University of Groningen

Enantioselective synthesis of natural products containing tertiary alcohols and contributions toa total synthesis of phorbasin BWu, Zhongtao

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Chapter 1

Methods for the Preparation of Chiral Tertiary Alcohols and

Ethers This chapter gives an introduction on the prominent asymmetric synthesis of tertiary alcohols and ethers and the applications of asymmetric dihydroxylation and epoxidation of olefins in natural product synthesis. The new developments in this field are also summarized.

Chapter 1

1.1 Introduction Quaternary stereocenters, that means, carbon stereocenters without a

carbon-hydrogen bond, are a widely encountered structural motif in natural compounds and pharmaceuticals. [1] Among these quaternary stereocenters, the preparation of chiral enantiopure tertiary alcohols and ethers represents an important, but also a very challenging field. To access these compounds, their asymmetric synthesis is of particular importance, due to the fact that racemic mixtures of tertiary alcohols are difficult to resolve.

Applicable on both small and large scale, the kinetic resolution of a racemic mixture is one of the most common approaches for the production of enantiomerically pure compounds.[2] Many (bio)catalysts have been developed for the kinetic resolution of secondary alcohols via esterification, or hydrolysis of the preformed ester.[3] The (enzymatic) kinetic resolution of tertiary alcohols has turned out to be way more difficult, however, and suffers from low enzyme activities and selectivities.[4] In addition, dynamic kinetic resolution involving in situ racemization of the unwanted enantiomer is not readily achieved in the case of tertiary alcohols.[5] The synthesis of enantiopure secondary alcohols is nowadays also readily accomplished by asymmetric hydrogenation of ketones with transition metals and alcohol dehydrogenases,[6] however, these strategies obviously do not apply for tertiary alcohols.

An additional complication is that chiral tertiary alcohols, and in particular benzylic and allylic tertiary alcohols, are prone to acid-catalyzed racemization via an SN1 pathway and elimination via an E1 pathway. All together this makes the development of new approaches for the synthesis of chiral enantiopure tertiary alcohols and ethers an important challenge.

HOR1

R2 O

1 Tocopherols (R1 = H or Me; R2 = H or Me)

OOH

OH

2 Pheromone of the Colorado potato beetle

O

HHO

OHO

OH

HH

3 Cortisol

R

OHO

4 (−)-Acylfulvene, R = H5 (−)-Irofulven, R = CH2OH

O

O

OOCH3

OH

H

6 (−)-Ovalicin

Figure 1. Natural compounds containing tertiary alcohols and ethers

2

Introduction

Over the past decade, progress has been made in the (asymmetric) synthesis of enantiopure tertiary alcohols not only via established approaches, e.g. the aldol reaction[7] and asymmetric hydroxylation,[8] but also applying new strategies. In 2008, the group of Aggarwal reported a novel method to prepare chiral tertiary alcohols with very high enantiospecificity from enantiopure secondary alcohols via an enantiodivergent conversion[9] (Scheme 1). Depending on the use of either a borane or a boronic ester, both enantiomers of a series of benzylic tertiary alcohols were obtained from one enantiomer of the secondary alcohol. Knochel et al., in 2005, presented a highly enantiospecific preparation of tertiary alcohols by copper-mediated allylic SN2 substitution.[10] Starting from enantiopure allylic pentafluoro benzoates, like 15, allylic substitution was followed by oxidation and Baeyer-Villiger rearrangement. This sequence afforded tertiary alcohol 17 with an ee of 92-99% (Scheme 2). Although from a retrosynthetic point of view not always elegant, the “good old” Baeyer-Villiger rearrangement, being strictly stereospecific, is somewhat underestimated.

Apart from these enantiospecific processes, the focus in research has mostly been on catalytic enantioselective processes, the most prominent ones being discussed below.

H

OCONiPr2Me

Ar

sBuLiEt2O

−78 oC20 min

Li

OCbMeAr

RB(OR')2Retention

InversionRB(R')2

B(OB')2

OCbMeAr

R∆

R

B(OR')2Me

Ar

H2O2NaOH

ArR OH

B(R')2

OCbArMe

R R

B(R')2ArMe

ArR OH∆

H2O2NaOH

7 8

9 10 11

12 13 14Cb = N,N-diisopropylcarbamoyl

Scheme 1. Lithiation-borylation of chiral secondary carbamates leading to tertiary alcohols

Me

Ph OCOC6F5Et2Zn

CuCN•2LiClTHF Me

Et Ph

16 (69%, 99% ee)

1) oxidation

2) Baeyer-Villiger rearrangement

17 (70%, 99% ee)

OH

EtPh

15OBn

BnO OBn

Scheme 2. Enantiospecific preparation of tertiary alcohol 17 by copper-mediated allylic SN2 substitution

