Synthesis of jaspine B regioisomers through palladium-catalyzed stereoselective tetrahydrofuran formation: Insight into the ligand recognition of sphingosine kinases

Accepted Manuscript Synthesis of jaspine B regioisomers through palladium-catalyzed stereoselective tetrahydrofuran formation: Insight into the ligand recognition of sphingosine kinases Takashi Miyagawa, Shinsuke Inuki, Maho Honda, Shinya Nakamura, Isao Nakanishi, Nobutaka Fujii, Shinya Oishi, Hiroaki Ohno PII:

S0040-4020(18)30186-8

DOI:

10.1016/j.tet.2018.02.042

Reference:

TET 29313

To appear in:

Tetrahedron

Received Date: 12 January 2018 Revised Date:

16 February 2018

Accepted Date: 17 February 2018

Please cite this article as: Miyagawa T, Inuki S, Honda M, Nakamura S, Nakanishi I, Fujii N, Oishi S, Ohno H, Synthesis of jaspine B regioisomers through palladium-catalyzed stereoselective tetrahydrofuran formation: Insight into the ligand recognition of sphingosine kinases, Tetrahedron (2018), doi: 10.1016/j.tet.2018.02.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Synthesis of jaspine B regioisomers through palladium-catalyzed stereoselective tetrahydrofuran formation: insight into the ligand recognition of sphingosine kinases

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Takashi Miyagawaa, Shinsuke Inukia, Maho Hondaa, Shinya Nakamurab, Isao Nakanishib, Nobutaka Fujiia, Shinya Oishia, Hiroaki Ohnoa a Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan b Faculty of Pharmacy, Department of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, HigashiOsaka, Osaka 577-8502, Japan

ACCEPTED MANUSCRIPT

Tetrahedron journal homepage: www.elsevier.com

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Synthesis of jaspine B regioisomers through palladium-catalyzed stereoselective tetrahydrofuran formation: insight into the ligand recognition of sphingosine kinases Takashi Miyagawaa, Shinsuke Inukia, Maho Hondaa, Shinya Nakamurab, Isao Nakanishib, Nobutaka Fujiia, Shinya Oishia, Hiroaki Ohnoa, ∗ b

Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan Faculty of Pharmacy, Department of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan

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ABSTRACT

Article history: Received Received in revised form Accepted Available online

We recently reported a structure-activity relationship study of 4-epi-jaspine B derivatives toward sphingosine kinase (SphK) and identified selective inhibitors of two SphK isoforms. In this study, we designed and synthesized jaspine B regioisomers on the basis of palladium-catalyzed tetrahydrofuran formation and late-stage cross metathesis reactions to investigate the influence of the substitution position of functional groups on SphK inhibition. Evaluation of the jaspine B regioisomers SphK inhibitory activities revealed that several of these compounds exhibited comparable SphK1/2 inhibitory potency to that of 4-epi-jaspine B.

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ARTICLE INFO

2009 Elsevier Ltd. All rights reserved.

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Keywords: Palladium Sphingosine kinase Kinase inhibitor Jaspine B Structure–activity relationship

——— ∗ Corresponding author. Tel.: +81-75-753-4571; fax: +81-75-753-4570; e-mail: [email protected]

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Tetrahedron

H N OH H N ACCEPTED MANUSCRIPT

1. Introduction

2

O

C 14H 29

jaspine B

O

C 14H 29

4-epi-jaspine B

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Figure 1. Structures of jaspine B derivatives.

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Sphingosine kinases (SphKs)1,2 catalyze phosphorylation of sphingosine to control the generation of sphingosine 1-phosphate (S1P).3 S1P is a small signaling molecule that plays a pivotal role in regulating various physiological processes, including lymphocyte trafficking and angiogenesis. S1P signaling is involved in multiple disorders such as cancer,4,5 and inflammatory6 or auto-immune diseases.7,8 SphKs have two isoforms, SphK1 and SphK2, which catalyze the same biochemical reaction and show different subcellular localization patterns: SphK1 is located mainly in the cytosol,1 whereas SphK2 appears primarily in the nucleus.1 In terms of their relation to disorders including cancers, an increase in cellular SphK1 levels can enhance cell survival, proliferation and migration. For example, overexpression of SphK1 is observed in a wide range of human solid tumors and hematologic malignancies.9 In addition, this upregulated expression was reported to be involved in the severity of malignancy.9 In contrast to SphK1, information describing the correlation between SphK2 and disease states is sparse. Several SphK2 inhibitors show anti-cancer and antiinflammatory activities,10,11 suggesting that SphK2 can be considered as a potential therapeutic target.10,12,13 Therefore, SphKs have recently garnered attention as therapeutic targets and several SphK inhibitors have been developed.14

OH

2

Our group has focused on a naturally occurring sphingosine analog, jaspine B, which inhibits SphKs.15-17 Jaspine B consists of a functionalized tetrahydrofuran ring and a lipid chain moiety (Figure 1). Among a number of total syntheses18-22 reported, our synthesis of jaspine B derivatives features a divergent strategy. Our stereodivergent route and the second-generation route including late-stage cross-metathesis afforded all the stereoisomers of jaspine B and lipid-chain modified analogues,16 which facilitated our structure-activity relationship (SAR) studies.23-25

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Our previous SAR study revealed that 4-epi-jaspine B exhibited the highest SphK inhibitory activity among the eight stereoisomers (Figure 1).16 We also conducted SAR studies focusing on the lipid chain moiety and demonstrated that modifications to the lipid chain had a significant effect on their inhibitory activities and isoform selectivities.26 Docking simulation on jaspine B and all its stereoisomers based on the Xray crystal structure of the SphK1-sphingosine complex27 predicted that one of the key interactions between jaspine B analogues and SphK1 was an electrostatic interaction involving the amino or hydroxy group and Asp81/Asp178/Leu268 residues of SphK1 (Figure 2a,b). Furthermore, we found that methylation of the C3-hydroxy group of 4-epi-jaspine B enhanced SphK1 binding selectivity. Given these findings, we sought to investigate the influence of the arrangement of these functional groups on the THF ring to this electrostatic interaction, which should provide insights into ligand recognition of SphKs and lead to the identification of novel potent SphK inhibitors.

In this study, we designed two novel jaspine B analogues, (3S,4S)- and (3R,4R)-regioisomers (1, 2) that contain the amino and hydroxy groups at C-3 and C-4 positions, respectively, on the THF ring (Figure 2c). For evaluation of a methyl group on the C3 or C-4 functional groups, several methylated analogues were also synthesized. Furthermore, we designed regioisomers with a lipid chain including a m-phenylene tether or cyclohexyl ether group, because these modifications improve SphK2 selectivity or inhibitory activity, respectively.26

Figure 2. (a) Docking model of 4-epi-jaspine B with SphK1. The amino acid residues of the binding pocket are shown. (b) Predicted electrostatic interaction between 4-epi-jaspine B and SphK1. (c) Design of jaspine B analogues.

2. Results and discussion Our synthetic strategy for the jaspine B regioisomer 1 is outlined in Scheme 1. The amino alcohol 4 could be prepared from D-mannitol through allylcyanate rearrangement developed by Ichikawa et al.28 using carbamate 3. The pivotal step toward the synthesis of regioisomer 1 was the construction of its tetrahydrofuran core structure having three contiguous stereogenic centers. We expected that palladium-catalyzed cyclization of 4 would provide the desired tetrahydrofuran core through formation of a π-allyl palladium intermediate followed by nucleophilic attack by the primary hydroxy group.29 The challenges in this cyclization are: (1) regioselective tetrahydrofuran ring formation in the presence of multiple nucleophiles (primary/secondary hydroxy and carbamate groups); and (2) control of stereoselectivity at the C-2 position. Although several groups have reported related palladium-catalyzed THF ring formation reactions,19,30-33 only a few examples for this type of reaction with the substrate including three nucleophilic functional groups have been reported.32 The C-2 alkyl side chain could be introduced easily to the expected cyclization product 5

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using the olefin cross-metathesis reaction,34-36 leading to the MANUSCRIPT Et3N and DMAP, and the removal of the acetonide group ACCEPTED jaspine B regioisomer 1. provided the cyclization precursor 4.

