Zinc catalyzed and mediated asymmetric propargylation of trifluoromethyl ketones with a propargyl boronate

Article

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Zinc Catalyzed and Mediated Asymmetric Propargylation of

Triﬂuoromethyl Ketones with a Propargyl Boronate

Daniel R. Fandrick,*^,†Jonathan T. Reeves,^†Johanna M. Bakonyi,^†Prasanth R. Nyalapatla,^†Zhulin Tan,^†

Oliver Niemeier,^‡Deniz Akalay,^‡Keith R. Fandrick,^†Wolfgang Wohlleben,^‡Swetlana Ollenberger,^‡

Jinhua J. Song,^†Xiufeng Sun,^†Bo Qu,^†Nizar Haddad,^†Sanjit Sanyal,^†Sherry Shen,^†Shengli Ma,^†

Denis Byrne,^†Ashish Chitroda,^†Victor Fuchs,^†Bikshandarkoil A. Narayanan,^†Nelu Grinberg,^†

Heewon Lee,^†Nathan Yee,^†Michael Brenner,^‡and Chris H. Senanayake^†

^†Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO BOX 368, Ridgeﬁeld, Connecticut

06877-0368, United States

^‡Boehringer Ingelheim GmbH & Co KG, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany

S

* Supporting Information

ABSTRACT: The development of zinc-mediated and -catalyzed asymmetric propargylations of triﬂuoromethyl ketones with a

propargyl borolane and the N-isopropyl-L-proline ligand is presented. The methodology provided moderate to high

stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048.

A mechanism for the boron−zinc exchange with a propargyl borolane is proposed and supported by modeling at the density

functional level of theory. A water acceleration eﬀect on the zinc-catalyzed propargylation was discovered, which enabled a

catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed

propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby

facilitating the reaction with triﬂuoromethyl ketones.

triﬂuoromethyl alcohol stereocenter to be established by a

late stage selective crystallization from a diastereomeric

mixture.^6,8The zinc-mediated propargylation to furnish the

homopropargylic alcohol 7a proceeded with no diastereose-

lectivity, but the subsequent crystallization was governed by an

eutectic mother liquor composition of approximately 4:1⁹of

the undesired to the desired diastereomer 7a. Accordingly,

diastereomerically pure homopropargylic alcohol 7a was able to

be obtained in a single crystallization but the yield was limited

to 30−33%. This low yield at an advanced operation became

the cost driver and bottleneck for subsequent campaigns.

Implementation of a stereoselective propargylation into the

process would signiﬁcantly reduce the raw material cost,

number of batches, and waste generated from the beginning of

the process through to the advanced intermediate 7a.¹⁰On the

basis of the homopropargylic alcohol 7a eutectic controlled

crystallization, a projected 3:1 diastereoselectivity for the key

propargylation would enable the isolated yield for the key

intermediate to be doubled.

INTRODUCTION

■

Chiral centers that contain a triﬂuoromethyl substituent have

increasingly been incorporated into agricultural, material and

medicinal compounds.¹In the latter application, the

pharmacophore was strategically designed into bioactive small

molecules for potency, selectivity, biological and physicochem-

ical properties.^1,2On the basis of these desired attributes, the

Glucocorticoid agonist BI 653048 was designed with a chiral

tertiary triﬂuoromethyl alcohol for the treatment of rheumatoid

arthritis.^2a,3Furthermore, propargylation of carbonyl species⁴

provides both an alcohol functional group as well as a

synthetically versatile alkyne for derivatization or coupling.⁵

Accordingly, the synthesis of BI 653048 was based on utilizing

a chiral homopropargylic triﬂuoromethyl alcohol intermediate

7a, which provided an eﬀective handle for a late stage coupling

with a suitably functionalized iodopyridine (Scheme 1).⁶After a

Sonogashira coupling of the fragments, the eastern azaindole

heterocycle was constructed through an in situ base-promoted

intramolecular cyclization.⁷This two-step sequence enabled a

late stage convergent approach toward the development

candidate. A resolution-based process for the drug substance

was utilized for the ﬁrst kilogram campaign wherein an α-

phenethyl stereocenter was employed to enable the key

Received: January 14, 2013

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Scheme 1. Initial Development Synthesis of BI 653048

Table 1. Zinc-mediated Asymmetric Propargylation through a di-Ligated Zinc Complex

a

b

c

d

entry

ligand

Zn(Lig)₂:10 ratio

time, temp

conv.

yield

dr

1

2

3

4

12

13

14

1

2

1

2 h, −20 °C

18 h −20 °C

4 h, −25 °C

1h, −25 °C

40%

<5%

32%

ND

1.5:1

ND

1:1

∼17%

∼50%

<35%

1:1

a

b

Reactions duration until no further conversion was observed. Relative conversion based on mole product/(mole product + mole starting material)

determined by HPLC. HPLC assay yield. Diastereomeric ratio determined by HPLC. ND = not determined.

c

d

Signiﬁcant progress has been reported for the asymmetric

propargylation of carbonyl compounds.^4,11In addition to chiral

reagent controlled¹²and catalyzed Barbier approaches,^5e,13

catalyzed processes through chiral Lewis acid/base,¹⁴Cu,¹⁵

Zn,¹⁶Ir,¹⁷Cr^5d,18and organo¹⁹based catalysts have expanded

the substrate scope for asymmetric propargylations. Although

reasonably to highly enantioselective asymmetric additions to

triﬂuoromethyl ketones^20,21including asymmetric allyla-

tions^22,23and organo-zinc additions^22b,24have been developed,

progress on the corresponding asymmetric propargylation has

been limited.^13b,25Only low asymmetric induction has been

reported for the necessary propargylation of triﬂuoromethyl

ketones.²⁶In order to achieve an economical process toward BI

653048, a novel asymmetric propargylation was engineered.

Herein, we report the development of a zinc-catalyzed

asymmetric propargylation of triﬂuoromethyl ketones using a

propargyl borolane and amino-acid-based ligands.²⁷

RESULTS AND DISCUSSION

■

The ﬁrst approach toward an asymmetric propargylation of

triﬂuoromethyl ketones was based on chelation of the allenyl

zinc reagent utilized in the nonselective propargylation with a

suitable chiral ligand. Due to the generally accepted closed 6-

membered transition state proposed for zinc-mediated

propargylations,²⁸chelation of the zinc metal with a chiral

B

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Table 2. Zinc Mediated Asymmetric Propargylation through a Mono-Ligated Zinc Complex

a

b

c

d

entry

ligand

time, temp

conv.

yield

dr

1

2

3

4

5

6

7

8

9

13

14

15

16

17

18

19

20

18 h, −25 °C

18 h, −20 °C

4 d, −70 °C

18 h, −25 °C

68%

46%

38%

53%

79%

23%

89%

64%

97%

53%

33%

31%

43%

1.0:1

1.2:1

3.1:1

1.0:1

e

52%

19%

78%

50%

84%

18 h, −25 °C

b

a

18 h reaction duration unless otherwise indicated. Relative conversion based on mole product/(mole product + mole starting material)

determined by HPLC. HPLC Assay Yield. Diastereomeric ratio determined by HPLC. Isolated yield on a 1g scale and 13% of the allene product

was observed.

c

d

e

a

Table 3. Zinc-Mediated and -Catalyzed Propargylations through a B/Zn Exchange

a

Reaction performed by charging the borolane (1.5 equiv) followed by the catalyst, if applicable, to a solution of the ketone 6a in reagent grade

b

c

d

THF. Mole percent to ketone 6a. Reaction duration until no further conversion was observed. Relative conversion based on mole product/(mole

product + mole starting material) determined by HPLC. Site selectivity between propargyl and allenyl products determined by HPLC or NMR

analysis on the crude reaction mixture. 88% Isolated yield. ND = not determined. Tol. = toluene.

e

f

ligand should allow a close proximity of the chiral ligand and

the addition transition state to facilitate discrimination between

the diastereo- or enantiotopic faces of a triﬂuoromethyl ketone.

The initial attempt to generate a chelated zinc complex

employed treatment of diethyl zinc with two equivalents of the

chiral protic ligands 12−14. The resulting solutions were

subsequently treated with the lithiated propyne 10²⁹followed

by subjection to the parent substrate 6a (Table 1). The ligand

modiﬁed reactions proceeded with only low diastereoselectivity

Furthermore, the conversion and ultimate yield were also

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signiﬁcantly lower than observed for the nonligated process. To

address these limitations, an alternative monoligated zinc

approach was subsequently pursued.

addition with the allenyl borolane 22 demonstrated a similar

reactivity and site selectivity for allenylation or propargylation

based on catalyst loading and solvent choice as we previously

reported for the zinc-catalyzed addition with this reagent.³⁷

These zinc-catalyzed and -mediated propargylations of ketone

6a through a B/Zn exchange proceeded with no diastereose-

lectivity but demonstrated a signiﬁcant improvement in the

reaction purity, conversion and yield in comparison to the

processes wherein a transmetalation approach was employed to

generate the allenyl zinc intermediate.

A monoligated zinc process was explored by treatment of n-

butyl zinc bromide³⁰with stoichiometric chiral protic ligands

13−20 prior to the sequential addition of the lithiated propyne

10 and substrate 6a (Table 2). This approach generally

improved the conversion and yield. However, the reaction with

amino-alcohol ligands 13 and 15 which are historically

employed for ligand-catalyzed and zinc-mediated asymmetric

additions of alkynyl, aryl, vinyl and alkyl zinc reagents to

aldehydes and ketones³¹provided no diastereoselectivity for

the desired propargylation. These results are consistent to the

poor enantioselectivity observed with related reagent based

zinc-mediated asymmetric propargylations using a stoichio-

metric chiral amino-alcohol ligand.³²In an eﬀort to develop a

class of ligands that can aﬀect stereoselective induction with a

focus on ligands that are economically viable as stoichiometric

chiral reagents, a series of per-methylated amino-acids 16−20

were examined. The proline based ligand 16 provided a modest

but observable degree of diastereoselectivity at −20 °C which

improved to 3:1 at −70 °C. The levorotatory ligand 16 favored

the desired diastereomer 11a for application to the drug

substance. Although the conversion was improved over the

diligated approach, the propargylation under cryogenic

conditions necessary for diastereoselectivity aﬀorded only a

modest conversion (entry 5).

We recently reported an operationally simple zinc-catalyzed

propargylation³³of aldehydes, ketones and t-butanesulﬁnyl

imines³⁴with a propargyl boronate based on a boron−zinc

exchange mechanism. The catalytic process was anticipated to

provide a facile entry into the allenyl zinc reagent necessary for

propargylation of the triﬂuoromethyl ketone 6a. Similar to the

previously reported reactivity, propargyl 21³⁵and allenyl 22

borolanes were unreactive to ketone 6a at ambient temperature.

A rapid and clean propargylation was achieved by subjecting a

solution of the borolane and ketone to diethyl zinc (Table 3).

Utilizing the propargyl borolane 21, the propargylation was

eﬃciently catalyzed by diethyl zinc and provided a high

conversion and site selectivity for the desired homopropargylic

alcohol 11a. This reactivity was consistent with the proposed

two step catalytic cycle based on a B/Zn exchange to generate

the allenyl zinc intermediate 25 for a site-selective propargy-

lation (Figure 1).^33,36The zinc-catalyzed and -mediated

After demonstrating the rapid and clean propargylation of

triﬂuoromethyl ketone 6a through a boron−zinc exchange

mechanism, this approach served as an eﬃcient platform to

optimize the chiral ligand for stereoselective induction. The

necessary stoichiometric ligated zinc complexes were prepared

by subjecting diethyl zinc to a chiral protic ligand at 40 °C for 3

h prior to the sequential addition of the borolane reagent 21

and ketone substrate 6a at −20 °C (Table 4). The initially

examined ligands were modiﬁcations of the initial N-methyl-^L-

proline 16 lead. Variation of the nitrogen substituent showed a

signiﬁcant eﬀect on the diastereoselectivity and achieved a dr of

7:1 (87.5:12.5) to 8.6:1 (89.5:10.5) by employing a N-isopropyl

30 or N-cyclopentyl 31 substituent respectively (entries 4 and

5). Although the diastereoselectivity was slightly higher with N-

cyclopentyl-^L-proline 31, the site selectivity for propargylation

and ultimate yield was higher for the N-isopropyl-^L-proline

ligand 30. Further increase in the steric hindrance of the N-

substituent with a N-t-butyl group (33) signiﬁcantly reduced

the diastereoselectivity to 1.6:1 (entry 7). Modiﬁcation of the

key N-isopropyl-^L-proline ligand 30 by variation of the

pyrrolidine ring to the azetidine 34 or piperidine 35 analogs

aﬀorded only low diastereoselectivity (entries 8 and 9). The

amino-alcohol analogs to the N-isopropyl-^L-proline ligand such

as the methylene 36, geminal methyl 37, and geminal phenyl

38 derivatives (entries 10 to 12) were also examined but

furnished only low diastereoselectivity. The amino-alcohol

ligands 15 and 39 also provided no diastereoselectivity for the

propargylation (entries 13 and 14) similar to the selectivities

observed in the transmetalation approaches (Tables 1 and 2).

Accordingly, the structural elements of an N-isopropyl

substituent, carboxylic acid functional group, and pyrrolidine

ring within the optimal N-isopropyl-L-proline ligand 30 proved

essential for stereoselective induction.

