Enantioselective synthesis of homosphingosine derivatives from L-aspartic acid

Article abstract of DOI:10.1055/S-0029-1219081

The sterically demanding 9-phenylfluorenyl N-protection of a number of amino acids allows the formation of amino acid derived β-ketophosphonate reagents and their Horner-Wadsworth-Emmons olefination. In an attempt to develop a synthesis of D-erythro-homosphingosine in enantiopure form, we have shown that the reactivity of the intermediates is influenced by the distinctive conformational requirements of this large protecting group. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0029-1219081

PAPER
757
Enantioselective Synthesis of Homosphingosine Derivatives from L-Aspartic
Acid
H
omosphingo
a
sine
D
eriva
m
tives from
L
-Aspart
iA
cid J. K. Sauerland,a Joel A. Castillo-Meléndez,a Kalle Nättinen,b Kari Rissanen,b Ari M. P. Koskinen*a
a
Department of Chemical Technology, Laboratory of Organic Chemistry, Helsinki University of Technology,
P.O. Box 6100, 02015 Helsinki, Finland
Fax +358(9)4512538; E-mail: ari.koskinen@tkk.fi
X-ray crystallography; Nanoscience Center, Department of Chemistry, University of Jyväskylä, P.O. Box 35, 40014 Jyväskylä, Finland
b
Received 2 November 2009; revised 6 November 2009
to the nitrogen from epimerization, even in difficult
cases.6 We therefore became interested in investigating
whether the b-ketophosphonate chemistry we have devel-
oped for the Boc-protected amino acid derivatives7 can be
Abstract: The sterically demanding 9-phenylfluorenyl N-protec-
tion of a number of amino acids allows the formation of amino acid
derived b-ketophosphonate reagents and their Horner–Wadsworth–
Emmons olefination. In an attempt to develop a synthesis of D-
erythro-homosphingosine in enantiopure form, we have shown that translated to the corresponding Pf-protected amino acid
the reactivity of the intermediates is influenced by the distinctive
conformational requirements of this large protecting group.
derivatives. Towards this end, we chose a homosphin-
gosine derivative as a first target molecule for testing the
Key words: diastereoselectivity, enantioselectivity, sphingosine,
ceramide
methodology.
Homosphingosine derivatives and homoceramides
(Figure 2) have been the targets of only a few synthetic
studies.8 A general synthetic approach to homoceramides
could lead to the development of a new class of anti-
cancer drugs,8 thus the synthesis of D-erythro-homo-
sphingosine (3) was investigated in this work, with the
aim of subsequently preparing a range of homoceramides.
Sphingolipids constitute a major membrane component of
eukaryotic cells, and important roles in cell recognition,
differentiation, cell–cell contact and cell growth have
been recognized.1 The backbone of sphingolipids is D-
erythro-sphingosine (1; Figure 1); ceramides (2) are
formed by acylation of the nitrogen with a fatty acid
(RCOOH). More complex sphingolipids are formed by
further addition of a polar head-group to the primary hy-
droxy group of sphingosine or ceramide.2
OH
OH
HO
HO
C13H27
C13H27
HN
R
NH2
O
4
OH
OH
3
HO
C13H27
HO
C13H27
Figure 2
NH2
HN
R
We envisioned that D-erythro-homosphingosine (3) could
be conveniently constructed from L-aspartic acid by inter-
nal asymmetric induction, whereby the two carboxy func-
tionalities of L-aspartic acid could be transformed into the
2-amino-1,4-diol structure present in 3.
O
1
2
Figure 1
We have previously developed a general and efficient
synthesis of sphingosine based on a serine derived b-keto-
phosphonate.3 However, although this chemistry is reli-
able and robust enough to be used for sphingolipid
synthesis and for several other targets, it still suffers from
the fact that the original a-center of the amino acid re-
mains vulnerable to epimerization.4 Although this epimer-
ization can, in most cases, be suppressed to levels where
it is not observed, in some highly sensitive cases these
problems can be insurmountable.5
Our general strategy (Scheme 1) was to convert a protect-
ed L-aspartic acid into homoserine 5, and protect it as the
N,O-acetal 6. The C-5 carbon would then be added with
the formation of a b-ketophosphonate 7, and the E double
bond as well as the aliphatic chain would be introduced
through
a
modified Horner–Wadsworth–Emmons
reaction7 to give enone 8. Selective reduction9 of the car-
bonyl and removal of the protecting groups would lead to
the desired compound homosphingosine (3). The diaste-
reoselectivity of the reduction was expected to be en-
hanced by bulky protecting groups: tert-butyl ester of the
a-amino acid and 9-phenyl-9-fluorenyl of the amino
group.
