A model study on installation of (Z)-γ-methylglutaconic acid onto the 3-aminophenol core of divergolide A

DOI: 10.1016/j.tet.2015.05.052

Source and publish data:

Tetrahedron p. 4779 - 4787 (2015)

Update date:2022-07-30

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Authors:

Zhao, Guanglian

Wu, Jinlong

Dai, Wei-Min

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Article abstract of DOI:10.1016/j.tet.2015.05.052

Divergolide A and its four congeners, divergolide E-H, possess an amido-substituted hydroquinone core, which is biosynthetically transformed from an aromatic starter unit, 3-amino-5-hydroxybenzoic acid (AHBA). The macrocyclic ring of divergolide A and F i

Full text of DOI:10.1016/j.tet.2015.05.052

Tetrahedron 71 (2015) 4779e4787

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Tetrahedron

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A model study on installation of (Z)-

-methylglutaconic acid onto

the 3-aminophenol core of divergolide A

,b,

Guanglian Zhao ^a, Jinlong Wu ^a, Wei-Min Dai ^a

^aLaboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China

^bLaboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay,

Kowloon, Hong Kong SAR, China

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 10 April 2015

Received in revised form 12 May 2015

Accepted 15 May 2015

Available online 22 May 2015

Divergolide A and its four congeners, divergolide EeH, possess an amido-substituted hydroquinone core,

which is biosynthetically transformed from an aromatic starter unit, 3-amino-5-hydroxybenzoic acid

(AHBA). The macrocyclic ring of divergolide A and F is assembled by linking the amido hydroquinone unit

with the polyketide backbone through (Z)-

glutaconic acid is found in divergolide E, G, and H. A model study has been conducted for installation of

(Z)- -methylglutaconic acid onto the 3-aminophenol core of divergolide A via two methods: (a) the

CuIeMeNHCH₂CH₂NHMe-catalyzed amidation of methyl (Z)-4-carbamoyl-2-methylbut-2-enoate with

an aryl bromide; and (b) regioselective aminolysis of (Z)- -methylglutaconic anhydride with an aniline

g-methylglutaconic acid as the tether while (E)-g-methyl-

Keywords:

Alkene

Amidation

derivative. Isomerization of the (Z)-conﬁguration under the CuI catalysis conditions was observed to give

mainly the (E)-product while (Z)-product was obtained exclusively under the aminolysis conditions.

These results might be useful for total synthesis of divergolide A and EeH.

Aminophenol

Carboxylic acid

Divergolide A

Isomerization

1. Introduction

proposed a revised model for polyketide diversiﬁcation in the

divergolide biosynthesis pathway,^2,3suggesting formation of diver-

Divergolides are a family of intriguing ansamycins (with some

related derivatives) produced by the endophytic strains isolated from

the stem of mangrove trees.¹The strain Streptomyces sp. HKI0576

from Bruguiera gymnorrhiza, one of the dominant mangrove species

along the Chinese coast, produced divergolide AeI and LeN^2e4while

the strain Streptomyces sp. HKI0595 from Kandelia candel,⁵a wide-

spread mangrove tree found in southern India, southeast China and

southern Japan, produced divergolide J and K.⁴The structure of

divergolide A (1, Fig. 1), as conﬁrmed by X-ray crystal structural

analysis,²features a 1-amino-3-hydroxybenzene core, a bridged ac-

etal subunit, and a macrocyclic ring. The latter is assembled from the

disrupted polyketide backbone and the aminophenol core through

golides from a common precursor similar to the structure 2 with

a C2⁰⁰-(E)-double bond instead of the C3⁰⁰-(E)-double bond as shown

in 2. Divergolide AeD were reported to exhibit strong activity against

Bacillus subtilis, Mycobacterium vaccae, methicillin-resistant Staphy-

lococcus aureus, and vancomycin-resistant Enterococcus faecalis.²

Also, divergolide D delivered pronounced anticancer activity with

a mean IC₅₀value of 2.4

mM against a panel of 40 tumor cell lines

including the most sensitive cell lines (IC₅₀values of 1.0e2.0

mM)

such as lung cancer (LXFA 629L), pancreatic cancer (PANC-1), renal

cancer (RXF 486L), and sarcoma (Saos-2).²The biological activity of

divergolide A and D renders them as the potential candidates for

further development as anti-infectives and anticancer agents, re-

spectively. We⁶and others^7,8have disclosed studies on the total

synthesis of divergolide A, C, and D. In our previous work,⁶a ring-

closing metathesis (RCM) strategy was envisioned to assemble the

macrocyclic ring and synthesis of a simpliﬁed amido hydroquinone

core and the C10eC15 diene fragment 5⁸was achieved. We report

(Z)-g-methylglutaconic acid as the tether. Divergolide A has four

congeners, divergolide EeH (structures not shown)³, which are the

diastereomers with C3⁰⁰-(E)-conﬁguration (divergolide E), epimeric

C2eMe (divergolide F), both C3⁰⁰-(E)-conﬁguration and epimeric

C2eMe (divergolide G), and both C3⁰⁰-(E)-conﬁguration and an ex-

panded macrolactone ring at C12eOH (divergolide H), respectively.

