Chemoenzymatic synthesis of hygromycin aminocyclitol moiety and its C2 epimer

DOI: 10.1002/ejoc.201801424

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Aminocyclitol Synthesis

Chemoenzymatic Synthesis of Hygromycin Aminocyclitol Moiety

and its C2 Epimer

Gonzalo Carrau,^[a]Ana Inés Bellomo,^[b]Leopoldo Suescun,^[c]and David Gonzalez*^[a]

Abstract: This manuscript describes the enantioselective syn- tection, azidation, hydrolysis) of the six-membered ring in order

thesis of the aminocyclitol moiety of the antibiotic hygromycin to achieve the target. The approach is also amenable to the

A in eight steps and 39 % overall yield from a non-chiral start- synthesis of other related unnatural analogues as exemplified

ing material. The sequence made use of an initial enzymatic by the synthesis of the C2 epimer of the natural aminocyclitol.

step to transfer chirality to an aromatic ring and was followed All the intermediates were fully characterized, and the absolute

by selective organic chemistry transformations (oxidation, pro- stereochemistry assigned by spectrometric methods.

Introduction

tive and some gram-negative bacteria,^[3]but exhibits potent

activity both in vitro^[4]and in vivo^[4,5]against the spirochete

Hygromycin A (Figure 1) is an antibiotic first isolated in 1953 responsible for swine dysentery. This fact encouraged a re-

from Streptomyces hygroscopicus,^[1]that inhibits peptidyl trans- search group from Pfizer to synthesize several analogues by a

ferase activity.^[2]It exerts moderate activity against gram-posi- semi-synthetic approach to develop new antibiotics of potential

Figure 1. Structure of antibiotics: hygromycin A, A201A, and puromycin.

veterinary use (see^[6]and references cited therein). To date, two

[a] Departamento de Química Orgánica, Facultad de Química,

Universidad de la República (UdelaR), Montevideo, Uruguay

E-mail: davidg@fq.edu.uy

https://www.researchgate.net/profile/David_Gonzalez3

total syntheses of hygromycin A have been described, the first

one by Ogawa group,^[7]and the second one by Donohoe et

al.^[8]One formal synthesis was also accomplished by Yan

[b] Centro de investigaciones en Bionanociencias (CIBION), Consejo Nacional

group,^[9]and Trost group has synthesized C-2′′-epi-hygromycin

de Investigaciones Científicas y Técnicas (CONICET)

Ciudad de Buenos Aires, Argentina

[c] Laboratorio de Cristalografía, estado sólido y materiales/Cátedra de Física/

A.^[10]

Hygromycin A structure is originated from the assembling of

DETEMA/Facultad de Química, Universidad de la República (UdelaR)

three independent subunits: a ketoaldose, a substituted caffeic

Montevideo, Uruguay

acid residue, and an aminocyclitol moiety.^[11]Both sugar and

Supporting information and ORCID(s) from the author(s) for this article are

available on the WWW under https://doi.org/10.1002/ejoc .201801424.

caffeic acid residues resemble those of A201A antibiotic (Fig-

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ure 1), and to a lesser extent, puromycin. However, the amino- of Hudlicky et al. since the early nineties of the last century

cyclitol moiety is unique and does not resemble any cyclitol have developed into a full stereodivergent strategy that has

of the aminoglycoside antibiotics family. Hygromycin particular been exploited around the world to render a wide diversity of

structure encouraged several groups to study its biosynthesis this nitrogen containing polyols.^[21]Recently, we have targeted

and embrace efficient synthetic approaches. To date, the litera- the synthesis of more complicated structures bearing a cyclitol

ture has described five synthetic approaches towards hygro- core such as pancratistatin analogues^[22]and linear molecules

mycin A aminocyclitol moiety (Table 1). The Yan group accom- inspired in the hygromycin A skeleton.^[23]

plished the shortest sequence to obtain the aminocyclitol core

in 2012,^[9]although Shashidhar group reported the sequence

with best global yield.^[12]

Results and Discussion

Synthesis of L-4,5-O-Methylene-2-neo-inosamine (25)

Table 1. Reported syntheses of the aminocyclitol moiety associated with hy-

gromycin A.^{[7,–10,12–15]}

Bromobenzene was enzymatically dihydroxylated by means of

a recombinant strain of E. coli (JM109 (pDTG601)), and a final

concentration of 40 g/L of culture medium of enantiomerically

pure (1S,2S)-3-bromo-3,5-cyclohexadiene-1,2-diol (1) was

achieved (Scheme 1).^[24]Our initial approach was to introduce

the methylenedioxy group directly on compound 1, not only

to avoid aromatization but also to sterically direct the following

reactions. Unfortunately, all attempts to protect the diol group

led only to aromatization products and we were not able to

obtain compound 2. We, therefore, decided to modify our strat-

egy and protect the diol function as an isopropylidene

(Scheme 2).

Herein we describe a chemoenzymatic approach towards hy-

gromycin A aminocyclitol moiety, as well as its C2 epimer. The

development of efficient synthetic routes, with good diastereo-

meric control while introducing new stereogenic centers, could

be of great value for synthesizing hygromycin A analogues. This

approach would allow exploring new compounds that cannot

be synthesized by a semi-synthetic approach.

Scheme 1. Attempts to introduce the methylenedioxy group on diol 1.

We have made use of enzymatic transformations, particularly

microbial dihydroxylations^[16]and, to a minor extent, yeast re-

The stereoselective transformation of epoxide 3 into hydroxy-

ductions^[17]to prepare a diverse array of optically pure chiral azide 4 was achieved by means of a two-step sequence first

molecules. Aminocyclitols have been preferred targets in che- described by Hudlicky et al. for the corresponding chloro-ana-

moenzymatic synthesis. In particular, the dioxygenase catalyzed logue of compound 3 (Scheme 2).^[25]The epoxide ring was ini-

oxidation of aromatics have resulted in a very efficient approach tially opened by lithium chloride. In this reaction, the presence

to optically pure aminoinositols,^[18]conduritols,^[19]as well as of ethyl acetoacetate provided the optimal acidity to catalyze the

their deoxygenated analogues and conjugates.^[20]Initial efforts reaction.^[26]In a second stage, the chloride was displaced to ren-

Scheme 2. Functionalization of the electron-richer olefin.

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der the desired azide 4 with overall retention of configuration. Along the study we observed that ketals 8, 9 and 10 were

Then the remaining hydroxyl group was protected as the benzyl formed if only moderate excess (1.5-fold excess) of DMM was

ether 5 and the acetonide group was deprotected to render diol used, but they were all converted to compound 7 under reflux-

6, which is ready to introduce the methylenedioxy group ing temperature (entries 13 and 14).

(Scheme 2).

At this point, the introduction of the methylenedioxy group

was successfully accomplished, however, it was still necessary

to introduce the acetonide first as a transient protective group,

then operate on the electron-richer olefin, remove the aceton-

ide and finally introduce the methylenedioxy group. Since the

acidic conditions used to introduce the methylenedioxy group

may allow the deprotection of the acetonide, we envisioned

that a transacetalization reaction over compound 5 might lead

directly to compound 7, without isolating diol 6. We gladly ob-

served that after 15 hours the reaction was completed and the

desired ketal 7 was obtained in 79 % yield (Scheme 3).

Conduritol 6 was completely resistant to acetalization under

basic conditions. The diol was unreactive from 0 °C to room

temperature and completely decomposed upon warming up

the reaction (Table 2, entries 1-5). On the other hand, the use

of silver oxide under neutral conditions to enhance the electro-

philicity of the dihalomethane (entries 6-8) led to the isolation

of the desired product, but only in 10 % yield (entry 6). Much

better results were obtained for the acid-catalyzed acetalization

with dimethoxymethane (DMM) as electrophile (entries 9-14).

Although pTsOH did not promote the reaction at room temper-

ature even using a vast excess of DMM (entry 9), the reaction

Attempts to oxidize the bromoalkene either with m-CPBA or

did take place under reflux in dichloromethane and yielded the with OsO₄led only to recovered starting material (Scheme 3).

desired ketal 7 in 91 % yield as the only product (entry 11). We assayed the use of the more reactive RuO₄(generated in

Scheme 3. Transacetalization reaction on 5 and functionalization of the electron-poorer olefin on the dioxolane 7.

Table 2. Protection of azido conduritol derivative 6.

Entry

Reagent (eq)

Catalyst (Eq)

Reaction temperature (°C)

Solvent

Reaction

time (h)

Product

(yield)

1

2

3

4

CH₂I₂(5)

NaH

K₂CO₃,

18-c-6

0 - r.t.

40 - 85

r.t.

DMF

CH₂Cl₂

7

7 (trace)

CH₂Br₂(3.4)

19

11

96

Recovered sm

Decomposition

Recovered sm (70 %)

5

6

7

8

CH₂Br₂(3.4)

CH₂I₂(15)

CH₂I₂(100)

DMM (100)

DMM (10)

DMM (100)

DMM (1.5)

K₂CO₃, 18-c-6

Ag₂O, TBAI

pTsOH

P₂O₅

reflux

r.t.

reflux

r.t.

CH₂Cl₂

THF

CH₂I₂

CH₂Cl₂

THF

CH₂Cl₂

4

24

4

10

48

24

19

3

Decomposition

7 (10 %)

7 (trace)

Decomposition

7, 8, 9, 10

7 (trace)

7 (91 %)

10 (quant.)

8, 9, 10

9

r.t.

10

11

12

13

14

reflux

r.t.

reflux

19

2

P₂O₅

7 (40 %)

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Scheme 4. Proposed mechanism for the transformation of 7 into 11.

situ) and observed complete consumption of the starting mate- and it was noticed that 14 was formed during the purification

rial. However, we did not obtain the desired hydroxy ketone, stage by column chromatography. Consequently, we decided

but a compound identified as 11. We assumed that unsaturated to perform a one-pot sequence adding the NaBH₄directly to

ketone 11 was derived from hydroxy ketone 12 by hydrazoic reaction flask once the consumption of epoxide 3 was verified.

acid loss followed by a 1,2-hydride shift as proposed in This approach rendered diol 15 in 60 % yield for both steps. In

Scheme 4.

the same reaction, bromodiol 16 was obtained as a by-product

As we were not able to isolate the desired hydroxy ketone

12, we decided to change the synthetic steps sequence. At-

tempts to functionalize the bromoalkene on epoxide 3 with

RuO₄(Scheme 5) led to a mixture of the hydroxy ketone 13

and the rearranged product 14. The stereochemistry of the new

stereogenic center in compound 13 was suggested by coupling

constant measurement (J_2-3= 1.4 Hz indicates a cis stereochem-

ical relationship) and NOE experiments (Figure 2). Crystallization

of compound 13 followed by X-ray diffraction analysis con-

firmed the assigned stereochemistry (Figure 2). Several at-

tempts were made to maximize the formation of epoxide 13,

Figure 2. NOE correlations of hydroxyl-ketone 13 and ORTEP diagram.

Scheme 5. Functionalization of the bromo-olefin on the epoxide 3.

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with 22 % yield. The latter probably formed by nucleophilic ring

opening of the oxirane by water over the allylic position in a

trans-diaxial fashion.

The stereochemistry of 15 could not be derived from the ¹H-

NMR spectra since the coupling constants could not be deter-

mined due to second order splitting. Therefore, the hydroxyl

groups were protected to render diacetate 17 (Scheme 5). The

coupling constant of H_3-4(Figure 3) was determined to be

4.6 Hz, an intermediate value that could arise either from a cis

or a trans relationship between the involved protons. Data from

a 1D NOE experiment suggested a cis relationship because

when irradiating the endo methyl group of the isopropylidene

an enhancement was observed in all ꢀ protons (including H₄).

In order to confirm the assignment, the epoxide was opened

with azide anion. The facial approach of the azide group is gov-

ernated by the Fürst–Plattner rule, and the regiochemistry of

Figure 4. Coupling constant of compound 18 and its ORTEP diagram.