Scheme 1. Strategy for the synthesis of jaspine B regioisomer 1

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The synthesis started with silyl protection of the primary hydroxy group of diol 6, easily prepared from D-mannitol following a literature procedure (Scheme 2).37 The resulting silyl ether 7 was converted to carbamate 3 by successive treatment with trichloroacetyl isocyanate and K2CO3/MeOH. The rearrangement reaction of 3 smoothly underwent with TFAA, and subsequent treatment with t-BuOH and n-BuLi gave Boc protected amine 8 in 84% yield.28,38 The cleavage of the silyl ether with TBAF, acetylation of the hydroxy group with Ac2O,

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Scheme 2. Synthesis of cyclization precursor 4

temp (°C)

recovery (%)

5 (%)a

5a:5bb

55

-

79

84:16

55

50

trace

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2.5

55

-

84

85:15

(S,S)-DACH-phenyl Trost ligand (18)

2.0

55

-

82

69:31

5

(R,R)-DACH-phenyl Trost ligand (18)

3.0

55

-

85

97: 3

6

(R,R)-DACH-naphthyl Trost ligand (18)

55 to 88

<86c

trace

-

55

-

89

98: 2

ligand (mol %)

1

PPh3 (36)

2

P(o-tolyl)3 (36)

3

dppf (18)

4

time (h)

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Table 1. Palladium-catalyzed tetrahydrofuran ring formation

(R,R)-DACH-phenyl Trost ligand (12) b

1

2.5 14

11 2.5

c

Combined isolated yields. Determined by H NMR. Containing small amounts of impurities.

We next investigated the palladium-catalyzed tetrahydrofuran ring formation reaction of the amino alcohol 4 (Table 1). Treatment of 4 with 3 mol % Pd2(dba)3·CHCl3 and 36 mol % PPh3 as a ligand in THF, gave the desired isomer 5 in 79% yield as an 84:16 diastereomixture (entry 1).19 The undesired cyclization initiated by the secondary hydroxy or carbamate group was not observed. Whereas changing the ligand from PPh3 to the more bulky ligand, P(o-tolyl)3, gave trace amounts of 5 (entry 2), the use of the bidentate ligand, dppf, yielded almost the same result as PPh3 (entry 3). This substrate-controlled stereoselectivity can be explained by a counteranion-directed trans-2-vinyl-4-hydroxy-THF ring formation.39,40 We next screened the Trost-type chiral ligands for improvement of

stereoselectivity by combining the catalyst control.41 While loading the (S,S)-DACH-phenyl Trost ligand decreased diastereoselectivity to 69:31 (entry 4), the (R,R)-DACH-phenyl Trost ligand significantly increased diastereoselectivity to 97:3 (entry 5). The use of the more bulky naphthyl ligand was not effective (entry 6). The reaction on a 500 mg scale was carried out under the conditions where the Trost ligand was reduced to 12 mol % (entry 7) and gave the desired product 5a in a satisfactory yield (89%) and selectivity (98:2). Next, we focused on the synthesis of the (3S,4S)-regioisomer series (Scheme 3). The conversion of 5a into jaspine B regioisomer 1 was performed according to our diversity-oriented

4

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NHBoc

NHBoc

5a

NaH, MeI THF, rt MeO

TFA, CH2Cl2 0 °C, quant

72%

C14H29

13 (R = Boc) 14 (R = H)

1) 17 or 18 HG II (10 mol %) CH2Cl2, reflux

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C7H15 O ( )8 17

18

NMe2

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4-epijaspine B

C14H29

OH

NH2

1

C14H29

NH2

OH

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C14H29

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OMe

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C14H29

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C14H29

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C14H2

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SphK2

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1.0

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NH2

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1.5

NH2

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3.6

2.7

9

NH2

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O ( )10

20(43%)

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O

HO

5a 2) Pd/C, H2, MeOH, rt 3) TFA, CH2Cl2, 0 °C

O

C14H29

Compound

C14H2

HO

NHMe O

NH2

formalin HCO2H 90 °C

LiAlH4 THF, reflux

97%

HO

NHR O

HO

C14H29 CH2Cl2 O 0 °C 12 89%

2) Pd/C, H2 MeOH, rt 54% (2 steps)

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synthesis of jaspine B derivatives. Thus, ACCEPTED the olefin cross- MANUSCRIPT metathesis reaction of 5a and tetradec-1-ene 11 in the presence of the Hoveyda–Grubbs second generation catalyst and subsequent hydrogenation allowed the required alkyl group to be introduced at the C-2 position to afford the Boc protected tetrahydrofuran 12. The removal of the Boc group of 12 with TFA provided the desired jaspine B regioisomer 1. We also synthesized the methylated derivatives 14–16. The treatment of 12 with NaH and MeI followed by the removal of the Boc group provided the methyl ether 14. The LiAlH4-reduction of 12 and dimethylation of 1 furnished an N-methylamine derivative 15 and N,N-dimethyl derivative 16, respectively. Next, we synthesized side chainmodified derivatives 19 and 20 containing a m-phenylene tether (expecting enhanced SphK2 selectivity) and cyclohexylmethyl ether (expecting increased SphK inhibitory activities), respectively, on the basis of our previous SAR study.26 The crossmetathesis reaction of 5a with the styrene derivative 17 followed Scheme 4. Synthesis of regioisomer 2 Abbreviation: HG II = Hoveyda-Grubbs II catalyst by hydrogenation and deprotection produced the desired mphenylene derivative 19 in 40% yield (3 steps). A similar protocol using the known alkene 18 bearing a cyclohexylmethyl Table 2. SphK inhibitory activities of jaspine B derivatives ether moiety as a metathesis partner gave 20 in 43% yield (3 steps).

2b

C14H29

IC50 values are the concentration for 50% inhibition of the sphingosine phosphorylation by SphK1 or SphK2. b(3R,4R)-regioisomer.

Next, we synthesized jaspine B regioisomer 2 from the known 4-epi-jaspine B derivative 2117 by switching the amino and hydroxy groups through aziridine formation (Scheme 4). After mesylation of 21 with MsCl and Et3N, the resulting 22 was successfully converted to aziridine 23 by treatment with Cs2CO3 in DMF. The regioselective ring-opening reaction of 23 with trichloroacetic acid followed by hydrolysis with aqueous NaOH furnished the tetrahydrofuran 25 with the desired regio- and stereoselectivities. The introduction of the alkyl chain was conducted in the same manner as described above (Scheme 3) to provide jaspine B regioisomer 2.