Moreover, divergolide IeL are the congeners of divergolide C while

divergolide M and N are the biosynthetic intermediates prematurely

released from the modular assembly line.⁴Hertweck and co-workers

here on the model study toward installation of (Z)-g-methyl-

glutaconic acid onto the 3-aminophenol core of divergolide A.

2. Results and discussion

According to the proposed divergolide biosynthetic pathway by

* Corresponding author. Tel./fax: þ86 571 87953128, tel.: þ852 23587365; fax:

þ852 23581594; e-mail addresses: chdai@zju.edu.cn, chdai@ust.hk (W.-M. Dai).

Hertweck,^2,3the C2 conﬁguration of divergolide A (1, Fig. 1) was

http://dx.doi.org/10.1016/j.tet.2015.05.052

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G. Zhao et al. / Tetrahedron 71 (2015) 4779e4787

by a modiﬁed sequence. Reaction of diethyl malonate with CHCl₃

in the presence of NaOEt in reﬂuxing EtOH gave sodio-1,1,3,3-

tetracarboethoxypropene (9) as a yellow solid in 95% yield. Meth-

ylation of 9 with MeI at room temperature in DMF afforded 1,1,3,3-

tetracarboethoxybutene (10) in 98% yield. Alkaline hydrolysis of 10

using aqueous KOH under reﬂux for 3 h furnished, after acidiﬁca-

tion with HCl, (E)-g-methylglutaconic acid [(E)-2-methylpent-2-

enedioic acid, (E)-11] in 62% yield. Kagan and co-workers exam-

ined isomerization of (E)-11 into (Z)-11 at 100 ^ꢀC in FSO₃H and

H₂SO₄, respectively, resulting in 46% yield of a mixture containing

2.5:1 ratio of (Z)-11 and (E)-11.¹²Golding and co-workers treated

(E)-11 in reﬂuxing triﬂic acid (TfOH, bp¼162 ^ꢀC) for 2 h to give, after

quenching with ice water, a 9:1 mixture of (Z)-11 and (E)-11 in 46%

combined yield.^13cWe repeated isomerization of (E)-11 in triﬂic

acid at 120 ^ꢀC for 2 h, leading to an improved yield of 68% of (Z)-11

in a similar (Z):(E) ratio of 9:1. Formation of (Z)-g-methylglutaconic

anhydride (12) from (E)-11 was reported by Kagan and co-

workers.¹²Thus, heating of a solution of (E)-11 in CF₃CO₂H for 62 h

at 100 ^ꢀC resulted in a 1:1 mixture of (E)-11 and 12 while treatment

of a solution of (E)-11 in reﬂuxing Ac₂O (ca. 140 ^ꢀC) for 2 h afforded

12, after distillation, in ca. 30% yield.¹²We found that (E)-11 could

be transformed into 12 in 91% yield by heating in (CF₃CO₂)O at 80 ^ꢀC

for 4 h. Alternatively, treatment of (Z)-11 in Ac₂O at 70 ^ꢀC for 30 min

gave 12 in 97% yield. Finally, regioselective amide formation from

12 was performed by exposure to an ethanolic solution of NH₄OH¹⁴

at reﬂux for 1 h to furnish an 84% yield of the corresponding (Z)-4-

carbamoyl-2-methylbut-2-enoic acid as an 82:18 mixture of (Z)-

and (E)-isomers. In the NMR spectra taken in DMSO-d₆, the major

isomer shows the

-Me and

-H signals at 1.85 (d, J¼1.2 Hz, 3H) and

6.11 (td, J¼7.2, 1.6 Hz, 1H) ppm while those for the minor isomer

appear at 1.73 (d, J¼1.2 Hz, 3H) and 6.77 (td, J¼7.2, 1.2 Hz, 1H) ppm.

