Diastereoselective nickel-catalyzed reductive couplings of aminoaldehydes and alkynylsilanes: application to the synthesis of d-erythro-sphingosine

Article abstract of DOI:10.1016/j.tet.2009.05.029

A strategy for the nickel-catalyzed reductive coupling of α-aminoaldehydes with silyl alkynes has been developed. The process proceeds with exceptional regiocontrol and diastereoselectivity. A variety of protected serinal derivatives were examined, and Garner aldehyde afforded the highest chemical yields of an easily deprotected coupling product. Use of a C-15 alkyne allowed a direct and efficient synthesis of d-erythro-sphingosine. With this silyl alkyne of interest, coupling reactions were most efficient when trace water was employed with THF as solvent. Using this procedure, d-erythro-sphingosine was prepared by a short sequence, wherein the alkene stereochemistry, C-3 stereocenter, and the C-3-C-4 carbon-carbon bond were all efficiently installed by the key nickel-catalyzed coupling process.

Full text of DOI:10.1016/j.tet.2009.05.029

Tetrahedron 65 (2009) 6707–6711
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective nickel-catalyzed reductive couplings of aminoaldehydes and
alkynylsilanes: application to the synthesis of -erythro-sphingosine
D
*
Kanicha Sa-ei, John Montgomery
Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A strategy for the nickel-catalyzed reductive coupling of a-aminoaldehydes with silyl alkynes has been
Received 31 March 2009
Received in revised form 5 May 2009
Accepted 8 May 2009
developed. The process proceeds with exceptional regiocontrol and diastereoselectivity. A variety of
protected serinal derivatives were examined, and Garner aldehyde afforded the highest chemical
yields of an easily deprotected coupling product. Use of a C-15 alkyne allowed a direct and efficient
Available online 18 May 2009
synthesis of
D
-erythro-sphingosine. With this silyl alkyne of interest, coupling reactions were most
-erythro-
efficient when trace water was employed with THF as solvent. Using this procedure,
D
sphingosine was prepared by a short sequence, wherein the alkene stereochemistry, C-3 stereocenter,
and the C-3–C-4 carbon–carbon bond were all efficiently installed by the key nickel-catalyzed cou-
pling process.
Ó 2009 Elsevier Ltd. All rights reserved.
O
OTIPS
(i-pr)3SiH
R2
+
R1
1. Introduction
R1
+
TMS
H
IMes·HCl, KO-t-Bu
R2
OTBS
Ni(COD)2
ð1Þ
TBSO
TMS
The reductive coupling of aldehydes and alkynes has been ex-
tensively developed as an entry to stereodefined allylic alcohols.1
Numerous variants have been developed that involve alteration of
the transition metal, ligand, or reducing agent.2 In processes that
involve nickel catalysis, both phosphine3 and N-heterocyclic car-
bene ligands4 and organosilane, organoborane, and organozinc
reducing agents have been employed. In addition to extensive
studies in the generation of racemic products, both enantiose-
lective5 and diastereoselective6–8 processes have been developed.
Highly diastereoselective processes have been illustrated involving
chiral ynals in intramolecular variants6 as well as chiral aldehydes7
or chiral alkynes8 in intermolecular variants.
IMes·HCl =
Mes
yields 75-85 %
dr up to >98:2
Cl –
N
N
Mes
In order to expand the scope and utility of this highly diaster-
eoselective process, we anticipated that -aminoaldehydes might
a
be similarly effective in the coupling process. In addition to pro-
viding general access to stereodefined unsaturated amino alcohols,
a method involving aminoaldehydes could additionally be applied
in a direct entry to compounds of the sphingosine class.9 While
possessing the anti-amino alcohol structural motif that could be
directly accessed by an aminoaldehyde alkyne reductive coupling,
A pair of recent reports illustrated that a-alkoxy and a-silyloxy
D
-erythro-sphingosine (Scheme 1) has been the target of many
synthetic approaches.10 Despite the many impressive advances that
have been made, assembly of the core structure by a single re-
ductive operation involving an aldehyde and alkyne, while avoiding
the stoichiometric generation of a reactive vinyl organometallic
reagent, has not been previously realized. With these goals in mind,
this report details an examination of the efficiency of reductive
couplings of aminoaldehydes with alkynes as well as application of
aldehydes were effective participants in diastereoselective re-
ductive couplings with various alkynes.7 Our contribution illus-
trated that couplings of a-silyloxy aldehydes were most selective
with silyl alkynes.7b In this prior report, we illustrated that a range
of substitution patterns were accessible to generate functionalized
anti-1,2-diols by this procedure. The best diastereselectivities and
chemical yields were accessed when unbranched aldehyde and
alkyne substrates were employed (Eq. 1).
the method in the synthesis of
D-erythro-sphingosine (Scheme 1).
OH
HO
(CH2)12Me
NH2
* Corresponding author. Tel.: þ1 734 764 4424; fax: þ1 734 763 1106.
E-mail address: jmontg@umich.edu (J. Montgomery).
Scheme 1. D-erythro-Sphingosine.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.029

6708
K. Sa-ei, J. Montgomery / Tetrahedron 65 (2009) 6707–6711
Table 2
Additions to aldehyde 9
2. Results and discussion
O
OSi(i-Pr)3
Among many known protecting groups for a-amino aldehydes,
(i-Pr)3SiH
R
Garner aldehyde 1 is particularly attractive from the standpoints of
ease of chemical synthesis and purification, resistance to epimeri-
zation, and effectiveness in promoting highly diastereoselective
transformations.11 In fact, several of the most efficient syntheses of
sphingosine have relied upon diastereoselective additions of either
vinyl organometallic reagents or acetylide nucleophiles to this
aldehyde. We therefore envisioned that the direct catalytic
reductive coupling of an alkyne with this aldehyde would provide
an attractive entry to stereodefined anti-1,2-aminoalcohols related
to the core structure of sphingosine.
