Synthesis 2016; 48(23): 4017-4037
DOI: 10.1055/s-0036-1588311
review
© Georg Thieme Verlag Stuttgart · New York

Recent Progress in Chemical Syntheses of Sphingosines and Phytosphingosines

Yangguang Gaoa, b, Xianran Hea, b, Fei Dinga, b, Yongmin Zhang*a, c
  • aInstitute for Interdisciplinary Research, Jianghan University, Wuhan Economic and Technological Development Zone, Wuhan­ 430056, P. R. of China
  • bKey Laboratory of Optoelectronic Chemical Materials and Devices of Ministry of Education, Jianghan University, Wuhan Economic and Technological Development Zone, Wuhan 430056, P. R. of China
  • cInstitut Parisien de Chimie Moléculaire, CNRS UMR 8232, Université Pierre et Marie Curie-Paris 6, 4 Place Jussieu, 75005 Paris, France   eMail: yongmin.zhang@upmc.fr
Weitere Informationen

Publikationsverlauf

Received: 15. Mai 2016

Accepted after revision: 20. Juni 2016

Publikationsdatum:
10.Oktober 2016 (eFirst)

 

Abstract

Sphingolipids and their derivatives, such as glycosphingolipids and sphingomyelins, are ubiquitous in the biomembrane of eukaryotic cells, and they play pivotal roles in cell proliferation, recognition, adhesion, and signal transduction. Sphingosine is predominantly the important lipid moiety of the glycosphingolipids and sphingomyelins, while phytosphingosine is a major long-chain moiety for glycosphingolipids. Due to the significance of these two bioactive lipids, tremendous efforts have been made to synthesize sphingosine or phytosphingosine, with chiral pool approaches, chiral auxiliaries, and asymmetric reactions used to construct their contiguous stereogenic centers. This review covers the synthetic literature published from 2000–2015.

1 Introduction

2 Chiral Approach

2.1 Chirality from Sugars

2.2 Chirality from Serine and Its Derivatives

2.3 Chirality from d-ribo-Phytosphingosine

2.4 Chirality from d-Tartaric Acid and Its Diester

2.5 Chirality from Other Chiral Precursors

3 Chiral Auxiliaries

3.1 Chiral Sulfur Auxiliaries

3.2 Chiral N-Containing Auxiliaries

4 Asymmetric Reactions

4.1 Sharpless Dihydroxylation Reaction

4.2 Sharpless Epoxidation and Shi’s Epoxidation Reaction

4.3 Asymmetric Aldol Reaction

4.4 Sharpless Kinetic Resolution

4.5 Asymmetric Aminohydroxylation and Amination

5 Conclusions


#

Biographical Sketches

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Yangguang Gao was born in 1983 and grew up in Chaohu, China. He obtained his Ph.D. degree in Organic Chemistry at the University of Chinese Academy of Sciences in 2014. In the same year, he took up his current position as assistant research fellow at Jianghan University. Now, his research interests include carbohydrate chemistry and the total synthesis of natural products with excellent biological activities.

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Xianran He was born in Xiangyang, China in 1983. He received his Ph.D. degree in Medicinal Chemistry at Wuhan University in 2010. Following postdoctoral research with Professor Hans-Joachim Lehmler at the University of Iowa, he returned to China in March 2013 and started his new position as associate professor at the Institute for Interdisciplinary Research, Jianghan University. His research focuses on drug molecular design.

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Fei Ding was born in Shiyan, China, in 1984. She received her Master degree in Applied Chemistry at Wuhan University in 2011. In the same year she started her Ph.D. degree under the supervision of Dr. Xiang Zhou. Her research interests concern the synthesis of antitumor agents based on monosaccharides and the biofunctionability of synthesized polysaccharides.

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Yongmin Zhang was born in Hohhot, China. He obtained his B.Sc. in 1982 at Beijing Medical College, China, and his Ph.D. in Medicinal Chemistry in 1986 from South-Paris University, France. After two years post doctoral research at Beijing Medical University, he worked as visiting associate professor then visiting professor at South-Paris University prior to taking a permanent position at CNRS (French National Scientific Research Centre) in 1991, where he is now research director at the CNRS-University of Paris 6 Joint Research Laboratory. He worked as visiting scholar at the University of Washington (USA) during 1995–1997. He was elected a member of the French National Academy of Pharmacy in 2012. His current research interests include biologically active­ oligosaccharides, glycosphingolipids, carbasugars, azasugars, modified cyclodextrins, and fullerene chemistry, aiming at carbohydrate-based drug development.

1

Introduction

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Scheme 1 Structures of sphingosine and phytosphingosines. Note: subscript s = serine, g = glyceraldehyde

Sphingolipids and glycosphingolipids are expressed on the surface of the cell membrane and distributed throughout all eukaryotic cells; they are of physiological importance for cell growth, recognition, adhesion, neuronal repair, and signal transduction.[1] Sphingosine [(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-ol)], an amino alcohol (Scheme [1]), is a major lipid moiety of various sphingolipids. It has displayed potent inhibitory activity against protein kinase C and plays key roles in cell signaling.[2] Sphingosine has been well studied since its first isolation by Thudichum from the human brain in 1884.[3] The correct relative structural conformation of the key functional groups was assigned by Carter and co-workers in 1947,[4] and its first total synthesis was by Shapiro and Segal in 1954.[5] Phytosphingosine, a major backbone of glycosphingolipids, is found in higher plants, protozoa, yeast, and fungi,[6] [7] [8] [9] and has a sphingoid base incorporating a long aliphatic chain and a polar 2-amino-1,3-diol group at the head end. The fixed amino function and variation in hydroxyl stereogenic centers of phytosphingosine leads to four diastereomers, which exhibit different activities and metabolisms. Phytosphingosine is also a bioactive lipid, and its glycosylated derivatives display potential antitumor and antivirus activity.[10] [11] For example, d-ribo-phytosphingosine has been shown to be a cytotoxic agent against human leukemic cell lines.[12] In addition, d-ribo-phytosphingosine is a potential heat-stress-signaling molecule in yeast.[13] Note, there is some underlying confusion related to stereochemical descriptors, d/l and D/L, the former descriptors could relate either to amino acid or carbohydrate nomenclature and the latter is a unique (and defunct) nomenclature for phytosphingosines (sphinganines).[14] For the sake of consistency, traditional carbohydrate nomenclature is used in this review unless otherwise stated.

