Asymmetric synthesis of vicinal amino alcohols: Xestoaminol C, sphinganine and sphingosine

Article abstract of DOI:10.1039/b801357h

The highly diastereoselective anti-aminohydroxylation of α,β-unsaturated esters, via conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide and subsequent in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine, has been used as the key step in the asymmetric synthesis of N,O-diacetyl xestoaminol C (41% yield over 8 steps), N,O,O-triacetyl sphinganine (30% yield over 8 steps) and N,O,O-triacetyl sphingosine (30% yield over 7 steps). The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b801357h

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis of vicinal amino alcohols: xestoaminol C, sphinganine
and sphingosine†
Elin Abraham, Stephen G. Davies,* Nicholas L. Millican, Rebecca L. Nicholson, Paul M. Roberts and
Andrew D. Smith
Received 24th January 2008, Accepted 20th February 2008
First published as an Advance Article on the web 19th March 2008
DOI: 10.1039/b801357h
The highly diastereoselective anti-aminohydroxylation of a,b-unsaturated esters, via conjugate addition
of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide and subsequent in situ enolate oxidation with
(+)-(camphorsulfonyl)oxaziridine, has been used as the key step in the asymmetric synthesis of
N,O-diacetyl xestoaminol C (41% yield over 8 steps), N,O,O-triacetyl sphinganine (30% yield over 8
steps) and N,O,O-triacetyl sphingosine (30% yield over 7 steps).
Previous investigations from within this laboratory have demon-
strated that the tandem conjugate addition of a homochiral, sec-
Introduction
ondary lithium amide (derived from a-methylbenzylamine)8 and
in situ enolate oxidation with (camphorsulfonyl)oxaziridine (CSO)
represents an efficient entry to anti-a-hydroxy-b-amino esters.9
This methodologyhas beenutilisedasthekeysyntheticstrategyfor
a number of natural product syntheses,10 and we delineate herein
the application of this useful transformation to the asymmetric
synthesis of the N,O-diacetyl derivative of xestoaminol C 2, and
the N,O,O-triacetyl derivatives of sphinganine 4 and sphingosine
6. Part of this work has been communicated previously.11
The vicinal amino alcohol motif is a recurring structural com-
ponent in a diverse range of biologically active natural products
and synthetic molecules.1 Numerous biologically active long-chain
vicinal amino alcohols such as xestoaminols A 1 and C 2,2
and obscuraminol A 33 have been isolated from marine sources,
whilst the sphingoid bases sphinganine 4, phytosphingosine 5 and
sphingosine 6 are ubiquitous components of biomolecules that
occur in eukaryotic cells (Fig. 1).4 The varied biological activity
of these compounds has ensured that a variety of methods for
the synthesis of vicinal amino alcohols have been developed,1
with the sphingoid bases in particular receiving considerable
attention.5 The majority of these routes use starting materials
derived from the chiral pool,6 although asymmetric routes, for
instance based upon Sharpless asymmetric dihydroxylation or
epoxidation, or asymmetric aldol reaction, have also received some
attention.7
Results and discussion
Asymmetric synthesis of N,O-diacetyl xestoaminol C
Our initial synthetic target for the development of a general
strategy towards the synthesis of saturated, long chain, vicinal
amino alcohols was xestoaminol C 2. This simple vicinal amino
alcohol was first reported as being isolated from the Fijian sponge
Xestospongia sp. in 1990 and shown to display reverse transcriptase
inhibition.2 It was subsequently isolated from the tunicate Pseu-
dodistoma obscurum3 and one enantiospecific synthesis, employing
L-alanine as the source of chirality, has been reported to date.12
Based on retrosynthetic analysis of xestoaminol C 2, it was
proposed that the alkyl chain could be introduced via olefination
of the functionalised aldehyde 8. Aldehyde 8 would be available
from ester 9 which, in turn, results from anti-aminohydroxylation
of an a,b-unsaturated ester. A synthetic strategy reliant on N- and
O-benzyl protection was therefore initially pursued in order to
facilitate global, hydrogenolytic deprotection of 7 to the natural
product (Fig. 2).
Aminohydroxylation of tert-butyl crotonate upon sequential
treatment with lithium (S)-N-benzyl-N-(a-methylbenzyl)amide
and (+)-CSO9 gave the known anti-a-hydroxy-b-amino ester 10
in >98% de,13 with chromatographic purification giving 109 in
77% yield and >98% de. Benzylation of 10 was accomplished upon
treatment with BnBr, 15-crown-5 and NaH, giving 11 in 88% yield.
Transformation of ester 11 to the corresponding aldehyde 13 was
achieved via reduction with LiAlH4 to give alcohol 12 in 91% yield,
Fig. 1 Structures of xestoaminols A 1 and C 2, obscuraminol A 3,
sphinganine 4, phytosphingosine 5 and sphingosine 6.
Department of Chemistry, Chemistry Research Laboratory, Univer-
sity of Oxford, Mansfield Road, Oxford, UK OX1 3TA. E-mail:
steve.davies@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Full experimental
details. See DOI: 10.1039/b801357h
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1655–1664 | 1655
©

View Article Online
14 in 95% yield. With construction of the skeletal framework com-
plete, global deprotection of (Z)-14 to give xestoaminol C 2 was
investigated. Hydrogenolysis of (Z)-14 in MeOH–H2O–AcOH
(40 : 4 : 1)8,17 returned N-a-methylbenzyl protected 15 contamin-
ated with unknown impurities. Attempted cleavage of the N-a-
methylbenzyl protecting group from 15 under a range of more
forcing hydrogenolysis conditions gave, in each case, a low mass
return of a complex mixture of unidentifiable products (Scheme 2).
Fig. 2 Retrosynthetic analysis of xestoaminol C 2.
>98% de and >98% ee,14 with subsequent Swern oxidation of 12
giving aldehyde 13 in 88% yield and >98% de (Scheme 1).15
Scheme 2 Reagents and conditions: (i) C10H21PPh3+Br−, BuLi, THF–hex-
ane (1
:
1), −78 ◦C to rt, 12 h; (ii) H2 (1 atm), Pd(OH)2/C,
MeOH–H2O–AcOH (40 : 4 : 1), rt, 6 h.
Following the recalcitrance of the N-a-methylbenzyl group to
hydrogenolysis, and in order for this methodology to be compatible
for the preparation of unsaturated vicinal amino alcohols, it
was proposed that removal of the N-benzyl-N-a-methylbenzyl
protecting groups at an earlier juncture in the synthesis would
be advantageous, and an alternative protecting group strategy
was envisaged. An N-Boc-N,O-acetal protecting group strategy, to
enable global hydrolysis, was therefore pursued. N-Debenzylation
of anti-a-hydroxy-b-amino ester 10 and concomitant N-Boc pro-
tection gave 1610f in 98% yield and >98% de, with subsequent N,O-
acetal protection being achieved upon treatment of 16 with 2,2-
dimethoxypropane and BF3·Et2O in acetone,18 giving oxazolidine
17 in 88% isolated yield and >98% de. Reduction of 17 with LiAlH4
at 0 ◦C gave alcohol 18 in quantitative yield. Oxidation of 18 using
a Swern protocol gave a sample of aldehyde 19 contaminated
with unidentified side-products; treatment with IBX in DMSO,19
however, afforded 19 in quantitative yield.20 Wittig olefination of
Scheme
1
Reagents and conditions: (i) lithium (S)-N-benzyl-N-
(a-methylbenzyl)amide, THF, −78 ◦C, 2 h, then (+)-CSO, −78 ◦C to rt,
12 h; (ii) NaH, 15-crown-5, BnBr, THF, 0 ◦C to rt, 12 h; (iii) LiAlH4, THF,
0
◦C to rt, 6 h; (iv) DMSO, (ClCO)2, Et3N, DCM, −78 ◦C to rt, 1 h.