The zinc-mediated diastereoselective propargylation with the

optimal N-isopropyl-^L-proline ligand 30 was also examined with

the commercially available³⁸allenyl borolane reagent 22 (eq 1).

Both the diastereoselectivity and site selectivity for propargy-

lation were signiﬁcantly lower than the corresponding reaction

utilizing the propargyl borolane reagent 21. In addition to the

improved selectivities, a large scale process for the propargyl

borolane 21 preparation was recently identiﬁed allowing for

facile access to kilogram scale applications.^35b

The reaction temperature demonstrated a moderate eﬀect on

the diastereoselectivity for the N-isopropyl-^L-proline ligand 30

modiﬁed zinc-mediated propargylation of ketone 6a employing

the propargyl borolane reagent 21. Increasing the temperature

from −20 to 20 °C decreased the diastereoselectivity from 7:1

(88:13) to 3:1 (75:25). The ultimate conversion remained

consistent at approximately 79−85% through the examined

temperature range albeit the conversion rate was improved by

conducting the reaction at a higher temperature. The

conversion and diastereoselectivity were dependent on the

rate and order of the substrate and borolane addition. For

Figure 1. Proposed mechanism for a zinc-catalyzed propargylation of

triﬂuoromethyl ketones with a propargyl boronate.

D

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a

Table 4. Ligand Screen for the Diastereoselective Propargylation of Ketone 6a

a

Reactions performed by the sequential charge at −20 °C of the borolane 21 followed by a THF solution of the ketone 6a to an aged solution of

b

diethyl zinc and ligand in reagent grade THF. Two day reaction duration regardless of conversion. Relative conversion based on mole product/

(mole product + mole starting material) determined by HPLC. HPLC area ratio. Diastereoselectivity determined by HPLC.

c

d

reasonable diastereoselectivity at ambient temperature, a

solution of the borolane reagent 21 and ketone substrate 6a

must be charged to a solution of the pregenerated ligated zinc

complex. The reverse addition aﬀorded a lower 2:1 dr. With the

appropriate addition order, the diastereomeric ratio increased

to 3.6:1 by conducting a 10 h metered addition (Table 5).

Minimal impact on the site selectivity was observed by

modiﬁcation of the addition time. The diethyl zinc and chiral

ligand loadings were also reduced from 2 to 1.2 equiv while

retaining the conversion and diastereoselectivity by employing

the metered addition (entries 4 and 5). However, the

stoichiometry between zinc and the chiral ligand was critical

for stereoselective induction. A 10 mol % excess of diethyl zinc

to the chiral ligand aﬀorded a rapid and clean propargylation

but proceeded with no diastereoselectivity (entries 6) indicative

of a facile and competitive nonligated background reaction vide

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laboratory and 10 pilot plant batches, 242 kg of the

triﬂuoromethyl ketone 6a were subjected to the optimized

conditions to provide 180 kg of the key diastereomerically pure

homopropargylic alcohol 7a in an overall yield of 68% wherein

the key propargylation proceeded with a weighted average of a

78:22 diastereomeric ratio. Overall, the principal objective to

double the isolated yield for the key operation was achieved by

utilizing an N-isopropyl-^L-proline 30 modiﬁed zinc-mediated

propargylation.

Further review of the scaleup batches showed variation in the

conversion and reaction diastereoselectivity (Table 6). The

diastereoselectivity varied between 75:25 (3:1) to 81:19

(4.3:1). Although most of the batches achieved >95%

conversion, the ﬁnal batch (entry 12) proceeded to 90%

conversion after agitation for 12 h after the substrate addition.

These combined factors resulted in variation of the isolated

yield between 58 and 75% for the isolated diastereomerically

pure homopropargylic alcohol 7a indicating that an unknown

factor inﬂuenced both the conversion and diastereoselectivity

for the zinc-mediated propargylation. Processes that are

advanced to a pilot plant scale are examined for robustness,

and factors that can reasonably aﬀect the process are examined

and the appropriate speciﬁcations established.⁴⁰Due to the

organo-metallic nature of the propargylation, the reaction

tolerance for water was proactively determined, and up to 2000

ppm water in the THF solvent showed no impact on the

process. This level is four times the <500 ppm speciﬁcation for

reagent grade THF that is routinely employed in the pilot plant.

However, trace amounts of water proved essential for good

conversion, reaction rate and diastereoselectivity (Table 7).

Under as dry as possible conditions,⁴¹a 45% conversion and

65:35 dr was obtained for the propargylation at 30 min after the

metered addition which improved to 89% conversion and 70:30

dr at 18 h. Addition of 4 to 18 mol % percent water relative to

the triﬂuoromethyl ketone 6a enabled complete conversion and

optimal diastereoselectivity (>80:20) within 30 min after the

metered addition. This amount of water is equivalent to 185 to

837 ppm water in the THF solvent.⁴²The water additive must

also be charged to the ligated zinc complex after its formation

infra. Accordingly, the stereoselective propargylation was

designed to utilize a slight excess of the chiral ligand to zinc.

Further reduction in the zinc and ligand loadings aﬀorded

irreproducible results wherein the conversion and diastereose-

lectivity varied between batches. The optimal ambient temper-

ature conditions for the zinc-mediated diastereoselective

propargylation employed 1.23 equiv of the chiral ligand 30

and 1.20 equiv of diethyl zinc relative to the ketone substrate

and a 5−10 h addition of the triﬂuoromethyl ketone substrate

6a and borolane 21 to the pregenerated ligated zinc complex.

These conditions for the stereoselective propargylation

reproduced well on multikilogram scales (Table 6). The

preparative process utilizing the optimal conditions aged the

batch for at least 3 h after the metered addition. The bulk of the

zinc salts³⁹and ligand were subsequently removed by an

aqueous hydrochloric acid wash. Proto-desilylation of inter-

mediate 11a was accomplished by treatment with a methanol

solution of sodium methoxide at 35 °C for 1h. Diastereomeri-

cally pure (>99:1 dr) homopropargylic alcohol 7a was

ultimately isolated after workup and a eutectic controlled

crystallization in isopropyl acetate and heptane. Through 2 kilo-

a

Table 5. Metered Addition and Zinc-Ligand Stoichiometry Optimization

b

c

d

entry

addition time (h)

X (equiv) 30

Y (equiv) Et₂Zn

conv.

11a:24

11a dr

1

2

3

4

5

6

7

1.5

5.2

10.4

10

2.2

2.0

85%

96%

20:1

2.8:1

3.5:1

3.6:1

4.0:1

1.0:1

2.2

2.0

2.2

2.0

>98%

>99%

>25:1

22:1

2.2

2.0

10

1.23

1.20

1.33

1.50

10

>30:1

10

a

Reactions were performed by the metered addition at the indicated interval of a ketone 6a and borolane 21 THF solution to an aged (40 °C for 3

b

h) solution of diethyl zinc and ligand 30 in reagent grade THF at 20 °C. Equivalents of zinc and ligand are relative to ketone 6a. Reactions were run

for 12 h regardless of conversion. Relative conversion based on mole product/(mole product + mole starting material) determined by HPLC.

c

d

HPLC Area ratio. Diastereoselectivity determined by HPLC.

F

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a

Table 6. Kilogram Scaleup of the Zinc-mediated Stereoselective Propargylation

b

c

d

entry

input 6a (kg)

reaction 11a dr

output 7a (kg)

yield

quality (wt%)

1

1.0

3.6

25

13

10

34

75:25

77:23

81:19

79:21

80:20

81:19

77:23

75:25

79:21

75:25

0.8

2.7

65%

68%

64%

69%

68%

71%

72%

75%

64%

66%

68%

58%

99

98

99

98

99

97

99

98

97

2

3

18

4

19

20

10

11

7

5

6

7

8

9

10

11

12

24

26

22

a

Reactions performed by the metered addition over 5−10 h of a ketone 6a and borolane 21 THF solution to an aged (40 °C for 3h) solution of

b

diethyl zinc and ligand 30 in reagent grade THF at 20 °C. Reactions were run for 3 to 12 h. Diastereoselectivity determined by HPLC of the crude

propargylation reaction before workup. Isolated yield of diastereomerically pure 7a after crystallization. Quality by weight percent determined by

c

d

1H NMR assay with dimethyl fumarate or by calibrated HPLC assay.

a

Table 7. Water Eﬀect on the Zinc-mediated Diastereoselective Propargylation of 6a

b

c

d

e

d

entry

water

0%

30 min conv.

18 h 11a dr

conv.

11a dr

1

2

3

4

5

6

7

8

9

45%

59%

65:35

71:29

81:10

82:18

80:20

81:19

75:25

71:29

ND

89%

94%

70:30

73:27

0.5%

4%

>99%

f

8%

14%

18%

40%

70%

100%

>99%

98%

91%

75%

36%

96%

92%

35%

80:20

75:25

ND

a

Reactions performed by the metered addition over 5 h of an anhydrous ketone 6a and borolane 21 THF solution to an aged (40 °C for 3 h)

b

solution of diethyl zinc, ligand 30, and the indicated amount of water in anhydrous THF at 20 °C. Mol percent water relative to starting ketone 6a.

c

d

Relative conversion at 30 min after the metered addition. Diastereoselectivity of the crude propargylation reaction before workup determined by

e

f

HPLC. Relative conversion at 18 h after the metered addition. 74% isolated yield of diastereomerically pure 7a was obtained after proto-desilylation

and crystallization. ND = not determined.

for a water eﬀect to be observed. Therefore, employing a

catalytic amount of water allowed a slight improvement in the

stereoselectivity with a more signiﬁcant impact on the rate of

the reaction.

The catalyst loading was able to be lowered and a zinc-

catalyzed stereoselective propargylation achieved by the

addition of catalytic water due to the resulting improvement

in the reaction rate. The catalyst loading and stoichiometry

between the ligated zinc catalyst and water were optimized

through a 2D design of experiment (DoE) approach with

ketone 6a (Figure 2).⁴³The design focused on a catalytic

process with the factors of catalysts loading (1 to 40 mol %)

and water (1 to 40 mol %) for the dimensions and employed a

3 h addition of the substrate 6a and borolane 21 to a solution

G

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Figure 2. DoE optimization for the zinc-catalyzed diastereoselective propargylation of ketone 6a. Reactions performed by the metered addition over

3 h of an anhydrous ketone 6a and borolane 21 THF solution to an aged (40 °C for 3 h) solution of diethyl zinc, ligand 30 and water in anhydrous

THF as the indicated stoichiometry and 20 °C. Reactions progressed for 10 h at which point the conversion, diastereoselectivity (normalized), and

site selectivity (normalized) were determined by HPLC.

of the pregenerated chiral zinc complex. The observable

responses which were optimized are those that directly aﬀect

the yield, namely the conversion, diastereoselectivity and site

selectivity after a 10 h reaction. The optimal conditions for all

three parameters were related to moderate zinc catalyst

loadings (25−40 mol %) with a low water content (∼2 mol

%). The lowest optimal catalyst loading was 25 mol % zinc

catalyst with 2 mol % water to provide 99% conversion, 80:20

diastereoselectivity, and 92:8 site selectivity for the propargy-

lation of ketone 6a at ambient temperature.

A parallel optimization of the catalyst loading and water was

conducted for the asymmetric propargylation of the triﬂuor-

omethyl ketone 6b, and a similar catalyst (30 mol %) and water

(3.7 mol %) loading were found for optimal conversion and

enantioselectivity. The asymmetric propargylation of the ketone

6b on a 70 g scale at ambient temperature with these catalytic

conditions aﬀorded a 91% reaction yield and 84:16 er for the

homopropargylic alcohol 7b after proto-desilylation (eq 2).

lead to incomplete and irreproducible conversions. The optimal

conditions for the catalytic stereoselective propargylation of

triﬂuoromethyl ketones with propargyl borolane 21 employed

25 mol % of diethyl zinc, 27 mol % amino-acid 30, and 2 mol %

water with a −40 °C reaction temperature

The optimized zinc-catalyzed asymmetric propargylation of

triﬂuoromethyl ketones proved reasonably general, tolerating

both aliphatic and aromatic substrates (Table 9). The

enantioselective propargylation of the achiral analogs 6b, 6c,

6d, 6e, and 6f aﬀorded a nearly identical degree of asymmetric

induction (89:11 to 93:7 er) as compared to the parent system

(90:10 dr) (entries 1−6). The asymmetric induction was

therefore predominately due to the ability of the N-iPr-^L-Pro

ligand to discriminate the enantiotopic or diastereotopic ketone

faces with a minimal inﬂuence from the α-phen-ethyl

stereocenter of the parent chiral ketone 6a.⁴⁴Furthermore,

the process proved compatible with halides, thioethers, and

Lewis basic amide functional groups. The asymmetric

propargylation of the aromatic triﬂuoromethyl ketones 6g,

6h, and 6i provided 81:19 to 86:14 enantiomeric ratios with no

apparent inﬂuence by a para-electronically donating or slightly

electron withdrawing substituent (entries 7−9). The analogous

aliphatic substrate to the parent system without the neopentyl

fragment also aﬀorded a high yield with only a slight decrease in

enantioselectivity (entry 10). In general, the zinc-catalyzed

asymmetric propargylation provided an operationally simple

process for the construction of chiral homopropargylic

triﬂuoromethyl alcohols.

