93

Chapter 3

Partial, Selective and Tandem Reductions of Esters of Garcinia and Hibiscus Acids Using Boranes and

Borohydrides. The 11B NMR Spectroscopy based Mechanistic Insight into Reduction Reactions of Hydroxy Esters

3.1 Introduction

3.1.1 Boron and Borohydrides

Neutral boron-containing compounds are widely used in organic and

inorganic molecular chemistry. Most of these species have Lewis acidity because

of a vacant p-orbital that accepts a lone pair from a Lewis base (Figure 3.1)202

BRR R

LBB

RR R

LB

LB=Lewis base

Figure 3.1

The uniqueness of boron is its existence as complex clusters in elemental

form, which is reflected in its high physical constants (mp 2079 °C, bp 4000 °C).

This is due to the formation of stable covalently bonded molecular networks.

Electron deficiency in BX3, BH3, and higher boron compounds such as B10H14 has

enormous chemical implications, including the existence of large numbers of

cluster compounds. For instance, polyhedral boranes, carboranes, metalloboranes,

boron nitrides, and heteroboranes. Another important aspect of boron is that it

forms a very complex series of hydrides. Carbon is the only other element which

forms similar hydrides. However, the structures of the boron hydrides (boranes)

are quite different from those of carbon hydrides (hydrocarbons). Instead of rings

and chains, they form cages and clusters.

Boranes and borohydride reagents have found utility in the synthesis of a

number of pharmaceuticals and other compounds. These reagents are mainly

classified as borane complexes, organoboranes and borohydrides. Due to the

electrophilic nature of borane and the ease of formation of complex with the

electron-rich center of the functional group, reductions with borane are very

94

selective and specific and exhibit a number of synthetic applications.203 The

Chloroborane–Methyl Sulphide204 (BCl3.SMe2) permitted the one-pot synthesis of

diboraadamentane via hydroboration of cyclooctatetraene followed by

depolymerisation. Development of 9-BBN-Pyridine complex (a boron reagent

stable in air) resulted from a quest for more selective reducing agent that could

distinguish between aldehydes and ketones.205a Direct oxidation of

organoboranes by Pyridinium Chlochromate (PCC) to aldeydes gave an

additional route to convert organoboranes to synthetically useful molecules.

Thexylborane opened a new path for the synthesis of unsymmetrical ketones

from olefins. Stepwise reduction/ hydroboration of haloboranes enabled the first

convenient synthesis of unsymmetrical organoboranes.205 Stereo specific

synthesis of cis- and trans- olefins via organoboranes opened options for

pheromone synthesis. The asymmetric hydroboration reactions employing

diisopinocamphenyl borane, (IPc2BH) pave way towards the development of

several chiral boron reagents for the preparation of enantiomerically enriched

compounds.205 Some other highlights include asymmetric reductions, Suzuki-

Miyaura cross-coupling,206 Matteson’s boronic ester homologation207 and Brown’s

asymmetric crotylboration.208 In the last 25 years, the development of new

synthetic methodologies using boranes has allowed the synthesis of very

complex molecular structures in high selectivity and excellent overall yields.

An account of the versatility of boron reagents towards organic functional

groups are available.209 Methods for the reduction of select class of functional

groups namely, carboxylic acids, esters and anhydrides have been summarized

by Larock.210 A review covering the diversity of boron in synthetic applications at

the pharmaceutical and industrial scales203 as well as a general review covering

large scale processes for carbonyl reduction has appeared recently.211

3.2 Tuning of Boron Reagents

The catalytic effect of ethers in the hydroboration reaction led to the

development of more stable borane ligand complexes (BH3-L) as the preferred

borane sources at commercial scale. Borane adducts of Lewis bases such as

tetrahydrofuran (THF), Borane Dimethyl Sulfide (BMS) and some aromatic and

hindered amines have been used very effectively for hydroboration of double and

triple bonds as well as in reductions of other functional groups.203

95

The strength of the Lewis base determines the reactivity of the borane

complex. Borane tetrahydrofuran complex (BTHF) is the most reactive. At the

other extreme, numerous amine boranes possess low reactivity even toward

proton sources such as water, alcohols and carboxylic acids. Sulfide boranes,

dialkylaniline boranes and bulky amine boranes are intermediate in reactivity. The

amine and sulfide borane complexes offer concentration advantages over BTHF.

For example, BMS is 10 times more concentrated than BTHF. Both amine and

sulfide borane complexes are more stable than BTHF at ambient or higher

temperatures. BH3·SMe2 (BMS) is the most commonly used stoichiometric

reducing agent despite the stench problems associated with its large-scale use,

such as the need for efficient scrubbing and disposal of large volumes of waste

contaminated with dimethyl sulfide (SMe2). Other borane sources include

BH3·Et2NH, catecholborane, and BH3· Et2NPh. BH3·Amine complexes offer several

advantages such as (a) storage at ambient temperature (unlike BTHF which

requires refrigeration) (b) lack of stench (unlike BMS) (c) lack of pyrophoricity.203

One of the most desirable characteristics of boranes is the mildness of the

reaction conditions required for reductions. The chemoselectivity of borane

reduction is highly valued. Aldehyde, ketone, amide and carboxylic acid

functional groups are effectively reduced by borane complexes in the presence of

other functional groups. Strictly anhydrous conditions are required to obtain high

enantioselectivities since even very slight amount of water can have a huge

impact on the selectivity of asymmetric reduction using borane reagents.203

3.2.1 Reduction of carboxylic acids to alcohols

Several methods have been reported for the reduction of carboxylic acids

to alcohols. The carboxylic acid functional group is reduced at a faster rate by

borane complexes212 than most other groups, including non conjugated alkene,

and is therefore the reagent of choice for the reduction of carboxylic acids.

Commonly, halogen, nitro, carbamate and ester groups remain intact under the

reduction of a carboxylic acid using borane reagents. The common reagents for

this purpose are either as BTHF213 (1 M in THF) or BMS.214 An aqueous, acidic

workup (e.g., HCl, citric acid) usually follows reduction with BTHF. For reductions

with BMS, THF and CH2Cl2 are the solvents of choice, and either aqueous,

96

methanolic KF214a or aqueous NaOH quenches have been employed after

reaction completion.

The mechanism of the reduction of carboxylic acid to alcohol is known to

occur stepwise. Initially, the acidic proton reacts giving diacyloxyborane

intermediate 253 and hydrogen is evolved (Scheme 3.1).203 The carbonyl group

in 253 is then reduced with two hydrides from free borane in the solution.

Redistribution occurs such that the intermediate before protic quenching is a

trialkoxyboroxin 255. Three hydride equivalents are required for the carboxylic

acid reduction since, in the redistribution process, borane is released from the

intermediates. The amount of borane required for the process could be minimized

by the addition of BF3 to the reaction mixture. Table 3.1 shows the examples of

reduction of carboxylic acids using borane reagents in the presence of other

groups such as ester and lactone carbonyls.203

R OH

O "BH 3"R O

O

BH

2

"BH 3"R O

OBH2

BH

2

"BH 3" OB

OBO

BOCH2R

RH2CO OCH2R

252 253 254 255

Scheme 3.1 Mechanism of carboxylic acid reduction i nvolving borane reagents

97

Table 3.1 Reduction of carboxylic acids using boran e reagents

Starting material Reagents and conditions

Product Yield (%)

References

Br

SHO

EtO

O

O

OO

256

BTHF,0-10 °C, THF

Br

SHO

EtO

O

OO

257

98 215

OHO2N

O

OH

258

2 equiv.BTHF,1 equiv.BF3-

etherate, RT OHO2N

OH

259

96 216

N

OOH

OO-t-Bu

260

BTHF, 0 °C to RT, THF

N

OH

OO-t-Bu

261

96 217

I O

OH

Me 262

BTHF, 0 °C to RT, THF

I

OH

Me 263

94 218

HO2CCl

Cl

CF3 264

BTHF, THF,RT

Cl

Cl

CF3

HO

265

75 219

O

O

O OHO

266

BMS, (MeO)3B, RT

O

O

O OH 267

85

220

OO

OHO

268

BMS, THF, RT OOHO

269

83 221

98

N

OO

COOEtHOOC

270

BMS, EtOH,-20 °C to RT

N

OO

COOEtHO

271

70 222

O OO

OH 272

BMS, THF, RT O O

OH 273

74 223

COOHO OMe

274

BMS, THF, RT

OO 275

78 224

HOOH

O

OBr

276

BMS, THF,-20 °C to RT HO

OH

Br

277

95 225

O OR'

HOOC SPh 278

BMS, THF, -10 °C

O OR'

SPhHO

279

88 226

O

O

O2N

O

HO

280

BMS, 0 °C to RT O

O

O2NHO

281

100 227

HOOC OO

NpβNp-naphthalene

282

BMS, THF, RT HOH2C

OO

Npβ 283

84 228

S

O OH

O O 284

1.BMS (1.2 equiv.)CH2Cl2,

37 °C, 1.5h

2.KF, (aq.50 wt %,37 °C, 45 min)

S

OH

O O 285

86 214a

COOCH3

COOH 286

NaBH4, I2, THF,0 °C

COOCH3

OH 287

82 229

Table 3.1 (Continued)

99

3.2.2 Reduction involving ester and lactone carbony ls

Esters and lactones are reduced to alcohols or diols by reagents like

LiAlH4, BMS, and NaBH4 etc. These classes of molecules can be partially reduced

to aldehydes with the participation of a single hydride. Starting from esters,

aldehydes are formed via the corresponding hemiacetals. Starting from lactones,

the products are generally lactols 211(Table 3.2, No. 312 and 314).

Reduction of the ester carbonyls with borane complexes generally

requires refluxing conditions to effectively push the reduction to completion.

Several examples are available on the use of BTHF or BMS for the reduction of

ester carbonyls. When BMS is used, the dimethyl sulfide is usually distilled from

the refluxing solution to drive the reduction to completion.203 At elevated

temperatures, BTHF can cleave the tetrahydrofuran ring233 (298), producing butyl

O

OMe

OOH 288

BMS, THF,0 °C O

OMe

OH 289

100 230

F3C NH2

OHO

290

1.LiBH4, (2min THF, 3.2 equiv)

TMSCl (6.4 equiv.)THF, 0 °C

to RT

2.MeOH, 0 °C

3.1 M aq.NaOH, 0 °C to RT

F3C NH2

HO

291

96 231

COOCH3

COOH 292

BMS, THF,

-10°C to 20 °C O

O

293

54 232

COOCH3

COOH 294

ClCO2Et, NaBH4, MeOH, 5 °C

O

O

295

37 232

COOH

COOCH3 296

BMS, THF,

-10°C to 20 °C O

O 297

55 232

Table 3.1 (Continued)

100

borate (299) and thus decreasing the amount of borane available for the desired

reduction (Figure 3.2). Table 3.2 shows examples of reduction of ester carbonyls

in the presence of other reducible groups.