With the requisite jaspine B derivatives in hand, we evaluated their SphK1 and SphK2 inhibitory activities using the off-chip mobility shift assay (Table 2). 4-epi-Jaspine B was employed as a reference SphK inhibitor. Although the regioisomer 1 exhibited comparable inhibitory activity to SphK2 with that of 4-epijaspine B, its SphK1 inhibitory activity was observed to have decreased by nearly 10-fold. Introduction of a methyl group(s) to the hydroxy (14) and amino groups (15 and 16) had a significant influence on SphK inhibitory potency: the methyl ether 14 and N,N-dimethylamine 16 showed significantly lower inhibitory activities toward both SphK1 and SphK2 (IC50 = >30 µM) than that of 4-epi-jaspine B. However, the N-methyl derivative 15 exhibited selectivity for SphK1 over SphK2 [IC50 (SphK1) = 14 µM; IC50 (SphK2) = >30 µM)], which is consistent with our previous SAR studies where the 4-epi-jaspine B derivative

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Scheme 3. Syntheses of (3S,4S)-regioisomer derivatives Abbreviation: HG II = Hoveyda-Grubbs II catalyst

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CHCl3); IR (neat cm−1): 3462 (OH), 1H-NMR (500 MHz, CDCl3) containing a methylated C-3 functional groupACCEPTED (methoxy group) MANUSCRIPT showed moderate SphK1 selectivity. Modification of the δ: 1.07 (s, 9H), 1.37 (s, 3H), 1.41 (s, 3H), 2.63 (s, 1H), 3.54-3.55 methylene tether with m-phenylene group (19) did not lead to any (m, 2H), 3.68 (dd, J = 10.0, 3.7 Hz, 1H), 4.04-4.07 (m, 1H), 4.25improvements in the inhibitory activities. In contrast, the 4.28 (m, 1H), 4.46-4.49 (m, 1H), 5.71-5.79 (m, 2H), 7.37-7.46 cyclohexyl group-containing derivative 20 displayed an (m, 6H), 7.65 (d, J = 7.4 Hz, 4H); 13C-NMR (125 MHz, CDCl3) δ: 19.2, 25.9, 26.6, 26.8 (3C), 67.6, 69.4, 71.9, 76.4, 109.3, 127.8 inhibitory activity comparable to that of 4-epi-jaspine B. Notably, jaspine B regioisomer 2 had approximately equal SphK1/2 (2C), 129.4 (2C), 129.9 (2C), 132.2 (2C), 132.9, 133.0, 135.49 inhibitory when compared with that of 4-epi-jaspine B. Taken (2C), 135.53 (2C); HRMS (ESI-TOF) calcd for C25H34NaO4Si: [M + Na]+, 449.2119, found: 449.2117. together, switching the functional groups at the C-3 and C-4 positions of the THF ring did not significantly affect their inhibitory activities, indicating that the binding pocket including Asp81, Asp178 and Leu268 could flexibly recognize the 4.3. (S,E)-1-[(tert-Butyldiphenylsilyl)oxy]-4-[(S)-2,2-dimethylfunctional groups on the THF ring of jaspine B derivatives 1,3-dioxolan-4-yl]but-3-en-2-yl carbamate (3). through electrostatic interactions. To a stirred solution of 7 (6.74 g, 15.8 mmol) in CH2Cl2 (158 mL) under argon was added Cl3CCONCO (2.25 mL, 19.0 mmol) dropwise at 0 °C. After the mixture was stirred for 80 min at this 3. Conclusion temperature, the solvent was removed under reduced pressure. The residue was dissolved in MeOH (66 mL) and water (47 mL), In this study, we synthesized the regioisomers of jaspine B and K2CO3 (6.55 g, 47.4 mmol) was added at 0 °C. After being derivatives. The synthesis of (3S,4S)-derivatives relied on stirred for 1 h at this temperature, the mixture was warmed up to palladium-catalyzed stereoselective tetrahydrofuran ring room temperature and stirred overnight. The solvent was formation by the aid of a Trost ligand. The jaspine B regioisomer removed under reduced pressure. The residue was dissolved in 2 was prepared efficiently by the aziridine formation reaction of CHCl3, washed with water, and dried over Na2SO4. The filtrate the known amino alcohol derivative followed by the regio- and was concentrated under reduced pressure to give an oily residue, stereoselective ring-opening reaction with trichloroacetic acid. which was purified by flash chromatography over silica gel with Some of the resulting jaspine B regioisomers showed inhibitory n-hexane–EtOAc (1:1) to give 3 as a colorless oil (6.70 g, 90% activities of SphKs comparable to that of 4-epi-jaspine B, yield): [α]26D +7.35 (c 1.04, CHCl3); IR (neat cm−1): 3360 (NH), suggesting flexible recognition of polar lipid head groups by 1730 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 1.05 (s, 9H), 1.38 (s, SphK. Our results thus provide insights into the structural basis 3H), 1.41 (s, 3H), 3.55 (dd, J = 7.7, 7.7 Hz, 1H), 3.71-3.74 (m, of SphK recognition and may guide the design of new potent 2H), 4.06-4.07 (m, 1H), 4.48 (ddd, J = 6.9, 6.9, 6.9 Hz, 1H), 4.59 ligands. (s, 2H), 5.32 (ddd, J = 5.5, 5.5, 5.5 Hz, 1H), 5.73 (dd, J = 15.8, 6.6 Hz, 1H), 5.80 (dd, J = 15.8, 5.4 Hz, 1H), 7.38-7.43 (m, 6H), 7.65 (d, J = 8.0 Hz, 4H); 13C-NMR (125 MHz, CDCl3) δ: 19.2, 4. Experimental section 25.8, 26.6, 26.7 (3C), 65.3, 69.3, 74.4, 76.3, 109.4, 127.7 (2C), 4.1. General methods. 129.4 (2C), 129.7 (2C), 130.5 (2C), 133.27, 133.30, 135.58 (2C), 135.60 (2C), 155.9; HRMS (ESI-TOF) calcd for C26H35NNaO5Si: 1 H NMR spectra were recorded using a JEOL ECA-500 [M + Na]+, 492.2177, found: 492.2186. spectrometer at 500 MHz frequency. Chemical shifts are reported in δ (ppm) relative to Me4Si (in CDCl3) as internal standard. 13C NMR spectra were recorded using a JEOL AL-500 and 4.4. tert-Butyl {(R,E)-4-[(tert-butyldiphenylsilyl)oxy]-1-[(S)-2,2referenced to the residual CHCl3 signal. IR spectra were obtained dimethyl-1,3-dioxolan-4-yl]but-2-en-1-yl}carbamate (8). on a JASCO FT/IR-4100 spectrometer. Exact mass (HRMS) spectra were recorded on a Shimadzu LC-ESI-IT-TOF-MS To a stirred solution of 3 (3.38 g, 7.20 mmol) in THF were added equipment (ESI). Optical rotations were measured with a JASCO Et3N (5.99 mL, 43.2 mmol) and TFAA (2.03 mL, 14.4 mmol) at P-1020 polarimeter. For column chromatography, Wakogel C−20 °C under argon. After being stirred for 30 min at this 300E (Wako) or Chromatorex NH-DM1020 (Fuji Silysia) was temperature, the mixture was slowly warmed to room employed. Known compounds 6,37 17,26 1826 and 2117 were temperature. In a separate flask, t-BuOH (6.84 mL, 72.0 mmol) prepared according to the literature. Compounds 11 is in THF was added n-BuLi (27.0 mL of a 1.6 M solution in commercially available, which was used without further hexane, 43.2 mmol) at 0 °C under argon. After being stirred for 5 purification. The purity of the compounds for bioassay was min, the mixture was warmed to room temperature and stirred for determined by HPLC analysis (>95%). 5 min. The resulting solution of t-BuOLi was cannulated to the reaction mixture at 0 °C and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was purified by flash chromatography over 4.2. (S,E)-1-[(tert-Butyldiphenylsilyl)oxy]-4-[(S)-2,2-dimethyl1,3-dioxolan-4-yl]but-3-en-2-ol (7). silica gel with n-hexane–EtOAc (9:1) to give 8 as a pale yellow oil (3.20 g, 84% yield): [α]26D –2.09 (c 0.519, CHCl3); IR (neat To a stirred solution of 6 (3.1 g, 16.5 mmol) and imidazole cm−1): 3350 (NH), 1716 (C=O); 1H-NMR (500 MHz, CDCl3) δ: (2.24 g, 32.9 mmol) in DMF (83 mL) was added TBDPSCl (4.7 1.05 (s, 9H), 1.35 (s, 3H), 1.44 (s, 3H), 1.45 (s, 9H), 3.70-3.71 (m, mL, 18.1 mmol) at room temperature under argon. After being 1H), 4.00 (dd, J = 8.3, 6.6 Hz, 1H), 4.12-4.14 (m, 1H), 4.21-4.21 stirred for 1.5 h at this temperature, the mixture was quenched by (m, 3H), 4.76 (s, 1H), 5.70 (dd, J = 15.5, 5.2 Hz, 1H), 5.77 (dt, J addition of saturated aqueous NH4Cl, and the whole was = 15.5, 4.0 Hz, 1H), 7.36-7.44 (m, 6H), 7.67 (d, J = 6.3 Hz, 4H); 13 extracted with EtOAc. The extract was washed with brine, and C-NMR (125 MHz, CDCl3) δ: 19.2, 25.1, 26.3, 26.8 (3C), 28.4 dried over Na2SO4. The filtrate was concentrated under reduced (3C), 52.6, 63.8, 66.3, 77.4, 79.6, 109.4, 127.6 (2C), 127.8 (2C), pressure to give an oily residue, which was purified by flash 129.6 (2C), 130.9 (2C), 133.58, 133.61, 135.5 (4C), 155.7; chromatography over silica gel with n-hexane–EtOAc (5:1) to HRMS (ESI-TOF) calcd for C30H43NNaO5Si: [M + Na]+, give 7 as a colorless oil (6.74 g, 96% yield): [α]27D –1.01 (c 0.499, 548.2803, found: 578.2803.