The key observation that enabled the catalyst loading to be

lowered for a catalytic process was the inclusion of catalytic

water to the reaction. To further deﬁne this eﬀect, the reaction

rate proﬁle for the zinc-catalyzed asymmetric propargylation

was examined. The reaction with the parent system

demonstrated signiﬁcant rate acceleration with 2 mol % water

(Figure 3). The reaction with catalytic water was complete in 1

The stereoselectivity for the optimized zinc-catalyzed

propargylation was improved under cryogenic conditions.

The diastereoselectivity for the parent system improved to

9:1 dr by conducting the zinc-catalyzed propargylation at −40

°C (Table 8). Complete conversion was able to be achieved at

−40 °C due to the improved reactivity by the addition of

catalytic water to the process. Reactions at lower temperatures

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a

Table 8. Temperature Eﬀect on the Zinc-catalyzed Diastereoselective Propargylation of 6a

b

c

d

e

entry

temp. (°C)

time (h)

conv.

dr 11a

11a:24

1

2

3

4

20

0

5

10

42

48

>98%

98%

4−4.4:1

5:1

15:1

14:1

19:1

−20

−40

6:1

>98%

9:1

a

Mole percent ligand 30, diethyl zinc and water to the starting ketone 6a. Reactions performed by the metered addition over 5 h of an anhydrous

ketone 6a and borolane 21 THF solution to an aged (40 °C for 3 h) solution of diethyl zinc, ligand 30 and water in anhydrous THF at the indicated

b

c

d

temperature. Reaction temperature for the zinc-catalyzed propargylation. Time until >97% molar conversion. Relative conversion.

e

Diastereoselectivity and site selectivity determined by HPLC.

h, and the anhydrous reaction required over 3 h when 1.7

equivalents of the borolane 21 were employed and the reaction

conducted at 20 °C.⁴¹With 2 mol % water, the reaction rate

initiated at a TOF of 10/h and gradually decreased as the

reaction progressed. Without water, the reaction demonstrated

a slow induction phase to peak at a rate of TOF 1.8/h. Catalytic

water in the diastereoselective propargylation eliminated the

induction phase of the reaction and increased the peak reaction

rate by over 500%.

slower parent triﬂuoromethyl ketone substrate 6a by employing

diﬀerent excesses between the substrate and borolane reagent

21 (Figure 4). No overlay between all the examined excesses

were observed in the graph analysis relating the reaction rate to

the substrate concentration or time as well as relating the

reaction rate divided by the borolane concentration to the

substrate concentration (Graphs a-c). However, an overlay

between the reaction rate divided by the borolane concen-

tration was observed between reactions with the same initial

substrate concentration (Graph c). The reaction rate under this

relationship showed a minor negative slope for approximately

75% of the reaction which changed slope and behavior when

less than 25% of the substrate remained. This pattern is

indicative of the rate limiting operation for the ﬁrst approximate

75% of the reaction dependent on the borolane concentration,

i.e. exchange, then changing to the substrate concentration, i.e.

addition, when the substrate concentration decreases to

become rate limiting. The reaction rate divided by the borolane

concentration at less than 75% conversion increased with

decreasing substrate concentration indicative of product

acceleration or starting material inhibition. Zinc complexes

and reactions are routinely inﬂuenced by the aggregation of the

zinc intermediates in solution.⁴⁹A reasonable rationalization for

this reaction rate behavior relates to the product facilitating the

deaggregation of the zinc complexes and thereby aﬀording a

slight rate increase with increasing product concentration. A

well ﬁt overlay regardless of the initial substrate concentration

was observed when the reaction rate divided by the borolane

concentration was compared to the product concentration

(graph d). No clear kinetic information could be ascertained

with diﬀerent concentrations of water or zinc or through

examination of the asymmetric ligated process. However, the

graph analysis for the reaction progress analysis supported the

exchange as the principal rate limiting operation while the

inﬂuence of the product contributes a minor component to the

reaction rate. Therefore, catalytic water reasonably led to an

acceleration of the predominately rate limiting exchange within

the zinc-catalyzed propargylation.

The inﬂuence of water on the nonligated and more facile

zinc-catalyzed propargylation was also examined by comparing

the peak reaction rate with and without catalytic water for

reaction with the aldehyde 40, methyl ketone 41 and parent

triﬂuoromethyl ketone 6a (Table 10). Initial analysis revealed a

signiﬁcant rate diﬀerence among the substrates. The zinc-

catalyzed nonligated propargylation of p-anisaldehyde 40

achieved a TOF of >10000/h wherein complete conversion

was obtained in less than 1 min with only 2 mol % diethyl zinc.

The acetophenone 41 substrate showed an approximate 15-fold

decrease in the peak reaction rate over the aldehyde. The peak

reaction rate for the parent triﬂuoromethyl ketone 6a was

approximately 10-fold decrease over that of the methyl ketone

41. For the methylketone 41 and triﬂuoromethyl ketone 6a

substrates wherein an accurate reaction rate could be measured,

the inﬂuence of 1 mol % water on the zinc-catalyzed (2 mol %)

propargylation increased the peak reaction rate by approx-

imately 20%. Furthermore, comparison of the peak reaction

rates for the diastereoselective ligated zinc-catalyzed propargy-

lation with 25 mol % catalyst (Figure 3) to the nonligated and

unselective zinc-catalyzed propargylation with 2 mol % catalyst

(Table 10) showed that the nonligated TOF was approximately

800% higher than the slower amino-acid ligated reaction.

Accordingly, the zinc-catalyzed propargylation was ligand

decelerating. Catalytic water inﬂuenced the reaction rate in

both the ligated and nonligated zinc-catalyzed propargylations,

and the inﬂuence was more signiﬁcant in the slower ligated

asymmetric process.

A reasonable mechanistic rationalization for the inﬂuence of

water on the rate of the zinc-catalyzed propargylation relates to

water facilitating the rate limiting step in the catalytic cycle

(Figure 1). The catalyst behavior was qualitatively determined

by application of Blackmond’s reaction progress analysis⁴⁸on

the nonligated zinc and water-catalyzed propargylation with the

In order to address the water eﬀect on the zinc-catalyzed

propargylation, a mechanistic rationalization for the key rate

limiting B/Zn exchange must be formulated. Since the

pioneering work of Zakharkin and Okhlobystin and Thiele

and co-workers,⁵⁰the B/Zn exchange has led to general access

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a

Table 9. Substrate Scope for the Zinc-catalyzed Stereoselective Propargylation

a

Reactions performed by the metered addition over 3−6 h of an anhydrous ketone and borolane 21 THF solution to an aged (40 °C for 3 h)

solution of diethyl zinc, ligand 30 and water in anhydrous THF at −40 °C. Enantiomeric ratio determined by Chiral HPLC.⁴⁵Absolute

stereochemistry assigned by analogy to the diastereoselective propargylation of triﬂuoromethyl ketone 6a. Isolated yield. Diastereomeric ratio

determined by HPLC. Enantiomeric ratio determined by chiral HPLC after proto-desilylation.

b

c

d

e

to organo-zinc complexes.⁵¹Several mechanisms for B/Zn

exchanges have been derived from DFT calculations⁵²wherein

the formulated exchange mechanisms between organozinc

complexes and organoboronate esters involve coordination of

the organozinc complex to the boronate oxygen to promote a

ligand transfer from zinc to boron and activate the system for

the exchange through a boron “ate” intermediate.^52c−e

Alternatively, six membered chairlike transition states with

inversion for the exchange of allyl borolanes with zinc ﬂuoride

or alkoxy complexes have been proposed based on

experimental observations.⁵³Two observations from our

previous publications on zinc-catalyzed additions based on a

B/Zn exchange should be rationalized by the transition state for

the key exchange involved in the zinc-catalyzed propargylation.

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Figure 3. Water eﬀect on the reaction rate for the zinc-catalyzed diastereoselective propargylation of triﬂuoromethyl ketone 6a.⁴⁶Reaction

performed by charging an aged (40 °C for 3 h) solution of diethyl zinc and ligand 30 in anhydrous THF to an anhydrous THF solution of the

borolane 21, ketone 6a and the indicated amount of water at 20 °C. Total concentration was 0.30 M borolane 21 and 0.18 M ketone 6a. Relative

reaction conversion monitored by React IR. Turnover Frequency (TOF) of the catalyst was per hour.

First, our zinc-catalyzed allenylation of aldehydes and ketones

with an allenyl boronate 22 demonstrated a highly selective

inversion process for the B/Zn exchange which was also

consistent for reactions with a propargyl boronate reagent.³⁷

Second, our zinc-catalyzed allylation of ketones with an allyl

borolane reagent demonstrated an increased exchange activity

for an alkoxy zinc complex in comparison to diethyl zinc toward

the allyl borolane, and the allylation reaction required an

alcohol additive with catalytic diethyl zinc for reactivity.^53bTo

account for these observations as well as maintain the

requirement of a boron “ate” intermediate necessary to activate

Table 10. Water Eﬀect on the Reaction Rate for the Zinc-

catalyzed Propargylation

a

41,47

,

the migration of the organo-ligand from boron to zinc,⁵²

a

reasonable exchange mechanism relates to boron coordination

to the zinc alkoxide ligand to directly position the system for a

closed six membered based B/Zn exchange transition state

(Figure 5). Accordingly, a Lewis acid−Lewis base interaction⁵⁴

can initiate a feasibly concerted and facile inversion based

exchange to directly generate the allenyl zinc intermediate 25.

A computation assessment on the proposed closed 6-

membered based B/Zn exchange with a propargyl boronate

and a model system supported a smooth inversion based

intramolecular mechanism. Computation analysis was per-

formed on a high performance computer with Gaussian 09⁵⁵

software at the density functional level of theory and employed

the B3LYP method and LANL2DZ bases set. All structures

were optimized, and the coordinated starting material and

product showed no imaginary frequencies. The proposed

exchange transition state showed one imaginary frequency and

a vibration mode consistent with the expected transition state

(Figure 6). Subsequent IRC plots demonstrated a smooth

connection between the starting material 42, transition state 43,

and product 44. The low calculated barrier for the exchange

was consistent to the facile zinc-catalyzed propargylation

observed at or below room temperature. Furthermore, an

equilibrium^52a,b,ebetween the starting material and allenyl zinc

a

Reaction performed by charging diethyl zinc (2 mol % relative to

substrate) in one portion to a solution of the substrate (0.3 M) and

borolane 21 (0.38 M) at −10 °C in anhydrous THF with the indicated

amount of water. Reaction progress monitored by React-IR. See

Supporting Information for conversion and rate proﬁle in relation to

b

time. Rate exceeded accurate measurement by React-IR and was

complete in less than 1 min. Reaction rate was at least 10000 TOF,

and the temperature rose to 6 °C during the reaction. ND = Not

determined.

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Figure 4. Reaction progress analysis for the zinc-catalyzed propargylation of ketone 6a. Reactions performed by charging diethyl zinc [Et₂Zn] =

0.0064 M to a solution of the ketone 6a, borolane, and water [H₂O] = 0.0031 M in anhydrous THF at −10 °C. Reaction progress monitored by

React IR and analyzed after ﬁtting to a 10th order polynomial regression.

Catalytic water has historically been observed to inﬂuence

the rate of numerous reactions.⁵⁷The eﬀect on zinc-mediated

additions is precedented but not well characterized nor

provided for an apparent rationalization for the exchange

acceleration observed for the zinc-catalyzed propargylation.^57,58

In the proposed closed 6-membered based exchange

mechanism, a coordination between the boron reagent and

the zinc alkoxide product derived from the propargylation is

required to initiate the exchange. Accordingly, the electronic

and steric properties of the zinc alkoxide ligand are expected to

inﬂuence the rate of the exchange. Larger alkoxide ligands

would hinder the key coordination to the boron reagent.

Additionally, electronically deﬁcient alkoxide ligands would

decrease the Lewis basicity of the zinc alkoxide complex and

also impede the key coordination. The tertiary and electroni-

cally deﬁcient zinc alkoxide products derived from propargy-

lation of triﬂuoromethyl ketones are expected to be poor

intermediates for the B/Zn exchange as demonstrated by the

decreased reaction rate in comparison to the aldehyde or

methyl ketone substrates. Furthermore, increasing the steric

environment around the zinc metal with a chiral ligand would

further inhibit the key boron to zinc alkoxide interaction and

account for the observed ligand deceleration for the stereo-

selective process. A reasonable rationalization for the water

inﬂuence on the zinc-catalyzed propargylation relates to water

generating an intermediate which can catalyze the rate limiting

Figure 5. Plausible closed 6-membered based B/Zn exchange with a

propargyl boronate.

intermediate was apparent wherein the starting coordinated

species 42 was slightly favored over the coordinated allenyl zinc

intermediate 44. The direction of the equilibrium between the

dissociated starting and product species will be dependent on

the complexation, solvation, and dissociated adduct energies⁵⁶

but will ultimately be driven to the allenyl zinc intermediate as

the allenyl zinc intermediate is consumed during the reaction

progression. Competitive mechanisms for the B/Zn exchange

can not be excluded, but the formulated B/Zn exchange which

was initiated by a Lewis-acid and Lewis-base interaction

provided a simple rationalization for the key facile exchange.

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Figure 6. Calculated reaction coordinate for a closed 6-membered based B/Zn exchange with a propargyl boronate.

exchange (Scheme 2).⁵⁹Treatment of an organo-zinc complex

with water is expected to generate a zinc hydroxide or dinuclear

However, the model predicted that pinacol boronic acid, due to

the expected facile reaction with an organo-zinc intermediate to

generate the key boro-oxo zinc intermediate 48, should have a

similar eﬀect on the rate of the propargylation as water. Nearly

identical conversions, rate and rate proﬁles for both the ligated

and nonligated zinc-catalyzed propargylations were observed

with equal catalyst loading of pinacol boronic acid⁶¹and water

(Figure 7 and 8) to support adduct 48 as a viable intermediate.

