Guanidine and guanidinium salt catalyzed enantioselective phosphorus carbon bond formation reactions 1

There are several general methods to generate P-C bonds: a addition to unactivated olefins promoted by radical initiators6 or transition metals.7 b the phospha-Michael reaction of electr

Chapter 1

Asymmetric Phosphorus-Carbon Bond Formation Reactions

Phosphorus is an essential element for synthetic chemistry and life science After the Wittig reaction was discovered in 1954, the organic chemistry of phosphorus became a highly active field.1 Phosphorus is not only critical for many reagents, but also probably the most prominent ligands, in terms of structural and electronic diversity in metal-catalyzed reactions2 and nucleophilic phosphine organocatalysis.3Molecules containing a phosphonic [P(O)(OH)2], a phosphinic [P(O)(OH)R] or a phosphonate [P(O)(OR)2] group and an amino group can be regarded as analogues of amino acids α-Amino phosphonic acids and their phosphonate esters are excellent inhibitors of protease and antibodies.4

The synthetic and biological abilities of phosphorus compounds depend on their enantiopurities Therefore, synthesis of enantiomerically pure organophosphorus compounds has received considerable attention Such compounds are typically prepared by resolution of the racemic phosphorus compounds5, which limits the scope

of the enantiopure organophosphorus compounds The direct approach to build phosphorus-carbon (P-C) bonds, which was a convenient method to generate structurally diversified organophosphorus compounds, provided many model reactions to develop the asymmetric P-C bonds formation reactions

There are several general methods to generate P-C bonds: (a) addition to unactivated olefins promoted by radical initiators6 or transition metals.7 (b) the phospha-Michael reaction of electron-deficient alkenes, most commonly promoted in the presence of a basic catalyst (e.g K2CO3,8 alkaline alkoxides in alcoholic solution9)

or by using a strong base10 (e.g NaH, nBuLi, Et2Zn) in stoichiometric amount, the use

of tetramethylguanidine (TMG),11 Lewis acid 12 or under microwave conditions;13Among various methods to generate P-C bonds, the direct addition of P(O)-H bonds (dialkyl phosphonate [(RO)2P(O)H] or dialkyl phosphine oxides [R2R(O)H]) across

alkenes is one of the most convenient and atom economical routes 14

1.1 Asymmetric phospha-Michael reactions

1.1.1 Asymmetric phospha-Michael reactions through chiral starting materials

and chiral auxiliaries

Asymmetric versions of phospha-Michael reactions mainly deal with controlled diastereoselective additions Yamamoto and co-workers15 developed the first substrate-controlled diastereoselective addition of phosphorus nucleophiles to unsaturated nitroalkenes derived from sugar Albeit only with moderate stereoselectivities under the reaction conditions (heated to 70 oC for 12 h), this work demonstrated a possible way for the preparation of sugar analogues with a phosphorus atom in place of oxygen in the hemiacetal ring (Scheme 1.1)

substrate-MeO O

O2N

O

O Me Me

Me PH

O OMe benzene, 70oC

MeO O

O2N

O

O Me Me

P OMe OMe

P

O Me HO

OR

HO HO OH

P

O Me HO

OR

HO HO OH +

1

2

Scheme 1.1 Yamamoto’s substrate-controlled diastereoselective addition of P

nucleophiles to unsaturated nitrosaccharides

Yamashita and co-workers16 described the diastereoselective addition of various

phosphorus nucleophiles to Z-configured nitroalkene acceptors 5 bearing the sugar

residue in the presence of Et3N at 90 oC (Scheme 1.2) The major product was L-Idose derivatives due to the steric hindrance caused by 3-O-alkyl group of the sugar, as well

as R2and R3 group of the phosphorous compounds The ratio of L-Idose and D-gluco

derivatives increased from 2:1 to 11:1 with different steric size of R1-R3 (11:1 was obtained when R1 = Me, R2= R3 = Ph, X = O) However, when primary phosphine (R1 = Bn, R2= mesityl, R3= H, X = lone pair) was employed, no reaction was observed

+

R2 P H X

P X

D-gluco

L-ido

R1= Me, Ac, Bn;

R2= OMe, OEt, Ph, OBn, Mes;

R3= H, OMe, OEt, Ph, OBn;

X: O or lone pair electrons

(2:1 - 11:1 dr)

