Synthesis of Deoxyaminosugar Cyclohexyl-L-callipeltose and its

19 hours ago - Cyclohexyl-L-callipeltose, an aminodeoxysugar subunit of Callipeltoside A, was synthesized in six steps and 40% overall yield from read...
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Synthesis of Deoxyaminosugar Cyclohexyl-L-callipeltose and its Diastereomer Using Pd-Catalyzed Asymmetric Hydroalkoxylation Sukhyun Lee, and Young Ho Rhee J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01059 • Publication Date (Web): 12 Jun 2019 Downloaded from http://pubs.acs.org on June 12, 2019

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The Journal of Organic Chemistry

Synthesis of Deoxyaminosugar Cyclohexyl-L-callipeltose and its Diastereomer Using Pd-Catalyzed Asymmetric Hydroalkoxylation Sukhyun Lee, Young Ho Rhee* Department of Chemistry, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk 37673, Republic of Korea Supporting Information Placeholder

OH

O

O NH

1) Pd2(dba)3 / L 2) Ru OCy

O

O

OCy

two steps 74% dr = 20 : 1

4 steps

OCy

L

O O cyclohexyl-L-callipeltose



PPh2 Ph2P

OMe

HN

HN

P(Cy)3 Ru Cl P(Cy) Ph 3

Cl

Ru

ABSTRACT: Cyclohexyl-L-callipeltose, an aminodeoxysugar subunit of Callipeltoside A, was synthesized in six steps and 40% overall yield from readily available (S)-4-methylpent-4-en-2-ol and cyclohexyloxyallene. The signature step is represented by Pd-catalyzed asymmetric intermolecular hydroalkoxylation that generates the key dihydropyran intermediate upon combination with the ring-closing-metathesis reaction. Notably, an unnatural diastereomer of the target compound could also be obtained with comparable efficiency simply by using the enantiomeric ligand.

Callipeltoside A and other related compounds were first isolated from shallow water lithistid sponge, Callipelta sp., which was found in the coast of New Caledonia in 1996.1 From a structural viewpoint, callipeltosides have a subunit containing 14-membered macrolactone connected to a trans-chlorocyclopropane as a common structure. However, they have differ in terms of the structure of the deoxysugar unit (Scheme 1). These natural products exhibited promising cytotoxic activities against NSCLC-N6 and P388 carcinoma cell line.

Scheme 1. Callipeltoside A and Other Related Family O Me O MeO

Me OH NHCHO MeO

NH

O O

O

Me

Me

Callipeltoside B

Me H MeO

O

Me

O

OH O O

Me OH OH MeO

Me O Callipeltoside A

Cl

O

Me

Callipeltoside C

Because of the densely functionalized structure containing oxazolidinone ring and the potential role for the biological activities, the deoxyaminosugar moiety in the callipeltoside A has drawn significant attention from the synthetic community. Until now, several methods for the preparation of callipeltose, the glycon part of callipeltoside A, have been reported.2 Here, we describe a short and modular approach towards cyclohexyl-Lcallipeltose (compound 1a) and its diastereomer (compound 1b). As depicted in Scheme 2, we envisioned that the target compounds can be accessed by using wellestablished Rh-catalyzed oxidative cyclizationof the carbamates generated from the diol 2, which has been

previously employed in the synthesis of callipeltose .2d,2e A salient feature of our approach is the

stereoselective synthesis of this diol from dihydropyran intermediates 3 driven by the chiral O,O-acetal moiety. The intermediate 3 can be easily assembled from readily available (S)-4-methylpent-4-en-2-ol 4 and alkoxyallene 5 using the Pd-catalyzed coupling reaction and the subsequent ring-closing-metathesis as the key event.3 Our previous work demonstrated that the chiral information of the O,O-acetal can be easily controlled by the ligandpromoted hydroalkoxylation reaction.4,5 (Scheme 2). Based upon this result, we envisioned that the diastereomer 1b can also be accessed with comparable efficiency to that of

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1a. This modular approach should be powerful in the development of new potentially active analogs of the natural product.

Scheme 2. Retrosynthetic Analysis Retrosynthetic Analysis O

O

OCy OMe

HN O

O (2S, 3R, 4R, 5R, 6S)-1a (cyclohexyl-L-callipeltose): natural O

O

OH HO CH3 2a

O

OCy

OCy 4

3a

OCy

O

+ OCy

5

OH HO CH3

OMe

HN

OCy

O

2b

O (2S, 3S, 4S, 5S, 6R)-1b (unnatural diastereomer)

(Scheme 4). From this compound, carbamate 8a was obtained in 90% yield by the treatment with trichloroacetyl isocyanate followed by methanol. The final catalytic oxidative cyclization of cyclohexyl glycoside 8a using Rh2(OAc)4 was sluggish. Oxazolidinone 1a was obtained in 39% yield even with the use of 20 mol % catalyst.6 After extensive optimization, we discovered that the use of Rh2(esp)2 catalyst (5 mol%) significantly improved the yield of 1a (up to 72%).7 Further increase of the yield was seen, upon the addition 4Å molecular sieves to the reaction mixture. Comparison of the spectral data of 1a with those of methyl-L-callipeltose confirmed formation of cyclohexyl glycoside of natural L-callipeltose 1a.8 Overall, 1a was obtained in 40% yield from 4 and 5 in six steps.