As the compound synthesized by the hydroxy-carbonylation/

reduction sequence over the epoxide was not a trans diol as

we expected, we decided to explore the reaction over the less

strained substrate 4 (Scheme 6). When we performed only the

oxidation stage, the main isolated product was 14 (≈60 %). Dur-

ing the reaction, another product was observed by TLC (possi-

bly the hydroxy ketone) but it decomposed during isolation as

the amount of 14 increased, so we returned to the one pot

dihydroxylation/reduction procedure. In this case, a mixture of

trans(19)/cis(20) diols was obtained in ratio 7.6/1. The diastereo-

mers could be separated by column chromatography, and the

desired product was obtained in 61 % yield for both steps.

Structure confirmation of the cis isomer 20 was achieved by

single-crystal X-ray diffraction analysis (Figure 5). On the other

hand, to verify that 19 had the assigned stereochemistry, the

compound was acetylated (21, Scheme 7), the acetonide was

1

the attack was determined by COSY experiment. The H-NMR

spectrum showed a triplet signal (J = 10.0 Hz) at 3.52 ppm that

was assigned to H₄(Figure 4). This suggested a chair conforma-

tion with H₁-H₂and H₂-H₃in a trans-diaxial relationship. If OH₆

was on the ꢀ face, then H₅-H₆should also have a trans-diaxial

disposition, but this is not what coupling constant suggested.

A measured J_1-6value of 3.0 Hz hinted two pseudo-equatorial

protons, confirming a cis relationship between H₅and H₆. We

were also able to crystallize compound 18, and its structure

was confirmed by single-crystal X-ray crystallography (Figure 4).

Figure 3. Coupling constants and NOE correlations of diacetate 17.

Figure 5. Crystal structure of triol 20.

Scheme 6. Functionalization of the bromo-olefin on compound 4.

Scheme 7. Confirmation of stereochemistry of compound 19.

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removed and the product was acetylated again. This rendered into the methylenedioxy group to deliver 29. Finally, a hydro-

meso compound 22, corroborating the assigned stereochemis- genolysis reaction rendered aminocyclitol 30 (C2-epimer).

try.

Once the stereochemistry of 19 was confirmed, the three

Conclusions

hydroxyl groups were protected as benzyl ethers (23,

Scheme 8), and the methylenedioxy group was introduced by

means of a transacetalization reaction. Finally, simultaneous re-

moval of the benzyl groups and reduction of the azide moiety

by hydrogenolysis rendered the natural aminocyclitol 25 in

95 % yield (Scheme 8). The recorded NMR spectroscopic data

of compound 25 is in full accordance with the reported by

Shashidhar.^[12]

The aminocyclitol core present in hygromycin A was prepared

in eight steps with an overall yield of 39 % from cyclohexadi-

enediol 1. The latter is commercially available or can be pre-

pared in high yield by whole-cell enzymatic dihydroxylation of

bromobenzene. The process has now been optimized in our 5-

liter fermenter to render optically pure diol in up to 40 g/L

of cell culture. Comparable yields have been described by the

Hudlicky group in Canada that has pioneered the technique for

over two decades. To the best of our knowledge, this is the

shortest synthesis of the hygromycin A core reported to date

and provides the highest overall yield.

The preparation of the C2 epimer in an even shorter se-

quence provided proof of concept that this approach is suitable

for the preparation of hygromycin A analogues of unnatural

stereochemistry. Our results in the synthesis of a series of ana-

logues are on development and will be reported in due course.

Experimental Section

General methods

Commercially available reagents were purchased from Sigma–

Aldrich and used without further purification. Melting pionts were

determined either on a capilar Gallenkamp apparatus or on a capi-

lar Electrothermal IA 9100 MK2 apparatus and are uncorrected. Op-

tical rotation was determined on a Kruss Optronic GmbH P8000 on

a 0.5 dm cell (concentration is expressed as W/V percentage). Nu-

clear Magnetic Resonance spectra were recorded either on a Bruker

AVANCE DPX-400 instrument or on a Bruker AVANCE III 500 spec-

trometer. Chemical shifts (δ) are given in parts per million downfield

from tetramethylsilane, and coupling constants (J) are reported in

Hertz. 1D-NOESY experiments were carried out at 25 °C using the

DPFGSE-NOE pulse sequence of Stott et al. and a mixing time of

300 ms.^[27]Selective excitation of specific protons was achieved

with Gaussian shaped pulses. Infrared spectra (IR) were recorded on

a Shimadzu FT-IR model IRprestige-21. Low-resolution mass spectra

(MS) were recorded on a Shimadzu GC–MS-QP2010 ultra instrument

Scheme 8. Synthesis of natural aminocyclitol 25.

Synthesis of D-1,2-O-Methylene-5-myo-inosamine [2-epi-

(L- 4,5-O-Methylene-2-neo-inosamine)] (30)

In order to synthesize the C2 epimer, the same strategy was

applied but starting from the trans-azidoalcohol 26 (obtained

from epoxide 3) instead of compound 4 (Scheme 9). The

bromo-olefin was functionalized by the same oxidation/

reduction sequence rendering the trans diol (27). The stereo-

chemistry was confirmed by coupling constant measurement:

J

_3-4≈ J_4-5≈ J_5-6≈ 10 Hz indicating a trans-diaxial relationship

between those protons. The hydroxyl groups were protected as

benzyl ethers (28) and then the acetonide was interconverted (70 eV electron impact mode), using either Direct Injection (DI) or

Scheme 9. Synthesis of C2 epimer of the natural aminocyclitol.

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by means of GC (column DB-WAX: Length 30m, diameter 0.25 mm

CDCl₃) δ ppm: 126.3 (C₃), 126.4 (C₄), 110.4 (C_{isopropylidene}), 76.1 (C₆),

and Film 0.25 μm). High-resolution mass spectra were performed

on a Bruker Daltonics model ToF_LC(ESI mode).

76.0 (C₅), 69.2 (C₁), 59.5 (C₂), 27.6 (CH₃), 26.0 (CH₃).

+

(1R,2R,5S,6S)-2-Azido-1-benzyloxy-4-bromo-5,6-isopropyl-

Analytical TLC was performed on silica gel 60F-254 plates and visu- idenedioxy-3-cyclohexene (5).

alized with UV light (254 nm) and/or anisaldehyde–H₂SO₄–EtOH or

vanillin–H₂SO₄–EtOH as detecting agent. Purifications by column

chromatography were performed on Merck 60 silica gel (0,040–

0.063 mm).

Single crystal X-ray diffraction data was collected on a Bruker D8

Venture diffractometer using Siemens Sealed-tube Mo-K_αradiation

monochromatized with a graphite single crystal (Compounds 13

and 18) and Incoatec I microfocus source 1.0 Cu-K_αradiation fo-

cused and monochromatized with a Quazar multilayer mirror (Com-

pound 20). A single crystal of each compounds was mounted on

122 mg of NaH 55 % dispersion in mineral oil (2.8 mmol, 1.6 eq.)

the four-circle kappa goniometer and data was collected in all cases

in shutterless mode using a PHOTON100 CMOS detector. The dif-

fractometer was operated using APEX2 control software providing

cell determination, data collection and processing and structure re-

port routines. Data scaling and absorption correction was per-

formed with SADABS.^[28]Structure determination was performed by

modern direct methods with SHELXT program^[29]and least-squares

structure refinement with SHELXL^[30]in shelXle environment.^[31]CIF

preparation and molecular graphics were prepared with enCIFer

(v 1.6.2) and Mercury CSD 3.10.1 respectively. Figures S1, S2 and S3

show ORTEP representations of compounds 13, 18 and 20 and

Tables S1, S2 and S3 the crystallographic data, processing and re-

finement details respectively. CCDC 1535525 (for 13), 1535526 (for

18), and 1535562 (for 20) contain the supplementary crystallo-

graphic data for this paper. These data can be obtained free of

charge from The Cambridge Crystallographic Data Centre.

were added to a solution of 511 mg of compound 4 (1.7 mmol, 1

eq.) in 8 mL of dry DMF at 0 °C under N₂atmosphere. The reaction

mixture was left to stir during 15 minutes, and then 0.67 mL of

BnBr (5.6 mmol, 3.2 eq.) were added. The reaction was kept at 0°C

for 10 minutes, and then it was warmed up to room temperature.

The reaction was monitored by TLC, and after completion of the

reaction, a saturated aqueous solution of NH₄Cl was added and the

system was extracted with three portions of AcOEt. The combined

organic phases were washed with three portions of saturated aque-

ous solution of CuSO₄, then washed with brine, dried with Na₂SO₄,

filtered and the solvent was evaporated under reduced pressure to

render an oily crude. Purification was accomplished by flash chro-

matography, using SiO₂as stationary phase, and performing the

following gradient elution: 0 %, then 5 % and finally 10 % (v/v of

AcOEt in Hexane). 663 mg of 5 were obtained as a colorless oil

1

(99 % yield). α_D²²= –36 (c = 3.4, AcOEt). H NMR (400 MHz, CDCl₃)

(1R,2R,3S,4S)-5-bromo-1,2-epoxy-3,4-isopropylidenedioxy-5-

cyclohexene (3)^[32]

δ (ppm): 7.41-7.28 (m, 5H, H arom), 6.17 (d, J_2-3= 3.6 Hz, 1H, H₃),

4.80 (d, J_gem= 12.0 Hz, 1H, -OCH₂Ph), 4.71 (d, J_gem= 12.0 Hz, 1H,

-OCH₂Ph), 4.64 (dd, J_5-6= 5.5 Hz, J_1-5= 1.4 Hz, 1H, H₅), 4.39 (t,

J_1-6= J_5-6= 5.5 Hz, 1H, H₆), 4.03-3.98 (m, 1H, H₁), 3.97 (dt, J_1-2

=

J_2-3= 3.6 Hz, J_2-6= 1.5 Hz, 1H, H₂), 1.40 (s, 3H, CH₃), 1.37 (s, 3H,

CH₃). ¹³C NMR (101 MHz, CDCl₃) δ (ppm): 137.4 (C_{Ph-quaternary}), 128.7

(C_Ph-m), 128.3 (C_Ph-p), 128.1 (C_Ph-o), 127.3 (C₃), 125.5 (C₄), 110.5

(C_{isopropylidene}), 76.5 (C_1or5), 76.5 (C_5or1), 75.0 (C₆), 73.6 (-OCH₂Ph),

The ¹H- and ¹³C-NMR spectra data of the compound were found to

57.9 (C₂), 27.7 (CH₃), 26.2 (CH₃). FT-IR (ν_max/cm): 3032 (=C-H arom),

˜

be in agreement with previous reports.^[32]α_D

= +101 (c = 1.55,

MeOH). H NMR (400 MHz, CDCl₃) δ (ppm): 6.48 (dd, J_1-6= 4.5 Hz,

21,0

2988 (CH₂), 2934 (CH₃), 2899 (CH₃), 2102 (N₃), 1645 (C=C), 1227 (C-

O-C), 1074 (O-C-O), 739 (=C-H arom), 698 (=C-H arom). DI-MS m/z

(Rel. Int): 352 (1), 350 (1), 324 (0.6), 322 (0.7), 191 (22), 91 (100).

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺Calcd for [C₁₆H₁₈BrN₃O₃Na]⁺

402.0424, found 402.0443.

1

J_4-6= 1.3 Hz, 1H, H₆), 4.87 (ddd, J_3-4= 6.7 Hz, J_2-3= 1.9 Hz, J_1-3

=

1.1 Hz, 1H, H₃), 4.42 (dd, J_3-4= 6.7 Hz, J_4-6= 1.3 Hz, 1H, H₄), 3.60

(dd, J_1-2= 3.7 Hz, J_2-3= 1.9 Hz, 1H, H₂), 3.34 (ddd, J_1-6= 4.6 Hz,

J_1-2= 3.7 Hz, J_1-3= 1.1 Hz, 1H, H₁), 1.46 (s, 3H, CH₃), 1.44 (s, 3H,

CH₃). ¹³C NMR (101 MHz, CDCl₃) δ (ppm): 130.0 (C₅), 126.6 (C₆),

111.5 (C_{isopropylidene}), 74.2 (C₄), 72.7 (C₃), 49.6 (C₂), 48.4 (C₁), 27.6

(CH₃), 26.1 (CH₃).

