Stereoselective Synthesis of Highly Functionalized 5- and 6

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Stereoselective synthesis of highly functionalized 5- and 6-membered aminocyclitols starting with a readily available 2-azetidinone Raghavendra Achary, Hyeong Rae Kim, and Hyeon-Kyu Lee J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00239 • Publication Date (Web): 14 Mar 2019 Downloaded from http://pubs.acs.org on March 14, 2019

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The Journal of Organic Chemistry

Stereoselective Synthesis of Highly Functionalized 5and 6-Membered Aminocyclitols Starting with a Readily Available 2-Azetidinone Raghavendra Achary,† Hyeong Rae Kim,†,‡ and Hyeon-Kyu Lee†,‡*

†Korea Chemical Bank, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon 305600, Korea; ‡Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 113 Gwahango, Yuseong, Daejeon 305-333, Korea. [email protected]

ABSTRACT O

BnO O

OBn N 4

Boc

O and

NHBoc

OBn NHBoc (2R,3S)-9

(2R,3S)-7

polyhydroxylated aminocyclitols

Abstract: Stereoselective transformations of the 4-vinyl-2-azetidinone derivative 4 to a variety of highly functionalized 6- and 5-membered carbocyclic compounds 7 and 9 were carried out using sequences involving sequential C1-N bond cleavage and Ru-catalyzed ring-closing metathesis. The derived carbocycles were further transformed to polyhydroxylated 6- and 5-membered aminocyclitols.

Introduction

Polyhydroxylated amino-cyclohexanes and -cyclopentanes, termed aminocyclitols, constitute an important class of natural and synthetic products, which display diverse biological activities.1 In particular, members of the aminocyclitol family serve as aminoglycoside antibiotics and others are glycosidase inhibitors and antiviral agents.2 Also, aminocyclitols are carbocyclic analogues of biologically important monosaccharides or aminosugars.3 Because of 1

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the important characteristics of these substances, many investigations have been conducted over the past several decades to develop general strategies to produce novel members of this family, especially those that have enhanced and/or more selective biological profiles.4 In these investigations it has been recognized that the presence of dense functionality as well as multiple contiguous chiral centers make aminocyclitols a major synthetic challenge.5 The 2-azetidinone moiety is a key structural element in a widely employed family of antibacterial agents known as β-lactam antibiotics.6 Owing to this, many studies, aimed at developing methods for practical and stereoselective synthesis of 2-azetidinones, have been carried out.7 Owing to the wealth of approaches that have been devised for their synthesis, 2azetidinones are now readily available to the point that they are now being utilized as chiral synthons in routes for the preparation of other important classes of compounds.8 Examples of these applications are found in transformations of 2-azetidinones to nonproteogenic amino acids, peptides9 and other bioactive nitrogen containing heterocycles8d through routes that employ ring expansion or rearrangement reactions to generate 2-pyrrolidinones10 and 2piperidones.8a,8b,11 As part of our recent efforts in this broad area, we developed a new, two-carbon ring homologation methodology for synthesis of 2-piperidones from readily accessible 2azetidinones,11 and routes for preparation of (phyto)sphingosines involving ring opening by phosphonate stabilized carbanions and subsequent Horner-Wadsworth-Emmons olefination.12 As part of our continuing investigations probing the utilization of 2-azetidinones as chiral synthons, we envisioned that optically active cyclohexenones and cyclopentenones (A and B) would be potentially accessible through ring-closing metathesis (RCM)8d,13 of the respective 1,6-dienes and 1,5-dienes (C and D) (Scheme 1). Moreover, we realized the possibility that the requisite dienes, C and D, could be prepared by using C1-N bond cleavage reactions of optically active N-Boc-4-vinyl-2-azetidinone (4) with corresponding allyl and vinyl organometallic reagents (Scheme 1). The investigation, designed to assess the validity of these proposals led to observations described below, which show that 2-azetidinones 4 can be readily transformed to highly functionalized 6- and 5-membered carbocyclic products A and B. In addition, the effort also demonstrated that A and B serve as valuable intermediates in concise 2


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routes for the preparation of complex polyhydroxylated aminocyclitols. Scheme 1. Proposed routes for the synthesis of 6- and 5-membered carbocyclic products A and B from 4-vinyl-2-azetidinone 4 and for transformation of these carbocycles to polyhydroxylated aminocyclitols.

O

1

2 3

( )n A, B

n=0,1

NHBoc

BnO

NHBoc

BnO

O

RCM

1

BnO

2 3

2 3 1

O

)n

( C, D

N

+

4 Boc

MgX ( )n NHBoc

BnO HO

1

2 3

( )n

OH

NHBoc

BnO and HO

OH

1

2 3

( )n

OH N3

polyhydroxylated aminocyclitols

Results and Discussion N-Boc-4-vinyl-2-azetidinone (4), the starting material employed in the new routes developed for synthesis of functionalized 6- and 5-membered carbocyclic products A and B, was prepared in enantiomerically pure form using the four-step sequence outlined in Scheme 2.

In the route,

the conversion of known optically pure Bose-Manhas 2-azetidinone 1, prepared by Staudinger reaction of the 4-anisidine imine of (R)-2,3-O-isopropylideneglyceraldehyde with benzyoxyacetyl chloride in the presence of Et3N,14 to the corresponding diol 2 was accomplished by using p-TsOH promoted hydrolysis in aqueous THF (89%).15 The resulting 1,2-diol moiety in 2 was then subjected to cleavage reaction with I2 and PPh316 to produce NPMP-4-vinyl-2-azetidinone 3 (91%). The PMP (p-methoxyphenyl) protecting group in 3 was transformed to a N-Boc group in 4 through sequential reactions with cerium(IV) ammonium nitrate (CAN) and (t-Boc)2O (53%, 4 steps from 1).

Scheme 2. Synthesis of 4-vinyl-2-azetidinone 4 from the Bose-Manhas lactam 1

3



O BnO O

N 1

HO

O

H PMP

a

BnO O

N 2

OH

H PMP

BnO

b O

N 3

c PMP

BnO N O Boc (3R,4S)-4

(a) p-TsOH, THF-H2O, reflux, 24 h, 89%; (b) PPh3, I2, imidazole, toluene, reflux, 5 h, 91%; (c) i. CAN, CH3CN-H2O, rt, 1 h, 71%; ii. (t-Boc)2O, Et3N, DMAP, CH2Cl2, 0 0C to rt, 12 h, 81%.

As stated above, we envisaged that 2-azetidinone 4 would serve as a versatile chiral synthon in sequences for the preparation of valuable enantiomerically pure substances. Relevant to this proposal is the expectation that the amide bond in 4 would be readily cleaved in reactions with various nucleophiles such as amines, alcohols, and organometallic reagents that form corresponding β–amino-amides, -esters, and -ketones.8a,8b We were aware of the earlier observation that ring opening reactions of 2-azetidinones with alkyl Grignard reagents invariably leads to mixtures of β–amino-ketones and -carbinols.17 However, we believed that formation of undesired carbinols in ring opening reactions of 4 with allyl and vinyl Grignards would be avoided if it is first converted to the Weinreb amide 5 by treatment with N,Odimethylhydroxylamine in the presence of Ti(OPr-i)4 (90%). An extensive optimization investigation led to the observation that addition of excess amounts of allylmagnesium bromide to 5 in THF at -30 0C for 2 h using a syringe pump generates the desired 1,6-diene 6 as the sole product in 95% isolated yield. Similarly, slow addition of vinylmagnesium bromide to 5 in Et2O at 0 0C produces 1,5-diene 8 in 78% yield (Scheme 3).

Scheme 3. Route for the conversion of 2-azetidinone 4 to functionalized carbocycles 7 and 9

4


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BnO

2 3

1

N

O

Boc

4

BnO b

a BnO N O

1

5

O

NHBoc

1

NHBoc

2 3

BnO

c

O

1

NHBoc 2 3

1

7

7

6

2 3

BnO

O d

O

1 2 3

BnO

NHBoc e

O

8

1

O OBn

2 3

NHBoc

O 1

NHBoc

2

2

3 3

9

9

OBn

NHBoc

(a) CH3ONHCH3∙HCl, Ti(OPr-i)4, dioxane, rt, 12 h, 90%; (b) allylMgBr, THF, -30 0C, 95%; (c) Grubb’s 2nd generation catalyst, toluene, 50 0C, 30 min, 93%; (d) vinylMgBr, Et2O, 0 0C, 78%; (e) Grubb’s 2nd generation catalyst, toluene, 50 0C, 20 min, 92%.

We next assessed the efficiencies of ring-closing metathesis13 reactions of 6 and 8 using Grubb’s 2nd generation Ru-catalyst. These processes, carried out in toluene, were observed to efficiently generate the corresponding (2R,3S)-2-benzyloxy-3-(N-Boc)aminocyclohex-4-en-1one 7 (93%) and (2R,3S)-2-benzyloxy-3-(N-Boc)aminocyclopent-4-en-1-one 9 (92%) (Scheme 3).