+
H
R
SiMe3
Ni(COD)2
IMes·HCl, t-BuOK
O
O
NBoc
N
Me3Si
Boc
8a-d
2a-d
7
Entry
R
Product (yield)
dr
1
2
3
4
CH3 (2a)
C6H5 (2b)
(CH2)3CH3 (2c)
8a (80%)
8b (80%)
8c (78%)
8d (78%)
>95:5
>95:5
>95:5
>95:5
(CH2)12CH3 (2d)
We initially examined the additions of silylalkynes 2a–c with
Garner aldehyde 1, and were pleased to find that the procedure
yield (Eq. 2). However, all attempts to deprotect the aminoalcohol
of 9 were unsuccessful. A broad range of Lewis acids and Brønsted
acids led to extensive decomposition, with at best only trace
quantities of sphingosine being observed.
initially developed for diastereoselective additions to
a-silyloxy-
aldehydes7b was highly effective for additions to aldehyde 1 (Table 1).
In these three examples, good chemical yields (68–80% yield) were
observed, and only the anti-diastereomer with the Z-alkene was
observed in the crude reaction mixtures (>95:5 dr, >95:5 Z/E).
With these highly encouraging early results, we examined the
couplings of the long-chain silyl alkyne 2d, which would directly
OH
OSi(i-Pr)3
(CH2)12CH3
SiMe3
n-Bu4NF
(CH2)12CH3
O
O
78 %
N
N
afford the core structure of D-erythro-sphingosine. However, al-
though stereoselectivities were high, much lower chemical effi-
ciency was observed than seen with the simpler silyl alkynes 2a–c.
9
Boc
ð2Þ
Boc
Brønsted &
Lewis acids
8d
decomposition
Table 1
Additions to Garner aldehyde 1
Since the Garner aldehyde-derived products 3a–d (Table 1) could
OSi(i-Pr)3
O
all be cleanly deprotected, we opted to re-examine the studies with
aldehyde 1 to avoid the inefficient deprotection of compound 9.
Desilylation of addition product 3a (Table 1, entry 1) proceeded
cleanly with n-Bu4NF to afford alkene 10, followed by cross me-
tathesis12 with 1-pentadecene (82% yield) to afford 11 and then 2 N
(i-Pr)3SiH
R
+
R
SiMe3
H
O
O
Ni(COD)2
IMes·HCl, t-BuOK
N
NBoc
Me3Si
Boc
2a-d
1
3a-d
HCl-mediated deprotection (82% yield) to afford D-erythro-sphingo-
sine, which was indistinguishable from natural material (Scheme 3).
Entry
R
Product (yield)
dr
1
2
3
4
CH3 (2a)
C6H5 (2b)
(CH2)3CH3 (2c)
(CH2)12CH3 (2d)
3a (78%)
3b (80%)
3c (68%)
3d (18%)
>95:5
>95:5
>95:5
>95:5
OH
n-Bu4NF
(CH2)12CH3
CH3
3a
O
90 %
2nd generation
Grubbs catalyst
(30 mol %)
N
Boc
10
Whereas the reasons for the poor efficiency of couplings of
alkyne 2d with 1 are unclear, we anticipated that chemical effi-
ciencies may be improved with alternate protecting groups for the
OH
2N HCl / THF
75 °C, 3h, 82%
(CH2)12CH3
a
-amino-b-alkoxy aldehyde of interest. We therefore examined
D-erythro-sphingosine
O
N
couplings of aldehydes 4–7 (Scheme 2), using the key silyl alkyne
2d as the coupling partner. While couplings of 2d with aldehydes
4–6 were very low yielding, chemical efficiencies with aldehyde 7
were much improved. Using aldehyde 7, reductive couplings using
alkynes 2a–d were again examined, and all four examples now
proceeded with similarly good chemical efficiencies and with
outstanding stereocontrol to produce compounds 8a–d (Table 2).
Boc
11 (82 %, >95:5 E:Z)
Scheme 3. Sphingosine synthesis by cross metathesis.
Although the above route involving a cross metathesis strategy
starting from vinyl silane 3a was relatively efficient, we were
nonetheless troubled by the inefficiency of the more direct strategy
involving coupling of Garner aldehyde 1 with silylalkyne 2d. We
therefore examined the reaction more extensively, and in analogy
to an observation made in our recent synthesis of aigialomycin D,13
we ultimately found that employing 2.0 equiv of Garner aldehyde 1
in couplings of 2d with trace water in THF allowed reasonably
efficient couplings,14 providing the desired vinyl silane 3d in 65%
isolated yield with complete stereocontrol (>98:2 dr, >98:2 Z/E,
Scheme 4). n-Bu4NF-mediated deprotection of 3d to 11 proceeded
in 91% isolated yield, which was followed by the 2 N HCl depro-
tection described above (73% yield) to complete a more direct
O
O
O
O
H
H
H
O
O
TBSO
H
O
NBoc
NCbz
NBoc
NHBoc
t-Bu
7
6
4
5
Scheme 2. Alternate protected aminoaldehydes.