(1R,2S,5R,6R)-5-Azido-3-bromo-6-benzyloxy-cyclohex-3-ene-

1,2-diol (6).

(1R,2R,5S,6S)-2-azido-4-bromo-5,6-isopropylidenedioxycyclo-

hexa-3-ene-1-ol (4).^[33]

7.06 g of DOWEX-H⁺50WX8-100 resin were added to a stirring solu-

tion of 706 mg of compound 5 in 18 mL of a mixture MeOH:H₂O

(8:2, V/V) at room temperature, and the mixture was warmed up to

45 °C by means of an oil bath. The reaction was monitored by TLC,

The ¹H- and ¹³C-NMR spectra data of the compound were found to

be in agreement with previous reports.^{[33] 1}H NMR (400 MHz, CDCl₃)

δ (ppm): 6.15 (d, J_3-2= 3.1 Hz, 1H, H₃), 4.66 (d, J_5-6= 5.3 Hz, 1H, H₅),

4.40 (t, J_1-6= J_5-6=5.3 Hz, 1H, H₆), 4.25-4.17 (m, 2H, H₁and H₂), 2.49 and once the starting material was consumed (approximately 48 h),

(bs, 1H, OH₁), 1.44 (s, 3H, CH₃), 1.40 (s, 3H, CH₃). ¹³C NMR (100 MHz,

the resin was filtered off and washed several times with methanol.

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The solvent was removed under reduced pressure, and a brownish General procedure for the synthesis of dioxolane under acidic

solid was obtained. The product was purified by column chroma-

tography, using SiO₂as stationary phase, and eluting with a solu-

tion 20 % (v/v) of AcOEt in Hexane. 516 mg of 6 were obtained as

a white solid (82 % yield). M.P. = 103-104 °C. α_D²²= –182 (c = 1.05,

MeOH). ¹H NMR ((CD₃)₂CO, 400 MHz) δ (ppm): 7.47-7.39 (m, 2H,

H_Ph), 7.39-7.25 (m, 3H, H_Ph), 6.18 (d, J_4-5= 4.1 Hz, 1H, H₄), 4.79 (s,

conditions using P₂O₅as catalyst.

A solution of 25 mg of diol 6 (0.074 mmol, 1 eq.) in 1 mL of dry

CH₂Cl₂, under N₂atmosphere, was treated with the corresponding

amount of DMM (Table 2) and 17 equiv. of P₂O₅were added. The

reaction mixture was stirred at room temperature until consump-

tion of the starting material, and then the reaction was cooled by

means of an ice bath. Cooled CH₂Cl₂was added, and P₂O₅excess

was destroyed with cooled saturated aqueous solution of NaHCO₃.

Then, the mixture was extracted with sat. NaHCO₃, washed with sat.

NaCl and dried with Na₂SO₄. The solvent was evaporated under

reduced pressure after the desiccant agent was filtered off, and the

product was then purified by flash chromatography.

2H, -OCH₂Ph), 4.48 (bs, 1H, OH₁), 4.45 (bs, 1H, OH₂), 4.31 (bd, J_5-6

=

4.1 Hz, 1H, H₆), 4.27 (dt, J_4-5= J_5-6= 4.1 Hz, J = 1.6 Hz, 1H, H₅), 4.16

(dd, J_1-2= 7.4 Hz, J_1-OH= 4.0 Hz, 1H, H₁), 4.03 (dd, J_1-2= 7.7 Hz, J_2-

= 4.0 Hz, 1H, H₂). ¹³C NMR ((CD₃)₂CO, 101 MHz) δ (ppm): 139.3

OH

(C_{Ph-quaternary}), 129.8 (C₃), 129.1 (C_Ph-m), 128.7 (C_Ph-o), 128.5 (C_Ph-p),

128.0 (C₄), 78.1 (C₂), 73.7 (OCH₂Ph), 71.8 (C₆), 69.9 (C₁), 59.5 (C₅). FT-

IR (ν_max/cm): 3296 (OH), 2124 (N₃), 1651 (C=C), 731 (=C-H arom),

˜

(1R,2R,5S,6S)- 2-Azido-1-benzyloxy-4-bromo-5,6-methylendi-

oxy-3-cyclohexene (7).

696 (=C-H arom). DI-MS m/z (Rel. Int): 312 (4), 310 (4), 254 (1), 252

(1), 150 (13), 91 (100). HRMS (ESI/Q-TOF) m/z: [M + Na]⁺Calcd for

[C₁₃H₁₄BrN₃O₃Na]⁺362.01108, found 362.01195.

General procedure for the synthesis of dioxolane under basic

media.

14 mg of NaH 55 % dispersion in mineral oil (0.32 mmol, 2.1 eq.)

were added to a solution of 50 mg of diol 6 (0.15 mmol, 1 eq.) in

1 mL of dry DMF at 0 °C under N₂atmosphere. The reaction mixture

was left to stir during 45 minutes, and then 35 μL of CH₂Br₂

(0.50 mmol, 3.4 eq.) were added in the absence of light. The reac-

tion was taken up to the temperature listed on Table 2. After com-

pletion of the reaction, a saturated aqueous solution of NH₄Cl was

added and the system was extracted with three portions of AcOEt.

The combined organic phases were treated with four portions of a

saturated aqueous solution of CuSO₄, then washed with one por-

tion of brine, dried with Na₂SO₄, filtered and the solvent was evapo-

rated under reduced pressure to render an oily crude. Purification

was accomplished by flash chromatography using SiO₂as stationary

phase.

Compound 7 was synthesized from 5, following the general proce-

dure for the synthesis of dioxolane under acidic conditions using p-

toluenesulfonic acid as catalyst. 10 eq. of DMM were used, and the

reaction was kept at reflux temperature for 19h. The crude was

purified by flash chromatography, performing a gradient elution:

first hexane, and then a 5 % v/v solution of AcOEt in hexane. Color-

less oil. α_D²²= –93 (c = 1.24, AcOEt). ¹H NMR (CDCl₃, 400 MHz) δ

(ppm): 7.39-7.30 (m, 5H, H_Ph), 6.26 (dd, J_2-3= 3.9 Hz, J_3-5= 0.7 Hz,1H,

H₃), 5.00 (s, 1H, -OCH₂O-), 4.98 (s, 1H, -OCH₂O-), 4.80 (d, J_gem

=

11.9 Hz, 1H, -OCH₂Ph), 4.72 (d, J_gem= 11.9 Hz, 1H, -OCH₂Ph), 4.65

(bd, J_5-6= 5.7 Hz, 1H, H₅), 4.31 (t, J_1-6= J_5-6= 5.7 Hz, 1H, H₆), 4.01-

3.94 (m, 2H, H₁and H₂). ¹³C NMR (CDCl₃, 101 MHz) δ (ppm): 137.2

(C_{Ph-quaternary}), 128.7 (C_Ph-p), 128.6 (C_Ph-m), 128.2 (C₃), 128.0 (C_Ph-o),

123.6 (C₄), 94.4 (-OCH₂O-), 76.4 (C₅), 75.9 (C₁), 74.9 (C₆), 73.5

General procedure for the synthesis of dioxolane under neutral

conditions.

41 mg of diol 6 (0.12 mmol, 1 eq.) were dissolved in 1 mL of dry

THF at room temperature under nitrogen atmosphere, and 145 μL

of CH₂I₂(1.81 mmol, 15 eq.) and 9.0 mg of TBAI (tetrabutilamonium

iodide, 0.024 mmol, 0.2 eq.) were added in the absence of light.

After stirring for 15 minutes, 224 mg of Ag₂O (0.97 mmol, 8eq.)

were added and the reaction was stirred until consumption of the

starting material (conditions listed in Table 2). Et₂O was added and

Ag₂O was filtered off through a pad of celite. The solvent was evap-

orated to render an oily crude product that was subjected to flash

chromatography on silica gel.

(-OCH₂Ph), 57.7 (C₂). FT-IR (ν_max/cm): 2870 (CH₂), 2104 (N₃), 1645

˜

(C=C), 1088 (O-C-O), 926 (O-C-O), 739 (=C-H arom), 698 (=C-H arom).

DI-MS m/z (Rel. Int): 324 (3), 322 (3), 296 (1), 294 (1), 91 (100). HRMS

(ESI/Q-TOF) m/z: [M + Na]⁺Calcd for [C₁₄H₁₄BrN₃O₃Na]⁺: 374.01108,

found 374.01139.

(1S,2S,5R,6R)-5-Azido-6-benzyloxy-3-bromo-2-(methoxy-

methoxyl)-cyclohex-3-ene-1-ol (8).

General procedure for the synthesis of dioxolane under acidic

conditions using p-toluenesulfonic acid as catalyst.

A solution of 516 mg of diol 6 (1.52 mmol, 1 eq.) in 80 mL of dry

CH₂Cl₂was treated with the corresponding amount of DMM

(Table 2) under N₂atmosphere and 72 mg of pTsOH (0.46 mmol,

0.3 eq.) were added. The reaction mixture was refluxed until con-

sumption of the starting material, then solid NaHCO₃was added

and the resulting system was left to stand at room temperature for

5 minutes. Saturated aqueous solution of NaHCO₃was added, and

Colorless oil. α_D²¹= –98 (c = 1.35, AcOEt). ¹H NMR (400 MHz, CDCl₃)

δ (ppm): 7.41 – 7.30 (m, 5H, H_Ph), 6.16 (dt, J_4-5= 3.9 Hz, J_2-4= J_4-6

=

the system was extracted with three portions of CH₂Cl₂. The com- 1.0 Hz, 1H, H₄), 4.84 (d, J_gem= 6.8 Hz, 1H, -OCH₂OMe), 4.80 (d, J_gem

bined organic layers were washed with one portion of brine, dried 6.8 Hz, 1H, -OCH₂OMe), 4.79 (d, J_gem= 11.8 Hz, 1H, -OCH₂Ph), 4.68

with Na₂SO₄, filtered and the solvent was removed under reduced

pressure rendering an oily crude that was purified over silica flash.

(d, J_gem= 11.8 Hz, 1H, -OCH₂Ph), 4.36 (bd, J_1-2= 3.9 Hz, 1H, H₂),

4.13 (dt, J_1-6= 7.6 Hz, J_1-2= J_1-OH= 3.9 Hz, 1H, H₁), 4.09 (td, J_4-5

=

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J_5-6= 4.0 Hz, J_4-6= 1.0 Hz, 1H, H₅), 3.99 (dd, J_1-6= 7.6 Hz, J_5-6

=

CDCl₃) δ (ppm): 137.5 (C_{Ph-quaternary}), 128.5 (C_Ph-m), 128.1 (C_Ph-p),

128.0 (C₃), 127.9 (C_Ph-o), 126.0 (C₄), 97.5 (-OCH₂OMe), 97.0

4.0 Hz, 1H, H₆), 3.45 (s, 3H, -OCH₃), 2.87 (d, J_1-OH1= 3.9 Hz, 1H, OH₁).

¹³C NMR (101 MHz, CDCl₃) δ (ppm): 137.5 (C_{Ph-quaternary}), 128.8 (-OCH₂OMe), 76.0 (C₁), 75.9 (C₅), 74.4 (C₆), 73.7 (-OCH₂Ph), 59.0 (C2),

(C_Ph-m), 128.6 (C₄), 128.4 (C_Ph-p), 128.3 (C_Ph-o), 125.5 (C₃), 56.4 (-OCH₃), 55.9 (-OCH₃). FT-IR (ν_max/cm): 2930 (CH₂), 2893 (CH₂),

˜

98.0 (-OCH₂OMe), 77.5 (C₂), 76.8 (C₆), 73.8 (-OCH₂Ph), 69.1 (C₁), 58.3

2824 (-OCH₃), 2102 (N₃), 1641 (C=C), 1030 (O-C-O), 920 (O-C-O), 739

(=C-H arom), 698 (=C-H arom). DI-MS m/z (Rel. Int): 296 (1), 294 (1),

250 (1), 248 (2), 194.1 (11), 91 (100). HRMS (ESI/Q-TOF) m/z: [M +

Na]⁺Calcd for [C₁₇H₂₂BrN₃O₅Na]⁺450.06350, found 450.06519.

