Stereoselective synthesis of β-amino alcohols: Practical preparation of all four stereomers of N-PMB-protected sphingosine from L- and D-serine

Article abstract of DOI:10.1016/S0957-4166(99)00147-0

Serine was efficiently converted to the N-p-methoxybenzyl (PMB) protected α'-amino enone derivative 6, which was reduced with Zn(BH₄)₂ to the corresponding anti-β-amino alcohol in >96% de. On the other hand, N- PMB-N-Boc-protected α'-amino enone derivative 8 was reduced by NaBH₄ to syn-product with a diastereoselectivity of ca. 90%.

Full text of DOI:10.1016/S0957-4166(99)00147-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1441–1444
Stereoselective synthesis of β-amino alcohols: practical
preparation of all four stereomers of N-PMB-protected
sphingosine from L- and D-serine
Sung-Kee Chung ∗ and Jae-Mok Lee
Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, Korea
Received 12 March 1999; accepted 12 April 1999
Abstract
Serine was efficiently converted to the N-p-methoxybenzyl(PMB) protected α0-amino enone derivative 6, which
was reduced with Zn(BH4)2 to the corresponding anti-β-amino alcohol in >96% de. On the other hand, N-PMB-
N-Boc-protected α0-amino enone derivative 8 was reduced by NaBH4 to syn-product with a diastereoselectivity of
ca. 90%. © 1999 Elsevier Science Ltd. All rights reserved.
The stereoselective synthesis of β-amino alcohols is a topic of current interest, since a number
of biologically important compounds contain this structural motif.1 Diastereoselective synthesis of β-
amino alcohols may in principle be approached by either the nucleophilic addition of organometallics
to N,N-dibenzylamino aldehydes giving primarily anti-adducts,2 or the reduction of the corresponding
α-amino ketones. Recently, we described a highly efficient synthetic route to syn-β-amino alcohols
via the diastereoselective reduction of α-N,N-dibenzylamino enones prepared from the corresponding
α-amino acid.3 Although the α-N,N-dibenzylamino moiety provides the bulkiness necessary for the
diastereoselection, and a degree of resistance to possible racemization at the α-amino ketone stage, it
is also a source of serious limitations to the subsequent functional group manipulation. In connection
with our interests in developing practical synthetic routes to various sphingosine related structures, it
was required to obviate the problems associated with the α-N,N-dibenzylamino-protecting method. We
wish to report herein a divergent synthesis of all four stereomers of sphingosine as an illustration of the
syn/anti-diastereoselectivity control in the synthesis of β-amino alcohols.
Naturally occurring D-erythro-sphingosine 1a is the major backbone component of glycosphingo-
lipids, important cell membrane constituents. The glycosphingolipids play crucial roles in cell re-
cognition events such as growth, differentiation, the immune response,4 and all of the sphingosine
diastereomers have been reported to be potent inhibitors of protein kinase C.5 In addition, certain
glycosphingolipid analogues exhibit significant antiinflammatory,6 immunosuppressive,7 antiviral,8 and
∗
Corresponding author. E-mail: skchung@chem.postech.ac.kr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00147-0