3b

Scheme 4. Synthesis of Cyclohexyl-L-callipeltose

OH

OCy

O

 4

O NH

HN

O

(R,R)-L

Aiming at the synthesis of 1a (Scheme 3), we first pursued preparation of the key intermediate diol 2a. In a preliminary test employing equimolar mixture of 4 and 5 along with Pd2(dba)3 (3.5 mol%) and ligand (R,R)-L (7 mol%) in toluene at 40oC slowly proceeded to generate the adduct 6a in low 48% yield. Simply increasing the amount of alcohol 4 (2 eq) significantly improved the yield of 6a (up to 87%). The subsequent RCM reaction using Grubbs’ 1st generation catalyst provided the dihydropyran 3a in 85% yield along with trace amount of the diastereomer (< 5%). Subjection of this compound to catalytic OsO4 proceeded smoothly to give the diol 2a in 88% yield. At this point, the absolute stereochemistry of 2a was tentatively assigned as shown in Scheme 3 on the basis of the analogy from our previous studies. It should be noted that the key diol intermediate 2a could be obtained from alcohol 4 in three steps consisting of sequential metal catalysis in a highly efficient manner.

Scheme 3. Synthesis of Diol 2a

OCy +



2eq

1eq

4

5

O

HO 88%

OH

Pd2(dba)3 (3.5 mol %) (R,R)-L (7 mol %) Et3N (1.5 eq)

O

Toluene (0.5 M), 40°C, 24 h

OCy

6a 87%

1st Grubbs Cat (5 mol %) DCM (0.1 M), r.t, 24 h

OsO4 (3 mol %) NMO (2 eq)

OCy

2a

NaH (1.1 eq) CH3I (2.2 eq)

OCy

PPh2 Ph2P

5

OH

Page 2 of 6

O

OCy

THF/Acetone (1:1, total 1M) 3a H2O (9 M) r.t, 24 h 89% (d.r 20:1)

From the diol intermediate 2a, preparation of the target compound 1a was rather straightforward. Regioselective methylation of 2a proceeded in 82% yield to give 7a

HO 2a

OH

O

THF (0.25 M), 0°C to r.t, 24 h

OCy OMe 7a

HO 82%

1) CCl3CONCO (1.3 eq) DCM (0.1 M), r.t, 1 h 2) K2CO3 (4 eq) H2O (0.5 M), CH3OH (0.05 M), r.t, 24 h

O HN O O

OCy

Rh catalyst (see below) PhI(OAc) (1.4 eq) MgO (2.3 eq)

O

OMe DCM (0.1 M), 40°C, 24 h H N 2 1a

O

OCy OMe 8a

O 90%

cat. Rh2(OAc)4 (20 mol%) Rh2(esp)2 (5 mol%) Rh2(esp)2 (5 mol%)

additive. --------4Å M.S

yield 39% 72% 83%

O esp =

O

O O

Having completed the synthesis of the naturally occurring diastereomeric form of the callipeltose, we then investigated the synthesis of unnatural diastereomer (compound 1b Scheme 5). Using enantiomeric chiral ligand (S,S)-L for the hydroalkoxylation generated dihydropyran 6b in 89% yield, which was efficiently converted into 3b by using ring-closing-metathesis in 79% yield. Acetal-driven dihydroxylation of this compound produced 2b in 91% as single diastereomer. After selective methylation of this compound (in 73% yield), the resulting ether 7b was converted into the carbamate 8b in 94% yield. Rh-catalyzed oxidative cyclization of this compound using Rh2(esp)2 provided the target 1b in 81% yield, whose structure was confirmed by the 2-dimensional 1H NMR spectra (for the detailed information of 2-D NMR, see the supporting information).9 Thus, the compound 1b was synthesized from 4 and 5 in overall 36% yield over six steps. In summary, we developed a flexible synthetic strategy towards cyclohexyl-L-callipeltose and its diastereomer in very short steps with high chemical efficiency and minimal generation of by-products. This de novo approach well illustrates the utility of metal-catalyzed asymmetric

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The Journal of Organic Chemistry hydroalkoxylation in the total synthesis of highly functionalized deoxyaminosugar compounds. Currently, we are working on expanding the scope of the Pd-catalyzed hydroalkoxylation to other complex natural products. The results of this study will be reported in a due course.

Scheme 5. Synthesis of 1b OH

Pd2(dba)3 (3.5 mol %) (S,S)-L (7 mol %) Et3N (1.5 eq)

OCy +



O

OCy

Toluene (0.5 M), 40°C, 24 h 2eq

1eq

4

5

O

OCy

HO

OH 2b

6b 89%

1st Grubbs Cat (5 mol %) DCM (0.1 M), r.t, 24 h OsO4 (3 mol %) NMO (2 eq)

O

OCy

THF/Acetone (1:1, total 1 M) 3b H2O (9 M) r.t, 24 h 81% (d.r >25:1)