9-Phenyl-9-fluorenyl (Pf) protection of the amino group
has been shown to efficiently protect the carbon atom next
Anticipating difficulties during the phosphonation/chain-
elongation of 6b because of steric hindrance from the a-
tert-butyl and 9-phenyl-9-fluorenyl groups, we initially
SYNTHESIS 2010, No. 5, pp 0757–0762
Advanced online publication: 16.12.2009
DOI: 10.1055/s-0029-1219081; Art ID: Z23009SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

758
S. J. K. Sauerland et al.
PAPER
O
O
O
HO
HO
OR
OH
OR
O
N
O
N
NH2
L-Asp
NHPf
Pf
5
8
6
O
O
P
O
OH
OMe
HO
C13H27
C13H27
OMe
O
O
N
NH2
Pf
Pf
7
3
Scheme 1
O
O
O
O
O
P
ref. 10
i
ii
OMe
OMe
OH
OH
Ot-Bu
NH2
L-Ala
NHPf
NHPf
NHPf
9
10
11
Scheme 2 Reagents and conditions: i) Cl3C(NH)OtBu, CH2Cl2, 35% from L-Ala; ii) LiCH2P(=O)(OMe)2, THF, –78 °C, 52%.
conducted a model study with the L-alanine derived com- method developed by Rapoport (Scheme 3).15 Encour-
pound 11 (Scheme 2).
aged by the successful phosphonation of model com-
pound 10, we submitted 6b to the conditions developed by
Lee [dimethyl methylphosphonate (6.5 equiv) and n-BuLi
(9.0 equiv)].12 However, 6b failed to react under these
conditions, and led to only extensive decomposition under
more forcing reaction conditions. Apparently, the steric
hindrance caused by the tert-butyl and 9-phenylfluorenyl
groups is enhanced by the rigid acetal ring of 6b.
Crude N-Pf-protected 96b,10 was directly esterified to give
compound 10 in 42% yield as yellow crystals.11 An ana-
lytical sample was recrystallized from hexanes, and the X-
ray crystal structure was determined (Figure 3).12
Phosphonation13 of the model compound 10, avoiding ex-
cess n-butyllithium [dimethyl methylphosphonate (5.5
equiv), n-BuLi (5.27 equiv)], gave 11 as a yellow oil in an
acceptable, although low, yield of 52%. Encouraged by
this finding, we embarked on the actual route with
homoserine. N-Pf-homoserine tert-butyl ester (5b)14 was
fully protected as the cyclic hemiaminal 6b utilizing the
Having failed to form the b-ketophosphonate from acetal
6b, we decided to opt for the less hindered methyl ester
(Scheme 4). Thus, a-methyl aspartate16 was converted
into the crystalline a-methyl N-Pf-aspartate 12 (Figure 4).
Borane reduction of 12 to the N-Pf-homoserine methyl es-
ter (5a)17 was performed using the Alberg protocol.18 The
starting material 12 needed to be heated and stirred for 2–
3 days to yield 52% of 5a. N,O-Acetal protection of 5a
proceeded smoothly, giving 6a in 85% yield. Simple re-
crystallization from hexanes gave pure 6a. The crystal
structure of 6a is shown in Figure 5. It is noteworthy that
both the methyl ester group and the bulky nitrogen pro-
O
O
CH2O, p-TsOH
HO
Ot-Bu
Ot-Bu
THF, r.t.
O
N
NHPf
5b
Pf
6b
99%
Scheme 3
O
O
O
i
ref. 15
HO
HO
HO
OH
OMe
OMe
O
NH2
L-Asp
O
NH2
O
NHPf
O
L-Asp-OMe
12
O
O
P
O
ii
iii
iv
OMe
OMe
HO
OMe
OMe
O
N
O
N
NHPf
Pf
Pf
5a
6a
7
O
OH
Pf
v
vi
HO
C13H27
C13H27
O
N
N
Pf
Me
8
13
Scheme 4 Reagents and conditions: i) TMSCl, Et3N, Pb(NO3)2, PfBr, CH2Cl2, r.t., 89%; ii) BH3·THF, THF, 40 °C, 52%; iii) CH2O, p-TsOH,
THF, r.t., 85%; iv) LiCH2P(=O)(OMe)2, THF, –78 °C, 64%; v) tetradecanal, K2CO3, MeCN, r.t., 67%; vi) DIBAL-H, toluene, –78 °C, 55%.
Synthesis 2010, No. 5, 757–762 © Thieme Stuttgart · New York

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Homosphingosine Derivatives from L-Aspartic Acid
759
Phosphonation of 6a with 3.3 equivalents of dimethyl
methylphosphonate and 3.0 equivalents of n-BuLi gave 7
in 64% yield. Horner–Wadsworth–Emmons olefination
gave the Z-olefin 8 in 67% yield.
DIBAL-H reduction9 of 8 in toluene was expected to give
the desired anti-alcohol. However, presumably due to the
conformational features of the ring substituents, the
oxazinane underwent reductive ring opening, leaving a
methyl group attached to the nitrogen (determined by
HMBC 2D-NMR). The yield was modest, reaching only
55%, but only the anti diastereomer could be detected by
1H NMR after HPLC.19
In conclusion, we have shown that the b-ketophospho-
nate/Horner–Wadsworth–Emmons olefination chemistry
developed previously for Boc-protected serine derivatives
can be successfully transferred to 9-phenylfluorenyl-pro-
tected amino acid derivatives for the synthesis of homo-
sphingosine derivatives. Olefination followed by highly
diastereoselective reduction of the enone were accompa-
nied by the unwanted reductive cleavage of the hemiami-
nal moiety. The development of milder methods for the
reduction of the sensitive enone will be reported in due
course.