6-Membered Carbocycles and Aminocyclitols To demonstrate that 7 and 9 are potentially valuable chiral synthons in synthetic routes to aminocyclitols, we first explored stereoselective reductions of their carbonyl groups, and then assessed the outcomes of ensuing reactions that introduce additional functional groups. A thorough evaluation of stereoselective carbonyl reduction reactions of (2R,3S)-7 led to the observation that this cyclohexenone can be transformed to either (1S,2R,3S)-10 or (1R,2R,3S)-11 (Scheme 4). Specifically, treatment of 7 with LiEt3BH in THF at -20 oC leads to formation of the 1,2-cis diol 10 in 98% yield, via a process in which hydride transfer from the bulky superhydride occurs on the carbonyl face that is trans to the neighbouring 2benzyoxy group. The absolute stereochemistry of (1S,2R,3S)-10 was assigned by using X-ray crystallographic analysis of the acetate 12 (CCDC 1848803), which is derived by acetylation and t-Boc removal (Scheme 5). In contrast, Luche reduction18 (NaBH4, CeCl3∙7H2O in MeOH) 5



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of 7 forms the 1,2-trans diol, (1R,2R,3S)-11 as the major product (10:11 = 1:9, 81%). It is likely that in this process cerate ions coordinates to the C-1 carbonyl oxygen and the neighbouring O-benzyl ether oxygen in 7. In this event, hydride delivery would take place to the carbonyl face trans to the 3-(t-Boc)amine group.

Scheme 4. Stereoselective carbonyl reduction of 7 to 10 and 11 OH

O 1

2 3

OBn NHBoc

reducing agents conditions

(2R,3S)-7

2 3

Agent (eq)

1

+

NHBoc

(1S,2R,3S)-10

Reducing

Entry

1

OH OBn

Solvent

Additive (eq)

2 3

OBn NHBoc

(1R,2R,3S)-11

Temp

Time

Yield

o

( C)

(h)

(%)

10:11

1

LiEt3BH (1.2)

THF

-

-20

0.5

98

1:0

2

NaBH4 (1.5)

MeOH

CeCl3.7H2O (1.1)

-78

0.5

81

1:9

Scheme 5. Conversion of 10 to 12 for X-ray crystallography analysis OAc

OH 1

2 3

OBn

NHBoc (1S,2R,3S)-10

i) Ac2O, Et3N ii) HCl/dioxane

1

2 3

OBn

NH2HCl (1S,2R,3S)-12

Having demonstrated that 1,2-dihydroxy-3-amino-cyclohex-4-ene derivatives 10 and 11 can be prepared in an efficient and sterocontrolled manner, we next explored applications of these substances to the synthesis of 6-membered aminocyclitols. Accordingly, 11 was subjected to dihydroxylation reaction using standard Upjohn conditions19 (cat. OsO4, 2 equiv NMO, acetone-H2O-tBuOH). The process forms the (1R,2R,3S,4S,5R)-diol 16 as the predominant product. The anti-selectivity (to the 3-(N-t-Boc)amino group) of this dihydroxylation reaction is in accordance with Donohoe’s earlier findings.20To facilitate structural determination, 16 was converted to the corresponding tri-acetate 17 (Scheme 6). The structure and stereochemistry of 17 were then assigned using 2D-NOESY spectroscopic analysis (see SI). 6


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Scheme 6. Stereoselective dihydroxylation of 10 and 11 under Upjohn conditions

1

2 3

OBn NHBoc

(1R,2R,3S)-11

cat. OsO4, NMO

1

Acetone/H2O/t-BuOH rt, 8h

HO

2 3

OBn NHBoc

Ac2O, Et3N,

cat. OsO4, NMO

1

Acetone/H2O/t-BuOH rt, 8h, 70%

81%

NHBoc

83%

2 3

1

AcO

NHBoc (1S,2R,3S)-20

cat. OsO4, NMO

OBn NHBoc

OAc (1R,2R,3R,4S,5R)-17 OH

OBn

+

1

2 3

OBn

OAc

OAc OBn

2 3

NHBoc NHBoc HO OH OH (1S,2R,3S,4S,5R)-18 (1S,2R,3S,4R,5S)-19 70:30 mixture HO

OAc 2 3

Ac2O, Et3N

OH

(1S,2R,3S)-10

1

2 3

OBn

OH (1R,2R,3S,4S,5R)-16 predominant

OH 1

OAc

OH

OH

1

CH3CN/H2O, 2,6-lutidine HO rt, 8h, 70%

2 3

OBn

NHBoc OH (1S,2R,3S,4S,5R)-21 predominant

Ac2O, Et3N 81%

1

2 3

OBn

NHBoc OAc (1S,2R,3R,4S,5R)-22

AcO

In contrast to the highly stereoselective nature of the reaction of 1,2-anti-11, 1,2-syn-10 undergoes Upjohn dihydroxylation to produce a 7:3 mixture of 18 and 19. However, the acetate derivative 20, formed by acetylation of 1,2-syn-10, undergoes highly anti-selective dihydroxylation to form 21 as the major diol product (70%) under slightly modified Upjohn conditions (cat. OsO4, 2 equiv NMO, 2,6-lutidine, CH3CN-H2O). For simplicity purposes, 21 was converted to the tri-acetate 22 whose structure and stereochemistry were assigned using 2D-NOESY spectroscopy (see SI), (Scheme 6). The observed anti-selective, relative to the 3(N-t-Boc)amino group, nature of dihydroxylation of 20 is also in accordance with Donohoe’s earlier observations.20 To expand the scope of their synthetic applications, the 6-membered carbocycles 10 and 11 were subjected to epoxidation with m-CPBA. Epoxidations of mono N-protected amide and carbamate derivatives of cyclic allylic amines with peracids are known to occur with high degrees of syn-selectivity, presumably as a consequence of hydrogen-bonding interactions between the amide carbonyl groups with the peracid.20b, 21 In fact, epoxidations of 10 and 11 were found to produce the corresponding epoxides 23 (84%) and 24 (86%) stereoselectively 7



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(Scheme 7). In an effort aimed at determining if more functionally rich aminocyclitols can be accessed using this chemistry, we observed that epoxides 23 and 24 undergo regioselective epoxide ring-opening reactions with NaN3 under acidic conditions1a,21a to generate the functionally more diverse aminocyclitols 25 and 26, respectively (Scheme 7). For example, treatment of epoxide 23 with NaN3 in the presence of NH4Cl in MeOH forms the highly functionalized cyclohexane derivatives 25 as the predominant product (78%) via regioselective, less hindered azide addition at C5. The stereochemical outcome of azide addition to the epoxide 23 affording 4,5-trans-diaxial-4-hydroxy-5-azide 25 is also in accordance with the FurstPlattner rule. Moreover, epoxide 24 is transformed to azide 26 under the similar reaction conditions. The structure and stereochemistry of epoxide 23 was deduced by X-ray crystal structure analysis (CCDC 1877126) of the corresponding azide-addition product 25 (see below) and those of 26 were identified by analysis of the the 2D-NOESY and HSQC spectra of diacetate derivative 27 (Scheme 7).

Scheme 7. Transformation of 10 and 11 to polyhydroxylated aminocyclitols through epoxidation and subsequent azide-induced epoxide ring-opening reactions

1

2 3

OBn

NHBoc (1S,2R,3S)-10

m-CPBA, NaHCO3 CH2Cl2 0 oC to rt, 12h 84%

1

2 3

2 3

OBn

1

NaN3, NH4Cl o

NHBoc

O (1S,2R,3R,4R,5S)-23

MeOH, 80 C 18h, 78%

N3

OBn NHBoc

(1R,2R,3S)-11

m-CPBA, NaHCO3 CH Cl , 2

2

0 oC to rt, 12h 86%

1

O

2 3

2 3

OBn

NHBoc OH (1S,2R,3S,4R,5R)-25 OAc

OH

OH

OH 1

OH

OH

OH

OBn NHBoc

1

NaN3, NH4Cl o

MeOH, 80 C 18h, 75%

(1R,2R,3R,4R,5S)-24

N3

2 3

OBn

Ac2O, Et3N

NHBoc OH (1R,2R,3S,4R,5R)-26

1

N3

2 3

OBn

NHBoc OAc (1R,2R,3R,4R,5R)-27

5-Membered Carbocycles and Aminocyclitols

The chemical transformations used for stereoselective transformations of the 6-membered carbocycle 7 to the diverse 6-membered aminocyclitols 10-26 were applied to the 5-membered analog 9. Firstly, stereoselective reduction of 9 under Luche conditions18 (NaBH4, CeCl3∙7H2O 8


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in MeOH) produces 1,2-trans diol 13 as the predominant product (96%) (Scheme 8). The structure and stereochemistry of (1R,2R,3S)-13 were indirectly assigned by employing X-ray crystallographic analysis of the ester-sulfonamide derivative 15 (CCDC 1867550), formed by sequential acetylation, t-Boc-deprotection and sulfonylation of 13 (Scheme 9). Similar to Luche reduction of 7, coordination of cerate ion to the C-1 carbonyl and neighbouring 2benzyloxy ether oxygens in 9 likely guides hydride delivery to the carbonyl face opposite side trans to the 3-(N-t-Boc)-amine group.