(C₅), 56.6 (-OCH₃). FT-IR (ν_max/cm): 3458 (OH), 2897 (CH₂), 2851 (CH₃),

˜

2102 (N₃), 1641 (C=C), 1105 (C-O-C), 1030 (C-O-C), 741 (=C-H arom),

700 (=C-H arom). DI -MS m/z (Rel. Int): 356 (0.9) 354 (0.9), 340 (0.4),

338 (0.4), 235 (4), 233 (4), 91 (100), 45 (62). HRMS (ESI/Q-TOF) m/z:

[M + Na]⁺Calcd for [C₁₅H₁₈BrN₃O₄Na]⁺: 406.0373, found 406.0378.

(5S,6S)-3-benzyloxy-2-hydroxy-5,6-methylendioxycyclohexa-2-

ene-1-one (11).

(1S,4R,5R,6R)-4-Azido-5-benzyloxy-2-bromo-6-(methoxy-

methoxyl)-cyclohex-2-ene-1-ol (9)

59 mg of compound 7 (0.17 mmol, 1 eq.) were dissolved in 3 mL

of CH₃CN, and the system was cooled to 0 °C. 43 mg of NaIO₄

(0.20 mmol, 1.2 eq.) and 2.4 mg of RuCl₃·2H₂O (0.010 mmol, 0.06

eq) were dissolved in 0.5 mL of water on a separated vial, and were

also cooled to 0 °C. Once both solutions were at 0°C, the aqueous

solution was added all at once over de organic solution, and the

reaction was kept at 0°C under vigorous stirring for 5 minutes, and

then it was quenched by the addition of 0.5 mL of an aqueous

solution of Na₂S₂O₃(20 % W/V). The reaction was filtered through

a SiO₂pad, washed with abundant AcOEt and the eluted was evap-

orated rendering 50 mg of a brownish oily crude. Purification was

accomplished by flash chromatography, using SiO₂as stationary

phase, and performing the following gradient elution: 10 % fol-

lowed by 20 %, 30 % and finally 40 % (v/v of AcOEt in Hexane).

33 mg of 11 were obtained as white solid (67 % yield). ¹H NMR

(400 MHz, CDCl₃) δ (ppm): 7.41 – 7.29 (m, 5H, H_Ph), 5.73 (s, 1H,

Colourless oil. α_D²¹= –54 (c = 0.85, AcOEt). ¹H NMR (400 MHz,

CDCl₃) δ (ppm): 7.38 – 7.29 (m, 5H, H_Ph), 6.15 (dt, J_3-4= 3.8 Hz,

J_1-3= J_3-5= 0.7 Hz, 1H, H₃), 4.78 (d, J_gem= 6.7 Hz, 1H, -OCH₂OMe),

4.75 (d, J_gem= 11.8 Hz, 1H, -OCH₂Oh), 7.71 (d, J_gem= 6.7 Hz, 1H,

-OCH₂OMe), 4.71 (d, J_gem= 11.8 Hz, 1H, -OCH₂Ph), 4.45-4.41 (m, 1H,

H₁), 4.08-4.03 (m, 2H, H₅+ H₆), 4.00 (td, J_3-4= J_4-5= 3.8 Hz, J =

1.5 Hz, 1H, H₄), 3.39 (s, 3H, -OCH₃), 2.99 (d, J_1-OH1= 6.6 Hz, 1H, OH).

¹³C NMR (101 MHz, CDCl₃) δ (ppm): 137.5 (C_{Ph-quaternary}), 128.7

(C_Ph-m), 128.3 (C_Ph-p), 128.1 (C_Ph-o), 128.0 (C₃), 127.4 (C₂), 98.0

(-OCH₂OMe), 76.5 (C₅or C₆), 76.1 (C₆or C₅), 73.9 (-OCH₂Ph), 70.6

-OCH₂O-), 5.49 (bs, 1H, OH₂), 5.43 (s, 1H, -OCH₂O-), 4.84 (d, J_gem

11.7 Hz, 1H, -OCH₂Ph), 4.80 (d, J_5-6= 8.2 Hz, 1H, H₆), 4.69 (d, J_gem

11.7 Hz, 1H, -OCH₂Ph), 3.99 (ddd, J_4′-5= 11.7 Hz, J_5-6= 8.2 Hz, J_4-5

5.4 Hz, 1H, H₅), 2.92 (dd, J_gem= 16.9 Hz, J_4-5= 5.4 Hz, 1H, H₄), 2.52

(dd, J_gem= 16.9 Hz, J_4′-5= 11.7 Hz, 1H, H_4′). ¹³C NMR (101 MHz,

CDCl₃) δ (ppm): 190.0 (C₁), 146.7 (C₃), 137.3 (C₂), 128.6 (C_Ph-m), 128.1

(C_Ph-p), 127.8 (C_Ph-o), 126.9 (C_{Ph-quaternary}), 99.9 (OCH₂O), 81.5

(OCH₂Ph), 75.5 (C₆), 72.2 (C₅), 39.2 (C₄). HRMS (ESI/Q-TOF) m/z: [M +

Na]⁺Calcd for [C₁₄H₁₄O₅Na]⁺285.0733, found 285.0735.

=

(C₁), 58.9 (C₄), 56.2 (-OCH₃). FT-IR (ν_max/cm): 3447 (OH), 2928 (CH₂),

˜

2897 (CH₂), 2102 (N₃), 1643 (C=C), 1115 (C-O-C), 1034 (C-O-C), 749

(=C-H arom), 698 (=C-H arom). DI -MS m/z (Rel. Int): 356 (0.4), 354

(0.6), 312 (1.0), 310 (1), 194 (11), 91 (100), 45 (54). HRMS (ESI/Q-

TOF) m/z: [M + Na]⁺Calcd for [C₁₅H₁₈BrN₃O₄Na]⁺406.0373, found

406.0371.

(1R,4R,5S,6R)-2-Azido-1-benzyloxy-4-bromo-5,6-bis(methoxy-

methoxyl)-3-cyclohexene (10)

(2S,3R,4R,5S,6S)-3,4-epoxy-2-hydroxy-5,6-isopropylidenedioxy-

1-cyclohexanone (13).^[34]

The same procedure described for compound 11 was applied to

synthesize 13, but the system was left to react for 2 minutes. Purifi-

Compound 10 was synthesized from 6, following the general proce-

dure for the synthesis of dioxolane under acidic conditions using cation was accomplished by flash chromatography, using deacti-

P₂O₅acid as catalyst. 100 eq. of DMM were used, and the reaction

was stirred at 0°C for 3h. The crude was purified by flash chroma-

tography, performing a gradient elution: first hexane, and then a

5 % v/v solution of AcOEt in hexane. Colorless oil (quantitative

yield). α_D²²= –74 (c = 0.50, AcOEt). ¹H NMR (400 MHz, CDCl₃)

δ (ppm): 7.41-7.29 (m, 5H, H_arom), 6.13 (d, J_2-3= 3.8 Hz, 1H, H₃), 4.86

(d, J_gem= 6.8 Hz, 1H, -OCH₂OMe), 4.82 (d, J_gem= 6.8 Hz, 1H,

-OCH₂OMe), 4.76 (d, J_gem= 6.7 Hz, 1H, -OCH₂OMe), 4.74 (d, J =

0.9 Hz, 2H, -OCH₂Ph), 4.71 (d, J_gem= 6.7 Hz, 1H, -OCH₂OMe), 4.43

vated SiO₂as stationary phase (deactivation was achieved by add-

ing 10 mL of distilled water to 100 g of SiO₂and stirring several

hours until it is homogeneous), and performing the following gradi-

ent elution: 20 % followed by 25 %, 30 %, 35 % and finally 40 %

(v/v of AcOEt in Hexane) (NOTE: The column should be done as

quickly as possible to avoid decomposition of the product, and

avoid absorbing the crude in SiO₂; load it in the less possible

amount of DCM). White solid. The spectroscopic data of the com-

pound were found to be in agreement with previous reports.^[34]

21.5

(d, J_5-6= 3.1 Hz, 1H, H₅), 4.12-4.08 (m, 1H, H₆), 4.08-4.03 (m, 2H, H₁M.P = 125 – 126 °C. α_D

= +77 (c = 0.60, MeOH). ¹H NMR

y H₂), 3.47 (s, 3H, -OCH₃), 3.37 (s, 3H, -OCH₃). ¹³C NMR (101 MHz,

(400 MHz, CDCl₃) δ (ppm): 5.11 (d, J_2-OH2= 5.0 Hz, 1H, H₂), 4.85 (dt,

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J_5-6= 6.0 Hz, J_4-6= J_3-6= 1.4 Hz, 1H, H₆), 4.41 (dd, J_5-6= 5.9 Hz,

J_4-5= 1.5 Hz, 1H, H₅), 3.66 (dt, J_3-4= 3.8 Hz, J_2-3= J_3-6= 1.4 Hz, 1H,

(400 MHz, CDCl₃) δ (ppm): 4.58 (dt, J_5-6= 5.8 Hz, J_1-6= J_2-6= 1.3 Hz,

1H, H₆), 4.51 (ddd, J_5-6= 5.8 Hz, J_4-5= 3.6 Hz, J_1-5= 1.3 Hz, 1H, H₅),

H₃), 3.38 (dt, J_3-4= 3.8 Hz, J_4-5= J_4-6= 1.4 Hz, 1H, H₄), 3.34 (d, J = 4.25 – 4.19 (m, 1H, H₃), 4.04 (dtd, J_4-OH4= 11.7 Hz, J_4-5= 3.6 Hz, J =

5.0 Hz, 1H, OH₂), 1.59 (s, 3H, CH₃), 1.38 (s, 3H, CH₃).¹³C NMR 3.6 Hz, J = 1.6 Hz, 1H, H₄), 3.53 (dq, J_1-2= 4.0 Hz, J_1-6= 1.3 Hz, J =

(101 MHz, CDCl₃) δ (ppm): 202.6 (C₁), 113.5 (C_{isopropylidene}), 78.3 (C₅),

77.5 (C₆), 70.2 (C₂), 59.7 (C₃), 54.2 (C₄), 27.5 (CH₃), 25.5 (CH₃). FT-IR

J = 1.3 Hz, 1H, H₁), 3.38 (dt, J_1-2= 4.0 Hz, J = J = 1.4 Hz, 1H, H₂),

3.10 (d, J_3-OH3= 9.4 Hz, 1H, OH₃), 2.87 (d, J_4-OH4= 11.8 Hz, 1H, OH₄),

1.41 (s, 3H, CH₃), 1.34 (s, 3H, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ

(ppm): 110.1 (C_{isopropylidene}), 77.0 (C₅), 69.8 (C₆), 68.6 (C₄), 64.3 (C₃),

(ν_max/cm): 3507 (OH), 2947 (CH₃), 2820 (CH₃), 1744 (C=O), 1383

˜

(gem dimethyl), 1244 (epox), 1219 (C-O), 1188 (C-O-C-O-C), 1159 (C-

O-C-O-C), 1101 (C-O-C-O-C), 1069 (C-O-C-O-C). DI-MS m/z (Rel. Int):

57.9 (C₁), 56.1 (C₂), 27.4 (CH₃), 25.1 (CH₃). FT-IR (ν_max/cm): 3318 (OH),

˜

185 (18, [M – Me]⁺), 142 (2), 100 (61), 85 (100), 71 (81). HRMS (ESI/ 3244 (OH), 2988 (C-H), 2945 (C-H), 2909 (C-H), 1385 (gem dimethyl),

Q-TOF) m/z: [M + Na]⁺Calcd for [C₉H₁₂O₅Na]⁺223.0577, found

223.0569.