The diverse biological activities and novel structural characteristics of sphingosines and phytosphingosines have drawn the attention of the biological and chemical communities, especially from the latter due to the scarcity of the two lipids in nature. To date, there have been several reviews.[15] Herein, we would like to introduce some recent advances in the chemical syntheses of sphingosines and phytosphingosines published from 2000 to 2015; synthetic procedures are discussed together based upon their structural similarity.


# 2

Chiral Approach

2.1

Chirality from Sugars

2.1.1

Chirality from Mannose or Mannitol

Pandey and Tiwari reported an enantioselective and concise synthesis of (2S,3R,4R)-d-xylo-phytosphingosine in seven steps in 36% overall yield utilizing d-mannitol triacetonide as a chiral template (Scheme [2]).[16] By this route, d-mannitol triacetonide (6) was converted into β-lactam 7 according to a literature procedure[17] to install all of the required stereogenic centers. Wittig olefination was employed for chain elongation followed by two-step reduction to give 8. Finally, full deprotection under acidic conditions, then peracetylation with acetic anhydride/pyridine, gave N,O,O,O-tetraacetyl-d-xylo-phytosphingosine (10) in good yield.

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Scheme 2 Synthesis of N,O,O,O-tetraacetyl-d-xylo-phytosphingosine (10) from d-mannitol triacetonide (6)

Mettu, Vaidya, and co-workers accomplished the syntheses of tetraacetyl-d-ribo-phytosphingosine 16 and tri­acetyl-d-erythro-sphingosine 18 using a common intermediate 11 obtained from cyclohexylidene-protected d-glyceraldehyde 12, which was readily prepared from d-mannitol (Scheme [3]).[18a] The key steps included a highly diastereoselective Sharpless asymmetric epoxidation, a regioselective epoxide-opening reaction by azide nucleophile, and Wittig olefination. Compound 12 was also adopted as a chiral pool component to synthesize 3-O-benzoylazidosphingosine 22.[18b] Nucleophilic addition of the Grignard reagent to d-glyceraldehyde gave propargylic alcohol 19 with low dia­stereoselectivity (syn/anti 4:6). The undesired anti-addition product was recycled through deacetylation followed by Mitsunobu inversion. In contrast to triflate or mesylate as the leaving group in the literature, chloromesylate (SO2­CH2Cl, Mc) was utilized, and was subjected to displacement by the azide nucleophile to afford azidosphingosine in a very satisfactory yield.

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Scheme 3 Syntheses of tetraacetyl-d-ribo-phytosphingosine 16, triacetyl-d-erythro-sphingosine 18, and 3-O-benzoylazidosphingosine 22 from cyclohexylidene-protected d-glyceraldehyde 12

In 2013, Martinková and co-workers described the total synthesis of protected l g-arabino-phytosphingosine 31 and l-ribo-phytosphingosine 28 from 2,3:5,6-di-O-isopropylidene-d-mannofuranose (Scheme [4]; g = glyceraldehyde).[19] The pivotal reactions involved [3,3]-sigmatropic rearrangement to introduce the desired amino functionality, and chain elongation through Wittig olefination. Notably, thermal Overman rearrangement of 24 furnished an inseparable mixture of rearranged products in low yield and poor diastereoselectivity, while the use of microwave heating afforded high yields of rearranged products and greatly shortened reaction times. The protected l-ribo-phytosphingosine 28 could be accessed from rearranged product 25b through several manipulations. Utilizing the same procedure as described for the preparation of protected l-ribo-phytosphingosine 28, the synthesis of 31 was achieved from 25a. An alternative route for the preparation of 31 commenced with allylic thiocyanate 29 according to a procedure similar to that for the synthesis of 28. Though aza-Claisen rearrangement of 29 was carried out in modest yield, it displayed better stereoselectivity than that observed for the Overman rearrangement of trichloroacetimidate 24.

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Scheme 4 Syntheses of compounds 28, 31, and 2 from compound 23

Also from 2,3:5,6-di-O-isopropylidene-d-mannofuranose, the Lin group reported a concise and efficient synthesis of d-ribo-phytosphingosine (2), which employed an eight-step conventional manipulation in 57% overall yield using Wittig olefination and azide nucleophilic replacement as the key reactions (Scheme [4]).[20]


# 2.1.2

Chirality from d-Lyxose

A short and very efficient route for synthesis of d-ribo-phytosphingosine from d-lyxose was reported by the Lin group in 2003 (Scheme [5]).[21] In this work, d-ribo-phytosphingosine (2) was prepared from d-lyxose in six steps in 28% overall yield using Wittig olefination and substitution by tetramethylguanidinium azide (TMGA) as crucial steps. A similar synthesis of d-ribo-phytosphingosine was also achieved by the Lin group, in which both Wittig olefination and olefin cross-metathesis (CM) were adequately employed to extend the carbon chain.[22] The latter strategy seemed less concise than the former; however, it afforded rapid access to phytosphingosine derivatives.

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Scheme 5 Synthesis of d-ribo-phytosphingosine (2) from d-lyxose

# 2.1.3

Chirality from d-Xylose

Panza and co-workers reported the synthesis of 3-O-benzoylazidosphingosine 22 from 3,5-O-isopropylidene-d-xylofuranose using Peterson olefination and allylic displacement by a Grignard reagent as key steps (Scheme [6]).[23] The deficiency of the strategy was its low trans selectivity (E/Z 2:1) in the allylic displacement. However, from the inexpensive starting material d-xylose, the Kocienski group have reported a twelve-step synthesis of d-erythro-sphingosine (1) utilizing a 1,2-metalate rearrangement as the key step. In addition, Brook rearrangement and substitution by diphenylphosphoryl azide (DPPA) via Mitsunobu reaction were equally indispensable in this approach.[24] This synthesis provided a novel strategy for the effective construction of the trans double bond.

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Scheme 6 Synthesis of d-erythro-sphingosine (1) and its derivative 22 from d-xylose and its derivative

# 2.1.4

Chirality from d-Glucose and Its Derivatives

In 2012, Rao and co-workers accomplished the synthesis of the acetyl derivative of l g-lyxo-phytosphingosine 48 commencing with known 1,2:5,6-di-O-isopropylidene-d-glucofuranose 45 derived from d-glucose (Scheme [7]).[25] In this work, Z-selective Wittig olefination was employed as the key step to elongate the carbon chain, although control of the stereochemistry of the double bond was unnecessary because of its subsequent hydrogenation. As shown in Scheme [7], the important intermediate 49 was also prepared from 1,2:5,6-di-O-isopropylidene-d-glucofuranose (45) in four steps. The synthesis of d-erythro-sphingosine (1) was achieved by Dhavale and co-workers via E-selective olefin cross-metathesis between 49 and a long-chain terminal alkene and subsequent deprotection, oxidative cleavage, and reduction in 65.4% overall yield.[26] The direct synthesis of 16 from d-glucosamine hydrochloride via the d-allosamine derivative 50 as key intermediate was reported by Hung and co-workers in 2002.[27] Similar to the synthesis of the acetyl derivative of l g-lyxo-phytosphingosine 48, a Z-selective Wittig olefination was employed for the chain elongation to synthesize tetraacetyl-d-ribo-phytosphingosine 16. In addition, amino–azido conversion and a highly regio­selective benzoylation were also essential to this work.