aldehyde 19 gave olefin (Z)-20 as a single diastereoisomer (J4,5
=
Attention was then turned to the installation of the
7.6 Hz) which was isolated in 85% yield and >98% de (Scheme 3).
With N-Boc-N,O-acetal protected (Z)-20 in hand, deprotection
to enable completion of the synthesis of xestoaminol C 2 was
investigated. Thus, catalytic hydrogenation with Pd/C furnished
21 in 90% yield and >98% de, with subsequent removal of the N-
Boc and N,O-acetal protecting groups within 21 being achieved
under acidic conditions,21 giving a crude reaction mixture from
which xestoaminol C 2 was isolated as its N,O-diacetyl derivative
22 in 80% yield and >98% de, in order that comparison with
literature data could be made. The spectroscopic properties of
22 were entirely consistent with those previously reported {[a]D22
−22.7 (c 0.6 in MeOH); lit.3 [a]D24 −21.8 (c 0.4 in MeOH); lit.12 [a]D24
−22.1 (c 0.2 in MeOH)}. The applicability of this strategy for the
preparation of unsaturated derivatives was next demonstrated by
alkyl chain via Wittig olefination of aldehyde 13. However,
treatment of aldehyde 13 with the ylide derived from (1-
decyl)triphenylphosphonium bromide in THF16 returned only
starting material, even when a large excess of reagent (5 eq) was
employed. Hypothesising that the low reactivity of the ylide might
be due to its lipophilic nature disfavouring reaction in a polar
solvent, the reaction was attempted in a mixture of THF–hexane
(1 : 1) giving 83% conversion to (Z)-alkene 14 (J4,5 = 10.9 Hz) as
the sole diastereoisomer, which was isolated in 56% yield. Reaction
optimisation led to a superior experimental protocol whereby de-
protonation of (1-decyl)triphenylphosphonium bromide in THF
prior to the addition of hexane, and the subsequent addition of
aldehyde 13 in THF, gave complete conversion and furnished (Z)-
1656 | Org. Biomol. Chem., 2008, 6, 1655–1664
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
(S)-N-benzyl-N-(a-methylbenzyl)amide and (+)-CSO proceeds
efficiently to generate the corresponding a-hydroxy-b-amino-c-
tert-butyldimethylsilyloxy ester.22 As the proposed strategy toward
the synthesis of sphinganine 4 and sphingosine 6 required several
deprotection and functional group interconversion steps, a range
of c-O-silyl protecting groups were screened for their suitability in
the synthetic sequence.
Fig. 3 Retrosynthetic analysis of sphinganine 4 and sphingosine 6.
Thus, c-silyloxy-a,b-unsaturated esters 26–30 were prepared
from cis-but-2-ene-1,4-diol,22 in >98% de in each case. Sub-
sequent conjugate addition of lithium (S)-N-benzyl-N-(a-
methylbenzyl)amide to 26–30 and enolate oxidation with (+)-CSO
proceeded in >98% de in each case13 to generate the corresponding
(2S,3S,aS)-a-hydroxy-b-amino-c-silyloxy esters 31–35 which were
isolated in good yield (75–91%), and in >98% de in each case. The
relative and absolute configurations within 31–35 were assigned by
analogy to the well-established stereochemical outcome resulting
from the conjugate addition and enolate oxidation reaction.9,10,22
Subsequent hydrogenolysis of 31–35 and in situ carbamate pro-
tection gave 36–40 in 68–94% yield and in >98% de in each case
(Scheme 5).
Scheme 3 Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, Boc2O,
EtOAc, rt, 12 h; (ii) 2,2-dimethoxypropane, BF3·Et2O, acetone, rt, 12 h;
(iii) LiAlH4, THF, 0 ◦C, 6 h; (iv) IBX, DMSO, rt, 12 h; (v) C10H21PPh3+Br−,
BuLi, THF–hexane (1 : 1), −78 ◦C to rt, 12 h.
global hydrolysis of (Z)-20, followed by acetylation, giving 23 in
80% yield and >98% de (Scheme 4).
Scheme 4 Reagents and conditions: (i) H2 (1 atm), Pd/C, EtOAc, rt, 6 h;
(ii) HCl (3 M, aq), MeOH, 50 ◦C, 3 h; (iii) Ac2O, DMAP, pyridine, rt, 12 h.
Asymmetric synthesis of N,O,O-triacetyl sphinganine and
N,O,O-triacetyl sphingosine
With an efficient asymmetric synthesis of N,O-diacetyl
xestoaminol C 22 complete, the successful N-Boc-N,O-acetal
protecting group strategy was applied to the synthesis of
sphinganine 4 and sphingosine 6. Retrosynthetic analysis re-
vealed that aminohydroxylation of a suitably c-O-protected-
a,b-unsaturated ester would give access to aldehyde 24 from
which both sphingoid bases could be derived (Fig. 3). Previ-
ous investigations from this laboratory have demonstrated that
tandem conjugate addition and enolate functionalisation of c-
tert-butyldimethylsilyloxy-a,b-unsaturated ester 26 with lithium
Scheme 5 Reagents and conditions: (i) [Si]Cl, imidazole, DMAP, DCM,
rt, 12 h; (ii) O3, DCM, −78 ◦C, 30 min, then DMS, rt, 12 h;
(iii) (EtO)2P(O)CH2CO2R, iPr2NEt, LiCl, MeCN, 48 h; (iv) lithium
(S)-N-benzyl-N-(a-methylbenzyl)amide, THF, −78 ◦C, 2 h, then (+)-CSO,
−78 ◦C to rt, 12 h; (v) H2 (5 atm), Pd(OH)2/C, Boc2O, EtOAc, rt, 12 h. [a
Yield over 3 steps from cis-but-2-ene-1,4-diol. All compounds 26–40 were
isolated as single diastereoisomers (>98% de).]
With 36–40 in hand N,O-acetal formation was investigated
utilising the conditions applied successfully to 16 in the synthesis
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1655–1664 | 1657
©

View Article Online
of xestoaminol C 2 (vide supra, Scheme 3). However, treatment of
c-O-TBDPS tert-butyl ester 40 with 2,2-dimethoxypropane and
BF3·Et2O in acetone returned a complex mixture of products
whilst under the same conditions c-O-TBDMS and c-O-TIPS
tert-butyl esters 37 and 39 gave, in both cases, a mixture of two
products, identified as the corresponding oxazolidine esters 42 and
45 and the oxazolidine acids 43 and 46; the latter presumably
arising from Lewis acid catalysed ester hydrolysis. The ratio
of these two products was found to depend markedly upon
reaction concentration although the formation of the undesired
acid products was minimised by performing the reactions at high
dilution with a minimal amount of Lewis acid catalyst, enabling
the isolation of 42 and 45 in 52 and 75% yield respectively.
Application of this protocol to c-O-TBDMS and c-O-TIPS methyl
esters 36 and 38 meanwhile gave incomplete conversion (∼50% in
both cases) to the corresponding oxazolidines 41 and 44, although
no trace of ester hydrolysis was observed. Further experimentation
with c-O-TIPS methyl ester 38 demonstrated that the reaction
could be driven to approximately 80% conversion upon heating
giving oxazolidine ester 44 in 75% isolated yield and returned
starting material 38 (20%), which could be recycled (Scheme 6).
Scheme 7 Reagents and conditions: (i) LiAlH4, THF, 0 ◦C, 6 h; (ii)
DIBAL-H, DCM, 0 ◦C, 6 h; (iii) IBX, DMSO, rt, 12 h.
of sphingosine 6 an alternative strategy for the stereoselective
preparation of the corresponding (E)-alkene isomer 52 was next
probed. The Schlosser modification of the Wittig reaction is
frequently employed to generate the (E)-alkene product from the
reaction of a non-stabilised ylide23 although recent studies by Kim
et al. have shown that high (E) selectivity is observed simply by
addition of excess of methanol to the reaction medium at low
temperature.24 Following this protocol, olefination of aldehyde 50
followed by quenching with methanol gave an (E) : (Z) ratio of
94 : 6, with chromatography giving (E)-52 in 73% yield and 88%
de [(E) : (Z) 94 : 6] (Scheme 8).
Scheme 6 Reagents and conditions: (i) 2,2-dimethoxypropane, BF3·Et2O,
acetone, rt, 12 h; (ii) 2,2-dimethoxypropane, BF3·Et2O, acetone, 50 ◦C,
12 h.
Attention next turned to the conversion of oxazolidine esters
42, 44 and 45 to the corresponding aldehydes via a two step
protocol. However, treatment of both O-TBDMS and O-TIPS
oxazolidine tert-butyl esters 42 and 45 with LiAlH4 at 0 ◦C resulted
in reduction of the ester and concomitant desilylation, giving diol
47 as the sole product in both cases. In an attempt to reduce
the tert-butyl ester without promoting desilylation the reactions
were performed at −78 ◦C but returned only starting material in
both cases. The use of DIBAL-H to effect ester reduction was
next probed and although treatment of O-TBDMS oxazolidine
ester 42 with DIBAL-H at 0 ◦C gave a mixture of diol 47 and O-
TBDMSalcohol 48 contaminated with unidentifiableby-products,
reduction of O-TIPS oxazolidine esters 44 and 45 gave O-TIPS
alcohol 49 as the sole product in both cases, with no trace of
desilylation being observed. Re-oxidation of 49 with IBX19 gave
aldehyde 50 in quantitative yield (Scheme 7).