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Tetrahedron

4.8. tert-Butyl [(2S,3S,4S)-4-hydroxy-2-vinyltetrahydrofuran-3ACCEPTED MANUSCRIPT

Compound 5a: colorless oil; [α]27D +26.6 (c 1.18, CHCl3); IR (neat cm−1): 3328 (NH and OH), 1690 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 1.43 (s, 9H), 3.62 (m, 1H), 3.71 (dd, J = 10.3, 2.9 Hz, 1H), 3.89-3.90 (m, 1H), 4.17 (dd, J = 10.0, 5.4 Hz, 1H), 4.34 (m, 1H), 4.65-4.65 (m, 2H), 5.35 (d, J = 10.9 Hz, 1H), 5.47 (d, J = 17.2 Hz, 1H), 5.81-5.84 (m, 1H); 13C-NMR (CDCl3) δ: 28.3 (3C), 60.8, 73.0, 77.1, 78.8, 80.2, 118.3, 132.6, 156.0; HRMS (ESI-TOF) calcd for C11H19NNaO4: [M + Na]+, 252.1206, found: 252.1208. Compound 5b: colorless crystals; mp 91–92 °C; [α]27D +9.69 (c 0.778, CHCl3); IR (neat cm−1): 3318 (NH and OH), 1685 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 1.46 (s, 9H), 3.59-3.62 (m, 1H), 3.89 (dd, J = 9.7, 4.6 Hz, 1H), 3.96-3.99 (m, 2H), 4.094.10 (m, 1H), 4.34-4.35 (m, 1H), 4.68 (m, 1H), 5.27 (d, J = 10.3 Hz, 1H), 5.37 (d, J = 17.2 Hz, 1H), 5.91-5.98 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 28.3 (3C), 64.7, 73.1, 78.0, 80.7, 83.7, 118.7, 135.9, 156.9; HRMS (ESI-TOF) calcd for C11H19NNaO4: [M + Na]+, 252.1206, found: 252.1204.

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4.6. (R,E)-4-[(tert-Butoxycarbonyl)amino]-4-[(S)-2,2-dimethyl1,3-dioxolan-4-yl]but-2-en-1-yl acetate (10).

To a dry flask charged with Pd2(dba)3·CHCl3 (3.1 mg, 0.003 mmol) and (R,R)-DACH-phenyl Trost ligand (12.5 mg, 0.0180 mmol) was added THF (1.0 mL) at room temperature under argon. The purple solution was stirred for 1 h at this temperature, which was turned to orange. The resulting catalyst solution was added to a solution of 4 (29 mg, 0.11 mmol) in THF (1.0 mL). After the mixture was stirred for 3 h at 55 °C, the solvent was removed under reduced pressure. The residue was purified by flash chromatography over silica gel with n-hexane–EtOAc (2:1) to give a mixture of 5a and 5b (19.5 mg, 85% yield, 5a:5b = 97:3).

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To a stirred solution of 8 (3.20 g, 6.09 mmol) in THF (31.1 mL) was added TBAF (8.09 mL of a 1.0 M solution in THF, 8.09 mmol) at room temperature under argon. After being stirred for 1 h 40 min at this temperature, the mixture was quenched by addition of saturated aqueous NH4Cl, and the whole was extracted with EtOAc. The extract was washed with brine, and dried over Na2SO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (1:3) to give 9 as a white solid (1.20 g, 67% yield): mp 88–89 °C; [α]26D +15.0 (c 1.14, CHCl3); IR (neat cm−1): 3413 (NH and OH), 1701 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 1.34 (s, 3H), 1.45 (s, 12H), 1.86 (s, 1H), 3.72-3.74 (m, 1H), 4.03 (dd, J = 8.3, 6.6 Hz, 1H), 4.18-4.20 (m, 4H), 4.87 (m, 1H), 5.71 (dd, J = 15.5, 5.7 Hz, 1H), 5.86-5.87 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 24.9, 26.2, 28.3 (3C), 52.5, 62.8, 66.2, 77.3, 79.8, 109.5, 129.2, 131.1, 155.7; HRMS (ESI-TOF) calcd for C14H25NNaO5: [M + Na]+, 310.1625, found: 310.1626.

yl]carbamate (5a) and tert-butyl [(2R,3S,4S)-4-hydroxy-2vinyltetrahydrofuran-3-yl]carbamate (5b).

SC

4.5. tert-Butyl {(R,E)-1-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4hydroxybut-2-en-1-yl}carbamate (9).

EP

TE D

To a stirred solution of 9 (2.0 g, 6.96 mmol) and DMAP (255 mg, 2.09 mmol) in CH2Cl2 (70 mL) were added Et3N (2.89 mL, 20.9 mmol) and Ac2O (1.32 mL, 13.9 mmol) at room temperature under argon. After being stirred for 1.5 h at this temperature, the mixture was quenched by addition of saturated aqueous NaHCO3, and the whole was extracted with CH2Cl2. The extract was washed with brine, and dried over MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (3:1) to give 10 as a colorless oil (2.57 g, quant): [α]26D +11.4 (c 1.16, CHCl3); IR (neat cm−1): 1739 and 1712 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 1.35 (s, 3H), 1.45 (s, 12H), 2.07 (s, 3H), 3.72 (dd, J = 7.4, 7.4 Hz, 1H), 4.03 (dd, J = 7.4, 7.4 Hz, 1H), 4.21-4.25 (m, 2H), 4.57 (d, J = 5.2 Hz, 2H), 4.82 (m, 1H), 5.77-5.80 (m, 2H).13C-NMR (125 MHz, CDCl3) δ: 20.9, 24.9, 26.2, 28.3 (3C), 52.3, 64.2, 66.2, 77.1, 79.9, 109.5, 125.9, 132.3, 155.6, 170.7; HRMS (ESI-TOF) calcd for C16H27NNaO6: [M + Na]+, 352.1731, found: 352.1728.

AC C

4.7. (4R,5S,E)-4-[(tert-Butoxycarbonyl)amino]-5,6dihydroxyhex-2-en-1-yl acetate (4).