Scheme 8. Stereoselective carbonyl reduction of 9 to 13 O

OH

OH

1 2

OBn

.

1

NaBH4/CeCl3 7H2O, MeOH

2

o

3

NHBoc (2R,3S)-9

-78 C, 45 min 96%

OBn

1

+

3

NHBoc (1R,2R,3S)-13 predominant

2

OBn

3

NHBoc (1S,2R,3S)-14

Scheme 9. Conversion of 13 to 15 for X-ray crystallography analysis OH 1 2 3

OBn

NHBoc

(1R,2R,3S)-13

i) Ac2O, Et3N ii) HCl/dioxane iii) 4-NO2PhSO2Cl

OAc 1 2

OBn

O N S H O (1R,2R,3S)-15 3

NO2

To demonstrate its use in routes for the production of more diversely functionalized 5membered aminocyclitols, (1R,2R,3S)-13 was subjected to dihydroxylation reaction under the Upjohn conditions (Scheme 10). This process stereoselectively generated 28, whose structure and stereochemistry were assigned by using COSY, HSQC and 2D-NOE spectroscopic analysis of its tri-acetate derivative 29. Like in the 6-membered series, this dihydroxylation reaction takes place on the alkene face that is anti to both of 3-(N-t-Boc)-amine and 1-hydroxyl groups in 13.20 Next, reaction of 13 with m-CPBA was observed to form the corresponding epoxide 30 (86%) in a manner that is syn to both of 1-hydroxyl and 3-(N-t-Boc)-amine groups.20b,21 9



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Finally, to show that more highly functionalized 5-membered aminocyclitols can be accessed using this protocol, epoxide 30 was subjected to reaction with NaN3 under acidic conditions (NaN3, NH4Cl in MeOH). However, under these conditions a mixture of regioisomers 31 and 32 was generated. In contrast, treatment of acetylated epoxide 33 with NaN3 under neutral conditions (NaN3, DMF-H2O, 100 oC) leads to production of the azide 31 as the predominant product in 85% yield through a pathway involving regioselective epoxide ring-opening promoted by azide addition to C4 (Scheme 10). The stereochemistry of 31 was assigned by analysis of the COSY, HSQC and NOE spectra of the corresponding diacetate 34 (see SI).

Scheme 10. Transformation of 13 to polyhydroxylated aminocyclitols through dihydroxylation, epoxidation and subsequent azide-induced epoxide ring-opening reactions OH 2

3

OAc

OH

1

OBn

cat. OsO4, NMO

1

HO

Acetone/H2O/t-BuOH rt, 5h NHBoc

2 3

HO

82%

NHBoc

2 3

AcO

OBn

NHBoc

(1S,2R,3R,4S,5S)-29

(1R,2R,3S,4S,5S)-28

(1R,2R,3S)-13

1

AcO

OBn Ac2O, Et3N

OH

OH

OH

1

1

1

2

OBn

3

NHBoc (1R,2R,3S)-13

m-CPBA, NaHCO3 o CH Cl , 0 C to rt 2

2

12h, 86%

O

2 3

NaN3, NH4Cl

OBn

HO

2

o

MeOH, 80 C

NHBoc

(1S,2R,3R,4R,5S)-30 Ac2O, Et3N

O

2 3

OBn

+

1

N3

2

HO NHBoc NHBoc 32 31 (1R,2R,3S,4R,5S)(1R,2R,3S,4S,5R)mixture of regio-isomers OAc

OH OBn

NHBoc

NaN3, H2O-DMF 30 85% from

(1S,2R,3R,4R,5R)-33

OBn

3

3

N3

OAc 1

OH

1

HO

2

N3

3

OBn

NHBoc (1R,2R,3S,4S,5R)-31 predominant

Ac2O Et3N

1

AcO

2

N3

OBn

3

NHBoc (1S,2R,3S,4S,5R)-34

Conclusion

In summary, in the effort described above we developed efficient pathways for stereoselective transformation of the readily available 4-vinyl-2-azetidinone 4 to highly functionalized 6- and 5-membered carbocycles 7 and 9, through allyl- or vinyl-Grignard addition followed by Ru10


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catalysed ring-closing metathesis of the resulting dienes 6 and 8. In addition, the results demonstrate that 7 and 9 can be transformed to a variety of highly functionalized aminocyclitols 10-34 through routes involving stereoselective carbonyl reductions, dihydroxylation, epoxidation and azide promoted epoxide ring opening.

Experimental Section General All commercial reagents were used as obtained from commercial sources unless otherwise specified. Reactions were performed with reagent grade solvents except dichloromethane (DCM), ether, THF which were dried and purified using a solvent purification system. The progress of reactions was monitored using thin layer chromatography (TLC) and visualized using UV light and by staining with ethanolic phosphomolybdic acid (PMA) solution or KMnO4 solution followed by heating. Flash column chromatography was carried out on silica gel (38-75 μm). Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60 F254 plates. Preparative thin layer chromatography (PLC) was performed on Merck silica gel 60 F254 2mm plates. Nuclear magnetic resonance (NMR) spectra were recorded using Bruker 500 MHz NMR instrument (1H NMR at 300, 500 MHz and 13C NMR at 75, 125 MHz). 1H NMR data are reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), integration, coupling constants (Hz). Data for 13C NMR are reported in terms of chemical shift (δ, ppm). Specific rotations were measured on a Rudolph Autopol IV (Automatic polarimeter). High-resolution mass spectra and elemental analysis were obtained from the Korea Research Institute of Chemical Technology. HR-MS were measured with fast atom bombardment (FAB) ionization via double focusing mass analyzer (magnetic and electric fields). (3R,4S)-3-(benzyloxy)-1-(4-methoxyphenyl)-4-vinylazetidin-2-one (3) A solution of iodine (2.2 g, 8.7 mmol) in toluene (15 mL) was added dropwise to

BnO O

a solution of 2 (2.0 g, 5.8 mmol), imidazole (1.6 g, 23.3 mmol), and PPh3 (6.12

N

g, 23.8 mmol) in toluene (20 mL) at reflux temperature. Once the addition was complete, the mixture was stirred under same temperature for 5 h, allowed to cool O

to rt, and quenched with a solution of Na2S2O3 (aq). The mixture was extracted

with EtOAc (150 mL X 3) and washed with H2O followed by saturated NaCl (aq). The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title 11



compound as a white solid. Yield: 91% (1.6 g as a white solid); mp: 138.4-140.1 oC; [α]D 23 = +48.5 (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.42-7.33 (m, 7H), 6.87 (d, J = 9.1 Hz, 2H), 6.03 (ddd, J = 17.3, 10.2, 8.4 Hz, 1H), 5.60-5.49 (m, 2H), 4.88 (d, J = 4.9 Hz, 1H), 4.79-4.70 (m, 2H), 4.62 (dd, J = 8.4, 4.9 Hz, 1H), 3.80 (s, 3H).; 13C{1H} NMR (75 MHz, CDCl3) δ 163.6, 156.4, 136.7, 132.8, 131.1, 128.5, 128.1, 128.1, 121.9, 118.6, 114.3, 82.2, 72.8, 61.1, 55.5.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C19H20NO3 310.1443; Found 310.1449. (3R,4S)-3-(benzyloxy)-4-vinylazetidin-2-one A solution of Ammonium cerium(IV) nitrate (5.66 g, 10.3 mmol) in H2O (30 mL) was

BnO O

added dropwise to a solution of (3R,4S)-3-(benzyloxy)-1-(4-methoxyphenyl)-4-

NH

vinylazetidin-2-one (1.0 g mg, 3.23 mmol) in CH3CN (60 mL) at 0 oC for 40 min. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (150

mL X 3). The combined organic layer was washed with NaHCO3 (aq) followed by 40% NaHSO3 (aq). The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (2:1) as an eluent to afford the title compound as a white solid. Yield: 71% (466 mg as a white solid); mp: 91.1-92.2 oC; [α]D 23 = +47.8 (c 0.75, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 6.07 (bs, 1H), 6.05-5.93 (m, 1H), 5.42-5.34 (m, 2H), 4.82-4.79 (m, 1H), 4.70 (dd, J = 19.5, 9.7 Hz, 2H), 4.26 (dd, J = 7.5, 4.8 Hz, 1H).; δ 7.37 – 7.31 (m, 5H), 6.26 (s, 1H), 6.02-5.95 (m, 1H), 5.41 – 5.35 (m, 2H), 4.81-4.79 (m, 1H), 4.70 (q, J = 11.7 Hz, 2H), 4.26 (dd, J = 7.5, 4.8 Hz, 1H).; 13C{1H} NMR (125 MHz, CDCl3) δ 167.8, 136.7, 133.9, 128.4, 128.1, 119.8, 83.9, 72.5, 57.2.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C12H14NO2 204.1025; Found 204.1048. Tert-butyl (3R,4S)-3-(benzyloxy)-2-oxo-4-vinylazetidine-1-carboxylate (4) A magnetically stirred mixture of (3R,4S)-3-(benzyloxy)-4-vinylazetidin-2-one (1.0

