Second-Generation Synthesis of the Northern Fragment of Mandelalide A: Role of π-Stacking on Sharpless Dihydroxylation of cis-Enynes

Article

Cite This: J. Org. Chem. XXXX, XXX, XXX −XXX

pubs.acs.org/joc

Second-Generation Synthesis of the Northern Fragment of

Mandelalide A: Role of π‑Stacking on Sharpless Dihydroxylation of

cis-Enynes

Ankan Ghosh, Alexander C. Brueckner, Paul Ha-Yeon Cheong,* and Rich G. Carter*

Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States

*

S Supporting Information

ABSTRACT: The development of a π-stacking-based approach

for increased stereoselectivity in Sharpless asymmetric and

diastereomeric dihydroxylation of cis-enynes is disclosed. The

use of neighboring, electron-rich benzoate esters proved key to

the success of this process. Density functional theory study

suggests that the substrate benzoate ester group rigidiﬁes the

dihydroxylation transition states by forming a favorable π-

stacking interaction in both Major-TS and Minor-TS. The

energetic preference for the Major-TS was found in part because

of the favorable eclipsing conformation of the alkene substituent

as opposed to the disfavored bisecting conformation found in the Minor-TS. The application to a second-generation synthesis

of the C15−C24 northern portion of mandelalide A is demonstrated.

1

. INTRODUCTION

moiety. The computational rationale for these ﬁndings and the

application of this discovery to a second-generation synthesis

of the C15−C24 portion of mandelalide A 16 is demonstrated

in Figure 1 and Scheme 4.

Asymmetric epoxidation and dihydroxylation of alkenes has

proven transformational for the eﬃcient introduction of

chirality into achiral substrates. For epoxidations, trans-

alkenes 1 tend to prove the most amenable substrates for

directed Sharpless-type

methods (e.g., Shi epoxidations ), whereas cis-alkenes 3 have

been shown to be superior with Jacobsen-type epoxidations

and recently developed Shi-type epoxidations (Scheme 1).

For 1,1-disubstituted and mono-substituted alkenes, indirect

methods for their net asymmetric epoxidation have been

1

,2

1b,3

epoxidations and organocatalytic

2. RESULTS AND DISCUSSION

4

14

During our total synthesis of mandelalide A, we required the

5

construction of 1,2-anti propargylic diol 13a for use in

subsequent Ag-catalyzed cyclization (AgCC) (Scheme 2).

Given the complexity of functional groups in this portion of

the carbon backbone, the most expedient route to access this

anti-diol was through the use of a diastereoselective

dihydroxylation of cis-enyne 12a. We had hoped that Sharpless’

6

7

widely demonstrated through kinetic resolution approaches.

In contrast, asymmetric methods of direct dihydroxylation of

an alkene are more limited in scope. While ample substrate

scope has been demonstrated for trans-alkenes 1 using the

Sharpless’ asymmetric dihydroxylation, the direct asymmetric

dihydroxylation of cis-alkenes 3 to the corresponding anti-diols

10

cis-alkene ligand system (DHQD)-IND would prove

8

eﬀective in our case; however, diastereoselectivity was actually

lower than that with the standard (DHQD) PHAL system

2

9

given approximately 78:22 dr with (DHQD)

2

PHAL as

6

remains a problem that has not yet been fully resolved.

compared to 69:31 dr with (DHQD)-IND. It should be

noted that the surrounding chiral environment of cis alkene

12a appears to have minimal impact on the diastereoselectivity

Wang and Sharpless did develop some speciﬁc ligands for the

1

0

dihydroxylation of cis-alkenes; however, these ligands have

proven only modestly eﬀective and have seen limited use.

Currently, the synthetic community is primarily limited to

multistep solutions involving the use of trans-alkenes 1 to

access anti-diols 6. For example, Shi epoxidation of trans-

alkene 1 followed by the opening of the epoxide with an

oxygen-based nucleophile does deliver the target anti-diol 6.

Alternatively, the trans-alkene 1 can be dihydroxylated

followed by inversion through activation as a cyclic sulfate

1

of the process (22:78 dr with (DHQ) PHAL). For our ﬁrst-

2

generation synthesis of this natural product 16, we took

advantage of the fact that these diastereomers proved separable

on silica gel chromatography. While eﬀective, this process

wasted approximately 20−30% of the valuable starting enyne

that had to be discarded.

Our continued eﬀorts for accessing other members of the

mandelalide family [for example, mandelalide B (17)] have

1

2

13

and displaced with an oxygen nucleophile. In this article, we

disclose the notable increase in enantioselectivity of the

Sharpless-type dihydroxylation of cis-1,2-disubstituted alkenes

Received: April 26, 2019

7

containing a neighboring, electron-rich propargylic benzoate

©

XXXX American Chemical Society

A

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Scheme 1. Asymmetric Oxidation of Alkenes and

Application to Mandelalide A

required production of larger quantities of desired diastereo-

meric diol 13a. Consequently, we set out to explore in depth

the potential controlling elements of dihydroxylations of 1,2-

disubstituted cis-enynes (Table 1). Prior researchers have

Table 1. Impact of Neighboring Ether/Ester Substitution on

Selectivity in Sharpless Dihydroxylation

entry

substrate

P₁

P₂

yield

dr

1

2

3

4

12a

12b

12c

12d

Piv

Bn

TES

Bn

TES

Bn

76% (13a)

73% (13b)

48% (13c)

67% (13d)

78:22

79:21

82:18

88:12

PMB

shown that tri-substituted cis-alkenes proved to be the most

eﬀective substrates for providing moderate to high enantiose-

15

lectivity. Brimble and co-workers have shown that 1,2-

disubstituted cis-oleﬁns are generally poor substrates for

1

6

Sharpless-type dihydroxylation reactions. Additionally,

1

5b

15a

15c

15d

Lera,

Tietze,

Myers,

and Bru

̈

ckner

demonstrated

that the presence of an aromatic allylic ether or ester moiety in

trisubstituted enynes and alkenes might help in achieving

higher stereoselectivity in the asymmetric dihydroxylation.₁

7,18

We hypothesized that the tactical use of π-stacking

could lead to improvements in our diastereoselectivity through

better controlling the spatial positioning of the substrate within

Scheme 2. Asymmetric Dihydroxylation of cis-Enyne and

First-Generation Synthesis of Mandelalide A

the extended π-systems of the (DHQD) PHAL−Os catalyst.

2

This approach showed initial promise as substitution of P and

1

P₂moieties with substituents that are capable of π-stacking did

lead to a marked improvement in the diastereoselectivity in

this sequence (88:12 dr, 67%, 13d, entry 4, Table 1).

Intrigued by the initial positive beneﬁts of π-stacking with

cis-enyne systems, we set out to explore the enantioselectivity

of this concept on an achiral substrate 18 (Table 2). Starting

from the simpliﬁed PMBO-protected propargylic ether 18a, we

found only a modest level of enantioselectivity using the

pseudoenantiomeric ligand pair (DHQD) PHAL and

2

(

DHQ) PHAL (entries 1 and 2). Inspired by Corey and co-

2

workers’ pioneering work with Sharpless dihydroxylations on

allylic benzoates,

17a

we decided to explore the impact of

propargylic benzoates on our enyne system. The parent

benzoate 18b showed no change in enantioselectivity, but an

improvement in chemical yield was noted. We are not certain

of the exact rationale for this yield improvement at this time.

One possible explanation for similar enantioselectivities

observed between these two substrates (18a and 18b) could

be the competing eﬀects of the comparatively less electron-rich

nature of benzoate 18b [that might negatively impact its donor

19

acceptor π-stacking ability with (DHQD) PHAL) versus the

2

gains in transition preorganization introduced through

restricted rotation and dipoles from the incorporation of the

2

20

sp -hybridized ester moiety in 18b]. Similar selectivity was

observed for the biphenylic benzoate 18c (entry 4). The

absolute conﬁguration of 19c was conﬁrmed by Mosher ester

21

analysis. cis-Alkenes are known to be challenging substrates

for Sharpless dihydroxylations, most likely due to poorer ﬁt

within the cavity created by the ligand−OsO complex. We

therefore believed it was critical to maximize the π-stacking

10a

4

B

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Table 2. Exploration of Enantioselectivity in Sharpless

Dihydroxylation of cis-Enynes

In order to conﬁrm that the propargylic benzoate was key to

the increased enantioselectivity observed, we synthesized the

precursors lacking the alkyne (compound 20) and lacking the

π-stacking moiety on propargylic alcohol (compound 22)

(

Scheme 3). Asymmetric dihydroxylation using our optimum

Scheme 3. Control Experiments To Verify Controlling

Elements in Asymmetric Dihydroxylation

time

(h)

entry substrate

ligand

% yield

er

1

2

3

4

5

6

7

8

9

1

18a

18b

18c

18d

18e

18f

18g

18h

18g

18i

22

20

21

48

24

18

14

23

5

24

15

23

19

18

12

(DHQD) PHAL

40 (19a)

42 (19a)

75 (19b)

72 (19c)

67 (19d)

90 (19e)

67:33

36:64

2

(DHQ) PHAL

2

(DHQD) PHAL

67.6:32.4

68.2:31.8

71.4:28.6

77:23

72.5:27.5

76:24

2

(DHQD) PHAL

2

(DHQD) PHAL

2

(DHQD) PHAL

2

a

(DHQD) PHAL

42 (19f)

2

conditions on the nonalkyne-containing substrate 20 gave low

enantioselectivity (55.8:44:2 er) (eq 1, note that the absolute

stereochemical assignment of 21 is based on analogy).

Interestingly, use of the propargylic alcohol enyne 22 led to

reversal in selectivityfavoring the opposite enantiomer (eq

(DHQD) PHAL

84 (19g)

2

b

(DHQD) PHAL

99 (19h)

66.4:33.6

78:22

2

b

0

1

2

3

4

5

(DHQD) PYR

80 (19g)

2

(Pr-DHQD) PHAL 81 (19g)

67.5:32.5

31.7:68.3

46.7:53.3

79.5:20.5

79:21

2

b

(DHQD) AQN

84 (19g)

45 (19g)

79 (19i)

2

). This stereochemical assignment was conﬁrmed by

DHQD-IND

derivatization of triol 23 to ester 19c.

(DHQD) PHAL

2

b

While not useful for our mandelalide work, we also became

intrigued about the potential for placing the benzoate more

proximal to the cis-alkene (Table 3). Use of PMB ether (24a)

18j

(DHQD) PHAL

74 (19j)

2

a

b

Yield over two steps. Based on recovery of starting material.

Table 3. Exploration of Enantioselectivity in Sharpless

Dihydroxylation of cis-Allyl Ether and Esters

interactions in our system to compensate. Subsequent use of

more electron-rich systems appeared to support this

hypothesis. Entries 5−7 containing additional oxygenation on

the benzoate moiety did lead to modest increases in

enantioselectivity (up to 54% ee with 18e in entry 6). The

use of a N,N-dimethyl amino group was potentially more

attractive on the benzoate moiety as it both increased the

electron-rich nature of the aromatic ring and also opened the

door for subsequent selective removal in the presence of other

ester moieties (through preactivation by quaternization of the

amino moiety). Wang and co-workers recently reported high

levels of enantioselectivity in the dihydroxylation of a series of

entry

substrate

time (h)

% yield

er

1

2

3

4

24a

24b

24c

24d

4.5

5.5

24

65 (25a)

63 (25b)

70 (25c)

73 (25d)

53:47

69:31

66:34

52.4:47.5

1

7b

1

,1-disubstituted alkenes.

Indeed, p-N,N-dimethylamino

benzoate (PDAB) 18g did give comparable to slightly

improved enantioselectivity (entry 8). As expected, with the

electron-poor benzoate substrate (18h), a drop in enantiose-

lectivity was observed (entry 9). Changing the ligand system to

20

gave essentially no enantioselectivity (53:47 er, entry 1). In

contrast, benzoates 24b and 24c gave improved levels of

enantioselectivity (entries 2 and 3)albeit slightly below the

levels observed for the propargylic series (entries 4 and 5;

Table 2). Interestingly, the PDAB substrate 24d gave no

selectivitypossibly pointing to a competing directing eﬀect

between the alkyne and the PDAB moiety (entry 4).

(

DHQD) PYR (entry 10) showed similar selectivity as

2

DHQD) PHAL (entry 8). Use of the more bulkier propyl

2

ligand [(Pr-DHQD) PHAL] led to slight reduction in

2

enantioselectivity (entry 11). A reversal in enantioselectivity

was observed for both the (DHQD) AQN and the Sharpless

2

ligand designed for cis alkenes [(DHQD)-IND] (entries 12−

Density functional theory (DFT) was employed to explore

the origins of selectivity for the dihydroxylation of cis-enynes.

1

3). We also explored the impact of substitution at the R and

R′ positions (entries 14−15); however, limited augmentation

Substrate 18g, (DHQD) PHAL ligand, and osmium tetroxide

2

in the enantioselectivity was observed with variants 18i and

were used in all computations. Geometry optimizations and

22

1

8j.

vibrational frequencies were computed using B3LYP with the

C

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

2

3

LanL2DZ basis set and eﬀective core potential for osmium

enyne in the Minor-TS are slightly more stabilizing than in the

2

4

25

⧧

and 6-31G(d) for all other atoms. Grimme’s D3BJ

dispersion corrections were calculated for the optimized

structures using the DFT-D3 software. Solvation corrections

were computed for 2-methyl-2-propanol using PCM and

B3LYP with LanL2DZ for osmium and 6-31+G(d,p) for all

other atoms. Single point energy reﬁnements were computed

Major-TS (ΔΔG = −0.5 kcal/mol) but do not make up for

i

greater distortion energy. The bulk of distortion in the minor

26

⧧

transition state arises from the substrate (ΔG = +0.9 kcal/mol

d

27

in substrate vs +0.6 kcal/mol in catalyst), rather than ligand or

catalyst distortion. Upon inspection, it is clear that the

substrate in the Minor-TS features a disfavored bisected

conformation between the alkyl substituent and the reacting

alkene (Figure 1 , bottom right, C −C −C −C = ∼180°; see

28

using B3LYP with the SDD basis set for osmium and the 6-

11++G(2df,p) basis set for all other atoms. All quantum

2

9

3

1

2

3

4

mechanical computations used the Gaussian 09 computational

Supporting Information). In contrast, the alkyl substituent in

the Major-TS substrate is in a more favorable eclipsing

conformation with the reacting alkene. We computed a model

substrate system in which we varied this torsion systematically.

The torsional angle corresponding to the Major-TS was found

to be ∼1.2 kcal/mol more stable than the one corresponding

to the Minor-TS. This suggests that the alkyl group orientation

relative to the reacting alkene may indeed be responsible for

the bulk of the distortion, and therefore the bulk of the

selectivity.

3

0

package.

The computed major and minor dihydroxylation transition

structures are shown in Figure 1, top. The Major-TS leading to

We hypothesize that the substrate benzoate ester group

rigidify the dihydroxylation transition states by forming a

favorable π-stacking interaction in both the Major-TS and

Minor-TS. With this anchoring interaction in place, the

substrate has limited conformational freedom, thereby leading

to enhanced selectivity observed by using experiments and

computations. The omission of groups capable of π-stacking

removes this rigidiﬁcation, thereby leading to poorer

transition-state preorganization, explaining the observed drop

in selectivity in experiments.

The application of this technology to a second-generation

synthesis of the C15−C24 northern portion of mandelalide A

is shown in Scheme 4. Starting from the previously prepared

14

pivaloate 12a, DIBAL-H reduction followed by benzyl ether

formation in acidic medium gave secondary alcohol 26. Next,

the PDAB moiety was installed smoothly into the dihydrox-

ylation precursor 9. To our delight, the key dihydroxylation

using (DHQD) PHAL gave outstanding levels of diastereose-

2

lectivity (93:7 dr) and excellent chemical yield. It is important

to mention here that dihydroxylation reaction of enyne 9 with

Figure 1. (Top) Computed stereodetermining dihydroxylation

pseudo-enantiomeric ligand (DHQ) PHAL provided a similar

2

transition structures. (DHQD) PHAL is shown as tubes; osmium

tetroxide and 18g are shown as balls and sticks. Yellow dotted lines

level selectivity favoring the opposite diastereomer 30 (94:6

dr) now. This pair of results would appear to indicate that

there is no matched/mismatched relationship between the

chiral Sharpless ligands and the inherent facial selectivity of the

enantioenriched system. Next, benzoylation at C20 and C21

provided the triester. Subsequent selective removal of the

PDAB in the presence of two benzoate esters was smoothly

accomplished by quaternarization of the dimethylamino

moiety followed by in situ saponiﬁcation to provide alcohol

27. We are unaware of a prior application of this approach for

the selective removal of an amino-benzoate in the presence of

other esters. Next, AgCC proceeded smoothly to yield

dihydropyran 28 which was processed in situ to ketone 29

because of its inherent instability. Finally, methylenation with

the Petasis reagent followed by hydrogenation incorporated

required methyl stereochemistry at C18 along with the

removal of the Bn group at the same steplinking this

route with our previously published total synthesis of

2

are the two forming C−O bonds. Distances are in ångstroms, and

̈

energies in kcal/mol (Bottom Left). Distortion/interaction model for

the two transition states (Bottom Right). Model substrate torsion

plotted against energy (see the Supporting Information).

the experimentally favored product is 0.9 kcal/mol more stable

than the Minor-TS, in good agreement with experiments

⧧

(

ΔG

= 0.7 kcal/mol). The reaction is concerted

(

exp)

asynchronous; vibrational analyses show that both bonds in

the transition structures are being formed at the same time but

at varying degrees. The forming C−O bond proximal to the

alkyne was consistently longer by ∼0.2 Å compared to the C−

O bond proximal to the alkyl chain. Importantly, both the

Major-TS and Minor-TS feature π-stacking between the

substrate p-N,N-dimethylaminobenzoate group and catalyst

quinoline ring.

31

14

The distortion/interaction model was used to understand

the origin of selectivity (Figure 1, bottom left; see the

mandelalide A.

In conclusion, we have identiﬁed possible generalized

controlling elements for the enantioselective dihydroxylations

of cis-enyne moieties. The importance of electron-rich π-

stacking moieties in this process should pave the way for

Supporting Infromation ). The catalyst and enyne in the

⧧

Minor-TS are more distorted than in the Major-TS (ΔΔG =

d

+

1.5 kcal/mol). The interactions between the catalyst and

D

DOI: 10.1021/acs.joc.9b01153

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The Journal of Organic Chemistry

Article

tetramethylsilane and referenced internally to the carbon resonance

of the solvent. HRMS data were acquired on a TOF-MS instrument

with an EI or ES source unless otherwise mentioned.

Scheme 4. Application to Northern Fragment of

Mandelalide A

Routine monitoring of reactions was performed using EM Science

DC-Alufolien silica gel, aluminum-backed TLC plates. Flash

chromatography was performed with the indicated eluents on EM

Science Gedurian 230−400 mesh silica gel.

Air and/or moisture sensitive reactions were performed under

usual inert atmosphere conditions. Reactions requiring anhydrous

conditions were performed under a blanket of argon, in glassware

dried in an oven at 120 °C or by ﬂame, then cooled under argon. Dry

tetrahydrofuran (THF) and dichloromethane (DCM) were obtained

via a solvent puriﬁcation system. All other solvents and commercially

available reagents were either puriﬁed via literature procedures or

used without further puriﬁcation.