91%

NaH (1.1 eq) / CH3I (2.2 eq) THF (0.25 M), 0°C to r.t, 24 h O

O

OCy 1) CCl CONCO (1.3 eq) 3 DCM (0.1 M), r.t, 1 h

HO

OMe 7b

H

H OH

OMe 8b

O

OCy

OCH3

H3C H

O

OCy

O

O

94% Rh2(esp)2 5 mol% PhI(OAc)2 (1.4 eq) MgO (2.3 eq) DCM (0.1 M), 40°C, 24 h

73%

H3C H

H2N

2) K2CO3 (4 eq) H2O (0.5 M), CH3OH (0.05 M), r.t, 24 h

OCy

H

7b Stereochemistry conf irmed by NOESY

OMe

HN O O

1b

81%

EXPERIMENTAL SECTION General Information. Air and moisture sensitive reactions were carried out in oven-dried glassware sealed with rubber septa under a positive pressure of nitrogen. Similarly, all solvents were dried and distilled according to the standard methods before use, then were transferred via syringe. Reactions were stirred using Teflon-coated magnetic stir bars. Reactions were heated in silicon oil bath when requiring heating. Pd2(dba)3, the Grubbs’ catalysts were purchased form a Aldrich Chemical, Strem Chemical Inc. Chiral Trost ligands were purchased from Strem Chemical Inc. and stored in glove box. Reactions were monitored by thin-layer chromatography on silicagel carried out on 0.25 mm E. Merck silica gel plates (60F254) using UV light as a visualizing agent and acidic panisaldehyde, and heat as developing agent. Flash chromatography on silicagel was carried out on Merck 60 silica gel (230-400 mesh). 1H and 13C NMR spectra were recorded on Bruker (300 MHz, 500 MHz, 600 MHz) spectrometer. 1H NMR spectra were referenced to CDCl3 (7.26 ppm) and CD2Cl2 (5.30 ppm), and reported as follows; chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet). Chemical shifts of the 13C NMR spectra were measured relative to CDCl (77.23 3

ppm) and CD2Cl2 (55.30 ppm). Infrared spectra were recorded on a Shimadzu IR-470 spectrometer. Specific rotation data were measured on JASCO P-1020 Polarimeter. Melting points were measured on Electrothermal 9100. Mass spectral data were obtained from the Korea Basic Science Institute (Daegu) on a Jeol JMS 700 high resolution mass spectrometer (FAB) and Organic Chemistry Research Center in Sogang university on a Bruker Ultra High Resolution ESI Q-TOF MS / MS Compact System (ESI). Homoallylic alcohol 4 was synthesized according to a literature procedure from (S)propylene oxide (purchased from Tokyo Chemical Industry Co. and used as is).3a, 3b (((S)-1-(((S)-4-methylpent-4-en-2yl)oxy)allyl)oxy)cyclohexane (6a). 4 (800.8 mg, 8 mmol) was reacted with Pd2(dba)3 (128.0 mg, 0.14 mmol), (R,R)DACH-phenyl Trost ligand (193.4 mg, 0.28 mmol), triethylamine (0.87 mL, 6 mmol), and cyclohexyloxyallene 5 (552.5 mg, 4 mmol) in toluene (8 mL). The resulting mixture was stirred at 40°C during 24 hours under positive nitrogen pressure. The solvent was removed under reduced pressure. Flash column chromatography (eluted with Hexane/EtOAc=95:5) afforded the compound 6a as a transparent oil (827 mg, 3.47 mmol, 87%). Rf=0.4 (Hexane:EtOAc=95:5) ; [α]D20 +9.6 (c 0.66, CH2Cl2) ; 1H NMR (500 MHz, CDCl3) δ 5.83-5.90 (ddd, J=5.37 Hz, 10.41 Hz, 17.24 Hz, 1H), 5.34-5.37 (d, J=17.25 Hz, 1H), 5,21-5.23 (d, J=10.1 Hz, 1H), 4.99-5.00 (d, J=6.75 Hz, 1H), 4.74 (s, 1H), 4.77 (s, 1H), 3.87-3.94 (m, 1H), 3.53-3.58 (m, 1H), 2.36-2.40 (m, 1H), 2.08-2.12 (m, 1H), 1.85-1.90 (m, 2H), 1.72-1.76 (m, 5H), 1.52-1.54 (m, 1H), 1.18-1.38 (m, 5H), 1.12-1.13 (d, J=6.09 Hz, 3H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 142.9, 137.2, 117.3, 112.9, 99.3, 73.9, 69.9, 46.1, 33.4, 32.9, 25.9, 24.5, 24.4, 23.0, 20.2 ; IR (NaCl) ν 3076, 2969, 2933, 2857, 1648, 1450, 1375, 1322, 1128, 1094, 1019, 931 cm-1 ; HRMS (ESI) calcd for C15H26O2Na (M+Na+) 261.1825, found 261.1826 (2S,6S)-6-(cyclohexyloxy)-2,4-dimethyl-3,6-dihydro-2Hpyran (3a). To a solution of 6a (821 mg, 3.45 mmol) dissolved in CH2Cl2 (34 mL) was added the Grubbs’ catalyst first generation (141 mg, 0.17 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 24 hours. The solvent was removed under pressure and then resulting crude oil was purified by flash column chromatography (eluted with Hexane/Et2O=95:5) to afford 3a as a yellowish oil (618 mg, 2.94 mmol, 85%). Rf=0.42 (Hexane:Et2O=95:5) ; [α]D20 +41.9 (c 0.565, CH2Cl2) ; 1H NMR (500 MHz, CDCl3) δ 5.43 (s, 1H), 5.10 (s, 1H), 4.03-4.10 (m, 1H), 3.59-3.65 (m, 1H), 1.87-1.92 (m, 3H), 1.78-1.82 (dd, J=3.44 Hz, 17.63 Hz, 1H), 1.71-1.74 (m, 5H), 1.53-1.55 (m, 1H), 1.18-1.40 (m, 8H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 137.4, 120.4, 93.9, 75.7, 62.6, 37.5, 34.4, 32.6, 25.9, 24.8, 24.6, 23.0, 21.2 ; IR (NaCl) ν 2969, 2931, 2856, 1683, 1449, 1390, 1172, 1136, 1110, 1056, 1015, 975 cm-1 ; HRMS (ESI) calcd for C13H22O2Na (M+Na+) 233.1512, found 233.1512 (2S,3R,4R,6S)-2-(cyclohexyloxy)-4,6-dimethyltetrahydro-2Hpyran-3,4-diol (2a). To a solution of 3a (609 mg, 2.9 mmol) in acetone/THF (1:1 ratio by volume, total volume 2.9 mL) was added 4-methylmorpholine N-oxide (667 mg, 5.8 mmol), and OsO4 solution (4wt % in H2O, 0.58 mL, 0.12 mmol) and dis. H2O (0.32 mL) was added. The reaction was