O BH3 BO

O O

298 299

Figure 3.2 Formation of butyl borate from BTHF

Table 3.2 Reduction of ester carbonyls using boran e reagents

Starting material Reagents and

conditions Product Yield References

OO HCO2C2H5

300

NaBH4, EtOH, reflux

OO HOH

301 88 234

NH N

HNH

OBz

O

BzO

CO2Me MeO2C

O

302

BMS, reflux NH N

HNH

OBz

O

BzO

O

HO OH

303

85 235

N

HN

BOC

CO2MeOAc

BnO

304

BMS, reflux N

HN

BOC

CH3OH

BnO

305

48 236

NOPMB

CO2Et

306

LiBH4,EtOH-THF, RT

NOPMB

OH

307

95 237

O

O

OHCO2Me

CO2MeAr

308

LiTEBH, THF, -78 °C

O

O

OH

CO2MeAr

OH

309

87 238

N

S

O

O NEt

310

LiTEBH, THF, 0 °C

N

S

HO N

311

66 239

101

N

O O

Ph F

312

LiTSBBH,-75 °C

CF3

CF3O

Cl

N

O O

O

F

CF3

CF3

313

70 240

NO

O O

Bn

314

I. Li(s-Bu)3BH (1 M in THF, 1.03 equiv), THF, -15- 5 °C, 2 h

2. aq.NaOH, -5 °C

3. aq.H2O2 (30 wt %), < 20 °C, 1 h

4. solid NaHSO3, 10 °C, 30 min.

NO

HO O

Bn

315

80 241

O

NOMe

O

MePh

316

LiBH4, 1.5 equiv. THF, -15 °C to

RT

OH

NOMe

MePh

OH

317

95 242

MeOOMe

O

OOH

318

BMS (1.02 equiv), NaBH4,

THF, 12-16 °C, 1 h

HOOMe

OOH

319

89 243

OMeOMe

O

O

HO

RO

320

BMS, NaBH4, THF, RT

OMeOH

O

HO

RO

321

80 244

OEtOEt

O

O

HO

N3

322

BMS, NaBH4, THF, RT

OEtOH

O

HO

N3

323

75 245

R1

R1

OH O

O

OMeOMe

R2

R3

R2

324

NaBH4,DMF,RT

R1

R1

OH

R2

R3

R2

O

O

325

88 246

COOCH3p-Tol

COOH

326

BMS, THF, 0 °C

CH2OHp-Tol

COOH 327

85 247

Table 3.2 (Continued)

102

3.2.3 Reduction of carbonyls of amides / imides

Amides can be selectively reduced to alcohols or amines with alkali metal

trialkyl borohydride reagents such as lithium triethylborohydride and lithium

dialkylaminoborohydrides. The attack of the amide carbonyl group by a hydride

occurs through a tetracoordinated intermediate, which can proceed either by

breaking of the C-N bond or by breaking of the C-O bond resulting in the

formation of aldehyde or amine respectively. The reactivity of amide carbonyl with

other carbonyl groups can be differentiated by their action with some of the

specific reducing agents. Few examples are listed in the Table 3.3

Table 3.3 Reduction of amide/ imide carbonyls usin g borane reagents

Starting material Reagents

and conditions

Product Yield References

NHHN

OHNPh

Ph

328

LiTEBH, THF, 20 °C

NHHN

Ph

HO

329

66 248

Ar NPh

O

330

LiNH2BH3, THF, RT

Ar OH

331

66 249

NPh

O

O

O2N

H

H

H

332

BTHF, THF, reflux

NPh

O2N

H

H

H

333

90 250

OO

N

O

O

Ph

334

BMS, THF, MeOH, HC,

0-5 °C

OO

N Ph

HCl

335

80 251

NH

H3COO Cl

336

BTHF, reflux

NH

H3COCl

337

252

103

HN

NH

MeOOMe

O

O

338

BTHF, THF, reflux

HN

NH

MeOOMe

339

80 253

NN

PhthNO

O

CO2t-Bu

340

BTHF, THF, reflux N

NPhthN

O CO2t-Bu

341

Yield not given

254

O

HN

O Ph

342

BTHF, aq.HCl, reflux

O

HN

Ph

HCl

343

82 255

HNOH

Cl

Cl

O

O

344

BTHF, THF, 66 °C

HNOH

Cl

Cl

345

84 256

NH

O

O

RO

ClCl

346

BMS, THF,reflux

NH

RO

ClCl

347

86 257

HN

NH2

O2NNH2

O

348

BTHF (7 equiv.),

THF

HN

NH2

O2NNH2

349

85 258

NOCO2CH3

CO2Et

OO

350

BMS, THF, RT

N

CO2CH3

CO2Et

OO

351

40 259

Table 3.3 (Continued)

104

350

1.DIBAL-H

2.TsOH, MeOH

NMeOCO2C(CH3)2

CO2Et

OO

352

86 259

NOCO2C(CH3)3

NCCO2Et

353

LiEt3BH, THF, -78°C

NCO2C(CH3)2

NCCO2Et

HO

354

78 260

O

NO O

PMB

355

BMS,(3 equi,)THF, 24 h, RT

O

NO

PMB

356

58 261

3.2.4 Reduction of carbonyls of anhydrides

Cyclic anhydrides are useful precursors for lactones using reduction

reactions262,265 (Table 3.4 No. 357, 360 and 365). The reduction of unsymmetrical

anhydrides is regioselective and appears to be nonselective with procedure

involving zinc/acetic acid.262b Hydride attack takes place on the carbonyl group

that is vicinal to the most substituted carbon.

Selectrides are conveniently used for the regioselective reduction of

anhydrides. Reaction of tri-sec-butylborane with potassium hydride or lithium

trimethoxyaluminium hydride gave potassium tri-sec-butylborohydride (and is

called K-Selectride) or lithium tri-sec-butylborohydride (and is called L-Selectride).

The potassium and Lithium derivatives are both effective for reductions, although

by analogy to other borohydrides, the lithium derivative may be somewhat

stronger. The selectivity of a given selectride reagent can be influenced by the

addition of metal salts like MgBr2 or ZnI2.262 Table 3.4 shows few examples for

the reduction of carbonyls of anhydrides using unconventional borane reagents.

Table 3.3 (Continued)

105

Table 3.4 Reduction of carbonyls of anhydrides usin g unconventional borane reagents

Starting material Reagents

and conditions

Product Yield References

O

OMe O

O

357

L-Selectride, RT

O

OMe O

+ 358

O

OMe

O 359

90:10

262

O

O

O 360

K-Selectride, RT O

O

O

O

+

361 & 362

19:1 263

O

O OMeO2C CO2Me

363

BER-Ni(OAc)2, RT

OHCO2Me

364

85 264

OO

O

365

NaBH4, DMF,0-20 °C,

O

O

366

55 265

X

HN

O O

O O

367

NaBH4,THF, MeOH,reflux X

HN

OH

368

91 266

3.3 Effect of Solvent on the Selective Reduction of Esters Using Sodium borohydride and Methanol

The introduction of various metal hydrides namely sodium borohydride

(NaBH4) lithium aluminum hydride (LAH) and Lithium borohydride have been

played important roles in the history of reduction of organic functional groups.267

Sodium borohydride, since its discovery by Schlesinger,268 Brown and co-

workers, is one of the most easily available among many complex metal

hydrides. It is easier to manipulate than lithium aluminium hydride or lithium

borohydride because of its lower sensitivity towards moisture. LAH is a poor

selective reducing agent because of its excessive reducing ability. It is very well

106

established that the reducing capacity of the borohydride is markedly affected by

changing the metal ion.267

Thus sodium borohydride reduces typical esters such as ethyl acetate and

ethyl benzoate in methanol and THF at refluxing temperature. However, the

reducing properties of sodium borohydride could be amplified by (a) varying the

solvent, (b) changing the cation, (c) the use of catalysts and (d) the presence of

activating substituent.269 It is known that LiBH4 reduces esters very easily. In

aqueous solutions, there is no measurable difference in the rate constants for the

reactions of sodium and lithium borohydrides. However in isopropyl alcohol the

rate constant for LiBH4 is several times greater than that of sodium salt. This

suggests that the enhancing effect of lithium ions will be the greatest in solvents

of the low dielectric constants.269 The reduction of esters by diborane, BTHF, or

by BMS is relatively slow. Accordingly, LiAlH4, LiBH4 or Ca(BH4)2 have been the

preferred reagents for such reductions. Calcium, strontium and barium

borohydrides are reducing agents of higher reducing activity than the

borohydrides of sodium, potassium and lithium. This may be ascribed perhaps to

the more covalent character of these compounds. However, the selectivity in

reducing properties of calcium borohydride resembles the selectivity of sodium

borohydride.269

As discussed above, sodium borohydride, either by itself 270 or in

combination with other reagents has been employed for a wide range of the

reduction of esters to alcohols. Heating or use of poly ethylene glycol of high

boiling point or metal salt additives is often required since esters are less reactive

than aldehydes or ketones.

Preferred solvents for the reductions using sodium borohydride include

alcohols (MeOH, EtOH), THF and 2-MeTHF but examples in NMP271 and DME272

also exist. After the completion of the reaction, aqueous acidic or basic quenches

consume residual borohydride. Alternatively, acetone can be added to consume

excess NaBH4 prior to the aqueous quench.

Thus the enhanced reactivity of sodium borohydride in protic solvents can

be utilized for the reduction of esters. At 60 °C a solution of sodium borohydride

in methanol rapidly releases 4 moles of hydrogen. Presumably, the reaction

107

involved loss of hydride, forming sodium alkoxyborohydrides, which are capable

of reducing esters.273 When methanol reacts with sodium borohydride the

reduction was implied to involve various alkoxyhydroborate, such as BH3(OMe)-,

BH2(OMe)2-, BH(OMe)3

-.274 These species or their aggregated forms acted as

Lewis acid and show higher reducing power than sodium borohydride and thus

facilitated the reduction of esters. In fact, it was previously reported that B(OCH3)3

catalyzed the reduction of esters by sodium borohydride in ether at 25 °C.

The effect of solvents and metal ion for the reduction of ketones and

esters using sodium borohydride have been well documented.273 Soai et al.

reported the effect of solvents on the reduction of esters using sodium

borohydride which is known to be incapable of reducing such functionalities.275 In

mixed solvents like t- butyl alcohol-methanol or THF- MeOH, various carboxylic

esters and lactones were found to be reduced by sodium borohydride to the

corresponding alcohols, diols or polyols in high yields. Table 3.5 shows examples

of reduction of ester carbonyls with NaBH4 and MeOH.