1370 (gem dimethyl), 1225 (epox), 1169 (C-O-C-O-C), 1144 (C-O-C-

O-C), 1088 (C-O-C-O-C), 1061 (C-O-C-O-C). DI-MS m/z (Rel. Int): 187

(100, [M – Me]⁺), 109 (72), 81 (52), 73 (53). HRMS (ESI/Q-TOF) m/z:

[M + Na]⁺Calcd for [C₉H₁₄O₅Na]⁺: 225.0733, found 225.0774.

(5S,6S)-2,3-dihydroxy-5,6-isopropylidenedioxycyclohexa-2-ene-

1-one (14).^[34]

(1S,2R,3S,4S)-5-bromo-3,4-isopropylidenedioxycyclohexa-5-en-

1,2-diol (16).^[36]

Structure I could be in equilibrium with structure II. As HMBC exper-

iments shows a long distance coupling of C₁-H₆and C₁-H_6′, as well

as C₃-H₄, we propose that the main structure in a methanolic solu-

tion is II. White solid. The spectroscopic data of the compound

were found to be in agreement with previous reports.^{[34] 1}H NMR

(400 MHz, CD₃OD) δ (ppm): 4.90-4.85 (m-signal partially overlapped

with water signal, 1H, H₄), 3.97 (ddd, J_5-6′= 11.6 Hz, J₄-₅= 8.5 Hz,

White solid. The ¹H- and ¹³C-NMR spectra data of the compound

were in agreement with previous reports.^{[36] 1}H NMR (400 MHz,

CDCl₃) δ (ppm): 6.26 (d, J_1-6= 2.5 Hz, 1H, H₆), 4.69 (d, J_3-4= 6.1 Hz,

1H, H₄), 4.21 (dd, J_2-3= 7.8 Hz, J_3-4= 6.1 Hz, 1H, H₃), 4.13 – 4.05 (m,

1H, H₁), 3.75 (t, J_1-2= J_2-3= 7.8 Hz, 1H, H₂), 1.55 (s, 3H, CH₃), 1.43

(s, 3H, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ (ppm): 134.3 (C₆), 119.8

(C₅), 111.3 (C_{isopropylidene}), 77.7 (C₄), 77.2 (C₃), 73.3 (C₁), 71.0 (C₂), 28.2

(CH₃), 26.2 (CH₃).

J_5-6= 5.3 Hz, 1H, H₅), 2.66 (dd, J_gem= 16.5 Hz, J_5-6= 5.3 Hz, 1H, H₆),

2.44 (dd, J_gem= 16.5 Hz, J_5-6′= 11.6 Hz, 1H, H_6′), 1.64 (s, 3H, CH₃),

1.59 (s, 3H, CH₃). ¹³C NMR (101 MHz, CD₃OD) δ (ppm): 192.5 (C₁),

152.0 (C₃), 128.1 (C₂), 118.5 (C_{isopropylidene}), 82.1 (C₄), 71.1 (C₅), 43.4

D-1,2-anhydro-3,4-di-O-acetyl-5,6-O-isopropyliden-allo-

inositol (17).

(C₆), 26.9 (CH₃), 24.3 (CH₃). FT-IR (ν_max/cm): 3441 (OH), 2992 (CH₃),

˜

2936 (CH₂), 1771 (enodiol-enone), 1385 (gem dimethyl), 1221 (C-

C(O)-C), 1152 (C-O-C-O-C), 1130 (C-O-C-O-C), 1192 (C-O-C-O-C),

1066 (C-O-C-O-C). DI-MS m/z (Rel. Int): 200 (63, [M]^.+), 142 (99), 114

(58), 71 (100), 68 (99). HRMS (ESI/Q-TOF) m/z: [M + Na]⁺Calcd for

[C₉H₁₂O₅Na]⁺223.0577, found 223.0575.

D-1,2-anhydro-5,6-O-isopropylidene-allo-inositol (15).^[35]

24 mg of compound 15 (0.12 mmol, 1 eq) were dissolved in 1.0 mL

of CH₂Cl₂under nitrogen atmosphere, and the system was cooled

to 0 °C. Then 132 μL of Et₃N (0.95 mmol, 8 eq), 45 μL of Ac₂O

(0.48 mmol, 4 eq) and a catalytic amount of 4-dimethylamino-

pyridine were added at 0°C. The reaction was kept at 0 °C for 10

minutes, then it was warmed up to room temperature and contin-

ued to stir during another 10 minutes. A saturated solution of

NaHCO₃was added, and the aqueous solution was extracted with

3.000 g of epoxide 3 (12.15 mmol, 1 eq.) were dissolved in 97.5 mL

of CH₃CN, and the system was cooled to 0 °C. 3.117 g of NaIO₄three portions of AcOEt. The combined organic layers were washed

(14.57 mmol, 1.2 eq.) and 88 mg of RuCl₃·2H₂O (0.36 mmol, 0.03

eq.) were dissolved in 16.3 mL of water on a separated vial, and

were also cooled to 0 °C. Once both solutions were at 0°C, the

aqueous solution was added all at once over de organic solution,

with three portions of saturated solution of CuSO₄and one portion

of brine, dried with Na₂SO₄, filtered and the solvent was removed

under reduced pressure. Purification was accomplished by flash

chromatography, using SiO₂as stationary phase, and eluting with a

and the reaction was kept at 0°C under vigorous stirring for 5 min- solution 20 % (v/v) of AcOEt in Hexane. 31 mg of 17 were obtained

21.5

utes, and then 923 mg of NaBH₄(24.29 mmol, 2 eq.) were added in

small portions. The reaction was kept at 0°C for 10 minutes, and NMR (400 MHz, CDCl₃) δ (ppm): 5.51 (dd, J_3-4= 4.6 Hz, J_2-3= 2.1 Hz,

then it was left to stir at room temperature for another 10 minutes. 1H, H₃), 5.41 (td, J_3-4= J_4-5= 4.6 Hz, J_2-4= 1.0 Hz, 1H, H₄), 4.53 (d,

The reaction was filtered through a SiO₂pad, washed with abun- J_5-6= 5.7 Hz, 1H, H₆), 4.25 (ddd, J_5-6= 5.7 Hz, J_4-5= 4.6 Hz, J_1-5

dant AcOEt and the eluted was evaporated rendering 2.830 mg of 1.4 Hz, 1H, H₅), 3.37 (ddt, J_1-2= 4.0 Hz, J_2-3= 2.1 Hz, J_2-4= J_¿2-6?

as a colorless oil (91 % yield). α_D

= +57 (c = 0.93, MeOH). ¹H

=

a brownish solid. Purification was accomplished by flash chroma- 3.28 (ddd, J_1-2= 4.0 Hz, J_1-5= 1.4 Hz, J_1-6= 0.8 Hz, 1H), 2.09 (s, 3H,

tography, using SiO₂as stationary phase, and performing the fol-

lowing gradient elution: 10 % followed by 20 %, 30 %, 35 % and

finally 40 % (v/v of AcOEt in Hexane). 1.470 g of 15 were obtained

C(O)CH₃), 2.09 (s, 3H, C(O)CH₃), 1.45 (s, 3H, CH₃), 1.34 (s, 3H, CH₃).

¹³C NMR (101 MHz, CDCl₃) δ (ppm): 170.3 (OC(O)CH₃), 170.2

(OC(O)CH₃), 110.2 (C_{isopropylidene}), 74.3 (C₅), 70.4 (C₆), 66.6 (C₃), 65.5

(C₄), 53.6 (C₁), 52.1 (C₂), 27.7 (CH₃), 25.5 (CH₃), 21.0 (OC(O)CH₃), 20.9

1

as white solid (60 % yield). α_D^21.5= +22 (c = 1.41, MeOH). H NMR

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(OC(O)CH₃). FT-IR (ν_max/cm): 2990 (CH₃), 2940 (CH₃), 1748 (C=O),

Me]⁺), 185 (2), 100 (18), 85 (26), 73 (100), 60 (31). HRMS (ESI/Q-TOF)

m/z: [M + Na]⁺Calcd for [C₉H₁₅N₃O₅Na]⁺: 268.0904, found 268.0903.

˜

1433 (gem dimethyl), 1373 (gem dimethyl), 1240 (epox), 1221

(epox), 1171 (C-O-C-O-C), 1155 (C-O-C-O-C), 1090 (C-O-C-O-C), 1065

(C-O-C-O-C). DI-MS m/z (Rel. Int): 271 (90, [M – Me]⁺), 229 (5), 184

(28), 127 (43), 109 (100), 81 (29). HRMS (ESI/Q-TOF) m/z: [M + Na]⁺

Calcd for [C₁₃H₁₈O₇Na]⁺: 309.0945, found 309.0946.

D-2-azido-2-deoxy-5,6-O-isopropyliden-allo-inositol (20).

L-4-azido-4-deoxy-1,2-O-isopropyliden-chiro-inositol (18).

White solid (8 % yield). M.P = 140.2 - 141.1 °C. α²_D^1.5= +23 (c = 1.55,

1

MeOH). H NMR (400 MHz, CD₃OD) δ (ppm): 4.29 – 4.22 (m, 2H, H₅

+ H₆), 4.08 – 4.00 (m, 2H, H₁+ H₃), 3.79 (dd, J = 5.0, 3.4 Hz, 1H, H₄),

3.64 (dd, J = 3.5, 2.5 Hz, 1H, H₂), 1.45 (s, 3H, CH₃), 1.35 (s, 3H, CH₃).

¹³C NMR (101 MHz, CD₃OD) δ (ppm): 110.2 (C_{isopropylidene}), 79.1

(C_5or6), 79.0 (C_5or6), 72.9 (C_1or3or4), 72.8 (C_1or3or4), 72.1 (C_1or3), 63.0

700 mg of epoxide 15 (3.47 mmol, 1 eq) were dissolved in 7 mL of

DMF under nitrogen atmosphere. 450 mg of NaN₃(6.93 mmol, 2

eq) and 371 mg of NH₄Cl (6.93 mmol, 2 eq) were added, and the

system was warmed up to 50 °C. The reaction was monitored by

(C ), 28.6 (CH ), 26.4 (CH ). FT-IR (ν_max/cm): 3412 (OH), 2990 (C-H),

˜

2

3

2938 (C-H), 2110 (N₃), 1383 (gem dimethyl), 1219 (C-O), 1163 (C-O-

TLC, and once the starting material was consumed (approximately C-O-C), 1101 (C-O-C-O-C), 1067 (C-O-C-O-C), 1055 (C-O-C-O-C). DI-

12h) the solid (inorganic salts) was filtered through filter paper, and

MS m/z (Rel. Int): 230 (24, [M – Me]⁺), 160 (15), 142 (9), 100 (61), 85

washed with methanol. The organic solution was evaporated at re- (33.9), 73 (100), 60 (44). HRMS (ESI/Q-TOF) m/z: [M + Na]⁺Calcd for

duced pressure rendering 1.192 g of a white solid. Purification was

accomplished by flash chromatography, using SiO₂as stationary

phase, and performing the following gradient elution: 30 % fol-

lowed by 40 %, 50 %, 60 % and finally 70 % (v/v of AcOEt in Hex-

ane). 739 mg of 18 were obtained as white solid (87 % yield). M.P =

153.2 – 154.1 °C. α_D^21.5= –122 (c = 1.27, MeOH). ¹H NMR (400 MHz,

CD₃OD) δ (ppm): 4.22 (dd, J_1-2= 5.4 Hz, J_1-6= 3.0 Hz, 1H, H₁), 4.10

(t, J_1-6= J_5-6= 3.0 Hz, 1H, H6), 4.04 (dd, J_2-3= 7.4 Hz, J_1-2= 5.4 Hz,

[C₉H₁₅N₃O₅Na]⁺: 268.0904, found 268.0904.

D-3,4,6-tri-O-acetyl-5-azido-5-deoxy-1,2-O-isopropyliden-neo-

inositol (21).