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conducted at room temperature and stirring was continued for 24 hours. After 24 hours, reaction mixture diluted with CH2Cl2 and washed with 1 mL of saturated Na2SO3 and 2 mL of saturated NH4Cl. The combined aqueous layers were extracted with CH2Cl2. The Organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Flash column chromatography (Hexane/EtOAc=50:50) afforded 2a as a yellowish oil (620 mg, 2.54 mmol, 88%). Rf=0.41 (Hexane:EtOAc=50:50) ; [α]D20 -74.6 (c 1.07, CH2Cl2) ; 1H NMR (500 MHz, CDCl3) δ 4.99 (s, 1H), 3.86-3.90 (m, 1H), 3.58-3.62 (m, 1H), 3.29 (d, 1H), 2.51 (s, 2H), 1.80 (br s, 2H), 1.69-1.70 (m, 2H), 1.50-1.59 (m, 3H), 1.39-1.44 (m, 4H), 1.241.35 (m, 4H), 1.87-2.00 (d, 3H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 98.5, 75.0, 73.2, 69.5, 64.1, 42.9, 33.5, 31.5, 25.9, 24.9, 24.1, 23.8, 21.4 ; IR (NaCl) ν 3403, 2970, 2933, 2857, 1592, 1450, 1384, 1169, 1124, 1087, 1056, 993 cm-1 ; HRMS (ESI) calcd for C13H24O4Na (M+Na+) 267.1567, found 267.1568 (2S,3R,4R,6S)-2-(cyclohexyloxy)-3-methoxy-4,6dimethyltetrahydro-2H-pyran-4-ol (7a). THF (0.64 mL) was added to sodium hydride (14 mg, 0.35 mmol, 60% dispersion in mineral oil) and the resultant suspension cooled to 0°C. A solution of diol 2a (78 mg, 0.32 mmol) in THF (0.64 mL) was added dropwise. After stirring at 0°C for 1-hour, neat methyl iodide (45 µL, 0.70 mmol) was added and the resulting mixture was stirred at the same temperature for 24 hours. The solution was poured into water:ice mixture (5 g) and extracted with ether. The organic layers were combined, and dried over anhydrous Na2SO4, and concentrated under reduced pressure. Flash column chromatography (Hexane/EtOAc=50:50) afforded 6a as a yellowish oil (67 mg, 0.26 mmol, 82%). Rf=0.66 (Hexane:EtOAc=50:50) ; [α]D20 -55.4 (c 0.93, CH2Cl2) ; 1H NMR (500 MHz, CDCl3) δ 5.05 (s, 1H), 3.81-3.85 (m, 1H), 3.58-3.62 (m, 1H), 3.48 (s, 3H), 2.90 (s, 1H), 2.82 (s, 1H), 1.791.81 (m, 2H), 1.68-1.71 (m, 2H), 1.47-1.53 (m, 3H), 1.22-1.44 (m, 8H), 1.16-1.18 (d, J=6.31Hz, 3H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 95.5, 82.9, 74.9, 68.8, 64.2, 57.3, 44.2, 33.5, 31.6, 25.9, 24.4, 24.2, 23.9, 21.4 ; IR (NaCl) ν 3500, 2971, 2933, 2857, 2827, 2659, 1450, 1336, 1273, 1214, 1170, 1127 cm-1 ; HRMS (ESI) calcd for C14H26O4Na (M+Na+) 281.1723, found 281.1726 (2S,3R,4R,6S)-2-(cyclohexyloxy)-3-methoxy-4,6dimethyltetrahydro-2H-pyran-4-yl carbamate (8a). To a stirred solution of alcohol 7a (428 mg, 1.66 mmol) in CH2Cl2 (16.6 mL) was added neat trichloroacetyl isocyanate (0.24 mL, 2.01 mmol) at 0°C and the resultant solution was stirred at rt for 1 hour. CH2Cl2 was removed by nitrogen purging and resulting foam was re-dissolved in methanol (33 mL). The mixture was cooled to 0 ° C and potassium carbonate (806 mg, 5.93 mmol) and water (3.3 mL) was added. The solution was stirred at rt for 24 hours. Methanol was removed under reduced pressure and residue was dissolved in EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Flash column chromatography (Hexane/EtOAc=50:50) afforded 8a as a white solid (449.5