With an efficient procedure now in hand for the preparation of
a suitably protected -amino- -alkoxy aldehyde with the desired
15-carbon alkyne, we next attempted the conversion of the cou-
pling product 8d to -erythro-sphingosine. Exhaustive desilylation
of 8d with n-Bu4NF proceeded cleanly to afford alkene 9 in 78%
a
b
synthesis of
D
-erythro-sphingosine. This highly direct procedure
thus allows the selective synthesis of
D
-erythro-sphingosine in
D
three steps from Garner aldehyde 1, without requiring the stoi-
chiometric use of a vinyl organometallic reagent.

K. Sa-ei, J. Montgomery / Tetrahedron 65 (2009) 6707–6711
6709
(i-Pr)3SiH
2174 cmꢀ1; HRMS EI (m/z): [M]þ calcd for C18H36Si 280.2586; found
280.2598.
1 (2.0 equiv)
+
3d (65 %)
(>95:5 dr, >95:5 Z:E)
Ni(COD)2
IMes·HCl, t-BuOK
THF/H2O (99:1)
2d (1.0 equiv)
4.3. General procedure for Ni(0)-catalyzed reductive coupling
reactions
2N HCl / THF
75 °C, 3h, 73%
n-Bu4NF
11
(>95:5 E:Z)
D-erythro-sphingosine
THF (4.0 mL) was added to a solid mixture of 1,3-dimesitylimi-
dazolium chloride (17.0 mg, 0.050 mmol), t-BuOK (6 mg,
0.05 mmol), and Ni(COD)2 (14 mg, 0.05 mmol) at rt. The resulting
solution was stirred for 5 min until the color turned dark blue.
i-Pr3SiH (2.0 equiv) was added, followed by addition of a THF
solution (1.0 mL) of the aldehyde (0.50 mmol) and alkyne
(0.60 mmol). The reaction mixture was stirred 1–4 h at rt until the
aldehyde was consumed as judged by TLC analysis. The reaction
mixture was quenched with saturated sodium bicarbonate solution
and was extracted with diethyl ether three times. The combined
organic layers were washed with brine, dried over magnesium
sulfate, filtered, and concentrated in vacuo. The residue was puri-
fied via flash chromatography (SiO2) to afford the desired product.
91 %
Scheme 4. Sphingosine synthesis using alkyne 2d.
3. Summary and conclusions
The nickel-catalyzed reductive coupling of Garner aldehyde 1
with silylalkynes employing triisopropylsilane as reducing agent
provides a direct and general strategy for the synthesis of un-
saturated anti-1,2-aminoalcohols. Application of the procedure in
a direct and efficient synthesis of
trated (Scheme 4).
D-erythro-sphingosine was illus-
4. Experimental
4.1. General
4.3.1. (S)-tert-Butyl 2,2-dimethyl-4-((S,E)-1-(triisopropylsilyloxy)-
2-(trimethylsilyl)but-2-enyl)oxazolidine-3-carboxylate (3a)
Following the general procedure, aldehyde 111 (114 mg,
0.50 mmol), trimethyl(prop-1-ynyl)silane (2a) (67 mg, 0.60 mmol),
Ni(COD)2 (14 mg, 0.05 mmol), 1,3-dimesitylimidazolium chloride
(17 mg, 0.05 mmol), t-BuOK (6 mg, 0.05 mmol), and i-Pr3SiH
(158 mg, 1.0 mmol) gave, after column chromatography (1:49
ether/hexanes), 195 mg of (S)-tert-butyl 2,2-dimethyl-4-((S,E)-1-
(triisopropylsilyloxy)-2-(trimethylsilyl)but-2-enyl)oxazolidine-
Unless otherwise noted, all reactions were conducted in flame-
dried glassware under a nitrogen atmosphere. THF was purified
with an Innovative Technologies SPS-400 solvent system under
nitrogen. Ni(COD)2 (Strem Chemicals Inc., used as received), 1,3-
dimesitylimidazolium chloride and t-BuOK (Acros, Fisher Scientific
International Inc., used as received) were stored and weighed in an
argon or nitrogen inert atmosphere glovebox. All alkynes (Sigma–
Aldrich) were distilled or prepared and stored under nitrogen gas.
All aldehydes were freshly prepared and flushed with nitrogen gas
before using. Optical rotations were obtained on a Rudolph Autopol
III polarimeter using a quartz cell with 1.0 mL capacity and 1 dm
cell path length. Optical rotations were determined in CHCl3, with
concentration reported in units of 1 g/100 mL. 1H and 13C spectra
were obtained in CDCl3 or benzene-d6 on a Varian Mercury 400 or
Varian Unity 500 MHz instrument. Chemical shifts of 1H NMR
3-carboxylate (3a) (78%) as a colorless oil as a (>95:5) ratio of
24
diastereomers. [
a
]
D
ꢀ5.4 (c 7.65, CHCl3). 1H NMR (400 MHz, C6D6,
80 ꢁC)
d
6.57 (q, J¼7.2 Hz, 1H), 5.22 (s, 1H), 4.25 (dd, J¼5.6, 8.4 Hz,
1H), 3.97–4.00 (m, 1H), 3.72 (t, J¼8.4 Hz, 1H), 1.70 (d, J¼7.2 Hz, 3H),
1.67 (s, 3H), 1.50 (s, 3H), 1.41 (s, 9H), 1.10–1.20 (m, 21H), 0.32 (s, 9H);
13C NMR (100 MHz, C6D6, 80 ꢁC)
d 153.4, 142.2, 137.7, 137.6, 95.2,
79.6, 73.8, 62.6, 62.1, 28.6, 27.2, 26.0, 18.6, 17.3, 13.6, 0.54; IR (film)
2944, 1693, 1615 cmꢀ1
C26H53NNaO4Si2 522.3411; found 522.3391.