BnO O

g, 4.92 mmol) in dry dichloromethane (10 mL) maintained at 0 oC was treated with N O

O

di-tert-butyl dicarbonate (1.29 g, 5.90 mmol), Et3N (0.89 mL, 6.39 mmol), and then DMAP (cat.). The reaction mixture was stirred at rt for 12 h, quenched with H2O and then extracted with dichloromethane (2 X 50 mL). The combined organic layer was

washed with 1 N HCl (aq) and sat’d NaHCO3 (aq). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:3) as an eluent to afford the title compound as a white solid. Yield: 81% (1.21 g as a white solid); mp: 55.1-56.6 oC; [α]D 23 = +65.8 (c 2.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.33 (m, 5H), 5.98-5.91 (m, 1H), 5.49-5.45 (m, 2H), 4.77-4.67 (m, 3H), 4.52 (dd, 12


Page 12 of 27

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J = 8.1, 5.8 Hz, 1H), 1.52 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 164.4, 147.8, 136.3, 131.1, 128.5, 128.2, 128.1, 121.6, 83.6, 81.6, 72.9, 60.2, 27.9.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C17H22NO4 304.1549; Found 304.1553. Tert-butyl((3S,4R)-4-(benzyloxy)-5-(methoxy(methyl)amino)-5-oxopent-1-en-3-yl)carbamate (5) BnO N O

NHBoc

O

A magnetically stirred mixture of 4 (1.1 g, 3.63 mmol) in dry 1,4-dioxane (15 mL) was treated with CH3NH(OCH3).HCl (531 mg, 5.44 mmol) followed by the addition of Ti(OPr-i)4 (5.5 mL). The reaction mixture was stirred at rt for

12 h, quenched with H2O, and treated with EtOAc (50 mL). The residue was filtered through celite pad and washed thoroughly with excess of EtOAc. The resulting filtrate was washed with H2O and the organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (2:1) as an eluent to afford the title compound as colorless oil. Yield: 90% (1.19 g as a colorless oil); [α]D 23 = +4.9 (c 1.9, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.387.29 (m, 5H), 5.90-5.84 (m, 1H), 5.28-5.18 (m, 2H), 5.14 (d, J = 8.3 Hz, 1H), 4.80 (d, J = 12.1 Hz, 1H), 4.69 (s, 1H), 4.40 (d, J = 12.1 Hz, 1H), 4.31 (d, J = 2.4 Hz, 1H), 3.59 (s, 3H), 3.21 (s, 3H), 1.44 (s, 9H).; C{1H} NMR (125 MHz, CDCl3) δ 170.4, 155.5, 137.1, 136.1, 128.4, 128.2, 127.9, 79.4, 71.8, 53.6,

13

32.8, 28.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C19H29N2O5 365.2076; Found 365.2099. Tert-butyl ((3S,4R)-4-(benzyloxy)-5-oxoocta-1,7-dien-3-yl)carbamate (6) BnO O

NHBoc

To a solution of 5 (540 mg, 1.48 mmol) in dry THF (10 mL) was added 1.0 N allyl magnesium bromide (10.4 mL, 0.54 mmol) dropwise using syringe pump for 2 hours at -30 oC. The reaction mixture was quenched with sat’d NH4Cl (aq) and extracted with EtOAc (2 X 50 mL). The combined organic layer was washed with

H2O followed by saturated NaCl (aq). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as colorless oil. Yield: 95% (461 mg as a colorless oil); [α]D 23 = -24.8 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.40-7.34 (m, 5H), 5.94-5.82 (m, 2H), 5.29-5.12 (m, 5H), 4.73-4.66 (m, 2H), 4.55 (d, J = 11.6 Hz, 1H), 4.01 (s, 1H), 3.41-3.29 (m, 2H), 1.44 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 208.2, 155.2, 136.9, 135.1, 129.8, 128.5, 128.2, 128.1, 119.2, 116.5, 84.7, 79.8, 73.0, 53.5, 44.3, 28.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C20H28NO4 346.2018; Found 346.2012. Tert-butyl ((1S,6R)-6-(benzyloxy)-5-oxocyclohex-2-en-1-yl)carbamate (7)

13



To a degassed solution of 6 (210 mg, 0.61 mmol) in dry toluene (20 mL) was added

O

Grubb’s 2nd generation catalyst (26 mg, 5.0 mol %) and the reaction mixture was

OBn

heated to 50 oC for 30 min. The solvent was evaporated under reduced pressure and

NHBoc

the crude residue was purified on silica gel column chromatography using

EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid. Yield: 93% (179 mg as a white solid); mp: 118.3-119.8 oC; [α]D 23 = +80.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.79 (q, J = 10.6 Hz, 2H), 4.85 (d, J = 11.8 Hz, 1H), 4.71 (s, 1H), 4.53 (d, J = 11.8 Hz, 1H), 4.44 (t, J = 7.4 Hz, 1H), 4.21 (s, 1H), 3.05 (s, 2H), 1.47 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 205.7, 155.0, 137.4, 128.5, 128.2, 128.0, 127.9, 124.3, 82.9, 80.0, 72.7, 54.8, 39.7, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H24NO4 318.1705; Found 318.1698. Tert-butyl ((3S,4R)-4-(benzyloxy)-5-oxohepta-1,6-dien-3-yl)carbamate (8) BnO

NHBoc

To a solution of 5 (250 mg, 0.68 mmol) in dry diethyl ether (5.0 mL) was added 1.0 N vinyl magnesium bromide (6.9 mL, 6.86 mmol) dropwise at 0 oC. The reaction

O

mixture was stirred at same temperature for additional 40 min., quenched with saturated NH4Cl (aq) and extracted with EtOAc (2 X 50 mL). The combined

organic layer was washed with H2O followed by saturated NaCl (aq). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as colorless oil. Yield: 78% (177 mg as a colorless oil); [α]D 23 = -12.7 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 6.80 (dd, J = 16.5, 10.8 Hz, 1H), 6.39 (d, J = 17.3 Hz, 1H), 5.89-5.82 (m, 1H), 5.79 (dd, J = 10.6, 1.5 Hz, 1H), 5.29-5.20 (m, 2H), 5.09 (s, 1H), 4.70 (d, J = 11.6 Hz, 1H), 4.65 (s, 1H), 4.49 (d, J = 11.6 Hz, 1H), 4.12 (s, 1H), 1.43 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 199.1, 155.1, 136.9, 135.2, 131.7, 129.6, 128.5, 128.2, 128.1, 116.4, 84.3, 79.7, 72.8, 54.0, 28.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C19H26NO4 332.1862; Found 332.1883. Tert-butyl ((1S,5R)-5-(benzyloxy)-4-oxocyclopent-2-en-1-yl)carbamate (9) To a degassed solution of 8 (90 mg, 0.27 mmol) in dry toluene (12 mL) was added

O OBn NHBoc

Grubb’s 2nd generation catalyst (11.5 mg, 5.0 mol %) and the reaction mixture was heated to 50 oC for 20 min. The solvent was evaporated under reduced pressure and the crude residue was purified on silica gel column chromatography using EtOAc/hexanes

(1:2) as an eluent to afford the title compound as a white solid. Yield: 92% (76 mg as a white solid); mp: 96.3-98.8 oC; [α]D 23 = +81.3 (c 0.5, CHCl3); 1H NMR (500 14


Page 14 of 27

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MHz, CDCl3) δ 7.437.31 (m, 6H), 6.25 (d, J = 5.7 Hz, 1H), 4.97 (d, J = 12.1 Hz, 1H), 4.87 (d, J = 12.1 Hz, 1H), 4.78 (s, 1H), 4.70 (s, 1H), 3.98 (d, J = 3.0 Hz, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 203.0, 159.4, 154.8, 137.3, 132.8, 128.5, 128.1, 128.0, 82.9, 80.5, 72.5, 57.3, 28.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C17H22NO4 304.1549; Found 304.1568. Tert-butyl ((1S,5S,6R)-6-(benzyloxy)-5-hydroxycyclohex-2-en-1-yl)carbamate (10) To a solution of 7 (100 mg, 0.32 mmol) in dry THF (5 mL) was added 1.0 M super-

OH OBn NHBoc

hydride solution in THF dropwise at -20 oC. The reaction mixture was stirred at same temperature for additional 30 min and quenched with 20% NaHSO4 (aq). The mixture was extracted with EtOAc (2 X 25 mL), washed with H2O, and saturated NaCl (aq).