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Scheme 7 Syntheses of compounds 1, 16 and 48 from d-glucose and its derivatives

Bundle and co-workers utilized selective iodination, a zinc-mediated reductive ring-opening reaction, and olefin cross-metathesis as crucial steps to prepare tetraacetyl-d-xylo- and d-ribo-phytosphingosines 10 and 16 starting from the methyl β-glycosides of d-GlcNAc 53a and d-AllNAc 53b, respectively (Scheme [8]).[28] The highlight of the synthesis was the excellent E/Z selectivity (E/Z 19:1 for 55a, only E for 55b) achieved for the olefin cross-metathesis, and olefin cross-metathesis could also be applied in the synthesis of phytosphingosine derivatives with varying alkyl chain lengths.

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Scheme 8 Syntheses of tetraacetyl-d-xylo- and d-ribo-phytosphingosines 10 and 16 starting from the methyl β-glycosides of d-GlcNAc 53a and d-AllNAc 53b, respectively

# 2.1.5

Chirality from d-Galactose and Its Derivatives

Duclos Jr. reported a concise and conventional synthesis of d-erythro-sphingosine (1) starting from d-galactose in seven steps in 2001 (Scheme [9]),[29a] which was based on the previous protocol adopted by Schmidt and Zimmermann in 1988.[30] The key step was Wittig olefination between 1,3-O-benzylidene-d-threose (56) and n-tetradecyl ylide to form, exclusively, a trans double bond. The same protocol was utilized by Demchenko and co-workers to synthesize l-erythro-sphingosine (ent-1) from 1,3-O-benzylidene-l-threose (prepared from l-arabitol) in 2010.[29b] In 2000, Schmidt also utilized 1,3-O-benzylidene-d-threose to prepare d-ribo-azidophytosphingosine 59.[31] Highlights of this work involved stereoselective addition of 1,3-O-benzylidene-d-threose by n-tetradecylmagnesium chloride to produce the chiral hydroxyl exclusively at C4, and regioselective mesylation at C2.

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Scheme 9 Syntheses of d-erythro-sphingosine (1) and d-ribo-azidophytosphingosine 59 from 1,3-O-benzylidene-d-threose

In 2008, the Ye group accomplished a facile synthesis of tetraacetyl-d-ribo-phytosphingosine 16 over five steps in 74% overall yield from 3,4,6-tri-O-benzyl-d-galactal (Scheme [10]).[32] The highlights of this synthesis included a high-yielding Wittig olefination of lactol 60 and a one-step azide substitution via the Mitsunobu reaction.

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Scheme 10 Synthesis of tetraacetyl-d-ribo-phytosphingosine 16 from 3,4,6-tri-O-benzyl-d-galactal

# 2.1.6

Chirality from d-Ribose

In 2013, Martinková and co-workers[33] accomplished the syntheses of tetraacetyl-d-arabino-phytosphingosine 66 and tetraacetyl-d-ribo-phytosphingosine 16 starting from d-ribose on the basis of the same procedures as described for preparation of their enantiomers in 2011 (Scheme [11]).[34] The key step involved aza-Claisen rearrangement of allylic thiocyanate 64 to afford rearranged products 65a and 65b in an approximate ratio of 3:1 in 50% yield, these were further used to synthesize compounds 66 and 16, respectively. Unlike this protocol, Sutherland and co-workers employed the Overman rearrangement of allylic trichloroacetimidate to install the chiral amino group of compound 70a as a single diastereomer in satisfactory yield (72%) (Scheme [12]).[35] The other two stereogenic centers of phytosphingosines were also derived from d-ribose. Thus, a new access to d-ribo-phytosphingosine (2) was achieved using an Overman rearrangement, a trans-selective cross-metathesis reaction, and a stereoselective reduction of the unsaturated ketone by way of a Corey–Bakshi–Shibata (CBS) reduction as key steps. l-arabino-Phytosphingosine (ent-3) was prepared from 69b according to the same procedure as described for 2.

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Scheme 11 Syntheses of tetraacetyl-d-arabino-phytosphingosine 66 and tetraacetyl-d-ribo-phytosphingosine 16 from d-ribose
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Scheme 12 Synthesis of d-ribo-phytosphingosine (2) from d-ribose

# 2.1.7

Chirality from d-Fructose

In 2011, a new methodology for the synthesis of d-ribo-phytosphingosine (2) and l-arabino-phytosphingosine (77) from d-fructose was developed by Perali and co-workers (Scheme [13]).[36] In this synthesis, the zinc-mediated fragmentation of 71 was used as a key step to give the corresponding ketone. Interestingly, subsequent reduction by NaBH4 yielded 72b, with 72a as the major product (72a/72b = 7:3) through reduction by LiAlH(O t Bu)3. Both 72a and 72b were subjected to crucial olefin cross-metathesis for chain extension, azido substitution, and other simple conversions to successfully afford 2. Note, the reason for the retention of configuration at the C2 position from 74b to 2 was that substitution of 74b by NaN3 underwent an SN1-type substitution. To invert this configuration, a Mitsunobu reaction was carried out, and thus l-arabino-phytosphingosine (77) was obtained from compound 75.