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mg, 1.49 mmol, 90%). m. p 143-144 ° C; Rf=0.55 (Hexane:EtOAc=50:50) ; [α]D20 -25.5 (c 0.45, CH2Cl2) ; 1H{1H} NMR (300 MHz, CDCl3) δ 5.01 (d, J=1.55Hz, 1H), 4.48 (br s, 2H), 3.88-3.95 (m, 1H), 3.77 (m, 1H), 3.56-3.63 (m, 1H), 3.46 (s, 3H), 1.68-1.83 (m, 8H), 1.27-1.57 (m, 7H), 1.19-1.23 (d, J=6.31Hz, 3H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 155.8, 95.8, 79.5, 79.4, 74.8, 62.9, 58.8, 41.1, 33.3, 31.3, 25.7, 23.9, 23.6, 22.6, 21.2 ; IR (NaCl) ν 3358, 2933, 2857, 1722, 1602, 1450, 1360, 1304, 1191, 1166, 1107, 1049 cm-1 ; HRMS (ESI) calcd for C15H27NO5Na (M+Na+) 324.1781, found 324.1784 Cyclohexyl-L-callipeltose (1a). A mixture of carbamate 8a (55 mg, 0.18 mmol), magnesium oxide (17 mg, 0.41 mmol), Rh2(esp)2 (7.4 mg, 0.009 mmol, 5 mol%) and diacetoxyiodobenzene (81mg, 0.25 mmol) was placed in a 4 mL vial and CH2Cl2 (1.8 mL) was added, and seal with Teflon tape. The reaction mixture was stirred at 40°C for 24 hours. After 24 hours, the reaction mixture was cooled to rt and water and CH2Cl2 was added. The organic phase was separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. Flash column chromatography (Hexane/EtOAc=30:70) afforded 1a as a white solid (39 mg, 0.13 mmol,72%, 10% SM recovery). When 112 mg of 4Å powder which was activated at 110°C for 2 days was added in vial, 44.8 mg (0.150 mmol, 83%) of product was gained. m. p 172-173 ° C ; Rf=0.58 (Hx/EA=10:90) ; [α]D20 -78.3 (c 1.99, CH2Cl2) ; 1H NMR (500 MHz, CDCl3) δ 6.81-6.93 (m, 1H), 4.84-4.85 (d, J=5.6Hz, 1H), 3.90-3.94 (d, J=1.7, 6.43Hz, 1H), 3.60-3.65 (m, 1H), 3.55 (s, 3H), 3.35 (d, J=1.7Hz, 1H), 3.20-3.21 (d, J=5.60Hz, 1H), 1.851.89 (m, 2H), 1.69-1.71 (m, 2H), 1.52 (m, 4H), 1.17-1.40 (m, 5H), 1.13-1.15 (d, J=6.43Hz, 3H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 159.5, 99.0 82.2, 81.7, 75.7, 63.7, 61.8, 60.9, 34.2, 32.2, 25.9, 24.3, 24.2, 23.6, 15.9 ; IR (NaCl) ν 3273, 2933, 2857, 1750, 1450, 1373, 1318, 1267, 1202, 1102, 1059, 1022 cm-1 ; HRMS (ESI) calcd for C15H25NO5Na (M+Na+) 322.1625, found 322.1627 (((R)-1-(((S)-4-methylpent-4-en-2yl)oxy)allyl)oxy)cyclohexane (6b). 4 (675 mg, 6.74 mmol) was reacted with Pd2(dba)3 (108 mg, 0.12 mmol), (S,S)-DACHphenyl Trost ligand (163 mg, 0.24 mmol), triethylamine (0.73 mL, 5.06 mmol), and cyclohexyloxyallene 5 (465.5 mg, 3.37 mmol) in toluene (6.7 mL). The resulting mixture was stirred at 40 ° C during 24 hours under positive nitrogen pressure. The solvent was removed under reduced pressure. Flash column chromatography (eluted with Hexane/EtOAc=95:5) afforded the compound 6b as a transparent oil (713 mg, 2.99 mmol, 89%). Rf=0.4 (Hexane:EtOAc=95:5) ; [α]D20 +2.8 (c 1.15, CH2Cl2) ; 1H NMR (500 MHz, CDCl3) δ 5.82-5.88 (ddd, J=5.52, 10.6, 17.1Hz, 1H), 5.33-5.36 (d, J=17.1Hz, 1H), 5.21-5.24 (d, J=10.6Hz, 1H), 4.974.99 (d, J=5.52Hz, 1H), 4.72-4.77 (d, J=25.43Hz, 2H), 3.863.90 (m, 1H), 3.50-3.55 (m, 1H), 2.33-2.36 (dd, J=5.38, 8.19Hz, 1H), 2.05-2.09 (dd, J=6.09, 7.73Hz, 1H), 1.85-1.90 (m, 2H), 1.72 (m, 5H), 1.52-1.56 (m, 1H), 1.22-1.40 (m, 5H), 1.18-1.19 (d, J=6.22Hz, 3H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 142.9, 137.0, 117.4, 113.1, 99.9, 73.9, 70.7, 45.5, 33.4, 33.1, 25.9, 24.5, 24.4, 23.1, 21.0 ; IR (NaCl) ν 3023, 2969, 2933, 2857, 1450, 1430,