Scheme 1.2 Yamashita’s diastereoselective addition of various phosphorus

nucleophiles to Z-configured nitroalkene acceptors 5

O MeO

P

NO2R

O MeO MeO

O AcO

Me Me

Me

M e

O BnO

Me Me

O OMe

Me

M e + (M eO) 2 P(O)H

Scheme 1.3 Yamamoto’s stereoselective addition of dimethyl phosphonate to the

E-configured nitro olefins

Yamamoto and co-workers17 carried out a systematic study on the stereoselective

addition of dimethyl phosphonate to the E-configured nitroalkenes 7a–f (Scheme 1.3)

Two different conditions were employed and it was found that the stereochemical outcome were opposite Condition A (0.3 eq of Et3N) gave predominantly the R stereoisomer, whereas the S stereoisomer was obtained as a major component in the

case of condition B (heated to 100 oC in the absence of base) In most cases (except e,

f), the yields obtained were moderate to good (55 to 94%)

O O Me Me

O P

O O H

Ph Ph

Ph Ph

a,b 98%

O O Me

Me

OH OH

Ph Ph

Ph Ph

10 9

NO 2

R

NO 2

P R

O HO HO

86-91 %

c

O O Me Me

O P

R = Ph, pBiph, 3,4,5-(MeO)3Ph, pMePh, 2-Naphthyl

12, de = 84-96%

11 ee = 81-95%

Scheme 1.4 Enders’s asymmetric phospha-Michael reaction to nitroalkenes

Reagents and conditions: (a) 1.3 eq PCl3/Et3N, THF, 0 oC; (b) H2O/Et3N, THF, 0 oC)

(R,R)-9, TMEDA, Et2Zn, -78 oC; (d) TMSCl, NaI, CH3CN, reflux; (e) DCM/H2O, r.t Enders and co-workers18 reported an asymmetric phospha-Michael reaction to nitroalkenes in the presence of Et2Zn and N,N,N’,N’-tetramethylenediamine

(TMEDA) The phosphorus nucleophile 10 was easily synthesized from TADDOL (9)

and PCl3 in excellent yield (Scheme 1.4) The C2-symmetry of the ligand avoided the formation of a new stereogenic center at phosphorus TMEDA played an essential

role to greatly improve the solubility of the organozinc-phosphorus compounds, which was reactive but insoluble The addition of TMEDA made the reaction possible even at -78 oC with higher de values This reaction was proven to be high yielding (86–91 %) and a high stereoselectivity (84–96 % de) was also achieved Moreover,

diastereomerically pure products could be obtained easily by recystallization or preparative HPLC The adducts could finally be converted into the phosphonic acid without racemization

The same group19 used the phosphonate 10 to carry out the asymmetric addition of acceptor 13 under heterogeneous conditions, Fe2O3 mediated KOH (Scheme 1.5) No reaction was observed when only KOH was used in the absence of metal oxide, which indicated that the presence of the solid support was essential for the activation of the

P-H bond towards deprotonation The phosphonates 16 were obtained in moderate to

good yields and with very good diastereoselectivities The auxiliary was easily

cleaved without detectable epimerization or racemization to give compound 15, by

refluxing the addition products in MeCN in the presence of TMSCl/NaI and

subsequently hydrolyzing the resulting silyl ester Due to their high polarity, 15 were

first converted into their respective methyl esters in order to facilitate their purification Although alkyl-substituted malonates showed even higher reactivity

leading to improved yields (85–87%), unsatisfactory ee values were obtained (15–30

%)

Haynes, Yeung and co-workers20 reported the conjugate addition reaction of

configurationally stable lithiated P-chiral tert-butyl(phenyl)phosphine oxide 17 with

α,β-unsaturated carbonyl compounds (Scheme 1.6) Whereas aldehydes exclusively

underwent 1,2-addition, the cyclic enones 18 and 19 and the unsaturated esters 22a–c yielded the 1,4-addition products 20, 21 and 23a–c, respectively, with moderate to

excellent diastereoselectivities It should be noted that this reaction proceeded with retention of configuration at the phosphorus center

O O H

Ph Ph

Ph Ph

CO2Me P

R

O MeO MeO

R

O HO HO

CO2H

d 72- 86 % (2 steps)

Scheme 1.5 Enders’s asymmetric phospha-Michael reaction under heterogeneous

conditions Reagents and conditions: (a) Fe2O3/KOH, DCM, rt; (b) TMSCl, NaI, MeCN, reflux; (c) DCM/H2O; (d) CH2N2, MeOH/H2O