1H, H₂), 3.58 (dd, J_4-5= 10.0 Hz, J_5-6= 3.0 Hz, 1H, H₅), 3.52 (t, J_3-4

=

J

_4-5= 10.0 Hz, 1H, H₄), 3.42 (dd, J_3-4= 10.0 Hz, J_2-3= 7.4 Hz, 1H, H₃),

1.44 (s, 3H, CH₃), 1.33 (s, 3H, CH₃). ¹³C NMR (101 MHz, CD₃OD) δ

70 mg of triol 19 (0.29 mmol, 1 eq) were dissolved in 0.5 mL of

pyridine under nitrogen atmosphere, and the system was cooled to

0 °C. 162 μL of Ac₂O (1.71 mmol, 6 eq) and a catalytic amount of

4-dimethylaminopyridine were added. The system was left to react

during 15 minutes at 0 °C, and was then warmed up to r.t. and left

to stir for another 15 minutes. The reaction was quenched by addi-

tion of saturated aqueous solution of NH₄Cl, and extracted with

three portions of AcOEt. The combined organic layers were washed

with four portions of saturated aqueous solution of CuSO₄, one

portion of brine, dried with Na₂SO₄, filtered and evaporated under

reduced pressure. 107 mg of a colorless oil were obtained. Purifica-

tion was accomplished by flash chromatography, using SiO₂as sta-

tionary phase and performing the following gradient elution: 10 %

and then 20 % (v/v of AcOEt in Hexane). 103 mg of 21 were ob-

tained as a colourless oil (97 % yield). α²_D^1.5= –8 (c = 0.91, MeOH).

(ppm): 110.5 (C_{isopropylidene}), 80.5 (C₂), 78.7 (C₁), 76.2 (C₃), 71.7 (C₅),

70.4 (C₆), 66.5 (C₄), 28.4 (CH₃), 26.3 (CH₃). FT-IR (ν_max/cm): 3350 (OH),

˜

2999 (C-H), 2986 (C-H), 2969 (C-H), 2914 (C-H), 2124 (N₃), 1387 (gem

dimethyl), 1223 (C-O-C-O-C), 1063 (C-O-C-O-C). DI-MS m/z (Rel. Int):

230 (100, [M – Me]⁺), 187 (2), 100 (17), 85 (24), 73 (75), 60 (25).

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺Calcd for [C₉H₁₅N₃O₅Na]⁺:

268.0904, found 268.0907.

D-5-azido-5-deoxy-1,2-O-isopropyliden-neo-inositol (19).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.44 (dd, J_3-4= 10.4 Hz, J_2-3

4.1 Hz, 1H, H₃), 5.36 (dd, J_3-4= 10.4 Hz, J_4-5= 3.0 Hz, 1H, H₄), 5.07

=

The same procedure described for compound 15 was applied to

synthesize 19. Purification was accomplished by flash chromatogra- (dd, J_1-6= 8.0 Hz, J_5-6= 3.0 Hz, 1H, H₆), 4.49 (t, J_1-2= J_2-3= 4.5 Hz,

phy, using SiO₂as stationary phase and performing the following 1H, H₂), 4.29 (dd, J_1-6= 8.0 Hz, J_1-2= 4.5 Hz, 1H, H₁), 4.16 (t, J_4-5

=

gradient elution: 30 % followed by 40 %, 50 %, 60 %, 70 % and fi- J_5-6= 3.0 Hz, 1H, H₅), 2.14 (s, 3H, OC(O)CH₃), 2.11 (s, 3H, OC(O)CH₃),

nally 80 % (v/v of AcOEt in Hexane). White solid (61 % yield). M.P =

2.09 (s, 3H, OC(O)CH₃), 1.53 (s, 3H, CH₃), 1.31 (s, 3H, CH₃). ¹³C NMR

(101 MHz, CDCl₃) δ (ppm): 170.3 (OC(O)CH₃), 170.0 (OC(O)CH₃),

169.7 (OC(O)CH₃), 110.9 (C_{isopropylidene}), 75.6 (C₁), 73.0 (C₂), 71.9 (C₆),

69.0 (C₄), 68.0 (C₃), 61.8 (C₅), 28.0 (CH₃), 26.2 (CH₃), 20.9 (OC(O)CH₃),

1

139.7 - 140.5 °C. α_D^21.5= –14 (c = 1.23, MeOH). H NMR (400 MHz,

CD₃OD) δ (ppm): 4.35 (t, J_1-2= J_2-3= 4.6 Hz, 1H, H₂), 4.04 (dd, J_1-6

=

7.9 Hz, J_1-2= 4.6 Hz, 1H, H₁), 3.94 (ddd, J_3-4= 10.6 Hz, J_2-3= 4.6 Hz,

J_¿3-5?= 0.9 Hz, 1H, H₃), 3.89 – 3.84 (m, 2H, H₄+ H₅), 3.77 (dd, J_1-6

=

20.9 (OC(O)CH ), 20.7 (OC(O)CH ). FT-IR (ν_max/cm): 2990 (C-H), 2938

(C-H), 2920 (C-H), 2110 (N₃), 1748 (C=O), 1433 (gem dimethyl), 1373

(gem dimethyl), 1225 (C-O-C-O-C), 1159 (C-O-C-O-C), 1007 (C-O-C-

˜

3

7.9 Hz, J_5-6= 3.0 Hz, 1H, H₆), 1.48 (s, 3H, CH3), 1.34 (s, 3H, CH3). ¹³C

NMR (101 MHz, CD₃OD) δ (ppm): 110.5 (C_{isopropylidene}), 80.3 (C₁), 77.5

(C₂), 72.8 (C₆), 71.1 (C₄), 70.0 (C₃), 69.7 (C₅), 28.7 (CH₃), 26.3 (CH₃). O-C), 1069 (=C-O-C), 1047 (=C-O-C). DI-MS m/z (Rel. Int): 356 (57,

FT-IR (ν_max/cm): 3399 (OH), 2988 (C-H), 2936 (C-H), 2911 (C-H), 2108 [M – Me]⁺), 328 (0.6), 184 (19), 166 (100), 142 (23), 124 (99), 109 (28),

˜

(N₃), 1375 (gem dimethyl), 1219 (C-O), 1163 (C-O-C-O-C), 1076 (C-

O-C-O-C), 1053 (C-O-C-O-C). DI-MS m/z (Rel. Int): 230 (80, [M –

73 (19). HRMS (ESI/Q-TOF) m/z: [M + Na]⁺Calcd for [C₁₅H₂₁N₃O₈Na]⁺:

394.1221, found 394.1215.

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meso-1,2,3,4,6-penta-O-acetyl-5-azido-5-deoxy-neo-inositol

(22).

(OCH₂Ph), 73.7 (OCH₂Ph), 72.0 (OCH₂Ph), 62.5 (C₂), 28.3 (CH₃), 26.1

(CH₃). FT-IR (ν_max/cm): 3032 (=C-H arom), 2987 (C-H), 2916 (C-H),

˜

2872 (C-H), 2106 (N₃), 1954 (Ph), 1877 (Ph), 1811 (Ph), 1748 (Ph),

1497 (Ph), 1454 (Ph), 1381 (gem dimethyl), 1371 (gem dimethyl),

1219 (C-O-C-O-C), 1155 (C-O-C-O-C), 1094 (C-O-C-O-C), 1076 (C-O-

C-O-C), 1051 (C-O-C-O-C), 737 (Ph), 698 (Ph). DI-MS m/z (Rel. Int):

500 (0.1, [M – Me]⁺), 424 (0.6), 396 (2), 106 (6), 91 (100), 65 (4).

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺Calcd for [C₃₀H₃₃N₃O₅Na]⁺:

538.2312, found 538.2305.

Compound 22 was synthesized from 21 following the same proce-

dure described for the synthesis of compound 6 (but at room tem-

perature). The crude was subjected to esterification following the

same procedure described for the synthesis of compound 17. Purifi-

cation was accomplished by flash chromatography, using SiO₂as

stationary phase and performing the following gradient elution:

20 % and then 30 % (v/v of AcOEt in Hexane). White solid (72 %

yield). α²_D^1.5= 0 (c = 0.67, MeOH). ¹H NMR (400 MHz, CDCl₃) δ (ppm):

5.57 (s, 1H, H₂), 5.30 (bs, 4H, H_{1 +}H_{3 +}H_{4 +}H₆), 4.35 (s, 1H, H₅), 2.14

(s, 3H, CH₃), 2.10 (s, 6H, 2xCH₃), 1.98 (s, 6H, 2xCH₃). ¹³C NMR

(101 MHz, CDCl₃) δ (ppm): 169.9 (2xAc), 169.9 (Ac), 169.5 (2xAc),

68.7 (C₁+ C₃or C₄+ C₆), 68.1 (C₂), 67.3 (C₄+ C₆or C₁+ C₃), 60.7

D-2-azido-1,3,4-tri-O-benzyl-2-deoxy-5,6-O-methylen-neo-

inositol (24).

The general procedure for the synthesis of dioxolane under acidic

conditions using pTsOH as catalyst was used, but changing DCM for

CHCl₃as solvent, in order to increase de boiling point temperature.

Purification was accomplished by flash chromatography, using SiO₂

as stationary phase, and performing the following gradient elution:

5 %, then 10 % and finally 20 % (v/v of AcOEt in Hexane). Colorless

oil (87 % yield). α²_D^5.5= –18 (c = 1.21, MeOH). ¹H NMR (400 MHz,

CDCl₃) δ (ppm): 7.34 – 7.27 (m, 15H, Phx3), 5.07 (s, 1H, OCH₂O), 4.97

(C₅), 20.8 (Ac), 20.7 (2xAc), 20.6 (2xAc). FT-IR (ν_max/cm): 2990 (C-H),

˜

2941 (C-H), 2106 (N₃), 1748 (C=O), 1372 (C-N), 1225 (C-O), 1076 (=

C-O-C), 1045 (=C-O-C). DI-MS m/z (Rel. Int): 356 (3, [M – OAc]⁺), 225

(35), 183 (54), 157 (46), 115 (100), 103 (35), 73 (26). HRMS (ESI/Q-

TOF) m/z: [M + Na]⁺Calcd for [C₁₆H₂₁N₃O₁₀Na]⁺: 438.1119, found

438.1138.

D-2-azido-1,3,4-tri-O-benzyl-2-deoxy-5,6-O-isopropyliden-neo-

inositol (23).

(s, 1H, OCH₂O), 4.83 (d, J_gem= 11.8 Hz, 1H, OCH₂Ph), 4.81 (d, J_gem

=

11.8 Hz, 1H, OCH₂Ph), 4.77 (d, J_gem= 11.8 Hz, 1H, OCH₂Ph), 4.73 (d,

J_gem= 12.2 Hz, 1H, OCH₂Ph), 4.68 (d, J_gem= 11.8 Hz, 1H, OCH₂Ph),

4.65 (d, J_gem= 12.2 Hz, 1H, OCH₂Ph), 4.30 (dd, J_1-6= 7.8 Hz, J_6-5

4.6 Hz, 1H, H₆), 4.12 – 4.04 (m, 2H, H₄+ H₅), 3.94 (t, J_1-2= J_2-3

=

2.9 Hz, 1H, H₂), 3.80 (dd, J_3-4= 9.0 Hz, J_2-3= 2.9 Hz, 1H, H₃), 3.39

(dd, J_1-6= 7.8 Hz, J_1-2= 2.9 Hz, 1H, H₁). ¹³C NMR (101 MHz, CDCl₃)

δ (ppm): 138.1 (Ph_quaternary), 138.0 (Ph_quaternary), 137.7 (Ph_quaternary),

128.7 (2xC_Ph), 128.6 (2xC_Ph), 128.5 (2xC_Ph), 128.1 (2xC_Ph), 128.0

(1xC_Ph), 128.0 (1xC_Ph), 127.9 (3xC_Ph), 127.8 (2xC_Ph), 95.0 (OCH₂O),

77.5 (C₃), 77.4 (C₆), 75.9 (C_{1 or 4 or 5}), 75.8 (C_{1 or 4 or 5}), 75.6 (C_{1 or 4 or 5}),

The same procedure described for the synthesis of compound 5

was followed for synthesizing compound 23, with the following

modifications: 300 mg of compound 19 (1.22 mmol, 1 eq) were

dissolved in 2 mL of DMF, 4.5 eq of NaH (55 % mineral oil disper-

sion) and 5 eq of BnBr were used. Purification was accomplished by

flash chromatography, using SiO₂as stationary phase, and perform-

ing the following gradient elution: 0 %, then 2 % and finally

5 % (v/v of AcOEt in Hexane). 619 mg of 23 were obtained as a

colorless oil (98 % yield).