3

.2. General Procedure for Esteriﬁcation (DCC or EDC

Coupling). To a stirred solution of alcohol (1 equvi) in CH Cl

2

(

0.06 M in SM) were added sequentially carboxylic acid (2 or 3

equiv), DCC or EDC·HCl (2 or 3 equiv), and DMAP (2 or 3 equiv)

at rt. After the alcohol was consumed (typically overnight), the

reaction was quenched by sat. aq NH Cl and extracted with CH Cl .

4

2

The dried (MgSO ) extract was concentrated and in vacuo puriﬁed by

4

chromatography over silica gel, eluting with it EtOAc/hexanes.

3

.3. General Procedure for Asymmetric Dihydroxylation. To

a stirred solution of cis-enyne (1 equiv) in t-BuOH/H O (1:1) (0.18

2

32

M in SM) (at 0 °C or rt) were added sequentially AD mix L**

generally 2.6 g for 1.0 mmol of alkene, unless otherwise mentioned)

and MeSO NH (1 equiv). After completion of the reaction, it was

(

2

quenched by addition of solid Na SO , stirred for another 5 min, and

2

3

extracted with EtOAc. The dried (Na SO ) extract was concentrated

2

4

in vacuo and puriﬁed by chromatography over silica gel (for

compounds containing the p-N,N-dimethylamino benzoate moiety:

the column was neutralized with 10% Et N in hexanes), eluting it with

3

EtOAc/hexanes.

3

.4. General Procedure for Racemic Dihydroxylation. To a

stirred solution of cis-enyne (1 equiv) in t-BuOH/H O (1:1) (0.02 M

2

in SM) at rt was added NMO (4.0 equiv, 4.8 M in H O) followed by

2

K OsO ·2H O (0.01 equiv). After consumption of alkene, the

2

4

2

reaction was quenched by sat. aq thiosulfate and extracted with

EtOAc. The dried (Na SO ) extract was concentrated in vacuo and

2

4

puriﬁed by chromatography over silica gel, eluting it with EtOAc/

hexanes.

3

.5. General Procedure for Mosher Ester Synthesis (for

Determination of ee). To a stirred solution of diol (1 equiv) in

CH Cl (0.05 M in SM) were added sequentially Mosher acid (4

2

equiv), DCC (4 equiv), and DMAP (4 equiv) at rt. After the diol was

consumed, the reaction was quenched by sat. aq NH Cl and extracted

4

1

9

1

with CH Cl . With the crude mass, F and H NMR analyses were

2

done to determine the ee.

further improvements for asymmetric dihydroxylation of the

most challenging class of oleﬁns (cis alkenes). Through a DFT

study, we propose that the benzoate ester groups rigidify the

dihydroxylation transition states, and the origin of selectivity is

due to favorable eclipsing alkyl group conformation in the

Major-TS as opposed to a disfavored bisecting conformation

in the Minor-TS. The subsequent application of this

technology to the formal synthesis of mandelalide A has

been demonstrated. In this application, the enantioselectivity

of the key diastereoselective dihydroxylation reaction has been

ampliﬁed from 69:31 to 93:7 through the careful selection of

nearby π-stacking substituents.

3

.5.1. tert-Butyldiphenyl(prop-2-yn-1-yloxy)silane (SI-2). To a

stirred solution of propargyl alcohol SI-1 (3.0 g, 53.51 mmol) in

CH Cl (107 mL) at 0 °C was added imidazole (4.0 g, 58.87 mmol)

2

followed by TBDPSCl (16.18 g, 15.3 mL, 58.87 mmol). After 5 min,

the reaction was warmed to rt. After overnight stirring, the reaction

was quenched by using H O (80 mL) and extracted with CH Cl (3

2

×

50 mL). The dried (MgSO ) extract was concentrated in vacuo and

4

puriﬁed by chromatography over silica gel, eluting with 2−5%

33

EtOAc/hexanes, to give the known compound SI-2 (15.63 g, 53.1

1

mmol, 99%) as a colorless liquid. H NMR (400 MHz, CDCl ): δ

7.75 (dd, J = 8.0, 1.7 Hz, 4H), 7.41−7.47 (m, 6 H), 4.34 (d, J = 2.4

Hz, 2H), 2.41 (t, J = 2.4 Hz, 1H), 1.10 (s, 9H) ppm; C{ H} NMR

3

. EXPERIMENTAL SECTION

1

3

1

3

.1. General Information. Infrared spectra were recorded neat

−

1 1

(

100 MHz, CDCl ): δ 135.6, 132.9, 129.8, 127.7, 82.0, 73.0, 52.5,

unless otherwise indicated and are reported in cm . H NMR spectra

were recorded in deuterated solvents and are reported in ppm relative

to tetramethylsilane and referenced internally to the residually

protonated solvent. C{ H} NMR spectra were recorded in

deuterated solvents and are reported in ppm relative to

3

26.7, 19.1 ppm.

1

3

1

E

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The Journal of Organic Chemistry

Article

3

.5.2. (Z)-1-Iodohept-1-ene (SI-4). To a stirred solution of the

min, the reaction was warmed up to rt. After 2 h, the reaction was

quenched by using sat. aq NaHCO (10 mL) and extracted with Et O

Wittig salt [made from CH I and PPh ] (6.35 g, 11.98 mmol) in

2

3

2

THF (40 mL) at rt was dropwise added NaHMDS (6.0 mL, 11.98

mmol, 2 M in THF). After 5 min, the reaction was cooled down to

(3 × 20 mL). The dried (MgSO ) extract was concentrated in vacuo

4

and puriﬁed by chromatography over silica gel, eluting it with 2−3%

−78 °C and DMPU (5.12 g, 4.81 mL, 39.92 mmol) was added and

Et O/hexanes, to give the compound 18a (173.0 mg, 0.635 mmol,

2

1

stirred for another 5 min before addition of hexanal SI-3 (1.0 g, 9.98

75%) as a yellow liquid. H NMR (700 MHz, CDCl ): δ 7.32 (d, J =

3

mmol) in THF (5 mL + 5 mL rinse). After 2.5 h, the reaction was

8.5 Hz, 2 H), 6.91 (d, J = 8.5 Hz, 2H), 5.97 (dt, J = 10.7, 7.5 Hz, 1H),

5.53 (d, J = 10.8 Hz, 1H), 4.58 (s, 2H), 4.32 (d, J = 1.4 Hz, 2H), 3.83

(s, 3H), 2.36 (q, J = 7.4 Hz, 2H), 1.43−1.47 (m, 2H), 1.34−1.47 (m,

quenched by using sat. aq NH Cl (50 mL) and extracted with EtOAc

4

(

3 × 40 mL). The dried (MgSO ) extract was concentrated in vacuo

4

1

3

1

and puriﬁed by chromatography over silica gel, eluting it with 2−2.2%

EtOAc/hexanes, to give the known commercially available compound

SI-4 (1.6 g, 7.1 mmol, 72%, Z/E > 11:1) as a colorless liquid. H

m, 4H), 0.92 (t, J = 6.9 Hz, 3H) ppm; C{ H} NMR (175 MHz,

CDCl ): δ 159.4, 144.8, 129.8, 129.7, 113.8, 108.4, 89.2, 83.4, 70.9,

3

1

+

57.6, 55.3, 31.4, 30.3, 28.5, 22.5, 14.1 ppm; HRMS (EI ): calcd for

C H O (M ), 272.1776; found, 272.1770.

18 24

+

NMR (400 MHz, CDCl ): δ 6.18−6.21 (m, 2H), 2.13−2.18 (m, 2H),

3

2

1

.45 (quint, J = 7.12 Hz, 2H), 1.32−1.36 (m, 4 H), 0.92 (t, J = 6.9

13 1

Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ): δ 141.5, 82.1,

3

4.7, 31.3, 27.6, 22.5, 14.0 ppm.

3

.5.6. (4R,5S)-1-((4-Methoxybenzyl)oxy)dec-2-yne-4,5-diol (19a).

Diol 19a (25.5 mg, 0.083 mmol, 40% yield, 35% ee determined by

Mosher ester analysis) was prepared by “General procedure B” from

3

.5.3. (Z)-tert-Butyl(dec-4-en-2-yn-1-yloxy)diphenylsilane (SI-5).

enyne 18a (56.8 mg, 0.208 mmol) using AD mix β** at rt for 22 h.

To a stirred suspension of Pd(PPh ) (379.0 mg, 0.328 mmol) and

CuI (125.0 mg, 0.656 mmol) in i-Pr NH (15 mL) at 0 °C was

dropwise added a solution of alkyne SI-2 (1.93 g, 6.56 mmol) and

iodide SI-4 (1.47 g, 6.56 mmol) in i-Pr NH (15 mL) and the reaction

was allowed to warm up to rt. After overnight stirring, the reaction

was quenched by sat. aq NH Cl (20 mL) and extracted with EtOAc

3

4

20

[

α] −0.48° (c = 0.84, CHCl ); IR (neat): 3389, 2932, 1613, 1514,

D

3

2

−1 1

1

2

1

250, 1075 cm ; H NMR (700 MHz, CDCl ): δ 7.29 (d, J = 8.5 Hz,

3

H), 6.90 (d, J = 8.5 Hz, 2H), 4.54 (s, 2H), 4.39 (s, 1H), 4.21 (s,

H), 3.82 (s, 3H), 3.69−3.71 (m, 1H), 2.73 (br s, 1H), 2.20 (br s),

.51−1.60 (m, 3H), 1.31−1.37 (m, 5H), 0.91 (t, J = 6.6 Hz) ppm;

2

4

13

1

C{ H} NMR (175 MHz, CDCl ): δ 159.5, 129.8, 129.3, 113.9, 83.9,

3

(

3 × 20 mL). The dried (MgSO ) extract was concentrated in vacuo

4

8

2.9, 74.1, 71.4, 66.4, 57.0, 55.3, 32.8, 31.7, 25.3, 22.5, 14.0 ppm;

and puriﬁed by chromatography over silica gel, eluting it with 1.6−

+

HRMS (ES ): calcd for C H O Na (M + Na), 329.1729; found,

1

8

26

4

2

9

1

.5% Et O/hexanes, to give the compound SI-5 (2.3 g, 5.90 mmol,

2

3

29.1714 (AG-VII-26).

Diol ent-19a (19.4 mg, 0.091 mmol, 42% yield, 27.5% ee

0%, Z/E > 11:1) as a yellow liquid. IR (neat): 2931, 2858, 1472,

113, 823, 701 cm ; H NMR (400 MHz, CDCl ): δ 7.76 (d, J = 7.4

Hz, 4H), 7.39−7.46 (m, 6H), 5.91 (dt, J = 10.8, 7.4 Hz, 1H), 5.47 (d,

J = 10.8 Hz, 1H), 4.50 (d, J = 1.8 Hz, 2H), 2.29 (q, J = 7.3 Hz, 2H),

−

1 1

3

determined by Mosher ester analysis) was prepared by “General

procedure B” from enyne 18a (58.8 mg, 0.216 mmol) using AD mix

2

0

α**at rt for 20 h. [α] −1.0° (c = 0.90, CHCl₃).

D

1

(

.42 (quint, J = 6.8 Hz, 2H), 1.31−1.33 (m, 4H), 1.10 (s, 9H), 0.92

13 1

t, J = 6.9 Hz, 3H) ppm; C{ H} NMR (100 MHz, CDCl ): δ 144.3,

3

1

2

35.6, 133.3, 129.7, 127.7, 108.6, 91.5, 82.0, 53.3, 31.4, 30.2, 28.5,

+

6.7, 22.5, 19.2, 14.0 ppm; HRMS (ES ): calcd for C H OSi (M +

2

6

35

H), 391.2457; found, 391.2463.

3

.5.7. (Z)-Dec-4-en-2-yn-1-yl Benzoate (18b). To a stirred

solution of alcohol 22 (30.5 mg, 0.20 mmol) in CH Cl /Et N (2

2

3

mL, 1:1) at 0 °C was added sequentially BzCl (42.3 mg, 0.30 mmol,

5 μL), DMAP (5.0 mg, 0.04 mmol). After 2.5 h, the reaction was

3

.5.4. (Z)-Dec-4-en-2-yn-1-ol (22). To a stirred solution of silyl

quenched by using sat. aq NaHCO (2 mL) solution and extracted

3

ether SI-5 (1.67 g, 4.27 mmol, Z/E > 11:1) in THF (64 mL) at 0 °C

was added TBAF (6.41 mL, 6.41 mmol, 1 M in THF) and the

reaction mixture was allowed to warm up to rt immediately. After

overnight stirring, the reaction was quenched with H O (50 mL). The

organic solvent (THF) was removed in vacuo and the resulting

aqueous layer was extracted with EtOAc (3 × 30 mL). The dried

MgSO ) extract was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting it with 5−9% Et O/hexanes,

to give the compound 22 (347.0 mg, 2.28 mmol, 53% only for Z-

with CH Cl (3 × 5 mL). The dried (MgSO ) extract was

2

4

concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting it with 10−30% EtOAc/hexanes, to give 18b (53.0 mg, 0.2

mmol, 100%) as a colorless liquid. IR (neat): 2955, 2928, 1727, 1267,

2

−1

1

7

108 cm ; H NMR (700 MHz, CDCl ): δ 8.09−8.11 (m, 2H),

3

.58−7.61 (m, 1H), 7.46−7.48 (m, 2H), 6.00 (dt, J = 10.8, 7.5 Hz,

(

4

1H), 5.50−5.53 (m, 1H), 5.11 (d, J = 2.0 Hz, 2H), 2.34 (dq, J = 7.5,

1.4 Hz, 2H), 1.41−1.45 (m, 2H), 1.30−1.35 (m, 4H), 0.89 (t, J = 7.1

2

13

1

Hz, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 165.9, 145.8,

3

isomer) as a yellow liquid. IR (neat): 3338, 2957, 2928, 2858, 1016

1

32.2 129.8, 129.7, 128.4, 108.1, 86.9, 83.7, 53.5, 31.3, 30.3, 28.4,

−

1 1

cm ; H NMR (700 MHz, CDCl ): δ 5.91 (dt, J = 10.9, 7.4 Hz, 1H),

+

3

22.5, 14.0 ppm; HRMS (ES ): calcd for C H O (M + H),

17 21 2

5

1

.48−5.50 (m, 1H), 4.43 (s, 2H), 2.29−2.32 (m, 2H), 1.77 (br s,

257.1542; found, 257.1548.

H), 1.42 (quint, J = 6.8 Hz, 2H), 1.30−1.36 (m, 4H), 0.91 (t, J = 6.9

13

1

Hz, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 144.9, 108.2,

3

+

9

1.2, 82.6, 51.7, 31.4, 30.2, 28.5, 22.5, 14.0 ppm; HRMS (ES ): calcd

for C H O (M + H), 153.1297; found, 153.1287.

10

17

3

.5.8. (4R,5S)-4,5-Dihydroxydec-2-yn-1-yl Benzoate (19b). Diol

1

9b (17.0 mg, 0.058 mmol, 75% yield, 35% ee) was prepared by

“

General procedure B” from enyne 18b (20.0 mg, 0.078 mmol) using

3

.5.5. (Z)-1-((Dec-4-en-2-yn-1-yloxy)methyl)-4-methoxybenzene

AD mix β** at 0 °C to rt for 21 h. The enantiomeric ratio was

(

18a). To a stirred solution of alcohol 22 (129.0 mg, 0.847 mmol)

determined by chiral HPLC [250 × 4.6 mm Phenomenex Lux 5u

i

and PMB-imidate (718.0 mg, 0.53 mL, 2.54 mmol) in Et O (11 mL)

at 0 °C was added TfOH (63 μL, 0.063 mmol, 1 M in Et O). After 20

Cellulose-1 column, 99:1 to 70:30 hexanes/ PrOH, 0.5 mL/min, 254

2

0

nm, retention times 22.3 min (minor) and 25.5 min (major)]; [α]

2

D

F

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

−

2.23° (c = 0.85, CHCl ); IR (neat): 3265, 2952, 1722, 1269, 1112

chromatography over silica gel, eluting it with 10−20% EtOAc/

hexanes to obtain SI-7 (6.5 mg, 13.8 μmol, 26%, 77% BRSM) as an

3

−

1

cm ; H NMR (700 MHz, CDCl ): δ 8.07−8.09 (m, 2H), 7.59−

3

2

0

7

1

.62 (m, 1H), 7.46−7.49 (m, 2H), 4.99 (d, J = 1.7 Hz, 2H), 4.41 (s,

H), 3.73 (s, 1H), 2.65 (d, J = 3.8 Hz, 1H), 2.06 (d, J = 5.0 Hz, 1H),

.56−1.59 (m, 2H), 1.49−1.55 (m, 1H), 1.35−1.40 (m, 1H), 1.27−

oil. [α] −5.5° (c = 0.2, CHCl ); IR (neat): 3347, 2919, 2850, 1724,

D

3

−

1 1

1262 cm ; H NMR (700 MHz, CDCl ): δ 8.15 (d, J = 8.3 Hz, 2H),

3

8.11 (d, J = 7.0 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.3 Hz,

2H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (q, J = 7.3 Hz, 4H), 7.42−7.44 (m,

1H), 5.70 (dt, J = 3.7, 1.6 Hz, 1H), 5.03 (d, J = 1.6 Hz, 2H), 3.97−

3.99 (m, 1H), 2.12 (d, J = 5.7 Hz, 1H), 1.71−1.76 (m, 1H), 1.64−

1.69 (m, 1H), 1.41−1.48 (m, 1H), 1.31−1.38 (m, 5H), 0.91 (t, J =

1

3

1

.34 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H) ppm; C{ H} NMR (175

MHz, CDCl ): δ 165.9, 133.4, 129.8, 129.4, 128.5, 84.3, 81.0, 74.1,

3

+

6

6.4, 52.8, 32.8, 31.7, 25.2, 22.5, 14.0 ppm; HRMS (ES ): calcd for

C H O Na (M + Na), 313.1416; found, 313.1414.

1

7

22

4

1

3

1

6

1

.9 Hz, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 165.7, 165.4,

3

46.1, 139.9, 133.5, 130.4, 129.9, 129.4, 128.9, 128.5, 128.3, 128.1,

27.3, 127.1, 81.8, 81.3, 72.8, 68.5, 52.7, 32.8, 31.7, 25.2, 22.5, 14.0

+

ppm; HRMS (ES ): calcd for C H O (M + H), 471.2171; found,

3

0

31

5

4

71.2161.

3

.6. Determination of Absolute Stereochemistry by Mosher

Ester Analysis. 3.6.1. (S)-MTPA Ester (SI-8).

3

.5.9. (Z)-Dec-4-en-2-yn-1-yl [1,1′-Biphenyl]-4-carboxylate (18c).

The propargylic ester 18c (69.0 mg, 0.207 mmol, 97% yield) was

prepared by “General procedure A” from alcohol 22 (32.6 mg, 0.214

mmol) and [1,1′-biphenyl]-4-carboxylic acid SI-6 (85.0, 0.428 mmol)

−

1

using EDC·HCl. IR (neat): 2931, 1724, 1609, 1267, 1099, 747 cm ;

1

H NMR (700 MHz, CDCl ): δ 8.17 (d, J = 8.3 Hz, 2H), 7.69 (d, J =

3

8

(

1

(

.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.43

t, J = 7.4 Hz, 1H), 6.01 (dt, J = 10.8, 7.5 Hz, 1H), 5.53 (dt, J = 10.8,

.3 Hz, 1H), 5.13 (d, J = 1.9 Hz, 2H), 2.35 (q, J = 7.6 Hz, 2H), 1.44

quin, J = 7.3 Hz, 2H), 1.32−1.34 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H)

To a stirred solution of alcohol SI-7 (6.5 mg, 13.8 μmol) in

CH Cl (0.2 mL) at rt was sequentially added (R)-(−)-α-

13

1

ppm; C{ H} NMR (175 MHz, CDCl ): δ 165.8, 145.9, 145.8,

3

2

1

3

methoxy-α-(triﬂuoromethyl)phenylacetyl chloride (14.0 mg,

+

1

0.0 μL, 55.3 μmol), DMAP (7.7 mg, 63.0 μmol). After 2.5 h,

the reaction mixture was quenched with H O (0.5 mL) and

(

M), 332.1874; found, 332.1877.