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Scheme 13 Syntheses of d-ribo-phytosphingosine (2) and l-arabino-phytosphingosine (77) starting from d-fructose

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# 2.2

Chirality from Serine and Its Derivatives

2.2.1

Chirality from Serine Ester

In 2002, the Chuang group presented a short and efficient route for the synthesis of all four stereoisomers of sphingosine from serine (Scheme [14]).[37] The authors employed a Horner–Wadsworth–Emmons olefination to form the trans double bond in high yield. Treatment of 3-ketosphingosine derivative 78 with NaBH4 in the presence of CeCl3·7H2O afforded the syn reduction product, further manipulation of which gave l-threo-sphingosine (79) and its acetyl derivative 80. However, the reduction of the deprotection product of 78 by Zn(BH4)2 gave the anti reduction product, which was subjected to further conversion to give d-erythro-sphingosine (1) and its acetyl derivative 18. According to the same procedure, l-erythro-sphingosine and d-threo-sphingosine were easily prepared from d-serine methyl ester hydrochloride. A similar stereoselective reduction protocol was also employed by the Katsumura and ­Bittman groups to synthesize d-erythro-sphingosine (1) from l-serine or N-Boc-l-serine methyl ester.[38] Olefin cross-metathesis and elimination of sulfoxide from an intermediate were respectively utilized to construct the trans double bond.

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Scheme 14 Syntheses of compound 1, 18, 79 and 80 from l-serine methyl ester hydrochloride

Liebeskind and Yang reported a concise and very efficient synthesis of d-erythro-sphingosine (1) from N-Boc-l-serine over six steps in 72% overall yield in 2007 (Scheme [15]).[39] In this work, new methodology for cross-coupling between thiol ester 81 and vinylboronic acid was developed to construct the classic alkenyl ketone intermediate 82, which was further subjected to stereoselective reduction to give the target compound 1.

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Scheme 15 Synthesis of d-erythro-sphingosine (1) from N-Boc-l-serine

An efficient, stereocontrolled synthetic method for the preparation of d-xylo-phytosphingosine (4) and d-arabino-phytosphingosine (3) was reported by Ham and co-workers in 2012 starting from l-serine methyl ester via chiral 1,3-oxazine intermediates (Scheme [16]).[40] The crucial reactions involved stereoselective intramolecular oxazine formation catalyzed by palladium(0) and cross-metathesis for chain elongation. Notably, both 85a and 85b could be separately obtained as major products by changing the reaction temperature; 85a ultimately gave d-xylo-phytosphingosine (4), and 85b gave d-arabino-phytosphingosine (3) in the same manner.

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Scheme 16 Syntheses of d-xylo- (4) and d-arabino-phytosphingosine (3) from l-serine methyl ester

# 2.2.2

Chirality from Garner’s Aldehyde

In 2002, Murakami and Furusawa[41a] achieved efficient and highly diastereoselective syntheses of N-Boc-d-erythro-sphingosine 88a and N-Boc-l-threo-sphingosine 88b using the addition of alk-1-enyl nucleophiles to Garner’s aldehyde as a pivotal step (Scheme [17]). Notably, the addition of alk-1-enylzirconocene chloride to Garner’s aldehyde in the presence of ZnBr2 gave the anti-isomer; conversely, addition of alk-1-enyl(ethyl)zinc to Garner’s aldehyde afforded the syn-isomer. An alternative synthesis of intermediate 87a was reported by Arenz and co-workers through the addition of vinylmagnesium bromide to Garner’s aldehyde and by subsequent cross-metathesis reaction in 37% yield.[41b] A similar addition of alk-1-enyl nucleophile to ­Garner’s aldehyde to prepare d-erythro-sphingosine was also employed in 2014 by Ferjančić and co-workers, who used an alkenylchromium(III) reagent instead; however, lower diastereoselectivity (7:1) and yield (46%) were achieved compared to the protocol of Murakami and Furusawa.[42a] In contrast, Montgomery and Sa-ei took advantage of a nickel-catalyzed reductive coupling of Garner’s aldehyde with a silylalkyne to give compound 87c in good yield (78%) and satisfactory diastereoselectivity (>95:5); the latter was easily converted into 87a over two steps.[42b]

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Scheme 17 Syntheses of N-Boc-d-erythro-sphingosine 88a, N-Boc-l-threo-sphingosine 88b, and d-erythro-sphingosine (1) from Garner’s aldehyde

A short and convenient synthesis of d-erythro-sphingosine (1) was accomplished in 2013 by the Cárdennas group, over four steps in 33% overall yield from Garner’s acid (Scheme [18]).[43] Key steps included an efficient addition of a terminal alkyne to benzotriazole esters 89a and 89b and a stereoselective reduction.

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Scheme 18 Synthesis of d-erythro-sphingosine (1) from Garner’s acid

The Kim group employed OsO4-catalyzed dihydroxylation reactions of (Z)-allylic amines derived from a Z-selective Wittig olefination of Garner’s aldehyde to set the stereochemistry at C3 and C4.[44] As shown in Scheme [19], dihydroxylation of (Z)-allylic amine 91 with an N-Boc group gave syn-selective isomer 92a; however, formation of the N,N-diBoc derivative of 91 followed by dihydroxylation gave anti-isomer 92b. This can be explained by severe 1,2-allylic strain between the N,N-diBoc groups and the vinylic hydrogen atom. The stereocontrol in the dihydroxylation of (Z)-allylic amines was better than Sharpless dihydroxylation to some degree, upon which syntheses of both tetraacetyl derivatives of d-ribo-phytosphingosine 16 and l-arabino-phytosphingosine 93 were achieved.

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Scheme 19 Syntheses of both tetraacetyl derivatives of d-ribo-phytosphingosine 16 and l-arabino-phytosphingosine 93 from Garner’s aldehyde

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# 2.3

Chirality from d-ribo-Phytosphingosine

Since d-ribo-phytosphingosine is easily accessible from a yeast fermentation process, it has been used as a chiral template to prepare sphingosine and other phytosphingosines. Several syntheses of d-erythro-sphingosine from d-ribo-phytosphingosine have been achieved in a concise manner (Scheme [20]).[45] The common point of these syntheses is the selective protection of the C1-hydroxy and C2-amine groups followed by elimination of a cyclic sulfate intermediate (95, 97, and 99) to exclusively construct the trans olefin. Aside from elimination of a cyclic sulfate intermediate, epoxide 101 [46] and alcohol 104 [47] were also eliminated to give a trans olefin. In a different approach from the above protocols, van Boom[48] employed the stereoselective transformation of 102 into the corresponding (Z)-enol triflate 103 followed by regiospecific reduction to install the trans double bond. Among these syntheses, Overkleeft and co-workers[45c] provided a short synthetic route with the highest overall yield (67%) to date.