With an efficient preparation of aldehyde 50 in hand, investi-
gations focused upon olefination to install the long alkyl chain
present in the targets sphinganine 4 and sphingosine 6. Under
the optimum conditions utilised in the synthesis of xestoaminol
C 2, Wittig olefination of aldehyde 50 with the ylide derived
from (1-tetradecyl)triphenylphosphonium bromide gave (Z)-51
(J4,5 = 7.2 Hz) as the sole reaction product in 90% isolated
yield after chromatography. In order to facilitate the preparation
Scheme 8 Reagents and conditions: (i) C14H29PPh3+Br−, BuLi, THF–hex-
ane (1 : 1), −78 ◦C to rt, 12 h; (ii) C14H29PPh3+Br−, BuLi, THF–hexane
(1 : 2), −78 ◦C, 2 h, then MeOH, −78 ◦C to rt, 12 h. [a Crude; b purified].
The synthesis of sphinganine 4 was completed through hy-
drogenation of (Z)-51 to give 53 in 86% yield and >98% de,
with subsequent global hydrolytic deprotection and acetylation
of the crude mixture giving N,O,O-triacetyl sphinganine 54 in
75% isolated yield and >98% de with spectroscopic properties
in excellent agreement with those of the literature {[a]2D2 +18.4
(c 0.3 in CHCl3); lit.25 [a]D22 +19.2 (c 1.0 in CHCl3); lit.26 [a]2D4
+17.2 (c 0.2 in CHCl3)}. In addition, sequential hydrolysis of (Z)-
51 and acetylation gave N,O,O-triacetyl (Z)-sphingosine 55 in
87% isolated yield and >98% de, with spectroscopic properties in
agreement with those of the literature {[a]2D2 +6.6 (c 0.9 in CHCl3);
lit.27 [a]2D4 +4.3 (c 0.9 in CHCl3)} (Scheme 9).
Meanwhile, hydrolysis of the protecting groups within (E)-
52 and acetylation, followed by purification by chromatography
and recrystallisation, gave N,O,O-triacetyl sphingosine 56 in 80%
1658 | Org. Biomol. Chem., 2008, 6, 1655–1664
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Flash column chromatography was performed on Kieselgel 60
silica.
Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford,
UK. Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. Optical rotations were recorded
on a Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm
cell. Specific rotations are reported in 10−1 deg cm2 g−1 and
concentrations in g/100 mL. IR spectra were recorded on Bruker
Tensor 27 FT-IR spectrometer as either a thin film on NaCl plates
(film) or a KBr disc (KBr), as stated. Selected characteristic peaks
are reported in cm−1. NMR spectra were recorded on Bruker
Avance spectrometers in the deuterated solvent stated. Spectra
were recorded at rt unless otherwise stated. The field was locked
by external referencing to the relevant deuteron resonance. Low-
resolution mass spectra were recorded on either a VG MassLab
20–250 or a Micromass Platform 1 spectrometer. Accurate mass
measurements were run on either a Bruker MicroTOF, and were
internally calibrated with polyalanine, or a Micromass GCT
instrument fitted with a Scientific Glass Instruments BPX5 column
(15 m × 0.25 mm) using amyl acetate as a lock mass.
Scheme 9 Reagents and conditions: (i) H2 (1 atm), Pd/C, EtOAc, rt, 6 h;
(ii) HCl (3 M, aq), MeOH, 50 ◦C, 3 h; (iii) Ac2O, DMAP, pyridine, rt, 12 h.
isolated yield and >98% de, with spectroscopic properties in
excellent agreement with those in the literature {[a]2D0 −12.0 (c
1.0 in CHCl3); lit.28 [a]D24 −11.4 (c 1.2 in CHCl3)} (Scheme 10).
(2S,3R)-2-Acetamido-3-acetoxy-tetradecane [N,O-diacetyl
xestoaminol C] 22
Scheme 10 Reagents and conditions: (i) HCl (3 M, aq), MeOH, 50 ◦C,
3 h; (ii) Ac2O, DMAP, pyridine, rt, 12 h.
3 M aq HCl (1 mL) was added to a solution of 21 (50 mg,
0.14 mmol) in MeOH (10 mL) and heated at 50 ◦C for 3 h.
The reaction mixture was concentrated in vacuo. The residue was
dissolved in pyridine (10 mL) and Ac2O (0.06 mL, 0.68 mmol)
and DMAP (2 mg) were added sequentially. The reaction mixture
was stirred for 12 h before being quenched with H2O (2 mL). The
reaction mixture was diluted with H2O (10 mL) and Et2O (10 mL)
and the layers were separated. The aqueous layer was extracted
with Et2O (2 × 10 mL). The combined organic layers were washed
sequentially with sat aq CuSO4 (2 × 10 mL), H2O (10 mL) and
brine (10 mL), dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30–40 ◦C petrol–EtOAc, 1 :
1) gave 22 as white solid (34 mg, 80%, >98% de); Rf 0.18 (30–40 ◦C
petrol–EtOAc, 1 : 1); mp 51–53 ◦C (30–40 ◦C petrol–EtOAc);
[a]2D2 −22.7 (c 0.6 in MeOH); {lit.3 [a]2D4 −21.8 (c 0.4 in MeOH),
lit.12 [a]2D4 −22.1 (c 0.2 in MeOH)}; mmax (KBr) 3354, 2980, 2935,
1791, 1755, 1714, 1519; dH (400 MHz, CDCl3) 0.87 (3H, t, J 6.8,
C(14)H3), 1.08 (3H, d, J 6.8, C(1)H3), 1.20–1.37 (18H, m, C(5)H2-
C(13)H2), 1.43–1.62 (2H, m, C(4)H2), 1.94 (3H, s, COMe), 2.08
(3H, s, COMe), 4.10–4.19 (1H, m, C(2)H), 4.80–4.86 (1H, ddd, J
8.5, 5.1, 3.4, C(3)H), 5.90 (1H, br d, J 8.2, NH); dC (125 MHz,
CHCl3) 14.1, 14.8, 21.1, 22.7, 23.5, 25.6, 29.31, 29.34, 29.4, 29.5,
29.6, 31.3, 31.9, 47.5, 77.0, 169.3, 171.6; m/z (ESI+) 336 ([M +
Conclusion
In conclusion, the highly diastereoselective anti-aminohydro-
xylation of readily available a,b-unsaturated esters, via the conju-
gate addition of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide
and in situ enolate oxidation with (+)-CSO, has been used as the
key step for the asymmetric synthesis of a range of long chain
vicinal amino alcohols, including the N,O-diacetyl derivative of
xestoaminol C and the N,O,O-triacetyl derivatives of sphinganine
and sphingosine, in good overall yield. The further application
of this methodology to the asymmetric synthesis of N,O,O,O-
tetra-acetyl D-lyxo-phytosphingosine, the anhydrophytosphingo-
sine jaspine B and its C(2)-epimer, and the Prosopis alkaloid
deoxoprosophylline is reported in the following manuscript.
Experimental
General experimental
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. Solvents were
dried according to the procedure outlined by Grubbs and co-
Na]+, 100%); HRMS (ESI+) C18H35NNaO3 ([M + Na]+) requires
+
336.2509; found 336.2502.
R
workers.29 Water was purified by an Elixꢀ UV-10 system. All other
Methyl (E)-4-tri-iso-propylsilyloxy-but-2-enoate 28
solvents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4. Thin
layer chromatography was performed on aluminium plates coated
with 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid.
TIPSCl (4.86 mL, 22.7 mmol) was added in one portion to a stirred
solution of but-2-ene-1,4-diol (0.93 mL, 11.4 mmol), imidazole
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1655–1664 | 1659
©

View Article Online
(2.33 g, 34.1 mmol) and DMAP (30 mg) in DCM (30 mL) at rt.