3

Chapter 1

1.2 Asymmetric dihydroxylation Generally, the dihydroxylation of olefins is achieved by oxidation with a transition

metal oxo-species. An important landmark in this field is the asymmetric dihydroxylation with OsO4/dihydroquinine acetate by Sharpless in 1980. In this initial system, stoichiometric amounts of ligand and OsO4 were required,[11] which made this reaction somewhat unattractive due to the high cost and the toxicity of OsO4. Subsequently, however, this stoichiometric procedure was transformed into a highly effective catalytic process due to the application of N-methyl morpholine N-oxide as the co-oxidant.[12] Inorganic co-oxidants were investigated as well[13] for the re-oxidation of Os(VI) glycolate in the reaction, and inexpensive K3Fe(CN)6 (potassium ferricyanide) turned out to be versatile.[14] According to the supposed mechanism, two competitive catalytic cycles exist in the Sharpless asymmetric dihydroxylation, the primary cycle (desired) affording high ee, and the secondary cycle (undesired) affording low ee (Scheme 3). The use of a two-phase system suppressed the secondary catalytic cycle,[15] and since then K3Fe(CN)6 together with the second generation ligands (DHQD)2PHAL and (DHQ)2PHAL, and K2OsO2(OH)4

are combined into the known commercial available “AD-mix-α or AD-mix-β”.[16] The absolute configuration of the diol products can be predicted using an empirical model (Scheme 4). In this mnemonic device, the olefin is oriented following the size constrains (RL = Large substituent, RM = Medium-sized substituent, and RS = Small substituent), and then this olefin is dihydroxylated from the top or the bottom face using AD-mix-β or AD-mix-α, respectively.[17]

OsO

O O

O

L

R1

R4

OOOs

LO

O

OsO

O OO

Ohigh ee

H2O

OHHO

Primary cylce

R2

R3

OHHO

H2O

L

Secondary cycleOs

O

O

OO

O

R1

R2R3

R4

oxidant

L

R1

R2R3

R4

R1 R3R2 R4

osmium(VI)glycolate

R1

R4R2

R3

R1

R2R3

R4

R1

R2

R3

R4

R2R1 R3

R4

low ee Scheme 3. Catalytic cycles in the Sharpless catalytic asymmetric dihydroxylation

4

Introduction

H

RMRS

RL

"HO OH"

"HO OH"

AD-mix-β

AD-mix-α

HORS

RL HRM

OH

RL

RSH

RM

HO OH

organic solvent/H2O

NNO O

N

MeO

N

OMeH H

N N

Et

(DHQ)2PHAL

NNO O

N

MeO

N

OMeH H

NN

(DHQD)2PHAL

Et

AD-mix-α: (DHQ)2PHAL + K2OsO2(OH)4 + K3Fe(CN)6 AD-mix-β: (DHQD)2PHAL + K2OsO2(OH)4 + K3Fe(CN)6

Et

Et

Scheme 4. Sharpless asymmetric dihydroxylation and the prediction of the

stereochemistry

Regarding the synthesis of chiral tertiary alcohols, the use of 1,1-disubstituted, trisubstituted and tetrasubstituted olefins are appropriate substrates[13] in the Sharpless asymmetric dihydroxylation, and give good yields and selectivities[16a, 18] (Table 1) . An important discovery was that the addition of CH3SO2NH2 accelerated the reaction dramatically,[16a] which is crucial for the application of this reaction for a number of steric hindered and in particular tetrasubstituted olefins,[19] and even α,β-unsaturated ketones.[20]

AD-mix-β AD-mix-α

ee ee

99 (R, R) 97 (S, S)

94 (R) 93 (S)

OMe95 (R) 96 (S)

OMe

99 (R) 98 (S)

OTBS

MeO99 (R) 97 (S)

AD-mix-β AD-mix-αee eeolefins olefins

Me

83 (R, R) 85 (S, S)

OTBS

93 (R) 95 (S)

O

98 (1S, 2R)

Table 1. Catalytic asymmetric dihydroxylation of olefins according to Sharpless

Since the first asymmetric dihydroxylation has been reported, the reaction has been

studied extensively not only with OsO4,[21] but also with osmium-free methodologies,[22] e.g. permanganate[23] and ruthenium oxide.[24] Different kinds of substrates, for example, divinyl ketones, symmetrical conjugated dienes,[25] dienes

5

Chapter 1

with isolated double bonds,[26] and 1,1-disubstituted allylic alcohols and derivatives have been explored as well.[27]

The construction of tertiary alcohols using dihydroxylation of alkenes is a very important approach in natural products synthesis.[28] Takano et al. reported the synthesis of (+)-verrucosidin 21 in 1988[29] (Scheme 5). In their work, allylic ether 18 was stereoselectively dihydroxylated into diol 19 by OsO4/NMO, and this tertiary alcohol subsequently afforded tetrahydrofuran 20 also containing a chiral tertiary alcohol. Paterson et al. accomplished the stereocontrolled introduction of the chiral tertiary hydroxyl groups at C6, C11 and C12 of (+)-(9S)-dihydro-erythronolide A 25 by osmylation[30] (Scheme 6). The dihydroxylation of silyl enol ether 22 gave a single α-hydroxy ketone 23 by using catalytic OsO4, NMO and quinuclidine. The C11-C12 double bond was not affected even after a longer reaction time. In subsequent work, the authors reduced the C5 ketone followed by TBS deprotection to give tetraol 24. Finally, selective dihydroxylation of the double bond of 24 could be achieved with excess OsO4 in moderate yield.