Additionally, catalytic pinacol boronic acid eliminated the

induction phase of the ligated zinc-catalyzed stereoselective

propargylation as observed with catalytic water. Therefore, a

parallel catalytic process⁶²initiated by catalytic water or pinacol

boronic acid reasonably accelerated the rate limiting boron−

zinc exchange within the zinc-catalyzed propargylation

(Scheme 3).

Scheme 2. Proposed Catalytic Cycle for the B/Zn Exchange

with a Dinuclear Zinc Oxo-Complex

An alternative experiment was designed to demonstrate

multiple mechanisms for the zinc and water-catalyzed

propargylation based on sequential charges of the propargyl

borolane to an excess of the triﬂuoromethyl ketone substrate 6a

wherein the experiment was designed to operate in the rate

limiting exchange phase of the reaction (Figure 9). The

reaction rate was monitored by calorimetry under isothermal

conditions. In each of the sequential 7 mol % borolane 21

additions to the ketone substrate 6a, a rapid reaction was

initially observed which proceeded to an apparent ﬁrst order

decay based on the borolane as the limiting reagent. The

reaction behavior supported a highly active catalyst adduct

accumulation after completion of a proceeding segment which

induced a rapid initial reaction at the subsequent borolane 21

charge. After consumption of the highly active intermediate, a

steady state catalytic cycle progressed until the borolane reagent

was consumed. This two phase reaction proﬁle under

sequential borolane 21 charges would not be consistent with

a reaction behavior involving a catalyst resting state at the zinc

alkoxide product 26 directly derived from the propargylation

reaction.

zinc oxo-complex 46, which have previously been demonstrated

as competent species for a B/Zn exchange,⁶⁰and produce the

allenyl zinc intermediate 25 and a boro-oxo-zinc byproduct 48

after an exchange. This resulting adduct 48 can undergo a

subsequent alkoxide ligand exchange^52bwith the alkoxide zinc

product 26 derived from the propargylation of a triﬂuoromethyl

ketone substrate to regenerate the dinuclear zinc oxo-complex

46 and complete a catalytic cycle. Direct detection of the key

intermediates or elucidation of the rate order for zinc and water

for the catalyzed propargylation proved challenging due to the

complex mixture of zinc complexes present in the reaction.

M

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Figure 7. Additive eﬀect on the zinc-catalyzed propargylation of ketone 6a. Reaction performed by charging diethyl zinc to a solution of the ketone

[6a] = 0.359 M and [21] = 0.449 M with the indicated additive in anhydrous THF at −10 °C. Reaction progress monitored by React IR. Turnover

Frequency (TOF) was per hour.

Figure 8. Additive eﬀect on the zinc-catalyzed diastereoselective propargylation of ketone 6a. Reaction performed by charging an aged (40 °C for 3

h) solution of diethyl zinc and ligand 30 in anhydrous THF to an anhydrous THF solution of the ketone [6a] = 0.285 M, borolane [21] = 0.346 M

and the indicated additive in anhydrous THF at 20 °C. Reaction progress monitored by React IR. Turnover Frequency (TOF) was per hour.

In contrast to zinc-mediated asymmetric alkynyl, vinyl, aryl,

alkyl, and propargyl additions to aldehydes and ketones

catalyzed by chiral amino-alcohol ligands,³¹no asymmetric

induction was observed with amino-alcohol ligands for the zinc-

mediated asymmetric propargylation utilizing the propargyl

borolane 21 reagent. Typical zinc-mediated asymmetric

additions operate by ligand acceleration which eﬀectively

compete with the nonligated and nonselective pathway and

proceed by a rapid Schlenk equilibration between the ligand,

alkoxide product, and zinc salts.^31,63Contrary to the classical

zinc-mediated additions, catalytic diethyl zinc without a ligand

promoted a rapid propargylation of carbonyl compounds with

the propargyl borolane reagent 21. Furthermore, the

asymmetric propargylation utilizing an amino-acid ligand was

shown to be ligand decelerating with a decrease in reaction rate

of approximately 800% over the nonligated process vide supra.

NMR analysis of the complex generated from diethyl zinc and

N-iPr-^L-Proline 30 showed clean consumption of diethyl zinc

and formation of the N-iPr-^L-Pro-Zn-Et complex 50 albeit with

broad peaks indicative of aggregation⁴⁹(Figure 10). Subjecting

N

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Scheme 3. Mechanistic Proposal for the Water Eﬀect on the Zinc-catalyzed Propargylation

the same complexation conditions to a solution of diethyl zinc

and a stoichiometric amino-alcohol ligand, N-Methyl ephedrine

13, aﬀorded a complex mixture in which the amino-alcohol zinc

complex was not identiﬁable.⁶⁴The eﬀective zinc complexation

with amino-acid ligands utilized in the zinc-catalyzed

asymmetric propargylation achieved asymmetric induction by

minimizing the amount of the nonligated zinc species which

can competitively catalyze a nonselective background reaction.

However, alternative mechanisms and competitive reactions are

reasonably expected for zinc-catalyzed asymmetric propargyla-

tions based on diﬀerent processes to generate an allenyl zinc

intermediate such as demonstrated by the good asymmetric

induction achieved by Trost et al. in an amino-alcohol-catalyzed

and zinc-mediated asymmetric propargylation utilizing an

iodopropyne or iodoallene reagent.¹⁶

eﬀective process to prepare pharmaceutically valuable chiral

homopropargylic triﬂuoromethyl alcohols.

EXPERIMENTAL SECTION

■

All reactions were conducted under a dry nitrogen or argon

atmosphere unless otherwise noted. Enantiomeric⁴⁵and diastereo-

meric ratios were determined by high performance liquid chromatog-

raphy (HPLC) with the noted conditions and analytical columns.

Water content was determined by Karl Fischer titration. NMR analysis

was performed on a 400 or 500 MHz instrument. Carbon NMR

spectroscopy was conducted with proton decoupling. Chemical shifts

(δ) are reported in ppm from tetramethylsilane (TMS, 0 ppm) and

calibrated to TMS or to the residual solvent resonances (1H: CDCl₃

7.26 ppm, CD₃OD 3.30, DMSO-d₆2.49; 13C: CDCl₃77.0, CD₃OD

49.0, DMSO-d₆39.5). NMR spectral data are reported as follows:

chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =

quartet, br = broad, m = multiplet), coupling constant, and number of

protons. High resolution mass spectroscopy was performed on a TOF

instrument with ESI and positive or negative ionization as indicated.

Propargyl Borolane 21 was prepared by our published procedure.^35b

Ligands 17,⁶⁵18,⁶⁶19,^65b,6728,⁶⁸29,⁶⁹32,⁷⁰34,⁷¹35,⁷²and 36⁷³were

prepared according to known procedures. Triﬂuoromethyl ketones

6a,⁶6b,^3b,25d6c,^3b6d,^6,8a6e,^3b6f,^25dand 6j⁷⁴were prepared according

to published procedures. Triﬂuoromethyl ketones 6g, 6h, and 6i were

obtained from commercial suppliers and utilized as received. Reagent

grade solvents were utilized unless otherwise speciﬁed. All other

reagents were utilized as received without further puriﬁcation.

Isothermal reactions were performed in a reactor system wherein

the internal temperature was automatically controlled by adjustment of

the jacket temperature. Reaction monitoring by React IR was

performed by Fourier transform infrared spectroscopy (FTIR)

utilizing a silver halide 9.5 mm × 1.5 m ﬁber probe interface.

CONCLUSION

■

A stereoselective zinc-catalyzed propargylation of triﬂuoro-

methyl ketones with a propargyl borolane and a chiral amino-

acid ligand was developed. The process provided reasonable

stereoselective induction for the propargylation of both

aliphatic and aromatic triﬂuoromethyl ketones with use of a

relatively inexpensive ligand and transition metal. Catalytic

water was shown to accelerate the zinc-catalyzed propargylation

with a pronounced eﬀect on the stereoselective reaction with

triﬂuoromethyl ketones. Based on the kinetically determined

rate limiting boron−zinc exchange, a reasonable rationalization

for the inﬂuence of catalytic water on the zinc-catalyzed

propargylation relates to water generating an intermediate

which can catalyze the key exchange. The proﬀered cocatalysis

model enabled the prediction of pinacol boronic acid as an

equivalent additive to water which provided a nearly identical

reaction rate acceleration and proﬁle as water. Furthermore, a

facile closed six member inversion transition state for the B/Zn

exchange with a propargyl borolane reagent was formulated

based on an exchange initiating Lewis acid−base interaction

between the propargyl borolane reagent and a zinc alkoxide

ligand. Overall, these developments enabled a zinc-catalyzed

asymmetric propargylation with an amino-acid ligand to be

developed and provided for an operationally simple and cost-

N-Me-^L-Pro (16). L-Proline (6.0 g, 52 mmol), formaldehyde (37%

in water, 6.2 mL, 83 mmol) methanol (70 mL) and 10 wt % Pd/C

(1.50 g, 1.41 mmol) were charged to a pressure reactor. The reactor

was ﬂushed with argon followed by hydrogen. The vessel was

pressurized with hydrogen to 200 psi and agitated at 50 °C for 2 d.

The reaction was cooled to 20 °C and ﬂushed with nitrogen. The

reaction was diluted with methanol (50 mL) and ﬁltered through a

Celite (10 g) plug eluting with methanol (50 mL). The ﬁltrate was

concentrated in vacuo to an oil. The oil was azeotropically dried by

distillation at 1 atm in toluene with a Dean−Stark trap. The resulting

mixture was cooled to ambient temperature and concentrated in vacuo

to a solid. The solid was dissolved in n-propanol (17 mL) at 90 °C.

O

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Figure 9. Calorimetric reaction proﬁle for the propargylation of ketone 6a with sequential additions of the propargyl borolane 21. Reaction

performed by the sequential addition, at the indicated time interval, of 7 mol % borolane 21 to triﬂuoromethyl ketone 6a [0.55 M] with 2 mol %

diethyl zinc and 1 mol % water in anhydrous THF at 20 °C under isothermal conditions. Calorimetry and reaction rate correlation under the

relationship that T_reaction− T_jacket= ΔT, ΔT α q, and q α d[11a]/dt.⁴⁸

1

Figure 10. H NMR analysis of complex 50. H NMR in THF-d⁸400 MHz at 20 °C.

P

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Scheme 4. Preparation of N-t-Bu-L-Pro 33

The homogeneous solution was diluted at 90 °C with toluene (100

mL). The solution was cooled to 50 °C; at which point, the solution

was seeded to induce crystallization. The mixture was gently agitated

and allowed to cool to 20 °C over 45 min. The mixture was diluted

with MTBE (60 mL) dropwise over 30 min. The mixture was agitated

for an addition hour. The solids were collected by ﬁltration, washed

with MTBE, and dried in a vacuum oven with a nitrogen stream at 70

°C for 14 h to aﬀord N-Me-^L-Pro 16 as an oﬀ white solid (4.38 g,

with nitrogen, the solids were removed by ﬁltration. The ﬁltrate was

concentrated in vacuo and dried to a solid. The solid was recrystallized

from n-propanol, toluene and MTBE to aﬀord the desired product 31

1

(13 g, 81%) as an oﬀ white solid. H NMR (400 MHz, DMSO-d₆) δ

3.65−3.55 (m, 2H), 3.55−3.46 (m, 1H), 2.89 (ddd, J = 6.2, 10.5, 10.5

Hz, 1H), 2.20−2.05 (m, 1H), 2.05−1.95 (m, 1H), 1.92−1.80 (m, 3H),

1.80−1.55 (m, 5H), 1.55−1.40 (m, 2H). ¹³C NMR (100 MHz,

DMSO-d₆) δ 169.6, 67.6, 65.3, 53.4, 29.4, 28.51, 28.46, 23.7, 23.5,

23.4. [α]_D= −54 (c = 0.52 in MeOH). HRMS-ESI C₁₀H₁₇NO₂calcd

for [M + H]⁺184.1332 found 184.1328.

1

65%). H NMR (400 MHz, DMSO-d₆) δ 3.47−3.34 (m, 2H), 2.86−

2.77 (m, 1H), 2.67 (s, 3H), 2.23−2.11 (m, 1H), 1.95−1.82 (m, 2H),

1.78−1.63 (m, 1H). ¹³C NMR (100 MHz, DMSO-d⁶) δ 169.1, 69.9,

55.4, 40.4, 28.7, 23.1. [α]_D= −80 (c = 1.12 in MeOH). (Lit.⁷⁵[α]_D=

−78, c = 1.5 in MeOH). HRMS-ESI C₆H₁₁NO₂calcd for [M + H]⁺

130.0863 found 130.0858.