2

extracted with CH Cl (3 × 2 mL). The dried (MgSO )

2

4

extract was concentrated in vacuo and puriﬁed by column

chromatography over silica gel, eluting it with 10−25%

EtOAc/Hexanes to obtain SI-8 (9.5 mg, 13.8 μmol, 100%,

2.2:1 dr) as an oil.

3

.5.10. (4R,5S)-4,5-Dihydroxydec-2-yn-1-yl [1,1′-Biphenyl]-4-car-

boxylate (19c). Diol 19c (20.8 mg, 0.056 mmol, 72% yield, 36.3% ee)

was prepared by “General procedure B” from enyne 18c (26.3 mg,

0

.079 mmol) using AD mix β** at rt for 48 h. The enantiomeric ratio

was determined by chiral HPLC [250 × 4.6 mm Phenomenex Lux 5u

Cellulose-3 column, 99:1 to 60:40 hexanes/ PrOH, 0.5 mL/min, 254

nm, retention times 24.2 min (minor) and 25.0 min (major)]; [α]

i

2

0

3.6.2. (Z)-Dec-4-en-2-yn-1-yl 4-Methoxybenzoate (18d). The

D

−

0.65° (c = 1.08, CHCl ); IR (neat): 3271, 2953, 1723, 1609, 1267,

propargylic ester 18d (36.7 mg, 0.128 mmol, 72% yield) was

prepared by “General procedure A” from alcohol 22 (27.0 mg, 0.177

mmol) and 4-methoxybenzoic acid SI-9 (81.0 mg, 0.532 mmol) using

3

−

1 1

1

099, 744 cm ; H NMR (700 MHz, CDCl ): δ 8.14 (dt, J = 8.6, 1.9

3

Hz, 2H), 7.69 (dt, J = 8.6, 1.9 Hz, 2H), 7.64−7.65 (m, 2H), 7.49 (t, J

−

1 1

=

7.5 Hz, 2H), 7.42 (tt, J = 7.4, 1.3 Hz, 1H), 5.01 (d, J = 1.8 Hz, 2H),

DCC. IR (neat): 2932, 2119, 1720, 1607, 1256, 1095, 769 cm ; H

NMR (700 MHz, CDCl ): δ 8.05 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9

4.41−4.43 (m, 1H), 3.72−3.75 (m, 1H), 2.69 (d, J = 7.1 Hz, 1H),

2.09 (d, J = 7.1 Hz, 1H), 1.57−1.61 (m, 2H), 1.51−1.56 (m, 1H),

1.36−1.41 (m, 1H), 1.30−1.35 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H)

3

Hz, 2H), 5.99 (dt, J = 10.8, 7.4 Hz, 1H), 5.51 (d, J = 10.8 Hz, 1H),

5.07 (d, J = 1.9 Hz, 2H), 3.88 (s, 3H), 2.33 (q, J = 7.4 Hz, 2H), 1.43

(quint, J = 7.4 Hz, 2H), 1.30−1.33 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H)

13

1

ppm; C{ H} NMR (175 MHz, CDCl ): δ 165.8, 146.1, 139.8,

3

1

3

1

30.3, 128.9, 128.2, 128.1, 127.3, 127.1, 84.4, 81.0, 74.1, 66.4, 52.7,

2.8, 31.7, 25.2, 22.5, 14.0 ppm; HRMS (ES ): calcd for C H O Na

ppm; C{ H} NMR (175 MHz, CDCl ): δ 165.7, 163.5, 145.6,

3

+

131.8, 122.1, 113.6, 108.1, 87.1, 83.4, 55.4, 53.2, 31.3, 30.3, 28.4, 22.4,

2

3

26

4

+

14.0 ppm; HRMS (EI ): calcd for C18

H O (M + H), 286.1569;

22 3

found, 286.1574.

3

.5.11. (4R,5S)-4-(Benzoyloxy)-5-hydroxydec-2-yn-1-yl [1,1′-Bi-

phenyl]-4-carboxylate (SI-7). To a stirred solution of diol 19c

3.6.3. (4R,5S)-4,5-Dihydroxydec-2-yn-1-yl 4-Methoxybenzoate

(19d). Diol 19d (15.0 mg, 0.047 mmol, 67% yield, 42.8% ee by

Mosher ester analysis) was prepared by “General procedure B” from

(

19.6 mg, 53.0 μmol) in CH Cl (0.5 mL) at rt was added imidazole

2 2

7.2 mg, 106.0 μmol) followed by benzoyl chloride (7.5 mg, 6.2 μL,

3.0 μmol). After 6 h, the reaction mixture was quenched with H O

2

0

5

enyne 18d (20.0 mg, 0.070 mmol) using AD mix β** at rt. [α]

2

D

(

1 mL) and extracted with CH Cl (3 × 4 mL). The dried (MgSO )

−0.91° (c = 0.55, CHCl ); IR (neat): 3318, 2928, 1715, 1608, 1259,

2

4

3

−

1 1

extract was concentrated in vacuo and puriﬁed by column

1168 cm ; H NMR (700 MHz, CDCl ): δ 8.02 (d, J = 8.9 Hz, 2H),

3

G

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

6

.93 (d, J = 8.9 Hz, 2H), 4.94 (d, J = 1.6 Hz, 2H), 4.40 (s, 1H), 3.88

3.6.7. 2-(Benzyloxy)-4-methoxybenzoic Acid (SI-13). To a stirred

(

s, 3H), 3.72 (s, 1H), 2.98 (d, J = 5.3 Hz, 1H), 2.31 (s, 1H), 1.56 (q, J

solution of aldehyde SI-12 (316.0 mg, 1.31 mmol) in t-BuOH/H O/

2

=

8.0 Hz, 2H), 1.49−1.54 (m, 1H), 1.26−1.37 (m, 5H), 0.89 (t, J =

THF (7 mL: 7 mL: 2 mL) at rt were added NaClO (369.0 mg, 3.26

2

.0 Hz, 3H) ppm; ¹C{ H} NMR (175 MHz, CDCl ): δ 165.8, 163.7,

3

1

7

1

2

3

mmol), NaH PO (271.0 mg, 1.97 mmol), and 2-Me-2-butene (919.0

3

2

4

31.9, 121.7, 113.7, 84.2, 81.1, 74.1, 66.4, 55.5, 52.5, 32.7, 31.7, 25.3,

2.5, 14.0 ppm; HRMS (ES ): calcd for C H O (M + H),

21.1702; found, 321.1718.

mg, 1.4 mL, 13.1 mmol) sequentially. After 32 h, H

added and extracted with EtOAc (3 × 10 mL). The dried (MgSO )

4

2

O (10 mL) was

+

1

8

25

5

extract was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting it with 20−100% EtOAc/hexanes, to give the

known commercially available compound SI-13 (234.0 mg, 0.907

1

mmol, 69%). H NMR (700 MHz, CDCl ): δ 10.68 (br s, 1H), 8.14

3

(

d, J = 8.7 Hz, 1H), 7.39−7.46 (m, 5H), 6.65 (dd, J = 8.8, 2.2 Hz,

1

H), 6.61 (d, J = 2.2 Hz, 1H), 5.25 (s, 2H), 3.86 (s, 3H) ppm;

1

3

1

C{ H} NMR (175 MHz, CDCl ): δ 165.4, 165.0, 158.9, 135.5,

3

134.4, 129.1, 129.1, 127.9, 110.8, 106.9, 99.9, 72.1, 55.7 ppm.

3.6.4. (Z)-Dec-4-en-2-yn-1-yl 2,4,6-Trimethoxybenzoate (18e).

The propargylic ester 18e (131.0 mg, 0.378 mmol, 90% yield) was

prepared by “General procedure A” from alcohol 22 (64.0 mg, 0.420

mmol) and 2,4,6-trimethoxybenzoic acid SI-10 (178.0 mg, 0.840

1

mmol) using EDC·HCl. H NMR (400 MHz, CDCl ): δ 6.10 (s,

3

2

H), 5.96 (dt, J = 10.8, 7.4 Hz, 1H), 5.49 (d, J = 10.8 Hz, 1H), 5.05

(

d, J = 1.8 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 6H), 2.33 (q, J = 7.2 Hz,

2

3

1

2

H), 1.37−1.45 (m, 2H), 1.27−1.35 (m, 4H), 0.89 (t, J = 6.9 Hz,

H) ppm; ¹³C{ H} NMR (100 MHz, CDCl ): δ 165.8, 162.7, 158.9,

1

3

3.6.8. (Z)-Dec-4-en-2-yn-1-yl 2-(Benzyloxy)-4-methoxybenzoate

(18f). The propargylic ester 18f was prepared by “General procedure

A” from alcohol 22 (40.0 mg, 0.263 mmol) and carboxylic acid SI-13

45.4, 108.3, 105.4, 90.6, 87.1, 83.4, 55.9, 55.4, 53.6, 31.3, 30.2, 28.5,

2.5, 14.0 ppm.

(

135.6 mg, 0.526 mmol) using EDC·HCl. After normal work up, the

dried (MgSO ) extract was concentrated in vacuo and passed through

4

a small plug of silica to give crude ester 18f which was used in the next

dihydroxylation step without further puriﬁcation.

3.6.5. (4R,5S)-4,5-Dihydroxydec-2-yn-1-yl 2,4,6-Trimethoxyben-

zoate (19e). Diol 19e (59.7 mg, 0.156 mmol, 90% yield, 54% ee by

Mosher ester analysis) was prepared by “General procedure B” from

enyne 18e (60.2 mg, 0.174 mmol) using AD mix β** at rt for 18 h.

2

0

[

α] +1.2° (c = 0.92, CHCl ); IR (neat): 3390, 2934, 1725, 1609,

D

3

.6.9. (4R,5S)-4,5-Dihydroxydec-2-yn-1-yl 2-(Benzyloxy)-4-me-

−

1

4

3

5

159, 1132 cm ; H NMR (400 MHz, CDCl ): δ 6.11 (s, 2H),

3

thoxybenzoate (19f). Diol 19f (46.9 mg, 0.110 mmol, 42% yield

over two steps, 45% ee) was prepared by “General procedure B” from

crude enyne 18f using AD mix β** at rt for 14 h. The enantiomeric

ratio was determined by chiral HPLC [250 × 4.6 mm Phenomenex

.90−4.91 (m, 2H), 3.83 (s, 3H), 3.81 (s, 6H), 3.67−3.71 (m, 1H),

.00 (br s, 1H), 2.32 (br s, 1H), 1.47−1.59 (m, 3H), 1.25−1.38 (m,

1

3

1

H), 0.89 (t, J = 6.7 Hz, 3H) ppm; C{ H} NMR (100 MHz,

CDCl ): δ 165.9, 162.9, 158.9, 104.9, 90.7, 84.2, 81.1, 74.3, 66.5, 56.0,

i

3

Lux 5u Cellulose-2 column, 99:1 to 60:40 hexanes/ PrOH, 0.5 mL/

5

5.5, 52.9, 32.8, 31.7, 25.3, 22.6, 14.0 ppm; HRMS (ES+): calcd for

min, 254 nm, retention times 35.7 min (minor) and 48.8 min

C H O Na (M + Na), 403.1733; found, 403.1737.

20

28

7

(major)]; [α]_D−0.4° (c = 1.0, CHCl ); IR (neat): 3307, 2931, 1725,

3

−

1 1

1

610, 1246, 1076 cm ; H NMR (700 MHz, CDCl ): δ 7.92 (d, J =

3

8.6 Hz, 1H), 7.54 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.33

(

t, J = 7.4 Hz, 1H), 6.52−6.54 (m, 2H), 5.18 (s, 2H), 4.94 (d, J = 1.6

Hz, 2H), 4.36 (s, 1H), 3.84 (s, 3H), 3.67−3.70 (m, 1H), 2.68 (d, J =

.0 Hz, 1H), 2.09 (d, J = 7.0 Hz, 1H), 1.46−1.58 (m, 3H), 1.23−1.37

7

(

1

3

1

m, 5H), 0.88 (t, J = 7.0 Hz, 3H) ppm; C{ H} NMR (175 MHz,

3

.6.6. 2-(Benzyloxy)-4-methoxybenzaldehyde (SI-12). To a

CDCl ): δ 164.8, 164.5, 160.6, 136.5, 134.2, 128.6, 127.8, 126.8,

3

stirred solution of 2-hydroxy-4-methoxybenzaldehyde SI-11 (5.00 g,

2.86 mmol) in acetone (60 mL) was added K CO (9.08 g, 65.72

mmol) followed by benzyl bromide (8.73 g, 6.06 mL, 49.29 mmol).

After 3 days of stirring, the reaction mixture was ﬁltered and the dried

111.9, 105.2, 100.6, 84.0, 81.4, 74.1, 70.5, 66.4, 55.5, 52.2, 32.7, 31.7,

3

2

3

2

5.2, 22.5, 14.0 ppm; HRMS (ES+): calcd for C H O Na (M +

2

5

30

6

Na), 449.1940; found, 449.1923.

(

MgSO ) extract was concentrated in vacuo and puriﬁed by

4

chromatography over silica gel, eluting it with 10−50% EtOAc/

hexanes, to give the known commercially available compound SI-12

1

(

6.00 g, 24.07 mmol, 73%). H NMR (700 MHz, CDCl ): δ 10.41 (d,

3

J = 0.5 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 7.5 Hz, 2H),

.42 (t, J = 7.4 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 6.58 (dd, J = 8.6, 2.0

7

Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 5.17 (s, 2H), 3.86 (s, 3H) ppm;

13

1

3.6.10. (Z)-Dec-4-en-2-yn-1-yl 4-(Dimethylamino)benzoate

C{ H} NMR (175 MHz, CDCl ): δ 188.2, 166.1, 162.8, 135.9,

3

(

18g). The propargylic ester 18g (63.2 mg, 0.211 mmol, 64% yield)

1

30.5, 128.7, 128.3, 127.3, 119.3, 106.2, 99.2, 70.4, 55.6 ppm.

was prepared by “General procedure A” from alcohol 22 (50.0 mg,

0

1

2

.328 mmol) and 4-(dimethylamino)benzoic acid SI-14 (109.0 mg,

.657 mmol) using EDC·HCl. IR (neat): 2922, 1709, 1608, 1368,

−1 1

273, 1183 cm ; H NMR (700 MHz, CDCl ): δ 7.96 (d, J = 9.0 Hz,

3

H), 6.66 (d, J = 9.0 Hz, 2H), 5.97 (dt, J = 10.8, 7.6 Hz, 1H), 5.51 (d,

J = 10.8 Hz, 1H), 5.04 (d, J = 1.5 Hz, 2H), 3.06 (s, 6H), 2.33 (q, J =

H

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

7

.5 Hz, 2H), 1.43 (quint, J = 7.3 Hz, 2H), 1.31−1.35 (m, 4H), 0.90

(dt, J = 10.8, 7.5 Hz, 1H), 5.51 (dt, J = 10.8, 1.5 Hz, 1H), 5.09 (d, J =

2.0 Hz, 2H), 2.33 (qd, J = 7.4, 1.1 Hz, 2H), 1.41−1.45 (m, 2H),

1

3

1

(

1

t, J = 7.0 Hz, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 166.2,

53.4, 145.4, 131.5, 116.3, 110.6, 108.2, 87.7, 83.1, 52.7, 40.0, 31.3,

3

1

3

1

1.30−1.34 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H) ppm; C{ H} NMR

+

3

0.2, 28.4, 22.4, 14.0 ppm; HRMS (EI ) calcd for C H NO (M +

(175 MHz, CDCl ): δ 165.9 (d, J = 254.3 Hz), 164.9, 145.9, 132.4 (d,

1

9

26

2

3

H): 300.1964; found, 300.1959.

+

C H O F (M), 274.1369; found, 274.1373.

1

7

19

2

3.6.11. (4R,5S)-4,5-Dihydroxydec-2-yn-1-yl 4-(Dimethylamino)-

benzoate (19g). Diol 19g (20.4 mg, 0.061 mmol, 84%, 52% ee) was

prepared by “General procedure B” from enyne 18g (22.0 mg, 0.073

mmol) using AD mix β** at rt for 23 h. The enantiomeric ratio was

determined by chiral HPLC [250 × 4.6 mm Phenomenex Lux 5u

3

.6.13. (4R,5S)-4,5-Dihydroxydec-2-yn-1-yl 4-Fluorobenzoate

(

3

(

19h). Diol 19h (17.6 mg, 0.057 mmol, 61% (99% BRSM) yield,

3% ee) was prepared by “General procedure B” from enyne 18h

25.7 mg, 0.094 mmol) using AD mix β** at rt for 5 h. The

i

Cellulose-2 column, 99:1 to 50:50 hexanes/ PrOH, 0.5 mL/min, 254

enantiomeric ratio was determined by chiral HPLC [250 × 4.6 mm

2

0

nm, retention times 30.1 min (minor) and 48.0 min (major)]; [α]

D

Phenomenex Lux 5u Cellulose-1 column, 90:10 to 70:30

−

1.08° (c = 1.75, CHCl ); IR (neat): 3274, 2926, 1702, 1611, 1277,

i

3

hexanes/ PrOH, 0.5 mL/min, 254 nm, retention times 13.4 min

(minor) and 16.3 min (major)]; [α]_D−1.69° (c = 0.83, CHCl ); IR

neat): 3260, 2928, 1728, 1604, 1268 cm ; H NMR (700 MHz,

−

1 1

1

2

3

1

185, 1094 cm ; H NMR (700 MHz, CDCl ): δ 7.93 (d, J = 9.1 Hz,

20

3

H), 6.65 (d, J = 9.1 Hz, 2H), 4.92 (d, J = 1.7 Hz, 2H), 4.39 (s, 1H),

.71 (s, 1H), 3.06 (s, 6H), 2.81 (s, 1H), 2.19 (d, J = 3.5 Hz, 1H),

.48−1.60 (m, 3H), 1.25−1.39 (m, 5H), 0.89 (t, J = 7.0 Hz, 3H)

−1

1

(

CDCl ): δ 8.09−8.11 (m, 2H), 7.13−7.17 (m, 2H), 4.98 (d, J = 1.7

3

Hz, 2H), 4.44 (br s, 1H), 3.73 (br s, 1H), 2.52 (d, J = 6.5 Hz, 1H),

1.96 (d, J = 4.6 Hz, 1H), 1.56−1.60 (m, 2H), 1.49−1.55 (m, 1H),

13

1

ppm; C{ H} NMR (175 MHz, CDCl ): δ 166.3, 153.5, 131.6,

3

1

15.9, 110.6, 83.8, 81.7, 74.2, 66.5, 52.0, 40.0, 32.7, 31.7, 25.3, 2.5,

1

.36−1.39 (m, 1H), 1.29−1.35 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H)

+

4.0 ppm; HRMS (ES ): calcd for C H NO (M + H), 334.2018;

13 1

1

9

28

4

ppm; C{ H} NMR (175 MHz, CDCl ): δ 166.0 (d, J = 254.7 Hz),

3

found, 334.2033.

1

64.9, 132.4 (d, J = 9.4 Hz), 125.6 (d, J = 3.0 Hz), 115.7 (d, J = 22.0

Hz), 84.4, 80.9, 74.1, 66.4, 52.8, 32.8, 31.7, 25.2, 22.5, 14.0 ppm;

HRMS (ES ): calcd for C H O FNa (M + Na), 331.1322; found,

331.1328.