Figure 3 X-ray crystal structure of 10
CH2Cl2 and MeCN were distilled over CaH2, THF was distilled
over sodium/benzophenone, MeOH over Mg(OMe)2, toluene over
sodium, EtOH over Mg(OEt)2, and Et3N over NaOH pellets. Pyri-
dine was simply distilled. All other reagents were used as obtained
from the supplier without further purification. Reactions were per-
formed under an inert argon atmosphere, and anhydrous conditions
were applied if dried solvents were used. Flash chromatography sil-
ica and TLC plates (silica gel 60 F254) were obtained from Merck.
TLC plates were visualized under UV irradiation (254 nm). Melting
points were measured with a Gallenkamp melting point apparatus
MFB 595 and are uncorrected. NMR spectra were recorded with a
Bruker Avance 400 (1H 400 MHz, 13C 100 MHz) instrument, and
chemical shifts (d) are reported in ppm relative to TMS (b = 0 ppm).
13C NMR spectra were calibrated with the solvent signal. Infrared
(IR) spectra were measured with a Perkin–Elmer Spectrum One in-
strument. Optical rotations were measured with a Perkin–Elmer Po-
larimeter 343, and elemental analyses (CHN) were performed with
a Perkin–Elmer Elemental Analyzer 2400 CHN. The high resolu-
tion mass spectra (HRMS) were measured at the University of Oulu
with a Micromass LCT mass instrument. HPLC was performed
with the following conditions: Shandon Hypersil (5 mm, 250 ×
4.6 mm), Shandon Hyperprep (12 mm, 250 × 4.6 mm) and Shandon
Hyperprep (12 mm, 250 × 10 mm); EtOAc–hexanes, 17–20%; flow
rates: 1–5 mL/min.
Figure 4 X-ray crystal structure of 12
(S)-tert-Butyl 3-(9-Phenyl-9H-fluoren-9-yl)-1,3-oxazinane-4-
carboxylate (6b)
Alcohol 5b (0.102 g, 0.25 mmol, 1.0 equiv) was dissolved in dis-
tilled THF (2 mL) under argon. Formaldehyde (0.3 mL, ~4 mmol,
16.0 equiv, 35–40% in H2O) was added, followed by a catalytic
amount of p-TsOH·H2O. The mixture was stirred for 1 d, and
quenched with sat. aq NaHCO3 (2 mL). The mixture was extracted
with EtOAc (3 × 10 mL), and the combined organic layers were
washed with brine (5 mL), dried over MgSO4 and evaporated. Puri-
fication by flash chromatography (EtOAc–hexanes, 5%) yielded
6b.
Figure 5 X-ray crystal structure of 6a
tecting group occupy axial positions. This unusual steric
disposition of the groups would surely affect the chemis-
try of such compounds, as we were soon to observe.
Yield: 0.106 g (99%); colorless oil; Rf = 0.56 (EtOAc–hexanes,
50%); [a]D20 +151 (c 0.43, CHCl3).
Synthesis 2010, No. 5, 757–762 © Thieme Stuttgart · New York

760
S. J. K. Sauerland et al.
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IR (NaCl): 3060–2843, 1724 cm–1.
(CH3)2P(=O)CHHC(=O)-C2], 2.60 [dd, J = 14.7, 21.2 Hz, 1 H,
(CH3)2P(=O)CHHC(=O)-C2], 1.02 (d, J = 7.0 Hz, 3 H,
CH3CHNHPf-C2).
13C NMR (CDCl3, 100 MHz): d = 205.83 and 205.77 (C=O), 149.6,
149.3, 144.3, 140.8, 140.1, 128.4, 128.3, 128.2, 128.1, 127.8, 127.2,
126.1, 126.0, 125.1, 119.9, 119.8 (Ar), 73.0 (quat. aliph.), 58.05 and
58.02 (COCHNPfCH3), 52.81, 52.74, 52.68 and 52.62
[(CH3)2P(=O)], 38.3 and 37.0 [PCH2C(=O)], 20.0 (CHNPfCH3).
1H NMR (CDCl3, 400 MHz): d = 7.82–7.80 (m, 1 H, ArH), 7.70–
7.67 (m, 1 H, ArH), 7.61–7.59 (m, 1 H, ArH), 7.52–7.13 (m, 10 H,
ArH), 4.96 (d, J = 11.7 Hz, 1 H, N-CHH-O), 4.84 (d, J = 11.7 Hz,
1 H, N-CHH-O), 3.77 (m, 1 H, C-CHH-O), 3.63 (m, 1 H, C-CHH-
O), 3.29 (m, 1 H, ROOC-CHNR-C), 1.48 (s, 9 H, t-Bu), 1.44–1.31
(m, 2 H, CHN-CH2-CH2O).
13C NMR (CDCl3, 100 MHz): d = 172.2 (CO, t-Bu ester), 149.2,
147.9, 143.8, 140.7, 139.2, 128.7, 128.4, 128.3, 128.2, 127.6, 127.5,
127.3, 127.1, 125.6, 119.8, 119.6 (Ar), 80.7 (t-Bu quat.), 78.1 (two
HRMS: m/z [M + Na] calcd. for C25H26NO4NaP: 458.1497; found:
458.1479.
peaks,
Pf
quat.
aliph.
and
NPfCH2OCH2),
64.4
(CHNCH2CH2OCH2NPf), 54.5 (t-BuOOCCHNPfCH2), 28.1
[(CH3)3CO], 25.4 (CHCH2CH2OCH2NPf).