The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid. Yield: 98% (99 mg as a white solid); mp: 166.9-168.7 oC; [α]D 23 = +45.1 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.78-5.76 (m, 1H), 5.58-5.55 (m, 1H), 4.81 (d, J = 12.0 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 6.1 Hz, 1H), 4.43 (s, 1H), 3.96 (s, 1H), 3.66-3.65 (m, 1H), 2.372.25 (m, 2H), 2.19 (d, J = 6.2 Hz, 1H), 1.50 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.3, 138.2, 128.5, 128.1, 127.9, 127.7, 125.4, 83.1, 79.6, 73.7, 69.0, 52.1, 31.8, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H26NO4 320.1862; Found 320.1854. Tert-butyl ((1S,5R,6R)-6-(benzyloxy)-5-hydroxycyclohex-2-en-1-yl)carbamate (11) To a solution of 7 (100 mg, 0.32 mmol) in MeOH (5 mL) was added CeCl3.7H2O (141

OH OBn NHBoc

mg, 0.38 mmol) followed by the dropwise addition of NaBH4 (18 mg, 0.47 mmol) in MeOH at -78 oC. The reaction mixture was stirred at same temperature for 30 min and quenched with NaHCO3 (aq). The solvents were evaporated under reduced

pressure, treated with H2O and extracted with EtOAc (2 X 25 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid. Yield: 81% (82 mg as a white solid); mp: 114.7-116.5 oC; [α]D 23 = +54.4 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 5.69-5.66 (m, 1H), 5.50 (d, J = 9.7 Hz, 1H), 4.88 (d, J = 11.3 Hz, 1H), 4.72-4.68 (m, 2H), 4.38 (s, 1H), 3.94 (q, J = 7.3, 6.6 Hz, 1H), 3.45-3.42 (m, 1H), 2.56-2.51 (m, 1H), 2.48 (s, 1H), 2.16-2.09 (m, 1H), 1.49 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.1, 138.3, 128.4, 127.8, 127.7, 124.8, 79.7, 79.6, 71.4, 65.6, 48.9, 30.7, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H26NO4 320.1862; Found 320.1862. 15



(1S,5S,6R)-5-amino-6-(benzyloxy)cyclohex-3-en-1-yl acetate hydrochloride (12) To a solution of 20 (50 mg, 0.14 mmol) in DCM (5 mL) was added 4 N HCl in 1,4-

OAc OBn

dioxane (1.0 mL) and the reaction mixture was stirred at rt for 4 h. The solvent was

NH2HCl

evaporated under reduced pressure and the crude product was recrystallized using DCM and hexanes to get 12 as colorless crystals.

Yield: 63% (26 mg as a crystal); mp: 208.1-211.7 oC; [α]D 23 = +57.8 (c 0.5, CHCl3); 1H NMR (500 MHz, CD3OD) δ 7.42-7.31 (m, 5H), 5.94-5.90 (m, 1H), 5.69-5.67 (m, 2H), 4.80 (d, J = 11.2 Hz, 1H), 4.57 (d, J = 11.2 Hz, 1H), 3.99-3.96 (m, 1H), 3.78 (dd, J = 9.1, 2.2 Hz, 1H), 2.60-2.54 (m, 1H), 2.452.39 (m, 1H), 2.08 (s, 3H).; 13C{1H} NMR (125 MHz, CD3OD) δ 170.5, 137.3, 128.7, 128.1, 128.0, 127.7, 121.4, 76.5, 70.5, 65.3, 49.9, 30.0, 19.5.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C15H20NO3 262.1443; Found 262.1425. Tert-butyl ((1S,4R,5R)-5-(benzyloxy)-4-hydroxycyclopent-2-en-1-yl)carbamate (13) To a solution of 9 (100 mg, 0.33 mmol) in MeOH (5 mL) was added CeCl3.7H2O (147

OH OBn NHBoc

mg, 0.38 mmol) followed by the dropwise addition of NaBH4 (25 mg, 0.66 mmol) in MeOH at -78 oC. The Reaction mixture was stirred at same temperature for 30 min and quenched with NaHCO3 (aq). The solvents were evaporated under reduced pressure,

treated with H2O and extracted with EtOAc (2 X 25 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid. Yield: 96% (97 mg as a white solid); mp: 115.7-116.6 oC; [α]D 23 = +42.7 (c 0.8, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 5.90 (s, br, 1H), 5.76 (d, J = 5.6 Hz, 1H), 4.86 (d, J = 7.3 Hz, 1H), 4.79 (d, J = 11.8 Hz, 1H), 4.71 (d, J = 11.8 Hz, 1H), 4.65 (d, J = 7.0 Hz, 1H), 4.43 (d, J = 7.1 Hz, 1H), 3.86 (s, 1H), 2.81 (d, J = 6.9 Hz, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.1, 138.1, 134.2, 132.6, 128.4, 127.9, 127.7, 93.2, 80.2, 79.9, 71.9, 60.7, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C17H24NO4 306.1705; Found 306.1711. Tert-butyl ((1S,5R)-5-(benzyloxy)-4-oxocyclopent-2-en-1-yl)carbamate (15) To a solution of 13 (60 mg, 0.196 mmol) in dry DCM (6 mL) was added

OAc

Ac2O (24 mg, 0.236 mmol), Et3N (0.055 mL, 0.392 mmol), and DMAP

OBn O HN S O

NO2

(cat.) at 0 oC. The reaction mixture was stirred at rt for 2 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was dried over

MgSO4, filtered, and evaporated under reduced pressure. The crude residue was dissolved in DCM (5 16


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mL) was added 4 N HCl in 1,4-dioxane (1.5 mL) and the reaction was stirred at rt for 6 h. The reaction mixture was quenched with saturated NaHCO3 (aq) and extracted with DCM (2 X 25 mL). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue (30 mg, 0.121 mmol) was dissolved in dry DCM (3 mL) and 4-nitrobenzenesulfonyl chloride (32 mg, 0.145 mmol), Et3N (0.034 mL, 0.242 mmol), and DMAP (cat.) were added successively to the solution at 0 C. The reaction mixture was stirred at rt for 8 h and after completion of reaction, it was quenched with

o

1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid. Yield: 60% (31 mg as a white solid); mp: 164.4-166.8 oC; [α]D 23 = -19.2 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.37-7.33 (m, 3H), 7.22-7.20 (m, 2H), 5.90-5.88 (m, 1H), 5.77-5.75 (m, 1H), 5.49-5.48 (m, 1H), 4.95 (d, J = 9.6 Hz, 1H), 4.61 (d, J = 11.7 Hz, 1H), 4.45-4.42 (m, 1H), 4.39 (d, J = 11.7 Hz, 1H), 3.92 (t, J = 3.5 Hz, 1H), 2.07 (s, 3H).; C{1H} NMR (125 MHz, CDCl3) δ 170.1, 150.0, 146.5, 137.1, 133.4, 132.3, 128.5, 128.3, 128.1, 127.5,

13

124.3, 89.6, 81.1, 72.1, 63.2.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C20H21N2O7S 433.1069; Found 433.1061. (1S,2R,4R,5R,6R)-5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)cyclohexane-1,2,4-triyl triacetate (17) To an ice cold solution of 11 (30 mg, 0.09 mmol) in acetone:water 9:1, NMO

OAc OBn NHBoc

AcO OAc

(22 mg, 0.19 mmol) was added followed by an OsO4 (0.6 mg, 2.5 mol%) solution in tBuOH, and the reaction was stirred at room temperature for 8 h. After completion of the reaction, it was quenched by addition of Na2S2O3 and

the acetone was evaporated under reduced pressure. The solution was extracted with DCM (2 X 25 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was dissolved in dry DCM (3.0 mL) and Ac2O (98 mg, 0.38 mmol), Et3N (0.03 mL, 0.24 mmol), and DMAP (cat.) were added successively to the solution. The reaction mixture was stirred at rt for 2 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid. Yield: 81% (36 mg as a white solid); mp: 157.2-159.1 oC; [α]D 23 = +5.7 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.38 (s, 1H), 5.25-5.19 (m, 1H), 5.02 (d, J = 10.6 Hz, 1H), 4.71 (s, 2H), 4.50 (d, J = 8.2 Hz, 1H), 3.99 (q, J = 9.5 Hz, 1H), 3.69 (t, J = 8.9 Hz, 1H), 2.28 (dt, J = 14.1, 4.4 Hz, 1H), 2.14 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 1.67-1.58 (m, 1H), 1.46 (s, 9H).; 13C{1H} NMR (125 17



MHz, CDCl3) δ 170.5, 170.0, 169.9, 155.3, 137.9, 128.4, 127.9, 127.8, 79.9, 79.8, 74.4, 71.2, 71.1, 67.4, 52.9, 30.8, 28.3, 21.1, 21.0, 20.7.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H28NO6 354.1917; Found 354.1929. (1S,5S,6R)-6-(benzyloxy)-5-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl acetate (20) To a solution of 10 (150 mg, 0.47 mmol) in dry DCM (10 mL) was added Ac2O (0.09

OAc OBn

mL, 0.94 mmol), Et3N (0.16 mL, 1.17 mmol), and DMAP (cat.) at 0 oC. The reaction

NHBoc

mixture was stirred at rt for 6 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was

dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid. Yield: 83% (141 mg as a white solid); mp: 87.8-89.2 oC; [α]D 23 = +87.5 (c 0.25, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 5.78-5.75 (m, 2H), 5.62 (dd, J = 10.0, 3.4 Hz, 1H), 5.18 (t, J = 4.8 Hz, 1H), 4.73 (q, J = 12.2 Hz, 1H), 4.52-4.51 (m, 1H), 4.41 (s, 1H), 3.68 (dd, J = 4.8, 2.1 Hz, 1H), 2.49-2.33 (m, 2H), 2.06 (s, 3H), 1.49 (s, 9H).; C{1H} NMR (125 MHz, CDCl3) δ 170.8, 155.1, 138.4, 128.3, 127.8, 127.6, 127.1, 125.4, 79.7, 79.7,