Diol 19g (7.0 mg, 0.021 mmol, 49% yield (80% brsm), 56% ee)

was prepared by “General procedure B” from enyne 18g (13.0 mg,

+

1

7

21

4

0

.043 mmol) using AD mix L** [L** = (DHQD) PYR] at rt for 24

2

h. The enantiomeric ratio was determined by chiral HPLC [250 × 4.6

mm Phenomenex Lux 5u Cellulose-2 column, 99:1 to 50:50

hexanes/ PrOH, 0.5 mL/min, 254 nm, retention times 30.0 min

i

(

minor) and 48.0 min (major)].

Diol 19g (16.4 mg, 0.049 mmol, 81% yield, 35% ee) was prepared

by “General procedure B” from enyne 18g (18.1 mg, 0.060 mmol)

using AD mix L** [L** = (Pr-DHQD) PHAL] at rt for 15 h. The

2

3

.6.14. (Z)-(2-Iodovinyl)cyclohexane (SI-17). To a stirred solution

enantiomeric ratio was determined by chiral HPLC [250 × 4.6 mm

of the Wittig salt [made from CH I and PPh ] SI-16 (9.1 g, 17.16

Phenomenex Lux 5u Cellulose-2 column, 99:1 to 50:50 hexane-

2 2

3

i

mmol) in THF (60 mL) at rt was added dropwise NaHMDS (8.58

mL, 17.16 mmol, 2 M in THF). After 5 min, the reaction was cooled

down to −78 °C and DMPU (8.8 g, 8.3 mL, 68.642 mmol) was added

and stirred for another 5 min before the addition of cyclo-

hexanecarbaldehyde SI-15 (1.6 g, 1.73 mL, 14.3 mmol) in THF (8

mL + 2 mL rinse). After 8 h, the reaction was quenched by using sat.

aq NH Cl (50 mL) and extracted with EtOAc (3 × 40 mL). The

dried (MgSO ) extract was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting it with pentane, to give the

known compound SI-17 (2.55 g, 10.80 mmol, 76%, Z/E = 11:1) as

s/ PrOH, 0.5 mL/min, 254 nm, retention times 30.1 min (minor) and

4

8.5 min (major)].

Diol ent-19g (8.3 mg, 0.025 mmol, 64% yield (84% brsm), 36.6%

ee) was prepared by “General procedure B” from enyne 18g (11.8 mg,

0

.039 mmol) using AD mix L** [L** = (DHQD) AQN] at rt for 23

2

h. The enantiomeric ratio was determined by chiral HPLC [250 × 4.6

mm Phenomenex Lux 5u Cellulose-2 column, 99:1 to 50:50

hexanes/ PrOH, 0.5 mL/min, 254 nm, retention times 30.0 min

4

i

4

2

0

(

major) and 48.1 min (minor)]; [α]_D−0.63° (c = 0.48, CHCl ).

3

34

Diol ent-19g (5.7 mg, 0.017 mmol, 45%, 6.6% ee) was prepared by

1

a colorless liquid. H NMR (700 MHz, CDCl ): δ 6.08 (d, J = 7.3 Hz,

“General procedure B” from enyne 18g (11.3 mg, 0.038 mmol) using

3

1

H), 5.99−6.02 (m, 1H), 2.31−2.36 (m, 1H), 1.73−1.75 (m, 4H),

AD mix L** [L** = DHQD-IND] at rt for 19 h. The enantiomeric

13 1

.33−1.38 (m, 2H), 1.13−1.24 (m, 4H) ppm; C{ H} NMR (175

ratio was determined by chiral HPLC [250 × 4.6 mm Phenomenex

i

MHz, CDCl ): δ 146.3, 79.5, 43.6, 31.3, 25.9, 25.5 ppm.

Lux 5u Cellulose-2 column, 99:1 to 50:50 hexanes/ PrOH, 0.5 mL/

3

min, 254 nm, retention times 30.1 min (major) and 48.5 min

(

minor)]; [α]²+3.14° (c = 0.51, CHCl₃).

0

D

3

.6.15. (Z)-5-Cyclohexylpent-4-en-2-yn-1-ol (SI-18). To a stirred

suspension of iodide SI-17 (2.55 g, 10.8 mmol) in THF (60 mL) at 0

C was added sequentially propagyl alcohol SI-1 (1.45 g, 25.9 mmol,

.54 mL), i-Pr NH (3.28 g, 32.4 mmol, 4.6 mL), Pd(PPh ) (250.0

mg, 0.216 mmol), and CuI (83.0 mg, 0.432 mmol) and the reaction

was allowed to warm up to rt. After overnight stirring, the reaction

°

1

2

3 4

3

.6.12. (Z)-Dec-4-en-2-yn-1-yl 4-Fluorobenzoate (18h). The

propargylic ester 18h (49.3 mg, 0.180 mmol, 91% yield) was

prepared by “General procedure A” from alcohol 22 (30.1 mg, 0.198

mmol) and carboxylic acid SI-19 (55.4 mg, 0.395 mmol) using EDC·

HCl. IR (neat): 2957, 2929, 1729, 1265, 1088 cm ; H NMR (700

MHz, CDCl ): δ 8.11−8.13 (m, 2H), 7.14 (t, J = 8.6 Hz, 2H), 6.01

was quenched by using sat. aq NH Cl (50 mL). After evaporating the

4

organic solvent (THF), the resulting aqueous solution was extracted

−

1 1

with EtOAc (3 × 40 mL). The dried (MgSO ) extract was

4

concentrated in vacuo and puriﬁed by chromatography over silica

3

I

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

gel, eluting it with 0−16% Et O/hexanes, to give the compound SI-18

2

(

910.0 mg, 5.54 mmol, 51%, pure Z isomer) as a yellow liquid. IR

neat): 3367, 2921, 2850, 1155, 1113 cm ; H NMR (700 MHz,

−

1

CDCl ): δ 5.77−5.79 (m, 1H), 5.40 (dtd, J = 10.8, 2.1, 0.6 Hz, 1H),

3.6.19. (Z)-Non-3-en-1-yne (SI-22). To a stirred solution of crude

3

4

5

1

.45 (dd, J = 6.1, 2.1 Hz, 2H), 2.56−2.61 (m, 1H), 1.67−1.75 (m,

SI-21 in Et O/THF (20 ml, 3:1) at rt was added TBAF (3.4 mL, 3.4

2

H), 1.58 (t, J = 6.2 Hz, 1H), 1.32−1.37 (m, 2H), 1.17−1.23 (m,

mmol, 1 M in THF). After overnight stirring, the reaction was

1

3

1

H), 1.09−1.15 (m, 2H) ppm; C{ H} NMR (175 MHz, CDCl ): δ

quenched with H O (10 mL) and extracted with Et O (3 × 15 mL).

2

3

The dried (MgSO ) extract was concentrated in vacuo at low

50.3, 106.1, 90.7, 82.7, 51.8, 39.3, 32.3, 25.9, 25.6 ppm; HRMS

4

+

temperature and the volatile enyne SI-22 was used in the next step

(

AP ): calcd for C H O (M), 164.1201; found, 164.1199.

11

16

without further puriﬁcation. An analytical sample was prepared for

1

spectroscopic determination. H NMR (700 MHz, CDCl ): δ 6.03

3

(

dt, J = 10.8, 7.5 Hz, 1H), 5.45−5.48 (m, 1H), 3.09 (d, J = 2.2 Hz,

1

H), 2.35 (qd, J = 7.5, 1.4 Hz, 2H), 1.42−1.46 (m, 2H), 1.32−1.36

1

3

1

(

m, 4H), 0.92 (t, J = 6.9 Hz, 3H) ppm; C{ H} NMR (175 MHz,

CDCl ): δ 146.3, 107.9, 81.1, 80.6, 31.4, 30.2, 28.4, 22.5, 14.0 ppm;

3

+

HRMS (AP ): calcd for C H (M + H), 123.1174; found, 123.1173.

3.6.16. (Z)-5-Cyclohexylpent-4-en-2-yn-1-yl 4-(Dimethylamino)-

9

15

benzoate (18i). The propargylic ester 18i (292.0 mg, 0.937 mmol,

9

1

9

9% yield) was prepared by “General procedure A” from alcohol SI-

8 (155.8 mg, 0.948 mmol) and 4-(dimethylamino)benzoic acid SI-

4 (313.0 mg, 1.90 mmol) using EDC·HCl. IR (neat): 2920, 1709,

−

1 1

608, 1182, 1095 cm ; H NMR (700 MHz, CDCl ): δ 7.97 (d, J =

3.6.20. (Z)-2-Methylundec-5-en-3-yn-2-ol (SI-23). To a stirred

solution of crude enyne SI-22 in THF (25 mL) at −78 °C was added

n-BuLi (1.7 mL, 3.07 mmol, 1.76 M in hexane). After 1 h, acetone

3

.1 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 5.79−5.82 (m, 1H), 5.41 (dt, J

10.8, 1.9 Hz, 1H), 5.05 (d, J = 2.0 Hz, 2H), 3.07 (s, 6H), 1.71−1.73

=

(

243.0 mg, 4.18 mmol, 0.31 mL) was added dropwise over 2 min.

(

1

3

m, 4H), 1.66−1.68 (m, 1H), 1.31−1.37 (m, 2H), 1.16−1.23 (m,

1

3

1

After 1 h, the reaction was allowed to warm up to rt over 2 h. After 4 h

H), 1.09−1.14 (m, 2H) ppm; C{ H} NMR (175 MHz, CDCl ): δ

3

stirring, the reaction was quenched with H O (10 mL) and extracted

2

66.3, 153.5, 150.7, 131.5, 116.3, 110.7, 106.3, 87.3, 83.2, 52.8, 40.1,

9.3, 32.3, 25.9, 25.6 ppm; HRMS (ES+): calcd. for C H NO (M +

with Et O (3 × 15 mL). The dried (MgSO ) extract was concentrated

2

4

2

0

26

2

in vacuo and puriﬁed by chromatography over silica gel, eluting it with

H), 312.1964; found, 312.1970.

5

3

1

−50% Et O/pentane, to give SI-23 (190.0 mg, 1.05 mmol, 38% over

2

steps) as a white solid. IR (neat): 3355, 2980, 2929, 1457, 1363,

−

1 1

164 cm ; H NMR (700 MHz, CDCl ): δ 5.93 (dt, J = 10.7, 7.4 Hz,

3

H), 5.48 (d, J = 10.8 Hz, 1H), 2.30 (q, J = 7.4 Hz, 2H), 1.94 (s, 1H),

.58 (s, 6H), 1.41−1.45 (m, 2H), 1.31−1.37 (m, 4H), 0.92 (t, J = 6.9

1

3

1

Hz, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 108.4, 97.8,

7

3

+

9.0, 65.7, 31.5, 31.4, 30.1, 28.4, 22.5, 14.1 ppm; HRMS (AP ): calcd

for C H O (M + H), 181.1592; found, 181.1599.

1

2

21

3

.6.17. (4R,5S)-5-Cyclohexyl-4,5-dihydroxypent-2-yn-1-yl 4-

Dimethylamino)benzoate (19i). Diol 19i (20.2 mg, 0.058 mmol,

9% yield, 59% ee) was prepared by “General procedure B” from

(

7

enyne 18i (23.1 mg, 0.074 mmol) using AD mix β** at rt for 18 h.

The enantiomeric ratio was determined by chiral HPLC [250 × 4.6

mm Phenomenex Lux 5u Cellulose-3 column, 99:1 to 50:50

i

hexanes/ PrOH, 0.5 mL/min, 254 nm, retention times 29.3 min

2

0

(

minor) and 30.7 min (major)]; [α]_D−2.95° (c = 0.61, CHCl ); IR

3.6.21. (Z)-2-Methylundec-5-en-3-yn-2-yl 4-(Dimethylamino)-

3

−

1

benzoate (18j). To a stirred solution of alcohol SI-23 (47.0 mg,

0

(

neat): 3421, 2924, 2852, 1705, 1608, 1183 cm ; H NMR (700

.26 mmol.) in 1,2-DCB (0.8 mL) were added sequentially 4-

dimethylamino)benzoic acid SI-14 (172.3 mg, 1.04 mmol), EDC·

MHz, C D ): δ 8.22 (d, J = 9.1 Hz, 2H), 6.30 (d, J = 9.1 Hz, 2H),

6

4

.77 (d, J = 1.7 Hz, 2H), 4.38−4.39 (m, 1H), 3.31 (dd, J = 7.9, 4.1

HCl (200.0 mg, 1.04 mmol), DMAP (128.0 mg, 1.04 mmol) and the

reaction was heated to 150 °C. After 10 h, the reaction was quenched

by using H O (1 mL) and extracted with CH Cl . The dried

Hz, 1H), 2.26 (s, 6H), 2.09−2.11 (m, 1H), 1.64−1.67 (m, 2H),

1

0

1

2

+

.48−1.58 (m, 3H), 1.13−1.20 (m, 2H), 0.97−1.06 (m, 2H), 0.80−

13 1

2

.86 (m, 1H) ppm; C{ H} NMR (175 MHz, C D ): δ 165.9, 153.2,

6

(

MgSO ) extract was concentrated in vacuo andpuriﬁed by

4

31.6, 116.7, 110.8, 85.0, 81.3, 78.2, 64.4, 51.7, 40.4, 38.9, 28.74,

8.70, 26.4, 25.9, 25.8 ppm; HRMS (ES+): calcd for C H NO (M

chromatography over silica gel (neutralized with 10% Et N in

3

2

0

28

4

hexanes), eluting it with 10−20% EtOAc/hexanes, to give the tertiary

H), 346.2018; found, 346.2022.

benzoate 18j (33.8 mg, 0.103 mmol, 40%) as a clear liquid. IR (neat):

−

1 1

2

7

923, 2855, 1708, 1608, 1098 cm ; H NMR (700 MHz, CDCl ): δ

3

.91 (d, J = 4.9 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 5.92 (dt, J = 10.7,

.5 Hz, 1H), 5.50 (dt, J = 10.7, 1.3 Hz, 1H), 3.05 (s, 6H), 2.31 (qd, J

=

7.4, 1.3 Hz, 2H), 1.84 (s, 6H), 1.39−1.43 (m, 2H), 1.29−1.31 (m,

3

.6.18. (Z)-Trimethyl(non-3-en-1-yn-1-yl)silane (SI-21). To a

13 1

4

H), 0.89 (t, J = 7.0 Hz, 3H) ppm; C{ H} NMR (175 MHz,

stirred suspension of iodide SI-4 (625.0 mg, 2.79 mmol) in THF/i-

CDCl ): δ 165.2, 153.2, 144.5, 131.3, 118.0, 110.6, 108.7, 94.9, 80.8,

3

+

Pr NH (16 mL, 1:1) at 0 °C was added sequentially TMS acetylene

72.2, 40.1, 31.4, 30.1, 29.4, 28.4, 22.4, 14.1 ppm; HRMS (ES ): calcd

for C H NO (M + H), 328.2277; found, 328.2285.

2

SI-20 (493.0 mg, 5.02 mmol, 0.7 mL), Pd(PPh ) (162.0 mg, 0.139

3

4

21 30

2

mmol), and CuI (53.0 mg, 0.279 mmol) and the reaction was allowed

to warm up to rt. After overnight stirring, the reaction was quenched

by using sat. aq NH Cl (20 mL). After evaporating the organic

4

solvent (THF), the resulting aqueous solution was extracted with

EtOAc (3 × 10 mL). The dried (MgSO ) extract was concentrated in

4

vacuo to give crude SI-21 which was used in the next step without

further puriﬁcation.

J

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

3

.6.22. (5R,6S)-5,6-Dihydroxy-2-methylundec-3-yn-2-yl 4-

Dimethylamino)benzoate (19j). Diol 19j (3.2 mg, 8.85 μmol,

4% yield, 58% ee) was prepared by “General procedure B” from

hexanes, to give 20 (251.8 mg, 0.83 mmol, 79%) as a colorless liquid.

IR (neat): 2955, 2923, 1705, 1609, 1277 cm ; H NMR (700 MHz,

−

1 1

(

7

CDCl ): δ 7.94 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 5.39−

3

enyne 18j (4.0 mg, 12.0 μmol) using AD mix β** at rt for 12 h. The

enantiomeric ratio was determined by chiral HPLC [250 × 4.6 mm

Phenomenex Lux 5u Cellulose-3 column, 90:10 to 70:30

hexanes/ PrOH, 0.5 mL/min, 254 nm, retention times 16.8 min

minor) and 17.5 min (major)]; [α]_D−10.0° (c = 0.17, CHCl ); IR

neat): 3404, 2920, 2852, 1690, 1606, 1290 cm ; H NMR (700

5.47 (m, 2H), 4.29 (t, J = 6.5 Hz, 2H), 3.06 (s, 6H), 2.22 (q, J = 7.2

Hz, 2H), 2.06 (q, J = 7.2 Hz, 2H), 1.81−1.85 (m, 2H), 1.34−1.40 (m,

1

3

1

2H), 1.26−1.33 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H) ppm; C{ H}

i

NMR (175 MHz, CDCl ): δ 167.0, 153.3, 131.2, 131.1, 128.3, 117.4,

3

2

0

(

110.7, 63.6, 40.0, 31.5, 29.4, 28.9, 27.2, 23.7, 22.5, 14.0 ppm; HRMS

3

−

1

+

(ES ): calcd for C H NO (typically M+ or M + H), 304.2277;

1

9

30

2

MHz, C D ): δ 8.17 (d, J = 4.9 Hz, 2H), 6.32 (d, J = 9.1 Hz, 2H),

6

found, 304.2277.

4

1

.18 (br s, 1H), 3.64 (br s, 1H), 2.95 (d, J = 6.6 Hz, 1H), 2.37 (s,

H), 2.27 (s, 6H), 1.69 (s, 3H), 1.67 (s, 3H), 1.59−1.64 (m, 1H),

.53−1.58 (m, 1H), 1.48−1.53 (m, 1H), 1.17−1.24 (m, 3H), 1.11−

1

3

1

.16 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H) ppm; C{ H} NMR (175

MHz, C D ): δ 165.9, 153.2, 131.5, 117.9, 110.7, 87.7, 83.8, 75.2,

6

3

.6.26. (4R,5S)-4,5-Dihydroxydecyl 4-(Dimethylamino)benzoate

7

1.5, 67.1, 38.9, 33.5, 31.9, 28.74, 28.70, 25.5, 22.6, 13.9 ppm; HRMS

(

21). Diol 21 (33.0 mg, 0.098 mmol, 54% yield, 11.6% ee) was

+

(

ES ): calcd for C H NO (M + H), 362.2331; found, 362.2334.