O

OBnOsO4 (5 mol%)

NMOacetone/H2O, 0 oC

O

OBn

OHOH

O

HO OH

OAc18 19 (dr>15:1) 20

O

O

OH O

O

OMe

(+)-verrucosidin 21 Scheme 5. Synthesis of (+)-verrucosidin 21

In 2000, Armstrong et al. accomplished the synthesis of (+)-zaragozic acid C 28

with four contiguous stereocenters, of which C3 to C6 were constructed by a double Sharpless asymmetric dihydroxylation reaction of diene 26. This double dihydroxylation could not be achieved in one-pot, but took two steps. The first dihydroxylation was performed with Super AD-Mix (commercial AD-Mix supplemented with extra ligand (5 mol%) and OsO4 (1 mol%)) while in the second step the resulting mixture of regioisomeric triols was subjected to 1 mol% of OsO4, 5 mol% of (DHQD)2-PHAL and 2 eq of NMO to afford the desired pentaol 27[31] (Scheme 7).

6

Introduction

O

O

OTBS

OTBS

OSiMe3 O

O

OTBS

OTBS

O

OsO4, NMOquinuclidineacetone/H2O20 oC, 1 h

22 23 (85%)

OHi. Zn(BH4)2

Et2O20 oC, 0.5 h

ii. 40% HF (aq)CH3CN

20 oC, 2 h

OsO4THF

20 oC, 5 d

O

O

OH

OH

OH

24 (66%)

OH

O

O

OH

OH

OH

OHOH

HO

(+)-(9S)-dihydroerythronolide A 25 (42%) Scheme 6. Synthesis of (+)-(9S)-dihydroerythronolide A 25

OBn

OBn

OH

BnO BnO

OH

OBn

OBn

OH

OH

OHOH

i. AD-mix-β, OsO4 (1 mol%)(DHQD)2PHAL (5 mol%)

CH3SO2NH2 (2 eq), K2S2O8

tBuOH/H2O0 oC to r.t., 4 d

ii. OsO4 (1 mol% ), NMO (2 eq) (DHQD)2PHAL (5 mol%)

acetone/H2O

27 (45%, ee 76%)

r.t. 3.5 d

Ph O

O

OO

HO2C

OH

HO2CCO2H

Ph

OAcOH

(+)-zaragozic acid C 28

26

Scheme 7. Synthesis of (+)-zaragozic acid C 28 1.3 Asymmetric epoxidation

The asymmetric epoxidation of olefins is another powerful method to synthesize chiral tertiary alcohols (which need a subsequent stereo-controlled ring-opening process) and ethers. Vanadium[32] and chiral molybdenum[33] catalysts were investigated for asymmetric epoxidation of allylic alcohols in as early as 1970, but the first practical method for asymmetric epoxidation was developed by Sharpless and Katsuki in 1980.[34] The prochiral or chiral allylic alcohols afforded epoxides with high yields and excellent ee by Ti(IV) alkoxide-catalyzed epoxidation with tert-butyl hydroperoxide. Initially, this epoxidation employed a stoichiometric amount of titanium (IV) tetraisopropoxide as well as enantiopure diethyl tartrate (DET). Later, Sharpless’ group developed this methodology into a catalytic asymmetric epoxidation, using 5-10% catalyst.[35] The substrates for the Sharpless asymmetric epoxidation are restricted to allylic alcohols due to the essential coordination of titanium to this hydroxyl group in the reaction.[36] With an empirical model, the enantioselectivity of the Sharpless asymmetric epoxidation can be predicted for prochiral allylic alcohols (Scheme 8). By using (+)- or (-)-tartrate, the system affords reagent controlled epoxidation of the allylic alcohols with good enantioselectivity regardless of the

7

Chapter 1

substitution pattern[34] of the substrate and, an important bonus, high chemoselectivity in the presence of other olefins.

R1 R2

R3 OH

(−)-tartrate

(+)-tartrate

Ti(iPrO)4, tBuOOHCH2Cl2, −20 oC

R3

OH

R2R1

O

R3

OH

R2R1

O

Scheme 8. Sharpless asymmetric epoxidation

In 1990, Jacobsen and Katsuki reported the enantioselective epoxidation of

unfunctionalized olefins using (salen)manganese complexes,[37] while more recently unfunctionalized cis-olefins also were used successfully in regioselective and enantioselective epoxidation catalyzed by metalloporphyrins.[38] In 1996, the Shi epoxidation of trans-olefins was disclosed[39] (Scheme 9). Using a fructose-derived ketone as catalyst and oxone as oxidant, trans and trisubstituted olefins could be epoxidized very effectively with high enantioselectivities orthogonal to a variety of functional groups. The pH of the Shi asymmetric epoxidation should be controlled carefully as Baeyer-Villiger reaction decomposes the catalyst at a lower pH and a higher pH the oxone is destroyed.

R2

R1 R3

R2

R1 R3

O

Shi's catalyst

H2O/CH3CNpH 7~10

Oxone, NaHCO3

O OO

OO

O

Shi's catalyst Scheme 9. The Shi asymmetric epoxidation

Yamamoto developed in 1999 a new chiral vanadium-based catalyst for the

asymmetric epoxidation of allylic alcohols with ligand 29 (figure 2), this catalyst gave much higher selectivity than the previous chiral vanadium complexes.[40] More recently, this catalyst system was improved by redesigning the hydroxamic acid-bearing binaphthyl group into a novel α-amino acid-based hydroxamic acid ligand.[41] With ligand 30, the asymmetric epoxidation of allylic alcohols could be carried out at a convenient temperature (0 oC) and a low catalyst loading (1% vanadium). Subsequently, a new C2-symmetric bishydroxamic acid 31 was designed by the same group.[42] This bidentate ligand solved several practical problems, e.g.