73.6 (OCH Ph), 73.6 (OCH Ph), 72.2 (OCH Ph), 62.5 (C ). FT-IR (ν /

˜

2

max

cm): 3030 (=C-H arom), 2974 (C-H), 2102 (N₃), 1956 (Ph), 1879 (Ph),

1813 (Ph), 1797 (Ph), 1454 (Ph), 1206 (C-O-C-O-C), 1098 (C-O-C-O-

C), 945 (-OCH₂O), 737 (Ph), 696 (Ph). DI-MS m/z (Rel. Int): 458 (0.2),

396 (1, [M – Bn]⁺), 368 (2), 106 (6), 91 (100), 65 (5). HRMS (ESI/Q-

TOF) m/z: [M + Na]⁺Calcd for [C₂₈H₂₉N₃O₅Na]⁺: 510.1999, found

510.1968.

L-2-amino-2-deoxy-4,5-O-methylen-neo-inositol (25).^[12]

α²_D^5.5= +18 (c = 1.16, MeOH:AcOEt 3:1). ¹H NMR (400 MHz, CDCl₃)

δ (ppm): 7.43 – 7.27 (m, 15H, 3xPh), 4.86 (d, J_gem= 12.2 Hz, 1H,

OCH₂Ph), 4.85 (d, J_gem= 11.9 Hz, 1H, OCH₂Ph), 4.76 – 4.63 (m, 4H,

2xOCH₂Ph), 4.22 (t, J_4-5= J_5-6= 4.7 Hz, 1H, H₅), 4.17 (dd, J_1-6

=

213 mg of 24 (0.44 mmol, 1 eq) were dissolved in 8 mL of a solution

THF:MeOH (1:1). 21 mg of Pd-C 10 % and 40 μL of HCl_cc(0.48 mmol,

1.1 eq) were added, and hydrogen was bubbled into the system

(P=1 atm). Once the reaction was completed (approximately 3 h),

nitrogen was bubbled during 10 minutes to remove dissolved H₂,

then the catalyst was removed by filtration and washed with a solu-

7.6 Hz, J_5-6= 4.7 Hz, 1H, H₆), 4.01 (dd, J_3-4= 9.6 Hz, J_4-5= 4.7 Hz,

1H, H₄), 3.94 (t, J_1-2= J_2-3= 3.0 Hz, 1H, H₂), 3.82 (dd, J_3-4= 9.6 Hz,

J_2-3= 3.0 Hz, 1H, H₃), 3.45 (dd, J_1-6= 7.6 Hz, J_1-2= 3.0 Hz, 1H, H₁),

1.37 (s, 3H, CH₃), 1.32 (s, 3H, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ

(ppm): 138.3 (Ph_quaternary), 138.2 (Ph_quaternary), 137.8 (Ph_quaternary),

128.6 (2xC_Ph), 128.6 (2xC_Ph), 128.5 (2xC_Ph), 128.2 (2xC_Ph), tion MeOH:H₂O (8:2, v/v). The solvent was evaporated under re-

128.0 (1xC_Ph), 128.0 (2xC_Ph), 127.9 (2xC_Ph), 127.8 (2xC_Ph), 109.6 duced pressure (absolute EtOH was used to remove H₂O by azeo-

(C_{isopropylidene}), 78.0 (C₆), 77.6 (C₁), 77.5 (C₃), 75.9 (C₄), 74.4 (C₅), 73.8 tropic distillation) rendering 100 mg of a very hygroscopic white

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solid (gum). Pure product was obtained as the hydrochloride, then

no purification was needed. Hydrochloride: H NMR (400 MHz, D₂O,

(ν_max/cm): 3447 (OH), 2986 (C-H), 2943 (C-H), 2880 (C-H), 2112 (N₃),

˜

1

1377 (gem dimethyl), 1331 (gem dimethyl), 1252 (O-H), 1157 (C-O-

C-O-C), 1084 (C-O-C-O-C), 1072 (C-O-C-O-C). DI-MS m/z (Rel. Int):

276 (52, [M – Me]⁺), 274 (53, [M – Me]⁺), 188 (2), 101 (48), 59 (35), 43

(100). HRMS (ESI/Q-TOF) m/z: [M + Na]⁺Calcd for [C₉H₁₂BrN₃O₃Na]⁺:

311.9954, found 311.9954.

with MeOH as internal reference at δ = 3.34 ppm^[37]) δ (ppm): 5.23

(s, 1H, OCH₂O), 4.81 (s, 1H, OCH₂O), 4.36-4.30 (m, 2H, H₄+ H₅), 4.21

(dd, J_1-6= 7.9 Hz, J_5-6= 2.3 Hz, 1H, H₆), 4.11 (dd, J_1-6= 7.9 Hz,

J_1-2= 6.5 Hz, 1H, H₁), 4.01 (t, J_2-3= J_3-4= 3.3 Hz, 1H, H₃), 3.78 (dd,

J_1-2= 6.5 Hz, J_2-3= 3.3 Hz, 1H, H₂). ¹³C NMR (101 MHz, D₂O, with

MeOH as internal reference at δ = 49.50 ppm^[37]) δ (ppm): 95.5

(OCH₂O), 76.8 (C_{4 o 5}), 76.2 (C_{5 o 4}), 70.5 (C₆), 67.7 (C_{1 o 3}), 67.7 (C_{3 o}

D-5-azido-5-deoxy-1,2-O-isopropyliden-myo-inositol (27).

The same procedure described for compound 15 was applied for

synthesizing 27. Purification was accomplished by flash chromatog-

raphy, using SiO₂as stationary phase and performing the following

gradient elution: 30 % followed by 40 %, 50 %, 60 %, 70 %, 80 %

and finally 90 % (v/v of AcOEt in Hexane). Colourless syrup (75 %

₁), 50.9 (C₂). FT-IR (ν_max/cm): 3402 (OH), 2930 (NH), 1630 (NH₃⁺),

˜

1508 (NH₃⁺), 1080 (C-O), 957 (methylenedioxy). ID-MS m/z (Int. Rel.):

192 (1, M⁺), 191 (3), 173 (6), 126 (9), 101 (26), 88 (100), 73 (65). Free

base: an ion exchange chromatography was employed for obtaining

the free base. DOWEX 50WX8-100 resin was used as stationary

phase, and a gradient elution was applied: first a solution 9:1

(MeOH:NH₄OH_cc), followed by a 8:2 solution (MeOH:NH₄OH_cc), then

a 7:3 solution (MeOH:NH₄OH_cc), followed by a 6:4 solution

(MeOH:NH₄OH_cc), and finally a 5:5 solution (MeOH:NH₄OH_cc). Meth-

anol was removed under reduced pressure, and the remaining wa-

ter was lyophilized rendering the free base aminocyclitol as a hygro-

scopic white solid. Spectroscopic data was in concordance with pre-

viously described values.^{[12] 1}H NMR (400 MHz, D₂O, HDO signal

was used as internal reference at δ = 4.79 ppm) δ (ppm): 5.19 (s,

1H, OCH₂O), 4.93 (s, 1H, OCH₂O), 4.28 (dd, J_3-4= 7.5 Hz, J_4-5= 5.1 Hz,

1H, H₄), 4.18 (t, J_4-5= J_5-6= 4.7 Hz, 1H, H₅), 4.13 (dd, J_1-6= 9.6 Hz,

J_5-6= 4.3 Hz, 1H, H₆), 3.87 (dd, J_1-6= 9.6 Hz, J_1-2= 3.9 Hz, 1H, H₁),

1

yield). α²_D^5.5= –52 (c = 1.54, MeOH). H NMR (400 MHz, (CD₃)₂CO) δ

(ppm): 4.74 (d, J_6-OH6= 5.0 Hz, 1H, OH₆), 4.58 (d, J_4-OH4= 4.2 Hz, 1H,

OH₄), 4.38 (dd, J_1-2= 5.2 Hz, J_2-3= 3.9 Hz, 1H, H₂), 4.07 – 3.99 (m,

2H, H₁+ OH₃), 3.79 (ddd, J_3-4= 9.3 Hz, J_3-OH3= 5.8 Hz, J_2-3= 3.9 Hz,

1H, H₃), 3.63 (td, J_3-4= J_4-5= 9.3 Hz, J_4-OH4= 4.2 Hz, 1H, H₄), 3.58

(ddd, J_5-6= 10.3 Hz, J_1-6= 7.3 Hz, J_6-OH6= 5.0 Hz, 1H, H₆), 3.18 (dd,

J_5-6= 10.3 Hz, J_4-5= 9.3 Hz, 1H, H₅), 1.41 (s, 3H, CH₃), 1.29 (s, 3H,

CH₃). ¹³C NMR (101 MHz, (CD₃)₂CO) δ (ppm): 109.8 (C_{isopropylidene}),

80.6 (C₁), 77.1 (C₂), 74.8 (C₆), 72.6 (C₄), 71.8 (C₃), 68.9 (C₅), 28.4 (CH₃),

26.1 (CH₃). FT-IR (ν_max/cm): 3383 (OH), 2990 (C-H), 2938 (C-H), 2922

˜

(C-H), 2110 (N₃), 1377 (O-H), 1221 (C-O), 1146 (C-O-C-O-C), 1099

(C-O-C-O-C), 1042 (C-O-C-O-C). DI-MS m/z (Rel. Int): 230 (100, [M –

Me]⁺), 109 (13), 96 (12), 85 (22), 73 (88), 60 (35). HRMS (ESI/Q-TOF)

m/z: [M + Na]⁺Calcd for [C₉H₁₅N₃O₅Na]⁺: 268.0904, found 268.0912.

3.74 (dd, J_3-4= 7.5 Hz, J_2-3= 3.5 Hz, 1H, H₃), 3.40 (t, J_1-2= J_2-3

=

3.7 Hz, 1H, H₂). ¹³C NMR (101 MHz, D₂O, CH₂O signal of EtOH was

used as internal reference at δ = 58.05 ppm^[37]) δ (ppm): 94.9

(OCH₂O), 77.7 (C₄), 77.5 (C₅), 70.3 (C_1o3), 70.2 (C_3o1), 68.8 (C₆), 55.1

D-5-azido-3,4,6-tri-O-benzyl-5-deoxy-1,2-O-isopropyliden-myo-

inositol (28).

(C₂). FT-IR (ν_max/cm): 3370 (OH), 2982 (C-H), 2929 (C-H), 1634 (N-H),

˜

1389 (O-H), 1138 (C-O-C-O-C), 1088 (C-O-C-O-C), 1045 (C-O-C-O-C),

972 (N-H). HRMS (ESI/Q-TOF) m/z: [M + H]⁺Calcd for [C₇H₁₄NO₅]⁺:

192.0866, found 192.0866.