N-t -Butyl-^L-Pro (33). (Scheme 4): A mixture of (S)-prolinol 51

(20.5 g, 203 mmol), 4A MS (20 g) in acetone (150 mL) was agitated

under argon at 20 °C for 2 h; at which point, GC analysis showed

complete conversion. The reaction mixture was ﬁltered through a

Celite plug eluting with MTBE. The ﬁltrate was concentrated in vacuo

to provide (S)-3,3-dimethylhexahydropyrrolo[1,2-c]oxazole 52 as a

yellow homogeneous oil (27.7g, 97%) which was used in the next

N,N-Dimethyl-^L-tert-Leucine (20). A mixture of L-tert-Leucine

(2.37 g, 18.1 mmol), aqueous formaldehyde (37 wt %, 2.96 mL, 40

mmol), Pd on carbon (10 wt % wet, 1.0 g) in methanol (4 mL) was

agitated under a 200 psi hydrogen atmosphere at 55 °C for 72 h. The

reaction was cooled to ambient temperature, ﬂushed with nitrogen and

ﬁltered through a Celite plug with a methanol rinse. The ﬁltrate was

concentrated in vacuo to an oil and azeotropically dried by distillation

with toluene at 1 atm with a Dean−Stark trap. The resulting

heterogeneous mixture was concentrated to a solid. The solid was

recrystallized with MeOH and MTBE to provide the ligand 20 as a

1

operation without further puriﬁcation. H NMR (500 MHz, C₆D₆) δ

3.73 (t, J = 7.7 Hz, 1H), 3.66−3.59 (m, 1H), 3.20 (dd, J = 6.6, 6.6 Hz,

1H), 2.66 (dd, J = 7.2, 7.2 Hz, 1H), 2.55−2.47 (m, 1H), 1.84−1.75

(m, 1H), 1.70−1.51 (m, 2H), 1.41 (s, 3H), 1.32 (s, 3H), 1.24−1.14

(m, 1H). Intermediate 52 (5.0 g, 35 mmol) was charged neat to a

solution of methyl magnesium chloride (3.0 M in THF, 29.5 mL, 88.5

mmol) in anhydrous THF (120 mL) at −20 °C under argon. The

resulting solution was agitated at 18−20 °C for 18 h. The reaction was

quenched by the addition of 3 M HCl (60 mL). Sodium potassium

tartrate tetrahydrate (22.5 g, 79.7 mmol) was charged to the reaction

mixture as a solid, and the reaction mixture was agitated at ambient

temperature for 2 h. Aqueous NaOH (3 M, 16 mL, 48 mmol) was

charged to the reaction, and the mixture was agitated at ambient

temperature for 18 h. The reaction was extracted with ethyl acetate (6

× 50 mL). The aqueous portion contained signiﬁcant amount of the

product. The aqueous portion was treated with aqueous NaOH (3M,

50 mL) followed by brine (10 mL) and extracted with methylene

chloride (6 × 50 mL). The combined organic portions were dried with

Na₂SO₄, ﬁltered and concentrated in vacuo to provide (S)-(1-tert-

butylpyrrolidin-2-yl)methanol 53 as an oil in approximately 80 wt %

purity (4.66 g, 80 wt %, 67%) which was used in the next operation

without further puriﬁcation. ¹H NMR (500 MHz, CDCl₃) δ 3.42 (dd,

J = 5.9, 9.8 Hz, 1H), 3.27 (dd, J = 3.4, 10.3 Hz, 1H), 3.20−3.14 (m,

1H), 3.0−2.9 (m, 1H), 2.77−2.70 (m, 1H), 1.82−1.64 (m, 5H), 1.09

(s, 9H). p-Toluenesulfonic acid monohydrate (8.8 g, 46 mmol) was

charged to a suspension of alcohol 53 (7.59 g, ∼80 wt %, 38.6 mmol)

in water (130 mL). After agitation until a homogeneous solution was

obtained, RuCl₃Hydrate (174 mg, 0.84 mmol) followed by NaIO₄

(24.8 g, 116 mmol) were charged to the reaction. The reaction was

agitated at ambient temperature for 1.5 h; at which point, LC-MS

showed >95% oxidation to the carboxylic acid product. The reaction

was slowly quenched by the portion wise addition of sodium sulﬁte

(68.5 g) at a rate to control the batch temperature at 20−40 °C until

no exothermic reaction was observed upon addition of additional

sodium sulﬁte. The reaction mixture was ﬁltered. The pH of the

aqueous ﬁltrate was adjusted to 7.5 by the addition of aqueous NaOH

(40 wt % in water). This aqueous portion was subjected to a

continuous extraction by distillation with methylene chloride for 5 d.

The extracted organic portion was concentrated to a solid. The solids

were suspended in methanol (100 mL) and polished ﬁltered through a

Celite plug. The ﬁltrate was concentrated in vacuo to a solid and

chased with toluene. The solid was recrystallized in a solvent system of

n-propanol, toluene and MTBE to provide N-t-Bu-^L-Pro 33 as an oﬀ-

white solid (1.4 g, 21%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.86 (d, J

1

which solid (2.18g, 76%). H NMR (400 MHz, MeOH-d₄) δ 3.31 (s,

1H), 2.98 (s, 6H), 1.21 (s, 9H). ¹³C NMR (100 MHz, MeOH-d⁴) δ

172.03, 81.38, 44.42, 33.82, 28.77. [α]_D= +23 (c = 0.55 in MeOH).

HRMS-ESI C₈H₁₇NO₂calcd for [M + H]⁺160.1332 found 160.1328.

N-Isopropyl-^L-Proline (30). Ligand 30 was prepared by modiﬁed

published procedures.^69,70aL-Proline (28 g, 240 mmol), 10 wt % Pd on

Carbon (7.8 g, 7.3 mmol) acetone (89 mL) and methanol (250 mL)

were charged to a pressure reactor. The reactor was ﬂushed with

nitrogen followed by hydrogen. The vessel was pressurized with

hydrogen to 200 psi and agitated at 80 °C for 2 d. The reaction was

cooled to 20 °C and ﬂushed with nitrogen. The reaction mixture was

diluted with methanol (200 mL) and ﬁltered through a Celite (30 g)

plug eluting with methanol (100 mL). The ﬁltrate was concentrated in

vacuo to a yellow oil and chased with toluene. Concentration in vacuo

provided a solid. The solid was suspended in toluene (70 mL), and the

solids were dissolved at 90 °C by the addition of n-propanol (70 mL).

The resulting solution was further diluted with toluene (250 mL) at 90

°C. The homogeneous solution was slowly cooled to 20 °C over 1 h to

induce crystallization. The mixture was diluted with MTBE (650 mL)

dropwise over 30 min at 20 °C. After agitating the slurry for 1 h, the

solids were collected by ﬁltration and washed with MTBE to provide

N-iPr-^L-Pro 30 as a slightly oﬀ white crystalline solid (35.6 g, 93%)

after drying in a vacuum oven at 70 °C with a nitrogen stream for 14 h.

Chiral HPLC with a Chirobiotic T (4.6 × 150 mm) column (200 nm

detection, 5% MeCN in HPLC grade water, 2.5 mL/min, 50 °C)

showed >99% ee favoring the 1.6 min over the 2.2 min peak. ¹H NMR

(400 MHz, MeOH-d₄) δ 3.93 (dd, J = 4.4, 9.3 Hz, 1H), 3.70 (ddd, J =

2.9, 6.9, 10.8 Hz, 1H), 3.57 (septet, J = 6.5, Hz, 1H), 3.16 (ddd, J =

6.8, 10.6, 10.6 Hz, 1H), 2.40−2.25 (m, 1H), 2.20−2.10 (m, 1H),

2.08−1.98 (m, 1H), 1.93−1.75 (m, 1H), 1.32 (d, J = 6.6 Hz, 3H), 1.33

(d, J = 6.5 Hz, 3H). ¹³C NMR (100 MHz, MeOH-d₄) δ 173.9, 67.4,

57.9, 53.2, 31.0, 25.0, 18.4. [α]_D= −55 (c = 1.28 in MeOH). HRMS-

ESI C₈H₁₅NO₂calcd for [M + H]⁺158.1176 found 158.1171.

N-Cyclopentyl-^L-Proline (31). A mixture of proline (10.1 g, 87.7

mmol), cyclopentanone (37 g, 0.44), and Pd on Carbon (10 wt %, 1

g) were agitated in methanol (174 mL) under hydrogen (50 psi) at

50−80 °C for 16 h. After cooling to ambient temperature and ﬂushing

Q

dx.doi.org/10.1021/jo400080y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

= 9.8 Hz, 1H), 3.52 (dd, J = 6.4, 11.8 Hz, 1H), 3.08 (ddd, J = 6.4, 11.5,

11.5 Hz, 1H), 2.15−2.07 (m, 1H), 1.96−1.80 (m, 2H), 1.60−1.46 (m,

1H), 1.26 (s, 9H). ¹³C NMR (100 MHz, DMSO-d₆) δ 169.5, 64.1,

59.8, 48.8, 29.7, 24.6, 24.0. [α]_D= −50 (c = 0.50 in MeOH). HRMS-

ESI C₉H₁₇NO₂calcd for [M + H]⁺172.1332 found 172.1332

(S)-2-(1-Isopropylpyrrolidin-2-yl)propan-2-ol (37). (S)-2-(pyr-

rolidin-2-yl)propan-2-ol⁷⁶(1.95 g, 15.1 mmol) was subjected to a

heterogeneous reaction with 10 wt % Pd on carbon (300 mg) in

acetone (14.2 mL) and methanol (22 mL) under hydrogen (40 psi) at

room temperature for 6 h. The reaction mixture was ﬁltered, and the

ﬁltrate was concentrated to an oil. Puriﬁcation by alumina

chromatography (ethyl acetate in hexanes) provided the intended

amino alcohol 37 as a nearly colorless oil (1.3 g, 50%). ¹H NMR (400

MHz, CD₃OD) δ 3.14 (septet, J = 6.6 Hz, 1H), 2.82−2.71 (m, 3H),

1.80−1.58 (m, 4H), 1.14 (s, 3H), 1.12 (d, J = 6.9 Hz, 3H), 1.11 (s,

3H), 0.95 (d, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 74.53,

sodium methoxide solution (25 wt % NaOMe, 16.77 kg, 77.6 mol) was

charged to the well agitated batch at 20 to 35 °C. The batched was

aged for an additional 90 min at 30 to 35 °C; at which point, >99%

deprotection was observed by HPLC vide infra. After cooling the batch

to 20 °C, aqueous HCl (3.0 M, 23.14 kg) was charged to the reactor at

a rate to maintain the batch temperature between 20 to 35 °C. Water

(47.71 kg) was subsequently charged to the batch. For an eﬀective

workup, the pH of the aqueous layer should be 5.0 to 7.0 and adjusted

if necessary. The pH of the aqueous layer for this batch was 6.9. The

contents of the batch were distilled under vacuum with a batch

temperature of no more than 65 °C to remove 117.4 kg of distillate

and aﬀorded an aqueous slurry. Isopropyl acetate (90.61 kg) was

charged to the batch at 60 °C, and the batch temperature was

subsequently adjusted to 20 °C. Aqueous HCl (3.0 M, 5.46 kg) was

charged to the batch. The batch was agitated for one hour; at which

point, the layers were separated. The organic portion was washed with

water (26.0 kg). The organic portion was concentrated under vacuum

with a batch temperature of no more than 75 °C to remove 75.3 kg of

distillate. The batch temperature was adjusted to 80 to 83 °C and held

at this temperature for 30 min to dissolve the solids. The batch

temperature was adjusted to 75 °C; at which point, a slurry of seeds

(33 g) in a solvent mixture of isopropyl acetate (91 g) and heptane

(221 g) was charged to the batch to induce crystallization. The batch

was cooled to 60 °C and aged at this temperature for 30 min followed

by cooling to 20 °C over one hour. Heptane (10.70 kg) followed by

isopropyl acetate (4.72 kg) were charged to the batch consecutively

over 90 min. Additional heptane (46.3 kg) was charged to the batch

over 90 min. After aging the batch at 20 °C for 10 h, the product was

isolated by ﬁltration. The solids were washed with 15 vol% isopropyl

acetate in heptane and dried in a vacuum oven at no higher than 55 °C

with a nitrogen stream until by thermogravimetric analysis (TGA) < 1

wt % loss up to 140 °C was observed. The homopropargylic alcohol 7a

was isolated as a white to oﬀ white solid (10.795 kg, 98.5 wt %, 75%)

in 99.2:0.8 dr and 99:1 site selectivity favoring the homopropargylic

alcohol 7a over the allenylic alcohol 23. ¹H NMR (500 MHz, CDCl₃)

δ 7.49 (dd, J = 5.1, 8.7 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.05 (ddd, J

= 3.1, 8.5, 8.5 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 6.84 (dd, J = 3.4, 8.7

Hz, 1H), 6.10 (d, J = 8.3 Hz, 1H), 6.05 (s, 1H), 5.29 (dddd, J = 7.1,

7.1, 7.1, 7.1 Hz, 1H), 3.82 (s, 3H), 2.56 (d, J = 15.3 Hz, 1H), 2.51 (d, J

= 18.5 Hz, 1H), 2.40 (d, J = 17.8 Hz, 1H), 2.29 (d, J = 15.3 Hz, 1H),

2.07 (t, J = 2.1 Hz, 1H), 1.62 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.42 (s,

3H). ¹³C NMR (125 MHz, CDCl₃) δ 171.8 (d, J = 1.8 Hz), 160.5 (d, J

= 249 Hz), 159.3, 140.5 (d, J = 3.5 Hz), 137.3 (d, J = 5.8 Hz), 133.9,

130.1 (d, J = 7.6 Hz), 127.5, 125.7 (q, J = 289 Hz), 116.5 (d, J = 19.4

Hz), 115.4 (d, J = 22.6 Hz), 114.3, 78.8, 75.4 (q, J = 26.7 Hz), 71.7,

55.3, 49.1, 42.8, 37.0, 33.3, 33.2, 23.9, 20.64. HRMS-ESI

C₂₅H₂₇F₄NO₃calcd for [M + H]⁺466.1998 found 466.1987.