After stirring for 12 h, the reaction mixture was concentrated in
vacuo. The residue was dissolved in Et2O (30 mL) and washed
with 1 M aq HCl (30 mL), dried and concentrated in vacuo to give
1,4-bis-(tri-iso-propylsilyloxy)but-2-ene as a colourless oil (4.41 g,
97%) that was used without purification; dH (400 MHz, CDCl3)
1.02–1.12 (42H, m, 2 × Si(CHMe2)3), 4.29–4.33 (4H, m, C(1)H2,
C(4)H2), 5.30–5.33 (2H, m, C(2)H, C(3)H).
O3 was bubbled through a stirred solution of 1,4-bis-(tri-iso-
propylsilyloxy)but-2-ene (4.41 g, 11.0 mmol) in DCM (30 mL)
at −78 ◦C until the solution turned blue. O2 was then bubbled
through the solution until it turned colourless. DMS (30 mL)
was added dropwise via syringe and the reaction mixture stirred
for 12 h. The reaction mixture was concentrated in vacuo. The
residue was redissolved in Et2O (30 mL) and washed with
H2O (30 mL), dried and concentrated in vacuo to give (tri-iso-
propylsilyloxy)acetaldehyde as a colourless oil (4.38 g, 92%) that
was used without purification; dH (400 MHz, CDCl3) 1.02–1.10
(21H, m, Si(CHMe2)3), 4.25 (2H, d, J 1.0, CH2), 9.73 (1H, t, J 1.0,
CHO).
combined organic extracts were washed sequentially with sat aq
NaHCO3 (50 mL) and brine (50 mL), dried and concentrated in
vacuo. The residue was dissolved in Et2O (50 mL), the insoluble
CSO residues were filtered off, and the filter cake was washed
with Et2O (2 × 20 mL). The filtrate was concentrated in vacuo
and the process was repeated. Purification via flash column
chromatography (eluent 30–40 ◦C petrol–Et2O, 20 : 1) gave 33
as a colourless oil (2.75 g, 75%, >98% de); Rf 0.18 (30–40 ◦C
petrol–Et2O, 20 : 1); C29H45NO4Si requires C, 69.7; H, 9.1; N,
2.8%; found C, 69.6; H, 9.1; N, 2.8%; [a]2D2 +37.0 (c 2.3 in CHCl3);
=
mmax (film) 3515 (O–H), 1737 (C O); dH (400 MHz, CDCl3) 1.02–
1.06 (21H, m, Si(CHMe2)3), 1.36 (3H, d, J 6.8, C(a)Me), 3.03
(1H, d, J 6.2, OH), 3.55–3.61 (1H, m, C(3)H), 3.67 (3H, s, OMe),
3.82 (1H, d, J 15.0, NCHA), 3.79–3.85 (1H, m, C(4)HA), 3.93–4.02
(2H, m, C(4)HB, C(a)H), 4.05–4.10 (1H, m, C(2)H), 4.14 (1H, d, J
15.0, NCHB), 7.20–7.46 (10H, m, Ph); dC (100 MHz, CDCl3) 11.9
(Si(CHMe2)3), 17.9 (Si(CHMe2)3), 18.1 (C(a)Me), 51.4 (NCH2),
52.1 (OMe), 58.0 (C(a)), 60.1 (C(3)), 62.2 (C(4)), 71.0 (C(2)),
126.6, 127.0 (p-Ph), 127.9, 128.1, 128.2, 128.3 (o-Ph, m-Ph), 141.7,
143.1 (i-Ph), 174.7 (C(1)); m/z (ESI+) 522 ([M + Na]+, 28%), 500
(100); HRMS (ESI+) C29H46NO4Si+ ([M + H]+) requires 500.3196;
found 500.3194.
Methyl diethylphosphonoacetate (4.97 g, 23.6 mmol), LiCl
i
(5.54 g, 132 mmol) and Pr2NEt (3.76 mL, 21.6 mmol) were
added to a stirred solution of (tri-iso-propylsilyloxy)acetaldehyde
(4.25 g, 19.7 mmol) in MeCN (50 mL). The reaction mixture
was stirred for 48 h and then quenched by addition of H2O
(5 mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc (40 mL). The combined organic extracts
were dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 ◦C petrol–Et2O, 30 : 1) gave 28 as
a colourless oil (2.79 g, 52%, >98% de); Rf 0.14 (30–40 ◦C petrol–
Methyl (2S,3S)-2-hydroxy-3-[N-(tert-butoxycarbonyl)amino]-4-
tri-iso-propylsilyloxy-butanoate 38
Pearlman’s catalyst (1.25 g, 25% w/w) was added to a vigorously
stirred solution of 33 (5.0 g, 10.0 mmol) and Boc2O (2.4 g,
11.0 mmol) in EtOAc (50 mL) and the mixture was placed
under H2 (5 atm). Stirring continued for 12 h, after which
time the reaction mixture was filtered through Celite (eluent
EtOAc) and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 ◦C petrol–Et2O, 10 : 1; then 30–
40 ◦C petrol–Et2O, 1 : 1) gave 38 as a colourless oil (3.81 g, 94%,
=
=
Et2O, 30 : 1); mmax (film) 1728 (C O), 1663 (C C); dH (400 MHz,
CDCl3) 1.04–1.09 (21H, m, Si(CHMe2)3), 3.75 (3H, s, OMe), 4.38
(2H, dd, J 3.1, 2.4, C(4)H2), 6.18 (1H, dt, J 15.4, 2.4, C(2)H),
7.02 (1H, dt, J 15.4, 3.1, C(3)H); dC (100 MHz, CDCl3) 11.9
(Si(CHMe2)3), 17.9 (Si(CHMe2)3), 51.5 (OMe), 62.4 (C(4)), 119.0
(C(2)), 147.8 (C(3)), 167.2 (C(1)); m/z (ESI+) 273 ([M + H]+,
100%); HRMS (ESI+) C14H29O3Si+ ([M + H]+) requires 273.1886;
found 273.1880.
◦
>98% de); Rf 0.08 (30–40 C petrol–Et2O, 10 : 1); C19H39NO6Si
requires C, 56.3; H, 9.7; N, 3.45%; found C, 56.2; H, 9.7; N,
3.5%; [a]2D1 +17.3 (c 0.4 in CHCl3); mmax (film) 3453 (O–H), 1732
Methyl (2S,3S,aS)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]-4-tri-iso-propylsilyloxy-butanoate 33
=
=
(C O), 1720 (C O); dH (400 MHz, CDCl3) 1.01–1.09 (21H, m,
Si(CHMe2)3), 1.45 (9H, s, CMe3), 3.54 (1H, br s, OH), 3.74–3.91
(2H, m, C(4)H2), 3.78 (3H, s, OMe), 3.95–4.05 (1H, m, C(3)H),
4.26–4.34 (1H, m, C(2)H), 5.19 (1H, d J 8.5, NH); dC (100 MHz,
CDCl3) 11.8 (Si(CHMe2)3), 17.8 (Si(CHMe2)3), 28.3 (CMe3), 52.5
(OMe), 53.5 (C(3)), 62.9 (C(4)), 72.1 (C(2)), 79.7 (CMe3), 155.4
(NCO), 173.1 (C(1)); m/z (ESI+) 428 ([M + Na]+, 44%), 406 (100);
HRMS (ESI+) C19H40NO6Si+ ([M + H]+) requires 406.2625; found
406.2615.
BuLi (2.5 M in hexanes, 8.14 mL, 11.4 mmol) was added
dropwise via syringe to a stirred solution of (S)-N-benzyl-N-
(a-methylbenzyl)amine (2.48 g, 11.8 mmol) in THF (50 mL) at
−78 ◦C. After stirring for 30 min a solution of 28 (2.0 g, 7.35 mmol)
in THF (20 mL) at −78 ◦C was added dropwise via cannula.
After stirring for a further 2 h at −78 ◦C the reaction mixture
was quenched with (+)-CSO (3.37 g, 14.7 mmol) and allowed
to warm to rt over 12 h. Sat aq NH4Cl (5 mL) was added and
the mixture was stirred for 5 min before being concentrated in
vacuo. The residue was partitioned between DCM (50 mL) and
10% aq citric acid (10 mL). The organic layer was separated and
the aqueous layer was extracted with DCM (2 × 50 mL). The
(4S,5S)-2,2-Dimethyl-N(3)-tert-butoxycarbonyl-4-tri-iso-
propylsilyloxymethyl-5-methoxycarbonyl-oxazolidine 44
BF3·Et2O (1 M in Et2O) was added dropwise to a stirred solution
of 38 (1.10 g, 2.72 mmol) and 2,2-dimethoxypropane (10 mL) in
1660 | Org. Biomol. Chem., 2008, 6, 1655–1664
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
acetone (20 mL) until a permanent colour change from colourless
to dark orange was observed. After stirring at 50 ◦C for 12 h
the reaction mixture was allowed to cool to rt and Et3N was
added dropwise until pH 7 was achieved. The reaction mixture
was then concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 ◦C petrol–Et2O, 10 : 1; then 30–
40 ◦C petrol–Et2O, 2 : 1) gave 44 as a colourless oil (first to elute,
907 mg, 75%, >98% de) and unreacted 38 as a colourless oil
(second to elute, 218 mg, 20%, >98% de).