A solution of 10 (2.59 g, 6.96 mmol) in 80% aqueous AcOH (92 mL) was stirred for 24 h at room temperature. The solvent was removed under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (1:3) to give 4 as a colorless oil (2.17 g, quant): [α]27D +15.0 (c 1.02, CHCl3); IR (neat cm−1): 3387 (NH and OH), 1687 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 1.46 (s, 9H), 2.08 (s, 3H), 2.28 (d, J = 4.0 Hz, 1H), 2.81 (m, 1H), 3.55 (m, 1H), 3.593.65 (m, 1H), 3.81 (m, 1H), 4.38 (m, 1H), 4.59-4.60 (m, 2H), 4.88 (m, 1H), 5.80-5.83 (m, 2H); 13C-NMR (CDCl3) δ: 20.9, 28.3 (3C), 52.7, 63.3, 64.3, 73.5, 80.3, 126.1, 132.2, 156.5, 170.9; HRMS (ESI-TOF) calcd for C13H23NNaO6: [M + Na]+, 312.1418, found: 312.1418.

4.9. tert-Butyl [(2S,3S,4S)-4-hydroxy-2tetradecyltetrahydrofuran-3-yl]carbamate (12). To a stirred solution of 5a (199 mg, 0.868 mmol) in CH2Cl2 (17.4 mL) were added tetradec-1-ene (11) (2.2 mL, 8.68 mmol) and second generation Hoveyda–Grubbs catalyst (54.4 mg, 0.0868 mmol) at room temperature under argon. After being stirred for 2.5 h under reflux, the reaction mixture was filtered through a short NH2 silica gel column eluting with EtOAc. The solvent was removed under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (4:1) to give the E/Z mixture of corresponding metathesis product as a white solid. To a stirred solution of the above metathesis product in MeOH (28.9 mL) was added 10% Pd/C (92.4 mg, 0.0868 mmol) at room temperature, and the mixture was stirred overnight under H2. The mixture was filtered through a short pad of Celite. The filtrate was concentrated under reduced pressure to give a white solid, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (2:1) to give 12 as a white solid (188 mg, 54% yield): mp 75–76 °C; [α]27D +26.6 (c 1.04, CHCl3); IR (neat cm−1): 3383 (NH and OH), 1686 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 0.88 (t, J = 6.9 Hz, 3H), 1.26-1.30 (m, 24H), 1.42 (s, 9H), 1.48-1.49 (m, 1H), 1.58-1.61 (m, 1H), 3.13 (d, J = 2.9 Hz, 1H), 3.60 (dd, J = 10.0, 2.6 Hz, 1H), 3.85-3.87 (m, 1H), 3.984.01 (m, 1H), 4.12 (dd, J = 10.0, 5.4 Hz, 1H), 4.26-4.26 (m, 1H), 4.67 (d, J = 8.6 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ: 14.1, 22.7, 26.2, 28.3 (3C), 28.8, 29.3, 29.46, 29.55, 29.65 (3C), 29.68 (3C), 31.9, 60.3, 73.1, 77.4, 78.7, 80.0, 155.9; HRMS (ESI-TOF) calcd for C23H45NNaO4: [M + Na]+, 422.3241, found: 422.3232.

To a stirred solution of LiAlH4 (17.9 mg, 0.472 mmol) in THF ACCEPTED MANUSCRIPT

4.11. tert-Butyl [(2S,3S,4S)-4-methoxy-2tetradecyltetrahydrofuran-3-yl]carbamate (13).

4.14. (3S,4S,5S)-4-(Dimethylamino)-5-tetradecyltetrahydrofuran3-ol (16).

To a stirred solution of 12 (40.4 mg, 0.101 mmol) in THF (0.624 mL) under argon was added NaH (60% oil dispersion, 6.1 mg, 0.152 mmol) at 0 °C. After the mixture was stirred for 30 min at this temperature, MeI (94.4 µL, 1.52 mmol) was added to the reaction mixture, and the mixture was stirred for 12 h at room temperature. The mixture was quenched by addition of saturated aqueous NH4Cl, and the whole was extracted with Et2O and dried over Na2SO4. The filtrate was concentrated under reduced pressure to give a white solid, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (10:1) to give 13 as a white solid (29.9 mg, 72% yield): mp 42–43 °C; [α]27D +44.8 (c 0.869, CHCl3); IR (neat cm−1): 3358 (NH); 1HNMR (500 MHz, CDCl3) δ: 0.88 (t, J = 7.2 Hz, 3H), 1.26-1.30 (m, 24H), 1.38-1.41 (m, 1H), 1.45 (s, 9H), 1.55-1.57 (m, 1H), 3.44 (s, 3H), 3.59 (dd, J = 10.3, 2.3 Hz, 1H), 3.75-3.76 (m, 1H), 3.83-3.85 (m, 1H), 4.02 (dd, J = 8.9, 3.2 Hz, 1H), 4.10 (dd, J = 10.3, 5.7 Hz, 1H), 4.58 (d, J = 9.2 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ: 14.1, 22.7, 26.2, 28.3 (3C), 28.7, 29.3, 29.46, 29.54, 29.6 (3C), 29.7 (3C), 31.9, 56.0, 57.3, 71.6, 79.2, 79.7, 86.7, 155.3; HRMS (ESI-TOF) calcd for C24H47NNaO4: [M + Na]+, 436.3397, found: 436.3398.

To a stirred mixture of 1 (20.0 mg, 0.0668 mmol) and formaldehyde (30.0 µL of a 37% solution in water, 0.367 mmol) was added formic acid (25.0 µL, 0.668 mmol) at 0 °C. After being stirred for 40 h at 90 °C, the mixture was quenched by addition of 1 M NaOH (0.45 mL), and the whole was extracted with Et2O, and dried over Na2SO4. The filtrate was concentrated under reduced pressure to give a white solid, which was purified by flash chromatography over NH2 silica gel with n-hexane– EtOAc (2:1) to give 16 as a white solid (14.8 mg, 68% yield): mp 94–95 °C; [α]27D −7.66 (c 0.732, CHCl3); IR (neat cm−1): 3341 (OH); 1H-NMR (500 MHz, CDCl3) δ: 0.88 (t, J = 6.9 Hz, 3H), 1.25-1.35 (m, 24H), 1.49-1.57 (m, 3H), 2.31 (s, 6H), 2.69 (dd, J = 5.7, 3.4 Hz, 1H), 3.61 (dd, J = 10.3, 3.4 Hz, 1H), 3.97-3.99 (m, 1H), 4.18 (dd, J = 10.3, 6.9 Hz, 1H), 4.46-4.49 (m, 1H); 13CNMR (125 MHz, CDCl3) δ: 14.1, 22.7, 26.6, 28.3, 29.3, 29.62 (3C), 29.64, 29.67 (4C), 31.9, 44.1 (2C), 72.6, 74.2, 75.8, 81.4; HRMS (ESI-TOF) calcd for C20H42NO2: [M + H]+, 328.3210, found: 328.3208.

AC C

EP

TE D

M AN U

SC

RI PT

To a stirred solution of 12 (40.0 mg, 0.100 mmol) in CH2Cl2 (2.0 mL) was added TFA (2.0 mL) at 0 °C. After the mixture was stirred for 1.5 h at this temperature, the solvent was removed under reduced pressure. The residue was portioned between 1M NaOH (5.4 mL) and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (5 times). The combined organic layer was dried over Na2SO4. The filtrate was concentrated under reduced pressure to give 1 as a white solid (26.8 mg, 89% yield): mp 79– 80 °C; [α]27D +5.59 (c 0.779, CHCl3); IR (neat cm−1): 3389 (NH and OH); 1H-NMR (500 MHz, CDCl3) δ: 0.88 (t, J = 6.9 Hz, 3H), 1.26-1.34 (m, 24H), 1.45-1.51 (m, 2H), 1.61-1.68 (m, 3H), 3.12 (d, J = 3.4 Hz, 1H), 3.59 (dd, J = 10.0, 2.0 Hz, 1H), 3.91-3.94 (m, 1H), 4.16 (d, J = 5.2 Hz, 1H), 4.20 (dd, J = 10.3, 5.2 Hz, 1H); 13 C-NMR (125 MHz, CDCl3) δ: 14.1, 22.7, 26.5, 28.8, 29.3, 29.56, 29.58, 29.64 (3C), 29.7 (2C), 29.8, 31.9, 60.9, 73.3, 79.1, 80.4; HRMS (ESI-TOF) calcd for C18H37NO2: [M + H]+, 300.2897, found: 300.2897.