8

Introduction

brought success in the asymmetric epoxidation of cis-substituted allylic alcohols, allowed a lower catalyst loading and a high tolerance to air and moisture. In contrast to the ligand-deceleration observed in other vanadium/ligand catalysts,[43] a ligand-accelerated vanadium-catalysed epoxidation of allylic alcohols was reported in the same year by Malkov.[44] Epoxide hydrolysis was successfully suppressed by choosing suitable ligands (Figure 3) and lowering the reaction temperature to – 20 oC in a mixture of water and methanol.

OMe

N

O

HO

29

N

O

O

O

NOH

30

N

N

OHOH

O R

RO

R = CHPh2, CH2CPh3, CH(3,5-dimethylphenyl)2, etc.

31

Figure 2. Ligands for vanadium-based epoxidation catalysts according to Yamamoto

NH

O NOH

Ph Ph

S OONH

O NOH

Ph Ph

S OON

O NOH

Ph Ph

O

O

32 33 34 Figure 3. Ligands for vanadium-catalysed epoxidation according to Malkov

Building on the vanadium catalyzed asymmetric epoxidation of allylic alcohols

with ligand 30, the Yamamoto group also achieved the asymmetric epoxidation of homoallylic alcohols in moderate to good enantioselectivities using ligand 35.[45] To show the utility of this method, it was applied to the total synthesis of (-)-α- and (-)-8-epi-α-bisabolol (38 and 39) starting from (S)-limonene. In this synthesis, homoallylic alcohol 36 was epoxidized to give 37 in 84% yield and 90% de (whereas (8R)-37 was obtained in 82% yield and 94% de using L-35). This key epoxide afforded the chiral tertiary alcohol structure in the target compound (-)-α-bisabolol 38 in a number of steps (Scheme 10).

9

Chapter 1

N

O

O

O

NOH

Ph

Ph

35

OH OHO2 mol% VO(OiPr)3

6 mol% D-35cumene hydroperoxide (1.5 eq)

toluene, 0 oC84%, 90% de

HO

(−)-(4S, 8S)-α-bisabolol 38

HO

(−)-(4S, 8R)-epi-α-bisabolol 39

36 37

using ligand L-35 Scheme 10. Concise and stereoselective synthesis of (-)-α- and (-)-8-epi-α-bisabolol

(38 and 39)

In recent years, additional progress has been achieved in the asymmetric epoxidation of allylic alcohols and homoallylic alcohols[46] with catalysts based on vanadium as well as other metals, for example, with zirconium(IV), hafnium(IV)[47] and iron.[48] This has been extended to bishomoallylic alcohols and β,β-disubstituted enones. Several reviews have been published on this topic.[49] Tandem reactions for the enantio- and diastereoselective one-pot generation of functionalized epoxy alcohols using titanium-based catalysts have also been summarized.[50] Chiral enantiopure epoxides are, as noted before, important starting materials for the construction of tertiary alcohols. McDonald prepared oxepanes containing a chiral tertiary alcohol by endo,endo-oxacyclizations of 1,5-diepoxides.[51] The key step in the total synthesis of (+)-madindoline A 41 and (-)-madindoline B 42, two chiral tertiary alcohols synthesized by Omura and Smith, was achieved by Sharpless asymmetric epoxidation.[52] In their work, the epoxidation of the indole double bond furnished the hydroxyfuroindole ring directly (Scheme 11). In 2002, Curran reported the first asymmetric total synthesis of (20R)-homocamptothecin 46 based on Stille coupling and Sharpless asymmetric epoxidation as key steps.[53] The chiral tertiary alcohol part of 45 resulted from the reductive ring-opening of epoxide 44 (Scheme 12). In 2005, Morimoto reported the total synthesis of (+)-aurilol 51, a cytotoxic bromotriterpene polyether.[54] In this synthesis, the chiral tertiary alcohols were derived from their corresponding epoxides, prepared in turn by either Sharpless epoxidation or Shi epoxidation. (Scheme 13)

10

Introduction

N

OH

OO

(+)-DETTi(OiPr)4tBuOOH

45%

N

OO

O

HO

H N

OO

O

HO

H

40 (+)-madindoline A 41 (−)-madindoline B 42

+

Scheme 11. A key step in the synthesis of (+)-madindoline A 41 and (-)-madindoline

B 42

N OMeTMS

CH2OH

OMOMO

N OMeTMS

CH2OH

OMOM

Ti(OiPr)4, tBuOOHL-(+)-DET

79%, 93% ee

N OMeTMS

CH2OH

OMOMOH

LAH

NN

O

OEtHO

O

(20R)-homocamptothecin 46

100%

43 44 45

Scheme 12. Key steps in the synthesis of (20R)-homocamptothecin 46

SEMO

OH

O

O1M NaOH

1,4-dioxanereflux, 5 h

O

SEMO OH

HO HH OH O

SEMO

HO HH OH

OO

O

CSACH2Cl2

r.t., 10 min O

SEMO

HO HHO

OO

H OHO

O

O OOH

Br

H OH

OH

H H

H

47 48 49

50 (+)-aurilol 51 Scheme 13. Key steps in the synthesis of (+)-aurilol 51

1.4 Asymmetric 1,2-Addition of organometallics to ketones

One of the most straightforward ways to prepare chiral enantio-enriched tertiary alcohols is, at least in principle, the asymmetric addition of carbon nucleophiles to ketones. This elementary transformation, and in particular the addition of organometallics, has been studied over a long period.[55] Many kinds of organometallics, e.g. organoboron, organolithium, organosilicon, organoaluminium, diorganozinc[56] and organomagnesium (Grignard) reagents have been used for this purpose.[57]