(4S,5S)-2,2-Dimethyl-N(3)-tert-butoxycarbonyl-4-tri-iso-
propylsilyloxymethyl-5-carbonylmethyl-oxazolidine 50
IBX (2.21 g, 7.89 mmol) was added to a solution of 49 (1.10 g,
2.63 mmol) in DMSO (20 mL) at rt and stirred for 12 h. The
reaction mixture was diluted with Et2O (20 mL), washed with
H2O (5 × 20 mL), dried and concentrated in vacuo to give
50 as a colourless oil (1.09 g, quant, >98% de) that was used
without purification; dH (400 MHz, CDCl3) 1.00–1.10 (21H, m,
Si(CHMe2)3), 1.43–1.57 (12H, m, C(2)MeA, CMe3), 1.63–1.69 (3H,
m, C(2)MeB), 3.67–3.97 (2H, m, C(4)CH2), 4.20–4.36 (1H, m,
C(4)H), 4.44–4.54 (1H, m, C(5)H), 9.72–9.82 (1H, m, CHO).
Data for 44: Rf 0.53 (30–40 ◦C petrol–Et2O, 2 : 1); [a]2D2 +15.2 (c
=
=
1.8 in CHCl3); mmax (film) 1739 (C O), 1699 (C O); dH (400 MHz,
CDCl3) 1.01–1.10 (21H, m, Si(CHMe2)3), 1.47 (9H, s, CMe3),
1.50–1.57 (3H, m, C(2)MeA), 1.63–1.69 (3H, m, C(2)MeB), 3.70–
3.98 (2H, m, C(4)CH2), 3.77 (3H, s, OMe), 4.12–4.29 (1H, m,
C(4)H), 4.62–4.69 (1H, m, C(5)H); dH (500 MHz, DMSO-d6,
363 K) 1.02–1.10 (21H, m, Si(CHMe2)3), 1.45 (9H, s, CMe3),
1.50 (3H, s, C(2)MeA), 1.56 (3H, s, C(2)MeB), 3.70 (3H, s, OMe),
3.73 (1H, dd, J 10.1, 3.0, C(4)CHA), 3.84 (1H, dd, J 10.1,
6.7, C(4)CHB), 4.12 (1H, dt, J 6.3, 3.0, C(4)H), 4.76 (1H, d,
C(5)H); dC (125 MHz, DMSO-d6, 363 K) 12.4 (Si(CHMe2)3), 18.6
(Si(CHMe2)3), 25.1 (C(2)MeA), 27.6 (C(2)MeB), 28.9 (CMe3), 52.2
(OMe), 60.7 (C(4)CH2), 61.3 (C(4)), 74.0 (C(5)), 80.6 (CMe3), 94.1
(C(2)), 151.8 (NCO), 168.5 (CO2Me); m/z (ESI+) 468 ([M + Na]+,
54%), 446 (100); HRMS (ESI+) C22H44NO6Si+ ([M + H]+) requires
446.2938; found 446.2934.
(4S,5R,1ꢀZ)-2,2-Dimethyl-N(3)-tert-butoxycarbonyl-4-tri-iso-
propylsiloxymethyl-5-pentadec-1ꢀ-en-1ꢀ-yl-oxazolidine (Z)-51
BuLi (2.5
added dropwise via syringe to
M
in hexanes, 2.1 mL, 5.29 mmol) was
stirred solution of (1-
a
(4S,5S)-2,2-Dimethyl-N(3)-tert-butoxycarbonyl-4-tri-iso-
propylsilyloxymethyl-5-hydroxymethyl-oxazolidine 49
tetradecyl)triphenylphosphonium bromide (3.25 g, 6.01 mmol)
in THF (60 mL) at −78 ◦C. After 30 min hexane (75 mL) was
added, followed by the dropwise addition of a solution of 50
(500 mg, 1.20 mmol) in THF (15 mL) via cannula. The reaction
mixture was allowed to warm to rt over 12 h and quenched
with sat aq NH4Cl (10 mL). Brine (100 mL) was added, the
organic layer was separated, and the aqueous layer was extracted
with Et2O (3 × 50 mL). The combined organic extracts were
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 ◦C petrol–Et2O, 200 : 1; increased
to 30–40 ◦C petrol–Et2O, 10 : 1) gave (Z)-51 as a colourless oil
(645 mg, 90%, >98% de); Rf 0.16 (30–40 ◦C petrol–Et2O, 10 : 1);
DIBAL-H (1 M in DCM, 5.38 mL, 5.38 mmol) was added
dropwise via syringe to a stirred solution of 44 (1.2 g, 2.69 mmol) in
DCM (20 mL) at 0 ◦C. After stirring for 6 h, the reaction mixture
was quenched with sat aq NH4Cl (0.5 mL), filtered through Celite
(eluent DCM) and concentrated in vacuo to give 49 as a colourless
oil (1.1 g, 98%, >98% de) that was used without purification.
Purification of an aliquot via flash column chromatography (eluent
30–40 ◦C petrol–Et2O, 2 : 1) gave an analytical sample; Rf 0.09
[a]2D2 −7.8 (c 1.7 in CHCl3); mmax (film) 2926 (C–H), 1702 (C O);
=
dH (400 MHz, CDCl3) 0.89–0.91 (3H, m, C(15ꢀ)H3), 1.02–1.09
(21H, m, Si(CHMe2)3), 1.20–1.65 (37H, m, C(2)Me2, C(4ꢀ)H2-
C(14ꢀ)H2, CMe3), 1.99–2.20 (2H, m, C(3ꢀ)H2), 3.64 (1H, dd, J
10.2, 2.0, C(4)CHA), 3.71–3.93 (1H, m, C(4)H), 4.00 (1H, dd, J
10.2, 4.6, C(4)CHB), 4.88–4.95 (1H, m, C(5)H), 5.62–5.77 (2H, m,
C(1ꢀ)H, C(2ꢀ)H); dH (500 MHz, PhMe-d8, 363 K) 0.92 (3H, t, J
6.9, C(15ꢀ)H3), 1.08–1.20 (21H, m, Si(CHMe2)3), 1.27–1.46 (22H,
m, C(4ꢀ)H2-C(14ꢀ)H2), 1.47 (9H, s, CMe3), 1.62 (3H, s, C(2)MeA),
1.70 (3H, s, C(2)MeB), 2.04–2.20 (2H, m, C(3ꢀ)H2), 3.86 (1H, dd, J
9.8, 2.5, C(4)CHA), 4.01 (1H, br s, C(4)H), 4.12 (1H, dd, J 9.8, 6.4,
C(4)CHB), 4.96–4.99 (1H, m, C(5)H), 5.62–5.67 (1H, m, C(2ꢀ)H),
5.91–5.96 (1H, m, C(1ꢀ)H); dC (125 MHz, PhMe-d8, 363 K) 12.2
(Si(CHMe2)3), 13.6 (C(15ꢀ)), 17.9 (Si(CHMe2)3), 22.5, 27.8, 28.2,
29.15, 29.23, 29.5, 29.55, 29.59, 29.61, 29.64, 29.7, 31.9 (C(2)Me2,
C(3ꢀ)-C(14ꢀ), CMe3), 61.3 (C(4)) 61.8 (C(4)CH2), 72.3 (C(5)), 79.0
(CMe3), 92.0 (C(2)), 125.7 (C(2ꢀ)), 133.9 (C(1ꢀ)), 151.5 (NCO);
m/z (CI+) 596.5 ([M + H]+, 100%); HRMS (CI+) C35H70NO4Si+
([M + H]+) requires 596.5074; found 596.5054.