108

Table 3.5 Reduction of ester carbonyls using NaBH 4 and MeOH

Starting material Reagents and

conditions Product Yield References

CO2Me

369

NaBH4,MeOH, THF, 70 °C, 2-4 h

OH

370

90 276

COOEtBoc-N

Ph

371

NaBH4,MeOH, THF, 50-55 °C Boc-N

Ph

OH

372

88 275

N

O

OMe

373

NaBH4,MeOH, THF, 70 °C N

OH

374

95 275,276

NO

t-BuOS

N

O

O

O

375

NaBH4 (2 equiv.), MeOH (4 equiv),

NaB(OAc)3H , THF, 25 °C

NO

t-BuOS

NOH

O

376

89 277

N CO2R

Cl

377

NaBH4,MeOH, THF, 70 °C, 1 h N

Cl

OH

378

93 278

O CO2Me

379

NaBH4,MeOH, THF, 70 °C, 2 h

OOH

380 56 278

N

COOCH3

381

NaBH4,MeOH, THF, 70 °C

N

OH

382

91 276

109

3.4 Results and Discussion

It has been seen that boron based reagents are widely used for the

selective reduction of a number of functional groups. Hence, attempts have been

made for the chemical and conditional modification of borane reagents such as

BMS and NaBH4, for the efficient selective reduction of carbonyls derived from

hydroxy acids. This has been carried out to modify (2S,3S) and (2S,3R)-

tetrahydro-3-hydroxy-5-oxo-2, 3- furan dicarboxylic acids (6 and 7) to desired

structures to accomplish the synthesis of useful enantiomerically pure

compounds (Figure 3.3) as boron based reagents are the most appropriate

reagents for cumulating mostly the reduction reactions. Even though many

reductions with borohydrides are selective and specific, borohydrides have

limited use when the substrates contains polar groups, such as –OH groups.279

However, a careful use of these reagents, in catalytic or stoichiometric conditions,

with appropriate solvents or metal ions, can impart amplification of their ability to

discriminate between reducible functional groups.269

O

OO

OHO

H

O

OO

HO

H O

OO

OH

HOH

COOCH3

O

OO

OO

H

OOO H

CH2OHOH

CH2OH

OO

OH

CH2OH

OHH

CH2OH

N R

O

O

HHO

HO

OO HN

OH

OH

O

OO

OH

RR=H,CH3

HOOHOH

HOOH

OOH

OHHO

HN

OHHOHO

OO HCOOH

R'R

6. R=COOH, R'=OH7.R=OH, R'=COOH

209

208

210

212

231

383

384

385

386

387

388

389

Figure 3.3 Enantiomerically pure γγγγ-butyrolactone based intermediates derived from 6 and 7

110

The carboxylic acid group is reduced selectively in presence of an ester

group by BTHF or BMS.280 Even though the reduction of a carboxylic acid group

in presence of an ester or a lactone is possible, the selective reduction of an

ester group in presence of a lactone is more challenging and only few reports

are available.227,281 Borohydrides also have been used as catalysts to expedite

reductions using BTHF and BMS reagents.244,245

For instance, epoxide can be reduced282 with BTHF complex much faster

in the presence of catalytic amount of NaBH4 or LiBH4. Borane coordinates to the

epoxide enhances the polarization of its C-O bond resulting in facile delivery of

hydride from added borate anion to the carbon concerned. One mole of hydride per

mole of compound is utilized; hydrogen is not evolved, and observed a predominant

anti-Markovnikov opening of the epoxide ring (Scheme 3.2). The use of higher

concentrations of the more soluble lithium borohydride gives faster reaction with

similar products.

OBH3

NaBH4catalyst

OH

+OH

26% 74%390 391 392

Scheme 3.2 Reduction of epoxide with BTHF

Saito and co-workers effectively extended the similar catalytic activity of

borohydrides for the selective reduction of α-hydroxy ester group of molecules

such as malate and tartarate diesters, using BMS and 5 mol% of catalytic NaBH4,

(Table 3.2 No.318-323) which in turn provides versatile chiral building blocks in

synthesis.244,245

Selective reduction using BMS and catalytic amount of sodium

borohydride, ester carbonyl of α-hydroxy esters in presence of azide group is

also demonstrated.244,245 Apparently, substituted benzene directed regio-selective

reduction of esters using BMS proceeds even without catalyst.283 Also phthalides

have been converted to the corresponding naphthalenic lignan lactones by the

selective reduction of the carbonyl group just using NaBH4 in DMF.246 In this

reduction, the ester carbonyl group adjacent to OH was reduced (Table 3.2,

No.324 & 325)

111

Saito and co-workers explained the mechanism of the selective reduction

using malic and tartaric diesters. When diethyl (S)-malate (DEM, 393) was

treated with one-mole equivalent borane dimethyl sulphide in dry tetrahydrofuran

at room temperature, evolution of hydrogen gas was observed immediately and

ceased after 45 minutes.The amount of which was equivalent to a molar quantity

of the diethyl malate employed (Scheme 3.3). The authors claimed that diagnosis

by TLC at this stage indicated that no reduction had proceeded yet, only one spot

corresponding to the starting diethyl malate being visualized. The authors

suggest that the initial product should be oxyborane – type intermediate (395)

(Figure 3.4). After sodium borohydride (5 mol %) was added to the reaction

mixture, immediate TLC monitoring indicated that reduction actually started and

required one hour at room temperature for completion followed by EtOH addition

for quenching the reduction. The authors also claimed that only a small amount of

hydrogen gas evolved on this operation, which probably means that nearly all the

hydrogen of the boron atoms were consumed for the reduction.

EtO2CCO2Et

OH

393

Cat.NaBH4

CO2EtHO

HO

major

51

EtOOCOH

HO

+minor

394

BMS, THF

Scheme 3.3 Selective reduction of DEM using BMS and catalytic amount of NaBH 4

The regio-selectivity of the reduction of malic diesters, using borane

dimethyl sulphide and catalytic amount of sodium borohydride, is controlled by

the steric factors of the ester groups. Dimethyl malate gives a mixture of products

in the ratio from 80:20 to 60:40. More sterically demanding diethyl or diisopropyl

malate gives better regio-selectivity.

Saito and co-workers proposed two possible transition states 396 (five

membered) and 397 (six membered) for the reduction of malic diesters (Figure

3.4). Neighboring group participation is most favored for five membered transition

state.244 In addition, severe 1, 3 diaxial interactions between the ester alkoxy-

group and the hydrogen on the boron atom destabilize 397 which in turn explains

the selectivity observed in the reduction of malic diesters.

112

CO2ROB

O

H H

RORO2C OR

O OB

H H

396 397

RO2CCO2R

OBH2

395

Figure 3.4 Transition state structures of DEM

In the case of diethyl (R, R)-tartrate, another acyclic hydroxy ester, the

authors proposed two possible transition states 398 and 399 (Figure 3.5) for the

site selective reduction using BMS and catalytic amount of sodium borohydride.

OR

OBO

HH

Z

O

RO2C ORZ

OB

O

H H

398 399

Figure 3.5 Transition state structures of DET

Though the reaction is highly potential, the experiment was limited to

only a few hydroxy esters and the mechanism proposed by Saito and co-

workers leaves few questions to be answered for generalizing the viability of the

reaction. For instance, when the reaction was performed using tartaric diesters

with protected hydroxyl groups (t-Bu or Benzyl) or in cases where the –OH

group of tartaric diester was replaced by halogens; the observed selectivity was

very poor.244

It was demonstrated that the accuracy of the selective reduction in the

case of esters of hydroxy acids namely malic and tartaric acids using BMS and

catalytic amount of NaBH4 at room temperature and tentatively proposed to

proceed through an alkoxy-BH2 (RO-BH2) intermediates.244 However, no 11B NMR

spectroscopic data was available to support this proposal. Hence the 11B NMR

spectroscopic analysis is an ideal tool for revealing the actual mechanism.

In this context, attempts have been made for the reduction of the acid 6

with BTHF at room temperature to get (4R,5R)-4-hydroxy-4,5-bis(hydroxymethyl)

dihydrofuran-2(3H)-one (400). However, repeated attempts for the reduction

under this condition failed to proceed in the expected line (Scheme 3.4).

However, the 11B NMR spectroscopy analysis of the commercial BTHF sample

113

indicates the unavailability of any B-H bonds, as the reagent might have

decomposed during shipping to tropical places in this case.

O H

OH

O OH

OH6

400

BTHF

Scheme 3.4 Reduction of 6 using BTHF

Reductions using BMS and NaBH4-I2 combination results in the formation

of insoluble polymeric intermediates which eventually inhibits the completion of

the reduction reaction. The laxity of the reaction could also be due to the

formation of stable acyloxy borane complexes (401) (Scheme 3.5).

O HCO2H

O"BH 3"

OB

O

O H6

401 Scheme 3.5 (Acyloxy)borane complex of 6

Since the direct reduction of 6 gave intractable product, attention has been

focused on the reduction of dimethyl and diisopropyl esters of 6 and 7 (Figure

3.6), using BMS and catalytic amount of sodium borohydride, developed by Saito

and co-workers.

OO H

COOROH

COOR153.R=-CH3155.R=-CH(CH3)2

OO H

COOROH

COOR158.R=-CH3160.R=-CH(CH3)2

Figure 3.6 Diesters of 6 and 7

In this context, for getting insight into the mechanism and to find out the

intermediate involved in the site selective reduction of α-hydroxy esters,

diastereomeric esters of garcinia and hibiscus acids (153, 155, 158 and 160,

(which in turn are derivatives of tartaric acids) are appropriate molecules for

further exploration of the site selectivity observed (Figure 3.7).

114

RO2CCO2R

OH

RO2C

HO O HCO2R

OHCO2R

O HCO2R

OHCO2R

Dialkyl malate Dialkyl tartarate Diesters of 6 & 7

O OOH

CO2R

Figure 3.7 Diesters of αααα-hydroxy acids

This chapter describes the results of the studies on the site selective,

partial and tandem reductions of esters of 6 and 7 and representative α-hydroxy

esters using conditionally modified BMS and NaBH4 reagents (Scheme 3.6).

OO

H

COOR

COOROH

6.R=-H153.R=-CH3, 155.R=CH(CH3)2

BMS/Cat.NaBH 4

OO

H

COOR

OHOH

NaBH4/MeOHHOOH

HO

H

OH

HO

THF, 0 C0 C

D

26 = + 72.78, (C = 0.143, Acetone ) mp, 55-60 oC

OO

H

COOR

O

H

1.BMS/THF2.MeOH, 0 C

OO

H

COOR

OHOH

BMS/Cat.NaOMeTHF, 0 C

D

26 = + 2.75, (C = 0.40,MeOH)

HO

204.R=-CH3406.R=-CH(CH3)2

αα

°

°

°

°

204.R=-CH3406.R=-CH(CH3)2

386

414

Scheme 3.6 Reduction of esters of 6 with (i) BMS an d catalytic amount of NaBH4 and

(ii) NaBH 4/MeOH at 0 °°°°C

3.4.1 Site selective reduction of dialkyl ( 2S, 3S)-tetrahydro-3-hydroxy -5-oxo-2, 3-furandicarboxylates (153 and 155) using BM S and catalytic amount of NaBH 4

To carry out the site selective reduction of α-hydroxy esters having

multiple carboxylic esters, using the combination of BMS and catalytic amount of

sodium borohydride in anhydrous tetrahydrofuran (THF), the dialkyl (2S, 3S) and

(2S, 3R)–tetrahydro-3-hydroxy -5-oxo-2, 3-furandicarboxylates (153,155,158

115

&160) (Figure 3.4) were selected. The progress of the reaction was continued by 11B NMR analysis of aliquots withdrawn periodically from the reaction mixture.

When dimethyl (2S, 3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate

(153) was treated with one mole equivalent of BMS in THF, at 0 °C (Scheme 3.7),

one equivalent of hydrogen gas evolved instantaneously and was measured by

gas buret technique (Figure 3.8).284 After the gas evolution, an aliquot of the

reaction mixture was analyzed by 11B NMR spectroscopy and observed the

complete consumption of BMS at 25 °C (Figure 3.11). The 11B NMR spectrum of

the reaction mixture displayed broad singlets at + 22 ppm attributable to

polymeric trialkoxyboranes, similar to Pin3B2.285 There observed no signals which

attributed to an intermediate corresponding to alkoxy-BH2, such as 402 (Figure

3.9). Addition of catalytic amount of NaBH4 failed to cause any significant change

in the 11B NMR spectrum except that the trialkoxyborane signal at +22 intensified

(Figure 3.12). When the reaction is quenched with MeOH after 3 h, very little

hydrogen was evolved and the predominant signal in the 11B NMR spectrum of

the reaction mixture was attributable to trimethoxyborane B(OMe)3 (δ +18 ppm).

A minor peak at +10 ppm, due to tetraalkoxyborate ion, was also visible in the

spectrum (Figure 3.13). Workup of the reaction mixture furnished the isolation of

methyl (2S,3R)-terahydro-3-hydroxy-3-hydroxymethyl-5-oxo-furan-2-carboxylate

(204) and methyl (2R,3S)-tetrahydro-3-hydroxy-2-(hydroxymethyl)-5-oxo-furan-3-

carboxylate (403) indicative of the reduction of the C2 and C3-carbonyl groups in

a ratio of 70:30.