11

Chapter 1

Ketones, being less reactive than aldehydes, usually require reactive organometallics to afford chiral tertiary alcohols via asymmetric addition. However, the use of Grignard and organolithium reagents causes side reactions like enolization and Meerwein-Ponndorf-Verley-type reduction of the substrate. A way to circumvent these problems is the use of less reactive organozinc reagents with activation of either the carbonyl group or the organozinc reagent, or even both. In 1998, Yus described the first enantioselective addition of Et2Zn and Me2Zn to ketones.[58] With camphor-derived hydroxysulfonamide 52, this system, in the presence of an excess of Ti(OiPr)4, gave a good performance in the 1,2-addition of Et2Zn and Me2Zn to in particular aryl alkyl ketones (Table 2). A practical limitation of this reaction is the long reaction time (4-14 days). Subsequently, different kinds of hydroxysulfonamide ligands were designed for the addition of diethylzinc to ketones (Figure 4). The development of bis(hydroxysulfonamide) 54 assisted the asymmetric addition of Et2Zn and Me2Zn to ketones affording tertiary alcohols with improved yields and excellent ee.[59] The reaction requires as low as 2% catalyst loading and also a much shorter reaction time (in most cases < 2 d). In 2008, Ramón and Yus synthesized the Fréchet dendrimer-based isoborneolsulfonamide ligand 55 for the continuous-flow synthesis of chiral tertiary alcohols.[60] The catalyst derived from 55 promoted the 1,2-addition of Et2Zn, Me2Zn and in situ generated phenylzinc to simple aryl alkyl ketones giving the products with ee’s up to 99%. A different type of ligand, chiral bifunctional phosphoramide 56, was developed by Ishihara in 2007 (Figure 5).[61] The chiral phosphoramide-Zn(II) complex 57 (1-10 mol%) catalyzed the addition of Ph2Zn and Et2Zn to ketones very efficiently with high enantioselectivities (ee up to 98%).

OHO2S

R1 R2

O+ R3

2Zn Ti(OiPr)4/CaH2/4 oC

52

52 (20%)/toluene R1 R2

R3 OH

R3 = Et, Me

Et

OHMe

nBuOHMe

nBuOHEt

89%, 89% ee 95%, 83% ee 78%, 86% ee

MeOHEt

Br

Et OH

83%, 81% ee

25%, 89% ee

MeOHEt

36%, 51% ee

MeOHEt

SOHEt

72%, 31% ee 42%, 43% ee

NH

Table 2. Asymmetric addition of Et2Zn and Me2Zn to ketones with

hydroxysulfonamide 52

12

Introduction

NHNH

SO2MeHO

SO2 Me

OH

NHNH

SO2

HO

SO2

OH

53 54

NHNH

SO2

SO2

OH

S

O

O

O

O

Ph

Ph

O

OPh

Ph

n

n

55 (n = 0, 1)

Figure 4. Hydroxysulfonamide ligands for the addition of Et2Zn to ketones

NHN P(1-Np)2

iPr

O

56

N N P(1-Np)2

iPr

O

57

ZnEtO

ZnEt

Et

Figure 5. A combined Lewis acid (Zn (II)) -Lewis base (phosphoramide) catalyst 57

In addition to the extensive studies on the Et2Zn, Me2Zn and Ph2Zn[62] addition to

ketones, the ethylation and methylation of α-ketoesters and the alkynylation of ketones using organozinc reagents were also investigated.[56]

Due to the advantages of Grignard reagents, being inexpensive, readily available and highly reactive, it has always been one of the most popular choices for carbon-carbon formation. The research on the asymmetric addition of organomagnesium reagents to ketones started in 1953,[63] but initially gave no useful results,[64] until Seebach’s first successful asymmetric addition of Grignard reagents to ketones (Table 3).[65] The TADDOL-derived reagents 59 were prepared by deprotonation of TADDOL with 2 equivalent of a primary alkyl Grignard reagent, and subsequently 1 additional equivalent of Grignard reagent was added to the resulted solution. The chiral tertiary alcohols were formed with the highest selectivity at -100 oC. In this system, steric hindrance either from the Grignard reagent or from the ketone decreased the rate of the reaction drastically. Given the reactivity of Grignard reagents, the control of this addition has always been difficult.