21 32 4

prepared by “General procedure B” from enyne 20 (55.0 mg, 0.181

mmol) using AD mix β** at rt for 2.5 h. The enantiomeric ratio was

determined by chiral HPLC [250 × 4.6 mm Phenomenex Lux 5u

Cellulose-3 column, 99:1 to 70:30 hexanes/ PrOH, 0.5 mL/min, 254

nm, retention times 20.5 min (major) and 21.5 min (minor)]; [α]

i

2

0

D

3.6.23. 4-Hydroxybutyl 4-(dimethylamino)benzoate (SI-25). To a

+

0.24° (c = 3.30, CHCl ); IR (neat): 3344, 2929, 1698, 1611, 1184

3

1

stirred solution of butane-1,4-diol SI-24 (3.49 g, 38.76 mmol) in

−1

cm ; H NMR (700 MHz, CDCl ): δ 7.92 (d, J = 9.1 Hz, 2H), 6.66

3

CH Cl (73 mL) at rt were added sequentially 4-(dimethylamino)-

2

(

d, J = 9.1 Hz, 2H), 4.33 (t, J = 6.5 Hz, 2H), 3.68 (d, J = 8.7 Hz, 1H),

benzoic acid SI-14 (6.04 g, 36.56 mmol), EDC·HCl (7.0 g, 36.56

mmol), and DMAP (4.5 g, 36.56 mmol). After 21 h, the reaction was

quenched by using H O (50 mL) and extracted with CH Cl (3 × 30

3

1

.65 (s, 1H), 3.05 (s, 6H), 2.37 (s, 1H), 2.15 (s, 1H), 1.98−2.04 (m,

H), 1.80−1.86 (m, 1H), 1.56−1.65 (m, 2H), 1.50−1.55 (m, 1H),

.44−1.47 (m, 2H), 1.27−1.34 (m, 5H), 0.90 (t, J = 6.9 Hz, 3H)

2

mL). The dried (MgSO ) extract was concentrated in vacuo and

13

1

4

ppm; C{ H} NMR (175 MHz, CDCl ): δ 167.2, 153.3, 131.3,

3

puriﬁed by recrystallization with toluene, to give SI-25 (6.0 g, 25.29

1

16.9, 110.7, 74.7, 74.2, 64.1, 40.1, 31.9, 31.4, 27.6, 25.7, 25.6, 22.6,

4.1 ppm; HRMS (ES ): calcd for C H NO (M + H), 338.2331;

found, 338.2329.

mmol, 69%) as a white solid. IR (neat): 3418, 2944, 1699, 1609, 1184

+

−

1

19 32 4

cm ; H NMR (700 MHz, CDCl ): δ 7.93 (d, J = 9.1 Hz, 2H), 6.67

3

(

d, J = 9.0 Hz, 2H), 4.33 (t, J = 6.5 Hz, 2H), 3.75 (t, J = 6.5 Hz, 2H),

.06 (s, 6H), 1.85−1.89 (m, 2H), 1.73−1.78 (m, 2H) ppm; C{ H}

1

3

1

3

NMR (175 MHz, CDCl ): δ 166.9, 153.3, 131.2, 117.3, 110.7, 63.9,

3

+

6

2.5, 40.0, 29.4, 25.4 ppm; HRMS (ES ): calcd for C H NO (M +

13 20 3

H), 238.1443; found, 238.1435.

3

.6.27. (4S,5R)-Dec-2-yne-1,4,5-triol (23). Triol 23 (41.4 mg, 0.22

mmol, 74%, 27.4% ee) was prepared by “General procedure B” from

enyne 22 (46.0 mg, 0.30 mmol) using AD mix β** at rt for 40 h. The

enantiomeric ratio was determined (by synthesizing the known

biphenyl-ester diol ent-19c) by chiral HPLC [250 × 4.6 mm

Phenomenex Lux 5u Cellulose-3 column, 99:1 to 60:40 hexane-

3

.6.24. 4-Oxobutyl 4-(Dimethylamino)benzoate (SI-26). To a

stirred solution of alcohol SI-25 (710.0 mg, 2.99 mmol) in CH Cl

30 mL) at rt was added DMP (3.20 g, 7.48 mmol). After 2 h, the

reaction was quenched by using sat. aq NaHCO (15 mL) and sat. aq

2

i

(

s/ PrOH, 0.5 mL/min, 254 nm, retention times 23.9 min (major) and

2

0

3

24.7 min (minor)]; [α] −23.5° (c = 0.2, CHCl ); IR (neat): 3347,

D

3

−1 1

Na S O ·5H O (15 mL) and extracted with CH Cl (3 × 20 mL).

2955, 2859, 1110, 1021 cm ; H NMR (700 MHz, CDCl ): δ 4.35

2

3

2

3

The dried (MgSO ) extract was concentrated in vacuo and puriﬁed by

(s, 1H), 4.32 (s, 2H), 3.98−4.03 (m, 1H), 3.86−3.90 (m, 1H), 3.74

4

chromatography over silica gel (neutralized with 2% Et N in hexanes),

eluting it with 20−50% EtOAc/hexanes, to give SI-26 (492.0 mg, 2.09

mmol, 70%). H NMR (400 MHz, CDCl ): δ 9.85 (t, J = 1.4 Hz,

3

(br s, 1H), 3.51−3.58 (m, 1H), 1.48−1.60 (m, 3H), 1.30−1.35 (m,

1

3

1

5

H), 0.92 (t, J = 6.9 Hz, 3H) ppm; C{ H} NMR (175 MHz,

1

3

CDCl ): δ 85.2, 83.2, 74.4, 66.4, 50.7, 32.8, 31.7, 25.4, 22.6, 14.0

3

+

1

H), 7.90 (d, J = 9.2 Hz, 2H), 6.67 (d, J = 9.1 Hz, 2H), 4.33 (t, J = 6.3

ppm; HRMS (ES ): calcd for C H O Na (M + H), 209.1154;

1

0

18

3

Hz, 2H), 3.0 (s, 6H), 2.64 (td, J = 7.2, 1.4 Hz, 2H), 2.08−2.15 (m,

found, 209.1156.

1

2

1

H) ppm; ¹³C{ H} NMR (100 MHz, CDCl ): δ 201.5, 166.8, 153.4,

3

31.3, 116.8, 110.7, 63.1, 40.7, 40.1, 21.7 ppm.

3

.6.28. (Z)-2,2,11,11-Tetramethyl-3,3,10,10-tetraphenyl-4,9-

dioxa-3,10-disiladodec-6-ene (SI-29). To a stirred solution of (Z)-

but-2-ene-1,4-diol SI-28 (3.0 g, 34.04 mmol) in CH Cl (68 mL) at 0

2

3

.6.25. (Z)-Dec-4-en-1-yl 4-(Dimethylamino)benzoate (20). To a

°C was added imidazole (7.0 g, 102.2 mmol) followed by TBDPSCl

stirred solution of the Wittig salt hexyltriphenylphosphonium bromide

SI-27 (716.0 mg, 1.67 mmol) in THF (11 mL) at −78 °C was

dropwise added NaHMDS (0.84 mL, 1.67 mmol, 2 M in THF). After

(28.0 g, 26.6 mL, 102.2 mmol). After 5 min, the reaction was warmed

to rt. After 2h 45 min, the reaction was quenched by using H

mL) and extracted with CH Cl (3 × 40 mL). The dried (MgSO )

4

O (60

2

5

min, the reaction was warmed up to −40 °C and stirred for 5 min

extract was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting it with 2.5−5% EtOAc/hexanes, to give the

before recooling down to −78 °C and aldehyde SI-26 (246.0 mg, 1.05

mmol) in THF (5 mL + 5 mL rinse) was added. After 1 h, the

reaction was warmed up to −40 °C and after overnight stirring, the

reaction was warmed up to rt and stirred for 15 min before quenching

by using H O (20 mL) and extracted with EtOAc (3 × 20 mL). The

dried (MgSO ) extract was concentrated in vacuo and puriﬁed by

35

known compound SI-29 (19.0 g, 33.7 mmol, 99%) as a colorless

1

liquid. H NMR (700 MHz, CDCl ): δ 7.66 (dd, J = 7.9, 1.3 Hz, 8H),

3

7.42−7.44 (m, 4H), 7.36−7.38 (m, 8H), 5.66 (t, J = 3.4 Hz, 2H),

1

3

1

4.15 (d, J = 4.2 Hz, 4H), 1.05 (s, 18H) ppm; C{ H} NMR (175

2

MHz, CDCl ): δ 135.56, 133.67, 129.94, 129.60, 127.65, 60.51, 26.79,

4

3

chromatography over silica gel, eluting it with 10−25% EtOAc/

19.12 ppm.

K

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

3

.6.33. (Z)-Non-2-en-4-yn-1-ol (SI-35). To a stirred solution of

3

.6.29. 2,2,11,11-Tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-

silyl ether SI-34 (1.06 g, 2.82 mmol) in THF (37 mL) at 0 °C was

added TBAF (3.1 mL, 3.1 mmol, 1 M in THF) and the reaction

mixture was allowed to warm up to rt immediately. After overnight

stirring, the reaction was quenched with H O (20 mL). The organic

solvent (THF) was removed in vacuo and the resulting aqueous layer

3

,10-disiladodecane-6,7-diol (SI-30). To a stirred solution of alkene

SI-29 (2.17 g, 3.84 mmol) in acetone/H O (7:7 mL) at rt was

sequentially added NMO (2.4 mL, 11.52 mmol, 4.8 M in H O) and

K OsO ·2H O (7.1 mg, 19.2 μmol). After overnight stirring, the

reaction was quenched by the addition of solid NaHSO (500 mg)

and extracted with EtOAc (3 × 20 mL). The dried (NaSO ) extract

was concentrated in vacuo and the crude diol SI-30 was used in the

next step without further puriﬁcation.

2

4

2

3

was extracted with EtOAc (3 × 30 mL). The dried (MgSO ) extract

4

was concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting it with 10−33% EtOAc/hexanes, to give the known

37

1

compound SI-35 (274.0 mg, 1.99 mmol, 70%) as a colorless oil. H

NMR (700 MHz, CDCl ): δ 6.00 (dt, J = 10.9, 6.3 Hz, 1H), 5.58

3

(

7

1

dquin, J = 10.9, 1.5 Hz, 1H), 4.39 (t, J = 5.6 Hz, 2H), 2.34 (td, J =

.1, 2.1 Hz, 2H), 1.90 (t, J = 5.8 Hz, 1H), 1.51−1.55 (m, 2H), 1.41−

13 1

.46 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm; C{ H} NMR (175

3

.6.30. 2-((tert-Butyldiphenylsilyl)oxy)acetaldehyde (SI-31). To

MHz, CDCl ): δ 139.8, 111.2, 96.7, 60.9, 30.7, 21.9, 19.2, 13.5 ppm.

3

the stirred crude diol SI-30 in CH Cl (20 mL) was added silica-

2

supported NaIO (made by mixing 1.23 g NaIO and 5.0 g silica gel in

4

2

.4 mL H O). After a week, the reaction mixture was ﬁltered and the

2

dried (MgSO ) ﬁltrate was concentrated in vacuo puriﬁed by

4

chromatography over silica gel, eluting it with 5−9% EtOAc/hexanes,

3.6.34. (Z)-1-Methoxy-4-((non-2-en-4-yn-1-yloxy)methyl)-

benzene (24a). To a stirred solution of NaH (23.0 mg, 0.563

mmol, 60%) in THF (0.5 mL) at 0 °C was added allyl alcohol SI-35

36

to give the known compound SI-31 (1.4 g, 4.7 mmol, 61% over two

1

steps) as a colorless liquid. H NMR (700 MHz, CDCl ): δ 9.75 (s,

3

(

51.8 mg, 0.375 mmol) and stirred at the same temperature for 10

min and at rt for 20 min. Then, the reaction mixture was recooled to 0

C and to it was added PMBCl (71.0 mg, 61.3 μL, 0.45 mmol)

1

4

H), 7.69 (d, J = 7.5 Hz, 4H), 7.47−7.49 (m, 2H), 7.42−7.44 (m,

13 1

H), 4.24 (s, 2H), 1.13 (s, 9H) ppm; C{ H} NMR (175 MHz,

°

CDCl ): δ 201.7, 135.5, 132.5, 130.1, 127.9, 70.0, 26.7, 19.3 ppm.

3

followed by TBAI (14.0 mg, 0.038 mmol). After 5 min, the reaction

was warmed up to rt and stirred for 20 h before reﬂuxing for another

4

h. The reaction was cooled down to 0 °C and was quenched by

using sat. aq NH Cl (1 mL) and extracted with EtOAc (3 × 5 mL).

The dried (MgSO ) extract was concentrated in vacuo and puriﬁed by

3

.6.31. (Z)-tert-Butyl((3-iodoallyl)oxy)diphenylsilane (SI-32). To

a stirred solution of the Wittig salt SI-16 (2.84 g, 5.35 mmol) in THF

18 mL) at rt was dropwise added NaHMDS (2.7 mL, 5.35 mmol, 2

M in THF). After 5 min, the reaction was cooled down to −78 °C

and DMPU (2.74 g, 2.6 mL, 21.4 mmol) was added and stirred for

another 5 min before addition of aldehyde SI-31 (1.33 g, 4.46 mmol)

in THF (2 + 2 mL rinse). After 2.5 h, the reaction was quenched by

4

chromatography over silica gel, eluting with 4−7% EtOAc/hexanes, to

give the compound 24a [57.0 mg, 0.221 mmol, 59%, (74% brsm)] as

a yellow liquid. IR (neat): 2958, 2873, 1717, 1613, 1514, 1249, 821

(

−

1 1

cm ; H NMR (700 MHz, CDCl ): δ 7.30 (d, J = 8.1 Hz, 2H), 6.90

3

(

0

(

0

d, J = 7.9 Hz, 2H), 5.99 (dt, J = 10.8, 6.4 Hz, 1H), 5.64 (dd, J = 10.8,

.8 Hz, 1H), 4.48 (s, 2H), 4.28 (d, J = 6.4 Hz, 2H), 3.82 (s, 3H), 2.34

t, J = 6.9 Hz, 2H), 1.50−1.54 (m, 2H), 1.44 (sextet, J = 7.4 Hz, 2H),

using sat. aq NH Cl (25 mL) and extracted with EtOAc (3 × 30 mL).

4

The dried (MgSO ) extract was concentrated in vacuo and puriﬁed by

4

13

1

.94 (t, J = 7.3 Hz, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ

3

chromatography over silica gel, eluting with 2−2.5% Et O/hexanes, to

2

36

159.2, 137.9, 130.4, 129.5, 113.7, 112.2, 96.5, 76.4, 71.9, 67.6, 55.3,

give the known compound SI-32 (1.35 g, 3.2 mmol, 72%, Z/E >

+

1

30.7, 21.9, 19.2, 13.6 ppm; HRMS (ES ): calcd for C17

H), 259.1698; found, 259.1687.

H O (M +

23 2

4

2:1) as a colorless liquid. H NMR (400 MHz, CDCl ): δ 7.72 (dd, J

3

=

7.9, 1.8 Hz, 4H), 7.41−7.47 (m, 6H), 6.54 (dt, J = 7.7, 5.2 Hz, 1H),

6

9

1

.25 (dt, J = 7.7, 1.8 Hz, 1H), 4.33 (dd, J = 5.3, 1.8 Hz, 2H), 1.09 (s,

H) ppm; ¹³C{ H} NMR (100 MHz, CDCl ): δ 140.9, 135.6, 133.4,

1

3

29.8, 127.8, 80.3, 67.5, 26.8, 19.2 ppm.

3

.6.35. (2S,3R)-1-((4-Methoxybenzyl)oxy)non-4-yne-2,3-diol

(

25a). The diol 25a (19.9 mg, 0.068 mmol, 65% yield, 6.5% ee

determined by Mosher ester analysis) was prepared by “General

3

.6.32. (Z)-tert-Butyl(non-2-en-4-yn-1-yloxy)diphenylsilane (SI-

procedure B” from enyne 24a (27.0 mg, 0.105 mmol) using AD mix

3

4). To a stirred suspension of Pd(PPh ) (185.0 mg, 0.16 mmol) and

3

4

20

β** at 0 °C for 4.5 h. [α]_D+1.37° (c = 0.95, CHCl ); IR (neat):

3

CuI (61.0 mg, 0.32 mmol) in i-Pr NH (15 mL) at 0 °C was dropwise

added a solution of hex-1-yne SI-33 (263.0 mg, 3.2 mmol) and iodide

SI-32 (1.35 g, 3.2 mmol) in i-Pr NH (8 mL) and the reaction was

allowed to warm up to rt. After overnight stirring, the reaction was

quenched by using sat. aq NH Cl (15 mL) and extracted with EtOAc

3 × 20 mL). The dried (MgSO ) extract was concentrated in vacuo

2

−1

1

3

403, 2932, 1613, 1514, 1248, 1035 cm ; H NMR (700 MHz,

CDCl ): δ 7.28−7.27 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H),

3

2

4

9

2

.52 (s, 2H), 4.49−4.51 (m, 1H), 3.80−3.84 (m, 5H), 3.67 (dd, J =

.4, 3.5 Hz, 1H), 2.78 (d, J = 7.5 Hz, 1H), 2.68 (d, J = 6.3 Hz, 1H),

.23 (td, J = 7.1, 1.9 Hz, 2H), 1.47−1.52 (m, 2H), 1.38−1.43 (m,

4

(

13

1

4

H), 0.92 (t, J = 7.4 Hz, 3H)ppm; C{ H} NMR (175 MHz,

and puriﬁed by chromatography over silica gel, eluting it with 2−3.3%

+

CDCl ): δ ppm; HRMS (ES ): calcd for C H O (M + H),

3

17 25

4

Et O/hexanes, to give the compound SI-34 (1.08 g, 2.87 mmol, 90%)

2

293.1753; found, 293.1745.

−

1 1

as a colorless liquid. IR (neat): 3072, 2932, 1472, 1114, 701 cm ; H

NMR (700 MHz, CDCl ): δ 7.72 (dd, J = 7.9, 1.3 Hz, 4H), 7.44−

3

7

5

.46 (m, 2H), 7.39−7.42 (m, 4H), 6.03 (dt, J = 10.9, 6.1 Hz, 1H),

.49 (dquin, J = 10.9, 1.9 Hz, 1H), 4.50 (dd, J = 6.1, 1.5 Hz, 2H), 2.24

(

1

td, J = 7.0, 2.1 Hz, 2H), 1.39−1.44 (m, 2H), 1.31−1.37 (m, 2H),

13 1

.09 (s, 9H), 0.88 (t, J = 7.3 Hz, 3H) ppm; C{ H} NMR (175

3.6.36. (Z)-Non-2-en-4-yn-1-yl 4-Methoxybenzoate (24b). The

MHz, CDCl ): δ 140.8, 135.6, 133.8, 129.6, 127.6, 109.7, 96.2, 62.5,

allylic ester 24b (48.0 mg, 0.176 mmol, 99% yield) was prepared by

“General procedure A” from alcohol SI-35 (24.6 mg, 0.178 mmol)

and 4-methoxybenzoic acid SI-9 (81.3 mg, 0.535 mmol) using DCC.

3

+

3

0.7, 26.8, 21.9, 19.2, 19.1, 13.6 ppm; HRMS (ES ): calcd for

C H OSi (M + H), 377.2301; found, 377.2302.

25

33

L

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

−

1

+

IR (neat): 2958, 2118, 1716, 1607, 1257, 1101, 770 cm ; H NMR

700 MHz, CDCl ): δ 8.03 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz,

21.9, 18.4, 13.5 ppm; HRMS (ES ): calcd for C H O (M + H),

22 25 4

353.1753; found, 353.1747.