(2S)-a-Methyl N-(9-Phenyl-9H-fluoren-9-yl)aspartate (12)
To a stirred solution of (S)-a-methyl aspartate (4.0 g, 27 mmol, 1.00
equiv) in anhydrous CH2Cl2 (50 mL) was added TMSCl (3.7 mL,
29 mmol, 1.07 equiv) under argon. After 2 h, Et3N (8.0 mL, 58
mmol, 2.15 equiv) was added and, after another 15 min, Pb(NO3)2
(5.96 g, 18 mmol, 0.67 equiv) and a solution of 9-bromo-9-phe-
nylfluorene (11.57 g, 36 mmol, 1.33 equiv) in anhydrous CH2Cl2
(50 mL) were added. After stirring for 3 d, MeOH (14 mL) was add-
ed and, after another 15 min, the mixture was filtered and evaporat-
ed. The viscous residue was partitioned between aq. citric acid (5%,
150 mL) and Et2O (150 mL). The layers were separated and the
aqueous layer was extracted with Et2O (2 × 100 mL). The combined
organic layers were washed with brine (60 mL), dried over MgSO4
and evaporated. The residue was dissolved in Et2O (70 mL) and ex-
tracted with sat. aq NaHCO3 (5 × 30 mL). The aqueous layers were
acidified with concd H3PO4 to pH 5 and extracted with Et2O (2 × 50
mL). The combined organic layers were washed with brine (30
mL), dried over MgSO4 and evaporated to give 12. An analytical
sample was recrystallised from CH2Cl2–hexanes and again from
EtOAc–hexanes.12
HRMS: m/z [M + Na] calcd. for C28H29NO3Na: 450.2045; found:
450.2052.
(S)-tert-Butyl 2-[(9-Phenyl-9H-fluoren-9-yl)amino]alanate (10)
Crude (S)-N-[9-(9-phenylfluorenyl)]alanine (9; 2.1 g, max. 6 mmol)
was dissolved in anhydrous CH2Cl2 (15 mL) under argon and the
solution was transferred to the reaction flask using a syringe. O-tert-
Butyl trichloroacetimidate (2.2 mL, 12.3 mmol) was added, and the
solution was stirred for 3 d. The mixture was filtered and evaporat-
ed, then the residue was submitted to the same conditions as de-
scribed above, and mixed for 3 d. The mixture was filtered,
evaporated and purified by flash chromatography (EtOAc–hexanes,
5%), MPLC (EtOAc–hexanes, 5%) and MPLC (EtOAc–hexanes,
2%) to give 10.
Yield: 1.03 g (35% from L-alanine); yellow crystalline solid; mp
114 °C; [a]D20 –153 (c 0.6, CHCl3).
IR (KBr): 3063–2873, 1727 cm–1.
20
1H NMR (CDCl3, 400 MHz): d = 7.68–7.65 (m, 2 H, ArH), 7.42–
7.15 (m, 11 H, ArH), 3.08 (br s, 1 H, CNHPf), 2.67 (q, J = 7.1 Hz,
1 H, ROOCCHNHPf-CH3), 1.20 [s, 9 H, (CH3)3COC(=O)], 1.08 (d,
J = 7.1 Hz, 3 H, ROOCCHNHPf-CH3).
13C NMR (CDCl3, 100 MHz): d = 175.8 (CO ester), 149.8, 149.6,
144.8, 140.6, 140.2, 128.1, 128.0, 127.9, 127.7, 127.6, 127.0, 126.1,
125.9, 125.2, 119.9, 119.6 (Ar), 80.3 (quat. aliph.), 73.1 (quat. aliph.),
52.0 (ROOCCNHPfCH3), 27.8 [(CH3)3C], 22.1 (CHNPfCH3).
Yield: 9.3 g (89%); yellow foam; mp 128–129 °C; [a]D –297 (c
1.0, CHCl3).
IR (KBr): 3059–2956, 2636, 1736 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.77–7.71 (m, 2 H, ArH), 7.46–
7.22 (m, 11 H, ArH), 3.42 [s, 3 H, CH3OC(=O)C], 3.05 (dd, J = 4.9,
7.9 Hz, 1 H, MeOOCCHN), 2.51 (dd, J = 7.9, 16.2 Hz, 1 H,
CHNPf-CHH-COOH), 2.18 (dd, J = 4.9, 16.2 Hz, 1 H, CHNPf-
CHHCOOH).
13C NMR (CDCl3, 100 MHz): d = 173.2 (CO), 171.7 (CO), 146.5,
146.4, 142.5, 141.4, 139.9, 129.3, 129.2, 128.8, 128.6, 128.0, 127.9,
126.0, 125.7, 125.6, 120.4, 120.2 (Ar), 72.7 (quat. aliph.), 52.7
[CH3OC(=O)], 51.9 (ROOCCHNPfC), 36.6 (CHNPfCH2COOH).
Anal. Calcd for C26H27NO2: C, 81.01; H, 7.06; N, 3.63. Found: C,
81.16; H, 7.01; N, 3.53.
(S)-Dimethyl {2-Oxo-2-[3-(9-phenyl-9H-fluoren-9-yl)-1,3-ox-
azinan-4-yl]ethyl}phosphonate (11)
Anal. Calcd for C24H21NO4: C, 74.40; H, 5.46; N, 3.62. Found: C,
74.39; H, 5.38; N, 3.54.