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antifungal activities.9 Various synthetic methods for the enantiomerically pure sphingosine diastereomers
have been reported.10 One of the most widely used methods involves the diastereoselective addition
of organometallics to suitably protected serinal derivatives. In addition to the fact that chiral α-amino
aldehydes are prone to racemization, obtaining a high level of diastereoselectivity by this method
is still problematic.11 Since α0-amino enones could be readily prepared from α-amino acids via the
Horner–Wadsworth–Emmons procedure,3 we have examined other N-protection methods than the N,N-
dibenzylation in order to gain a direct access to either syn- or anti-β-amino alcohols by reduction.
Initially, we examined the N-trityl protection, but diastereoselectivity of the reduction was found to vary
widely depending on the structure of α0-amino enones. More successful results were obtained with the
N-p-methoxybenzyl (N-PMB) protection.
L-Serine was esterified with methanolic hydrogen chloride, the amino group protected as the N-PMB
group with p-methoxybenzaldehyde followed by reduction of the imine intermediate,12 and introduction
of the acetonide gave 3 as a crystalline solid in 56% yield from serine (Scheme 1). The ester 3 was
converted to the β-keto phosphonate 4 by treatment with 2.2 equiv. of lithium dimethyl methylphos-
phonate in THF at −78°C. The Horner–Wadsworth–Emmons olefination of 4 with tetradecylaldehyde
under Masamune conditions13 provided the O,N-protected enone 5, which was subjected to one-pot
deacetonidation to generate the N-protected α0-amino enones 6 as a stable HCl salt in 65% yield from 3.
The E-stereochemistry of compound 6 was assigned on the basis of 1H NMR (J=15.8 Hz, trans-olefinic
CH). The enantiomeric purity of 6 was determined to be >99% ee by a chiral HPLC (Daicel-OD, 10%
i-PrOH in n-hexane), which also showed no epimerization at the stereogenic center throughout the entire
sequence of transformation.
Scheme 1. Reagents: (a) AcCl/MeOH; (b) p-methoxybenzaldehyde/Et3N/MgSO4/MeOH then NaBH4; (c)
(MeO)2CMe2/PPTS/toluene; (d) CH3PO(OMe)2/n-BuLi/THF; (e) C13H27CHO/DBU/LiCl/THF; (f) 10% HCl–THF
Our initial attempts to obtain 2a or 2b from the O,N-protected enone 5 by stereoselective reduction
and subsequent removal of the isopropylidene group resulted in poor yield and diasteroselectivity.14 Thus,
the diastereoselective reduction was examined on 6 and the results are shown in Table 1 (entries 1–6).

S.-K. Chung, J.-M. Lee / Tetrahedron: Asymmetry 10 (1999) 1441–1444
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Table 1
Virtually all reducing agents examined except Me4NBH(OAc)3 (entry 6), provided the anti-diastereomer
2a as the major product in accord with the expected α-chelated transition state.15 The highest anti-
diastereoselectivity (>96% de) was obtained with Zn(BH4)2, presumably due to the high chelating ability
of zinc.16 The syn-preference in the case of entry 6 with Me4NBH(OAc)3 is consistent with the β-
hydroxy-directed reduction.17 In order to assess the effect of the chelation by the free hydroxy group
on the diastereoselectivity, the O-silylated ketone 7 was examined (entries 7–12). This modification
was found generally to increase the anti-selectivity, probably due to the increased α-chelation. Finally,
enone 6 was diprotected as the N-p-methoxybenzyl-N-tert-butoxycarbonyl derivative 8. Reduction of 8
with NaBH4 afforded the expected syn-amino alcohol 2b in high yield and excellent diastereoselectivity
(>90% de) after in situ removal of the Boc group with dil. HCl (entry 13). It is evident that the reduction
proceeds through a non-chelated transition state, in which the bulky N-protecting groups both prevent
the chelation and control the diastereoselectivity.
The stereochemical assignments for diastereomers 2a and 2b were made based on spectral analyses
of the corresponding oxazolidinone derivatives.18 The erythro-derivative showed Jvicinal H value slightly
larger (8.2 Hz) than that of the threo-isomer (6.5 Hz). The compounds 2a and 2b were also converted
to the known triacetates by acetylation with Ac2O, followed by removal of the PMB group with cerium
ammonium nitrate in 70% and 65% overall yields, respectively.19 Their physical properties were identical
with the reported values.20
Employing the identical procedures, D-serine was also transformed to 2c and 2d. Thus, all four
stereomers of the N-PMB-protected sphingosine were divergently synthesized in good yield and excellent
enantiomeric excess (Table 2).

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Table 2
Acknowledgements
Financial support by the Korea Science and Engineering Foundation for this work is gratefully
acknowledged (981-0302-008-2 and 985-0300-002-2). We also thank Professor G. Piancatelli (University
of Rome) for helpful discussions.
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25
20. Triacetyl-D-erythro-sphingosine: mp 101–102°C; [α]D −13.18 (c 1.04, CHCl3) [lit.11a mp 102.5–103°C; [α]D −13.0 (c
1.08, CHCl3), triacetyl-L-threo-sphingosine: mp 42–43°C; [α]D 25 +7.92 (c 1.28, CHCl3) [lit.11a mp 42–44°C; [α]D +7.02
(c 2.05, CHCl3).