The structure of 204 was confirmed on the basis of IR, 1H, 13C NMR and

mass spectra. The IR spectrum displayed absorption bands at 3416 cm-1

(presence of -OH group), at 1771 cm-1 (presence of lactone carbonyl) and at

1735 cm-1 (the presence of ester carbonyl). The 1H NMR spectrum displayed

signals at δ 4.5 - 4.24 (AB quartet; corresponds to the methylene protons), at δ

3.02-2.47 (AB quartet; due to methylene protons in the lactone ring), at δ 4.44

(singlet; corresponds to methine proton) and at δ 3.76 (singlet; corresponds to -

OCH3 protons). The 13C NMR spectrum displayed nine different signals at

174.776, 167.826, 105.161, 97.307, 79.196, 77.426, 76.326, 49.6 and 37.556 which

confirmed the structure of 204 (Figure 3.14a-d).

116

Figure 3.8 Gas burette apparatus

OO CO2R

CO2R

OBH2

402

Figure 3.9 Oxyborane intermediate of 153 with BMS

OO HCOOCH3

HO OH+

OO H

HO COOCH3

OHBMS/THF

NaBH4 (5 mol%)153

204 40370:30

Scheme 3.7 Selective reduction of 153 using BMS and catalytic amount of NaBH 4

117

Figure 3.10 11B NMR spectrum of solution of 153 immediately after the addition of BMS

Figure 3.11 11B NMR spectrum of a mixture of 153 and BMS after th e gas evolution

118

Figure 3.12 11B NMR spectrum of a mixture of 153 and BMS after th e addition of Sodiumborohydride

Figure 3.13 11B NMR spectrum of a mixture of 153, BMS and NaBH 4 after quenching with MeOH

119

IR (liquid film)

OO HCOOCH3OH

OH204

Figure 3.14a

1H NMR, 400 MHz, Solvent : Acetone-d6

OO HCOOCH3OH

OH204

Figure 3.14b

120

The structure of 204 was further confirmed by the preparation of chloral 286(dioxolane) derivative namely methyl (5R, 6S) 8-oxo-2-trichloromethyl-1,3,7-

trioxa-spiro[4.4]nonane-6-carboxylate (404) and acetyl derivative namely methyl

(2S, 3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo-furan-2-carboxylate

(405) (Scheme 3.8)

3.4.2 Conversion of methyl (2 S, 3R)-terahydro-3-hydroxy-3-hydroxymethyl-5-oxo-furan-2 carboxylate (204) to methyl (5 R, 6S) 8-oxo-2-trichloromethyl-1,3,7-trioxaspiro[4.4]nonane-6-carb oxylate (404)

Treatment of 204 with anhydrous trichloroacetaldehyde in presence of con.

H2SO4 gave methyl (5R, 6S) 8-oxo-2-trichloromethyl-1,3,7-trioxaspiro[4.4]nonane-6-

carboxylate as a diastereomeric mixture (Scheme 3.9). Purification and

recrystallisation (diethyl ether:hexane) resulted in the isolation of 404 as a solid

(mp, 162 –164 °C) in 89% yield, 29D][α +13.14, (c 0.25, CHCl3) (Scheme 3.5).

Structure was confirmed on the basis of IR, 1H, 13C NMR and mass spectra. The IR

spectrum exhibited the characteristic absorption bands at 1824, 1747, 1712 cm-1

13C NMR 100 MHz, Solvent : Acetone-d6

OO HCOOCH3OH

OH204

Figure 3.14c

OO HCOOCH3OH

OH204

Figure 3.14d

121

(due to carbonyl stretching frequencies). The 1H NMR displayed signals at 6.0487

(singlet; due to the protons in dioxolane ring), at 4.8 (singlet; due to methine proton),

at δ 4.4762- 4.3727(AB quartet; due to methylene protons), at 3.6971 (singlet; due to

-OCH3 protons) and at 2.9686- 2.74505 (AB quartet; due to methylene protons in the

lactone ring). Nine different signals in 13C NMR spectrum at 174.776, 167.826,

105.161, 97.307, 79.196, 77.426, 76.326, 49.6 and 37.55 also confirmed the

structure of 404 (Figure 3.15a-d). Mass spectrum indicated FAB+ (M+H)+ at m/e

305.07 due to the hydrolysed compound (5R,6S)-8-oxo-2-(trichloromethyl)-1,3,7-

trioxaspiro[4.4]nonane-6-carboxylic acid.

CCl3CHO

H2SO4

OO HCOOCH3

O

OCCl3

404

204

Scheme 3.8 Preparation of 404

IR (KBr pellet)

OO HCOOCH3

O

O

CCl3

404

Figure 3.15a

122

1H NMR 300 MHz, Solvent : CDCl3

OO HCOOCH3

O

O

CCl3

404

Figure 3.15b

13C NMR 75 MHz, Solvent : CDCl3

OO HCOOCH3

O

O

CCl3

404

Figure 3.15c

123

OO HCOOCH3

O

O

CCl3

404

Figure 3.15d

3.4.3 Conversion of methyl (2 S, 3R)-terahydro-3-hydroxy-3-hydroxymethyl-5-oxo-furan-2 carboxylate (204) to methyl (2 S, 3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo- furan-2-carboxyl ate (405)

Acetyl chloride was added dropwise to 204 under stirring (continued for 12

hours). It is clear from the physical data that both the hydroxyl groups were

protected and methyl (2S, 3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo-

furan-2-carboxylate (405) was isolated in quantitative yield (Scheme 3.8).

204

OO OCH3

O

OCOCH3H3COCO

405

CH3COCl

Scheme 3.9 Preparation of 405

The IR spectrum displayed the characteristic absorption bands at 2969

cm-1 (characteristic of C-H stretch) and at 1780, 1748 cm-1 (shows the presence

of lactone and ester carbonyls). The 1H NMR spectrum displayed two sets of

diasterotopic hydrogens. Signals at δ 4.4 - 4.6 (AB quartet; presence of

methylene protons), at δ 2.8 - 3.2 (AB quartet; indicate the presence of methylene

protons in the lactone ring), at δ 3.9 (singlet; corresponds to -OCH3 protons) and

at 2.2 (singlet; corresponds to –OCOCH3 protons) confirmed the number of

protons in the molecule. The 13C spectrum displayed 11 different signals at δ

124

172.16, 169.8, 169.6, 167.02, 83.82, 80. 66, 61.59, 53.09, 37.66, 21.49 and 20.38

which confirmed the number of carbon atoms of the molecule (Figure 3.16a-d).

IR (liquid film)

OO OCH3

O

OCOCH3H3COCO

405

Figure 3.16a

1H NMR 300 MHz, Solvent : CDCl3

OO OCH3

O

OCOCH3H3COCO

405

Figure 3.16b

125

13C NMR 75 MHz, Solvent : CDCl3

OO OCH3

O

OCOCH3H3COCO

405

Figure 3.16c

OO OCH3

O

OCOCH3H3COCO

405

Figure 3.16d

The diisopropyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate

(155) was also reduced in the same way as that of 153 (Scheme 3.10) using

BMS and catalytic amount of NaBH4. The progress of the reaction was monitored

by recording the 11B NMR spectrum and is found to be similar as that of 153.

After the gas evolution, an aliquot of the reaction mixture was analyzed by 11B

NMR spectroscopy and observed that all the BMS was consumed and the 11B

NMR does not show any peak corresponds to unreacted BMS at 25 °C. The

reaction mixture displayed broad singlets at + 22 ppm and +28 ppm attributable

to polymeric trialkoxyboranes, similar to Pin3B2 and dialkoxyborane respectively

(Figure 3.18). There were no signals attributable to an intermediate

corresponding to alkoxy-BH2, such as 402. Addition of catalytic amount of NaBH4

126

did not show any significant change in the 11B NMR spectrum except that the

dialkoxyborane signal at +28 ppm disappeared and the trialkoxyborae signal at

+22 intensified (Figure 3.19). When the reaction is quenched with MeOH after 3

h, very little was hydrogen evolved and the predominant signal in the 11B NMR

spectrum of the reaction mixture was attributable to trimethoxyborane B(OMe)3 (δ

+19 ppm). A minor peak at +10 ppm, due to tetraalkoxyborate ion, was also

visible in the spectrum (Figure 3.20). Workup of the reaction mixture gave the C2

and C3-carbonyl reduced isopropyl (2S,3R)-tetrahydro-3-hydroxy-3-(hydroxymethyl)-

5-oxo-furan-2-carboxylate (406) and Isopropyl (2R,3S)- tetrahydro-3-hydroxy-2-

(hydroxymethyl)-5-oxo-furan-3-carboxylate (407). However, the site selectivity

has turned out to be 90:10 as verified by TLC analysis. The subsequent

chromatographic purification of the reaction mixture over silica gel (60-120 mesh,

ethyl acetate–hexane 7:3) afforded the isopropyl (2S,3R)-tetrahydro-3-hydroxy-3-

(hydroxymethyl)-5-oxo-furan-2-carboxylate (406) as major product in 80% yield

as a crystalline solid. Mp 55-60 °C, 26D][α +72.78 (c 0.143, Acetone). Structure

was confirmed on the basis of IR, 1H, 13C NMR and mass spectra.

The IR absorption spectrum displayed peaks at 3443 cm-1 (indicating the

presence of –OH groups), at 1776.39, 1730 cm-1 (due to the lactone and ester

carbonyls). The 1H NMR displayed signals at δ 5.151 (singlet; due to the methine

proton in isopropyl group), at 4.75 (singlet; due to methine proton in lactone ring),

at δ 4.4- 4.3 (AB quartet; corresponds to methylene protons on CH2O group), at δ

2.8-2.6 (AB quartet; corresponds to the methylene protons in the lactone ring)

and at δ 1.3 (doublet; due to protons in methyl groups). The 13C NMR displayed

nine different signals at δ 174.80, 170.79, 78.08, 76.70, 74.02, 71.64, 38.93,

21.75 and 21.73 also confirmed the number of carbon atoms of the molecule

(Figure 3.23a-e). The DEPT 135 shows two -ve signals at δ 74 and 38

corresponds to CH2 carbon atoms. The HRMS (ES+) calculated for C9H14O6Na:

241.0688, Found: 241.0686 (Figure 3.21)

127

BMS/THFOO

OH

O

O

HO

406

155

OO

O

O

OH

HO+

90:10

407

NaBH4, 0 C°

Scheme 3.10 Selective reduction of 155 using BMS an d catalytic amount of NaBH 4

Figure 3.17 11B NMR spectrum of solution of 155 immediately after the addition of

BMS

Figure 3.18 11B NMR spectrum of a mixture of 155 and BMS after th e gas evolution

128

Figure 3.19 11B NMR spectrum of a mixture of 155 and BMS after th e addition of sodiumborohydride

Figure 3.20 11B NMR spectrum of a mixture of 155, BMS and NaBH 4 after quenching with MeOH

Figure 3.21 Single mass analysis of 406

129

IR (KBr pellet)

OO O

O

OHO

O155

Figure 3.22a

1H NMR 400 MHz, Solvent : CDCl3

OO O

O

OHO

O155

Figure 3.22b

13C NMR 100 MHz, Solvent : CDCl3

OO O

O

OHO

O155

Figure 3.22c

130

OO O

O

OHO

O155

Figure 3.22d

IR (KBr pellet)

OO O

O

OHHO

406

Figure 3.23a

1H NMR 400 MHz, Solvent : CDCl3

OO O

O

OHHO

406

Figure 3.23b

131

13C NMR 100 MHz, Solvent : CDCl3

OO O

O

OHHO

406

Figure 3.23c

DEPT 135

OO O

O

OHHO

406

Figure 3.23d

OO O

O

OHHO

406

Figure 3.23e

132

The regioselective reduction of the C3 carboxylate group in 153 and 155 is

sensitive to the steric-requirement of the ester groups. The ester 153 gave a

mixture of products arising from the reduction of both proximal and distal ester

groups in a ratio ranging from 70:30 to 60:40. An improved site-selectivity (90:10)

was observed in the case of 155.