To a stirred solution of dimethyl methylphosphonate (0.153 mL,
1.43 mmol, 5.5 equiv) in anhydrous THF (4 mL) under argon at
–78 °C, was added dropwise n-BuLi (2.5 M in hexanes, 0.55 mL,
1.37 mmol, 5.27 equiv). The mixture was stirred for 10 min then a
solution of 10 (0.10 g, 0.26 mmol, 1.0 equiv) in anhydrous THF (1
mL) was added dropwise. The solution was stirred for 5.5 h while
slowly warming to –6 °C. The reaction was quenched with sat. aq
NH4Cl (3 mL), which formed a white solid. A little water was added
to dissolve the solid, and the mixture was extracted with EtOAc
(3 × 10 mL). The combined organic layers were dried over Na2SO4
and evaporated. Purification by flash chromatography (EtOAc–
hexanes, 50→75%) gave 11.
Yield: 0.059 g (52%); yellow oil; Rf = 0.3 (EtOAc, 100%); [a]D20 –55
(c 0.4, CH2Cl2).
IR (NaCl): 3295, 2954, 1713, 1258 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.70–7.66 (m, 2 H, ArH), 7.41–
7.13 (m, 11 H, ArH), 3.62 [dd, J = 11.2, 15.19 Hz, 6 H,
(CH3)2P(=O)-C4], 3.12 (br s, 1 H, C-NHPf), 2.81 (q, J = 7.0 Hz,
1 H, C(=O)CHNHPfCH3), 2.77 [dd, J = 14.7, 22.2 Hz, 1 H,
(S)-Methyl 4-Hydroxy-2-[(9-phenyl-9H-fluoren-9-yl)amino]bu-
tanoate (5a)
To a stirred solution of 12 (2.0 g, 5 mmol, 1.00 equiv) in anhydrous
THF (10 mL) at –5 °C under argon, borane–THF (1.5 M in THF–
Et2O, 6.7 mL, 10 mmol, 2.00 equiv) was added dropwise. After stir-
ring for 4 h, further borane (3.3 mL, 5 mmol, 1.00 equiv) was added
and the cooling bath was removed. After 22 h, the mixture was heat-
ed to 40 °C for 45 h and the reaction was quenched by adding aq cit-
ric acid (10%, 30 mL). Et2O (50 mL) was added, the layers were
separated, and the aqueous layer was extracted with Et2O (3 × 25
mL). The combined organic layers were washed with brine (30
mL), dried over Na2SO4 and evaporated. Purification twice with
flash chromatography (EtOAc–hexanes, 10→20→50→75→100%
then EtOAc–hexanes, 40%) gave 14. Partial recrystallisation from
benzene–hexanes yielded colorless crystals for analytical purposes.
Yield: 0.97 g (52%); yellow oil; mp 96–97 °C (Lit.16 96–97 °C).
Synthesis 2010, No. 5, 757–762 © Thieme Stuttgart · New York

PAPER
Homosphingosine Derivatives from L-Aspartic Acid
CC(=O)CHNPfC], 52.94, 52.88, 52.85 and
[(CH3O)2P(=O)C], 37.5 and 36.2 [PCH2C(=O)C], 22.2
(CHNPfCH2CH2O).
761
(S)-Methyl 3-(9-Phenyl-9H-fluoren-9-yl)-1,3-oxazinane-4-car-
boxylate (6a)
52.79
To a stirred solution of 5a (3.55 g, 9.5 mmol, 1.00 equiv) in distilled
THF (80 mL), formaldehyde (11.5 mL, 152 mmol, 16.00 equiv, 35–
40 wt% in H2O) and p-TsOH·H2O (0.133 g, 0.95 mmol, 10 equiv)
were added under argon. The solution was stirred for 2 d then sat.
aq NaHCO3 (20 mL) was added, which formed a white solid, and
the mixture was extracted with EtOAc (3 × 30 mL). A little water
was added to the aqueous layer to dissolve the white solid. The
aqueous layer was extracted with EtOAc (2 × 30 mL) and the com-
bined organic layers were washed with brine (30 mL), dried over
Na2SO4 and evaporated. Recrystallisation of the mother liquor three
times with EtOAc–cyclohexane, cyclohexane, and hexanes yielded
three crops of 6a.
Anal. Calcd for C27H28NO5P: C, 67.92; H, 5.91; N, 2.93. Found: C,
67.87; H, 5.91; N, 2.88.
(S,E)-1-[3-(9-Phenyl-9H-fluoren-9-yl)-1,3-oxazinan-4-yl]hexa-
dec-2-en-1-one (8)
Compound 7 (0.50 g, 1.0 mmol, 1.00 equiv) was dissolved in anhy-
drous MeCN (10 mL) in a Morton-flask under argon, and K2CO3
(0.42 g, 3.0 mmol, 3.00 equiv) was added. After 20 min, tetradeca-
nal (0.40 g, 1.1 mmol, 1.10 equiv, 58 wt% mixture) was added. The
white suspension was stirred for 48 h, then tetradecanal (0.21 g,
0.57 mmol, 0.57 equiv, 58 wt% mixture) was added. After stirring
for a further 2 d, the reaction was quenched with aq citric acid (5%,
40 mL) and diluted with Et2O (40 mL). The layers were separated,
and the aqueous layer was extracted with Et2O (3 × 20 mL). The
combined organic layers were dried over Na2SO4 and evaporated.