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Scheme 20 Synthesis of d-erythro-sphingosine (1) from d-ribo-phytosphingosine (2) through different routes

d-ribo-Phytosphingosine works as an important chiral template, as it was also used to prepare other phytosphingosines. Kim and co-workers reported high-yielding and concise syntheses of d-arabino- (3), d-lyxo- (5), and d-xylo- (4) phytosphingosines from d-ribo-phytosphingosine (2) (Scheme [21]).[49] The configurational inversion of the C4 center of 2, which afforded d-lyxo-phytosphingosine (5), was carried out via cyclic sulfate intermediate 105 or oxonium ion intermediate 108 attacked by a nucleophile. On the other hand, inversion of C3 and C4 led to d-arabino-phytosphingosine (3), and inversion of C3 gave d-xylo-phytosphingosine (4). Both were carried out via a mesylate intermediate attacked by a nucleophile (H2O).

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Scheme 21 Syntheses of d-arabino-phytosphingosine (3), d-lyxo-phytosphingosine (5), and d-xylo-phytosphingosine (4) from d-ribo-phytosphingosine (2)

# 2.4

Chirality from d-Tartaric Acid and Its Diester

In 2004, Basu and Rai[50] employed two contiguous hydroxyl groups of d-tartrate diester as a chiral template to accomplish the synthesis of protected d-erythro-azidosphingosine 113 (Scheme [22]). The highlight of this work was the selective benzoylation of azidotriol 111 and exclusive formation of the trans olefin via cross-metathesis. However, compound 113 was obtained in low yield (36%). Another formal synthesis of d-erythro-azidosphingosine from d-tartrate diester was reported by Panza and co-workers[51] in 2002, who took advantage of the Julia olefination of sulfone 115 to construct the trans olefin in an E/Z ratio of 5:1 in 53% yield.

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Scheme 22 Syntheses of compound 113 and 116 from d-tartrate diester

Bittman and Lu[52] achieved the synthesis of l g-lyxo-phytosphingosine (5) by employing the diastereoselective addition of a Grignard reagent to aldehyde 117, derived from d-tartaric acid, to give a mixture of 118a and 118b in a ratio of 9:1 (Scheme [23]). Another crucial step was conversion of the diol into azide 119 by Mitsunobu reaction. According to the same synthetic procedure for 5, d-ribo-phytosphingosine (2) was also prepared from compound 118b, which itself was obtained from 118a via Mitsunobu reaction.

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Scheme 23 Syntheses of l g-lyxo-phytosphingosine (5) and d-ribo-phytosphingosine (2) from d-tartaric acid

Shiozaki and Nakamura[53] provided an alternative access to d-erythro-sphingosine (1) and l g-lyxo-phytosphingosine (5) using chiral β-lactam 120 derived from d-tartrate diester as a chiral template (Scheme [24]). The ring opening of β-lactam 120 by 4-tolyl tetradecyl sulfone, followed by elimination, afforded key ketone 122 in a satisfactory yield (93%). Isomerization of ketone 122 to enol triflate 123, then reductive elimination and deprotection, yielded N-Boc-d-erythro-sphingosine 88a in moderate yield. On the other hand, diastereoselective reduction of 122 by LiEt3BH gave protected aminotriol 124 in good yield and stereoselectivity, leading to 5 in excellent yield (96%).

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Scheme 24 Syntheses of l g-lyxo-phytosphingosine (5) and N-Boc-d-erythro-sphingosine 88a from d-tartrate diester

# 2.5

Chirality from Other Chiral Precursors

Concise, efficient, and enantiodivergent syntheses of d-erythro-sphingosine (1) and l-erythro-sphingosine (ent-1) were achieved by Merino and co-workers in 2006.[54] As shown in Scheme [25], the key steps involved a stereocontrolled Mannich-type reaction between d-glyceraldehyde nitrone 125 and a 2-(silyloxy)silylketene acetal, as well as a trans-selective Wittig olefination. Interestingly, the ­Mannich-type reaction conducted in the presence of SnCl2, Yb(OTf)3, or Zn(OTf)2 gave 126a as the major product; in contrast, the use of SnCl4 as a promoter gave compound 126b as the major product. l-erythro-Sphingosine (ent-1) was prepared according to the same procedure as described for 1 from 126a.

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Scheme 25 Syntheses of d-erythro-sphingosine (1) and l-erythro-sphingosine (ent-1) from d-glyceraldehyde nitrone

The Rao group[55a] reported a stereoselective synthesis of N,O,O,O-tetraacetyl-d-lyxo-phytosphingosine (ent-48) over ten steps from a known intermediate[55b] derived from l-ascorbic acid. The crucial reactions involved Grignard addition on epoxide 129 and stereoselective addition of chiral imine 131 by vinylmagnesium bromide (Scheme [26]).

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Scheme 26 Synthesis of N,O,O,O-tetraacetyl d-lyxo-phytosphingosine (ent-48) from l-ascorbic acid

Aside from the above chiral precursors, Sarabia and co-authors employed l-methionine as a chiral template to synthesize cyclic sulfonium salt 133, which was successfully applied in the synthesis of d-erythro-sphingosine (1) and d-ribo-phytosphingosine (2) over seven or thirteen steps, respectively (Scheme [27]).[56] The highlights of this work were the stereoselective formation of an epoxide amide 134, 135, or 138 and the regioselective epoxide-opening reaction by an amino or azido nucleophile at C2.

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Scheme 27 Syntheses of d-erythro-sphingosine (1) and d-ribo-phytosphingosine (2) from l-methionine

#
# 3

Chiral Auxiliaries

3.1

Chiral Sulfur Auxiliaries

A high-yielding and facile synthesis of d-erythro-sphingosine (1) was achieved by Castillón and co-workers in 2008 in 42% overall isolated yield in six steps (Scheme [28]).[57] The success of this work was in employing an asymmetric sulfur ylide reaction between the sulfonium salt 139 and the aldehyde 140 to construct the epoxide 141 with the desired configuration. In addition, E-selective cross-metathesis for chain elongation and a regio- and stereoselective intramolecular epoxide-opening reaction to form oxazolidinone 142 were also crucial for the synthesis.