Also Saito and co-workers pointed out that the oxyborane intermediate is

more stable in toluene when compared to THF. To observe the formation of

oxyborane intermediate, the selective reduction of 155 was also carried out in

toluene in place of THF and the progress of the reaction was monitored by

recording the 11B NMR spectra. When 155 was treated with one mole

equivalent of BMS in toluene at 0 °C, the evolution of gas was likewise, and the 11B NMR spectra of the supernatant liquid displayed similar results as in the

conditions described above. Upon addition of NaBH4, the spectrum shows only

the formation of trialkoxyboranes. When the reaction is quenched with MeOH

the predominant signal in the 11B NMR spectrum is attributable to

trialkoxyborane (Figure 3.24-3.26).

Figure 3.24 11B NMR spectrum of a solution of 155 in toluene imme diately after the addition of BMS

133

Figure 3.25 11B NMR spectrum of a mixture of 155 and BMS after th e gas evolution

Figure 3.26 11B NMR spectrum of a mixture of 155, BMS and NaBH 4 after quenching

with MeOH

3.4.4 Mechanism of the site selective reduction of dialkyl ( 2S, 3S)- tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylates (153 and 155) using BMS and catalytic amount of NaBH 4

It is observed that one equivalent of hydrogen was evolved when BMS

was added to an equimolar amount of the ester 153 or 155 in THF at 0 °C. This is

indicative of the fact that the carbonyls of the hydroxy esters reacted with BMS in

a 1:1 stoichiometry to give alkoxy-BH2 (ROBH2) (402) type intermediates or the

reaction proceeds through a 3:1 stoichiometry to give an intermediate (408)

(Figure 3.27). The 3:1 stoichiometry will leave 66% of the BMS unreacted after

the initial reaction. However, the 11B NMR spectrum of an aliquot of the reaction

mixture after the gas evolution did not show any significant signal due to

unreacted BMS or due to the ROBH2 type intermediates. Apparently, esters 153

and 155 reacted with BMS in a 1:1 fashion and the initially formed ROBH2 type

134

intermediates quickly transfered a hydride to the proximal ester carbonyl to give a

dialkoxyborane intermediate (409) that was visible in the 11B NMR spectrum

(Figure 3.27).

OO CO2R

OB

O

H

HOR

409

OO CO2R

CO2R

O B3

408

Figure 3.27

Hetero atom containing dihydrido compound such as BH2X.L (X= -Cl,

Br,I,PR2, NR2) has been described in the literature.287 However, RO-BH2 type

compounds are usually known as transient species and tend to undergo

disproportionation to (RO)2BH and B(OR)3 compounds. Several recent reports

indicated the formation of a free RO-BH2 or complexed to carbonyl groups in the

reduction of α-hydroxy esters using BMS or BMS-NaBH4 reagents. It intrigued us

that such RO-BH2 species were not detected in the reduction of esters 153 and

155 as evidenced by 11B NMR spectral analysis.

Consequently it was decided to undertake a 11B NMR spectroscopic study

for understanding the regioselective reduction of diethyl (S)-malate (DEM) and

diethyl (R, R)-tartarate (DET) using BMS and catalytic amount of sodium

borohydride in THF and toluene independently, under the conditions described

above to check for the formation of intermediates RO-BH2. The 11B NMR

spectrum of the selective reduction of DEM, displayed peaks due to BMS at δ -

21 to-18 ppm and a minor peaks at δ 27 and 28 ppm immediately after the

addition of BMS at 0 °C (Figure 3.28). After the gas evolution, an aliquot of the

reaction mixture was analyzed by 11B NMR spectroscopy and observed that all

the BMS was consumed and the 11B NMR does not show any peak corresponds

to unreacted BMS at 25 °C (Figure 3.29). The 11B NMR spectrum of the reaction

mixture displayed broad singlets at + 22 ppm attributable to polymeric

trialkoxyboranes as described in the above reductions. There were no signals

attributable to an intermediate corresponding to alkoxy-BH2, such as 395.

Addition of catalytic amount of NaBH4 gives the polymeric trialkoxyborane and did

not show any significant change in the 11B NMR spectrum (Figure 3.30).

135

Quenching the reaction with MeOH after 3 h gave monomeric trialkoxyborane

B(OMe)3 (Figure 3.31). Reductions in THF gave similar 11B NMR data.

Figure 3.28 11B NMR spectrum of a solution of DEM immediately aft er the addition of

BMS

Figure 3.29 11B NMR spectrum of a mixture of DEM and BMS after th e gas evolution

136

Figure 3.30 11B NMR spectrum of a mixture of DEM and BMS after th e addition of sodium borohydride

Figure 3.31 11B NMR spectrum of a mixture of DEM, BMS and NaBH 4 after quenching with MeOH

The DET was also subjected to the site selective reduction using the above

procedure and the 11B NMR analysis supports the similar conclusions described in

earlier reductions (Figure 3.32-3.34).

137

Figure 3.32 11B NMR spectrum of a mixture of DET and BMS after th e gas evolution

Figure 3.33 11B NMR spectrum of a mixture of DET and BMS after th e addition of sodiumborohydride

Figure 3.34 11B NMR spectrum of a mixture of DET, BMS and NaBH 4 after quenching with MeOH

138

Again, the 11B NMR spectrum of an aliquot of the reaction mixture failed to

show any signal due to unreacted BMS or ROBH2 type intermediates. Apparently,

esters of DEM reacted with BMS in a 1:1 fashion and the initially formed ROBH2 395

type intermediates quickly transfered a hydride to the proximal ester carbonyl to give

a dialkoxyborane intermediate (410) that was visible in the 11B NMR spectrum

(Scheme 3.11). Obviously, a fast uncatalyzed hydride transfers from ROBH2 to the

proximal ester carbonyl occurs at 25 °C

EtO2CCO2Et

OBH2

395

hydride transfer CO2EtOB

O

H

HRO

Cat.NaBH4 CO2EtOB

O

OR

HH

411410

CO2EtHO

HO

major

MeOH

51

OHHO

EtO

+

O

minor

394

Scheme 3.11 Proposed mechanism of selective reducti on of DEM using BMS and catalytic amount of NaBH 4 on the basis of 11B NMR studies

Similarly, the 11B NMR spectra of 153 and 155 showed three signals

corresponding to 409, 412 and/or 413 and the polymeric form of 412. Addition of

catalytic NaBH4, resulted in the formation of the polymeric form of 412 similar to the

polymeric form of pinacol boronate esters, which exhibited broad signals in the 11B

NMR spectrum at δ+22 ppm. The intermediate 413 is expected to exhibit a singlet at

δ +19. On methanolysis, only trimethylborate is present as the boron containing

compound as evidenced by 11B NMR spectral analysis. There is a small amount of

tetramethyl borate corresponding to the catalytic amount of NaBH4 used in the

reaction. Apparently, reduction of 153 and 155 proceeds through the initial formation

of 402 and gives significant amounts of 409 and 412 even in the absence of NaBH4.

Addition of NaBH4 accelerates the formation of polymeric form of 412 (Scheme 3.12)

139

OO CO2RO

OROBH2

hydride transferOO CO2R

OB

O

H

HOR

Cat.NaBH4

OO CO2R

OB

O

OR

HH

402 409 412

R'OH

OO CO2R

OB

O

OR'

HOR

413

OO CO2RO

HHO

work up

414

OO CO2RO

ORHO

BMS

153.R=-CH3155.R=-CH(CH3)2

OO CO2R

HO OH

204.R=-CH3406.R=-CH(CH3)2

Scheme 3.12 Proposed mechanism of selective reducti on of esters of 6 using BMS and catalytic amount of NaBH 4 on the basis of 11B NMR studies

It was observed that NaOMe also catalyze the hydride transfer from the

dialkoxyborane 409 to the final alkyl (2S,3R)-tetrahydro-3-hydroxy-3-

(hydroxymethyl)-5-oxo-2 furancarboxylate (204 and 406) in BMS reduction. The 11B NMR spectroscopic study of the regioselective reduction of 155, using BMS

and catalytic amount of sodium methoxide (NaOMe), instead of NaBH4, in THF

has been carried out under the same conditions described above to check for the

involvement of catalytic NaBH4 in the site selective reduction. The 11B NMR

spectrum of the aliquot of reaction mixture recorded immediately after the

addition of BMS at 0°C which displayed the peaks due to BMS at δ -21 to-18 ppm

and a minor peaks at 9 ppm (Figure 3.35). After the gas evolution, an aliquot of

the reaction mixture was analyzed by 11B NMR spectroscopy and observed that

all the BMS was consumed and the 11B NMR did not show any peak corresponds

to unreacted BMS at 25 °C (Figure 3.36). The 11B NMR spectrum of the reaction

mixture displayed broad singlets at + 21 ppm and +27 ppm attributable to

polymeric trialkoxyboranes as described in the above reductions. There were no

signals attributable to an intermediate corresponding to alkoxy-BH2, such as 402.

Addition of catalytic amount of freshly prepared NaOMe gave the polymeric

trialkoxyborane and failed to cause any significant change in the 11B NMR

spectrum (Figure 3.37).

140

Figure 3.35 11B NMR spectrum of a solution of 155 immediately aft er the addition of BMS

Figure 3.36 11B NMR spectrum of a mixture of 155 and BMS after th e gas evolution

141

Figure 3.37 11B NMR spectrum of a mixture of 155 and BMS after th e addition of NaOMe

3.4.5 The partial reduction of propan-2-yl (2 R)-hydroxy(phenyl)ethanoate (415) using BMS

It was also observed that the dialkoxyborane initially formed during the

addition of BMS to the α-hydroxy ester could lead to the formation of a α-hydroxy

aldehyde and could be trapped as bisulfite adduct. Attempts were made for the

partial reduction of α-hydroxy esters, using BMS and subsequent quenching with

MeOH, to the α-hydroxy aldehydes.

Reports are available on bisulfite adducts which are known to give

chemical stability to the parent aldehyde and exhibit desirable physical properties

such as crystallinity, which facilitate the isolation and purification techniques.288

Hence the purification of the aldehyde via the bisulfite adduct appeared attractive

and efficient.

The propan-2-yl (2R)-hydroxy(phenyl)ethanoate (isopropyl mandelate,

415) was selected for the partial reduction using BMS in anhydrous

142

tetrahydrofuran (THF) (Scheme 3.13). The progress of the reaction was followed

by 11B NMR analysis of aliquots withdrawn periodically from the reaction mixture.