Helmchen and co-worker21 utilized Ph2PLi for the addition to (–)-(1R)-tert-butyl

myrtenate (24) (Scheme 1.7) The reaction proceeded smoothly and diastereoselectively to give 25, which was further transformed to the phosphine ligand

27 in 4 steps This ligand was then employed in palladium-catalyzed asymmetric

allylic alkylation reactions with the cyclic substrates 28 Good yields of the

substitution products along with good to excellent enantioselectivities were easily achieved in the case of six- and seven-membered rings

P O H

Ph 1 LDA or nBuLi

n18: n = 1 19: n = 2

17

P O

R

OMe O

20 or 21

P O

P O

P O

P O

Scheme 1.6 Haynes’s conjugate addition reaction of P-chiral

tert-butyl(phenyl)phosphine oxides

CO2tBu

CO2H PPh2

CO2tBu PPh2

CO2H PPh2BH3

24

X n

26, overall 54% yield

a

b

c

Scheme 1.7 Helmchen’s stereoselective addition of lithiated phosphines Reagents

and conditions: (a) Ph2PH/BuLi (1.8 euqiv.), THF, -78 oC, 3h, then Na2SO4 10H2O; (b) i BH3.THF, -50 oC; ii CF3CO2H, then NaOH, 90%; iii NaH, THF, 25 oC,

BH3.THF, -78 oC, 1N HCl; (c) DABCO, 1.1 eq., 100 oC, 1h

Feringa and co-workers 22 presented the Michael reaction of

lithio-diphenylphosphine to γ-butenolides (Scheme 1.8) The reaction with

methoxy-2(5H)-furanone (30a) furnished the lactone (31) in high yield and with high

diastereoselectivity in favor of trans-isomer Moreover, using the enantiomerically

pure butenolide synthon (5R)-menthyloxy-2(5H)-furanone 30b, the asymmetric

Michael addition of lithio-diphenylphosphide followed by trapping the intermediate

with chlorodiphenylphosphine to afford lactone 32 as a single diastereoisomer The

enantiomerically pure (S,S)-CHIRAPHOS 33 was obtained from 32 in an overall yield

Scheme 1.8 Feringa’s Michael reaction of lithio-diphenylphosphine to γ-butenolides

Phosphine-boranes can react as nucleophiles like their analogs of the corresponding secondary phosphines which are unstable in air Such phosphorus nucleophiles are usually uncommon, since their synthetic method (prepared by complexation of phosphines and boranes) involved handling of highly corrosive and air-sensitive phosphines

Corre and co-workers23 used an in-situ protocol for the synthesis of

phosphine-boranes 34 from diphenylphosphine oxides (Scheme 1.9) The borane moiety can be

regarded as a protecting group, because it prevents oxidation of the phosphorus atom and its cleavage can be easily achieved in the presence of an excess of a highly

nucleophilic amine 34 was shown to be applicable in NaH-catalyzed Michael reactions to the biselectrophile 35 Although 35 was reacted as a mixture of E/Z isomers, a single diastereomer 36c was obtained from the reaction of Ph2P(BH3)Na

and 35 in THF On the other hand, the utilization of a stoichiometric amount of KOH yielded both diastereoisomers 36a and 36b, which could be separated by

crystallization

P O H Ph

Ph LiAlH4 , NaBH4, CeCl3

65 %

P H Ph Ph

BH3

34

O

O MeO2C

MeO2C

Me Me

34, NaH, THF

-30 to 0oC

O MeO2C

MeO2C

Me Me PPh2

MeO2C

Me Me PPh2

MeO2C

Me Me PPh2

PPh2

BH3

BH3+

Quirion and co-workers24 described a diastereoselective synthetic route to obtain

chiral amidophosphonates The nucleophilic attack of lithiated 34 occured from the Si

face to give the tertiary phosphine-boranes 38 in moderate yields and diastereomeric

excesses (Scheme 1.10)