71.01, 53.93, 46.81, 28.78, 27.71, 26.68, 26.10, 23.00, 14.59. [α]_D

=

−39 (c = 0.57 in MeOH). HRMS-ESI C₁₀H₂₁NO calcd for [M + H]⁺

172.1696 found 172.1702.

(S)-(1-Isopropylpyrrolidin-2-yl)diphenylmethanol (38). (S)-

diphenyl(pyrrolidin-2-yl)methanol⁷⁷(12.0 g, 47.3 mmol) was

subjected to a reaction with acetone (13.8, 237 mmol), sodium

cyanoborohydride (6.0 g, 95 mmol) in acetonitirle (100 mL) and

acetic acid (0.1 mL) at ambient temperature for 18 h. The reaction was

concentrated to an oily solid. The residue was dissolved in ethylacetate

and water. The layers were separated. The organic layer was diluted

with brine and subjected to a thorough back extraction with ethyl

acetate. The organic layers were concentrated to a solid. Puriﬁcation

by silica gel chromatography (ethyl acetate in hexanes) provided the

1

intended amino alcohol 38 as a which solid (3.5 g, 25%). H NMR

(400 MHz, CD₃OD) δ 7.65−7.60 (m, 2H), 7.58−7.53 (m, 2H), 7.28−

7.19 (m, 4H), 7.15−7.08 (m, 2H), 4.11 (dd, J = 4.6, 8.8 Hz, 1H),

2.90−2.83 (m, 1H), 2.82−2.74 (m, 1H), 2.08 (septet, J = 6.8, 1H),

1.89−1.76 (m, 1H), 1.70−1.51 (m, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.81

(d, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 149.95, 148.10,

128.82, 128.81, 127.15, 127.13, 127.00, 126.62, 78.93, 68.98, 50.69,

46.44, 31.06, 25.85, 22.95, 13.60. [α]_D= −6.9 (c = 0.73 in MeOH).

HRMS-ESI C₂₀H₂₅NO calcd for [M + H]⁺296.2009 found 296.2015.

GENERAL PROCEDURE FOR THE ZINC MEDIATED

ASYMMETRIC PROPARGYLATION

■

5-Fluoro-2-((S)-4-hydroxy-2-methyl-4-(triﬂuoromethyl)hept-

6-yn-2-yl)-N-((S)-1-(4-methoxy-phenyl)ethyl)benzamide (7a).

N-iPr-^L-Pro 30 (5.993 kg, 98.7 wt %, 37.63 mol) was charged to a

dried 200 L reactor under nitrogen followed by THF (KF < 500 ppm,

76.7 kg). After obtaining adequate agitation at 20 °C, diethyl zinc⁷⁸

(2.30 M in toluene, d = 0.941 g/mL, 14.95 kg, 36.5 mol) was charged

to the slurry subsurface at a rate to maintain the batch temperature

between 20 to 35 °C. The heterogeneous slurry with a gentle gas

evolution was agitated at 40 to 45 °C for 3 h to aﬀord a homogeneous

solution with no gas evolution. The batch was cooled to 20 °C. [Note:

Additional water was not charged to the batch since an unknown and

adequate amount of water introduced from the ketone 6a, borolane

21, and solvent THF at the next addition was suﬃcient for good

conversion and diastereoselectivity. For reproducibility, 22 g of water

as a THF (100−200 mL) solution is recommended to be charged to

the batch at this point for reasons detailed in this manuscript.] A

solution of triﬂuoromethyl ketone 6a (13.29 kg, 97.8 wt %, 30.6 mol)

and propargyl borolane 21 (9.36 kg, 93.5 wt %, 36.7 mol) in THF

(<500 ppm water, 23.1 kg) prepared under nitrogen was charged to

the reactor slowly over 10 h at 20 °C. After agitation for an additional

3 h, HPLC analysis (TSKgel SuperODS, 4.6 mm × 5 cm, 10 to 90%

gradient of MeCN in water over 8 min) showed 99% conversion and

81:19 diastereoselectivity for the homopropargylic alcohol 11a

intermediate. The reaction was quenched by the exothermic slow

addition of aqueous HCl (3.0 M, 38.5 kg) at a rate such that the gas

evolution was controlled and the batch temperature was maintained

between 20 to 35 °C. The resulting mixture was agitated for an

additional 1 h; at which point, the layers were separated. A methanolic

GENERAL PROCEDURE FOR THE ZINC CATALYZED

ASYMMETRIC PROPARGYLATION

■

5-Fluoro-2-((R)-4-hydroxy-2-methyl-4-(triﬂuoromethyl)-7-

(trimethylsilyl)hept-6-yn-2-yl)-N-((S)-1-(4-methoxyphenyl)-

ethyl)benzamide (11a). Diethyl zinc⁷⁸(2.3 M in toluene, 326 μL,

0.75 mmol) was charged to an anhydrous suspension of N-isopropyl-^L-

proline 30 (127 mg, 0.81 mmol) in THF (2.1 mL) under argon at

ambient temperature. The reaction slurry with a gentle gas evolution

was agitated at 40 °C for 3 h; at which point, no gas evolution was

observed and a homogeneous solution of the N-iPr-^L-Pro-Zn-Et 50

was obtained. The solution was cooled to ambient temperature; at

which point, a water-THF solution (0.26 wt % water in THF, 416 mg,

0.06 mmol water) was charged to the catalyst solution. The solution

was agitated for 30 min. The homogeneous solution was cooled to

−40 °C. An anhydrous homogeneous solution of ketone 6a (1.25 g,

97.9 wt %, 2.9 mmol) and borolane 21 (855 mg, 3.6 mmol) in THF

(3.5 mL) held at ambient temperature was charged to the catalyst

solution at −40 °C dropwise over 6 h. The reaction was agitated at

−40 °C for 2 d; at which point, complete conversion, 90:10 dr

favoring the 7.76 over the 7.66 min diastereomer determined by

HPLC (TSKgel SuperODS, 4.6 mm × 5 cm, 10 to 90% gradient of

R

dx.doi.org/10.1021/jo400080y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

MeCN in water over 8 min), and 93:7 site selectivity favoring

propargylation over allenylation were observed. The reaction was

quenched by the addition of 3 M aqueous HCl (1 mL) and allowed to

warm to ambient temperature. Diethanolamine (1.5 mL) was charged

to the reaction, and the reaction was agitated for 2 h. The reaction was

diluted with isopropyl acetate (40 mL) and washed with water (2 × 20

mL). The organic portion was concentrated to an oil. Puriﬁcation by

silica gel chromatography (ethyl acetate and hexanes) provided

homopropargylic alcohol 11a as an inseparable diastereomeric mixture

of 90:10 dr favoring the desired diastereomer 11a (1.25 g, 78%).

reaction mixture from the zinc-mediated diastereoselective propargy-

lation of ketone 6a and isolated as an amorphous white solid in less

than 5% yield. Mixture of Diastereomers: ¹H NMR (500 MHz,

CDCl₃) δ 7.40−7.33 (m, 1H), 7.33−7.28 (m, 2H), 7.04−6.96 (m,

1H), 6.94−6.81 (m, 3H), 6.12−6.03 (m, 1H), 5.36−5.22 (m, 2H),

4.56−4.43 (m, 2H), 3.81 (s, 1.66 H), 3.80 (s, 1.39 H), 2.70 (d, J = 15.9

Hz, 0.62 H), 2.58 (d, J = 15.2 Hz, 0.43 H), 2.25 (d, J = 15.1 Hz, 0.62

H), 2.17 (d, J = 15.2 Hz, 0.44 H), 1.64−1.58 (m, 3H), 1.50 (s, 1.2 H),

1.49 (s, 1.8 H), 1.34 (s, 1.8 H), 1.16 (s, 1.2 H), 0.05 (s, 3.4 H), 0.03 (s,

5.6 H). ¹³C NMR (125 MHz, CDCl₃) δ 210.01, 209.89, 171.58 (d, J =

1.8 Hz), 171.54 (d, J = 1.8 Hz), 160.26 (d, J = 248 Hz), 160.25 (d, J =

248 Hz), 159.19, 159.19, 141.53 (d, J = 3.8 Hz), 141.45 (d, J = 3.8

Hz), 137.20 (d, J = 5.8 Hz), 137.13 (d, J = 5.8 Hz), 134.05, 133.82,

130.35 (d, J = 7.4 Hz), 130.33 (d, J = 7.4 Hz), 127.73, 127.55, 126.02

(q, J = 288 Hz), 125.98 (q, J = 288 Hz), 116.10 (d, J = 19.9 Hz),

116.04 (d, J = 19.3 Hz), 115.26 (d, J = 22.5 Hz), 115.22 (d, J = 22.5

Hz), 114.23, 114.14, 98.02, 97.82, 77.93 (q, J = 26.4 Hz), 77.86 (q, J =

26.4 Hz), 71.72, 71.61, 55.30, 55.30, 49.10, 49.08, 45.57, 45.46, 37.69,

37.62, 34.50, 34.39, 31.43, 31.43, 20.77, 20.67, 0.47, 0.46. HRMS-ESI

C₂₈H₃₅F₄NO₃Si calcd for [M + H]⁺538.2395 found 538.2390.

(R)-6-(5-Fluoro-2-methylphenyl)-6-methyl-4-(triﬂuorometh-

yl)-1-(trimethylsilyl)hept-1-yn-4-ol (11b). Homopropargylic alco-

hol (S)-11b was prepared by the general procedure for the zinc-

catalyzed asymmetric propargylation with 1,1,1-triﬂuoro-4-(5-ﬂuoro-2-

methylphenyl)-4-methylpentan-2-one 6b (0.787 g, 3.0 mmol) to

provide alcohol (S)-11b as a colorless oil (1.01 g, 90%) in 90:10

enantiomeric ratio determined by chiralcel AD-H of the terminal

alkyne derivative 7b prepared by proto-desilylation with potassium

carbonate in methanol (1% IPA in heptane, 2.0 mL/min, 210 nm)

1

Major Diastereomer: H NMR (500 MHz, CDCl₃) δ 7.50 (dd, J =

5.6, 9.0 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.04 (ddd, J = 2.5, 7.9, 7.9

Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 2.9, 8.4 Hz, 1H), 6.10

(d, J = 8.8 Hz, 1H), 6.02 (s, 1H), 5.28 (dddd, J = 7.1, 7.1, 7.1, 7.1 Hz,

1H), 3.82 (s, 3H), 2.54 (d, J = 15.2 Hz, 1H), 2.51 (d, J = 17.9 Hz, 1H),

2.40 (d, J = 17.9 Hz, 1H), 2.29 (d, J = 15.2 Hz, 1H), 1.63 (s, 3H), 1.59

(d, J = 7.1 Hz, 3H), 1.42 (s, 3H), 0.16 (s, 9H). ¹³C NMR (125 MHz,

CDCl₃) δ 171.8 (d, J = 1.7 Hz), 160.5 (d, J = 248 Hz), 159.2, 140.6 (d,

J = 3.85 Hz), 137.3 (d, J = 5.7 Hz), 133.9, 130.1 (d, J = 7.5 Hz), 127.5,

125.8 (q, J = 291 Hz), 116.5 (d, J = 19.4 Hz), 115.4 (d, J = 22.9 Hz),

114.3, 101.4, 88.6, 75.6 (q, J = 25.9 Hz), 55.3, 49.0, 42.7, 36.9, 33.35,

1

33.28, 25.1, 20.6, −0.17. Minor Diastereomer: H NMR (500 MHz,

CDCl₃) δ 7.48 (dd, J = 5.4, 9.6 Hz, 1H), 7.33−7.27 (m, 2H), 7.04

(ddd, J = 3.0, 7.7, 7.7 Hz, 1H), 6.99−6.87 (m, 2H), 6.82 (dd, J = 2.9,

8.9 Hz, 1H), 6.07 (d, J = 8.3 Hz, 1H), 5.96 (s, 1H), 5.27 (dddd, J =

7.1, 7.1, 7.1, 7.1 Hz, 1H), 3.81 (s, 3H), 2.52 (d, J = 15.4 Hz, 1H), 2.43

(d, J = 17.5 Hz, 1H), 2.41 (d, J = 17.5 Hz, 1H), 2.23 (d, J = 15.1 Hz,

1H), 1.62 (d, J = 7.2 Hz, 3H), 1.60 (s, 3H), 1.18 (s, 3H), 0.15 (s, 9H).

¹³C NMR (125 MHz, CDCl₃) δ 171.8 (d, J = 1.7 Hz), 160.5 (d, J =

248 Hz), 159.2, 140.7 (d, J = 3.85 Hz), 137.4 (d, J = 5.7 Hz), 133.5,

130.1 (d, J = 7.5 Hz), 127.7, 125.8 (q, J = 291 Hz), 116.4 (d, J = 19.4

Hz), 115.5 (d, J = 22.9 Hz), 114.2, 101.3, 88.6, 75.7 (q, J = 25.9 Hz),

55.3, 49.2,42.7, 36.8, 33.21, 33.16, 25.2, 20.9, −0.18. HRMS-ESI for

diastereomeric mixture C₂₈H₃₅F₄NO₃Si calcd for [M + H]⁺538.2395

found 538.2383.