O

OHO

BMS

THF, 0 C

OR

OBO

H

MeOH

OR

OBO

R

H

OHO

415 416 417 418

SO3Na

OHHO

419

bisulfite

°

Scheme 3.13 Partial reduction of 415 using BMS

When one mole equivalent of BMS was added to a solution of 415 in THF,

at 0 °C, one equivalent of hydrogen gas evolved immediately and was measured

by gas buret technique. After the gas evolution, an aliquot of the reaction mixture

was analyzed by 11B NMR spectroscopy and observed that all the BMS was

consumed and the 11B NMR does not show any peak corresponds to unreacted

BMS at 25 °C (Figure 3.39). The 11B NMR spectrum of the reaction mixture

displayed a doublet at +28.99 ppm and clearly indicates the formation of an

aldehyde. The reaction is quenched with MeOH after 4 h, very little hydrogen

evolved and the predominant signal in the 11B NMR spectrum of the reaction

mixture was attributable to trimethoxyborane B(OMe)3 (δ +18 ppm) (Figure 3.40).

The 1H NMR analysis of the crude reaction mixture displayed a singlet at δ 9 ppm

attributable to aldehyde proton (Figure 3.42a). The reaction mixture was

concentrated under vacuum and the residue was treated with sodium bislfite

solution. However, the conversion of (2R)-hydroxy(phenyl)ethanal (418) to the

bisulfite adduct (419) was unsuccessful. Further studies for the isolation of the

aldehydes are underway.

Figure 3.38 11B NMR spectrum of a solution of 415 immediately aft er the addition of

BMS

143

Figure 3.39 11B NMR spectrum of a mixture of 415 and BMS after th e gas evolution

Figure 3.40 11B NMR spectrum of a mixture of 415 and BMS after qu enching with MeOH

144

1H NMR 400 MHz, Solvent : CDCl3

O

OHO

415

Figure 3.41a

13C NMR 400 MHz, Solvent : CDCl3

O

OHO

415

Figure 3.41b

145

1H NMR 400 MHz, Solvent : CDCl3

H

OHO

418

Figure 3.42a

3.4.6 The tandem reduction of dialkyl (2 S,3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylates (153 and 155) using NaBH 4 and MeOH at 0 °°°°C

The use of sodium borohydride for the simple chemoselective reductions

of aldehydes and ketones to the corresponding alcohols is well established.211

The reaction is normally carried out at reflux temperature using ethanol or

methanol as solvent. Although, theoretically, one equivalent of sodium

borohydride provides four equivalents of hydride, a slight excess of the reagent is

typically used to counter consumption by reaction with the solvent. Under these

conditions, carboxylic acids, esters, epoxides, lactones, nitro groups, imides,

amides and nitriles are not reduced. Therefore, reduction of these functional

groups is carried out using stronger reducing agents like lithium aluminum

hydride. Sodium borohydride can, however, be easily modified to a stronger or

more selective reducing agent.275 Examples include the borohydride reduction

step in the industrial synthesis of D-biotin (vitamin H)289 and the selective hydroxy

ester reduction in presence of non-substituted esters, employed in the synthesis

of R-lipoic acid.290 Reports are available for the successful reduction of esters by

utilizing a mixture of sodium borohydride and lithium chloride269a in ethanol.

146

Thus Sodium borohydride is versatile as a reducing agent for both chemo-

and diastereo-selectivity and have been used in the stereoselective reductions.

Sodium borohydride in diglyme in the presence of aluminum chloride267 or sodium

borohydride and ethane dithiol in THF at ambient or reflux temperature is known

to reduce carbonyls belong to esters, acids and even nitriles. The reduction of

esters in non-polar solvents like THF has traditionally required long reaction times

and forcing conditions.

As discussed in section 3.3, the addition of a precise amount of methanol

to the reaction mixture enhances the reactivity of sodium borohydride-THF

system275 and have been successfully used for the reduction of various esters

such as aliphatic, aryl, heteroaryl, α-keto, α-hydroxy esters. It is most likely,

BH3(OMe)- is the active reducing agent involving sodium borohydride and

methanol. It was also reported that hydroxyborohydride BH3OH- has reducing

power relative to lithium aluminium hydride.291 Soai et al. has reported a

convenient method for the rapid and selective reduction of esters of N-protected

amino acid and N- protected peptides with NaBH4 and methanol in THF or t-butyl

alcohol at refluxing conditions. The reaction consumed large excess (tenfold or

higher) of NaBH4 and which was wasted by liberating hydrogen from NaBH4.275

With this back ground, the ester 153 was reduced using sodium

borohydride in methanol (Soai’s condition). Since methanol is known to react

rapidly with NaBH4 at 60 °C, the reaction was carried out at 0 °C. Dry MeOH (3

mL) was added over a period of 20 min to a suspension of 153 and NaBH4 in

THF (Scheme 3.14). After the gas evolution the 11B NMR spectrum of the aliquot

of reaction mixture was recorded (Figure 3.43). The spectrum showed broad

singlet at δ +10 ppm attributable to tetraalkoxyborate ion. When the reaction was

quenched with 2N HCl after 2 h the predominant signal in the 11B NMR spectrum

of the reaction mixture was attributable to trimethoxyborane B(OMe)3 (δ +19

ppm) (Figure 3.44). The reaction mixture was concentrated under vacuum and the

chromatographic purification of the residue over silica gel (60-120 mesh CHCl3:

MeOH) afforded (2R,3R)-3-hydroxymethyl-pentane-1,2,3,5-tetraol (386) in 75%

yield as a colourless oil. 26D][α +2.752 (c 0.40, MeOH). The structure of the

compound was confirmed on the basis of the IR, 1H, 13C NMR and mass spectra.

The IR spectrum displayed absorption bands at 3325 cm-1 (indicate the presence of

147

–OH groups). The 1H NMR spectrum displayed signals at δ 3.7 and 1.8 (multiplets;

due to methylene protons). The 13C NMR spectrum displayed six different signals at

δ δ 76.88, 75.31, 66.01, 63.17, 58.79 and 37.05 which confirmed the number of

carbon atoms of the molecule (Figure 3.46a-e). The DEPT 135 showed –ve signals

at δ 66, 63, 58 and 37 (indicate the presence of -CH2 carbons) and +ve signal at 75

(shows the presence of CH carbon) (Figure 3.47a-e). HRMS (ES+) calculated for

C6H14O5Na: 189.0739, Found: 189.0735 (Figure 3.45)

HO OH

OHHO

HO

386

1. NaBH4, 0 C, THF

2. MeOH, 0 C, 2 h

3. aq HCl

153°

°

Scheme 3.14 Tandem reduction of 153 using NaBH 4 and MeOH

Figure 3.43 11BNMR spectrum of a mixture of 153 and NaBH 4 after the addition of MeOH

148

Figure 3.44 11BNMR spectrum of a solution of 153, NaBH 4 and MeOH after the addition of HCl

Figure 3.45 Single mass analysis of 386

149

IR (Liquid film)

HO OHOH

HOHO

386

Figure 3.46a

1H NMR 400 MHz, Solvent : CD3OD

HO OHOH

HOHO

386

Figure 3.46b

13C NMR 100 MHz, Solvent : CD3OD

HO OHOH

HOHO

386

Figure 3.46c

150

DEPT 135

HO OHOH

HOHO

386

Figure 3.46d

HO OHOH

HOHO

386

Figure 3.46e

The 2D HMQC (Heteronuclear Multiple Quantum Coherence) data was

obtained to support the structure of 386. The assignments of the CH2 carbon shifts

were made on the basis of the 1H-13C short range correlations observed in the 2D

HMQC spectrum which confirms the structure of the polyol 386 (Figure 3.47).

151

Figure 3.47 HMQC obtained for 386

The ester 155 was also subjected to reduction using NaBH4 and MeOH

following the same procedure as that of 153 (Scheme 3.15). The progress of the

reaction was followed by 11B NMR analysis. The 11B NMR spectrum displayed

similar results as in the case of 153. TLC analysis of the reaction mixture after 2 h

indicated the formation of mixture of products 406 and 386 in equal amounts.

This could be explained on the basis of the bulkiness of the isopropyl ester group

present in 155 which in turn reduced the rate of the reduction. Workup of the

reaction mixture and further purification furnished 406 in 40% yield as a

crystalline solid (mp 55-60 °C), { 26D][α +72.78 (c 0.143, Acetone)} and 386 in 35%

yield as a clear oil. The structure of the compounds was confirmed on the basis

of IR, 1H, 13C NMR and mass spectra and compared with the data obtained in

earlier cases.

HO OHOH

HOHO

386

1. NaBH4, 0 oC, THF

2. MeOH, 0 oC, 2 h

3. aq HCl

155

OO O

O

OHHO

406

+

Scheme 3.15 Reduction of 155 using NaBH 4 and MeOH

152

3.4.7 The attempted reduction of C3 carboxylate of dimethyl ( 2S, 3R)-tetrahydro-3-hydroxy-5-oxo-2, 3 furan dicarboxylate (158)

The reduction of the diastereomeric ester 158 was carried out using BMS

and catalytic amount of NaBH4 under the same conditions carried out for the

esters of 6 (Scheme 3.16). The progress of the reaction was followed by 11B

NMR analysis which displayed similar results as in the case of 153 and 155

(Figure 3.50-3.52). The 11B NMR spectrum did not show any signal attributable to

oxyborane intermediate (423) (Figure 3.49). However, the final product contained

was a mixture of alcohols methyl (2S,3S)-3-hydroxy-3-(hydroxymethyl)-5-

oxotetrahydrofuran-2-carboxylate (205) and methyl (2R,3R)-3-hydroxy-2-

(hydroxymethyl)-5-oxotetrahydrofuran-3-carboxylate (420) and was difficult to

purify. It is possible that ester 158 forms both five and six membered

dialkoxyboranes (421 and 422) (Figure 3.48) with BMS due to favorable

stereochemical orientations of the ester and the hydroxy functional groups and

eventually afford a mixture of reduction products. It is impossible to distinguish

the dialkoxyborane intermediates obtained from the BMS reduction of garcinia

and hibiscus esters by 11B NMR spectroscopy as this technique is not sensitive

enough to distinguish between five and six membered dialkoxyboranes.

158BMS,NaBH4

THF

OO OCH3

O

OHHO

OO OH

OCH3HO

O

+

205 420

Scheme 3.16 Reduction of 158 using BMS and catalyti c amount of NaBH 4

When 158 was treated with one equivalent of BMS in THF at 0 °C, the

evolution of one mole equivalent of hydrogen gas was observed. It is inferred that

the hydroxy esters reacted with BMS in a 1:1 stoichiometry to give alkoxy-BH2

(ROBH2) type intermediates (423) or the reaction proceeds through a 3:1

stoichiometry to give an intermediate (424). The 3:1 stoichiometry is expected to

leave 66% of the BMS unreacted after the reaction. However, 11B NMR spectrum

of an aliquot of the reaction mixture did not show any significant signal due to

unreacted BMS or due to the ROBH2 type intermediates (Figure 3.50-3.52).

Apparently, the ester 158 react with BMS in a 1:1 fashion and the initially formed

153

ROBH2 type intermediates quickly transfers a hydride to the proximal ester

carbonyl to give a dialkoxyborane intermediate (421) (Figure 3.48) that was

visible in the 11B NMR spectrum .

OO CO2R

OB

O

H

HOR

OO

O BO

ROOC H

H

OR

421 422

OO

ROOC

O

OB

ORH

Figure 3.48 Five and six membered transition state structures of esters of 7

OO CO2R

OBH2

423

CO2R

OO CO2R

CO2R

O B3

424

Figure 3.49

Figure 3.50 11B NMR spectrum of a solution of 158 immediately aft er the addition of BMS

154

Figure 3.51 11B NMR spectrum of a mixture of 158 and BMS after th e gas evolution

Figure 3.52 11B NMR spectrum of a mixture of 158, BMS and NaBH 4 after quenching

with MeOH

The structure of 205 and 420 was further confirmed by preparing the

acetyl derivatives namely methyl (2S, 3S)-terahydro-3-acetyloxy-3-[(acetyloxy)

methyl]-5-oxo-furan-2-carboxylate (425) and methyl (2R,3R)-terahydro-3-

acetyloxy-2-[(acetyloxy) methyl]-5-oxo-furan-3-carboxylate (426).