13

Chapter 1

O

OAr Ar

Ar Ar

OHOH

O

OAr Ar

Ar Ar

OO

Mg + RMgX +MgX23 eq RMgX R1 R2

O

THF−100 oC, 9-14h

OH

RR1R2

Ar = Ph, 2-naphthyl R = primary alkyl groups

OH

60%, >98% eeBr

Et

OH

60%, 98% eeMeO

Et

OH

76%, 92% ee

Et OH

28%, 89% ee

Et

OH

75%, 98% ee

SEt

OH

43%, 96% ee

N

Et

OH

51%, 96% ee

NEt

OH

96%, >99% ee

Et

OH

64%, 83% ee

OEt

OH

53%, 66% ee

S Et

OH

24%, 90% ee

Et

OH

55%, 71% ee

5958

Table 3. Enantioselective addition of primary alkyl Grignard reagents to ketones

The state of the art in the preparation of chiral enantio-enriched tertiary alcohols by

catalyzed enantioselective addition of carbon nucleophiles to ketones has been summarized in two contributions to Chemical Reviews, in 2008[7a] and 2011.[66] this revealed that the catalytic asymmetric 1,2-addition of Grignard and organolithium reagents to ketones was lacking.

In 2012, Harutyunyan and Minnaard reported the first copper catalyzed enantioselective 1,2-addition of alkyl Grignard reagents to α-methyl-α,β-unsaturated ketones.[67] The reaction was carried out with 5 mol% CuBr⋅SMe2 and 6 mol% of the ligand rev-Josiphos in tBuOMe at –78 oC (Table 4). This catalyst system does not require the use of stoichiometric amounts of additives though needs β-branched Grignard reagents to obtain tertiary alcohols with excellent enantioselectivities. A complete shift of the, normally overwhelming, selectivity of Cu(I)-organometallics for conjugate addition to 1,2-addition took place using this catalyst/substrate combination. Later, this method was also applied in the catalytic asymmetric addition of Grignard reagents to aryl alkyl ketones[68] and α-bromo-α,β-unsaturated ketones (Scheme 14).[69] The corresponding tertiary alcohols were obtained in good yields and enantioselectivities of up to 98%. This system provides a convenient, though not unrestricted, route to enantio-enriched allylic and benzylic tertiary alcohols which are important classes of building blocks for organic synthesis.[70]

14

Introduction

61 6 mol% FeCy2P

Ph2P

61

Ph R1

Me

O

Ph R1

Me

HO R2R2MgBr

tBuOMe, −78 oC

CuBr.SMe2 5 mol%

PhMe

HO 3

95%, ee 66%

Ph PhMe

HOPh

83%, ee 62%

Ph PhMe

HO

94%, ee 84%

Ph PhMe

HO

87%, ee 76%

PhMe

HO

96%, ee 84%

PhMe

HO

95%, ee 92%

Et

Et

PhMe

HO Cy

95%, ee 88%

Ph iBuMe

HO

92%, ee 96%

Et

Et

60 62

Table 4. Cu(I) catalyzed 1,2-addition of Grignard reagents to α-methyl enones

X

R1

O R2MgBr

61 6 mol%tBuOMe, −78 oC

CuBr.SMe2 5 mol%

X

R1

HO R2

X = Me, CF3, Br, Cl, FR1 = Me, Et

R2 = branched alkyl groups

R1

Br

O

R1

Br

HO R2R2MgBr

61 6 mol%tBuOMe, −78 oC

CuBr.SMe2 5 mol%

R2 = branched alkyl groupsR1 = Ph, pBrC6H4, pCF3C6H4, Cy

63 64

65 66

Scheme 14. Cu(I) catalyzed 1,2-addition of Grignard reagents to aryl alkyl ketones

and α-bromo-enones.

A large asymmetric amplification in the catalytic enantioselective 1,2-addition of Grignard reagents to enones was observed during recent studies.[71] This amplification originates from the solubility differences between the enantiopure and the racemic complexes of a transition metal with diphosphine ligands. To understand this amplification phenomenon, structural characterization of the copper complexes of both racemic and enantiopure ferrocenyl diphosphine ligands was carried out.[72]

To investigate the influence of the electronic and steric properties of the ligand in this 1,2-addition, five new chiral ferrocenyl diphosphine ligands of the Josiphos family were synthesized (Figure 6).[73] Some improvement was obtained in the regio- and enantioselectivity of the addition to α-H-substituted enones using the ligand 70, containing tert-butyl substituents in the diarylphosphine moiety. The clear message from this study is that the precise structure of the ligand is very critical, with rev-Josiphos (close to) optimal.

15

Chapter 1

68

Cy2P

(o-tolyl)2P

FeCy2P

(3,5-(CF3)2C6H3)2P

FeCy2P

(p-methoxyphenyl)2P

Fe

70

Cy2P

(3,5-tBu2-4-methoxy-C6H3)2P

Fe Cy2P

Ph2PiBu

Fe

6967

71 Figure 6. Ligand variation based on rev-Josiphos.

Important new developments in this connection were reported very recently and

involve the catalytic asymmetric alkylation of acylsilanes[74] and aryl heteroaryl ketones.[75] The alkylation of acylsilanes 72 gives access to aryl- and vinyl-substituted α-hydroxysilanes 73 with quaternary stereocenters in high yields and enantioselectivities (Scheme 15). In this system, β-branched Grignard reagents are not a requirement for high enantioselectivity, the chiral catalyst could be recovered and re-used without loss in activity, and a mixture of two Lewis acids led to the best results.