(0.236 mL) was added a solution of 12 (41.0 mg, 0.103 mmol) in THF (0.395 mL) at room temperature under argon. After being stirred for 28 h under reflux, the mixture was cooled to room temperature and quenched by addition of water (20 µL), 15% NaOH (20 µL), and water (60 µL) and the resulting suspension was stirred for 30 min. The suspension was filtered through a short pad of Celite, washed with hot EtOAc (1 mL). The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with CHCl3–MeOH–28% NH4OH (95:4:1) to give 15 as a white solid (31.2 mg, 97% yield): mp 92–93 °C; [α]28D +9.84 (c 1.03, CHCl3); IR (neat cm−1): 3341 (NH and OH); 1H-NMR (500 MHz, CDCl3) δ: 0.88 (t, J = 6.9 Hz, 3H), 1.27-1.31 (m, 24H), 1.48-1.60 (m, 3H), 1.90 (m, 2H), 2.49 (s, 3H), 2.86-2.87 (m, 1H), 3.61 (dd, J = 9.7, 2.3 Hz, 1H), 4.01-4.04 (m, 1H), 4.15 (dd, J = 9.7, 5.2 Hz, 1H), 4.30-4.31 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 14.1, 22.7, 26.6, 28.8, 29.3, 29.55, 29.57, 29.63 (2C), 29.65 (3C), 29.73, 31.9, 34.9, 69.3, 73.5, 75.1, 80.2; HRMS (ESI-TOF) calcd for C19H40NO2: [M + H]+, 314.3054, found: 314.3054.

4.10. (3S,4S,5S)-4-Amino-5-tetradecyltetrahydrofuran-3-ol (1).

4.12. (2S,3S,4S)-4-Methoxy-2-tetradecyltetrahydrofuran-3amine (14). By a procedure identical with that described for the preparation of 1, 13 (29.9 mg, 0.0693 mmol) was converted to 14 as a white solid (21.8 mg, quant): mp 99–100 °C; [α]28D +11.9 (c 0.634, CHCl3); 1H-NMR (500 MHz, CDCl3) δ: 0.88 (t, J = 6.9 Hz, 3H), 1.32-1.36 (m, 26H), 1.49-1.55 (m, 1H), 1.59-1.66 (m, 1H), 3.23 (d, J = 2.3 Hz, 1H), 3.37 (s, 3H), 3.64-3.66 (m, 2H), 3.783.81 (m, 1H), 4.15 (dd, J = 10.3, 5.2 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ: 14.1, 22.7, 26.5, 28.7, 29.3, 29.56, 29.64 (6C), 29.8, 31.9, 57.06, 57.10, 71.0, 80.5, 88.8; HRMS (ESI-TOF) calcd for C19H40NO2: [M + H]+, 314.3054, found: 314.3047.

4.13. (3S,4S,5S)-4-(Methylamino)-5-tetradecyltetrahydrofuran3-ol (15).

4.15. (3S,4S,5S)-4-Amino-5-(3-heptylphenethyl)tetrahydrofuran3-ol (19). To a stirred solution of 5a (100 mg, 0.436 mmol) in CH2Cl2 (8.7 mL) were added 17 (353 mg, 1.74 mmol) and second generation Hoveyda–Grubbs catalyst (27.3 mg, 0.0436 mmol) at room temperature under argon. After the mixture was stirred for 3 h under reflux, the solvent was removed under reduced pressure to give an oily residue, which was purified by flash chromatography over NH2 silica gel with n-hexane–EtOAc (3:1) to give the E/Z mixture of corresponding metathesis product as a colorless oil. To a stirred solution of the above metathesis product in MeOH (7.3 mL) was added 10% Pd/C (23.2 mg, 0.0218 mmol) at room temperature, and the mixture was stirred overnight under H2. The mixture was filtered through a short pad of Celite. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (2:1) to give an oily residue, a portion of which (40.8 mg, 0.101 mmol) was dissolved in CH2Cl2 (2 mL). To this solution was added TFA (2 mL) at 0 °C, and the mixture was stirred for 1 h at this temperature. The solvent was removed under reduced pressure. The residue was

8

Tetrahedron

TE D

4.17. (2S,3S,4R)-4-[(tert-Butoxycarbonyl)amino]-2vinyltetrahydrofuran-3-yl methanesulfonate (22).

M AN U

SC

RI PT

CHCl3); IR (neat cm−1): 1713 (C=O); 1H-NMR (500 MHz, portioned between 1M NaOH (5.5 mL) and CH2Cl2. The MANUSCRIPT ACCEPTED aqueous layer was extracted with CH2Cl2 (5 times). The CDCl3) δ: 1.47 (s, 9H), 3.01-3.02 (m, 1H), 3.12-3.13 (m, 1H), combined organic layer was dried over Na2SO4. The filtrate was 3.75 (d, J = 9.7 Hz, 1H), 4.13 (d, J = 10.3 Hz, 1H), 4.69 (d, J = concentrated under reduced pressure to give 19 as a colorless oil 5.7 Hz, 1H), 5.25 (d, J = 10.9 Hz, 1H), 5.36 (d, J = 17.2 Hz, 1H), (28.9 mg, 40% yield): [α]26D −1.45 (c 1.41, CHCl3); IR (neat 5.76-5.82 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 28.0 (3C), cm−1): 3355 (NH and OH); 1H-NMR (500 MHz, CDCl3) δ: 0.88 39.9, 42.7, 63.7, 75.6, 81.1, 117.1, 133.6, 158.5; HRMS (ESI(t, J = 6.9 Hz, 3H), 1.19-1.31 (m, 8H), 1.56-1.62 (m, 2H), 1.69 TOF) calcd for C11H17NNaO3: [M + Na]+, 234.1101; found: (br s, 3H), 1.78-1.85 (m, 1H), 1.90-1.98 (m, 1H), 2.57 (t, J = 7.7 234.1101. Hz, 2H), 2.63-2.66 (m, 1H), 2.79-2.85 (m, 1H), 3.10 (d, J = 2.9 Hz, 1H), 3.60 (dd, J = 10.3, 2.3 Hz, 1H), 3.96-3.98 (m, 1H), 4.15-4.15 (m, 1H), 4.21 (dd, J = 9.7, 5.2 Hz, 1H), 7.01-7.03 (m, 4.19. (3R,4S,5S)-4-[(tert-Butoxycarbonyl)amino]-53H), 7.19 (dd, J = 7.7, 7.7 Hz, 1H); 13C-NMR (125 MHz, CDCl3) vinyltetrahydrofuran-3-yl 2,2,2-trichloroacetate (24). δ: 14.1, 22.7, 29.2, 29.4, 30.8, 31.6, 31.8, 32.7, 35.9, 61.0, 73.2, To a stirred solution of 23 (413 mg, 1.95 mmol) in CH2Cl2 (13 79.1, 79.9, 125.6, 126.1, 128.3, 128.5, 141.6, 143.1; HRMS (ESI+ mL) was added Cl3CCO2H (1.60 g, 9.77 mmol) at room TOF) calcd for C19H31NO2: [M + H] , 306.2428, found: 306.2429. temperature. After being stirred for 3 h at this temperature, the mixture was quenched by addition of saturated aqueous NaHCO3, and the solution was washed with brine, and dried over MgSO4. 4.16. (3S,4S,5S)-4-Amino-5-[10The filtrate was concentrated under reduced pressure to give an (cyclohexylmethoxy)decyl]tetrahydrofuran-3-ol (20). oily residue, which was purified by flash chromatography over By a procedure identical with that described for the silica gel with n-hexane–EtOAc (5:1) to give 24 as a colorless oil preparation of 19, 5a was reacted with 18 followed by reduction (705 mg, 81% yield): [α]28D +22.4 (c 0.957, CHCl3); IR (neat and N-Boc deprotection to give 20 as a white solid (21.4 mg, cm−1): 3336 (NH), 1766 and 1702 (C=O); 1H-NMR (500 MHz, 27 43% yield): mp 128–129 °C; [α] D +5.05 (c 0.987, CHCl3); IR CDCl3) δ: 1.46 (s, 9H), 3.90-3.92 (m, 1H), 4.06 (d, J = 11.5 Hz, (neat cm−1): 3333 (NH and OH); 1H-NMR (500 MHz, CDCl3) δ: 1H), 4.22-4.24 (m, 2H), 4.87 (s, 1H), 5.27 (d, J = 10.3 Hz, 1H), 5.38 (d, J = 17.2 Hz, 2H), 5.91-5.97 (m, 1H); 13C-NMR (125 0.90 (qd, J = 12.0, 2.9 Hz, 2H), 1.11-1.33 (m, 16H), 1.42-1.76 (m, 14H), 3.12 (d, J = 3.4 Hz, 1H), 3.19 (d, J = 6.3 Hz, 2H), 3.37 (t, J MHz, CDCl3) δ: 28.2 (3C), 61.9, 71.1 (2C), 80.6, 83.7, 89.4, = 6.6 Hz, 2H), 3.59 (dd, J = 9.7, 1.7 Hz, 1H), 3.92-3.93 (m, 1H), 118.4, 134.8, 154.8, 161.5; HRMS (ESI-TOF) calcd for C13H18Cl3NNaO5: [M + Na]+, 396.0143; found: 396.0142. 4.17-4.20 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ: 25.9 (2C), 26.1, 26.5, 26.7, 28.8, 29.46, 29.49, 29.51, 29.54, 29.7, 29.8, 30.2 (2C), 38.0, 60.9, 71.1, 73.3, 76.8, 79.1, 80.4; HRMS (ESI-TOF) calcd for C21H42NO3: [M + H]+, 356.3159, found: 356.3158. 4.20. tert-Butyl [(2S,3R,4R)-4-hydroxy-2-vinyltetrahydrofuran-3yl]carbamate (25).