;
HRMS ES (m/z): [MþNa]þ calcd for
spectra were recorded in parts per million (ppm) on the
d scale
4.3.2. (S)-tert-Butyl 2,2-dimethyl-4-((S,E)-3-phenyl-1-
(triisopropylsilyloxy)-2-(trimethylsilyl)allyl)oxazolidine-3-
carboxylate (3b)
from an internal standard of residual chloroform (7.27 ppm) or
benzene (7.15 ppm). Chemical shifts of 13C NMR spectra were
recorded in parts per million from the central peak of CDCl3
Following the general procedure, aldehyde
1
(114 mg,
(77.0 ppm) or benzene-d6 (128.0 ppm) on the
d scale. High reso-
0.50 mmol), 1-phenyl-2-(trimethylsilyl)acetylene (2b) (104 mg,
0.60 mmol), Ni(COD)2 (14 mg, 0.05 mmol), 1,3-dimesitylimidazo-
lium chloride (17 mg, 0.05 mmol), t-BuOK (6 mg, 0.05 mmol), and
i-Pr3SiH (158 mg, 1.0 mmol) gave, after column chromatography
(2% ether/hexanes), 237 mg of (S)-tert-butyl 2,2-dimethyl-4-((S,E)-
1-(triisopropylsilyloxy)-2-(trimethylsilyl)but-2-enyl)oxazolidine-
lution mass spectra (HRMS) were obtained on a VG-70-250-s
spectrometer manufactured by Micromass Corp. (Manchester, UK)
at the University of Michigan Mass Spectrometry Laboratory.
4.2. Trimethyl(pentadec-1-ynyl)silane (2d)
3-carboxylate (3b) (80%) as a light yellow oil as a (>95:5) ratio of
24
Pentadec-1-yne (624 mg, 3.0 mmol) was dissolved in THF
(15 mL) and then cooled to ꢀ78 ꢁC, followed by dropwise addition
of n-BuLi (1.34 mL, 2.25 M in THF). The solution was allowed to
warm to rt over 30 min, followed by cooling back to ꢀ78 ꢁC. Tri-
diastereomers. [
a
]
ꢀ1.5 (c 1.0, CHCl3). 1H NMR (400 MHz, C6D6,
D
60 ꢁC)
d
7.95 (s, 1H), 7.33–7.34 (m, 2H), 7.16–7.27 (m, 3H), 5.69 (s,
1H), 4.50 (dd, J¼6.0, 8.8 Hz, 1H), 4.28–4.31 (m, 1H), 3.99 (dd, J¼7.6,
8.8 Hz, 1H), 1.85 (s, 3H), 1.66 (s, 3H), 1.54 (s, 9H), 1.34–1.39 (m, 21H),
13
methylsilylchloride (844
mL, 3.3 mmol) was then added dropwise to
0.31 (s, 9H); C NMR (100 MHz, C6D6, 75 ꢁC)
d
153.7, 145.7, 142.3,
the solution. The mixture was allowed to warm to rt and was stirred
for 10 min. The resulting colorless solution was quenched with
saturated sodium bicarbonate solution and was extracted with
diethyl ether three times. The combined organic layer was washed
with brine, dried over magnesium sulfate, filtered, and concen-
trated in vacuo. The residue was distilled under vacuum (100 ꢁC,
0.02 mmHg) to afford 780 mg (93%) of 2d as a colorless oil. 1H NMR
142.2, 140.8,128.8,128.2,127.3, 95.4, 79.8, 73.5, 62.3, 62.1, 28.6, 27.2,
26.0, 18.77, 18.72, 13.7, 1.0; IR (film) 2945,1691, 1592 cmꢀ1; HRMS ES
(m/z): [MþNa]þ calcd for C31H55NNaO4Si2 584.3567; found
584.3572.
4.3.3. (S)-tert-Butyl 2,2-dimethyl-4-((S,Z)-1-(triisopropylsilyloxy)-
2-(trimethylsilyl)hept-2-enyl)oxazolidine-3-carboxylate (3c)
(400 MHz, CDCl3)
d
2.16 (t, J¼7.2 Hz, 2H), 1.46 (m, 2H), 1.19–1.38 (m,
Following the general procedure, aldehyde 1 (259 mg,
20H), 0.83 (t, J¼7.2 Hz, 3H), 0.09 (s, 9H); 13C NMR (100 MHz, CDCl3)
1.0 mmol), hex-1-ynyltrimethylsilane (2c) (185 mg, 1.2 mmol),
Ni(COD)2 (28 mg, 0.10 mmol), 1,3-dimesitylimidazolium chloride
(34 mg, 0.10 mmol), t-BuOK (11 mg, 0.10 mmol), and i-Pr3SiH
d
107.8, 84.2, 31.9, 29.69, 29.66, 29.60, 29.5, 29.4, 29.1, 28.8, 28.6,
22.7, 19.8, 14.1, 0.2 (one peak is unresolved); IR (film) 2923,

6710
K. Sa-ei, J. Montgomery / Tetrahedron 65 (2009) 6707–6711
(316 mg, 2.0 mmol) gave, after column chromatography (2% ether/
hexanes), 352 mg of (S)-tert-butyl 2,2-dimethyl-4-((S,Z)-1-(triiso-
propylsilyloxy)-2-(trimethylsilyl)hept-2-enyl)oxazolidine-3-car-
boxylate (3c) (68%) as a colorless oil as a (>95:5) ratio of
9H), 1.21–1.32 (m, 4H), 1.04–1.17 (m, 21H), 0.84 (t, J¼7.2 Hz, 3H),
13
0.29 (s, 9H); C NMR (100 MHz, C6D6, 75 ꢁC)
d 154.0, 143.5, 139.8,
80.9, 79.9, 73.3, 66.2, 60.0, 32.3, 31.9, 28.6, 22.8, 18.52, 18.50, 13.9,
13.3, 0.42; IR (film) 2945, 1705 cmꢀ1; HRMS ES (m/z): [MþNa]þ
calcd for C27H55NNaO4Si2 536.3567; found 536.3572.