Purification by flash chromatography (EtOAc–hexanes,
0→1→2→5%) gave 8. An analytical sample was recrystallised
from hexanes.
Yield: 3.109 g (85%); colorless to pale-yellow crystalline solid; mp
141 °C; [a]D20 +253 (c 0.74, CHCl3).
IR (KBr): 3437, 2961–2850, 1732 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.80–7.77 (m, 1 H, ArH), 7.70–
7.68 (m, 1 H, ArH), 7.62–7.60 (m, 1 H, ArH), 7.48–7.15 (m, 10 H,
ArH), 4.97 (d, J = 11.5 Hz, 1 H, CNPfCHHOC), 4.86 (d, J = 11.5
Hz, CNPfCHHOC), 3.79–3.74 (m, 1 H, CHNPfCH2CHHO), 3.64
[s, 3 H, CH3OC(=O)], 3.65–3.58 (m, 2 H, CHNPfCH2CHHO, over-
lapping with the 3.64 singlet), 3.41–3.40 (m, 1 H,
ROOCCHNPfCH2CH2O), 1.50–1.42 (m, 2 H, CHNPfCH2CH2O).
20
Yield: 0.38 g (67%); white solid; mp 97 °C; [a]D –191 (c 0.43,
CHCl3).
IR (KBr): 3436, 2923, 2852 cm–1.
13C NMR (CDCl3, 100 MHz): d = 173.5 (CO), 148.7, 147.7, 143.5,
140.7, 139.3, 128.6, 128.5, 128.4, 128.3, 127.8, 127.6, 127.4, 127.1,
125.6, 119.8, 119.7 (Ar), 78.0 and 77.9 (quat. aliph. and NCH2O),
64.4 (CCH2O), 54.0 (ROOCCHNPfC), 51.8 [CH3OC(=O)], 25.7
(CHNPfCH2CH2O).
1H NMR (CDCl3, 400 MHz): d = 7.73–7.70 (m, 1 H, ArH), 7.65–
7.62 (m, 1 H, ArH), 7.57–7.54 (m, 1 H, ArH), 7.47–7.16 (m, 10 H,
ArH), 5.50 [td, J = 6.6, 15.4 Hz, 1 H, CCH=CHC(=O)C], 5.06 (d,
J = 7.2 Hz, 1 H, NCHHO), 5.01 (d, J = 7.2 Hz, 1 H, NCHHO), 4.62
[td, J = 1.51, 15.4 Hz, 1 H, CCH=CHC(=O)C], 4.06 (td, J = 6.0, 8.8
Hz, 1 H, CHNPfCH2CHHO), 3.77 (td, J = 3.9, 8.1 Hz, 1 H,
CHNPfCH2CHHO), 2.78 [dd, J = 2.2, 7.1 Hz, 1 H,
C(=O)CHNPfC], 1.89 (dddd, J = 2.5, 3.8, 6.2, 12.7 Hz, 1 H,
Anal. Calcd for C25H23NO3: C, 77.90; H, 6.01; N, 3.63. Found: C,
77.73; H, 5.93; N, 3.60.
CHNPfCHHCH2O),
1.78–1.69
[m,
3 H,
overlapping
(S)-Dimethyl {2-Oxo-2-[3-(9-phenyl-9H-fluoren-9-yl)-1,3-ox-
azinan-4-yl]ethyl}phosphonate (7)
CHNPfCHHCH2O and CCH2CH=CHC(=O)], 1.35–1.10 [m, 22 H,
CH3(CH2)11CH2CH=CHC(=O)], 0.88 (t, J = 6.9 Hz, 3 H,
CH3(CH2)11C).
13C NMR (CDCl3, 100 MHz): d = 149.4, 147.0, 144.3, 141.7, 139.1
(Ar), 131.9 [C13H27CH=CHC(=O)], 128.8, 128.5, 128.2, 128.0,
127.8, 127.4, 127.3, 127.0 (Ar), 126.9 [C13H27CH=CHC(=O)],
125.6, 119.8, 119.5 (Ar), 113.7, 84.9 (NCH2O), 77.2 (quat. aliph.),
To a stirred solution of dimethyl methylphosphonate (2.65 mL,
24.75 mmol, 3.30 equiv) in anhydrous THF (50 mL) at –78 °C, n-
BuLi (2.5 M in hexanes, 9.0 mL, 22.5 mmol, 3.00 equiv) was added
over 15 min under argon. The solution was stirred for 10 min then
6a (2.874 g, 7.5 mmol, 1.00 equiv) in anhydrous THF (20 mL) was
added over 35 min at –78 °C (the reaction mixture turned slowly or-
ange). The mixture was allowed to warm slowly to 0 °C over 3.6 h.
The reaction was quenched with sat. aq NH4Cl (30 mL) and a little
H2O was added to dissolve the formed solid. The mixture was ex-
tracted with EtOAc (3 × 30 mL) and the combined organic layers
were dried over Na2SO4 and evaporated. Purification by flash chro-
matography (EtOAc–hexanes, 50→75%) gave 7 as a pale-yellow
oil, which solidified on standing. The solid was recrystallised from
EtOAc–hexanes for analytical purposes
68.8
(CHNPfCH2CH2O),
67.3
[C(=O)CHNPfC],
34.4
(CHNPfCH2CH2O), 31.9, 31.7, 29.7, 29.7, 29.6, 29.5, 29.4, 29.2,
28.6, 22.7 (aliphatic chain), 14.1 [CH3(CH2)11C].