13

71.4, 68.2, 49.7, 28.4, 27.9, 21.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C20H28NO5 362.1967; Found 362.1996. (1S,2R,3S,4S,5R)-2-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4,5-dihydroxycyclohexyl acetate (21) To an ice cold solution of 20 (41 mg, 0.11 mmol) in CH3CN:H2O (3:1), NMO

OAc OBn HO

NHBoc OH

(27 mg, 0.23 mmol), and 2,6-lutidine (cat.) were added followed by an OsO4 (1.5 mg, 5 mol%), and the reaction was stirred at water bath for 8 h. After completion of the reaction, it was quenched by addition of Na2S2O3 and the

solvents were evaporated under reduced pressure. The solution was extracted with DCM (2 X 25 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (2:1) as an eluent to afford the title compound as a white solid. Yield: 70% (31 mg as a white solid); mp: 146.8-149.5 oC; [α]D 23 = +13.8 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.44 (s, 1H), 4.74-4.70 (m, 2H), 4.47 (d, J = 11.4 Hz, 1H), 4.024.96 (m, 2H), 3.59 (d, J = 6.3 Hz, 1H), 3.47 (s, 1H), 2.86 (s, 1H), 2.30 (d, J = 14.5 Hz, 1H), 2.11 (s, 3H), 1.72 (d, J = 14.5 Hz, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 170.4, 157.5, 137.3, 128.6, 128.2, 128.1, 80.5, 73.9, 71.9, 68.0, 66.9, 52.1, 30.2, 29.7, 28.3, 21.3.; HRMS (FAB, double 18


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focusing) m/z: [M+H]+ Calcd for C20H30NO7 396.2022; Found 396.1995. (1S,2R,4S,5R,6R)-5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)cyclohexane-1,2,4-triyl triacetate (22) To a solution of 21 (30 mg, 0.076 mmol) in dry DCM (4 mL) was added Ac2O

OAc OBn NHBoc

AcO OAc

(0.014 mL, 0.152 mmol), Et3N (0.026 mL, 0.190 mmol), and DMAP (cat.) at 0 oC. The reaction mixture was stirred at rt for 4 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was dried over MgSO4, filtered, and

evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid. Yield: 81% (29 mg as a white solid); mp: 169.3-171.4 oC; [α]D 23 = +9.8 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.36-7.28 (m, 5H), 5.47-5.45 (m, 1H), 5.26-5.24 (m, 1H), 4.92-4.90 (m, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.34 (d, J = 8.7 Hz, 1H), 4.30-4.24 (m, 1H), 3.46 (d, J = 8.8 Hz, 1H), 2.36-2.32 (m, 1H), 2.12 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.73-1.68 (m, 1H), 1.47 (s, 9H).; C{1H} NMR (125 MHz, CDCl3) δ 170.5, 170.4, 170.2, 155.6, 137.5, 128.5, 128.1, 127.9, 79.7, 97.6,

13

71.6, 71.1, 67.9, 66.3, 50.1, 28.9, 28.4, 21.2, 21.1, 20.7.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C24H34NO9 480.2234; Found 480.2228. Tert-butyl((1R,2R,3R,4S,6S)-3-(benzyloxy)-4-hydroxy-7-oxabicyclo[4.1.0]heptan-2-yl)carbamate (23) To a solution of 10 (60 mg, 0.19 mmol) in dry DCM (7 mL) was added m-CPBA (84

OH OBn O

NHBoc

mg, 0.38 mmol) followed by NaHCO3 (32 mg, 0.38 mmol) and the reaction mixture was stirred at rt for 12 h. After completion of reaction, it was quenched with Na2SO3 and diluted with H2O. The mixture was extracted with DCM (2 X 25 mL), washed

with H2O, and saturated NaHCO3 (aq). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid. Yield: 84% (53 mg as a white solid); mp: 118.9-120.9 oC; [α]D 23 = +14.1 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ δ 7.38-7.28 (m, 5H), 4.88 (d, J = 8.6 Hz, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.39 (dt, J = 7.8, 3.3 Hz, 1H), 3.89 (s, 1H), 3.36-3.32 (m, 3H), 2.22-2.09 (m, 3H), 1.51 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.4, 137.9, 128.5, 127.9, 127.8, 79.9, 78.5, 54.2, 53.8, 48.0, 29.1, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H26NO5 336.1811; Found 336.1805.

19



Tert-butyl((1R,2R,3R,4R,6S)-3-(benzyloxy)-4-hydroxy-7-oxabicyclo[4.1.0]heptan-2-yl)carbamate (24) To a solution of 11 (60 mg, 0.19 mmol) in dry DCM (7 mL) was added m-CPBA (84

OH OBn O

NHBoc

mg, 0.38 mmol) followed by NaHCO3 (32 mg, 0.38 mmol) and the reaction mixture was stirred at rt for 12 h. After completion of reaction, it was quenched with Na2SO3 and diluted with H2O. The mixture was extracted with DCM (2 X 25 mL), washed

with H2O, and saturated NaHCO3 (aq). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid. Yield: 86% (54 mg as a white solid); mp: 148.1-150.2 oC; [α]D 23 = +14.5 (c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 4.97 (d, J = 9.4 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.61 (d, J = 11.4 Hz, 1H), 4.28 (s, 1H), 3.74 (q, J = 6.9 Hz, 1H), 3.40-3.33 (m, 3H), 2.78 (s, 1H), 2.39 (dt, J = 15.5, 4.7 Hz, 1H), 2.06 (dd, J = 15.5, 7.2 Hz, 1H), 1.50 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.2, 137.8, 128.5, 128.0, 127.9, 79.9, 79.7, 73.4, 68.6, 55.4, 53.1, 50.4, 31.4, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H26NO5 336.1811; Found 336.1831. Tert-butyl ((1S,2R,3R,5S,6R)-3-azido-6-(benzyloxy)-2,5-dihydroxycyclohexyl)carbamate (25) To a solution of 23 (30 mg, 0.089 mmol) in MeOH (4 mL) was added NaN3 (58

OH OBn N3

NHBoc OH

mg, 0.89 mmol) followed by the addition of 1.2 M NH4Cl solution (1.0 mL). The reaction mixture was heated to 80 oC for 18 h, after completion of reaction, it was evaporated under vacuum and the residue was diluted with H2O. The mixture was extracted with DCM (2 X 25 mL) and washed with saturated NaCl

(aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid. Yield: 78% (26 mg as a white solid); mp: 136.8-138.5 oC; [α]D 23 = -20.8 (c 1.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.38-7.28 (m, 5H), 4.87 (s, 1H), 4.74 (d, J = 11.5 Hz, 1H), 4.64 (d, J = 11.5 Hz, 1H), 4.12 (s, 1H), 4.03-3.96 (m, 3H), 3.60 (s, 1H), 2.36 (s, 1H), 2.12-2.06 (m, 1H), 1.92-1.85 (m, 1H), 1.49 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 156.9, 137.7, 128.6, 128.1, 127.8, 80.6, 72.5, 70.9, 66.4, 65.9, 59.7, 51.3, 30.8, 28.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H27N4O5 379.1981; Found 379.1951.

20


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Tert-butyl ((1S,2R,3R,5R,6R)-3-azido-6-(benzyloxy)-2,5-dihydroxycyclohexyl)carbamate (26) To a solution of 24 (30 mg, 0.089 mmol) in MeOH (4 mL) was added NaN3 (58

OH OBn N3

NHBoc OH

mg, 0.89 mmol) followed by the addition of 1.2 M NH4Cl solution (1.0 mL). The reaction mixture was heated to 80 oC for 18 h, after completion of reaction, it was evaporated under vacuum and the residue was diluted with H2O. The mixture

was extracted with DCM (2 X 25 mL) and washed with saturated NaCl (aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid. Yield: 75% (25 mg as a white solid); mp: 122.8-124.4 oC; [α]D 23 = +1.8 (c 1.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.56 (s, 1H), 4.74 (d, J = 11.5 Hz, 1H), 4.61 (d, J = 11.5 Hz, 1H), 4.06-4.01 (m, 3H), 3.82 (q, J = 7.2 Hz, 1H), 3.68 (s, 1H), 3.56 (s, 1H), 2.30 (s, 1H), 2.06-1.95 (m, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 157.2, 137.8, 128.6, 128.0, 127.8, 80.5, 79.2, 73.2, 72.2, 69.3, 58.9, 53.1, 32.0, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H27N4O5 379.1981; Found 379.2000. (1R,2R,3S,4R,5R)-5-azido-2-(benzyloxy)-3-((tert-butoxycarbonyl)amino)cyclohexane-1,4-diyl diacetate (27) To a solution of 26 (20 mg, 0.05 mmol) in dry DCM (2 mL) was added Ac2O (14

OAc OBn N3

NHBoc OAc

mg, 0.13 mmol), Et3N (0.022 mL, 0.16 mmol), and DMAP (cat.) at 0 oC. The reaction mixture was stirred at rt for 4 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced

pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes as an eluent to afford the title compound as a white solid. Yield: 78% (19 mg as a white solid); mp: 109.9-111.1 oC; [α]D 23 = -6.2 (c 0.34, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.31 (m, 5H), 5.19 (q, J = 4.0 Hz, 1H), 5.11 (dd, J = 9.0, 3.9 Hz, 1H), 5.01 (d, J = 8.1 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 4.61-4.57 (m, 2H), 3.92-3.87 (m, 1H), 3.65 (t, J = 4.5 Hz, 1H), 2.13 (s, 3H), 2.11 (s, 3H), 2.06-2.03 (m, 2H), 1.47 (s, 9H).; 13C{1H} NMR (75 MHz, CDCl3) δ 169.8, 168.9, 155.2, 137.2, 128.5, 127.9, 127.9, 79.9, 75.9, 72.8, 72.3, 70.4, 55.1, 49.3, 30.4, 28.3, 21.1, 20.9.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C22H31N4O7 463.2193; Found 463.2171.