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The Journal of Organic Chemistry 1407, 1375, 1322, 1153, 1131 ,1092 cm-1 ; HRMS (ESI) calcd for C15H26O2Na (M+Na+) 261.1825, found 261.1827 (2S,6R)-6-(cyclohexyloxy)-2,4-dimethyl-3,6-dihydro-2Hpyran (3b). To a solution of 6b (710 mg, 2.98 mmol) dissolved in CH2Cl2 (30 mL) was added the Grubbs’ catalyst first generation (122 mg, 0.149 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 24 hours. The solvent was removed under pressure and then resulting crude oil was purified by flash column chromatography (eluted with Hexane/Et2O=95:5) to afford 3b as a yellowish oil (495 mg, 2.35 mmol, 79%). Rf=0.36 (Hexane:Et2O=95:5) ; [α]D20 +128.8 (c 0.14, CH2Cl2) ; 1H NMR (300 MHz, CDCl3) δ 5.345.36 (m, 1H), 5.17-5.18 (m, 1H), 3.66-3.82 (m, 2H), 1.92-2.02 (m, 4H), 1.69-1.80 (m, 5H), 1.50-1.56 (m, 1H), 1.18-1.41 (m, 8H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 137.2, 122.3, 96.2, 76.1, 68.1, 37.3, 34.1, 32.5, 25.9, 24.7, 24.5, 22.9, 21.6 ; IR (NaCl) ν 2969, 2931, 2856, 2606, 1449, 1390, 1379, 1159, 1136, 1103, 1082, 1014 cm-1 ; HRMS (ESI) calcd for C13H22O2Na (M+Na+) 233.1512, found 233.1514 (2R,3S,4S,6S)-2-(cyclohexyloxy)-4,6-dimethyltetrahydro-2Hpyran-3,4-diol (2b). To a solution of 3b (574 mg, 2.35 mmol) in acetone/THF (1:1 ratio by volume, total volume 2.3 mL) was added 4-methylmorpholine N-oxide (551 mg, 4.7 mmol), and OsO4 solution (4wt % in H2O, 0.47 mL, 0.071 mmol) and dis. H2O (0.26 mL) was added. The reaction was conducted at room temperature and stirring was continued for 24 hours. After 24 hours, reaction mixture diluted with CH2Cl2 and washed with 1 mL of saturated Na2SO3 and 2 mL of saturated NH4Cl. The combined aqueous layers were extracted with CH2Cl2. The Organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Flash column chromatography (Hexane/EtOAc=50:50) afforded 2b as a yellowish oil (523 mg, 2.14 mmol, 91%). Rf=0.67 (Hexane:EtOAc=50:50) ; [α]D20 +46.9 (c 0.35, CH2Cl2) ; 1H NMR (500 MHz, CD2Cl2) δ 4.56-4.58 (d, J=7.83Hz, 1H), 3.86-3.92 (m, 1H), 3.59-3.65 (m, 1H), 3.08-3.10 (dd, J=1.86, 7.83Hz, 1H), 2.47-2.48 (d, J=2.03Hz, 1H), 2.41-2.42 (d, J=2.17Hz, 1H), 1.87-1.91 (m, 2H), 1.68-1.73 (m, 3H), 1.52-1.55 (m, 1H), 1.23-1.37 (m, 10H), 1.14-1.15 (d, J=6.3Hz, 3H) ; 13C{1H} NMR (125 MHz, CD2Cl2) δ 99.8, 77.2, 75.5, 71.1, 67.5, 45.4, 34.4, 32.7, 27.6, 26.2, 24.8, 24.7, 21.1; IR (NaCl) ν 3469, 2970, 2933, 2857, 1452, 1413, 1371, 1329, 1271, 1247, 1174, 1155 cm-1 ; HRMS (ESI) calcd for C13H24O4Na (M+Na+) 267.1567, found 267.1569 (2R,3S,4S,6S)-2-(cyclohexyloxy)-3-methoxy-4,6dimethyltetrahydro-2H-pyran-4-ol (7b). THF (3.16 mL) was added to sodium hydride (70 mg, 1.74 mmol, 60% dispersion in mineral oil) and the resultant suspension cooled to 0°C. A solution of diol 2b (384 mg, 1.58 mmol) in THF (3.16 mL) was added dropwise. After stirring at 0°C for 1-hour, neat methyl iodide (0.22 mL, 3.48 mmol) was added and the resulting mixture was stirred at the same temperature for 24 hours. The solution was poured into water:ice mixture (5 g) and extracted with ether. The organic layers were combined, and dried over anhydrous Na2SO4, and concentrated under reduced pressure. Flash column chromatography (Hexane/EtOAc=50:50) afforded