HRMS: m/z [M + H]+ calcd for C39H50NO2: 564.3842; found:
564.3860.
Anal. Calcd for C39H49NO2: C, 83.08; H, 8.76; N, 2.48. Found: C,
83.19; H, 8.84; N, 2.44.
Yield: 2.29 g (64%); white needles; mp 127 °C; [a]D20 +168 (c 0.47,
(3S,4S,E)-3-[Methyl(9-phenyl-9H-fluoren-9-yl)amino]nonadec-
5-ene-1,4-diol (13)
CHCl3).
IR (KBr): 3409, 3051–2847, 1713, 1271 cm–1.
Compound 8 (0.04 g, 0.07 mmol, 1.00 equiv) was dissolved in an-
hydrous toluene (3 mL) and cooled to –78 °C under argon. DIBAL-
H (1.0 M in toluene) was added in three portions: First portion (0.21
mL, 0.21 mmol, 3.00 equiv), after 22 min second portion (0.1 mL,
0.1 mmol, 1.40 equiv) and, after another 15 min, third portion (0.04
mL, 0.04 mmol, 0.57 equiv). 14 min after the last addition the reac-
tion was quenched with acetone (1 mL) and the mixture was al-
lowed to warm to r.t. A little H2O was added, followed by sat aq
Na2SO4 (1.5 mL). After 15 min stirring, the mixture was filtered
through Celite, and the Celite was washed with toluene. The filtered
solution was concentrated under reduced pressure, H2O (2 mL) was
added and the layers separated. The aqueous layer was extracted
with Et2O (3 × 5 mL) and the combined organic layers were dried
over Na2SO4 and evaporated. Purification by flash chromatography
(EtOAc–hexanes, 25→75%) gave 13.
1H NMR (CDCl3, 400 MHz): d = 7.89–7.87 (m, 1 H, ArH), 7.72–
7.69 (m, 1 H, ArH), 7.64–7.61 (m, 1 H, ArH), 7.49–7.18 (m, 10 H,
ArH), 5.09 (dd, J = 1.65, 12.1 Hz, 1 H, NCHHO), 4.54 (d, J = 12.1
Hz, 1 H, NCHHO), 3.76 [dd, J = 11.2, 18.6 Hz, 6 H,
(CH3O)2P(=O)C], 3.65–3.50 (m, 2 H, CHNPfCH2CH2O), 3.54 (dd,
J = 15.3, 21.0 Hz, 2 H, PCHHC(=O)C, overlapping with 3.65–3.50
multiplet), 3.37 [dd, J = 15.3, 21.0 Hz, 1 H, PCHHC(=O)C], 3.16
[br d, J = 5.9 Hz, CC(=O)CHNPfC], 1.51–1.47 (m, 1 H,
CHNPfCHHCH2O), 1.11–1.01 (m, 1 H, CHNPfCHHCH2O).
13C NMR (CDCl3, 100 MHz): d = 203.5 and 203.4 (CO), 148.6,
147.2, 142.3, 140.9, 139.6, 130.1, 128.7, 128.7, 128.6, 128.0, 127.7,
127.5, 127.1, 125.5, 120.0, 119.6 (Ar), 78.4 and 78.3 (quat. aliph.
and NCH2O), 64.1 (CHNPfCH2CH2O), 60.5 [two peaks,
Synthesis 2010, No. 5, 757–762 © Thieme Stuttgart · New York

762
S. J. K. Sauerland et al.
PAPER
Yield: 0.022 g (55%); colorless oil; Rf = 0.45 (EtOAc–hexanes,
50%); [a]D20 +246 (c 0.95, CHCl3).
IR (NaCl): 3369, 2924, 2853 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.80–7.78 (m, 1 H, ArH), 7.65–
7.62 (m, 1 H, ArH), 7.56–7.19 (m, 11 H, ArH), 5.65 (td, J = 6.8,
15.2 Hz, 1 H, CCH=CHCHOHC), 4.99 (dd, J = 8.2, 15.2 Hz, 1 H,
CCH=CHCHOHC), 3.73 (t, J = 8.2 Hz, 1 H, CH=CHCHOHCH-
NPf), 2.98–2.91 (m, 1 H, CCHHOH), 2.70–2.63 (m, 1 H, CCH-
HOH), 2.57 (s, 3 H, CHNPfCH3), 2.25 (ddd, J = 3.7, 5.7, 9.1 Hz,
(6) (a) Christie, B. D.; Rapoport, H. J. Org. Chem. . (b) Lubell,
W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 236.
(c) Koskinen, A. M. P.; Rapoport, H. J. Org. Chem. 1989,
54, 1859. (d) Koskinen, A. M. P.; Schwerdtfeger, J.;
Edmonds, M. Tetrahedron Lett. 1997, 38, 5399.
(7) Koskinen, A. M. P.; Koskinen, P. M. Synlett 1993, 501.
(8) (a) Shikata, K.; Niiro, H.; Azuma, H.; Tachibana, T.; Ogino,
K. Bioorg. Med. Chem. Lett. 2003, 13, 613. (b) Shikata, K.;
Niiro, H.; Azuma, H.; Ogino, K.; Tachibana, T. Bioorg.