1

favoring the 3.26 min over the 2.97 min enantiomer. H NMR (400

MHz, CDCl₃) δ 7.13 (dd, J = 2.7, 12.1 Hz, 1H), 7.07 (dd, J = 7.0, 8.0

Hz, 1H), 6.83 (ddd, J = 2.9, 8.0, 8.0 Hz, 1H), 2.52 (s, 3H), 2.51 (d, J =

15.7 Hz, 1H), 2.46 (d, J = 18.9 Hz, 1H), 2.36 (s, 1H), 2.34 (d, J = 18.9

Hz, 1H), 2.27 (d, J = 15.7 Hz, 1H), 1.57 (s, 3H), 1.51 (s, 3H) 0.12 (s,

9H). ¹³C NMR (100 MHz, CDCl₃) δ 161.3 (d, J = 243.1 Hz), 147.2

(d, J = 6.1 Hz), 134.5 (d, J = 7.8 Hz), 131.6 (d, J = 3.0 Hz), 125.7 (q, J

= 287.8 Hz), 114.6 (d, J = 22.7 Hz), 113.1 (d, J = 20.4 Hz), 99.5, 90.1,

75.1 (q, J = 26.4 Hz), 40.4, 38.6, 31.4, 30.7, 26.6 (q, J = 1.4 Hz), 22.7,

−0.26. HRMS-ESI C₁₉H₂₆F₄OSi calcd for [M + NH₄]⁺392.2027

found 392.2020.

Allene Isomer 23. Diethyl zinc (1.1 M in toluene, 64 μL, 70

μmol) was charged to a solution of ketone 6a (600 mg, 1.41 mmol)

and allenyl borolane 22 (328 mg, 1.97 mmol) in toluene (10 mL)

under argon at ambient temperature. The homogeneous reaction was

agitated for 3 h; at which point, HPLC showed complete conversion.

Diethanolamine (1 g) was charged to the reaction, and the reaction

was agitated at ambient temperature for 45 min. The reaction was

diluted with isopropyl acetate (20 mL) and washed with aqueous HCl

(1.5 M, 2 × 30 mL) followed by water (2 × 30 mL). The organic

portion was concentrated to an oil. ¹H NMR analysis on the oil

showed 95:5 site selectivity favoring allenylation over propargylation.

The product was puriﬁed by silica gel chromatography (12% EtOAc in

hexanes) to provide the intended allenyl alcohol 23 as a nearly equal

mixture of diastereomers and as a white foam (575 mg, 88% yield).

Mixture of Diastereomers: ¹H NMR (500 MHz, CDCl₃) δ 7.39−7.32

(m, 1H), 7.32−7.25 (m, 2H), 7.02−6.95 (m, 1H), 6.92−6.79 (m, 3

H), 6.37 (t, J = 7.0 Hz, 0.5H), 6.27 (t, J = 6.0 Hz, 0.5 H), 5.41 (bs,

0.5H), 5.30−5.18 (m, 1H), 5.16−5.08 (m, 1H), 5.05 (bs, 0.5 H),

4.89−4.80 (m, 1H), 4.73−4.64 (m, 1H), 3.79 (s, 1.5 H), 3.78 (s, 1.5

H), 2.61 (d, J = 15.6 Hz, 0.5 H), 2.57 (d, J = 15.6 Hz, 0.5 H), 2.06 (d, J

= 15.6 Hz, 0.5 H), 2.03 (d, J = 15.6 Hz, 0.5 H), 1.61−1.50 (m, 6H),

1.37 (s, 1.5 H), 1.22 (s, 1.5 H). ¹³C NMR (125 MHz, CDCl₃) δ

207.33, 207.07, 171.43 (d, J = 1.7 Hz), 171.30 (d, J = 1.7 Hz), 160.42

(d, J = 248 Hz), 160.40 (d, J = 248 Hz), 159.08, 159.04, 140.22 (d, J =

4.0 Hz), 140.02 (d, J = 3.6 Hz), 137.83 (d, J = 5.9 Hz), 137.53 (d, J =

5.7 Hz), 134.02, 133.97, 130.51 (d, J = 7.4 Hz), 130.38 (d, J = 7.4 Hz),

127.55, 127.48, 125.16 (q, J = 287 Hz), 125.10 (q, J = 287 Hz), 115.59

(d, J = 19.6 Hz), 115.43 (d, J = 19.6 Hz), 115.25 (d, 22.6 Hz), 115.17

(d, J = 22.6 Hz), 114.13, 114.05, 90.94, 90.84, 79.86, 79.45, 74.20 (q, J

= 27.2 Hz), 55.23, 55.21, 49.00, 48.89, 44.87, 44.62, 37.13, 37.10,

32.70, 32.70, 32.11, 31.98, 20.90, 20.57. HRMS-ESI C₂₅H₂₇F₄NO₃

calcd for [M + H]⁺466.1998 found 466.1996.

( S ) - 6 - ( 5 - F l u o r o - 2 - m e t h y l p h e n y l ) - 6 - m e t h y l - 4 -

(triﬂuoromethyl)hept-1-yn-4-ol (7b). N-iPr-^L-Pro 30 (16.338 g,

97.6 wt %, 0.101 mol) was charged under nitrogen followed by THF

(technical grade, 350 mL) to a reactor. After obtaining adequate

agitation for the slurry at 22 °C, diethyl zinc⁷⁸(2.30 M in toluene, d =

0.941 g/mL, 35.0 mL, 0.080 mol) was charged to the batch subsurface

at a rate to maintain the batch temperature between 20 to 30 °C. The

heterogeneous slurry with a gentle gas evolution was agitated at 40 to

45 °C for 45 min to aﬀord a homogeneous solution. The batch was

cooled to 20 °C and water (0.19 g, 0.01 mol) and THF (2 mL) were

added. A solution of triﬂuoromethyl ketone 6b (70 g, 0.267 mol) and

propargyl borolane 21 (73.935 g, 86.0 wt %, 0.267 mol) in THF (206

mL) prepared under nitrogen was charged to the reactor slowly over

100 min at 20 °C. After rinsing the charge with THF (10 mL) and

agitation for an additional 30 min, HPLC analysis showed 99%

conversion. The reaction was quenched by the exothermic slow

addition of aqueous HCl (3.0 M, 320 mL) at a rate such that the batch

temperature was maintained between 20 to 25 °C. The resulting

mixture was agitated for an additional 10 min; at which point, the

layers were separated. A methanolic sodium methoxide solution (30 wt

% NaOMe, 122.56 g, 0.681 mol) was charged to the well agitated

batch at 20 to 35 °C followed by rinsing the charge with methanol (10

mL). The batched was agitated for an additional 40 min at 30 to 35

°C; at which point, >99% deprotection was observed by HPLC. After

cooling the batch to 20 °C, aqueous HCl (3.0 M, 280 mL) was

charged to the reactor at a rate to maintain the batch temperature

between 20 to 30 °C. The resulting mixture was agitated for an

additional 10 min; at which point, the layers were separated. The

organic solution was concentrated under reduced pressure to the crude

homopropargylic alcohol 7b (94 g, 77.8 wt %, 91%). The desired

Allene Isomer 24. An analytical standard for the diastereomeric

mixture of allene 24 was obtained after extensive puriﬁcation by silica

gel chromatography (EtOAc and hexanes) of the crude propargylation

S

dx.doi.org/10.1021/jo400080y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

product 7b was isolated after puriﬁcation by distillation in vacuo as a

yellow oil (63.7 g, 89.9 wt %, 71%). Chiral HPLC with a Chiralpak

AD-3 column (1.6% IPA in hexanes, 0.5 mL/min, 10 °C, 215 nm)

showed 84.2:15.8 er favoring the 17.72 min peak over the 12.67 min

peak. ¹H NMR (500 MHz, CDCl₃) δ 7.14 (dd, J = 2.6, 12.0 Hz, 1H),

7.08 (dd, J = 7.8, 8.1 Hz, 1H), 6.84 (ddd, J = 2.8, 8.0, 8.0 Hz, 1H), 2.53

(s, 3H), 2.51−2.43 (m, 2H), 2.37−2.29 (m, 2H), 2.27 (s, 1H), 2.08 (t,

J = 2.5 Hz, 1H), 1.57 (s, 3H), 1.53 (s, 3H). ¹³C NMR (123 MHz,

CDCl₃) δ 161.3 (d, J = 243 Hz), 147.0 (d, J = 6.1 Hz), 134.6 (d, J =

7.7 Hz), 131.7 (d, J = 3.2 Hz), 125.7 (q, J = 288 Hz), 114.7 (d, J = 23

Hz), 113.2 (d, J = 20 Hz), 77.5, 75.1 (q, J = 27 Hz), 72.9 (q, J = 0.8

Hz), 40.3, 38.7 (d, J = 1.3 Hz), 31.3, 30.8, 25.4 (q, J = 1.64 Hz), 22.6.

HRMS-ESI C₁₆H₁₈F₄O calcd for [M + H]⁺303.1367 found 303.1343.

(R)-6-(2-Methylphenyl)-6-methyl-4-(triﬂuoromethyl)-1-

(trimethylsilyl)hept-1-yn-4-ol (11c). Homopropargylic alcohol (S)-

11c was prepared by the general procedure for the zinc-catalyzed

asymmetric propargylation with 1,1,1-triﬂuoro-4-(2-methylphenyl)-4-

methylpentan-2-one 6c (0.787 g, 3.22 mmol) to provide alcohol (S)-

11c as a colorless oil (1.03 g, 90%) in 92:8 enantiomeric ratio

determined by chiralpak OJ-RH HPLC (45% 0.1% AcOH in water to

55% MeCN, 1.2 mL/min, 220 nm) favoring the 10.13 min over the

determined by chiralpak AD-H HPLC of the terminal alkyne

derivative after proto-desilylation with potassium carbonate in

methanol (10% IPA in heptane, 2 mL/min, 210 nm). ¹H NMR

(500 MHz, CDCl₃) δ 7.40 (d, J = 2.75 Hz, 1H), 7.32 (dd, J = 2.4, 8.6

Hz, 1H), 6.75 (d, J = 8.70 Hz, 1H), 3.83 (s, 3H), 2.57 (d, J = 15.3 Hz,

1H), 2.50 (s, 1H), 2.48 (d, J = 17.2 Hz, 1H), 2.42 (d, J = 15.3 Hz, 1H),

2.34 (d, J = 17.2 Hz, 1H), 1.48 (s, 3H), 1.46 (s, 3H), 0.15 (s, 9H). ¹³C

NMR (125 MHz, CDCl₃) δ 157.1, 137.7, 130.63, 130.5, 125.7 (q, J =

287 Hz), 113.6, 113.2, 99.9, 89.8, 75.0 (q, J = 26.2 Hz), 55.2, 39.9,

37.5, 30.7, 30.0, 26.5, −0.20. HRMS-ESI C₁₉H₂₆BrF₃O₂Si calcd for [M

+ NH₄]⁺468.1176 found 468.1177.

(S)-2-(4-(Dimethylamino)phenyl)-1,1,1-triﬂuoro-5-

(trimethylsilyl)pent-4-yn-2-ol (11g). Homopropargylic alcohol

(R)-11g was prepared by the general procedure for the zinc-catalyzed

asymmetric propargylation with 1-(4-(dimethylamino)phenyl)-2,2,2-

triﬂuoroethanone 6g (0.625 g, 2.9 mmol) to provide alcohol (R)-11g

as a colorless oil (0.867 g, 91%) in 86:14 enantiomeric ratio favoring

the 3.65 over the 3.34 min enantiomer determined by chiralpak AD-H

HPLC (1% IPA in heptane, 2 mL/min, 220 nm). ¹H NMR (400 MHz,

CDCl₃) δ 7.40 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.9 Hz, 2H), 3.13 (d, J

= 17.1 Hz, 1H), 3.07 (bs, 1H), 3.00 (d, J = 17.1 Hz, 1H), 2.97 (s, 6H),

0.10 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 150.6, 127.1, 125.2 (q, J

= 286 Hz), 123.7, 111.7, 99.1, 90.7, 74.9 (q, J = 28.5 Hz), 40.3, 28.9,

−0.24. HRMS-ESI C₁₆H₂₂F₃NOSi calcd for [M + H]⁺330.1510 found

330.1491.

(S)-1,1,1-Triﬂuoro-2-(3-(triﬂuoromethyl)phenyl)-5-

(trimethylsilyl)pent-4-yn-2-ol (11h). Homopropargylic alcohol

(R)-11h was prepared by the general procedure for the zinc-catalyzed

asymmetric propargylation with 2,2,2-triﬂuoro-1-(3-(triﬂuoromethyl)-

phenyl)ethanone 6h (0.726 g, 3.0 mmol) to provide alcohol (R)-11h

as a colorless oil (0.887 g, 83%) in 81:19 enantiomeric ratio favoring

the 2.72 over the 3.04 min enantiomer determined by chiralpak OJ-H

HPLC (2% IPA in heptane, 2 mL/min, 220 nm). ¹H NMR (400 MHz,

CDCl₃) δ 7.87 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.1 Hz,

1H), 7.54 (dd, J = 7.6, 7.7 Hz, 1H), 3.19 (s, 1H), 3.17 (d, J = 17.3 Hz,

1H), 3.06 (d, J = 17.3 Hz, 1H), 0.65 (s, 9H). ¹³C NMR (100 MHz,

CDCl₃) δ 137.8, 130.8 (q, J = 32 Hz), 129.8, 128.8, 125.7 (q, J = 3.7

Hz), 124.7 (q, J = 287 Hz), 124.1 (q, J = 273 Hz), 123.5 (q, J = 3.4

Hz), 97.6, 91.8, 75.1 (q, J = 28 Hz), 29.1, −0.44. HRMS-ESI

C₁₅H₁₆F₆OSi calcd for [M + TFA]⁻467.0731 found 467.0728.