R1 SiPh2Me

O

R1 SiPh2MeHO R2

R2MgBr

61 6mol%

tBuOMe, −78oC

CuBr.SMe2 5mol%

R1 = Aryl- or vinyl- subtituents

CeCl3 (1 eq), BF3.Et2O (1 eq)

72 73

Scheme 15. Catalytic asymmetric alkylation of acylsilanes 72

1.5 Recent developments The method reported by Aggarwal et al. in 2008 for the preparation of enantiopure tertiary alcohols from enantiopure secondary alcohols was a new development in this field (Scheme 1).[9] Initially, the reaction worked well only for simple substrates not containing sterically hindered carbamates, boronic esters or aryl groups with electron withdrawing substituents. It was found that erosion of the ee resulted from reversibility of the second step, leading back to the starting lithiated carbamate which is prone to racemization upon warming. The remedy to suppress this dissociation-racemization was the use of either MgBr2/MeOH or less sterically hindered neopentyl boronic esters instead of pinacol boronic esters.[76] In 2013, this lithiation-borylation methodology also afforded access to several α-heterocyclic tertiary alcohols in good to excellent yields and excellent enantioselectivity.[77] Starting with the enantioselective synthesis of boron-substituted quaternary carbons as well, a different approach was reported in 2010 by Hoveyda for the synthesis of 16

Introduction

chiral tertiary alcohols.[78] This was achieved via NHC-Cu-catalyzed enantioselective conjugate boronate additions to trisubstituted alkenes in acyclic α,β-unsaturated carboxylic esters, ketones, and alkyl thioesters. The resulting boron-substituted quaternary stereocenters were oxidized to the corresponding tertiary alcohols 76 (Scheme 16). Meanwhile, the enantioselective synthesis of allylboronates bearing a quaternary boron-substituted stereocenter, as precursors for tertiary allylic alcohols, succeeded.[79] A different NHC-catalyzed intramolecular crossed benzoin reaction was developed by Ema and Sakai in 2009.[80] In their work, bicyclic tertiary alcohols 78 with two consecutive quaternary stereocenters were synthesized with high stereoselectivity (Scheme 17).

G R

O R1chiral Cu-NHC complex

B2(pin)2oxidation

R = alkyl or arylG = alkoxy, alkyl or alkylthio

G R

O R1 B(pin)

G R

O R1 OH

74 75 76

Scheme 16. Hoveyda’s strategy to chiral tertiary alcohols 76

mn

O

O

CHO

n = 1 or 2 or 3m = 1 or 2

O

OOH

n m

up to > 99% ee (> 99% de)

NHC cat.base

solvent77 78

Scheme 17. Intramolecular crossed benzoin reaction catalyzed by an NHC

organocatalyst With a chiral sulfoxide as an auxiliary, Ready et al. showed the asymmetric addition of simple alkynyl, aryl and vinyl organometallics to aryl ketones.[81] Tertiary alcohols are generated in diastereomerically pure form, and enantiopure after removal of the tolyl sulfoxide via reductive lithiation (Scheme 18).

O

CH3

S

(p-Tol)

O −78 oC, THF, 3 h

H3C OH

PhS

H3C OH

79 80 (95%, dr ~ 50:1) 81 (97%, ee 96%)

Ph Li/CeCl3Ph

nBuLi−78 oC, THF, 0.5 hO

(p-Tol)

Scheme 18. Asymmetric synthesis of tertiary benzylic alcohols using chiral sulfoxide An important direction in the construction of enantiopure tertiary alcohols is the

17

Chapter 1

preparation of tertiary homoallyl alcohols. This could be realized by the asymmetric allylation of ketones via different approaches, e.g. Nozaki-Hiyama-Kishi reactions, allylborations, indium-mediated allylations, titanocene-catalyzed Barbier-type allylations and auxiliary-mediated or catalytic allylsilane transfer.[7a, 82] In 2005, Soderquist designed 10-Ph-9-BBD reagent 82 (Figure 7), B-allyl-10-Ph-9-borabicyclo[3.3.2]decanes, for the asymmetric allylboration of ketones to prepare chiral homoallylic tertiary alcohols.[83] This new BBD reagent showed high selectivity for a wide range of prochiral ketones. In their subsequent research, B-allenyl- and B-(γ-trimethylsilylpropargyl)-10-Ph-9-BBDs (83 and 84) were designed for the asymmetric synthesis of propargyl and α-allenyl tertiary alcohols from ketones.[84] And the design of borabicyclodecane (BBD)-derived 1,3-diborylpropenes 85 in 2009 led to selective asymmetric allylboration, first of ketones and subsequently of aldehydes.[85] Recently, they also achieved access to highly functionalized tert-carbinols via asymmetric γ-alkoxyallylboration of ketones with 86. Loh, in 2009, developed a highly enantioselective indium(III)-pybox catalyzed ketone-ene reaction (Scheme 19).[86] This asymmetric keton-ene reaction of methyl trifluoropyruvate 87 with various olefins gave enantioenriched homoallylic alcohols 90 with ee’s up to 98%. In Laschat’s work, the Evans aldol reaction was employed for the preparation of the required chiral tertiary homoallylic alcohols.[82]

(−)-82R

B

PhTMS

(−)-84R

B•

Ph

(+)-83S

B BTMS

Ph

trans-85SS

B

Ph

(±)-86

B

PhOMe

Figure 7. BBD reagents developed by Soderquist.