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Scheme 28 Synthesis of d-erythro-sphingosine (1) from a chiral sulfur auxiliary; EtP2 = Et-N=P(NMe2)2(N=P(NMe2)3)

Aside from the above sulfur auxiliary, Wei and co-workers[58a] introduced a novel chiral N-tert-butanesulfinamide 145 for cross-coupling with bulky long-chain aliphatic aldehydes 144 derived from d-glutamic acid to stereoselectively install the amino functionality at C2 and the hydroxyl functionality at C3. In this way, an efficient synthesis of d-ribo-phytosphingosine (2) was accomplished (Scheme [29]) in five steps and 27% overall yield from known compound 143.[58b]

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Scheme 29 Synthesis of d-ribo-phytosphingosine (2) from d-glutamic acid

# 3.2

Chiral N-Containing Auxiliaries

Similar to the protocol of Wei and co-workers,[58a] chiral iminoglycinate 147 was used by Bundle and co-workers[59] to condense with an aldehyde to build the amino group at C2 and the hydroxyl group at C3; the iminoglycinate 147 was condensed with acrolein to give truncated sphingosine 149 in a concise manner. On the other hand, iminoglycinate 147 was condensed with an R- or S-configured hydroxy aldehyde to give d-ribo-phytosphingosine (2) or l-lyxo-phytosphingosine (5), respectively, in more than 45% overall yield in both cases (Scheme [30]).

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Scheme 30 Syntheses of truncated sphingosine 149, d-ribo-phytosphingosine (2) and l-lyxo-phytosphingosine (5) from chiral iminoglycinate 147

Ishikawa and Disadee[60] reported a synthesis of d-erythro-sphingosine (1) using chirality transfer from chiral guanidinium ylide 151 to give 3-alk-1-enylaziridine-2-carboxylates 153a and 153b for the construction of the chiral amino alcohol unit in 1 (Scheme [31]). In this work, chiral guanidinium ylide 151 reacted with α,β-unsaturated aldehyde 152 to give a mixture of cis/trans-3-pentadec-1-enylaziridine-2-carboxylates 153a and 153b (ca. 1:1) without diastereoselectivity. However, both diastereomers can be further converted into compound 1 via oxazolidinone intermediates 155a or 155b. Notably, the cis-aziridine-2-carboxylate 153b was subjected to a ring-opening reaction followed by an SN2-type substitution in order to invert the hydroxyl configuration at the C3 position.

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Scheme 31 Synthesis of d-erythro-sphingosine (1) from chiral guanidinium ylide 151

#
# 4

Asymmetric Reactions

A number of syntheses of sphingosines and phytosphingosines have been accomplished from achiral starting materials using asymmetric reactions to set the chiral hydroxyl groups, or chiral amino groups, or both. An extensive literature search revealed they could be classified into five categories: Sharpless dihydroxylation, Sharpless epoxidation and Shi epoxidation, catalytic asymmetric aldol reactions, Sharpless kinetic resolution, and asymmetric aminohydroxylation and amination.

4.1

Sharpless Dihydroxylation Reaction

In 2015, Sudalai and co-workers[61] reported an enantio­selective synthesis of tetraacetyl-d-ribo-phytosphingosine 16 starting from hexadecan-1-ol taking advantage of an l-proline-catalyzed α-aminooxylation, a Horner–Wadsworth–Emmons olefination for the E-selective olefin, and a Sharpless asymmetric dihydroxylation as the pivotal reactions (Scheme [32]). In addition, regioselective sulfonylation of diol 157 at the α-position of the ester was also necessary for the synthesis. Prior to this synthesis, Bittman and co-workers[62] employed a similar synthesis of 16 via the common intermediate 156 from hexadec-1-ene. The Sharpless dihydroxylation reaction was utilized twice by Bittman to install the three contiguous stereogenic centers in 16. A minor difference from the strategy of Sudalai and co-workers was that the synthesis of α-azido ester 158 was carried out through regioselective α-azidation of the cyclic sulfate of dihydroxyl ester 157. This strategy was also successfully employed by Bittman to synthesize d-erythro-sphingosine (1) commencing with pentadec-1-yne.[63]

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Scheme 32 Syntheses of tetraacetyl-d-ribo-phytosphingosine 16 and d-erythro-sphingosine (1)

Castillón, Matheu and co-workers reported the efficient and high-yielding syntheses of d-erythro-sphingosine (1) and d-ribo-phytosphingosine (2) via common cyclic sulfate intermediate 164 over seven steps in 44% and 53% overall yield, respectively (Scheme [33]).[64] The desired chirality was obtained by dynamic kinetic resolution of butene epoxide and sequential Sharpless hydroxylation. Elimination from 164 gave 1; on the other hand, ring opening by BzOH/CsCO3 further provided 2.

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Scheme 33 Syntheses of d-erythro-sphingosine (1) and d-ribo-phytosphingosine (2) from butadiene monoepoxide

# 4.2

Sharpless Epoxidation and Shi Epoxidation Reactions

Somfai and co-workers[65] reported the synthesis of benzyl-protected d-erythro-sphingosine 168 utilizing a Shi epoxidation and the regioselective opening reactions of vinyl epoxide 166 and vinylaziridine 167 in the allylic position as crucial steps (Scheme [34]). Notably, no regioselectivity was observed during the Shi epoxidation of diene 165, and a mixture of 2,3-epoxy olefin 166 and 4,5-epoxy olefin was formed. They also described an improved strategy for the synthesis of d-erythro-sphingosine (1) from penta-1,4-dien-3-ol over five steps in 51% overall yield. The highlights of the strategy were a Sharpless epoxidation, the subsequent Payne rearrangement, a regioselective ring-opening reaction, and the E-selective cross-metathesis for chain elongation.

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Scheme 34 Syntheses of Bn-protected d-erythro-sphingosine 168 and d-erythro-sphingosine (1)

Righi and co-workers[66] described an efficient approach to the synthesis of d-erythro-sphingosine (1) and d-lyxo-phytosphingosine (5) based on Wittig olefination and stereoselective addition of the common aldehyde 174, respectively (Scheme [35]). The aldehyde 174 was derived from (Z)-4-(benzyloxy)but-2-en-1-ol through a Sharpless epoxidation and a subsequent regioselective ring-opening reaction as the key steps. Notably, Wittig olefination of 174 did not give the trans olefin with satisfactory selectivity (E/Z = 7:3).