◦
(30–40 C petrol–Et2O, 2 : 1); [a]2D2 +9.8 (c 0.8 in CHCl3); mmax
=
(film) 3495 (O–H), 1700 (C O); dH (400 MHz, CDCl3) 1.04–1.44
(21H, m, Si(CHMe2)3), 1.44–1.57 (15H, m, C(2)Me2, CMe3), 3.09–
3.33 (1H, br m, OH), 3.67–3.82 (2H, m, C(5)CH2), 3.84–3.92
(2H, m, C(4)CH2), 3.98–4.16 (1H, m, C(4)H), 4.25–4.33 (1H, m,
C(5)H); dH (500 MHz, DMSO-d6, 363 K) 1.05–1.12 (21H, m,
Si(CHMe2)3), 1.45 (9H, s, CMe3), 1.48 (3H, s, C(2)MeA), 1.50
(3H, s, C(2)MeB), 3.72–3.91 (4H, m, C(4)CH2, C(5)CH2), 4.12–
4.22 (1H, m, C(4)H), 4.35 (1H, app t, J 5.8, C(5)H); dC (125 MHz,
DMSO-d6, 363 K) 12.5 (Si(CHMe2)3), 18.7 (Si(CHMe2)3), 29.0
(CMe3), 32.2 (C(2)Me2), 60.2 (C(4)), 60.7 (C(4)CH2, C(5)CH2),
79.8 (C(5)), 80.8 (CMe3), 93.1 (C(2)), 152.0 (NCO); m/z (ESI+)
440 ([M + Na]+, 14%), 418 (100); HRMS (ESI+) C21H44NO5Si+
([M + H]+) requires 418.2989; found 418.2997.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1655–1664 | 1661
©

View Article Online
(4S,5R,1ꢀE)-2,2-Dimethyl-N(3)-tert-butoxycarbonyl-4-tri-iso-
propylsiloxymethyl-5-pentadec-1ꢀ-en-1ꢀ-yl-oxazolidine (E)-52
m, Si(CHMe2)3), 1.20–1.37 (26H, m, C(2ꢀ)H2-C(14ꢀ)H2), 1.45–1.54
(15H, m, C(2)Me2, CMe3), 1.55–1.85 (2H, m, C(1ꢀ)H2), 3.59–3.89
(3H, m, C(4)H, C(4)H2), 4.00–4.06 (1H, m, C(5)H); dH (500 MHz,
PhMe-d8, 363 K) 0.88–1.68 (65H, m, C(2)Me2, C(2ꢀ)-C(13ꢀ)H2,
C(14ꢀ)H3, CMe3, Si(CHMe2)3), 1.80–1.92 (2H, m, C(1ꢀ)H2), 3.78–
4.05 (4H, m, C(4)HCH2, C(5)H); dC (125 MHz, PhMe-d8, 363 K)
12.2, 13.5, 17.8, 22.5, 23.9, 26.8, 27.4, 28.0, 28.1, 29.2, 29.3, 29.6,
29.7, 31.8, 61.2, 76.7, 78.9, 92.0, 151.5; m/z (ESI+) 598.5 ([M
+ H]+, 100%); HRMS (ESI+) C35H72NO4Si+ ([M + H]+) requires
598.5231; found 598.5252.
BuLi (2.5
M
in hexanes, 2.1 mL, 5.29 mmol) was
stirred solution of (1-
added dropwise via syringe to
a
tetradecyl)triphenylphosphonium bromide (3.25 g, 6.01 mmol) in
THF (60 mL) at −78 ◦C. After 30 min hexane (75 mL) was added,
followed by the dropwise addition of a solution of 50 (500 mg,
1.20 mmol) in THF (15 mL) via cannula. The reaction mixture was
stirred at −78 ◦C for 2 h before the addition of MeOH (50 mL).
The reaction mixture was allowed to warm to rt over a further 12 h
and quenched with sat aq NH4Cl (10 mL). Brine (100 mL) was
added, the organic layer was separated, and the aqueous layer was
extracted with Et2O (3 × 50 mL). The combined organic extracts
were dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 ◦C petrol–Et2O, 10 : 1) gave (E)-52
as a colourless oil (523 mg, 73%, (E) : (Z) 94 : 6); Rf 0.16 (30–40 ◦C
petrol–Et2O, 10 : 1); [a]2D0 +3.5 (c 2.2 in CHCl3); mmax (film) 2926
(2S,3R)-1,3-Diacetoxy-2-acetamido-octadecane [N,O-diacetyl
sphinganine] 54
3 M aq HCl (1 mL) was added to a solution of 53 (30 mg,
0.05 mmol) in MeOH (10 mL) and heated at 50 ◦C for 3 h.
The reaction mixture was concentrated in vacuo. The residue was
dissolved in pyridine (10 mL) and Ac2O (0.1 mL, excess) and
DMAP (2 mg) were added sequentially. The reaction mixture was
stirred for 12 h before being quenched with H2O (2 mL). The
reaction mixture was diluted with H2O (10 mL) and Et2O (10 mL)
and the layers were separated. The aqueous layer was extracted
with Et2O (2 × 10 mL). The combined organic layers were washed
sequentially with sat aq CuSO4 (2 × 10 mL), H2O (10 mL) and
brine (10 mL), dried and concentrated in vacuo. Recrystallisation
from CHCl3–pentane (1 : 1) gave 54 as a white solid (11 mg, 75%,
=
(C–H), 1703 (C O); dH (400 MHz, CDCl3) 0.95–0.99 (3H, m,
C(15ꢀ)H3), 1.10–1.23 (21H, m, Si(CHMe2)3), 1.31–1.72 (37H, m,
C(2)Me2, C(4ꢀ)H2-C(14ꢀ)H2, CMe3), 2.10–2.19 (2H, m, C(3ꢀ)H2),
3.70–3.78 (1H, m, C(4)CHA), 3.84–4.12 (2H, m, C(4)H, C(4)CHB),
4.59–4.64 (1H, m, C(5)H), 5.80–5.96 (2H, m, C(1ꢀ)H, C(2ꢀ)H); dH
(500 MHz, PhMe-d8, 363 K) 0.92 (3H, t, J 6.9, C(15ꢀ)H3), 1.11–
1.18 (21H, m, Si(CHMe2)3), 1.26–1.50 (31H, m, C(4ꢀ)H2-C(14ꢀ)H2,
CMe3), 1.58 (3H, s, C(2)MeA), 1.68 (3H, s, C(2)MeB), 2.10–2.14
(2H, m, C(3ꢀ)H2), 3.80–3.86 (1H, m, C(4)CHA), 3.93 (1H, br s,
C(4)H), 4.04 (1H, dd, J 9.8, 7.6, C(4)CHB), 4.50–4.52 (1H, m,
C(5)H), 5.77–5.85 (1H, m, C(2ꢀ)H), 5.87–5.93 (1H, m, C(1ꢀ)H);
dC (125 MHz, PhMe-d8, 363 K) 12.2 (Si(CHMe2)3), 13.6 (C(15ꢀ)),
17.9 (Si(CHMe2)3), 22.5, 24.1, 27.3, 28.1, 29.2, 29.27, 29.30, 29.53,
29.57, 29.61, 29.7, 31.9 (C(2)Me2, C(3ꢀ)-C(14ꢀ), CMe3), 61.3 (C(4)),
62.0 (C(4)CH2), 77.2 (C(5)), 79.0 (CMe3), 92.4 (C(2)), 125.7
(C(2ꢀ)), 134.1 (C(1ꢀ)), 151.5 (NCO); m/z (CI+) 596.5 ([M + H]+,
100%); HRMS (CI+) C35H70NO4Si+ ([M + H]+) requires 596.5074;
found 596.5084.
◦
>98% de); mp 83–85 C (CHCl3–pentane); [a]2D2 +18.4 (c 0.25 in
CHCl3); {lit.25 [a]2D2 +19.2 (c 1.0 in CHCl3); lit.26 [a]D24 +17.2 (c
0.2 in CHCl3)}; mmax (KBr) 3306, 2912, 2853, 1732, 1649, 1545,
1232; dH (400 MHz, CDCl3) 0.87 (3H, t, J 6.7, C(18)H3), 1.21–
1.38 (22H, m, C(7)H2-C(17)H2), 1.52–1.70 (2H, m, C(6)H2), 2.01
(3H, s, COMe), 2.07 (3H, s, COMe), 2.08 (3H, s, COMe), 4.07 (1H,
dd, J 11.6, 3.9, C(1)HA), 4.26 (1H, dd, J 11.6, 6.1, C(1)HB), 4.34–
4.45 (1H, m, C(2)H), 4.88–4.95 (1H, m, C(3)H), 5.85 (1H, d, J 8.9
NH); dC (100 MHz, CDCl3) 14.1, 20.8, 21.0, 22.7, 23.3, 25.3, 29.3,
29.4, 29.5, 29.60, 29.63, 29.7, 31.5, 31.9, 50.5, 62.6, 73.9, 169.8,
170.9, 171.0; m/z (ESI+) 450 ([M + Na]+, 100%); HRMS (ESI+)
C24H45NNaO5 ([M + Na]+) requires 450.3190; found 450.3180.