(1R,2S,5S,6S)-2-azido-4-bromo-5,6-isopropylidenedioxycyclo-

hexa-3-ene-1-ol (26).^[38]

The same procedure described for the synthesis of compound 23

was followed for synthesizing compound 28. Purification was ac-

complished by flash chromatography, using SiO₂as stationary

phase, and performing the following gradient elution: 0 %, then

6.008 g of epoxide 3 (24.32 mmol, 1 eq) were dissolved in 175 mL 2 %, 5 % and finally 10 % (v/v of AcOEt in Hexane). Colorless oil

of a solution THF:EtOH:H₂O (3:2:2). 4.743 g of NaN₃(72.97 mmol, 3

(74 % yield). α²_D^5.5= +19 (c = 1.37, MeOH). ¹H NMR (400 MHz, CDCl₃)

eq) and 2.863 g of NH₄Cl (53.51 mmol, 2.2 eq) were added. The δ (ppm): 7.44 – 7.27 (m, 15H, 3xPh), 4.91 – 4.70 (m, 6H, 3xOCH₂Ph),

system was heated to reflux temperature and kept stirring at that 4.26 (dd, J_1-2= 5.5 Hz, J_2-3= 3.6 Hz, 1H, H₂), 4.10 (dd, J_1-6= 6.9 Hz,

temperature until consumption of the starting material (approxi- J_1-2= 5.5 Hz, 1H, H₁), 3.74 (t, J_3-4= J_4-5= 8.9 Hz, 1H, H₄), 3.68 (dd,

mately 2 h). Water was added, and the system was extracted with J_3-4= 8.9 Hz, J_2-3= 3.6 Hz, 1H, H₃), 3.56 (dd, J_5-6= 10.3 Hz, J_1-6

=

three portions of AcOEt. The combined organic layers were washed 6.9 Hz, 1H, H₆), 3.34 (dd, J_5-6= 10.3 Hz, J_4-5= 8.9 Hz, 1H, H₅), 1.51

with brine, dried with Na₂SO₄, filtered and concentrated under re- (s, 3H, CH₃), 1.36 (s, 3H, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ (ppm):

duced pressure, rendering 7 g of a white solid. Purification was

accomplished by flash chromatography, using SiO₂as stationary

phase, and performing the following gradient elution: 10 %, then

15 % and finally 20 % (v/v of AcOEt in Hexane). 6.597 g of a white

solid were obtained (94 % yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm):

6.12 (d, J_2-3= 1.6 Hz, 1H, H₃), 4.69 (dd, J_5-6= 6.2 Hz, J_2-5= 1.6 Hz,

1H, H₅), 4.17 (dd, J_1-6= 8.6 Hz, J_5-6= 6.2 Hz, 1H, H₆), 3.92 (dt,

138.0 (Ph_quaternary), 138.0 (2xPh_quaternary), 128.6 (2xPh), 128.6 (2xPh),

128.5 (2xPh), 128.4 (2xPh), 128.2 (2xPh), 128.2 (2xPh), 128.1 (Ph),

128.0 (Ph), 127.9 (Ph), 110.2 (C_{isopropylidene}), 80.9 (C₆), 79.4 (C_{1 or 4}),

79.3 (C_{4 or 1}), 77.4 (C₃), 75.6 (OCH₂Ph), 74.6 (C₁), 73.7 (OCH₂Ph), 73.4

(OCH₂Ph), 65.9 (C₅), 28.0 (CH₃), 25.9 (CH₃). FT-IR (ν_max/cm): 3063 (=

˜

C-H arom), 3032 (=C-H arom), 2988 (C-H), 2911 (C-H), 2874 (C-H),

2106 (N₃), 1952 (Ph), 1877 (Ph), 1811 (Ph), 1497 (Ph), 1454 (Ph), 1371

(gem dimethyl), 1265 (C-O), 1242 (C-O-C-O-C), 1219 (C-O-C-O-C),

J_1-2= 8.6 Hz, J_2-3= J_2-5= 1.6 Hz, 1H, H₂), 3.71 (t, J_1-2= J_1-6= 8.6 Hz,

1H, H₁), 2.84 (bs, 1H, OH₁), 1.56 (s, 3H, CH₃), 1.44 (s, 3H, CH₃). 1153 (C-O-C-O-C), 1072 (C-O-C-O-C), 1047 (C-O-C-O-C), 737 (Ph),

¹³C NMR (101 MHz, CDCl₃) δ (ppm): 131.0 (C₃), 120.6 (C₄), 111.4 696 (Ph). DI-MS m/z (Rel. Int): 500 (0.3, [M – Me]⁺), 424 (0.4), 290

(C_{isopropylidene}), 77.9 (C₅), 77.2 (C₅, signal overlapped with the central

(1), 181 (2), 106 (6), 91 (100), 65 (4). HRMS (ESI/Q-TOF) m/z: [M +

peak of CDCl₃), 73.0 (C₄), 62.3 (C₂), 28.3 (CH₃), 26.0 (CH₃). FT-IR Na]⁺Calcd for [C₃₀H₃₃N₃O₅Na]⁺: 538.2312, found 538.2278.

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D-5-azido-3,4,6-tri-O-benzyl-5-deoxy-1,2-O-methylen-myo-

inositol (29).

Keywords: Cyclitols · Biocatalysis · Amino alcohols ·

Dihydroxylation · Asymmetric synthesis

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Carrera, Org. Lett. 2015, 17, 684–687.

The general procedure for the synthesis of dioxolane under acidic

conditions using pTsOH as catalyst was used, but changing DCM for

CHCl₃as solvent, in order to increase de boiling point temperature.

Purification was accomplished by flash chromatography, using SiO₂

as stationary phase, and performing the following gradient elution:

5 %, then 10 % (v/v of AcOEt in Hexane). Colorless oil (89 % yield).

α²_D^5.5= +10 (c = 0.73, MeOH). ¹H NMR (400 MHz, CDCl₃) δ (ppm):

7.42 – 7.26 (m, 15H, 3xPh), 5.18 (s, 1H, OCH₂O), 4.99 (s, 1H, OCH₂O),

4.86 (d, J_gem= 11.3 Hz, 1H, OCH₂Ph), 4.82 – 4.69 (m, 5H, OCH₂Ph),

4.20 – 4.12 (m, 2H, H₁+ H₂), 3.75 (dd, J_3-4= 8.3 Hz, J_2-3= 3.2 Hz,

1H, H₃), 3.69 (t, J_3-4= J_4-5= 8.3 Hz, 1H, H₄), 3.61 – 3.50 (m, 1H, H₆),

3.39 (dd, J_5-6= 10.3 Hz, J_4-5= 8.3 Hz, 1H, H₅). ¹³C NMR (101 MHz,

CDCl₃) δ (ppm): 137.9 (2xPh_quaternary), 137.8 (Ph_quaternary), 128.6

(2xPh), 128.6 (2xPh), 128.5 (2xPh), 128.4 (2xPh), 128.3 (2xPh), 128.1

(Ph), 128.1 (Ph), 128.0 (2xPh), 128.0 (Ph), 95.5 (OCH₂O), 79.3 (C₄),

79.0 (C₆), 78.9 (C_{1 or 2}), 77.3 (C₃), 75.3 (C_{2 or 1}), 75.2 (OCH₂Ph), 73.9

(OCH₂Ph), 73.2 (OCH₂Ph), 65.8 (C₅). FT-IR (ν_max/cm): 3030 (=C-H

˜

arom), 2876 (C-H), 2106 (N₃), 1954 (Ph), 1877 (Ph), 1811 (Ph),

1497 (Ph), 1454 (Ph), 1207 (C-O-C-O-C), 1094 (C-O-C-O-C), 920

(-OCH₂O-), 737 (Ph), 698 (Ph). DI-MS m/z (Rel. Int): 458 (0.2), 396

(0.6, [M – Bn]⁺), 262 (2), 106 (7), 91 (100), 65 (5). HRMS (ESI/Q-

TOF) m/z: [M + Na]⁺Calcd for [C₂₈H₂₉N₃O₅Na]⁺: 510.1999, found

510.1966.

D-5-amino-5-deoxy-1,2-O-methylen-myo-inositol (30).

[17] C. Coronel, G. Arce, C. Iglesias, C. M. Noguera, P. R. Bonnecarrère, S. R.

Giordano, D. Gonzalez, J. Mol. Catal. B 2014, 102, 94–98.

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Seoane, I. Carrera, Tetrahedron Lett. 2017, 57, 2484–2487; b) J. A. Griffen,

J. C. White, G. Kociok-Köhn, M. D. Lloyd, A. Wells, T. C. Arnot, S. E. Lewis,

Tetrahedron 2013, 69, 5989–5997; c) S. Pilgrim, G. Kociok-Köhn, M. D.

Lloyd, S. E. Lewis, Chem. Commun. 2011, 47, 4799–4801; d) B. J. Paul, J.

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Soc. 2002, 124, 10416–10426.

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Lett. 2017, 58, 2182–2185; b) C. Vitelio, A. Bellomo, M. Brovetto, G. Seo-

ane, D. Gonzalez, Carbohydr. Res. 2004, 339, 1773–1778; c) A. Bellomo,

C. Giacomini, B. Brena, G. Seoane, D. Gonzalez, Synth. Commun. 2007,

37, 3509.

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Tetrahedron: Asymmetry 2009, 20, 2061–2064; b) G. Carrau, N. Veiga, L.

Suescun, G. F. Giri, A. G. Suárez, R. Spanevello, D. González, Tetrahedron

Lett. 2016, 57, 4791–4794.

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Lett. 1991, 32, 6077–6080.

The same procedure described for compound 25 was applied for

synthesizing 30. Colorless syrup (85 % yield). Hydrochloride: α_D^25.5

=

–42 (c = 1.41, MeOH). ¹H NMR (400 MHz, D₂O, HDO signal was used

as internal reference at δ = 4.79 ppm) δ (ppm): 5.22 (s, 1H, OCH₂O),

4.98 (s, 1H, OCH₂O), 4.26 – 4.13 (m, 2H, H₁and H₂), 3.95 – 3.86 (m,

1H, H₃), 3.71 (t, J_3-4= J_4-5= 9.9 Hz, 1H, H₄), 3.65 – 3.55 (m, 1H, H₆),

2.96 (t, J_4-5= J_5-6= 9.9 Hz, 1H, H₅). ¹³C NMR (101 MHz, D₂O, CH₃

signal of EtOH was used as internal reference at δ = 17.47 ppm) δ

(ppm): 95.4 (OCH₂O), 78.7 (C₁), 77.9 (C₂), 70.9 (C₃), 70.4 (C₆), 70.1

(C₄), 55.3 (C₅). FT-IR (ν_max/cm): 3404 (OH), 2922 (CH₂), 2851 (C-H),

˜

1636 (N-H), 1240 (C-N), 1165 (C-O-C-O-C), 1069 (C-O-C-O-C), 924

(-OCH₂O-). DI-MS m/z (Rel. Int): 191 (2, [M]^·+), 173 (4), 126 (3), 113

(6), 101 (20), 88 (100) 72 (38), 60 (31). HRMS (ESI/Q-TOF) m/z: [M +

H]⁺Calcd for [C₇H₁₄NO₅]⁺: 192.0866, found 192.0866.

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Org. Chem. 2017, 2017, 3912–3916.

Acknowledgments

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The authors are grateful to PEDECIBA and CSIC-UdelaR for sup-

port of this project. GC acknowledges Agencia Nacional de In-

vestigación e Innovación (ANII) and Comisión Académica de

Posgrado (CAP) for a PhD fellowship. The authors also acknowl-

edge Prof. Alejandra Rodriguez for HRMS experiments.

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Received: September 24, 2018

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Aminocyclitol Synthesis

G. Carrau, D. A. I. Bellomo, L. Suescun,

D. Gonzalez* ..................................... 1–16

Chemoenzymatic Synthesis of Hy-

gromycin Aminocyclitol Moiety and

its C2 Epimer

This article describes the synthesis of hydroxylation of an electron-poor ole-

hygomycin

A aminocyclitol moiety fin, and introduction of a methylenedi-

and its C2 epimer from bromobezene oxy group. The aminocyclitols were

by a chemoenzymatic strategy. The se- obtained in high chemical and optical

quence involved epoxidation, stereo- purity.

controlled oxirane ring opening, di-

DOI: 10.1002/ejoc.201801424

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Article Doi

Chemoenzymatic synthesis of hygromycin aminocyclitol moiety and its C2 epimer

DOI: 10.1002/ejoc.201801424

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201801424

Full text of DOI:10.1002/ejoc.201801424

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