7b as a yellowish oil (300 mg, 1.15 mmol, 73%). Rf=0.7 (Hexane:EtOAc=60:40) ; [α]D20 +34.7 (c 0.67, CH2Cl2) ; 1H NMR (500 MHz, CD2Cl2) δ 4.56-4.57 (d, J=7.79Hz, 1H), 3.79-3.83 (m, 1H), 3.58-3.61 (m, 1H), 3.55 (s, 3H), 2.64-2.65 (d, J=7.79Hz, 1H), 2.28 (m, 1H), 1.84-1.86 (m, 2H), 1.63-1.71 (m, 3H), 1.39-1.50 (m, 1H), 1.24-1.36 (m, 6H), 1.17 (s, 3H), 1.101.11 (d, J=6.37Hz, 3H) ; 13C{1H} NMR (125 MHz, CD2Cl2) δ 100.5, 84.4, 77.0, 71.9, 66.8, 61.5, 45.3, 34.3, 32.4, 27.8, 26.2, 24.5, 24.3, 21.0 ; IR (NaCl) ν 3478, 2932, 2857, 1737, 1451, 1366, 1328, 1177, 1156, 1089, 1037, 985 cm-1 ; HRMS (ESI) calcd for C14H26O4Na (M+Na+) 281.1723, found 281.1726 (2R,3S,4S,6S)-2-(cyclohexyloxy)-3-methoxy-4,6dimethyltetrahydro-2H-pyran-4-yl carbamate (8b). To a stirred solution of alcohol 7b (304 mg, 1.15 mmol) in CH2Cl2 (11.5 mL) was added neat trichloroacetyl isocyanate (169 µL, 1.39 mmol) at 0°C and the resultant solution was stirred at rt for 1 hour. CH2Cl2 was removed by nitrogen purging and resulting foam was re-dissolved in methanol (23 mL). The mixture was cooled to 0°C and potassium carbonate (559 mg, 4.11 mmol) and water (2.3 mL) was added. The solution was stirred at rt for 24 hours. Methanol was removed under reduced pressure and residue was dissolved in EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Flash column chromatography (Hexane/EtOAc=50:50) afforded 8b as a white solid (324 mg, 1.08 mmol, 94%). m. p 67-68 ° C ; Rf=0.24 (Hexane:EtOAc=60:40) ; [α]D20 +60.0 (c 0.82, CH2Cl2) ; 1H NMR (500 MHz, CDCl3) δ 4.72-4.74 (m, 3H), 3.73-3.76 (m, 1H), 3.63-3.68 (m, 1H), 3.61 (s, 3H), 2.84-2.87 (dd, J=1.36, 14.57Hz, 1H), 2.67-2.69 (d, J=7.90Hz, 1H), 1.90-1.97 (m, 2H), 1.72-1.77 (m, 2H), 1.60 (s, 3H), 1.23-1.53 (m, 7H), 1.17-1.18 (d, J=6.3Hz, 3H) ; 13C{1H} NMR (125 MHz, CDCl3) δ 155.9, 99.7, 85.8, 82.5, 77.8, 66.5, 62.2, 41.6, 34.0. 32.3, 25.9, 24.3, 24.2, 22.2, 21.0 ; IR (NaCl) ν 3439, 3354, 3205, 2977, 2934, 2858, 1722, 1608, 1448, 1363, 1269, 1159 cm-1 ; HRMS (ESI) calcd for C15H27NO5Na (M+Na+) 324.1781, found 324.1786 (3aS,4S,6S,7S,7aS)-6-(cyclohexyloxy)-7-methoxy-4,7adimethylhexahydro-2H-pyrano[3,4-d]oxazol-2-one (1b). A mixture of carbamate 8b (55 mg, 0.18 mmol), magnesium oxide (16.6 mg, 0.41 mmol), Rh2(esp)2 (7.4 mg, 0.009 mmol, 5 mol%) and diacetoxyiodobenzene (81mg, 0.25 mmol) was placed in a 4 mL vial and CH2Cl2 (1.8 mL) was added, and seal with Teflon tape. The reaction mixture was stirred at 40°C for 24 hours. After 24 hours, the reaction mixture was cooled to rt and water and CH2Cl2 was added. The organic phase was separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. Flash column chromatography (Hexane/EtOAc=30:70) afforded 1b as a white solid (43 mg, 0.145 mmol, 81%). m. p 129-130° C; Rf=0.14 (Hx/EA=10:90) ; [α]D20 +59.4 (c 0.36, CH2Cl2) ; 1H NMR (500 MHz, CD2Cl2) δ 6.25 (s, 1H), 4.70-4.71 (d, J=6.63Hz, 1H), 3.62-3.70 (m, 1H), 3.60 (s, 3H), 3.45-3.51 (m, 1H), 3.05-3.10 (m, 2H), 1.84-1.90 (m, 2H), 1.71-1.72 (m, 2H), 1.51 (s, 3H), 1.26-1.46 (m, 6H), 1.22-1.23 (d, J=6.17Hz, 3H) ; 13C{1H} NMR (125 MHz, CD Cl ) δ 159.0, 100.1, 84.1, 82.3, 77.2, 2 2

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72.9, 62.7 62.0, 34.2, 32.3, 26.2, 24.5, 24.3, 24.1, 19.2 ; IR (NaCl) ν 3290, 2933, 2857, 1756, 1451, 1379, 1317, 1254, 1198, 1170, 1089, 1030 cm-1 ; HRMS (ESI) calcd for C15H25NO5Na (M+Na+) 322.1625, found 322.1628

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H

and 13C NMR spectra for all new compounds (PDF)

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]

ORCID Young Ho Rhee: 0000-0002-2094-4426

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT Financial support for this work was provided by the National Research Foundation of Korea, which is funded by the Korean Government (NRF-2015R1A2A1A15056116, NRF2017R1A2B1010757 and nanomaterial technology program).