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Scheme 35 Syntheses of d-erythro-sphingosine (1) and d-lyxo-phytosphingosine (5) from (Z)-4-(benzyloxy)but-2-en-1-ol

# 4.3

Asymmetric Aldol Reaction

In 2006, the Enders group[67a] reported concise and straightforward syntheses of d-arabino-phytosphingosine (3) and protected l-ribo-phytosphingosine 181 via the common ketone 178 in six steps with 49% and 38% overall yields, respectively (Scheme [36]). The stereogenic centers at C3 and C4 were introduced by the (S)-proline-catalyzed aldol reaction of 2,2-dimethyl-1,3-dioxan-5-one and pentadecanal with excellent diastereo- and enantiomeric excess (>99% and 95% respectively). The configuration at the C2 position was installed by stereoselective reduction of the ketone. To improve the diastereoselectivity during the reduction, the hydroxyl group at C4 was protected as its silyl ether. On the other hand, the aldol reaction was catalyzed by (R)-proline to give ent-178 in 59% yield and good diastereo- and enantioselectivity (>99%, 95% respectively); ent-178 was further converted into d-ribo-azidophytosphingosine 182.[67b]

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Scheme 36 Syntheses of d-arabino-phytosphingosine (3), protected l-ribo-phytosphingosine 181, and d-ribo-azidophytosphingosine 182 from 2,2-dimethyl-1,3-dioxan-5-one

Kobayashi and co-workers[68] reported an efficient synthesis of l-erythro-sphingosine (ent-1) from (E)-4-(tert-butyldiphenylsiloxy)but-2-enal over seven steps in 16% overall yield. The key steps involved a chiral zirconium complex catalyzed aldol reaction of aldehyde by silicon enolate 183 and the cross-coupling of an acetate with a Grignard reagent (Scheme [37]). Notably, the aldol reaction successfully introduced the desired chiral hydroxyl and amino groups of 184 in high yield (95%) and moderate stereoselectivity ­(anti/syn = 8:2).

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Scheme 37 Synthesis of l-erythro-sphingosine (ent-1) from (E)-4-(tert-butyldiphenylsiloxy)but-2-enal

# 4.4

Sharpless Kinetic Resolution

Barua and co-workers[69] reported a facile and flexible synthesis of d-ribo-phytosphingosine (2) from achiral trans-cinnamaldehyde over thirteen steps in 15.6% overall yield (Scheme [38]). The stereocenters at C3 and C4 were obtained by Sharpless kinetic resolution of homoallylic alcohol 186, while the stereocenter at C2 was obtained by a regioselective epoxide-opening reaction. Another highlight of the synthesis was the oxidative cleavage of the phenyl ring by NaIO4/RuCl3·H2O.

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Scheme 38 Synthesis of d-ribo-phytosphingosine (2) from trans-cinnamaldehyde

Like Barua and co-workers, Kumar and co-workers[70] also employed a Sharpless kinetic resolution to introduce the stereocenter at C3 in the syntheses of N-Boc-l-threo-sphingosine 88b and tetraacetyl-d-arabino-phytosphingosine 66 (Scheme [39]). The syn stereochemistry of the amino group at C2 was installed by a tethered aminohydroxylation in moderate yield (65–66%). Both compounds 88b and 66 were synthesized over eight steps in 8% and 11% overall yields, respectively.

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Scheme 39 Syntheses of N-Boc-l-threo-sphingosine 88b and tetraacetyl-d-arabino-phytosphingosine 66 from pentadec-1-yne and pentadecan-1-ol, respectively

# 4.5

Asymmetric Aminohydroxylation and Amination

In 2008, the Davies group reported divergent and efficient syntheses of N,O,O-triacetyl-d-erythro-sphingosine (18), tetraacetyl-d-lyxo-phytosphingosine ent-48, and tetraacetyl-d-ribo-phytosphingosine 16 from the common intermediate oxazolidine aldehyde 197 (Scheme [40]).[71] Wittig olefination of oxazolidine aldehyde 197 gave compound 18 with very good E-selectivity (E/Z = 94:6) by quenching the reaction with methanol. On the other hand, addition of 197 by a Grignard reagent gave a 90:10 mixture of alcohols 199a and 199b, which were further converted into compounds ent-48 and 16, respectively. The highlight of the protocol was the highly diastereoselective conjugate addition of unsaturated ester 195 followed by in situ enolate oxidation with (camphorsulfonyl)oxaziridine (CSO).

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Scheme 40 Syntheses of N,O,O-triacetyl-d-erythro-sphingosine (18), tetraacetyl-d-lyxo-phytosphingosine ent-48, and tetraacetyl-d-ribo-phytosphingosine 16 from cis-but-2-ene-1,4-diol

Like the Davies group, Han and co-workers[72] employed an asymmetric aminohydroxylation reaction of α,β-unsaturated ester 200 to introduce the stereocenters at C2 and C3 with high regioselectivity (>20:1) and enantioselectivity (>99%). The stereochemistry at C4 was set by the highly ­diastereoselective (>10:1) addition of aldehyde 201 by a Grignard reagent. Thus, N-acetyl-l-xylo-phytosphingosine (202) was obtained over five steps in 22% overall yield (Scheme [41]). An alternative synthesis of 202 could also be achieved through a two-step manipulation of 203. On the other hand, the stereochemical interconversion of the hydroxyl group at C4 was carried out by treatment of 203 with MsCl/Et3N via oxazine intermediate 204, which was further converted into N-acetyl-l-arabino-phytosphingosine (206).

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Scheme 41 Syntheses of N-acetyl-l-xylo-phytosphingosine (202) and N-acetyl-l-arabino-phytosphingosine (206) from α,β-unsaturated ester 200

In 2013, Helmchen[73] reported a novel synthesis of d-erythro-sphingosine (1) in nine linear steps and 5% overall yield (Scheme [42]). The highlight of the scheme was a chiral-iridium-catalyzed allylic amination to give the chiral carbamate 207 in high yield (87%) and excellent enantioselectivity (98%). The other pivotal reactions involved ring-closing metathesis and stereoselective epoxidation–regioselective elimination.

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Scheme 42 Synthesis of d-erythro-sphingosine (1) from N,N-diacylamine

#
# 5

Conclusions

Sphingosines and phytosphingosines have attracted increased attention from synthetic chemists in recent years because of their various physiological activities. Two key points of these syntheses are the introduction of stereochemistry and extension of a long aliphatic chain. Chiral pool approaches, chiral auxiliaries, and asymmetric reactions are the three main strategies to set stereogenic centers. Among them, the chiral pool strategy, which is concise and efficient with short synthetic routes, high yields, and high optical purities, usually seem to be more acceptable. Meanwhile, the use of chiral auxiliaries and asymmetric reactions provide candidate strategies to synthesize sphingosines and phytosphingosines from various starting materials, and could be more flexible and straightforward in some cases. The protocol for chain elongation often employs Wittig olefination, olefin cross-metathesis, or nucleophilic addition by a Grignard reagent. Protocols with higher yields, shorter synthetic routes, higher enantioselectivities, higher diastereoselectivies, and better versatility for the syntheses of the library of sphingosines and phytosphingosines are still expected in future.