(

3

2

H), 6.05 (dt, J = 10.7, 6.5 Hz, 1H), 5.72 (d, J = 10.7 Hz, 1H), 5.05

(

3

d, J = 6.5 Hz, 2H), 3.88 (s, 3H), 2.37 (td, J = 7.0, 1.8 Hz, 2H), 1.55

quint, J = 7.2 Hz, 2H), 1.45 (sex, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz,

H) ppm; ¹³C{ H} NMR (175 MHz, CDCl ): δ 166.2, 163.3, 134.9,

1

3

1

31.7, 122.5, 113.6, 113.4, 97.6, 75.9, 62.7, 55.4, 30.7, 22.0, 19.2, 13.6

+

3.6.40. (Z)-Non-2-en-4-yn-1-yl 4-(Dimethylamino)benzoate

ppm; HRMS (ES ): calcd for C H O (M + H), 273.1491; found,

1

7

21

3

(

24d). The allylic ester 24d (35.6 mg, 0.125 mmol, 81% yield) was

2

73.1495.

prepared by “General procedure A” from alcohol SI-35 (21.4 mg,

0

.155 mmol) and 4-(dimethylamino)benzoic acid SI-14 (52.0 mg,

.31 mmol) using EDC·HCl. IR (neat): 2922, 1708, 1608, 1365, 1270

−

1 1

cm ; H NMR (700 MHz, CDCl ): δ 9.47 (d, J = 9.0 Hz, 2H), 6.66

3

(

1

d, J = 9.0 Hz, 2H), 6.06 (dt, J = 10.8, 6.4 Hz, 1H), 5.69−5.71 (m,

3

.6.37. (2S,3R)-2,3-Dihydroxynon-4-yn-1-yl 4-Methoxybenzoate

H), 5.04 (dd, J = 6.5, 1.4 Hz, 2H), 3.06 (s, 6H), 2.37 (td, J = 7.1, 2.1

(

25b). Diol 25b (15.4 mg, 0.050 mmol, 63% yield, 38% ee) was

Hz, 2H), 1.53−1.58 (m, 2H), 1.43−1.48 (m, 2H), 0.94 (t, J = 7.3 Hz,

3

1

ppm; HRMS (ES ): calcd for C H NO (M + H), 286.1807; found,

2

prepared by “General procedure B” from enyne 24b (21.6 mg, 0.079

mmol) using AD mix β** at rt for 5.5 h. The enantiomeric ratio was

determined by chiral HPLC [250 × 4.6 mm Phenomenex Lux 5u

13

1

H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 166.8, 153.3, 135.6,

3

31.4, 116.9, 112.9, 110.7, 97.4, 76.0, 62.3, 40.1, 30.7, 22.0, 19.3, 13.6

+

i

18 24

2

Cellulose-2 column, 99:1 to 70:30 hexanes/ PrOH, 0.5 mL/min, 254

86.1810.

nm, retention times 104.4 min (minor) and 111.2 min (major)];

2

D

0

[

1

α] +3.43° (c = 1.4, CHCl ); IR (neat): 3405, 2958, 1714, 1607,

3

−

1 1

259, 770 cm ; H NMR (700 MHz, CDCl ): δ 8.03 (d, J = 8.9 Hz,

3

2

4

5

H), 6.94 (d, J = 8.9 Hz, 2H), 4.53−4.56 (m, 2H), 4.50 (dd, J = 11.7,

.0 Hz, 1H), 4.04 (quint, J = 4.3 Hz, 1H), 3.88 (s, 3H), 2.71 (d, J =

.9 Hz, 1H), 2.55 (d, J = 6.4 Hz, 1H), 2.22 (td, J = 7.1, 1.9 Hz, 2H),

.50 (quint, J = 7.2 Hz, 2H), 1.41 (sext, J = 7.3 Hz, 2H), 0.92 (t, J =

3

.6.41. (2S,3R)-2,3-Dihydroxynon-4-yn-1-yl 4-(Dimethylamino)-

benzoate (25d). Diol 25d (14.0 mg, 0.044 mmol, 73% yield, 4.9% ee)

was prepared by “General procedure B” from enyne 24d (18.4 mg,

1

7

.3 Hz, 3H) ppm; ¹C{ H} NMR (175 MHz, CDCl ): δ 166.8, 166.6,

3

1

3

0

.060 mmol) using AD mix β** at rt for 20 h. The enantiomeric ratio

1

31.8, 122.0, 113.7, 88.6, 76.7, 72.8, 65.4, 64.1, 55.5, 30.5, 21.9, 18.4,

was determined by chiral HPLC [250 × 4.6 mm Phenomenex Lux 5u

Cellulose-3 column, 90:10 to 50:50 hexanes/i-PrOH, 0.5 mL/min,

2

+

3.5 ppm; HRMS (ES ): calcd for C H O (M + H), 307.1545;

1

7

23

5

found, 307.1536.

54 nm, retention times 28.3 min (minor) and 30.0 min (major)];

2

0

[

1

α] +0.8° (c = 0.5, CHCl ); IR (neat): 3404, 2926, 1702, 1608,

D 3

1 1

−

279, 1185 cm ; H NMR (700 MHz, C D ): δ 8.21 (d, J = 9.0 Hz,

6 6

2H), 6.32 (d, J = 9.0 Hz, 2H), 4.65 (dd, J = 6.6, 6.5 Hz, 1H), 4.58

(dd, J = 11.7, 4.1 Hz, 1H), 4.47 (quint, J = 2.1 Hz, 1H), 3.97 (dt, J =

6

.5, 4.2 Hz, 1H), 2.29 (s, 6H), 1.92 (td, J = 6.9, 2.0 Hz, 2H), 1.20−

3

.6.38. (Z)-Non-2-en-4-yn-1-yl [1,1′-Biphenyl]-4-carboxylate

24c). The allylic ester 24c (74.6 mg, 0.234 mmol, 85% yield) was

prepared by “General procedure A” from alcohol SI-35 (38.0 mg,

13 1

1.28 (m, 4H), 0.75 (t, J = 7.2 Hz, 3H) ppm; C{ H} NMR (175

(

MHz, C D ): δ 167.3, 153.2, 131.6, 117.1, 110.7, 87.1, 77.9, 73.2,

6

C H NO (M + H), 320.1862; found, 320.1866.

6

+

5.3, 64.3, 38.9, 30.5, 21.8, 18.2, 13.3 ppm; HRMS (ES ): calcd for

0

1

.275 mmol) and (1,1′-biphenyl)-4-carboxylic acid SI-6 (110.0 mg,

.551 mmol) using EDC·HCl. IR (neat): 2926, 1722, 1609, 1269,

18 26

4

−

1 1

113, 747 cm ; H NMR (700 MHz, CDCl ): δ 8.15 (dt, J = 8.6, 1.8

3

Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.49 (t, J

7.6 Hz, 2H), 7.42 (tt, J = 7.2, 1.1 Hz, 1H), 6.08 (dt, J = 10.7, 6.5

Hz, 1H), 5.75 (dquint, J = 10.7, 1.4 Hz, 1H), 5.11 (dd, J = 6.5, 1.3 Hz,

=

2

7

H), 2.38 (td, J = 7.2, 2.0 Hz, 2H), 1.54−1.57 (m, 2H), 1.46 (sext, J =

13 1

3.6.42. (S,Z)-8-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-

.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H) ppm; C{ H} NMR (175 MHz,

(

(triethylsilyl)oxy)oct-6-en-4-yn-1-ol (SI-36). To a stirred solution

CDCl ): δ 166.3, 145.7, 140.0, 134.6, 130.2, 128.9, 128.1, 127.3,

1

3

of known (S,Z)-8-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-

27.0, 113.7, 97.7, 75.9, 62.9, 30.7, 22.0, 19.2, 13.6 ppm; HRMS

14

(

(triethylsilyl)oxy)oct-6-en-4-yn-1-yl pivalate 12a (255.0 mg, 0.58

+

(

ES ): calcd for C H O (M + H), 319.1698; found, 319.1709.

22 23 2

mmol) in CH Cl (6 mL) at −78 °C was added DIBAL-H (1.16 mL,

2

1

.16 mmol, 1.0 M in hexane). After 15 min, the reaction was

quenched by using MeOH (1 mL) and sat. aq Rochelle’s salt (5 mL)

and stirred until two layers got separated and was extracted with

CH Cl (3 × 5 mL). The dried (MgSO ) extract was concentrated in

vacuo to give crude alcohol SI-36 which was used in the next step

without further puriﬁcation.

2

4

3

.6.39. (2S,3R)-2,3-Dihydroxynon-4-yn-1-yl [1,1′-Biphenyl]-4-

carboxylate (25c). Diol 25c (18.50 mg, 0.052 mmol, 70% yield,

2% ee) was prepared by “General procedure B” from enyne 24c

23.90 mg, 0.075 mmol) using AD mix β** at rt for 18 h. The

3

(

enantiomeric ratio was determined by chiral HPLC [250 × 4.6 mm

Phenomenex Lux 5u Cellulose-2 column, 99:1 to 70:30 hexanes/i-

PrOH, 0.5 mL/min, 254 nm, retention times 79.3 min (minor) and

2

0

8

2

8

2

3

⁷^.¹^mⁱⁿ⁽^m^a^j^o^r⁾^]^;^[^α^]D +7.53° (c = 0.73, CHCl ); IR (neat): 3367,

3

3.6.43. (S,Z)-1-(Benzyloxy)-8-((S)-2,2-dimethyl-1,3-dioxolan-4-

−

1 1

958, 1717, 1609, 1277, 1125 cm ; H NMR (700 MHz, CDCl ): δ

yl)oct-6-en-4-yn-3-ol (26). To a stirred solution of crude alcohol

3

.14 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 7.4 Hz,

H), 7.49 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 4.55−4.61 (m,

H), 4.09 (quint, J = 5.7 Hz, 1H), 2.70 (d, J = 6.0 Hz, 1H), 2.54 (d, J

6.4 Hz, 1H), 2.24 (td, J = 7.1, 1.6 Hz, 2H), 1.51 (quint, J = 7.4 Hz,

H), 1.42 (sext, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H) ppm;

SI-36 in Et O (6 mL) at 0 °C was added sequentially benzyl

2

acetimidate (176.0 mg, 0.69 mmol, 129.0 μL) and TfOH (0.23 mmol,

136.0 μL, 1M in Et O). The reaction was allowed to warm up to rt.

2

=

After being kept overnight (8 h), the reaction was quenched by using

2

sat. aq NaHCO (6 mL) and extracted with Et O (3 × 5 mL). The

3

2

13

1

C{ H} NMR (175 MHz, CDCl ): δ 166.9, 146.0, 139.9, 130.3,

dried (MgSO ) extract was concentrated in vacuo and puriﬁed by

3

4

1

28.9, 128.4, 128.2, 127.3, 127.1, 88.7, 76.6, 72.7, 65.6, 64.1, 30.5,

chromatography over silica gel, eluting it with 10−30% EtOAc/

M

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

hexanes, to give 26 (100.0 mg, 0.30 mmol, 52% over 2 steps) as a

yellow liquid. [α]²−10.23° (c = 1.3, CHCl ); IR (neat): 3426, 2930,

3.6.46. (((S,Z)-3-(Benzyloxy)-8-((S)-2,2-dimethyl-1,3-dioxolan-4-

yl)oct-6-en-4-yn-1-yl)oxy)triethylsilane (12c). To a stirred suspen-

sion of NaH (3.6 mg, 0.09 mmol, 60% in mineral oil) in THF (1.2

mL) at 0 °C was added sequentially BnBr (31.0 mg, 22.0 μL, 0.18

mmol) and crude alcohol SI-36 (made from 0.06 mmol of 12a, in a

similar procedure discussed earlier) in THF (0.3 mL) and TBAI (4.4

mg, 0.01 mmol). After 15 min, the reaction was warmed to rt. After

0

D

3

−

1 1

2

7

5

870, 1454, 1370, 1103 cm ; H NMR (700 MHz, CDCl ): δ 7.35−

3

.38 (m, 4H), 7.30−7.32 (m, 1H), 5.97 (dt, J = 10.8, 7.4 Hz, 1H),

.64 (dd, J = 10.8, 1.5 Hz, 1H), 4.78−4.79 (m, 1H), 4.57 (d, J = 11.9

Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.19 (quint, J = 6.3 Hz, 1H), 4.03

(

2

d, J = 4.8, 6.0 Hz, 1H), 3.88 (ddd, J = 9.4, 8.5, 4.1 Hz, 1H), 3.71

ddd, J = 10.0, 6.0, 4.6 Hz, 1H), 3.63 (dd, J = 8.0, 6.8 Hz, 1H), 3.15

d, J = 5.5 Hz, 1H), 2.59−2.61 (m, 2H), 2.11−2.16 (m, 1H), 1.98−

being kept overnight, the reaction was quenched by using H O (2

2

mL) at 0 °C and extracted with EtOAc (3 × 5 mL). The dried

1

3

1

(

MgSO ) extract was concentrated in vacuo and puriﬁed by

.03 (m, 1H), 1.45 (s, 3H), 1.37 (s, 3H) ppm; C{ H} NMR (175

4

chromatography over silica gel, eluting it with 5−10% EtOAc/

MHz, CDCl ): δ 138.3, 137.8, 128.5, 127.8, 127.7, 111.4, 109.1, 94.6,

3

hexanes, to give 12c (16.3 mg, 0.036 mmol, 61%) as a clear liquid. IR

8

1.3, 74.9, 73.4, 68.7, 67.7, 61.9, 36.9, 34.3, 26.9, 25.6 ppm; HRMS

−

1

+

(

neat): 2954, 2875, 1455, 1092, 744 cm ; H NMR (700 MHz,

(

ES ): calcd for C H O Na (M + Na), 353.1729; found, 353.1723.

20 26 4

CDCl ): δ 7.34−7.38 (m, 4H), 7.29−7.30 (m, 1H), 5.98−6.01 (m,

3

1

4

H), 5.68 (d, J = 10.8 Hz, 1H), 4.82 (d, J = 11.5 Hz, 1H), 4.53 (d, J =

1.6 Hz, 1H), 4.49 (t, J = 6.5 Hz, 1H), 4.22 (quint, J = 6.3 Hz, 1H),

.04−4.06 (m, 1H), 3.81−3.84 (m, 1H), 3.76−3.79 (m, 1H), 3.63 (t,

J = 7.4 Hz, 1H), 2.63−2.65 (m, 2H), 2.06−2.09 (m, 1H), 1.96−2.00

(

m, 1H), 1.44 (s, 3H), 1.38 (s, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.60 (q,

3.6.44. (((S,Z)-1-(Benzyloxy)-8-((S)-2,2-dimethyl-1,3-dioxolan-4-

1

3

1

J = 7.9 Hz, 6H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 138.0,

yl)oct-6-en-4-yn-3-yl)oxy)triethylsilane (12b). To a stirred solution

of alcohol 26 (27.7 mg, 0.08 mmol) in CH Cl (1.5 mL) at 0 °C was

3

1

6

37.9, 128.1, 127.7, 127.4, 111.2, 108.9, 93.2, 82.1, 74.7, 70.5, 68.6,

6.2, 58.6, 38.9, 34.2, 26.6, 25.4, 6.5, 4.2 ppm.

2

sequentially added 2,6-lutidine (43.0 mg, 0.40 mmol, 46.0 μL) and

TESOTf (66.0 mg, o.25 mmol, 57.0 μL). After 10 min, the reaction

was quenched by using sat. aq NaHCO (2 mL) and extracted with

3

CH Cl (3 × 4 mL). The dried (MgSO ) extract was concentrated in

2

4

vacuo and puriﬁed by chromatography over silica gel, eluting it with

−12% EtOAc/hexanes, to give 12b (33.0 mg, 0.07 mmol, 93%) as a

4

20

3.6.47. (2S,3R,6S)-6-(Benzyloxy)-1-((S)-2,2-dimethyl-1,3-dioxo-

yellow liquid. [α] −3.18° (c = 1.1, CHCl ); IR (neat): 2954, 2876,

D

3

−

1

lan-4-yl)-8-((triethylsilyl)oxy)oct-4-yne-2,3-diol (13c). To a stirred

1

(

455, 1097, 744 cm ; H NMR (700 MHz, CDCl ): δ 7.35−7.38

3

solution of cis-enyne 12c (14.8 mg, 0.033 mmol) in t-BuOH/H O

2

m, 4H), 7.29−7.31 (m, 1H), 5.94 (dt, J = 10.8, 7.4 Hz, 1H), 5.62

(

0.2 mL, 1:1 mixture) at 0 °C were added sequentially AD mix β**

dd, J = 10.8, 1.5 Hz, 1H), 4.76 (td, J = 7.3, 1.4 Hz, 1H), 4.55 (d, J =

73.0 mg) and MeSO NH (6.4 mg, 0.06 mmol). After 36 h, the

2

1

4

1

1.9 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 4.19 (quint, J = 6.5 Hz, 1H),

.03 (dd, J = 8.0, 6.0 Hz, 1H), 3.65−3.68 (m, 1H), 3.61−3.64 (m,

H), 3.59 (dd, J = 7.9, 7.1 Hz, 1H), 2.59−2.60 (m, 2H), 1.99−2.07

reaction was quenched by using sat. aq Na S O ·5H O (0.5 mL),

2

3

2

stirred for another 5 min, and extracted with EtOAc. The dried

Na SO ) extract was concentrated in vacuo and puriﬁed by

(

2

4

(

m, 2H), 1.44 (s, 3H), 1,37 (s, 3H), 0.99 (t, J = 7.9 Hz, 9H), 0.63−

chromatography over silica gel, eluting it with 20−80% Et O/hexanes

1

3

1

2

0

1

6

.72 (m, 6H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 138.4,

3

to give 13c (10.4 mg, 0.022 mmol, 67%, 82:18 dr) as a yellow liquid.

37.8, 128.4, 127.6, 127.5, 111.4, 109.0, 95.7, 80.5, 74.9, 73.1, 68.8,

6.4, 60.2, 39.0, 34.2, 26.8, 25.6, 6.8, 4.7 ppm.

−1

1

Major diastereomer: IR (neat): 3395, 2912, 1658, 1097 cm ; H

NMR (700 MHz, CDCl ): δ 7.35−7.37 (m, 4H), 7.31−7.32 (m, 1H),

3

4

.79 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 2.3

Hz, 1H), 4.39−4.41 (m, 2H), 4.12 (dd, J = 8.1, 6.0 Hz, 1H), 3.95 (br

s, 1H), 3.79−3.82 (m, 1H), 3.74−3.78 (m, 1H), 3.60−3.62 (m, 1H),

2

1

.53 (br s, 1H), 2.43 (br s, 1H), 2.03−2.07 (m, 1H), 1.94−1.98 (m,

H), 1.84−1.88 (m, 2H), 1.44 (s, 3H), 1.39 (s, 3H), 0.96 (t, J = 7.9

3

.6.45. (2S,3R,6S)-8-(Benzyloxy)-1-((S)-2,2-dimethyl-1,3-dioxo-

+

Hz, 9H), 0.60 (q, J = 8.0 Hz, 6H) ppm; HRMS (ES ): calcd for

C H O Si (M + H), 479.2829; found, 479.2822.

lan-4-yl)-6-((triethylsilyl)oxy)oct-4-yne-2,3-diol (13b). To a stirred

2

6

43

6

solution of cis-enyne 12b (32.0 mg, 0.07 mmol) in t-BuOH/H O (0.3

2

mL, 1:1 mixture) at 0 °C were added sequentially AD mix β** (161.0

mg) and MeSO NH (14.0 mg, 0.14 mmol). After 17 h, the reaction

2

was quenched by using sat. aq Na S O ·5H O (0.5 mL), stirred for

2

3

2

another 5 min, and extracted with EtOAc. The dried (Na SO )

2

4

extract was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting it with Et O/hexanes:CH Cl (1:4:1 → 1:3:1

3

.6.48. (S)-4-((S,Z)-8-(Benzyloxy)-6-((4-methoxybenzyl)oxy)oct-2-

2

en-4-yn-1-yl)-2,2-dimethyl-1,3-dioxolane (12d). To a stirred sol-

ution of alcohol 26 (404.3 mg, 1.22 mmol) in THF (6 mL) at 0 °C

was added NaH (98.0 mg, 2.44 mmol, 60% dispersion in mineral oil).