diastereomers. 1H NMR (400 MHz, C6D6, 80 ꢁC)
d
6.57 (t, J¼7.6 Hz,
1H), 5.30 (major rotamer isomer, br s, 0.85H), 5.18 (minor rotamer,
br s, 0.15H), 4.27–4.34 (m, 1H), 4.03 (s, 1H), 3.78 (t, J¼8.4 Hz, 1H),
2.10–2.23 (m, 2H), 1.70 (s, 3H), 1.69 (s, 3H), 1.52 (s, 3H), 1.42 (s, 9H),
4.3.7. (S)-tert-Butyl 4-((S,Z)-1-(triisopropylsilyloxy)-2-
(trimethylsilyl)hexadec-2-enyl)oxazolidine-3-carboxylate (8d)
Following the general procedure, (S)-tert-butyl 4-formyloxazolidine-
3-carboxylate (7) (100 mg, 0.50 mmol), trimethyl(pentadec-1-ynyl)silane
(2d) (168 mg, 0.60 mmol), Ni(COD)2 (14 mg, 0.50 mmol), 1,3-dimesityli-
midazolium chloride (14 mg, 0.10 mmol), t-BuOK (6 mg, 0.50 mmol),
and i-Pr3SiH (158 mg,1.0 mmol) gave, aftercolumn chromatography
(2% ether/hexanes), 249 mg of (S)-tert-butyl 4-((S,Z)-1-(triisopro-
pylsilyloxy)-2-(trimethylsilyl)hept-2-enyl)oxazolidine-3-carboxyl-
ate (8d) (78%) as a colorless oil as a (>95:5) ratio of diastereomers.1H
1.27–1.44 (m, 4H), 1.14–1.22 (m, 21H), 0.87 (t, J¼7.2 Hz, 3H), 0.36 (s,
13
9H); C NMR (100 MHz, C6D6, 80 ꢁC)
d 153.5, 143.8, 140.8, 95.3,
79.6, 74.2, 62.7, 62.2, 32.3, 31.9, 28.6, 27.2, 26.2, 22.8, 18.7, 18.4, 13.9,
13.6, 0.78; IR (film) 2924, 1705 cmꢀ1; HRMS ES (m/z): [MþNa]þ
calcd for C29H59NNaO4Si2 564.3880; found 564.3875.
4.3.4. (S)-tert-Butyl 4-((S,E)-1-(triisopropylsilyloxy)-2-
(trimethylsilyl)but-2-enyl)oxazolidine-3-carboxylate (8a)
Following the general procedure, (S)-tert-butyl 4-formylox-
azolidine-3-carboxylate (7)15 (100 mg, 0.50 mmol), trimethyl-
(prop-1-ynyl)silane (2a) (67 mg, 0.60 mmol), Ni(COD)2 (14 mg,
0.05 mmol), 1,3-dimesitylimidazolium chloride (17 mg, 0.05 mmol),
t-BuOK (6 mg, 0.05 mmol), and i-Pr3SiH (158 mg, 1.0 mmol) gave,
after column chromatography (2% ether/hexanes), 182 mg of (S)-
tert-butyl 4-((S,E)-1-(triisopropylsilyloxy)-2-(trimethylsilyl)but-2-
enyl)oxazolidine-3-carboxylate (8a) (80%) as a colorless oil as
NMR (400 MHz, C6D6, 75 ꢁC)
d
6.23 (t, J¼7.2 Hz, 1H), 5.23 (s, 2H),
4.75 (d, J¼4.0 Hz, 1H), 4.23 (t, J¼7.6 Hz, 1H), 4.03 (t, J¼7.2 Hz, 1H),
3.83 (t, J¼8.0 Hz, 1H), 2.11–2.29 (m, 2H), 1.41 (s, 9H), 1.27–1.38 (m,
22H), 1.12–1.18 (m, 21H), 0.90 (t, J¼7.2 Hz, 3H), 0.30 (s, 9H); 13C
NMR (100 MHz, C6D6, 75 ꢁC)
d 153.5, 143.5, 139.8, 80.9, 79.9, 73.2,
66.2, 60.1, 32.2, 30.2, 30.1, 30.0, 29.9, 29.8, 29.7, 28.6, 23.0, 18.54,
18.48, 14.1, 13.3, 0.44; IR (film) 2925, 1705, 1612 cmꢀ1; HRMS ES
(m/z): [MþNa]þ calcd for C36H73NNaO2Si2 662.4976; found
642.4979.
1
a (>95:5) ratio of diastereomers. H NMR (400 MHz, C6D6, 75 ꢁC)
d
6.62 (qd, J¼7.2, 1.2 Hz, 1H), 5.22 (br s, 1H), 5.18 (s, 1H), 4.75 (d,
J¼4.4 Hz,1H), 4.16 (dd, J¼8.0, 7.2 Hz,1H), 3.99 (td, J¼7.2, 2.4 Hz,1H),
3.75 (t, J¼8.0 Hz, 1H), 1.67 (dd, J¼7.2, 1.2 Hz, 3H), 1.41 (s, 9H), 1.12–
4.4. Synthesis of
(Scheme 3)
D-erythro-sphingosine from compound 3a
1.14 (m, 21H), 0.27 (s, 9H); 13C NMR (100 MHz, C6D6, 75 ꢁC)
d 154.0,
141.2, 137.4, 80.8, 79.9, 73.4, 73.2, 66.2, 60.1, 28.5, 18.44, 18.39, 17.2,
13.29, 13.27, 0.13;IR (film) 2944, 2867, 1705, 1616 cmꢀ1; HRMS
ES (m/z): [MþNa]þ calcd for C24H49NNaO4Si2 494.3098; found
494.3100.