AC C

EP

To a stirred solution of 21 (924.8 mg, 4.03 mmol) in CH2Cl2 (20 mL) were added Et3N (2.24 mL, 16.1 mmol) and MsCl (0.624 mL, 8.07 mmol) at 0 °C under argon. After being stirred for 10 min at room temperature, the mixture was quenched by addition of saturated aqueous NH4Cl, and the solution was washed with water and brine, and dried over Na2SO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (2:1) to give 22 as a colorless oil (1.56 g, quant): [α]27D +8.41 (c 1.15, CHCl3); IR (neat cm−1): 3334 (NH), 1691 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 1.46 (s, 9H), 3.20 (s, 3H), 3.66 (dd, J = 9.5, 2.6 Hz, 1H), 4.25-4.30 (m, 2H), 4.55 (t, J = 5.4 Hz, 1H), 4.78 (s, 1H), 5.01 (dd, J = 4.0, 1.1 Hz, 1H), 5.37 (d, J = 10.3 Hz, 1H), 5.45 (dt, J = 17.2, 1.4 Hz, 1H), 5.87-5.94 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 28.3 (3C), 38.5, 57.8, 70.4, 80.7, 80.9, 85.2, 119.6, 131.3, 155.1; HRMS (ESI-TOF) calcd for C12H21NNaO6S: [M + Na]+, 330.0982; found: 330.0987.

4.18. tert-Butyl (1R,2S,5S)-2-vinyl-3-oxa-6azabicyclo[3.1.0]hexane-6-carboxylate (23). To a stirred solution of 22 (307 mg, 1.17 mmol) in DMF (23 mL) was added Cs2CO3 (1.15 g, 3.52 mmol). After being stirred for 22 h at 50 °C, the mixture was diluted with Et2O, and washed with water (4 times) and brine. The organic layer was dried over Na2SO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (10:1) to give 23 as a colorless oil (146.6 mg, 59% yield): [α]26D −25.7 (c 1.03,

To a stirred solution of 24 (669 mg, 1.50 mmol) in EtOH (15 mL) was added 3M NaOH (15 mL) at room temperature. After being stirred for 40 min at 90 °C, the mixture was extracted with CH2Cl2. The extract was washed with water and brine, and dried over MgSO4. The filtrate was concentrated under reduced pressure to give a white solid, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (2:1) to give 25 as a white solid (128 mg, 37% yield): mp 90–91 °C; [α]28D −7.69 (c 1.10, CHCl3); IR (neat cm−1): 3361 (NH and OH), 1679 (C=O); 1H-NMR (500 MHz, CDCl3) δ: 1.46 (s, 9H), 3.593.62 (m, 1H), 3.89 (dd, J = 9.7, 5.2 Hz, 1H), 3.96-3.99 (m, 2H), 4.09-4.11 (m, 1H), 4.34-4.35 (m, 1H), 4.67 (m, 1H), 5.27 (d, J = 10.3 Hz, 1H), 5.37 (d, J = 17.2 Hz, 1H), 5.91-5.98 (m, 1H); 13CNMR (125 MHz, CDCl3) δ: 28.3 (3C), 64.6, 73.1, 77.9, 80.7, 83.7, 118.5, 135.9, 156.8; HRMS (ESI-TOF) calcd for C11H19NNaO4: [M + Na]+, 252.1206; found: 252.1207.

4.21. (3R,4R,5S)-4-Amino-5-tetradecyltetrahydrofuran-3-ol (2). By a procedure identical with that described for the preparation of 19, 25 was reacted with tetradec-1-ene (11) followed by the reduction and the removal of N-Boc group to give 2 as a white solid (34.9 mg, 22% yield): mp 124–125 °C; [α]28D −11.6 (c 0.692, CHCl3); IR (neat cm−1): (NH and OH); 1HNMR (500 MHz, CDCl3) δ: 0.88 (t, J = 6.9 Hz, 3H), 1.26-1.30 (m, 24H), 1.47-1.49 (m, 2H), 1.63-1.65 (m, 3H), 2.97 (dd, J = 6.0, 3.7 Hz, 1H), 3.38-3.41 (m, 1H), 3.78 (dd, J = 10.0, 3.2 Hz, 1H), 3.95 (dd, J = 9.7, 4.6 Hz, 1H), 4.00-4.02 (m, 1H);13C-NMR (125 MHz, CDCl3) δ: 14.1, 22.7, 26.1, 29.3, 29.56, 29.58, 29.63 (2C), 29.66 (2C), 29.9, 31.9, 34.0, 62.6, 65.0, 72.7, 79.5, 86.2; HRMS (ESI-TOF) calcd for C18H38NO2: [M + H]+, 300.2897; found: 300.2896.

Inuki, S.; Fujii, N.; Oishi, S. Bioorg. Med. Chem. 2017, 25, ACCEPTED MANUSCRIPT

References and notes

8. 9. 10.

11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

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2. 3. 4. 5.