37d: R= Ph

P Ph Ph

BH3

R

H N O

OH Ph

P Ph Ph

BH3

Me

H N O

OH Ph

38a: 61%, 68% de

P Ph Ph

BH3

Et

H N O

OH Ph

38b: 62%, 74% de

P Ph Ph

BH3

iPr

H N O

OH Ph

38c: 75%, 64% de

P Ph Ph

BH3

Ph

H N O

OH Ph

HO O

N O O

Scheme 1.11 Ebetino’s asymmetric Michael addition of phosphinic and

aminophosphinic acid

An asymmetric Michael addition of phosphinic and aminophosphinic acid have been developed by Ebetino and co-workers25 The phosphinic acids 39a-c were first

treated with TMSCl and transformed into the corresponding bis(trimethylsilyl)

phosphinites 40a–c These compounds were then reacted with the enantiopure acrylimides 41a, b yielding the addition products 42a–f These enol ethers were

assumed to adopt the Z configuration as depicted 43 A diastereoselective protonation

process employing EtOH finally yielded the desired products phosphinic acids 42a–f

in very good yields The diphenylmethyl-substituted oxazolidinone 41b gave much better diastereoselectivities than its benzyl analogue 41a The auxiliary could be

cleaved successfully using LiOH (Scheme 1.11)

1.1.2 Metal-catalyzed asymmetric phospha-Michael reactions

The phospha-Michael addition of secondary phosphines was conducted via

organonickel complex catalyst.26 A range of phosphines 44 were tested Higher steric

hindrance led to a better result (46e, 95% yield, 94% ee), albeit longer reaction time

was required (Scheme 1.12)

44a-e

CN P

Cy

Cy

CN P

Ph

Ph

CN P

iPr

iPr

CN P

tBu

tBu

CN P

Ad Ad

46a: 8h 71%yield 70% ee 46b: 24h 10%yield 32% ee 46c: 24h 70% ee

46d: 8h 87%yield 89% ee 46e:96h, 95%yield 94% ee

46a-e 45

Scheme 1.12 Organonickel complex catalyzed enantioselective phospha-Michael

addition of secondary phosphines

1.1.3 Organocatalyst catalyzed asymmetric phospha-Michael reactions

Recently, Melchiorre and co-workers27 reported an organocatalytic asymmetric

hydrophosphination of nitroalkenes A bifunctional Cinchona alkaloid catalyst 47

provided a new organocatalytic strategy for the enantioselective addition of diphenylphosphine to a wide range of nitroalkenes, yielding optically active β-nitrophosphines Considering the instability of phosphine adducts, a sequential one-

pot formation of the air-stable phosphine-borane complex derivative 49a-e facilitated

the purification process (Scheme 1.13) Due to the background reactions, only

moderate enantioselectivities (highest 67% ee) were observed The synthetic potential

of this method was evaluated, affording the enantiopure aminophosphine 50 (ee of

49a was improved to 99% through a single crystallization), which could be a

potentially useful class of P, N-ligands

N MeO

S HN

α,β-unsaturated aldehydes by the protected diarylprolinol on the same issue of Angew Chem Int Ed independently The former group employed the chiral pyrrolinol

derivative salts 50 as catalyst, affording the 1,4-addition products exclusively along

with up to 94% ee Furthermore, an enantioenriched aminophosphine 54 was

synthesized to demonstrate the synthetic utility (Scheme 1.14A) Comparable results

were achieved by the latter group In this case, the same catalyst 50 with different anion was utilized A β-phosphine oxide acid 55 was obtained from 52 through

oxidation by NaClO2 (Scheme 1.14B)

O R + Ph 2 H

N H

Ar OTMS Ar

52a-d

52a

1 BnNH2/NaBH4toluene

53a: 85% yield, 83% ee 53e: 79% yield,92% ee

Ph O Ph

Wang and co-workers30 developed the enantioselective conjugate addition of

diphenyl phosphonate to various nitroolefins catalyzed by quinine (56) The substrates

included acceptors derived from aromatic, hetero-aromatic and aliphatic aldehydes

To increase the level of ee, the reaction temperature was decreased to -50 oC, and

moderate to good results were observed (45 – 88% ee) However, fairly long reaction

time (6 days) was required (Scheme 1.15)

P

OPh O PhO

56 =

N HO

H

N MeO

57a: 82% yield, 70% ee

P

NO 2

OPh O PhO

57e: 77% yield, 45% ee

P

NO2

OPh O PhO

guanidine 58 In order to obtain good results (85 – 97% ee), the reactions were

conducted under low reaction temperature (-40 oC) More importantly, the low catalyst loading (1 to 5 mmol %) did not affect the reaction rate (0.5 to 7h) and chemical yields (84 to 98%) A broad range of nitroalkenes, bearing not only aromatic but also aliphatic substituents, was applied to obtain enantioenriched products β-