4.4.1. (S)-tert-Butyl 4-((R,E)-1-hydroxybut-2-enyl)-2,2-
dimethyloxazolidine-3-carboxylate (10)
n-Bu4NF (15.0 mL of 1.0 M in THF, 10.0 equiv) was added to
dissolve (S)-tert-butyl 2,2-dimethyl-4-((S,E)-1-(triisopropylsily-
loxy)-2-(trimethylsilyl)but-2-enyl)oxazolidine-3-carboxylate (3a)
(750 mg, 1.5 mmol) at rt. The solution was stirred for 12 h at rt, and
the mixture was quenched with saturated sodium bicarbonate and
extracted with ethyl acetate three times. The combined organic
layers were washed with brine and dried over magnesium sulfate,
filtered, and concentrated in vacuo. The residue was purified via
flash column chromatography (30% ether/hexanes) to afford
369 mg of (S)-tert-butyl 4-((R,E)-1-hydroxybut-2-enyl)-2,2-dimethyl-
oxazolidine-3-carboxylate (10) (91%) as a colorless oil. 1H NMR
4.3.5. (S)-tert-Butyl 4-((S,E)-3-phenyl-1-(triisopropylsilyloxy)-2-
(trimethylsilyl)allyl)oxazolidine-3-carboxylate (8b)
Following the general procedure, (S)-tert-butyl 4-formylox-
azolidine-3-carboxylate (7) (100 mg, 0.50 mmol), 1-phenyl-2-(tri-
methylsilyl)acetylene (2b) (104 mg, 0.60 mmol), Ni(COD)2 (14 mg,
0.05 mmol), 1,3-dimesitylimidazolium chloride (17 mg, 0.05 mmol),
t-BuOK (6 mg, 0.05 mmol), and i-Pr3SiH (158 mg, 1.0 mmol) gave,
after column chromatography (2% ether/hexanes), 213 mg of (S)-
tert-butyl 4-((S,E)-3-phenyl-1-(triisopropylsilyloxy)-2-(trimethyl-
silyl)allyl)oxazolidine-3-carboxylate (8b) (80%) as a light yellow oil
as a (>95:5) ratio of diastereomers. 1H NMR (400 MHz, C6D6, 75 ꢁC)
(400 MHz, C6D6, 75 ꢁC)
d
5.57 (dq, J¼15.2, 6.4 Hz, 1H), 5.42 (dd,
J¼15.2, 6.0 Hz, 1H), 4.21–4.28 (m, 1H), 3.86–3.96 (m, 1H), 3.74–3.82
(m, 1H), 3.64 (dd, J¼8.8, 6.8 Hz, 1H), 3.00 (v. br s, 1H), 1.61 (s, 3H),
1.55 (d, J¼6.4 Hz, 3H), 1.45 (s, 3H), 1.37 (s, 9H); 13C NMR (100 MHz,
d
7.81 (s, 1H), 7.03–7.17 (m, 5H), 5.44 (s, 1H), 5.24 (s, 1H), 4.77 (d,
J¼4.0 Hz, 1H), 4.25 (t, J¼7.6, 1.6 Hz, 1H), 4.16 (dt, J¼1.6, 7.6 Hz, 1H),
C6D6, 75 ꢁC)
d 131.7,126.8, 94.5, 80.0, 73.7, 64.9, 62.7, 28.4, 26.8, 24.4,
3.91 (t, J¼7.6 Hz, 1H), 1.42 (s, 9H), 1.82–1.90 (m, 21H), 0.12 (s, 9H);
17.6; IR (film) 3432, 2923, 1703 cmꢀ1; HRMS ES (m/z): [MþNa]þ
13C NMR (100 MHz, C6D6, 75 ꢁC)
d
154.1, 144.6, 142.1, 140.7, 128.7,
calcd for C14H25NNaO4 294.1681; found 294.1676.
128.2, 127.3, 80.9, 80.1, 73.84, 73.76, 66.1, 60.0, 28.6, 18.6, 18.5, 13.41,
13.43, 0.73; IR (film) 2944, 2867, 1702 cmꢀ1; HRMS ES (m/z):
[MþNa]þ calcd for C29H51NNaO4Si2 556.3254; found 556.3249.
4.4.2. (S)-tert-Butyl 4-((R,E)-1-hydroxyhexadec-2-enyl)-2,2-
dimethyloxazolidine-3-carboxylate (11)
Dichloromethane was added to dissolved (S)-tert-butyl 4-((R,E)-
1-hydroxybut-2-enyl)-2,2-dimethyloxazolidine-3-carboxylate (10)
(85 mg, 0.40 mmol) and pentadec-1-ene (170 mg, 0.80 mmol).
Second generation Grubbs catalyst (33 mg, 0.04 mmol) was added
to the solution and the reaction mixture was heated at reflux for
2 h. Additional pentadec-1-ene (170 mg, 0.80 mmol) and second
generation Grubbs catalyst (33 mg, 0.04 mmol) were then added.