After 5 min, the reaction was warmed to rt and after 40 min, it was

recooled to 0 °C. Next, PMBCl (267.5 mg, 1.71 mmol, 0.23 mL) and

TBAI (90.0 mg, 0.24 mmol) were sequentially added After 22 h, the

→

1:2:1 → 1:1:1 → 4:2:1 → 3:1:1 → 4:1:1) to give 13b (24.5 mg,

0

.05 mmol, 73%, 79:21 dr) as a yellow liquid. Major diastereomer:

2

0

[

1

(

α] −12.5° (c = 0.32, CHCl ); IR (neat): 3395, 2919, 1667, 1455,

D

3

−

1 1

097 cm ; H NMR (700 MHz, CDCl ): δ 7.34−7.38 (m, 4H), 7.31

3

t, J = 7.0 Hz, 1H), 4.66 (t, J = 6.6 Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H),

4

1

.49 (d, J = 11.6 Hz, 1H), 4.39 (t, J = 4.2 Hz, 1H), 4.35−4.37 (m,

reaction was quenched by using H O (5 mL) and the organic solvent

THF) was removed in vacuo and the aqueous phase was extracted

with EtOAc (3 × 5 mL). The dried (MgSO ) extract was

2

H), 4.10 (dd, J = 8.0, 6.2 Hz, 1H), 3.88−3.92 (m, 1H), 3.58−3.63

(

2

m, 3H), 2.54 (d, J = 5.2 Hz, 1H), 2.37 (d, J = 3.8 Hz, 1H), 1.96−

4

.04 (m, 2H), 1.79−1.86 (m, 2H), 1.44 (s, 3H), 1.38 (s, 3H), 0.99 (t,

concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting it with 3−14% EtOAc/hexanes, to give 12d (470 mg, 1.04

13 1

J = 7.9 Hz, 9H), 0.62−0.71 (m, 6H) ppm; C{ H} NMR (175 MHz,

CDCl ): δ 138.3, 128.4, 127.7, 127.6, 108.9, 88.6, 81.2, 73.3, 73.0,

20

D

3

mmol, 85%) as a colorless oil. [α] −48.07° (c = 0.57, CHCl ); IR

3

7

1.5, 69.4, 66.5, 66.1, 59.7, 38.8, 35.8, 26.9, 25.7, 6.8, 4.7 ppm; HRMS

−1

1

(

neat): 2986, 2868, 1612, 1514, 1249, 826 cm ; H NMR (700

+

(

ES ): calcd for C H O Si (M + H), 479.2829; found, 479.2822.

26 43 6

MHz, CDCl ): δ 7.34−7.36 (m, 2H), 7.29−7.31 (5H), 6.88 (d, J =

.5 Hz, 2H), 5.99 (dt, J = 10.8, 7.4 Hz, 1H), 5.68 (dd, J = 10.8, 1.3

3

8

Hz, 1H), 4.74 (d, J = 11.2 Hz, 1H), 4.44−4.51 (m, 4H), 4.22 (quint, J

=

6.2 Hz, 1H), 4.04 (dd, J = 8.0, 5.9 Hz, 1H), 3.81 (s, 3H), 3.62−3.69

(m, 3H), 2.59−2.67 (m, 2H), 2.11−2.15 (m, 1H), 2.03−2.08 (m,

N

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1

H), 1.44 (s, 3H), 1.37 (s, 3H) ppm; ¹³C{ H} NMR (175 MHz,

1:1 mixture (1.4 mL) of t-BuOH and H O was added AD mix β**

2

CDCl ): δ 159.2, 138.4, 138.2, 130.0, 129.6, 128.3, 127.6, 127.5,

(360.0 mg) followed by MeSO NH (13.0 mg, 0.13 mmol) at rt. After

3

2

1

3

13.8, 111.4, 109.1, 93.2, 82.2, 74.8, 73.0, 70.4, 68.8, 66.4, 66.0, 55.2,

29 h, the reaction was quenched with sat. aq Na S O ·5H O (2 mL)

2 2 5 2

+

6.2, 34.4, 26.9, 25.6 ppm; HRMS (ES ): calcd for C H O (M +

and extracted with EtOAc (5 × 4 mL). The dried (Na SO ) extract

2 4

2

8

35

5

H), 451.2484; found, 451.2480.

was concentrated in vacuo and puriﬁed by chromatography over silica

gel (neutralized with 2% Et N in hexanes), eluting it with 25−90%

3

EtOAc/hexane to give 10 (54.7 mg, 0.107 mmol, 82%) as colorless

1

oil. The diastereomeric ratio was determined from H NMR analysis

2

0

of the crude reaction mixture to be 93:7 dr (10:30). [α]_D+5.22° (c =

−

1

0

.44, CHCl ); IR (neat): 3386, 2918, 1704, 1607, 1371 cm ; H

3

.6.49. (2S,3R,6S)-8-(Benzyloxy)-1-((S)-2,2-dimethyl-1,3-dioxo-

NMR (700 MHz, C D ): δ 8.22 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 7.5

6 6

lan-4-yl)-6-((4-methoxybenzyl)oxy)oct-4-yne-2,3-diol (13d). To a

stirred solution of enyne 12d (750 mg, 1.66 mmol) in a 1:1 mixture

(

Hz, 2H), 7.15−7.17 (m, 2H), 7.06−7.08 (m, 1H), 6.33 (d, J = 8.7 Hz,

2H), 6.09 (t, J = 6.8 Hz, 1H), 4.29 (s, 2H), 4.18−4.22 (m, 2H),

3.83−3.87 (m, 2H), 3.54−3.57 (m, 1H), 3.48−3.51 (m, 1H), 3.43 (t,

J = 7.7 Hz, 1H), 2.27 (s, 6H), 2.23−2.26 (m, 1H), 2.16 (dd, J = 12.4,

5.6 Hz, 1H), 1.80 (ddd, J = 14.1, 7.9, 2.9 Hz, 1H), 1.69 (ddd, J = 13.8,

6.6 mL) of t-BuOH and H O was added AD mix β** (2.2 g)

followed by MeSO NH (158 mg, 95.1 mmol) at rt. After 36 h,

another portion of AD mix β** (540 mg) was added and after 7 h, the

reaction was quenched with Na SO₃(2.0 g) and extracted with

EtOAc (5 × 10 mL). The dried (Na SO ) extract was concentrated in

vacuo and puriﬁed by chromatography over silica gel, eluting it with

:1:1 EtOAc/hexanes/CH Cl to give 13d (539.0 mg, 1.11 mmol,

2

1

3

1

2

9.6, 4.5 Hz, 1H), 1.38 (s, 3H), 1.29 (s, 3H) pppm; C{ H} NMR

2

4

(175 MHz, C D ): δ 165.8, 153.2, 138.6, 131.6, 128.2, 127.9, 127.3,

6

116.9, 110.8, 108.4, 84.7, 84.2, 73.4, 72.7, 71.7, 69.6, 66.5, 65.8, 61.7,

+

1

6

=

38.9, 36.5, 35.3, 26.9, 25.7 ppm; HRMS (ES ): calcd for C H NO

2

29 37

7

2

0

7%, 88:12 dr) as colorless oil. Major diastereomer: [α]_D−49.86° (c

(M + H), 512.2648; found, 512.2640.

0.74, CHCl ); IR (neat): 3408, 2918, 2868, 1612, 1514, 1249, 1074

3

−

1

cm ; H NMR (700 MHz, CDCl ): δ 7.34−7.36 (m, 2H), 7.29−

3

7

(

1

.30 (m, 3H), 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.71

d, J = 11.3 Hz, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.47 (d, J = 12.0 Hz,

H), 4.43−4.45 (m, 2H), 4.35−4.38 (m, 2H), 4.10 (dd, J = 8.1, 6.0

Hz, 1H), 3.91−3.94 (m, 1H), 3.81 (s, 3H), 3.62−3.64 (m, 2H), 3.60

dd, J = 7.7 Hz, 1H), 2.58 (d, J = 5.5 Hz, 1H), 2.45 (d, J = 6.0 Hz,

3

.6.52. (3S,6S,7R)-1-(Benzyloxy)-8-((S)-2,2-dimethyl-1,3-dioxo-

lan-4-yl)-6,7-dihydroxyoct-4-yn-3-yl 4-(Dimethylamino)benzoate

30). To a stirred solution of enyne 9 (12.6 mg, 0.026 mmol) in a

:1 mixture (0.4 mL) of t-BuOH and H O was added AD mix α**

(

1

8

2

5

H), 2.06−2.12 (m, 1H), 2.00−2.05 (m, 1H), 1.80−1.88 (m, 2H),

.43 (s, 3H), 1.38 (s, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ

59.3, 138.3, 129.8, 129.6, 128.3, 127.7, 127.6, 113.8, 119.0, 86.1,

3.2, 73.3, 73.0, 71.5, 70.5, 69.4, 66.5, 66.1, 65.6, 55.2, 36.1, 35.9,

6.9, 25.6 ppm; HRMS (ES ): calcd for C H O Na (M + Na),

(

1

3

1

3

1

2

(114.0 mg) followed by MeSO NH (3.0 mg, 0.026 mmol) at rt. After

2 2

2

0 h, the reaction was quenched with sat. aq Na S O ·5H O (1 mL)

+

2 2 5 2

2

8

36

7

and extracted with EtOAc (5 × 3 mL). The dried (Na SO ) extract

was concentrated in vacuo and puriﬁed by chromatography over silica

2

4

07.2359; found, 507.2350.

gel (neutralized with 2% Et N in hexanes), eluting it with 50−100%

3

EtOAc/hexane to give 30 (12.8 mg, 0.025 mmol, 96%) as colorless

1

oil. The diastereomeric ratio was determined from H NMR analysis

of the crude reaction mixture to be 94:6 dr (30:10). [α]²+14.24° (c

0

D

−

1 1

=

1.32, CHCl ); IR (neat): 3333, 2918, 1700, 1606, 1371 cm ; H

3

.6.50. (S,Z)-1-(Benzyloxy)-8-((S)-2,2-dimethyl-1,3-dioxolan-4-

3

NMR (700 MHz, C D ): δ 8.24 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 7.5

yl)oct-6-en-4-yn-3-yl 4-(Dimethylamino)benzoate (9). To a stirred

solution of alcohol 26 (62.0 mg, 0.187 mmol.) in CH Cl (4 mL) was

6

Hz, 2H), 7.15−7.16 (m, 2H), 7.07 (t, J = 7.4 Hz, 1H), 6.32 (d, J = 9.0

2

Hz, 2H), 6.18−6.19 (m, 1H), 4.36 (dd, J = 3.9, 1.4 Hz, 1H), 4.28 (s,

added sequentially 4-(dimethylamino)benzoic acid SI-14 (62.0 mg,

2

H), 3.96−4.00 (m, 1H), 3.78 (dt, J = 8.6, 3.7 Hz, 1H), 3.74 (br s,

H), 3.68 (dd, J = 8.0, 6.1 Hz, 1H), 3.56−3.59 (m, 1H), 3.49−3.52

0

.375 mmol), EDC·HCl (72.0 mg, 0.375 mmol), and DMAP (46.0

1

mg, 0.375 mmol). After 40 h, the reaction was quenched by using sat.

(

m, 1H), 3.28 (t, J = 7.7 Hz, 1H), 2.26−2.29 (m, 8H), 2.16−2.21 (m,

aq NH Cl (4 mL) and extracted with CH Cl (3 × 5 mL). The dried

4

2

1

H), 1.88 (dt, J = 14.1, 8.7 Hz, 1H), 1.63 (dt, J = 14.1, 3.7 Hz, 1H),

(

MgSO ) extract was concentrated in vacuo and puriﬁed by

4

1

3

1

.29 (s, 3H), 1.19 (s, 3H), ppm; C{ H} NMR (175 MHz, C D ): δ

chromatography over silica gel (neutralized with 2% Et N in hexanes),

6

3

65.7, 153.2, 138.7, 131.6, 128.2, 128.0, 127.3, 117.0, 110.7, 108.9,

eluting it with 10−33% EtOAc/hexanes, to give the benzoate 9 (74.2

2

0

mg, 0.155 mmol, 83%) as a clear liquid. [α] +40.3° (c = 1.03,

84.4, 84.2, 74.3, 72.8, 72.7, 69.4, 65.9, 65.8, 61.6, 38.9, 35.5, 35.4,

26.6, 25.6 ppm.

D

−

1 1

CHCl ); IR (neat): 2918, 1705, 1607, 1528, 1093 cm ; H NMR

3

(

7

700 MHz, CDCl ): δ 7.93 (d, J = 9.1 Hz, 2H), 7.32−7.36 (m, 4H),

3

.26−7.28 (m, 1H), 6.66 (d, J = 9.1 Hz, 2H), 6.00 (dt, J = 10.8, 7.4

Hz, 1H), 5.91−5.93 (m, 1H), 5.62 (dq, J = 10.7, 1.5 Hz, 1H), 4.54 (s,

2

3

2

H), 4.18 (quint, J = 6.3 Hz, 1H), 4.01 (dd, J = 8.1, 6.0 Hz, 1H),

.68−3.74 (m, 2H), 3.59 (dd, J = 8.1, 7.0 Hz, 1H), 3.07 (s, 6H),

.58−2.60 (m, 2H), 2.29−2.33 (m, 1H), 2.21−2.25 (m, 1H), 1.43 (s,

3

.6.53. (2S,3R,6S)-8-(Benzyloxy)-1-((S)-2,2-dimethyl-1,3-dioxo-

1

3

1

3

H), 1.36 (s, 3H), ppm; C{ H} NMR (175 MHz, CDCl ): δ 165.7,

3

lan-4-yl)-6-((4-(dimethylamino)benzoyl)oxy)oct-4-yne-2,3-diyl Di-

benzoate (SI-37). To a stirred solution of diol 10 (320.0 mg, 0.63

mmol) in CH Cl (7.5 mL) and Et N (7.5 mL) at 0 °C was added

1

2

53.4, 139.0, 138.2, 131.5, 128.4, 127.6, 127.5, 116.5, 111.2, 110.7,

09.0, 91.9, 81.6, 74.9, 73.1, 68.8, 66.1, 61.6, 40.1, 35.4, 34.2, 26.8,

2

3

+

5.7 ppm; HRMS (ES ): calcd for C H NO (M + H), 478.2593;

2

9

36

5

DMAP (15.0 mg, 0.12 mmol) followed by benzoyl chloride (354.2

mg, 0.29 mL, 2.52 mmol). After 5 min, the reaction mixture was

warmed to rt. After 28 h, the brown reaction mixture was quenched

with sat. aq NaHCO (10 mL) and extracted with CH Cl (3 × 10

found, 478.2585.

3

2

mL). The dried (MgSO ) extract was concentrated in vacuo and

4

puriﬁed by column chromatography over silica gel, eluting it with 5−

2

5% EtOAc/hexanes to obtain SI-37 (435.3 mg, 0.60 mmol, 96%) as

2

0

a sticky yellow oil. [α] −52.8° (c = 0.66, CHCl ); IR (neat): 2930,

2868, 1725, 1607, 1270 cm ; H NMR (700 MHz, CDCl ): δ 8.00

3

.6.51. (3S,6R,7S)-1-(Benzyloxy)-8-((S)-2,2-dimethyl-1,3-dioxo-

lan-4-yl)-6,7-dihydroxyoct-4-yn-3-yl 4-(Dimethylamino)benzoate

10). To a stirred solution of enyne 9 (62.0 mg, 0.13 mmol) in a

D

3

−1 1

3

(

(t, J = 7.9 Hz, 4H), 7.93 (d, J = 9.0 Hz, 2H), 7.55−7.58 (m, 1H),

O

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

7

.52−7.54 (m, 1H), 7.30−7.36 (m, 6H), 7.25−7.27 (m, 1H), 6.65 (d,

J = 8.9 Hz, 2H), 6.07−6.08 (m, 1H), 5.88 (t, J = 6.8 Hz, 1H), 5.66

dt, J = 9.5, 3.0 Hz, 1H), 4.48−4.52 (m, 2H), 4.21−4.25 (m, 1H),

.04 (dd, J = 8.1, 6.1 Hz, 1H), 3.66−3.72 (m, 2H), 3.63 (d, J = 7.3

Hz, 1H), 3.07 (s, 6H), 2.26−2.32 (m, 2H), 2.17−2.24 (m, 2H), 1.43

3.6.56. (2S,5S)-2-(2-(Benzyloxy)ethyl)-5-((S)-1-((tert-

butyldimethylsilyl)oxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-

ethyl)dihydrofuran-3(2H)-one (29). To a stirred solution of crude

(

4

alcohol 28a in CH Cl (5.6 mL) at −78 °C was added 2,6-lutidine

2

(

254.0 mg, 0.28 mL, 2.37 mmol) followed by TBSOTf (418.0 mg,

1

3

1

0.36 mL, 1.58 mmol). After 2 h, the reaction was quenched with aq

(

s, 3H), 1.33 (s, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ

3

sat. NaHCO (5 mL) and extracted with CH Cl (3 × 5 mL). The

3

2

1

7

65.6, 165.5, 165.0, 153.5, 138.2, 133.3, 133.1, 131.6, 129.9, 129.8,

29.7, 129.4, 128.4, 128.3, 127.6, 127.5, 116.4, 110.7, 109.1, 85.7,

dried (MgSO ) extract was concentrated in vacuo and puriﬁed by

4

chromatography over silica gel, eluting it with 5−17% EtOAc/hexanes

8.9, 73.1, 72.7, 71.8, 69.6, 65.9, 65.8, 60.8, 40.1, 35.1, 34.6, 27.0, 25.7

+

to obtain 29 (119.0 mg, 0.248 mmol, 63% over 3 steps) as a colorless

ppm; HRMS (ES ): calcd for C H NO (M + H), 720.3173; found,

4

3

46

9

20

oil. [α]_D−13.33° (c = 0.51, CHCl ); IR (neat): 2927, 2857, 1761,

3

7

20.3171.

−1 1

1

472, 1251, 1104 cm ; H NMR (700 MHz, CDCl ): δ 7.29−7.36

3

(

4

5

m, 5H), 4.52 (d, J = 12.1 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.25−

.29 (m, 1H), 4.09−4.12 (m, 1H), 4.04−4.08 (m, 2H), 3.93 (dd, J =

.9, 5.3 Hz, 1H), 3.70 (dt, J = 9.2, 6.6 Hz, 1H), 3.59 (dt, J = 9.4, 6.2

Hz, 1H), 3.5 (t, J = 7.5 Hz, 1H), 2.37 (dd, J = 17.9, 6.2 Hz, 1H), 2.31

(

dd, J = 17.9, 10.6 Hz, 1H), 2.05−2.10 (m, 1H), 1.94−1.99 (m, 1H),

3

.6.54. (2S,3R,6S)-8-(Benzyloxy)-1-((S)-2,2-dimethyl-1,3-dioxo-

lan-4-yl)-6-hydroxyoct-4-yne-2,3-diyl Dibenzoate (27). To a stirred

solution of tribenzoate SI-37 (14.4 mg, 20.0 μmol) in CH Cl (0.3

1

3

.68 (ddd, J = 12.9, 9.2, 2.2 Hz, 1H), 1.55−1.57 (m, 1H), 1.42 (s,

H), 1.36 (s, 3H), 0.90 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H) ppm;

2

13

1

C{ H} NMR (175 MHz, CDCl ): δ 215.1, 138.2, 128.3, 127.6,

3

mL) at 0 °C were added sequentially NaHCO (3.0 mg, 36.0 μmol)

and MeOTf (3.9 mg, 2.6 μL, 24.0 μmol). After 15 min, the reaction

was warmed up to rt. After 12 h, the solvent (CH Cl ) was evaporated

with Ar ﬂush and MeOH (0.2 mL) was added. After an additional 1 h,

3

1

2

27.5, 108.8, 78.9,78.4, 72.7, 72.2, 71.2, 69.8, 65.8, 38.8, 36.8, 30.9,

+

7.1, 25.9, 25.7, 18.2, −4.1, −4.6 ppm; HRMS (ES ): calcd for

2

C H O Si (M + H), 479.2829; found, 479.2846.