+
(4S,5R)-2,2-Dimethyl-N(3)-tert-butoxycarbonyl-4-tri-iso-
(2S,3R,4Z)-1,3-Diacetoxy-2-acetamido-octadec-4-ene
[N,O,O-triacetyl-(Z)-sphingosine] 55
propylsiloxymethyl-5-pentadecan-1ꢀ-yl-oxazolidine 53
Pd/C (5 mg, 10% w/w) was added to a stirred solution of (Z)-
51 (50 mg, 0.08 mmol) in EtOAc (5 mL) at rt. The reaction
mixture was stirred under H2 (1 atm) for 6 h. The reaction mixture
was filtered through Celite (eluent EtOAc) and concentrated in
vacuo. Purification via flash column chromatography (eluent 30–
40 ◦C petrol–Et2O, 2 : 1) gave 53 as a colourless oil (43 mg,
3 M aq HCl (1 mL) was added to a solution of (Z)-51 (30 mg,
0.05 mmol) in MeOH (10 mL) and heated at 50 ◦C for 3 h.
The reaction mixture was concentrated in vacuo. The residue was
dissolved in pyridine (10 mL) and Ac2O (0.1 mL, excess) and
DMAP (2 mg) were added sequentially. The reaction mixture was
stirred for 12 h before being quenched with H2O (2 mL). The
reaction mixture was diluted with H2O (10 mL) and Et2O (10 mL)
and the layers were separated. The aqueous layer was extracted
with Et2O (2 × 10 mL). The combined organic layers were washed
◦
86%, >98% de); Rf 0.8 (30–40 C petrol–Et2O, 2 : 1); [a]D17
=
+10.0 (c 2.2 in CHCl3); mmax (film) 2925 (C–H), 1702 (C O); dH
(400 MHz, CDCl3) 0.85–0.91 (3H, m, C(15ꢀ)H3), 1.02–1.12 (21H,
1662 | Org. Biomol. Chem., 2008, 6, 1655–1664
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
sequentially with sat aq CuSO4 (2 × 10 mL), H2O (10 mL) and
brine (10 mL), dried and concentrated in vacuo. Recrystallisation
from CHCl3–pentane (1 : 1) gave 55 as a white solid (13 mg, 87%,
Synthesis, 1998, 1075. For a review of the synthesis of phytosphingosine
see: A. R. Howell and A. J. Ndakala, Curr. Org. Chem., 2002, 6, 365.
6 For the enantiospecific synthesis of sphinganine and/or sphingosine
see: H. Azuma, S. Tamagaki and K. Ogino, J. Org. Chem., 2000, 65,
3538; R. I. Duclos, Chem. Phys. Lipids, 2001, 111, 111; T. Nakamura
and M. Shiozaki, Tetrahedron, 2001, 57, 9087; J. Chun, G. Li, H.-S.
Byun and R. Bittman, Tetrahedron Lett., 2002, 43, 375; J. E. Milne, K.
Jarowicki, P. J. Kocienski and J. Alonso, Chem. Commun., 2002, 426;
J.-M. Lee, H.-S. Lim and S.-K. Chung, Tetrahedron: Asymmetry, 2002,
13, 343; R. J. B. H. N. van den Berg, C. G. N. Korevaar, G. A. van der
Marel, H. S. Overkleeft and J. H. van Boom, Tetrahedron Lett., 2002,
43, 8409; T. Murakami and K. Furusawa, Tetrahedron, 2002, 58, 9257;
H. K. Lee, E.-K. Kim and C. S. Pak, Tetrahedron Lett., 2002, 43, 9641;
S. Raghavan, A. Rajender and J. S. Yadav, Tetrahedron: Asymmetry,
2003, 14, 2093; S. Raghavan and A. Rajender, J. Org. Chem., 2003, 68,
7094; R. C. So, R. Ndonye, D. P. Izmirian, S. K. Richardson, R. L.
Guerra and A. R. Howell, J. Org. Chem., 2004, 69, 3233; X. Lu, H.-S.
Byun and R. Bittman, J. Org. Chem., 2004, 69, 5433; R. J. B. H. N. van
den Berg, C. G. N. Korevaar, H. S. Overkleeft, G. A. van der Marel and
J. H. van Boom, J. Org. Chem., 2004, 69, 5699; M. Shimizu, H. Ando
and Y. Niwa, Lett. Org. Chem., 2005, 2, 512; W. Lu and R. Bittman,
Tetrahedron Lett., 2005, 46, 1873; V. D. Chaudhari, K. S. A. Kumar
and D. D. Dhavale, Org. Lett., 2005, 7, 5805; M. G. Capdevila, F. Pasi
and C. Trombini, Org. Lett., 2006, 8, 3303; P. Merino, P. Jiminez and T.
Tejero, J. Org. Chem., 2006, 71, 4685; S. Kim, S. Lee, T. Lee, H. Ko and
D. Kim, J. Org. Chem., 2006, 71, 8661; T. Yamamoto, H. Hasegawa, T.
Hakogi and S. Katsumura, Org. Lett., 2006, 8, 5569; V.-T. Pham, J.-E.
Joo, Y.-S. Tian, C.-Y. Oh and W.-H. Ham, Arch. Pharmacol. Res., 2007,
30, 22; M. Lombardo, A. Sharma, S. Gamre and S. Chattopadhyay,
Tetrahedron Lett., 2007, 48, 633; Y. S. Tian, J.-E. Joo, V.-T. Pham, K.-Y.
Lee and W.-H. Ham, Arch. Pharmacol. Res., 2007, 30, 167; A. S. Kale,
P. S. Sakle, V. K. Gumaste, A. Rakeeb and A. S. Deshmukh, Synthesis,
2007, 2631; H. Yang and L. S. Liebeskind, Org. Lett., 2007, 9, 2993.
7 For the asymmetric synthesis of sphinganine and/or sphingosine see:
E. J. Corey and S. Choi, Tetrahedron Lett., 2000, 41, 2765; B. Olofsson
and P. Somfai, J. Org. Chem., 2003, 68, 2514; S. Torssell and P. Somfai,
Org. Biomol. Chem., 2004, 2, 1643; J. Kobayashi, M. Nakamura, Y.
Mori, Y. Yamashita and S. Kobayashi, J. Am. Chem. Soc., 2004, 126,
9192; D. Enders and A. Mu¨ller-Hu¨wen, Eur. J. Org. Chem., 2004, 1732;
W. Disadee and T. Ishikawa, J. Org. Chem., 2005, 70, 9399; D. Enders,
J. Palecˇek and C. Grondal, Chem. Commun., 2006, 655; Y. Cai, C.-C.
Ling and D. R. Bundle, Org. Biomol. Chem., 2006, 4, 1140; G. Righi,
S. Ciambrone, C. D’Achille, A. Leonelli and C. Bonini, Tetrahedron,
2006, 62, 11821.
◦
>98% de); mp 83–85 C (CHCl3–pentane); [a]2D2 +6.6 (c 0.9 in
CHCl3); {lit.27 [a]D24 +4.3 (c 0.9 in CHCl3)}; mmax (KBr) 3336, 2926,
2851, 1734, 1655, 1539, 1236; dH (400 MHz, CDCl3) 0.88 (3H, t, J
6.8, C(18)H3), 1.14–1.43 (22H, m, C(7)H2-C(17)H2), 1.99 (3H, s,
COMe), 2.05 (3H, s, COMe), 2.08 (3H, s, COMe), 2.00–2.27 (2H,
m, C(6)H2), 4.04 (1H, dd, J 11.6, 3.9, C(1)HA), 4.34 (1H, dd, J
11.6, 6.5, C(1)HB), 4.39–4.47 (1H, m, C(2)H), 5.28–5.36 (1H, m,
C(3)H), 5.60–5.73 (2H, m, C(4)H, C(5)H); dC (125 MHz, CDCl3)
14.1, 20.8, 21.1, 22.7, 23.4, 28.0, 29.3, 29.35, 29.42, 29.5, 29.6,
29.64, 29.66, 29.67, 31.9, 51.1, 62.6, 69.6, 77.2, 123.8, 137.0, 169.8,
170.0, 171.0; m/z (ESI+) 448 ([M + Na]+, 100%); HRMS (ESI+)
C24H43NNaO5 ([M + Na]+) requires 448.3033; found 448.3030.