Med. Chem. 2003, 11, 2723. (c) De Jonghe, S.; Lamote, I.;
Venkataraman, K.; Boldin, S. A.; Hillaert, U.; Rozenski, J.;
Hendrix, C.; Busson, R.; De Keukeleire, D.;
1 H,
CHOHCHNPfCH3C),
1.95–1.89
(m,
2 H,
C12H25CH2CH=CHC), 1.35–1.15 [m, 22 H, CH3(CH2)11C], 1.12–
1.05 (m, 2 H, CHNPfCH3CH2CH2OH), 0.90 [t, J = 6.9 Hz, 3 H,
CH3(CH2)11C].
Van Calenbergh, S.; Futerman, A. H.; Herdewijn, P. J. Org.
Chem. 2002, 67, 988. (d) Tarnowski, A.; Retz, O.; Bär, T.;
Schmidt, R. R. Eur. J. Org. Chem. 2005, 1129.
13C NMR (CDCl3, 100 MHz): d = 148.0, 146.6, 142.7, 141.3, 139.1
(Ar), 135.7 (CCH=CHCHOH), 129.8 (CCH=CHCHOH), 128.9,
128.6, 128.5, 128.4, 127.4, 127.3, 126.9, 126.6, 126.1, 120.4, 119.8
(Ar), 77.8 (quat. aliph.), 73.9 (CCH=CHCHOHCHNPfCH3C), 61.5
(CCH2OH), 58.2 (CHOHCHNPfCH3C), 32.3 (CCH2CH=CHC),
31.9 (aliphatic chain), 31.4 (CHNPfCH3CH2CH2OH), 30.4 (NCH3),
29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 28.9, 22.7 (aliphatic chain), 14.1
(CH3).
(9) Koskinen, A. M. P.; Koskinen, P. M. Tetrahedron Lett.
1993, 34, 6765.
(10) Jamison, T. F.; Rapoport, H. Org. Synth. 1993, 71, 226.
(11) Compound 10 has been reported in the literature, however,
without data, see: Kaul, R.; Brouillette, Y.; Sajjadi, Z.;
Hansford, K. A.; Lubell, W. D. J. Org. Chem. 2004, 69,
6131.
(12) X-ray crystallography was performed at the University of
Jyväskylä with a Nonius Kappa CCD diffractometer. Crystal
data for 10: Orthorhombic; P212121 (No. 19); a = 9.0028 (3)
Å, b = 9.4284 (3) Å, c = 25.0491 (8) Å; R1 = 0.0453,
wR2 = 0.0847 (I > 2s). 12: Monoclinic; P21 (No. 4);
a = 9.8177 (7) Å, b = 8.8352 (5) Å, c = 11.3458 (8) Å,
b = 92.366 (3)°; R1 = 0.0490, wR2 = 0.0955 (I > 2s).
6a: Orthorhombic; P212121 (No. 19); a = 14.9329 (6) Å,
b = 15.1590 (5) Å, c = 17.2261 (5) Å; R1 = 0.0573,
wR2 = 0.0936 (I > 2s). CCDC 255363–255365 contain the
supplementary crystallographic data (excluding structure
factors) for this paper. These data can be obtained online free
of charge or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ UK [fax:
(+44)1223336033; or deposit@ccdc.cam.ac.uk].
(13) Lee, J.-M.; Lim, H.-S.; Chung, S.-K. Tetrahedron:
Asymmetry 2002, 13, 343.
(14) Gosselin, F.; Lubell, W. D. J. Org. Chem. 1998, 63, 7463.
(15) Lubell, W. D.; Jamison, T. F.; Rapoport, H. J. Org. Chem.
1990, 55, 3511.
(16) Kovacs, J.; Kovacs, H. N.; Ballina, R. J. Am. Chem. Soc.
1963, 85, 1839.
(17) Itaya, T.; Shimizu, S.; Nakagawa, S.; Morisue, M. Chem.
Pharm. Bull. 1994, 42, 1927.
(18) Garrard, E. A.; Borman, E. C.; Cook, B. N.; Pike, E. J.;
HRMS: m/z [M + H]+ calcd for C39H54NO2: 568.4155; found:
568.4159.
Acknowledgment
This work was financially supported by the National Technology
Agency, Finland (TEKES).
References
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Koskinen, A. M. P. Curr. Org. Chem. 2004, 8, 1629.
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(2) (a) Pruett, S. T.; Bushnev, A. A.; Hagedorn, K.; Adiga, M.;
Haynes, C. A.; Sullards, M. C.; Liotta, D. C.; Merrill, A. H.
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A. H. Jr. J. Biol. Chem. 2002, 277, 25841.
(3) (a) Koskinen, A. M. P.; Krische, M. J. Synlett 1990, 665.
(b) Koskinen, P. M.; Koskinen, A. M. P. Methods Enzymol.
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(4) Koskinen, A. M. P.; Kallatsa, O. A. Tetrahedron 2003, 59,
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Alberg, D. G. Org. Lett. 2000, 2, 3639.
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(19) The stereochemistry was assigned based on analogy with
previous reductions, as well as on the coupling constants for
similar compounds; see, for example, ref. 8d.
Synthesis 2010, No. 5, 757–762 © Thieme Stuttgart · New York