155

3.4.8 Conversion to methyl (2 S, 3S)-terahydro-3-acetyloxy-3-[(acetyloxy)methyl]-5-oxo-furan-2-carboxylate (425) and methyl (2R,3R)-terahydro-3-acetyloxy-2-[(acetyloxy)methyl]-5-oxo -furan-3-carboxylate (426)

To confirm the structure of both 205 and 420 obtained during the reduction

of 158, acetylation of the reaction mixture was carried out128 using acetyl chloride

following the same procedure as in the case of 405 using 205 and 420. As

expected, a mixture of the acetyl derivatives 425 and 426 were obtained in

quantitative yield (Scheme 3.17).

OO OCH3

O

OHHO

205 CH3COCl

OO OCH3

O

OCOCH3H3COCO

OO OH

OCH3HO

O

420

OO OCOCH3

OCH3H3COCO

O

+ +

425

426

Scheme 3.17 Acetylation of 205 and 420

IR (liquid film)

OO OCH3

O

OCOCH3H3COCO

OO OCOCH3

OCH3H3COCO

O

+

425

426

Figure 3.53a

156

1H NMR 300 MHz, Solvent : CDCl3

OO OCH3

O

OCOCH3H3COCO

OO OCOCH3

OCH3H3COCO

O

+

425

426

Figure 3.53b

13C NMR 75 MHz, Solvent : CDCl3

OO OCH3

O

OCOCH3H3COCO

OO OCOCH3

OCH3H3COCO

O

+

425

426

Figure 3.53c

157

OO OCH3

O

OCOCH3H3COCO

OO OCOCH3

OCH3H3COCO

O

+

425

426

Figure 3.53d

3.5 Conclusion

In summary, this chapter deals with the precise tuning of boron reagents for

cumulating the syntheses of natural product intermediates by the chemical

modification of (2S, 3S) and (2S, 3R) –tetrahydro-3-hydroxy -5-oxo-2, 3-

furandicarboxylic acids. A systematic selective (site as well as chemo) carbonyl

reduction of the dialkyl (2S, 3S) and (2S, 3R) –tetrahydro-3-hydroxy -5-oxo-2, 3-

furandicarboxylates were carried out, using borane-dimethyl sulfide (BMS) and

sodium borohydride at 0 °C. This regioselective reduction is general and has been

extended to other representative α-hydroxy esters, such as malate and tartrate

diesters. The reduction of 153, using BMS and catalytic amount of sodium

borohydride, furnished a mixture of products formed by the reduction of the

proximal as well as distal ester groups in a ratio ranging from 70:30 to 60:40.

Very good regio-selectivity was observed when 155 was reduced under the same

conditions.

The 11B NMR spectroscopic study revealed the formation of a transient

alkoxy-BH2 (RO-BH2) intermediate initially and its subsequent rapid, uncatalyzed

transfer of a hydride to the proximal ester carbonyl to give a dialkoxyborane

intermediate at 25 °C. The hydride transfer from dialkoxyborane intermediate to

the final trialkoxyborane derivatives is catalyzed either by sodium borohydride or

by sodium methoxide. Alternatively, attempts were made to develop a simple

methodology for trapping the α-hydroxy aldehyde intermediate by the partial

158

reduction of α-hydroxy esters by quenching the dialkoxyborane intermediates with

methanol. The isopropyl mandelate was partially reduced with BMS and

subsequently quenched the reaction mixture with MeOH. The 11B NMR spectrum

showed a doublet at δ 28.99 ppm clearly indicating the formation of an aldehyde.

However, attempts for the isolation of aldehyde as their bisulfite adduct was

unsuccessful. Further studies for the isolation of α-hydroxy aldehydes are

underway. On the other hand, sodium borohydride in methanol at 0 °C behaved

very similar to that of lithium aluminum hydride and tandemly reduced the lactone

and ester carbonyls of both garcinia and hibiscus esters. Under this condition

dimethyl ester of garcinia acid underwent tandem reductions to furnish 386.

However, their analogue 155 furnished a mixture of 406 and 386 in equal amounts.

The 11B NMR spectrum of a solution of sodium borohydride in methanol at 0 °C

showed the signals due to sodium monomethoxyborohydride (NaBH3OMe),

plausible active tandem reducing agent. This active reducing agent is stable only

at or below 0 °C and rapidly decomposes at elevated temperatures. Hence, the

optimum condition for carrying out the reductions involving sodium borohydride in

methanol is at or below 0 °C. Thus the results presented here demonstrate

further insight into the regioselective, partial and tandem reductions of various α-

hydroxy esters employing borohydride reagents.

3.6 Experimental Section

3.6.1 General methods

All operations were carried out under a nitrogen atmosphere. All

glassware, syringes, and needles were oven-dried and cooled under nitrogen gas

before use. THF was freshly distilled from sodium benzophenone ketyl.

Anhydrous MeOH was freshly distilled from calcium hydride. Toluene was

distilled from sodium wire. Sodium methoxide was freshly prepared from

methanol and excess Na metal in anhydrous THF. BMS, BTHF, Sodium

borohydride, diethyl malate, diethyl tartarate, mandelic acid, and malic acid were

commercial products and used without further purification. 1H NMR (400 MHz)

and 13C NMR (100 MHz) were measured on a Brucker AV 400, W M 300 MHz or

Avance 300 MHz spectrometer. Chemical shifts are expressed in parts per million

(ppm) relative to TMS (δ = 0) and coupling constants are reported as Hertz (Hz).

159

Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet,

t = triplet, q = quartet, p = pentet, br = broad, m = multiplet), coupling constant,

and integration. Boron NMR samples were recorded in CDCl3 at 128.4 MHz

and are reported relative to external standard BF3·Et2O (δ = 0). Melting points

were determined on ‘’Sunbim’’ make electrically heated melting point

apparatus and were uncorrected. IR spectra were recorded using a Shimadzu

IR 470 spectrophotometer as KBr pellets (solids) or thin films (liquids) and

ThermoFisher Is 10 FTIR spectrometer with diamond ATR and are reported as

wavenumber (cm–1). Electron impact mass spectra were recorded on a

Finnigan MAT MS 8230 or Jeol D-300, Jeol-JMS600 HRMS were recorded on

Micromass UK, Q-TOF. Optical rotations were measured on a Rudolph IV

Autopol polarimeter operating at the sodium D line with a 100 mm path length

cell, and are reported as follows: TD][α (concentration (g/100 ml), solvent).

Column chromatography was carried out with Merck product silica (silica

gel 60-120 mesh) and thin layer chromatography was carried out with Merck

product silica (silica gel G for TLC).

3.6.2 Methyl (2 S,3R)-tetrahydro-3-hydroxy-3-(hydroxymethyl)-5-oxo-2 furancarboxylate (204)

A 100 mL two-necked round- bottom flask equipped with a magnetic stir

bar and fitted with a rubber septum was filled with a solution of dimethyl (2S,3S)-

tetrahydro-3-hydroxy-5-oxo-furandicarboxylate, 153 ( 1.0 g, 4.6 mmol) in dry

tetrahydrofuran (10 mL). Through the septum one equivalent of borane dimethyl

sulphide, 10 M (0.8 mL, 4.6 mmol) was added dropwise via syringe over a period

of 10 min at 0 °C with constant stirring. Hydrogen evolution was rapid and

essentially complete at 30 min at 25 °C. After the gas evolution, an aliquot of the

reaction mixture was analyzed by 11B NMR spectroscopy and observed that all

the BMS was disappeared and the appearance of broad singlets at + 21 ppm and

+28 ppm attributable to polymeric trialkoxyboranes, and dialkoxyborane

respectively at 25 °C. The reaction mixture was cooled to 0 °C and powdered

NaBH4 (catalytic) was added in one portion under vigorous stirring. After 20 min

of stirring, the reaction mixture was warmed to 25 °C. The 11B NMR analysis of

an aliquot of reaction mixture displayed the disappearance of signal at δ +28 ppm

and the intensification of signal at δ +21. The reaction mixture was left aside for

160

an additional 2.5 h to ensure the complete reaction. The reaction mixture was

quenched with dry methanol (3mL) (Caution! Hydrogen evolution) and stirred for

further 30 min at room temperature. Again the 11B NMR of the reaction mixture

was analyzed which displayed signals at δ +18 and +10 ppm, corresponds to

trimethoxyborane B(OMe)3 and tetraalkoxyborate ion respectively. Upon

concentration under reduced pressure gave a clear transparent gum. The gum

was dissolved in dry MeOH (5 mL) and again concentrated under reduced

pressure. The operation was repeated to eliminate B (OMe)3 as thoroughly as

possible.

Yield : 70%

26D][α : +27.47 (c 1.02, CHCl3)

IR (liquid film) : νmax 3416, 2959, 1771, 1735, 1634, 951

cm-1

1H NMR (Acetone-d6, 400 MHz) : δ 4.44 (s, 1H), 4.5 (d, 10.4 Hz, 1H), 4.24

(d, 10 Hz, 1H), 3.762 (s, 3H), 3.02 (d, J =

17.6 Hz, 1H), 2.47 (d, J = 17.60 Hz, 1H)

13C NMR (Acetone-d6, 100 MHz) : δ 176.25, 172.6, 79.16, 77.2, 75.29, 52.59,

40.44

11B NMR (CDCl3, 128.37 MHz) : +28(s), +21(bs) [After the gas evolution]

+18(s) [After the addition of NaBH4]

Mass spectrum (EIMS) : 191 (5, M+1), 159 (90), 141 (13), 131 (27),

104(60), 99 (100), 59 (17), 43 (30),

28(20%)

Molecular formula : C7H10O6

Molecular mass : 190.15

3.6.3 Methyl (5 S, 6S) 8-oxo-2-trichloromethyl-1,3,7-trioxa-spiro[4.4]no nane-6-carboxylate (404)

To an ice-cold two-necked round bottom flask fitted with a CaCl2 guard

tude containing methyl (2S,3R)-tetrahydro-3-hydroxy-3-(hydroxymethyl)-5-oxo-2

161

furancarboxylate (204), (1.0 g, 5.26 mmol) anhydrous chloral (0.8 mL, 5.26

mmol) was added dropwise under stirring followed by 2.5 mL of conc. H2SO4.

The reaction mixture was stirred overnight in the dark at room temperature.

Crushed ice (50 g) was added to the reaction mixture, followed by diethyl ether

(50 mL). After stirring for 10 minutes, the ether layer was separated and the

process was repeated thrice (3x20 mL). Combined ether extracts were dried

with Na2SO4 and concentrated. The crude solid obtained was crystallized from

chloroform –hexane (7:3).

Yield : 89%

Mp : 162-164 °C

29D][α

: +13.14 (c 0.25, CHCl3)

IR (KBr pellet) : νmax 3008, 2360, 2341, 1824, 1747, 1712, 1411,

1346, 1203, 1107, 829 cm-1.