2

6

43

6

another portion of NaHCO (2.1 mg, 25.0 μmol) was added. After 4

3

h, the reaction was diluted with EtOAc (1 mL) and quenched with

sat. aq NH Cl (1 mL) and extracted with EtOAc (3 × 3 mL). The

4

dried (MgSO ) extract was concentrated in vacuo and puriﬁed by

4

column chromatography over silica gel, eluting it with 5−25%

EtOAc/hexanes to obtain 27 (8.0 mg, 13.97 μmol, 70%) as a sticky

_y_e_l_l_o_w_o_i_l_._[_α_]20 −50.37° (c = 0.81, CHCl ); IR (neat): 3428, 3064,

3.6.57. ((S)-1-((2S,5S)-5-(2-(Benzyloxy)ethyl)-4-methylenetetra-

D

3

hydrofuran-2-yl)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)-

−

1

2

985, 2871, 1726, 1274, 1095, 1026 cm ; H NMR (700 MHz,

(

tert-butyl)dimethylsilane (SI-38). To a stirred solution of ketone 29

CDCl ): δ 8.03 (ddd, J = 18.5, 8.0, 1.0 Hz, 4H), 7.56−7.59 (m, 2H),

38

3

(119.0 mg, 0.248 mmol) in toluene (2.6 mL) was added Cp TiMe

2

7

2

4

1

9

8

.43 (td, J = 7.8, 3.5 Hz, 4H), 7.32−7.34 (m, 2H), 7.28−7.29 (m,

H), 6.06 (dd, J = 3.3, 1.5 Hz, 1H), 5.64 (dt, J = 9.7, 3.3 Hz, 1H),

.68−4.71 (m, 1H), 4.51 (d, J = 11.8 Hz, 1H), 4.48 (d, J = 11.8 Hz,

H), 4.23−4.27 (m, 1H), 4.05 (dd, J = 8.0, 5.9 Hz, 1H), 3.86 (td, J =

.1, 4.0 Hz, 1H), 3.68 (ddd, J = 9.9, 5.4, 4.6 Hz, 1H), 3.64 (dd, J =

.0, 6.7 Hz, 1H), 3.12 (d, J = 6.6 Hz, 1H), 2.33 (ddd, J = 14.4, 8.1, 3.4

(

2.8 mL, 1.244 mmol, 0.46 M in THF) and the reaction mixture was

heated to 78 °C in the dark. After 16.5 h, another portion of

Cp TiMe (2.8 mL, 1.244 mmol, 0.46 M in THF) was added. After

another 4 h, the reaction mixture was passed through a small silica

plug and the organic solvent (toluene) was removed in vacuo and

puriﬁed by chromatography over silica gel, eluting it with 5−8%

EtOAc/hexanes to obtain the alkene SI-38 (89.1 mg, 0.187 mmol,

2

Hz, 1H), 2.19 (ddd, J = 14.6, 9.7, 5.0 Hz, 1H), 2.12 (ddt, J = 14.5, 8.7,

.4 Hz, 1H), 1.96 (dtd, J = 14.5, 5.9, 4.0 Hz, 1H), 1.44 (s, 3H), 1.33

2

0

4

(

75%) as colorless oil. [α] −28.37° (c = 0.49, CHCl ); IR (neat):

D

3

s, 3H) ppm; ¹³C{ H} NMR (175 MHz, CDCl ): δ 165.6, 165.1,

1

−1 1

2926, 2854, 1463, 1369, 1100, 837 cm ; H NMR (700 MHz,

CDCl ): δ 7.36 (d, J = 4.5 Hz, 4H), 7.29−7.31 (m, 1H), 4.97 (d, J =

3

1

2

5

37.7, 133.4, 133.3, 129.9, 129.8, 129.7, 129.4, 128.4, 127.8, 127.6,

09.0, 88.1, 78.6, 73.4, 72.7, 71.9, 69.5, 67.6, 65.6, 61.4, 36.4, 34.4,

7.0, 25.6 ppm; HRMS (ES ): calcd for C H O Na (M + Na),

3

1.8 Hz, 1H), 4.85 (d, J = 1.9 Hz, 1H), 4.56 (d, J = 11.8 Hz, 1H), 4.51

(d, J = 11.9 Hz, 1H), 4.39 (d, J = 8.6 Hz, 1H), 4.26−4.29 (m, 1H),

4.06 (dd, J = 5.9, 7.8 Hz, 1H), 3.96 (ddd, J = 9.7, 6.2, 2.4 Hz, 1H),

+

3

4

36

8

95.2308; found, 595.2286.

3

.80 (dt, J = 10.0, 6.1 Hz, 1H), 3.66 (dd, J = 7.5, 6.2 Hz, 2H), 3.51 (t,

J = 7.6 Hz, 1H), 2.49 (dd, J = 15.7, 5.9 Hz, 1H), 2.32−2.36 (m, 1H),

2

1

3

0

1

6

.03 (dtd, J = 15.2, 7.6, 3.4 Hz, 1H), 1.82 (ddt, J = 14.5, 8.7, 5.9 Hz,

H), 1.67 (ddd, J = 13.6, 8.8, 2.4 Hz, 1H), 1.54 (ddd, J = 13.8, 10.0,

.8 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H), 0.91 (s, 9H), 0.11 (s, 3H),

1

3

1

.11 (s, 3H) ppm; C{ H} NMR (175 MHz, CDCl ): δ 151.1, 138.5,

3

28.3, 127.7, 127.5, 108.6, 104.4, 81.4, 78.0, 73.1, 72.5, 71.5, 69.9,

3

.6.55. (2S,5S)-2-(2-(Benzyloxy)ethyl)-5-((S)-2-((S)-2,2-dimethyl-

7.3, 36.8, 35.5, 34.7, 27.1, 26.0, 25.8, 18.2, −4.1, −4.7 ppm; HRMS

1

,3-dioxolan-4-yl)-1-hydroxyethyl)dihydrofuran-3(2H)-One (28a).

+

(

ES ): calcd for C H O NaSi (M + Na), 499.2856; found,

2

7

44

5

To a stirred solution of alcohol 27 (226.0 mg, 0.395 mmol) in

toluene (4 mL) was added AgBF (7.0 mg, 0.04 mmol). The reaction

4

99.2867.

4

mixture was reﬂuxed in dark. After 40 min, the reaction was cooled

down to −78 °C and diluted with Et O (4 mL). After 5 min, MeLi·

2

LiBr (1.44 mL, 3.16 mmol, 2.2 M in Et O) was added. After 2 h, the

2

reaction was quenched with aq sat. NH Cl (4 mL) and extracted with

4

EtOAc (3 × 10 mL). The dried (MgSO ) extract was concentrated in

4

vacuo to obtain the crude alcohol 28a as colorless oil, which was used

in the next step without further puriﬁcation.

3

.6.58. 2-((2S,3S,5S)-5-((S)-1-((tert-Butyldimethylsilyl)oxy)-2-((S)-

2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-methyltetrahydrofuran-2-

yl)ethan-1-ol (11). To a stirred solution of alkene SI-38 (42.0 mg,

8

8.10 μmol) in EtOAc (1.4 mL) under argon atmosphere at rt was

added 10% Pd/C (13.2 mg, 30% by wt). Argon was then removed by

ﬂushing with H gas. After 5 min, the reaction was sealed under 1 atm

2

of H (balloon). After 30 h, the hydrogen was removed by ﬂushing

2

with argon, and the reaction mixture was ﬁltered through Celite-

P

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

washing with EtOAc (10 mL). The ﬁltered extract was concentrated

in vacuo and puriﬁed by chromatography over silica gel, eluting it with

J = 2.5 Hz, 2H), 7.45 (d, J = 4.5 Hz, 2H), 7.40 (dd, J = 9.1, 2.6 Hz,

2H), 6.97 (d, J = 6.0 Hz, 2H), 6.09−6.15 (m, 2H), 5.48 (dq, J = 17.3,

1.5 Hz, 2H), 5.31 (dq, J = 10.6, 1.3 Hz, 2H), 4.64−4.71 (m, 4H),

3.41−3.44 (m, 2H), 2.76−2.83 (m, 4H), 2.65−2.74 (m, 4H), 1.95−

1.98 (m, 2H), 1.71 (br s, 2H), 1.52−1.59 (m, 4H), 1.44−1.48 (m,

39

1

7−50% EtOAc/hexanes to obtain the known compound 11 (29.0

1

mg, 74.62 μmol, 85%, 5.5:1 dr) as colorless oil. H NMR (700 MHz,

CDCl ): δ 4.23−4.27 (m, 1H), 4.06 (dd, J = 7.6, 6.0 Hz, 1H), 4.01

3

1

3

1

(

ddd, J = 10.3, 7.2, 2.6 Hz, 1H), 3.95 (ddd, J = 8.6, 5.5, 2.8 Hz, 1H),

2H), 1.39−1.43 (m, 6H), 0.82 (t, J = 7.1 Hz, 6H) ppm; C{ H}

NMR (175 MHz, CDCl ): δ 156.5, 156.4, 147.5, 144.9, 144.8, 132.9,

132.1, 131.6, 127.3, 122.8, 122.5, 122.0, 118.8, 117.9, 103.4, 76.5,

9.1, 60.2, 50.9, 50.0, 37.5, 27.3, 26.3, 25.3, 23.5, 11.9 ppm.

3

2

1

3

.78−3.82 (m, 3H), 3.50 (t, J = 7.7 Hz, 1H), 2.55 (br s, 1H), 2.33−

.37 (m, 1H), 1.97 (dt, J = 12.4, 6.9 Hz, 1H), 1.66−1.75 (m, 3H),

.57−1.60 (m, 2H), 1.41 (s, 3H), 1.36 (s, 3H), 0.96 (d, J = 7.1 Hz,

3

6

1

3

1

H), 0.92 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H) ppm; C{ H} NMR

(

175 MHz, CDCl ): δ 108.7, 82.1, 81.3, 72.5, 70.8, 69.9, 61.9, 37.2,

3

5.7, 34.9, 33.1, 27.1, 25.9, 25.8, 18.2, 15.3, −4.1, −4.6 ppm.

3

.6.61. 1,4-Bis((S)-((1S,2R,4S,5R)-5-ethylquinuclidin-2-yl)(6-pro-

poxyquinolin-4-yl)methoxy)phthalazine (SI-43). To a stirred

solution of alkene SI-42 (74.0 mg, 90.0 μmol) in EtOAc (2 mL)

under argon atmosphere at rt was added 10% Pd/C (10.0 mg, 10% by

3

.6.59. (S)-(6-(Allyloxy)quinolin-4-yl)((1S,2R,4S,5R)-5-ethylquinu-

clidin-2-yl)methanol (SI-40). To a stirred solution of known 4-((S)-

(1S,2R,4S,5R)-5-ethylquinuclidin-2-yl)(hydroxy)methyl)quinolin-6-

wt). Argon was then removed by ﬂushing with H gas. After 5 min,

2

the reaction was sealed under 1 atm of H (balloon). After 24 h,

2

(

39

hydrogen was removed by ﬂushing with argon, and the reaction

mixture was ﬁltered through Celite- washing with EtOAc (10 mL).

The ﬁltered extract was concentrated in vacuo and puriﬁed by

ol (SI-39) (670.0 mg, 2.145 mmol) in acetone (214 mL) at rt was

added Cs CO (1.75 g, 5.362 mmol). After 30 min, allyl bromide

285.0 mg, 2.36 mmol, 0.2 mL) was added. After 24 h, the reaction

was quenched by using sat. aq NH Cl C (15 mL) and evaporated the

2

3

(

chromatography over silica gel (neutralized with 1% Et N in hexanes),

3

4

eluting it with 16−25% MeOH/EtOAc to obtain [(Pr-

organic solvent (acetone) before extracting with 10% MeOH in

20

DHQD) PHAL] SI-43 (70.0 mg, 83.7 μmol, 93%). [α] −125.0°

2

D

CH Cl (3 × 50 mL). The dried (MgSO ) extract was concentrated

−1 1

2

4

(

c = 0.16, CHCl ); IR (neat): 2923, 2871, 1620, 1461 cm ; H NMR

3

in vacuo and puriﬁed by chromatography over silica gel (neutralized

with 2% Et N in CH Cl ), eluting it with 5−7% MeOH/CH Cl , to

700 MHz, CD OD at 60 °C): δ 8.56 (d, J = 4.7 Hz, 1H), 8.48 (dd, J

6.2, 3.2 Hz, 1H), 8.12 (dd, J = 6.0, 3.3 Hz, 1H), 7.95 (d, J = 9.2 Hz,

3

2

=

2

0

give SI-40 (527.6 mg, 1.497 mmol, 70%). [α] +28.0° (c = 1.05,

D

1

4

2

H), 7.58−7.59 (m, 2H), 7.44 (dd, J = 9.2, 2.6 Hz, 1H), 7.13 (d, J =

.9 Hz, 1H), 4.05−4.11 (m, 2H), 3.48 (td, J = 9.1, 5.0 Hz, 1H), 2.87−

.95 (m, 3H), 2.75−2.79 (m, 1H), 2.26−2.29 (m, 1H), 1.83−1.88

−

1 1

CHCl ); IR (neat): 3252, 2961, 1619, 1508, 1241 cm ; H NMR

700 MHz, CD OD): δ 8.74 (d, J = 4.6 Hz, 1H), 8.01 (d, J = 9.2 Hz,

H), 7.80 (d, J = 4.5 Hz, 1H), 7.51 (dd, J = 9.2, 2.6 Hz, 1H), 7.47 (d,

J = 2.6 Hz, 1H), 6.16−6.22 (m, 2H), 5.52 (dq, J = 17.3, 1.6 Hz, 1H),

.32 (dq, J = 10.7, 1.4 Hz, 1H), 4.86−4.87 (m, 1H), 4.82−4.85 (m,

H), 3.98 (ddd, J = 11.8, 8.6, 2.1 Hz, 1H), 3.59 (t, J = 9.3 Hz, 1H),

.46−3.49 (m, 2H), 3.27−3.31 (m, 1H), 2.43−2.47 (m, 1H), 2.00 (s,

H), 1.83−1.95 (m, 3H), 1.61−1.73 (m, 2H), 1.23 (ddd, J = 13.6,

.7, 4.3 Hz, 1H), 0.99 (t, J = 7.4 Hz, 3H) ppm; C{ H} NMR (175

MHz, CD OD): δ 157.6, 146.9, 145.8, 143.4, 133.1, 130.3, 126.1,

3

(

3

1

(

m, 2H), 1.79 (br s, 1H), 1.65−1.69 (m, 1H), 1.55−1.58 (m, 5H),

1

3

1

8

.29 (t, J = 7.4 Hz, 1H), 1.05 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.1 Hz,

5

1

3

1

9

13

1

H) ppm; C{ H} NMR (175 MHz, CD OD): δ 157.9, 156.3,

3

46.4, 144.4, 143.5, 133.1, 129.9, 127.0, 122.8, 122.7, 122.1, 118.0,

01.7, 75.1, 69.7, 59.3, 50.4, 49.4, 36.4, 26.1, 25.6, 24.9, 22.2, 21.2,

+

0.6, 9.5 ppm; HRMS (ES ): calcd for C H N O (M + H),

5

2

63

6

4

1

3

1

35.4911; found, 835.4924.

3

1

2

3

22.5, 118.9, 116.3, 101.9, 69.2, 67.4, 59.9, 50.1, 49.2, 34.9, 25.1, 24.0,

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.9b01153.

+

■

*

3.3, 17.5, 10.4 ppm; HRMS (ES ): calcd for C H N O (M + H),

2

29

2

S

53.2229; found, 353.2222.

Electronic Supplementary Information of NMR Spectra-

(PDF )

Electronic Supplementary Information of HPLC

Spectra(PDF )

Electronic Supplementary Information of Computa-

tional Section (PDF)

3

.6.60. 1,4-Bis((S)-(6-(allyloxy)quinolin-4-yl)((1S,2R,4S,5R)-5-eth-

ylquinuclidin-2-yl)methoxy)phthalazine (SI-42). To a stirred sol-

ution of alcohol SI-40 (91.4 mg, 0.259 mmol) in THF (1.5 mL) at 0

°

C was added NaH (12.0 mg, 0.287 mmol, 60% dispersion in mineral

AUTHOR INFORMATION

Corresponding Authors

E-mail: paul.cheong@oregonstate.edu (P.H.-Y.C.).

E-mail: rich.carter@oregonstate.edu (R.G.C.).

■

*

oil). After 5 min, the reaction was reﬂuxed for 50 min and then cooled

to rt and 1,4-dichlorophthalazine SI-41 (26.0 mg, 0.130 mmol) was

added and reﬂuxed. After an additional 5 h, another portion of NaH

12.0 mg, 0.287 mmol, 60% dispersion in mineral oil) was added at rt

and reﬂux was continued. After 18 h, the reaction was cooled to 0 °C

(

ORCID

and quenched by using H O (2 mL) and extracted with EtOAc (3 × 5

Paul Ha-Yeon Cheong: 0000-0001-6705-2962

Rich G. Carter: 0000-0002-9100-1791

Funding

Financial support provided by the National Science Founda-

tion (CHE-1665246) and Oregon State University (Milton

Harris fellowship for A.G.).

2

mL). The dried (MgSO ) extract was concentrated in vacuo and

4

puriﬁed by chromatography over silica gel (neutralized with 2% Et N

3

in CH Cl ), eluting it with 10−20% MeOH/EtOAc, to give [(Allyl-

2

1

DHQD) PHAL] SI-42 (56.6 mg, 0.068 mmol, 52%). H NMR (700

2

MHz, CDCl ): δ 8.67 (d, J = 4.5 Hz, 2H), 8.33 (dd, J = 6.1, 3.2 Hz,

3

2

H), 8.01 (d, J = 9.2 Hz, 2H), 7.94 (dd, J = 6.0, 3.4 Hz, 2H), 7.61 (d,

Q

DOI: 10.1021/acs.joc.9b01153

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Notes

A. Total Synthesis of 7′,8′-Dihydroaigialospirol. Org. Lett. 2012, 14,

5154−5157.

The authors declare no competing ﬁnancial interest.

(

12) (a) Araki, S.; Butsugan, Y. Electrophilic substitution reaction of

meso-ionic sesquifulvalene. Tetrahedron Lett. 1984, 25, 441−444.

b) Palazon, J. M.; Anorbe, B.; Martin, V. S. General method to

ACKNOWLEDGMENTS

■

(

́

̃

Prof. Claudia Maier (OSU) and Jeﬀ Morre

acknowledged for mass spectra data.

́

(OSU) are

transform chiral 2,3-epoxyalcohols into erythro or threo 1,2-

epoxyalcohols with total stereochemical control. Tetrahedron Lett.

1

986, 27, 4987−4990. (c) Prestwich, G. D.; Graham, S. M.; Kuo, J.

W.; Vogt, R. G. Tritium-labeled enantiomers of disparlure. Synthesis

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J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Second-Generation Synthesis of the Northern Fragment of Mandelalide A: Role of π-Stacking on Sharpless Dihydroxylation of cis-Enynes

DOI: 10.1021/acs.joc.9b01153

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