#
#

Acknowledgment

This work was supported by NSFC (No. 21602082), Natural Science Foundation of Hubei Province of China (No. 2015CFB333) for Youth Fund and Hubei Chenguang Talented Youth Development Foundation, China.

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Scheme 1 Structures of sphingosine and phytosphingosines. Note: subscript s = serine, g = glyceraldehyde
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Scheme 2 Synthesis of N,O,O,O-tetraacetyl-d-xylo-phytosphingosine (10) from d-mannitol triacetonide (6)
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Scheme 3 Syntheses of tetraacetyl-d-ribo-phytosphingosine 16, triacetyl-d-erythro-sphingosine 18, and 3-O-benzoylazidosphingosine 22 from cyclohexylidene-protected d-glyceraldehyde 12
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Scheme 4 Syntheses of compounds 28, 31, and 2 from compound 23
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Scheme 5 Synthesis of d-ribo-phytosphingosine (2) from d-lyxose
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Scheme 6 Synthesis of d-erythro-sphingosine (1) and its derivative 22 from d-xylose and its derivative
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Scheme 7 Syntheses of compounds 1, 16 and 48 from d-glucose and its derivatives
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Scheme 8 Syntheses of tetraacetyl-d-xylo- and d-ribo-phytosphingosines 10 and 16 starting from the methyl β-glycosides of d-GlcNAc 53a and d-AllNAc 53b, respectively
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Scheme 9 Syntheses of d-erythro-sphingosine (1) and d-ribo-azidophytosphingosine 59 from 1,3-O-benzylidene-d-threose
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Scheme 10 Synthesis of tetraacetyl-d-ribo-phytosphingosine 16 from 3,4,6-tri-O-benzyl-d-galactal
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Scheme 11 Syntheses of tetraacetyl-d-arabino-phytosphingosine 66 and tetraacetyl-d-ribo-phytosphingosine 16 from d-ribose
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Scheme 12 Synthesis of d-ribo-phytosphingosine (2) from d-ribose
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Scheme 13 Syntheses of d-ribo-phytosphingosine (2) and l-arabino-phytosphingosine (77) starting from d-fructose
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Scheme 14 Syntheses of compound 1, 18, 79 and 80 from l-serine methyl ester hydrochloride
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Scheme 15 Synthesis of d-erythro-sphingosine (1) from N-Boc-l-serine
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Scheme 16 Syntheses of d-xylo- (4) and d-arabino-phytosphingosine (3) from l-serine methyl ester
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Scheme 17 Syntheses of N-Boc-d-erythro-sphingosine 88a, N-Boc-l-threo-sphingosine 88b, and d-erythro-sphingosine (1) from Garner’s aldehyde
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Scheme 18 Synthesis of d-erythro-sphingosine (1) from Garner’s acid
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Scheme 19 Syntheses of both tetraacetyl derivatives of d-ribo-phytosphingosine 16 and l-arabino-phytosphingosine 93 from Garner’s aldehyde
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Scheme 20 Synthesis of d-erythro-sphingosine (1) from d-ribo-phytosphingosine (2) through different routes
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Scheme 21 Syntheses of d-arabino-phytosphingosine (3), d-lyxo-phytosphingosine (5), and d-xylo-phytosphingosine (4) from d-ribo-phytosphingosine (2)
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Scheme 22 Syntheses of compound 113 and 116 from d-tartrate diester
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Scheme 23 Syntheses of l g-lyxo-phytosphingosine (5) and d-ribo-phytosphingosine (2) from d-tartaric acid
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Scheme 24 Syntheses of l g-lyxo-phytosphingosine (5) and N-Boc-d-erythro-sphingosine 88a from d-tartrate diester
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Scheme 25 Syntheses of d-erythro-sphingosine (1) and l-erythro-sphingosine (ent-1) from d-glyceraldehyde nitrone
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Scheme 26 Synthesis of N,O,O,O-tetraacetyl d-lyxo-phytosphingosine (ent-48) from l-ascorbic acid
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Scheme 27 Syntheses of d-erythro-sphingosine (1) and d-ribo-phytosphingosine (2) from l-methionine
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Scheme 28 Synthesis of d-erythro-sphingosine (1) from a chiral sulfur auxiliary; EtP2 = Et-N=P(NMe2)2(N=P(NMe2)3)
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Scheme 29 Synthesis of d-ribo-phytosphingosine (2) from d-glutamic acid
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Scheme 30 Syntheses of truncated sphingosine 149, d-ribo-phytosphingosine (2) and l-lyxo-phytosphingosine (5) from chiral iminoglycinate 147
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Scheme 31 Synthesis of d-erythro-sphingosine (1) from chiral guanidinium ylide 151
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Scheme 32 Syntheses of tetraacetyl-d-ribo-phytosphingosine 16 and d-erythro-sphingosine (1)
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Scheme 33 Syntheses of d-erythro-sphingosine (1) and d-ribo-phytosphingosine (2) from butadiene monoepoxide
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Scheme 34 Syntheses of Bn-protected d-erythro-sphingosine 168 and d-erythro-sphingosine (1)
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Scheme 35 Syntheses of d-erythro-sphingosine (1) and d-lyxo-phytosphingosine (5) from (Z)-4-(benzyloxy)but-2-en-1-ol
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Scheme 36 Syntheses of d-arabino-phytosphingosine (3), protected l-ribo-phytosphingosine 181, and d-ribo-azidophytosphingosine 182 from 2,2-dimethyl-1,3-dioxan-5-one
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Scheme 37 Synthesis of l-erythro-sphingosine (ent-1) from (E)-4-(tert-butyldiphenylsiloxy)but-2-enal
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Scheme 38 Synthesis of d-ribo-phytosphingosine (2) from trans-cinnamaldehyde
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Scheme 39 Syntheses of N-Boc-l-threo-sphingosine 88b and tetraacetyl-d-arabino-phytosphingosine 66 from pentadec-1-yne and pentadecan-1-ol, respectively
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Scheme 40 Syntheses of N,O,O-triacetyl-d-erythro-sphingosine (18), tetraacetyl-d-lyxo-phytosphingosine ent-48, and tetraacetyl-d-ribo-phytosphingosine 16 from cis-but-2-ene-1,4-diol
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Scheme 41 Syntheses of N-acetyl-l-xylo-phytosphingosine (202) and N-acetyl-l-arabino-phytosphingosine (206) from α,β-unsaturated ester 200
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Scheme 42 Synthesis of d-erythro-sphingosine (1) from N,N-diacylamine