1H NMR (CDCl3+ CD3OD, 300 MHz): δ 6.0487 (s, 1H), 4.8 (s, 1H) 4.4762 (d, J

=10.23 Hz, 1H), 4.3727 (d, J =10.23 Hz, 1H),

3.6971 (s, 3H), 2.9686 (d, J = 18.06 Hz, 1H),

2.74505 (d, J = 18.03 Hz, 1H)

13C NMR (CDCl3 + CD3OD, 75 MHz) : δ 174.776, 167.826, 105.161, 97.307, 79.196, 77.426, 76.326, 49.6, 37.556

Mass spectrum (FAB+) : 305.07 (M+1), 176.14 (25), 151 (100), 137.12

(100), 89.39 (56), 77.58 (48), 40.14 (30)

Molecular formula : C9H9Cl3O6

Molecular mass : 319.50

Elemental analysis : Calculated : C: 33.83, H: 2.84

Found : C: 30.81, H: 2.92

3.6.4 Methyl (2 S, 3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo-furan-2-carboxylate (405)

Acetyl chloride (2equ.) was added dropwise to the alcohol 204 (1 g, 3.5

mmol) under stirring and the stirring was continued for 12 hours. The reaction

162

mixture was concentrated under vacuum and the compound 405 was extracted in

to dichloromethane.

Yield : 86%

29D][α

: +53.14 (c 0.52, CHCl3)

IR (liquid film) : νmax 3494, 3009, 2969, 1780, 1748, 1452, 1128,

1081, 1013 cm-1

1H NMR

(CDCl3, 300 MHz) : δ 5.3 (s, 1H), 4.6 (d, 2H), 3.9 (s, 3H) 3.0 (d, J =

18.0 Hz, 1H), 2.80 (d, J = 18.0 Hz, 1H), 2.2 (d,

6H)

13C NMR (CDCl3, 75 MHz) : δ 172.16, 169.8, 169.6, 167.02, 83.82,80. 66,

61.59, 53.09, 37.66, 21.49, 20.38

Mass spectrum (EIMS) : 275 (2, M+1), 219 (23), 191 (32), 159 (50), 143

(3), 13 (4.5), 99 (10.5), 90 (15), 59 (6), 43

(15%);

Molecular formula : C11H14O8

Molecular mass : 274.22

Elemental analysis

Found : C 48.28, H 5.20

Calculated : C 48.21, H 5.14

3.6.5 Diisopropyl (2 S,3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate (155)

To a pre-cooled (-5-0 oC) suspension of 152 (1.0 g, 4.4 mmol) in isopropyl

alcohol (10 mL) and thionyl chloride (0.7 mL, 10 mmol) were added. The mixture

was then stirred for 48 h at room temperature. After filtration of the reaction

mixture, pH of the filtrate was adjusted to 7.0, by adding saturated aqueous sodium

bicarbonate and was extracted with chloroform (3X10 mL). The combined extract

upon drying and evaporation gave the compound 155 as pale yellow oil.

163

Yield : 0.5 g (41%)

25D][αααα : +32.0° (c 1.0, CHCl 3)

IR (KBr pellet) : ν max 3454, 2985, 1801, 1752, 1469, 1246, 1214

cm-1

1H NMR (CDCl3, 400 MHz) : δ 5.08 (m, 2H), 4.843 (s, 1H), 3.071 (d, J = 17.6,

1H), 2.822 (d, J = 17.6, 1H), 1.297 (m, 12H)

13C NMR (CDCl3, 100 MHz) : δ 171.59, 169.94, 165.58, 83.92, 78.38, 76.7,

72.41, 70.62, 39.87, 21.66, 21.5, 21.35

Mass spectrum (E.I) : 274 (M+, 7.4), 246 (60.3), 232 (34.2), 216 (21.8),

204 (37.1), 190 (15.8), 174 (23), 162 (52.3), 144

(58.7), 132 (43.6), 117 (12), 98 (15), 76 (52), 42

(100%)

Molecular formula : C12H18O7

Molecular mass : 274.11

Elemental analysis

Found : C, 52.32, H, 6.59

Calculated : C, 52.55, H, 6.57

3.6.6 Isopropyl (2S, 3 R)-terahydro-3-hydroxy-3-hydroxymethyl-5-oxo-furan-2-carboxylate (406)

Reduction was carried out using a solution of diisopropyl (2S,3S)-

tetrahydro-3-hydroxy-5-oxo-furandicarboxylate (155) (1 g, 3.6 mmol) in dry

tetrahydrofuran (10 mL), and borane dimethyl sulphide, 10 M (0.35 mL, 3.65

mmol) and catalytic sodium borohydride as in the case of 153. The progress of

the reaction mixture was followed by the 11B NMR analysis of aliquots of reaction

mixture. The residue obtained was purified through silica column (60-120 mesh,

Ethyl acetate –hexane 7:3) to afford 406 as a colorless crystalline solid.

Yield : 80%

26D][α : +72.78o (c 0.143, Acetone)

Mp : 55-60 °C

164

IR (ATR) : 3443, 2984, 1776.39, 1730, 1467, 1375, 1276,

1237, 1103, 1024 cm-1;

1H NMR (CDCl3, 400 MHz): δ 5.151 (m, 1H), 4.759 (s, 1H), 4.3983 (d, J = 10.44

Hz, 1H), 4.2713 (d, J = 10.39 Hz, 1H), 2.8895 (d, J

= 18 Hz, 1H), 2.6175 (d, J = 18 Hz, 1H) 1.3 (m,

6H).

13C NMR (CDCl3, 100 MHz): δ 174.80, 170.79, 78.08, 76.70, 74.02, 71.64, 38.93, 21.75, 21.73

11B NMR (CDCl3, 128.37 MHz): δ + 28 (s), +22 (s) [After the gas evolution]

+22 (s) [After the addition of NABH4]

Molecular formula : C9H14O6

Molecular mass : 218.08

HRMS (ES+) calculated for C9H14O6 Na: 241.0688, Found: 241.0686.

3.6.7 Methyl (2 S, 3S)-terahydro-3-acetyloxy-3-[(acetyloxy)methyl]-5-oxo -furan-2-carboxylate (425) and Methyl (2 R,3R)-terahydro-3-acetyloxy-2-[(acetyloxy)methyl]-5-oxo-furan-3-carbo xylate (426)

Acetyl chloride (4 equ.) was added dropwise to the mixture of alcohol 205

and 420 (1 gm, 5.26 mmol) under stirring and the stirring was continued for 12

hours. The reaction mixture was concentrated under vacuum and the compounds

425 and 426 were extracted in to dichloromethane.

IR (liquid film) : νmax 3490, 3000, 2969, 1780, 1748, 1452, 1138,

1071, 1010 cm-1

1H NMR (CDCl3, 300 MHz): δ 5.3 (s, 1H), 5.1 (t, 1H), 4.6-4.4 (d, 4H), 3.9 (s, 3H), 3.8 (s, 3H), 3.0 (d, 2H), 2.80 (d, 2H), 2.2-2 (d,12H)

13C NMR (CDCl3, 75 MHz): δ 172.16, 171.0, 169.8, 169.2, 169.6, 168.5, 167.02, 167.5 83.82, 82.2, 80. 66, 79.4, 61.59, 62.3, 53.09, 53.2, 37.66, 38.2, 21.49, 20.38 22.3, 21.8

Mass spectrum (EIMS) : 275 (2, M+1), 219 (23), 191 (32), 159 (50), 143 (3),

13 (4.5), 99 (10.5), 90 (15), 59 (6), 43 (15%)

3.6.8 Reduction of diethyl ( S)-malate

Reduction was carried out using a solution of diethyl (S)-malate (1 gm, 5.2

mmol) in dry toluene (10 mL), and borane dimethyl sulphide, 10 M,(1 equ, 0.45

mL, 5.2 mmol)) and catalytic powdered sodium borohydride at 0 °C as in the

165

case of 153.The progress of the reaction mixture was followed by the 11B NMR

analyzis of aliquots of reaction mixture.

11B NMR (CDCl3, 128.37) : δ +22.42 (s) [After the gas evolution]

22.55, 19.7(s) [After the addition of NaBH4]

3.6.9 Reduction of Diethyl ( R,R)-tartrate

Reduction was carried out using a solution of diethyl (R,R)-tartarate

(1.0 gm, 4.8 mmol) in dry tetrahydrofuran (10 mL), borane dimethyl sulphide

(1 equ,0.459 mL) was added drop wise at 0 °C under stirring, as in the case of

153. The progress of the reaction mixture was followed by the 11B NMR analysis

of aliquots of reaction mixture.

11B NMR (CDCl3, 128.37) : δ +22.42 (s) [After the gas evolution]

22.49 (s) [After the addition of NaBH4]

3.6.10 Procedure for the partial reduction of propa n-2-yl (2 R)-hydroxy(phenyl)ethanoate using BMS and MeOH

Reduction was carried out using a solution of propan-2-yl (2R)-

hydroxy(phenyl)ethanoate (415) (500 mg, 2.6 mmol) in dry THF (5 mL), BMS (1

equiv.0.4 mL, 2.6 mmol) was added drop wise at 0 °C under stirring, as in the

case of 153. The progress of the reaction mixture was followed by the 11B NMR

analysis of aliquots of reaction mixture. After the gas evolution, an aliquot of the

reaction mixture was analyzed by 11B NMR spectroscopy and observed that all

the BMS was disappeared. The reaction mixture was cooled to 0 °C and MeOH

(2 mL) was added over a period of 20 min and stirred for another 30 min. 11B

NMR analysis of aliquots of reaction mixture indicated the presence of aldehydic

intermediate. The solvents were concentrated under vacuum and the reaction

mixture was charged a solution of Na2S2O5 in water and stirred for 4 h. However

the formation of the aldehydic adducts was unsuccessful.

11B NMR (CDCl3, 128.37 MHz) : δ +28.12 (d) [After the gas evolution]

δ 18.7 (s) [After quenching with MeOH]

166

3.6.11 (2R, 3R)-3-hydroxymethyl-pentane-1,2,3,5-tetraol (386)

A 100 mL two necked round- bottom flask equipped with a magnetic stir

bar and fitted with a rubber septum was charged with a suspension of sodium

borohydride (0.19 g, 5 mmol) and dimethyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-

furandicarboxylate (153) (1.0 g, 4.6 mmol) in dry tetrahydrofuran (10 mL) at 0 °C.

Anhydrous methanol (2 mL) was injected through the septum to this suspension

via syringe over 20 min at the same temperature with constant stirring. The

progress of the reaction was followed by the 11B NMR analysis. The reaction

mixture was stirred for 2 h at 25 °C. The reaction was quenched by the addition

of 2N HCl. The resultant solution was evaporated under vacuum, and the residue

was extracted with CH2Cl2 (5X10 mL). The combined extracts were dried over

anhydrous sodium sulphate. After the evaporation of the solvent under reduced

pressure, the residue obtained was purified through silica gel column (60-120

mesh, CHCl3: MeOH) to give (2R,3R)-3-hydroxymethyl-pentane-1,2,3,5-tetraol

(386) as colourless oil in good yield. The 2D NMR data was recorded to support the

assignment of the structure of the compound.

Yield : 75%

[α]D26 : +2.752° (c 0.40, MeOH)

IR (ATR) : νmax 3307, 2950, 1645, 1416, 1011 cm-1

1H NMR (CD3OD, 400 MHz) : δ 3.711 (m, 7H), 1.8687 (m, 2H)

13C NMR (CD3OD, 100 MHz) : δ 76.88, 75.31, 66.01, 63.17, 58.79, 37.05

11B NMR (CDCl3, 128.37 MHz) : δ + 10 (s), +19 (s).

Molecular formula : C6H14O5

Molecular mass : 166.08

HRMS (ES+) calculated for C6H14O5Na: 189.0739, Found: 189.0735