(S)-2-(4-Chlorophenyl)-1,1,1-triﬂuoro-5-(trimethylsilyl)pent-

4-yn-2-ol (11i). Homopropargylic alcohol (S)-11i was prepared by

the general procedure for the zinc-catalyzed asymmetric propargyla-

tion with 1-(4-chlorophenyl)-2,2,2-triﬂuoroethanone 6i (0.626 g, 3.0

mmol) to provide alcohol (S)-11i as a colorless oil (0.671 g, 70%) in

85:15 enantiomeric ratio determined by chiralcel OJ-RH HPLC (45%

0.1 AcOH in water pH adjusted to 4.5 with NH₄OH and 55% MeCN,

1.2 mL/min, 220 nm) favoring the 6.43 min over the 5.46 min

enantiomer. ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 8.6 Hz, 2H),

7.34 (d, J = 8.6 Hz, 2H), 3.14 (d, J = 17.3 Hz, 1H), 3.15 (bs, 1H), 3.00

(d, J = 17.3 Hz, 1H), 0.09 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃) δ

135.2, 135.0, 128.5, 127.9, 124.7 (q, J = 284.8), 98.0, 91.6, 74.9 (q, J =

28.8), 29.0 (q, J = 1.5 Hz), −0.32. HRMS-ESI C₁₄H₁₆ClF₃OSi calcd

for [M + TFA]⁻433.0467 found 433.0436.

1

9.58 min enantiomer. H NMR (400 MHz, CDCl₃) δ 7.44−7.38 (m,

1H), 7.20−7.10 (m, 3H), 2.57 (s, 3H), 2.53 (d, J = 15.7 Hz, 1H), 2.48

(d, J = 17.5 Hz, 1H), 2.34 (d, J = 17.5 Hz, 1H), 2.32 (d, J = 15.7 Hz,

1H), 2.31 (s, 1H), 1.58 (s, 3H), 1.55 (s, 3H), 0.14 (s, 9H). ¹³C NMR

(100 MHz, CDCl₃) δ 144.4, 136.3, 133.5, 127.3, 126.9, 126.5, 125.7

(q, J = 287.6 Hz), 99.9, 89.7, 75.4, (q, J = 27.0 Hz), 40.5, 38.6, 31.6,

31.0, 26.8 (q, J = 1.5 Hz), 23.5, −0.21. HRMS-ESI C₁₉H₂₇F₃OSi calcd

for [M+NH₄]+ 374.2122 found 374.2115.

(R)-6-(2-Bromo-4-ﬂuorophenyl)-6-methyl-4-(triﬂuorometh-

yl)-1-(trimethylsilyl)hept-1-yn-4-ol (11d). Homopropargylic alco-

hol (R)-11d was prepared by the general procedure for the zinc-

catalyzed asymmetric propargylation with 4-(2-bromo-4-ﬂuorophen-

yl)-1,1,1-triﬂuoro-4-methylpentan-2-one 6d (1.04g, 3.2 mmol) to

provide alcohol (R)-11d as a colorless oil (1.04 g, 75%) in 89:11

enantiomeric ratio favoring the 2.31 min over the 2.17 min enantiomer

determined by chiralpak IA HPLC (2% IPA in heptane, 2 mL/min,

1

220 nm). H NMR (400 MHz, CDCl₃) δ 7.48 (dd, J = 6.1, 9.0 Hz,

1H), 7.34 (dd, J = 2.8, 8.2 Hz, 1H), 7.00 (ddd, J = 2.8, 7.3, 9.0 Hz,

1H), 2.89 (d, J = 15.6 Hz, 1H), 2.45 (d, J = 15.2 Hz, 2H), 2.43 (s, 1H),

2.37 (d, J = 15.6 Hz, 1H), 1.63 (s, 3H), 1.59 (s, 3H), 0.14 (s, 9H). ¹³C

NMR (100 MHz, CDCl₃) δ 160.60 (d, J = 249 Hz), 141.01 (d, J = 3.7

Hz), 130.3 (d, J = 7.9 Hz), 125.7 (q, J = 289.7 Hz), 122.9 (d, J = 24.1

Hz), 122.1 (d, J = 8.7 Hz), 114.4 (d, J = 19.6 Hz), 99.2, 90.4, 74.9 (q, J

= 26.5 Hz), 39.2, 38.9, 31.0, 30.4, 26.5, −0.24. HRMS-ESI

C₁₈H₂₃BrF₄OSi calcd for [M + NH₄]⁺456.0976 found 456.0975.

(R)-6-Methyl-6-(2-(methylthio)phenyl)-4-(triﬂuoromethyl)-1-

(trimethylsilyl)hept-1-yn-4-ol (11e). Homopropargylic alcohol

(R)-11e was prepared by the general procedure for the zinc-catalyzed

asymmetric propargylation with 1,1,1-triﬂuoro-4-methyl-4-(2-

(methylthio)phenyl)pentan-2-one 6e (0.829 g, 3.0 mmol) to provide

alcohol (R)-11e as a colorless oil (0.980g, 84%) in 93:7 enantiomeric

ratio favoring the 2.44 over the 2.32 min enantiomer determined by

1

chiralpak IA HPLC (0.2% IPA in heptane, 2 mL/min, 220 nm). H

NMR (400 MHz, CDCl₃) δ 7.44 (dd, J = 1.5, 7.7 Hz, 1H), 7.33 (dd, J

= 1.5, 7.8 Hz, 1H), 7.22 (ddd, J = 1.7, 7.3, 7.3 Hz, 1H), 7.16 (ddd, J =

1.6, 7.4, 7.4 Hz, 1H), 2.90, (d, J = 15.4 Hz, 1H), 2.64 (s, 1H), 2.60 (d,

J = 15.6 Hz, 1H), 2.52 (s, 3H), 2.51 (d, J = 17.8 Hz, 1H), 2.39 (d, J =

17.5 Hz, 1H), 1.63 (s, 3H), 1.62 (s, 3H), 0.14 (s, 9H). ¹³C NMR (100

MHz, CDCl₃) δ 145.6, 137.1, 129.7, 127.6, 127.2, 126.0, 125.8 (q, J =

286.7 Hz), 100.0, 89.7, 75.4, (q, J = 25.7 Hz), 40.9, 39.0, 31.4, 30.9,

26.2, 18.2, −0.21. HRMS-ESI C₁₉H₂₇F₃OSSi calcd for [M + NH₄]⁺

406.1842 found 406.1842.

(R)-6-(5-Bromo-2-methoxyphenyl)-6-methyl-4-(triﬂuoro-

methyl)-1-(trimethylsilyl)hept-1-yn-4-ol (11f). Homopropargylic

alcohol (R)-11f was prepared by the general procedure for the zinc-

catalyzed asymmetric propargylation with 4-(5-bromo-2-methoxy-

phenyl)-1,1,1-triﬂuoro-4-methylpentan-2-one 6f (1.02 g, 3.0 mmol)

to provide alcohol (R)-11f as a slightly yellow oil (1.28 g, 94%) in 91:9

enantiomeric ratio favoring the 3.09 over the 2.42 min enantiomer

(R)-1-Phenyl-3-(triﬂuoromethyl)-6-(trimethylsilyl)hex-5-yn-

3-ol (11j). Homopropargylic alcohol (R)-11j was prepared by the

general procedure for the zinc-catalyzed asymmetric propargylation

with 1,1,1-triﬂuoro-4-phenylbutan-2-one 6j (0.606 g, 3.0 mmol) to

provide alcohol (R)-11j as a colorless oil (0.836 g, 89%) in 80:20

enantiomeric ratio favoring the 4.27 over the 3.88 min enantiomer

determined by chiralpak IA HPLC (1.5% IPA in heptane, 2 mL/min,

1

210 nm). H NMR (500 MHz, CDCl₃) δ 7.29−7.24 (m, 2H), 7.21−

7.16 (m, 3H), 2.75 (t, J = 8.6 Hz, 2H), 2.71 (s, 2H), 2.55 (s, 1H),

2.16−2.00 (m, 2H), 0.16 (s, 9H). ¹³C NMR (125 MHz, CDCl₃) δ

141.1, 128.6, 128.3, 126.2, 125.8, (q, J = 287 Hz), 99.0, 90.1, 74.0, (q, J

= 27.3 Hz), 35.84, 29.1 (q, J = 1.1 Hz), 26.2 (q, J = 1.7 Hz), −0.20.

HRMS-ESI C₁₆H₂₁F₃OSi calcd for [M + NH₄]⁺332.1652 found

332.1641.

T

dx.doi.org/10.1021/jo400080y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(c) Trost, B. M.; Dong, G. Nature 2008, 456, 485−488. (d) Liu, S.;

Kim, J. T.; Dong, C.-G.; Kishi, Y. Org. Lett. 2009, 11, 4520−4523.

(e) Francais, A.; Leyva, A.; Etxebarria-Jardi, G.; Ley, S. V. Org. Lett.

2010, 12, 340−343. (f) Huang, J.; Yang, J. SynLett 2012, 23, 737−740.

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(6) (a) Fandrick, D. R.; Yee, N.; Song, J. J.; Reeves, J. T. PCT Int.

Appl. WO 2010141334, 2010. (b) Reeves, J. T.; Fandrick, D. R.; Tan,

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2013, DOI: jo400079z.

ASSOCIATED CONTENT

* Supporting Information

■

S

Preparation of pinacol boronic acid, and experimental details

for kinetic analysis, computation analysis, and DoE. Copies of

¹H and ¹³C for all products and chromatographs for

diastereomeric and enantiomeric ratio determinations. This

material is available free of charge via the Internet at http://

pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: daniel.fandrick@boehringer-ingelheim.com.

Notes

■

The authors declare no competing ﬁnancial interest.

(7) Harcken, C.; Ward, Y.; Thomson, D.; Riether, D. SynLett 2005,

3121−3125.

ACKNOWLEDGMENTS

■

(8) (a) Fandrick, D. R.; Reeves, J. T.; Song, J. J.; Tan, Z.; Qu, B.; Yee,

N.; Rodriguez, S. PCT Int. Appl. WO 2010141331, 2010. (b) Kim, S.

PCT Int. Appl. WO 2010141333, 2010.

The authors acknowledge and thank Professors Donna

Blackmond, Erick Carreira, Scott Denmark, Barry Trost, and

Peter Wipf for insightful discussions throughout the develop-

ment of the zinc-mediated and -catalyzed asymmetric

propargylation of triﬂuoromethylketones. Analytical support

provided by Andreas Mohr, Dr. Anja Papke, Dr. Uwe

Zimmermann, Heike Roth, Alexandra Backes and Irina Peters

is gratefully acknowledged. Furthermore, the authors thank Dr.

Eric Winter for helpful discussions. The authors acknowledge

CHEMBIOTEK for the preparation of ligands 31, 32, 36, 37,

and 38 and Princeton Global Synthesis for the preparation of

ligands 29, 34 and 35.

(9) Eutectic point determined by melting point analysis on

diastereomeric mixtures of the homopropargylic alcohol 7a wherein

a minimum was observed at a diastereomeric composition of ∼4:1

favoring the opposite diastereomer to alcohol 7a.

(10) For selected examples of other approaches towards the chiral

triﬂuoromethyl tertiary alcohol stereocenter in the BI 653048 class of

compounds, see refs 3 and 8 as well as: (a) Lee, T. W.; Proudfoot, J.

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(b) Song, J. J.; Reeves, J.; Roschangar, F.; Tan, Z.; Yee, N. K. PCT Int.

Appl. WO 2007040959, 2007. (c) Song, J. J.; Xu, J.; Tan, Z.; Reeves, J.

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Z.; Song, J. J.; Yee, N. K.; Xu, Y.; Tang, W.; Reeves, J. T.; Tan, Z.;

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PCT Int. Appl. WO 2009134737, 2009. (f) Fandrick, D. R.; Kuzmich,

D.; Reeves, J. T.; Song, J. J.; Tan, Z. Lee, T. PCT Int. Appl. WO

2010141332, 2010.

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the same degree, within experimental error, of diastereoselectivity but

favored the opposite diastereomers.

(45) Chiral HPLC compared to racemic products generated by the

diethyl zinc-catalyzed propargylation without a ligand.

(46) Reactions were preformed by charging a ligated catalyst solution

to a solution of the ketone substrate and borolane. Reaction without

water aﬀorded a 59:41 diastereoselectivity and 14:1 site selectivity

favoring the propargylation product. Reaction with 2 mol% water

aﬀorded a 60:40 diastereoselectivity and 19:1 site selectivity favoring

the propargylation product.

(47) Reaction preformed in a reaction system wherein the internal

temperature was automatically maintained by adjustment of the jacket

temperature.

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1

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Zinc catalyzed and mediated asymmetric propargylation of trifluoromethyl ketones with a propargyl boronate

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