Enantioenriched tertiary allylic alcohols containing a tetrahydrofuran or tetrahydropyrrole are important structural units in natural compounds. A rhodium-catalyzed asymmetric tandem cyclization developed by Xu in 2014 afforded a new access to this kind of heterocyclic tertiary allylic alcohols.[87] The reaction was carried out with nitrogen- or oxygen-bridged 5-alkynones and arylboronic acids in the presence of [Rh(COE)2Cl]2 as the metal precursor and a commercially available chiral BINAP ligand. The corresponding chiral tertiary alcohols were obtained with ee’s up 18

Introduction

to 99%.

OMeF3C

O

OR2

R1+

InCl3 (10 mol%)AgSbF6 (20 mol%)

87 88

(+)-894Å MS, r.t.

ClCH2CH2Cl

R1 OMeR2

O

F3C OH

90

yield up to 99%,ee up to 98%

NO

N N

OH

H H

H

(+)-89

Scheme 19. In(III)-pybox catalyzed asymmetric ketone-ene reactions of methyl

trifluoropyruvate 87 with olefins

With an improved RhI/BINAP-catalyzed 1,2-addition of organoaluminum reagents to cyclic enones, Zezschwitz et al. in 2013 synthesized 5-7 membered cyclic tertiary allylic alcohols with excellent enantioselectivity and in high yield using only 1 mol% catalyst [88] compared to 5 mol% in the previously reported system.[89]

In 2007, Cheng published a cobalt-catalyzed diastereoselective reductive [3 + 2] cycloaddition of allenes and enones.[90] In this reductive coupling, enones act as the three-carbon nucleophile adding exclusively to the internal double bond of allenes to form cyclopentanols with high diastereoselectivity in the presence of zinc as reducing agent and water as proton source. And in 2012, the authors reported a new synthesis, also catalyzed by cobalt, of bicyclic tertiary alcohols 93 with high regio- and enantioselectivity via [3 + 2] cycloaddition of alkynes and cyclic enones 92 (Scheme 20).[91] Cheng’s system provides an advantage from a practical point of view, e.g. the cobalt catalyst is air-stable, relatively inexpensive, zinc is a mild reducing agent, and uses water as proton source.

R2

R1

OH

R3R4nR1 R2

O

R3R4

n+

CoI2, Zn, ZnI2(R,R,S,S)-Duanphos

1,4-dioxane

n = 1 or 2up to 99% ee

91 92 93

R1, R2 = alkyl or arylR3, R4 = H or Me

Scheme 20. The enantioselective reductive [3 + 2] cycloaddition of alkynes 93 with cyclic enones 92.

1.6 Conclusion

In this chapter, different approaches for the asymmetric synthesis of tertiary

19

Chapter 1

alcohols and ethers have been introduced. In these approaches, the catalytic asymmetric dihydroxylation and epoxidation of olefins have gained wide acceptance and applications in natural products synthesis. The catalytic asymmetric addition of organometallics to ketones as a straightforward, and from a retrosynthesis point of view preferred, way to prepare enantio-enriched tertiary alcohols attracts more and more attention and has been realized by several transition metal-catalyzed systems. This approach is however far from mature. 1.7 Outline of this thesis

In this thesis, the copper-catalyzed asymmetric 1,2-addition of Grignard reagents to α-bromo-α,β-unsaturated ketones has been applied in the asymmetric synthesis of dihydrofurans and cyclopentenols and in the total synthesis of (R,R,R)-γ-tocopherol. The second part of this thesis gives an introduction to a novel, protecting group-free, synthesis of the Colorado potato beetle pheromone and efforts on the total synthesis of phorbasin B.

In chapter 2, a novel asymmetric synthesis of dihydrofurans and cyclopentenols has been developed, based on the copper-catalyzed 1,2-addition of Grignard reagents to enones in combination with Sonogashira coupling/cyclization and ring-closing metathesis. Employing this approach, dihydrofurans with an oxygen-containing tertiary stereocenter, and chiral tertiary cyclopentenols are efficiently prepared. The absolute stereochemistry of the products has been established as well.

In chapter 3, based on the asymmetric copper-catalyzed 1,2-addition of Grignard reagents to ketones, (R,R,R)-γ-tocopherol has been synthesized in 36% yield over 12 steps (longest linear sequence). The chiral center in the chroman ring was constructed with 73% e.e. by the 1,2-addition of a phytol-derived Grignard reagent to an α-bromo enone prepared from 2,3-dimethylquinone.

In chapter 4, a novel synthesis of the aggregation pheromone of the Colorado potato beetle, Leptinotarsa decemlineata, has been developed based on a Sharpless asymmetric epoxidation in combination with a chemoselective alcohol oxidation using catalytic [(neocuproine)PdOAc]2OTf2. Employing this approach, the pheromone was synthesized in 3 steps, 80% yield and 86% ee from geraniol.

Finally, in chapter 5, progress in the asymmetric synthesis of phorbasin B is described. Starting from readily available materials, the required chiral centers of the substituted 2-cyclohexen-1-one part were constructed by Evans aldol reaction and Rubottom reaction, whereas the chiral center in the side chain is provided by copper-catalyzed asymmetric allylic alkylation of a diene bromide. 20

Introduction

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24

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25

Chapter 1

26