21



(1S,2S,3S,4R,5R)-4-(benzyloxy)-5-((tert-butoxycarbonyl)amino)cyclopentane-1,2,3-triyl triacetate (29) To an ice cold solution of 13 (40 mg, 0.131) in acetone:water 9:1, NMO (31 mg,

OAc AcO

OBn

AcO

NHBoc

0.262) was added followed by an OsO4 solution (0.8 mg, 2.5 mol%) in tBuOH, and the reaction was stirred at room temperature for 5 h. After completion of the reaction, it was quenched by addition of Na2S2O3 and the acetone was evaporated

under reduced pressure. The solution was extracted with DCM (2 X 25 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was dissolved in dry DCM (5 mL) was added Ac2O (0.06 mL, 0.655 mmol), Et3N (0.09 mL, 0.655 mmol), and DMAP (cat.) at 0 oC. The reaction mixture was stirred at rt for 2 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid. Yield: 82% (50 mg as a white solid); mp: 89.9-91.1 oC; [α]D 23 = -9.9 (c 0.9, CHCl3); 1H NMR (500 MHz, acetone-d6) δ 7.35-7.28 (m, 5H), 6.24 (d, J = 8.5 Hz, 1H), 5.49-5.46 (m, 1H), 5.42-5.41 (m, 1H), 5.23 (t, J = 5.7 Hz, 1H), 4.69 (s, 2H), 4.34-4.33 (m, 1H), 4.22-4.19 (m, 1H), 2.06 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.43 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ169.5, 169.3, 169.0, 154.8, 137.5, 128.4, 127.8, 127.7, 86.6, 80.1, 74.7, 71.8, 70.8, 70.4, 54.5, 28.4, 20.6.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C23H32NO9 466.2077; Found 466.2079. Tert-butyl((1R,2R,3R,4S,5S)-3-(benzyloxy)-4-hydroxy-6-oxabicyclo[3.1.0]hexan-2-yl)carbamate (30) To a solution of 13 (48 mg, 0.157 mmol) in dry DCM (5 mL) was added m-CPBA

OH O

OBn NHBoc

(71 mg, 0.314 mmol) followed by NaHCO3 (26 mg, 0.314 mmol) and the reaction mixture was stirred at rt for 12 h. After completion of reaction, it was quenched with Na2SO3 and diluted with H2O. The mixture was extracted with DCM (2 X 25 mL),

washed with H2O, and saturated NaHCO3 (aq). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid. Yield: 86% (43.4 mg as a white solid); mp: 136.4-138.2 oC; [α]D 23 = +4.2 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.37-7.30 (m, 5H), 4.99 (d, J = 8.3 Hz, 1H), 4.70 (d, J = 11.9 Hz, 1H), 4.64 (d, J = 11.9 Hz, 1H), 4.18 (s, 1H), 3.61 (s, br, 1H), 3.57 (s, br, 1H), 3.31 (t, J = 6.0 Hz, 1H), 2.38 (s, 1H), 1.51 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.3, 137.9, 128.5, 127.8, 127.8, 85.0, 84.9, 80.0, 72.1, 56.7, 56.3, 55.8, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C17H24NO5 322.1654; Found 22


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322.1658. Tert-butyl ((1S,2S,3R,4R,5R)-2-azido-5-(benzyloxy)-3,4-dihydroxycyclopentyl)carbamate (31) To a solution of 30 (30 mg, 0.09 mmol) in dry DCM (4 mL) was added Ac2O (12

OH HO

OBn N3

NHBoc

mg, 0.12 mmol), Et3N (0.025 mL, 0.19 mmol), and DMAP (cat.) at 0 oC. The reaction mixture was stirred at rt for 2 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined

organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was dissolved in DMF:H2O (5:1) was added NaN3 (60 mg, 0.93 mmol) and heated to 100 oC in sealed tube for 12 h. The solvent was evaporated under reduced pressure and the crude residue was treated with H2O. The mixture was extracted with DCM (2 X 25 mL), washed with H2O, and saturated NaHCO3 (aq). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid. Yield: 85% (29 mg as a white solid); mp: 107.8-109.4 oC; [α]D 23 = +24.3 (c 0.85, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.31 (m, 5H), 5.17 (d, J = 7.1 Hz, 1H), 4.65-4.60 (m, 2H), 4.02-4.95 (m, 3H), 3.87 (s, 1H), 3.72 (s, br, 1H), 3.48-3.42 (m, 1H), 3.03 (s, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.6, 137.4, 128.5, 127.9, 127.8, 85.8, 81.1, 75.5, 74.4, 71.9, 68.5, 60.2, 28.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C17H25N4O5 365.1825; Found 365.1803. (1S,2R,3S,4S,5R)-3-azido-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)cyclopentane-1,2-diyl diacetate (34) To a solution of 31 (15 mg, 0.04 mmol) in dry DCM (2 mL) was added Ac2O (11 mg, 0.10 mmol), Et3N (0.017 mL, 0.12 mmol), and DMAP (cat.) at 0 oC. The reaction mixture was

OAc AcO

OBn N3

NHBoc

stirred at rt for 2 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes

(1:2) as an eluent to afford the title compound as a white solid. Yield: 81% (15 mg as a white solid); mp: 100.6-102.8 oC; [α]D 23 = +21.7 (c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.26 (dd, J = 5.3, 2.2 Hz, 1H), 5.11 (dd, J = 8.7, 5.5 Hz, 1H), 4.80 (s, 1H), 4.70 (d, J = 12.2 Hz, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.12 (s, br, 1H), 3.86 (s, br, 10H), 3.74 (s, br, 1H), 2.10 (s, 3H), 2.09 (s, 3H), 1.50 (s, 9H).; 13C{1H} NMR (75 MHz, CDCl3) δ 169.5, 169.4, 154.6, 137.3, 128.5, 127.9, 127.8, 73.4, 71.8, 60.4, 31.6, 28.3, 22.7, 21.1, 20.8, 20.6, 14.2, 14.1.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C21H29N4O7 449.2036; Found 449.2047. 23



Supporting Information. 1H- and 13C-NMR spectra for all new compounds, COSY, HSQC, and 2DNOESY spectra for 17, 22, 27, 29, and 34, X-ray crystallographic data in CIF for 12 (CCDC-1848803), 15 (CCDC-1867550), and 25 (CCDC-1877126). ACKNOWLEDGMENTS This research was financially supported by grants from the National Research Foundation (NRF) funded by the Korea government (MSIT) (2017M3A9A5051181) and Korea Research Institute of Chemical Technology (SI1807 & SI1951-30).

REFERENCES (1) (a) Rinehart, K. L.; Suami, T. Aminocyclitol Antibiotics. ACS Symposium Series 125; American Chemical Society: Washington, DC, 1980. (b) Berecibar, A.; Grandjean, C.; Siriwardena, A. Synthesis and Biological Activity of Natural Aminocyclopentitol Glycosidase Inhibitors: Mannostatins, Trehazolin, Allosamidins, and Their Analogues. Chem. Rev. 1999, 99, 779. (c) Duchek, J.; Adams, D. R.; Hudlicky, T. Chemoenzymatic Synthesis of Inositols, Conduritols, and Cyclitol Analogues. Chem. Rev. 2011, 111, 4223. (2) (a) Wardrop, D. J.; Waidyarachchi, S. L. Synthesis and biological activity of naturally occurring αglucosidase inhibitors. Nat. Prod. Rep. 2010, 27, 1431. (b) Chakraborty, C.; Vyavahare, V. P.; Dhavale, D. D. Intra-molecular nitrone-olefin cycloaddition of D-glucose derived allylic alcohol: synthesis of new aminocyclohexitols. Tetrahedron 2007, 63, 11984. (3) (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Recent Developments of Transition-State Analogue Glycosidase Inhibitors of Non-Natural Product Origin. Chem. Rev. 2002, 102, 515. (b) de Melo, E. B.; Gomes, A. d S.; Carvalho, I. α- and β-Glucosidase inhibitors: chemical structure and biological activity. Tetrahedron, 2006, 62, 10277. (4) (a) Jana, S.; Deb, J. K. Molecular targets for design of novel inhibitors to circumvent aminoglycoside resistance. Curr. Drug Targets 2005, 6, 353−361. (b) Das, S. K.; Panda, G. Stereoselective approach to aminocyclopentitols from Garner aldehydes. RSC Adv. 2013, 3, 9916. (c) Barry, M. T.; Joseph, D.; Jr; Erik, J. H. Asymmetric Induction of Conduritols via AAA Reactions: Synthesis of the Aminocyclohexitol of Hygromycin A. Chem. Eur. J. 2001, 7, 1619. (5) (a) Arjona, O.; Gomez, A. M.; López, J. C.; Plumet, J. Synthesis and Conformational and Biological Aspects of Carbasugars. Chem. Rev. 2007, 107, 1919. (b) Serrano, P.; Casas, J.; Zucco, M.; Emeric, G.; Egido-Gabás, M.; Llebaria, A.; Delgado, A. Combinatorial Approach to N-Substituted Aminocyclitol Libraries by Solution-Phase Parallel Synthesis and Preliminary Evaluation as Glucocerebrosidase 24