After another 4 h, more second generation Grubbs catalyst (33 mg,
0.04 mmol) was added. The mixture was then concentrated, and
the residue was purified via flash chromatography (30% ether/
hexanes) to provide 144 mg of (S)-tert-butyl 4-((R,E)-1-hydroxy-
hexadec-2-enyl)-2,2-dimethyloxazolidine-3-carboxylate (11) (82%)
as a colorless oil. 1H NMR data (400 MHz, C6D6, 60 ꢁC) were iden-
tical to that previously reported.10a
4.3.6. (S)-tert-Butyl 4-((S,Z)-1-(triisopropylsilyloxy)-2-
(trimethylsilyl)hept-2-enyl)oxazolidine-3-carboxylate (8c)
Following the general procedure, (S)-tert-butyl 4-formylox-
azolidine-3-carboxylate (7) (100 mg, 0.50 mmol), hex-1-ynyltri-
methylsilane (2c) (92 mg, 0.60 mmol), Ni(COD)2 (14 mg, 0.50 mmol),
1,3-dimesitylimidazolium chloride (14 mg, 0.10 mmol), t-BuOK
(6 mg, 0.50 mmol), and i-Pr3SiH (158 mg, 1.0 mmol) gave, after
column chromatography (2% ether/hexanes), 200 mg of (S)-tert-
butyl 4-((S,Z)-1-(triisopropylsilyloxy)-2-(trimethylsilyl)hept-2-enyl)-
oxazolidine-3-carboxylate (8c) (78%) as a colorless oil as a (>95:5)
ratio of diastereomers. 1H NMR (400 MHz, C6D6)
1H), 5.25 (br s, 2H), 4.75 (d, J¼4.0 Hz, 1H), 4.21 (t, J¼7.6 Hz, 1H),
4.00–4.10 (m, 1H), 3.84 (t, J¼7.6 Hz, 1H), 2.00–2.18 (m, 2H), 1.39 (s,
d
6.57 (t, J¼7.2 Hz,

K. Sa-ei, J. Montgomery / Tetrahedron 65 (2009) 6707–6711
6711
24
4.4.3.
D
-erythro-Sphingosine
oxazolidine-3-carboxylate (11) (91%) as a colorless oil. [
a
]
ꢀ28 (c
D
(S)-tert-Butyl-4-((R,E)-1-hydroxyhexadec-2-enyl)-2,2-dimethy-
loxazolidine-3-carboxylate (11) (100 mg, 0.23 mmol) was dissolved
in THF (1.0 mL) and 2 N HCl (1.0 mL), and the reaction mixture was
stirred at 75 ꢁC for 12 h. THF was removed in vacuo, and the less
polar impurities were extracted with ether/hexanes (1:1, 10 mL).
The aqueous layer was basified with 2 N NaOH to pH 12 and
extracted with dichloromethane. The combined organic layers
were washed with brine, dried over magnesium sulfate, filtered,
and concentrated in vacuo. The residue was purified via flash
chromatography (SiO2) eluting with CHCl3/MeOH/NH4OH
0.65, CHCl3). 1H NMR data (400 MHz, C6D6, 60 ꢁC) and optical ro-
tation data were identical to that previously reported.10a
4.5.3.
D-erythro-Sphingosine
The identical procedure to that described above (Section 4.4.3)
was performed using 11 (50 mg, 0.11 mmol) to afford 24 mg of
erythro-sphingosine 1 (0.080 mmol, 73% yield).
D-
Acknowledgements
(130:25:4) to afford 56 mg of 1 (0.19 mmol, 82% yield) as a white
The authors thank the NIH (GM 57014) for generous financial
support of this work.
24
solid. Mp¼73–74 ꢁC; [
a
]
ꢀ1.0 (c 0.45, CHCl3). 1H NMR data
D
(500 MHz, CDCl3) were identical with that previously reported.10a,i
References and notes
4.5. Synthesis of
(Scheme 4)
D-erythro-sphingosine from compound 3d
1. Metal-Catalyzed Reductive C–C Bond Formation: A Departure from Preformed
Organometallic Reagents; Krische, M. J., Ed.; Springer: Heidelberg, 2007.
2. (a) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890; (b) Montgomery, J.;
Sormunen, G. J. Top. Curr. Chem. 2007, 279, 1; (c) Iida, H.; Krische, M. J. Top. Curr.
Chem. 2007, 279, 77; (d) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem.
Commun. 2007, 4441.
3. (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065; (b) Huang, W.-
S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221; (c) Takai, K.; Sakamoto, S.;
Isshiki, T. Org. Lett. 2003, 5, 653.
4. Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698.
5. (a) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442;
(b) Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007,
129, 9568; For metals other than nickel: (c) Komanduri, V.; Krische, M. J. J. Am.
Chem. Soc. 2006, 128, 16448; (d) Kong, J.-R.; Ngai, M.-Y.; Krische, M. J. J. Am.
Chem. Soc. 2006, 128, 718; (e) Rhee, J. U.; Krische, M. J. J. Am. Chem. Soc. 2006,
128, 10674.
6. (a) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098; (b) Tang, X.-Q.;
Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950; (c) Colby, E. A.; O’Brien, K. C.;
Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 4297.
