
REFERENCES AND FOOTNOTES
(1) For a review on sphingofungins and related metabolites, see: Byun, H.-S.; Lu, X.;
Bittman, R. Synthesis 2006, 2477.
(2) Shibasaki, M.; Kanai, M.; Fukuda, N. Chem. Asian J. 2007, 2, 20.
(3) Takahashi, A.; Kurasawa, S.; Ikeda, D.; Okami, Y.; Takeuchi, T. J. Antibiot. 1989,
42, 1556.
(4) For a review on the stereoselective construction of a,a-disubstituted a-amino acids,
see: (a) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517.
(b) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645; (c)
Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127. (d) Kang, S. H.; Kang, S. Y.;
ACS Paragon Plus Environment

Page 15 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
Lee, H.-S.; Buglass, A. J. Chem. Rev. 2005, 105, 4537. (e) Cativiela, C.; Díaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 2007, 18, 569.
7
8
9
(5) (a) Tendler, S. J. B.; Threadgill, M. D.; Tisdale, M. J. J. Chem. Soc., Perkin Trans. 1
1987, 2617. (b) Pedersen, M. L.; Berkowitz, D. B. J. Org. Chem. 1993, 58, 6966. (c)
Berkowitz, D. B.; Jahng, W.-J.; Pedersen, M. L. Bioorg. Med. Chem. Lett. 1996, 6,
2151. (d) Berkowitz, D. B.; McFadden, J. M.; Chisowa, E.; Semerad, C. L. J. Am.
Chem. Soc. 2000, 122, 11031.
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
(6) (a) Boumendjel, A.; Miller, S. P. F. Tetrahedron Lett. 1994, 35, 819. For a review
on inhibitors of sphingolipid metabolism enzymes, see: (b) Delgado, A.; Casas, J.;
Llebaria, A.; Abad, J. L.; Fabrias, G. Biochim. Biophys. Acta 2006, 1758, 1957. (c)
Delgado, A.; Casas, J.; Llebaria, A.; Abad, J. L.; Fabrias, G. ChemMedChem 2007, 2,
580. (d) Sanllehí, P.; Abad, J. L.; Casas, J.; Delgado, A. Chem. Phys. Lipids 2016, 197,
69.
(7) (a) For the synthesis of protected 2-amino-2-vinyl-1,3-diols, see: Kumar, V.;
Klimovica, K.; Rasina, D.; Jirgensons, A. J. Org. Chem. 2015, 80, 5934 and references
therein. (b) For related 2-amino 2-vinyl alcohols, see: Cai, A.; Guo, W.; Martínez-
Rodríguez, L.; Kleij, A. W. J. Am. Chem. Soc. 2016, 138, 14194 and references therein.
(8) Boyer, J.; Allenbach, Y.; Ariza, X.; Garcia, J.; Georges, Y. Vicente, M. Synlett
2006, 1895.
(9) Ariza, X.; Cornellà, J.; Font-Bardia, M.; Garcia, J.; Ortiz, J.; Sánchez, C.; Solans, X.
Angew. Chem., Int. Ed. 2009, 48, 4202.
(10) Isomerization of 3 to 5 is an equilibrium process in which the cyclic carbamate 5 is
clearly favored in basic media and other non-hydrolytic solvents tested. Related base-
catalyzed rearrangement processes involving N-acyl or N-alkyl cyclic carbamates have
previously been reported in the literature: (a) Roush, W. R.; Adam, M. A. J. Org. Chem.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 16
1
2
3
4
5
6
7
8
9
1985, 50, 3752. (b) Boger, D. L.; Ledeboer, M. W.; Kume, M. J. Am. Chem. Soc. 1999,
121, 1098. (c) Bew, S. P.; Bull, S. D.; Davies, S. G.; Savory, E. D.; Watkin, D. J.
Tetrahedron 2002, 58, 9387.
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
(11) Horino, Y.; Kimura, M.; Tanaka, S.; Okajima, T.; Tamaru, Y. Chem. Eur. J. 2003,
9, 2419.
(12) For a similar migration, see: McCombie, S. W.; Nagabhushan, T. L. Tetrahedron
Lett. 1987, 28, 5395.
(13) The relative stereochemistry was correlated with the known stereochemistryof
tosylated products 3 (ref. 9). Thus, O-benzoylated products 6 were N-tosylated to afford
the doubly protected carbamates and the corresponding N-tosylated products 3 were O-
benzoylated to yield the same compound.
(14) Michel, P.; Ley, S. V. Angew. Chem. Int. Ed. 2002, 41, 3898.
(15) Massad, S. K.; Hawkins, L. D.; Baker D. C. J. Org. Chem. 1983, 48, 5180.
ACS Paragon Plus Environment