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Inhibitors. J. Comb. Chem. 2007, 9, 43. (6) (a) For some reviews on β-lactam antibiotics see: (a) Chemistry and Biology of β-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic Press: New York, 1982; Vol. 1-3. (b) Recent Advances in the Chemistry of β-Lactam Antibiotics; Brown, A. G., Roberts, S. M., Eds.; The Royal Society of Chemistry, Burling House: London, 1984. (c) The Chemistry of β-Lactams; Page, M. I., Ed.; Chapman and Hall: London, 1992. (7) (a) Brandi, A.; Cicchi, S.; Cordero, F. M. Novel Syntheses of Azetidines and Azetidinones. Chem. Rev. 2008, 108, 3988. (b) Hosseyni, S.; Jarrahpourb, A. Recent advances in β-lactam synthesis. Org. Biomol. Chem. 2018, 16, 6840. (8) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. β-Lactams:  Versatile Building Blocks for the Stereoselective Synthesis of Non-β-Lactam Products. Chem. Rev. 2007, 107, 4437. (b) Kamath, A.; Ojima, I. Advances in the chemistry of β-lactam and its medicinal applications. Tetrahedron 2012, 68, 10640. (c) Alcaide, B.; Almendros, P.; Aragoncillo, C. Synthesis of Five-Membered Heterocycles Through β-Lactam Ring-Expansion Reaction. In β-Lactam, Novel Synthetic Pathways and Applications; Banik, B. K. Ed.; SpringerLink: 2017, p163-218. (d) Pepe, A.; Pamment, M.; Georg, G. I.; Malhotra, S. V. Synthesis of Fused Bicyclic Systems with Nitrogen Atom at the Bridgehead, Including Indolizidines and Quinolizidines. J. Org. Chem. 2011, 76, 3527. (9) Palomo, C.; Aizpurua., J. M.; Ganboa, I. In Enantioselective Synthesis of β-Amino Acids; Juaristi, E. Ed.; Wiley-VCH: New York, 1997, p 279. (10) Ha, D.-C.; Kang, S.; Chung, C.-M.; Lim, H.-K. Stereospecific ring expansion of β-lactams to γlactams with trimethylsilyldiazomethane. Tetrahedron Lett. 1998, 39, 7541. (11) (a) Lee, H. K.; Chun, J. S.; Pak, C. S. Facile transformation of 3,4-disubstituted 2-azetidinones to chiral 5,6-dihydro-2-pyridones. Tetrahedron Lett. 2001, 42, 3483. (b) Lee, H. K.; Chun, J. S.; Pak, C. S. Facile Transformation of 2-Azetidinones to 2-Piperidones:  Application to the Synthesis of the Indolizidine Skeleton and (8S,8aS)-Perhydro-8-indolizinol. J. Org. Chem. 2003, 68, 2471. (c) Lee, H. K.; Chun, J. S.; Pak, C. S. Facile conversion of 2-azetidinones to 2-piperidones: application to a formal synthesis of Prosopis and Cassia alkaloids. Tetrahedron 2003, 59, 6445. (12) Lee, H. K.; Kim, E.-K.; Pak, C. S. Facile transformation of 2-azetidinones to unsaturated ketones: application to the formal synthesis of sphingosine and phytosphingosine. Tetrahedron Lett. 2002, 43, 9641. (13) (a) Grubbs, R. H.; Chang, S. Recent advances in olefin metathesis and its application in organic synthesis. Tetrahedron 1998, 54, 4413. (b) Trnka, T. M.; Grubbs, R. H. The Development of L2X2RuCHR Olefin Metathesis Catalysts:  An Organometallic Success Story. Acc. Chem. Res. 2001, 34, 18. 25



(14) (a) Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.; Kurys, B. E.; Strohmeyer, T. W.; Hegde, V. R.; Manhas, M. S.; Bose, A. K. Studies on lactams. 81. Enantiospecific synthesis and absolute configuration of substituted β-lactams from D-glyceraldehyde acetonide. J. Org. Chem. 1988, 53, 4227. (b) Hubschwerlen, C.; Schmid, G. An Enantioselective β-Lactam Synthesis Starting from L-(S)Glyceraldehyde Acetonide. Helv. Chim. Acta 1983, 66, 2206. (15) Alcaide, B.; Martín-Cantalejo, Y.; Pérez-Castells, J.; Sierra, M. A.; Monge, A. C4,C4‘-Bis-β-lactam to Fused Bis-γ-lactam Rearrangement. J. Org. Chem. 1996, 61, 9156. (16) Frelek, J.; Kowalska, P.; Masnyk, M.; Kazimierski, A.; Korda, A.; Woźnica, M.; Chmielewski, M.; Furche, F. Circular Dichroism and Conformational Dynamics of Cephams and Their Carba and Oxa Analogues. Chem. Eur. J. 2007, 13, 6732. (17) Palomo, C.; Aizpurua, J. M.; Garcia, J. M.; Iturburu, M.; Odriozola, J. M. Concise General Synthesis of α,γ-Disubstituted β-Amino Ketones from β-Lactams. J. Org. Chem.1994, 59, 5184. (18) Gemal, A. L.; Luche, J. L. Lanthanoids in organic synthesis. 6. Reduction of α-enones by sodium borohydride in the presence of lanthanoid chlorides: synthetic and mechanistic aspects. J. Am. Chem. Soc. 1981, 103, 5454. (19) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. An improved catalytic OsO4 oxidation of olefins to cis-1,2-glycols using tertiary amine oxides as the oxidant. Tetrahedron Lett. 1976, 17, 1973. (b) Cha, J. K.; Kim, N.-S. Acyclic Stereocontrol Induced by Allylic Alkoxy Groups. Synthetic Applications of Stereoselective Dihydroxylation in Natural Product Synthesis. Chem. Rev. 1995, 95, 1761. (20) (a) Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.; Winter, J. J. G.; Helliwell, M.; Newcombe, N. J.; Stemp, G. Directed Dihydroxylation of Cyclic Allylic Alcohols and Trichloroacetamides Using OsO4/TMEDA. J. Org. Chem. 2002, 67, 7946. (b) Ahmad, S.; Thomas, L. H.; Sutherland, A. Stereoselective synthesis of polyhydroxylated aminocyclohexanes. Org. Biomol. Chem. 2011, 9, 2801. (c) Cherepanova, M.; Kiss, L.; Fülöp, F. Stereocontrolled transformation of cyclohexene β-amino esters into syn- or anti-difunctionalized acyclic β2,3-amino acid derivatives. Tetrahedron 2014, 70, 2515. (21) (a) Kiss, L.; Forró, E.; Fülöp, F. Selective syntheses of novel highly functionalized βaminocyclohexanecarboxylic acids. Tetrahedron 2012, 68, 4438. (b) Raghavan, S.; Babu, V. S. Enantioselective synthesis of oseltamivir phosphate. Tetrahedron 2011, 67, 2044. (c) Kocovsky, P.; Stary, I. Steric control of epoxidation by carbamate and amide groups. Evidence for the carbonyldirected epoxidation. J. Org. Chem. 1990, 55, 3236. (d) Trost, B. M.; Malhotra, S. Asymmetric Stereodivergent Strategy Towards Aminocyclitols. Chem. Eur. J. 2014, 20, 8288. (e) O'Brien, P.; Childs, A. C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.; Dearden, M. J.; Oxenford, S. J.; Rosser, C. M. cis- and transStereoselective Epoxidation of N-Protected 2-Cyclohexen-1-ylamines. Org. Lett. 2003, 5, 4955. (f) Kiss, 26


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L.; Forró, E.; Sillanpää, R.; Fülöp, F. Diastereo- and Enantioselective Synthesis of Orthogonally Protected 2,4-Diaminocyclopentanecarboxylates:  A Flip from β-Amino- to β,γ-Diaminocarboxylates. J. Org. Chem. 2007, 72, 8786.

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Stereoselective Synthesis of Highly Functionalized 5- and 6

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