4.5.1. (S)-tert-Butyl 2,2-dimethyl-4-((S,E)-1-(triisopropylsilyloxy)-
2-(trimethylsilyl)hexadec-2-enyl)oxazolidine-3-carboxylate (3d)
A modification of the general procedure was followed: 30 mL of
water was added immediatelyafter the addition of the aldehyde and
alkyne. Garner aldehyde 1 (92 mg, 0.4 mmol), trimethyl(pentadec-
1-ynyl)silane (2d) (56 mg, 0.2 mmol), 1,3-dimesitylimidazolium
chloride (7.0 mg, 0.02 mmol), t-BuOK (2 mg, 0.02 mmol) and
Ni(COD)2 (6 mg, 0.02 mmol), i-Pr3SiH (63 mg, 0.4 mmol), and water
(30 mL) gave, after column chromatography (2% ether/hexanes),
87 mg of (S)-tert-butyl 2,2-dimethyl-4-((S,E)-1-(triisopropylsily-
loxy)-2-(trimethylsilyl)hexadec-2-enyl)oxazolidine-3-carboxylate
24
(3d) (65%) as a colorless oil (>95:5 dr). [
a]
ꢀ4.0 (c 2.30, CHCl3). 1H
D
NMR (400 MHz, C6D6, 75 ꢁC)
d
6.58 (t, J¼7.6 Hz, 1H), 5.30 (br s, 1H),
7. (a) Luanphaisarnnont, T.; Ndubaku, C. O.; Jamison, T. F. Org. Lett. 2005, 7, 2937;
(b) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441.
8. (a) Moslin, R. M.; Jamison, T. F. Org. Lett. 2006, 8, 455; (b) Moslin, R. M.; Miller,
K. M.; Jamison, T. F. Tetrahedron 2006, 62, 7598.
4.32 (dd, J¼5.6, 8.8 Hz,1H), 4.00–4.04 (m,1H), 3.78 (t, J¼8.4 Hz,1H),
2.16–2.26 (m, 2H),1.68 (s, 3H),1.50 (s, 3H),1.40 (s, 9H),1.25–1.35 (m,
22H),1.18–1.20 (m, 21H), 0.87 (t, J¼6.8 Hz, 3H), 0.35 (s, 9H); 13C NMR
(100 MHz, C6D6, 80 ꢁC)
d
153.5, 143.9, 143.8, 140.9, 95.3, 79.6, 73.8,
9. For description of the bioactivity of the sphingolipids, see: (a) Brown, D. A.;
London, E. J. Biol. Chem. 2000, 275, 17221; (b) Hannun, Y. A.; Bell, R. M. Science
1989, 243, 500; (c) Hannun, Y. A.; Loomis, C. R.; Merrill, A. H.; Bell, R. M. J. Biol.
Chem. 1986, 261, 2604.
10. For representative syntheses, see: (a) Garner, P.; Park, J. M.; Maleki, E. J. Org.
Chem. 1988, 53, 4395; (b) Nimkar, S.; Menaldino, D.; Merrill, A. H.; Liotta, D.
Tetrahedron Lett. 1988, 29, 3037; (c) Herold, P. Helv. Chim. Acta 1988, 71, 354; (d)
Radunz, H.-E.; Devant, R. M.; Eiermann, V. Liebigs Ann. Chem. 1988, 1103; (e)
Hertweck, C.; Boland, W. J. Org. Chem. 1999, 64, 4426; (f) Azuma, H.; Tamagaki,
S.; Ogino, K. J. Org. Chem. 2000, 65, 3538; (g) Murakami, T.; Furusawa, K. Tet-
rahedron 2002, 58, 9257; (h) Chun, J.; Li, G.; Byun, H.-S.; Bittman, R. Tetrahedron
Lett. 2002, 43, 375; (i) Yang, H.; Liebeskind, L. S. Org. Lett. 2007, 9, 2993.
11. Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
12. For cross metathesis approaches to sphingosine: (a) Rai, A. N.; Basu, A. Org. Lett.
2004, 6, 2861; (b) Chang, C.-W.; Chen, Y.-N.; Adak, A. K.; Lin, K.-H.; Tzou, D.-L.
M.; Lin, C.-C. Tetrahedron 2007, 63, 4310; (c) Yamamoto, T.; Hasegawa, H.; Ha-
kogi, T.; Katsumura, S. Org. Lett. 2006, 8, 5569; (d) Torssell, S.; Somfai, P. Org.
Biomol. Chem. 2004, 2, 1643.
13. Chrovian, C. C.; Knapp-Reed, B.; Montgomery, J. Org. Lett. 2008, 10, 811.
14. Ribe, S.; Wipf, P. Chem. Commun. 2001, 299.
15. Falorni, M.; Conti, S.; Giacomelli, G.; Cossu, S.; Soccolini, F. Tetrahedron: Asym-
metry 1995, 6, 287.
62.7, 62.2, 32.3, 30.3, 30.2, 30.01, 30.00, 29.9, 29.7, 28.6, 27.2, 26.2,
23.0, 18.7, 13.6, 0.81; IR (film) 2924, 2854, 1693 cmꢀ1; HRMS ES (m/
z): [MþNa]þ calcd for C38H77NNaO4Si 690.5289; found 690.5298.
4.5.2. (S)-tert-Butyl 4-((R,E)-1-hydroxyhexadec-2-enyl)-2,2-
dimethyloxazolidine-3-carboxylate (11)
n-Bu4NF (0.5 mL of 1.0 M in THF, 10.0 equiv) was added to dis-
solve (S)-tert-butyl 2,2-dimethyl-4-((S,E)-1-(triisopropylsilyloxy)-
2-(trimethylsilyl)hexadec-2-enyl)oxazolidine-3-carboxylate (3d)
(35 mg, 0.05 mmol) at rt. The solution was stirred for 12 h at rt. The
mixture was quenched with saturated sodium bicarbonate and
extracted with ethyl acetate (10 mL) three times. The combined
organic layers were washed with brine and dried over magnesium
sulfate, filtered, and concentrated in vacuo. The residue was puri-
fied via flash chromatography (30% ether/hexanes) to afford 34 mg
of (S)-tert-butyl 4-((R,E)-1-hydroxyhexadec-2-enyl)-2,2-dimethyl-