REFERENCES (1) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis, C. Callipeltoside A:  A Cytotoxic Aminodeoxy Sugar-Containing Macrolide of a New Type from the Marine Lithistida Sponge Callipelta sp.. J. Am. Chem. Soc. 1996, 118, 11085-11088 (2) (a) Smith, G. R.; Finley, J. J., IV; Giuliano, R. M. Synthesis of methyl α-l-callipeltoside. Carbohydr. Res. 1998, 308, 223237. (b) Pihko, A. J.; Nicolaou, K. C.; Koskinen, A. M. P. An expedient synthesis of d-callipeltose. Tetrahedron: Asymmetry. 2001, 12, 937-942. (c) Evans, D. A.; Hu, E.; Tedrow, J. S. An Aldol-Based Approach to the Asymmetric Synthesis of l-Callipeltose, the Deoxyamino Sugar of lCallipeltoside A. Org. Lett. 2001, 3, 3133-3136. (d) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. Callipeltoside A: Total Synthesis, Assignment of the Absolute and Relative Configuration, and Evalua-tion of Synthetic Analogues, J. Am. Chem. Soc. 2002, 124, 10396-10415. (e) Huang, H.; Panek, J. S. Organosilanes in Synthesis:  Application to an

Enantioselective Synthesis of Methyl-l-callipeltose. Org. Lett. 2003, 5, 1991-1993 (3) For synthesis of alcohol 4 and allene 5, see: (a) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Copper-catalysed reactions of grignard reagents with epoxides and oxetane. Tetrahedron Lett. 1979, 17, 1503-1506. (b) Castaldi, M. P.; Troast, D. M.; Porco, J. A. Stereoselective Synthesis of Spirocyclic Oxindoles via Prins Cyclizations. Org. Lett. 2009, 11, 3362-3365. (c) Trost, B. M.; Xie, J.; Sieber, J. D. The Palladium Catalyzed Asymmetric Addition of Oxindoles and Allenes: An Atom-Economical Versatile Method for the Construction of Chiral Indole Alkaloids. J. Am. Chem. Soc. 2011, 133, 20611-20622 (4) For O,O acetals, (a) Lim, W.; Kim, J.; Rhee, Y. H. PdCatalyzed Asymmetric Intermolecular Hydroalkoxylation of Allene: An Entry to Cyclic Acetals with Activating GroupFree and Flexible Anomeric Control. J. Am. Chem. Soc. 2014, 136, 13618-13621. (b) Kim, M.; Kang, S.; Rhee, Y. H. De Novo Syn-thesis of Furanose Sugars: Catalytic Asymmetric Synthesis of Apiose and Apiose-Containing Oligosaccharides. Angew. Chem. Int. Ed. 2016, 55, 9733-9737. (c) Lee, J.; Kang, S.; Kim, J.; Moon, D.; Rhee, Y. H. A Convergent Synthetic Strategy towards Oligosaccharides containing 2,3,6-Trideoxypyranoglycosides. Angew. Chem. Int. Ed. 2019, 58, 628-631 (5) For N,O acetals, (a) Kim, H.; Rhee, Y. H. A Perspective on the Stereodefined N,O-Acetals: Synthesis and Potential Applications. Synlett. 2012, 23, 2875-2879. (b) Jang, S. H.; Kim, H. W.; Jeong, W.; Moon, D.; Rhee, Y. H. PalladiumCatalyzed Asymmetric Nitrogen-Selective Addition Reaction of Indoles to Alkoxyallenes. Org. Lett. 2018, 20, 1248-1251 (6) For some reviews on the Rhodium-catalyzed C-H insertion, see: (a) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C-H bonds. Acc. Chem. Res. 2012, 45, 911-912. (b) Du Bois, J. Rhodium-Catalyzed C–H Amination. An Enabling Method for Chemical Synthesis. Org. Process. Res. Dev. 2011, 15, 758-762 (7) (a) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. Expanding the Scope of C−H Amination through Catalyst Design. J. Am. Chem. Soc. 2004, 126, 15378-15379. (b) Zalatan, D. N.; Du Bois, J. Under-standing the Differential Performance of Rh2(esp)2 as a Catalyst for C−H Amination. J. Am. Chem. Soc. 2009, 131, 7558-7559 (8) The chemical shifts and coupling constants in the glycosidic part of 1a are in full accord with that of-methyl-Lcallipeltose. (9) This analysis also confirms stereochemical assignment of cyclohexyl-L-callipeltose.

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