Plano, D.; Amin, S.; Sharma, A. K. J. Med. Chem 2014, 57, 5509. Santos, W. L.; Lynch, K. R. ACS Chem. Biol. 2015, 10, 225. Blaho, V. A.; Hla, T. J. Lipid Res. 2014, 55, 1596. Pyne, N. J.; Pyne, S. Nat. Rev. Cancer. 2010, 10, 489. Patmanathan, S. N.; Wang, W.; Yap, L. F.; Herr, D. R.; Paterson, I. C. Cell. Signal. 2017, 34, 66. Wollny, T.; Wątek, M.; Durnaś, B.; Niemirowicz, K.; Piktel, E.; Żendzian-Piotrowska, M.; Góźdź, S.; Bucki, R. Int. J. Mol. Sci. 2017, 18, 741. Brinkmann, V.; Billich, A.; Baumruker, T.; Heining, P.; Schmouder, R.; Francis, G.; Aradhye, S.; Burtin, P. Nat. Rev. Drug Discov. 2010, 9, 883. Nielsen, O. H.; Li, Y.; Johansson-Lindbom, B.; Coskun, M. Trends Mol. Med. 2017, 23, 362. Pitman, M. R.; Costabile, M.; Pitson, S. M. Cell. Signal. 2016, 28, 1349. French, K. J.; Zhuang, Y.; Maines, L. W.; Gao, P.; Wang, W.; Beljanski, V.; Upson, J. J.; Green, C. L.; Keller, S. N.; Smith, C. D. J. Pharmacol. Exp. Ther. 2010, 333, 129. Pyne, N. J.; Adams, D. R.; Pyne, S. Trends Pharmacol. Sci. 2017, 38, 581. Liu, K.; Guo, T. L.; Hait, N. C.; Allegood, J.; Parikh, H. I.; Xu, W.; Kellogg, G. E.; Grant, S.; Spiegel, S.; Zhang, S. PLoS One 2013, 8, e56471. Lim, K. G.; Sun, C.; Bittman, R.; Pyne, N. J.; Pyne, S. Cell. Signal. 2011, 23, 1590. Gao, Y.; Gao, F.; Chen, K.; Tian, M.-l.; Zhao, D.-l. Drug Des. Dev. Ther. 2015, 9, 3239. Yoshimitsu, Y.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2010, 75, 3843. Yoshimitsu, Y.; Oishi, S.; Miyagaki, J.; Inuki, S.; Ohno, H.; Fujii, N. Bioorg. Med. Chem. 2011, 19, 5402. Yoshimitsu, Y.; Miyagaki, J.; Oishi, S.; Fujii, N.; Ohno, H. Tetrahedron 2013, 69, 4211. Reddipalli, G.; Venkataiah, M.; Mishra, M. K.; Fadnavis, N. W. Tetrahedron: Asymmetry 2009, 20, 1802. Passiniemi, M.; Koskinen, A. M. P. Org. Biomol. Chem. 2011, 9, 1774. Rao, G. S.; Rao, B. V. Tetrahedron Lett. 2011, 52, 4861. Cruz-Gregorio, S.; Espinoza-Rojas, C.; Quintero, L.; Sartillo- Piscil, F. Tetrahedron Lett. 2011, 52, 6370. Martinková, M.; Mezeiová, E.; Gonda, J.; Jacková, D.; Pomikalová, K. 2014, 25, 750. Canals, D.; Mormeneo, D.; Fabriàs, G.; Llebaria, A.; Casas, J.; Delgado, A. Bioorg. Med. Chem. 2009, 17, 235. Jayachitra, G.; Sudhakar, N.; Anchoori, R. K.; Rao, B. V.; Roy, S.; Banerjee, R. Synthesis 2009, 2010, 115. Jeon, H.; Bae, H.; Baek, D. J.; Kwak, Y.-S.; Kim, D.; Kim, S. Org. Biomol. Chem. 2011, 9, 7237. Ohno, H.; Honda, M.; Hamada, N.; Miyagaki, J.; Iwata, A.; Otsuki, K.; Maruyama, T.; Nakamura, S.; Nakanishi, I.;

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This work was supported by the JSPS KAKENHI (Grant Numbers JP15KT0061 and JP15H04654), and the Platform Project for Supporting Drug Discovery and Life Science Research from the Japan Agency for Medical Research and Development (AMED).

3046. 27. Wang, Z.; Min, X.; Xiao, S.-H.; Johnstone, S.; Romanow, W.; Meininger, D.; Xu, H.; Liu, J.; Dai, J.; An, S.; Thibault, S.; Walker, N. Structure 2013, 21, 798. 28. Ichikawa, Y. Synlett 1991, 238. 29. Stanton, S. A.; Felman, S. W.; Parkhurst, C. S.; Godleski, S. A. J. Am. Chem. Soc. 1983, 105, 1964. 30. Lee, C.-S.; Audelo, M. Q.; Reibenpies, J.; Sulikowski, G. A. Tetrahedron 2002, 58, 4403. 31. Roulland, E. Angew. Chem. Int. Ed. 2008, 47, 3762. 32. As far as we know, only one example for this type of reaction with the substrate including three nucleophilic functional groups has been reported: (a) Arthuis, M.; Beaud, R.; Gandon, V.; Roulland, E. Angew. Chem. Int. Ed. 2012, 51, 10510. For a related reaction of diol derivatives, see: (b) Caumes, X.; Jeanne-Julien, L.; Khelifi, C.; Gandon, V.; Roulland, E. Org. Chem. Front. 2016, 3, 1462. 33. Roy, S.; Spilling, C. D. Org. Lett. 2012, 14, 2230. 34. Prasad, K. R.; Penchalaiah, K. Tetrahedron: Asymmetry 2011, 22, 1400. 35. Mu, Y.; Kim, J.-Y.; Jin, X.; Park, S.-H.; Joo, J.-E.; Ham, W.-H. Synthesis 2012, 44, 2340. 36. Lee, D. Synlett 2012, 23, 2840. 37. Sharma, G. V. M.; Srikanth, G.; Reddy, P. P. Org. Biomol. Chem. 2012, 10, 8119. 38. Piotr, S.; Agnieszka, P.-H.; Urszula, K.; Sebastian, S. J. Org. Chem. 2014, 79, 11700. 39. It is possible to explain the observed stereoselectivity by the preferential transition state [5a]‡ over [5b]‡: H-bonding interaction between the π-allyl system and acetate anion can stabilize [5a]‡. For more details, see reference 32.

SC

Acknowledgement

OH

‡ BocHN O

NHBoc Pd(0)

HO

[Pd]

NHBoc

H

O H O H O [5a]‡ more stable

O 5a

OAc

OH 4

‡

H BocHN O O H H

[Pd]

O

O [5b]‡ less stable

HO

NHBoc O 5b

40. Another factor that might rationalize the observed stereoselectivity is a Pd(0)-catalyzed cis-selective aziridine formation followed by THF ring formation. Pd(0)-catalyzed aziridine formation and isomerization would preferentially give the thermodynamically more stable cis-isomer A over the corresponding trans-isomer B. The subsequent SN2 reaction of A would provide the major isomer 5a. For thermodynamic preference and Pd(0)-catalyzed isomerization of vinylaziridines, see: (a) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y. J. Org. Chem. 1997, 62, 999. For a related palladium-catalyzed aziridine formation reaction of allylic carbonates, see: (b) Ohno, H.; Ishii, K.; Honda, A.; Tamamura, H.; Fujii, N.; Takemoto, Y.; Ibuka, T. Perkin Trans. 1 1998, 3703.

10

Tetrahedron

HO

NHBoc OAc

HO

Pd(0)

NBoc

HO ACCEPTED MANUSCRIPT Pd(0)

OH

OH 4

NBoc

OH A

HO

B

NHBoc O

HO

NHBoc O

5a

5b

RI PT

41. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.

Supplementary Material

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Supplementary material was provided by the authors.