+
(2S,3R,4E)-1,3-Diacetoxy-2-acetamido-octadec-4-ene
[N,O,O-triacetyl sphingosine] 56
3 M aq HCl (1 mL) was added to a solution of (E)-52 (50 mg,
0.05 mmol, (E) : (Z) 94 : 6) in MeOH (10 mL) and heated at
50 ◦C for 3 h. The reaction mixture was concentrated in vacuo.
The residue was dissolved in pyridine (10 mL) and Ac2O (0.1 mL,
excess) and DMAP (2 mg) were added sequentially. The reaction
mixture was stirred for 12 h before being quenched with H2O
(2 mL). The reaction mixture was diluted with H2O (10 mL) and
Et2O (10 mL) and the layers were separated. The aqueous layer
was extracted with Et2O (2 × 10 mL). The combined organic
layers were washed sequentially with sat aq CuSO4 (2 × 10 mL),
H2O (10 mL) and brine (10 mL), dried and concentrated in vacuo.
Recrystallisation from CHCl3–pentane (1 :◦1) gave 56 as a white
solid (29 mg, 80%, >98% de); mp 99–101 C (CHCl3–pentane);
[a]D20 −12.0 (c 1.0 in CHCl3); {lit.28 [a]D24 −13.0 (c 1.6 in CHCl3)};
mmax (KBr) 3287, 2919, 2850, 1734, 1656, 1552, 1232; dH (400 MHz,
CDCl3) 0.88 (3H, t, J 6.8, C(18)H3), 1.19–1.40 (22H, m, C(7)-
C(17)H2), 1.95–2.09 (2H, m, C(6)H2) overlapping 1.99 (3H, s,
COMe) and 2.07 (6H, s, 2 × COMe), 4.04 (1H, dd, J 11.6, 4.1,
C(1)HA), 4.30 (1H, dd, J 11.6, 6.1, C(1)HB), 4.39–4.48 (1H, m,
C(2)H), 5.26–5.28 (1H, m, C(3)H), 5.39 (1H, dd, J 15.4, 7.5,
C(4)H), 5.68 (1H, d, J 9.2, NH), 5.79 (1H, dd, J 15.4, 6.8,
C(5)H); dC (100 MHz, CDCl3) 14.1, 20.8, 21.1, 22.7, 23.4, 28.9,
29.2, 29.3, 29.4, 29.6, 29.7, 31.9, 32.3, 50.6, 60.4, 62.6, 73.8, 124.1,
137.5, 169.7, 170.0, 171.0; m/z (ESI+) 448 ([M + Na]+, 100%);
8 For a review see: S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron:
Asymmetry, 2005, 16, 2833.
9 M. E. Bunnage, A. N. Chernega, S. G. Davies and C. J. Goodwin,
J. Chem. Soc., Perkin Trans. 1, 1994, 2373.
10 (a) M. E. Bunnage, S. G. Davies and C. J. Goodwin, Synlett, 1993, 731;
M. E. Bunnage, S. G. Davies and C. J. Goodwin, J. Chem. Soc., Perkin
Trans. 1, 1993, 1375; (b) M. E. Bunnage, A. J. Burke, S. G. Davies
and C. J. Goodwin, Tetrahedron: Asymmetry, 1994, 5, 203; (c) M. E.
Bunnage, S. G. Davies and C. J. Goodwin, J. Chem. Soc., Perkin Trans.
1, 1994, 2385; (d) M. E. Bunnage, A. J. Burke, S. G. Davies and C. J.
Goodwin, Tetrahedron: Asymmetry, 1995, 6, 165; (e) A. J. Burke, S. G.
Davies and C. J. R. Hedgecock, Synlett, 1996, 621; (f) M. E. Bunnage,
A. J. Burke, S. G. Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts
and A. D. Smith, Org. Biomol. Chem., 2003, 1, 3708; (g) S. G. Davies,
D. G. Hughes, R. L. Nicholson, A. D. Smith and A. J. Wright, Org.
Biomol. Chem., 2004, 2, 1549.
HRMS (ESI+) C24H43NNaO5 ([M + Na]+) requires 448.3033;
11 E. Abraham, J. I. Candela-Lena, S. G. Davies, M. Georgiou, R. L.
Nicholson, P. M. Roberts, A. J. Russell, E. M. Sa´nchez-Ferna´ndez,
A. D. Smith and J. E. Thomson, Tetrahedron: Asymmetry, 2007, 18,
2510.
+
found 448.3023.
12 M. Ichihashi and K. Mori, Biosci., Biotechnol., Biochem., 2002, 67, 329.
13 The reaction diastereoselectivity was assessed by peak integration of
the 1H NMR spectrum of the crude reaction mixture.
References
1 S. C. Bergmeier, Tetrahedron, 2000, 56, 2561.
14 The ee of 12 was determined by derivatisation with both homochiral
and racemic Mosher’s acid chloride, and subsequent analysis of the
resultant esters by 1H and 19F NMR spectroscopy; see J. A. Dale, D. L.
Dull and H. S. Mosher, J. Org. Chem., 1969, 34, 2543.
15 Aldehyde 13 was partially characterised and used immediately.
16 T. J. Wilkinson, N. W. Stehle and P. Beak, Org. Lett., 2000, 2, 155.
17 S. G. Davies, A. W. Mulvaney, A. J. Russell and A. D. Smith,
Tetrahedron: Asymmetry, 2007, 18, 1554.
2 C. Jime´nez and P. Crews, J. Nat. Prod., 1990, 53, 978.
3 L. Garrido, E. Zubia, M. J. Ortega, S. Naranjo and J. Salva,
Tetrahedron, 2001, 57, 4579.
4 B. Cinque, L. Di Marzio, C. Centi, C. Di Rocco, C. Riccardi and M. G.
Cifone, Pharmacol. Res., 2003, 47, 421.
5 For a review of the synthesis of sphinganine see: A. R. Howell, R. C. So
and S. K. Richardson, Tetrahedron, 2004, 60, 11327. For a review of the
synthesis of sphingosine see: P. M. Koskinen and A. M. P. Koskinen,
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1655–1664 | 1663
©

View Article Online
18 A. D. Campbell, T. M. Raynham and R. J. K. Taylor, Synthesis, 1998,
1707.
23 M. Schlosser and K. F. Christman, Angew. Chem., Int. Ed. Engl., 1966,
5, 126.
19 M. Frigerio and M. Santagostino, Tetrahedron Lett., 1994, 35, 8019;
M. Frigerio, M. Santagostino, S. Sputore and G. Palmesano, J. Org.
Chem., 1995, 60, 7272. IBX was prepared from 2-iodobenzoic acid
according to the procedure of; M. Frigerio, M. Santagostino and S.
Sputore, J. Org. Chem., 1999, 64, 4537.
24 J. S. Oh, B. H. Kim and Y. G. Kim, Tetrahedron Lett., 2004, 45,
3925.
25 H. E. Carter and D. Shapiro, J. Am. Chem. Soc., 1953, 75, 5131.
26 R. A. Fernandes and P. Kumar, Tetrahedron: Asymmetry, 1999, 10,
4797.
20 Aldehyde 20 was partially characterised and used immediately.
21 M. Jayaraman, M. Nandi, K. M. Sathe, A. R. A. S. Deshmukh and
B. M. Bhawal, Tetrahedron: Asymmetry, 1993, 4, 609.
22 E. Abraham, J. W. B. Cooke, S. G. Davies, A. Naylor, R. L. Nicholson,
P. D. Price and A. D. Smith, Tetrahedron, 2007, 63, 5855.
27 H. Shibuya, K. Kawashima, N. Narita, M. Ikeda and I. Kitagawa,
Chem. Pharm. Bull., 1992, 40, 1154.
28 W. Disadee and T. Ishikawa, J. Org. Chem., 2005, 70, 9399.
29 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and F. J.
Timmers, Organometallics, 1996, 15, 1518.
1664 | Org. Biomol. Chem., 2008, 6, 1655–1664
This journal is
The Royal Society of Chemistry 2008
©