The ¹³C NMR signals for the

a-Me groups are found at 21.4 (major

isomer) and 13.5 (minor isomer) ppm. These NMR data are

Fig. 1. The structure and retrosynthetic analysis of divergolide A (1).

epimerized during formation of the tricyclic acetal subunit. In this

connection, we formulated our retrosynthetic analysis of 1 as

shown in Fig. 1. The macrocyclic intermediate 2 could be derived by

acetal cleavage and epimerization at C2 position of 1. The (1S,2R)-

conﬁguration in 2 is the same as that of the proposed biosynthesis

intermediates. Further bond disconnections were followed via the

RCM reaction at the C9eC10 double bond, the ester bond cleavage,

and the aldoleoxidation sequence at the C3eC4 single bond,

leading to the ketone fragment 4, the alcohol fragment 5,⁸and the

amido hydroquinone fragment 3a (R¹,R²¼OH). The latter was

sought to form from the precursor 3b through a biomimetic redox

process.^2,3,6,9Finally, the compound 3b could be assembled by the

anti-selective aldol reaction of the chiral norephedrine-derived

propionate 8¹⁰and CuI-catalyzed amidation¹¹of the amide 6

from the functionalized 3-bromobenzaldehyde 7a, a synthetic

equivalent to the ansamycin biosynthesis starter unit, 3-amino-5-

hydroxybenzoic acid (AHBA). Alternatively, the same trans-

formations starting from the 3-bromobenzaldehyde 7b should give

the protected amido hydroquinone fragment 3a (R¹,R²¼OMe).

Our synthesis of methyl (Z)-4-carbamoyl-2-methylbut-2-enoate

(6) is illustrated in Scheme 1. The known anhydride 12¹²was pre-

pared from (Z)- or (E)-

-methylglutaconic acid [(Z)- or (E)-11]^12,13

Scheme 1. Synthesis of g-methylglutaconic anhydride 12 and the amide 6.

G. Zhao et al. / Tetrahedron 71 (2015) 4779e4787

4781

consistent with those observed for the known (Z)-11 and (E)-

11.^12,13cUpon treatment with TMSCHN₂, the above crude acids were

converted into the methyl esters in 95% yield and the minor (E)-

isomer 6⁰could be separated out by column chromatography over

silica gel to give isomer pure 6.

bromide 14 afforded the expected products in 92% combined yield

and in an 88:12 ratio of 16 and 3b. It is not surprising to note that

the (Z)-conﬁguration in 6 isomerized into the (E)-conﬁguration

under the basic conditions used for the CuI-catalyzed amidation.

This observation further conﬁrms the lability of the double bond

In our previous work,⁶we reported synthesis of the enantiomer

(en-14) of the aryl bromide 14 using (1S,2R)-8¹⁰as the chiral pro-

pionate in the anti-selective aldol reaction with the 3-

bromobenzaldehyde 7a. As shown in Scheme 2, the same aldol

reaction of (1R,2S)-8 with 7a afforded the anti-aldol product 13 in

88% yield and in a 91:9 diastereomeric ratio. Protection of the hy-

droxy group in 13 as the TBS ether (98% yield) and DIBAL-H re-

duction of the ester moiety gave the corresponding primary alcohol

(96% yield). The latter was then converted into the bis-TBS ether 14

in 99% yield. We have reported the CuI-catalyzed amidation of en-

14 with acetamide and triﬂuoroacetamide, respectively, using N,N⁰-

dimethylethylenediamine as the ligand to form the N-arylated

amides in 91e94% yields.⁶In the same manner, the amidation of 14

with triﬂuoroacetamide produced 15 in 94% yield. Under the same

amidation conditions, the reaction of the amide 6 with the aryl

conﬁguration in (Z)-g-methylglutaconic acid [(Z)-11] and its de-

rivatives such as 3b and 6 toward acidic and basic conditions.¹²

In order to suppress isomerization of the (Z)-double bond

during the amidation process, we envisioned to use aminolysis of

the anhydride 12 with the aniline derivative 17 in the absence of

other basic species (Scheme 3).¹⁵Thus, alkaline hydrolysis of the

N-aryl triﬂuoroacetamide 15 in reﬂuxing EtOH in the presence of

NaOH furnished the aniline 17 in 99% yield. Heating a mixture of

17 with the anhydride 12 in benzene at reﬂux for 3.5 h regiose-

lectively gave the amide 18 with (Z)-conﬁguration in 96% yield in

an isomer pure form. Treatment of 18 with TMSCHN₂gave the

corresponding methyl ester 3b in 96% yield. The conﬁguration of

the tri-substituted conjugated double bond in 3b and 16 is

assigned according to the

spectra taken in CDCl₃. The compound 3b has the

-Me and

-H signals in their NMR

-Me and -H

signals at 1.97 (s, 3H) and 6.27 (t, J¼8.0 Hz,1H) ppm while those for

the compound 16 are found at 1.93 (s, 3H) and 7.00 (td, J¼8.0,

0.5 Hz, 1H) ppm. The ¹³C NMR signals of the

a-Me group appear at

20.4 (for 3b) and 12.9 (for 16) ppm. By referencing to the NMR data

of (Z)-11/(E)-11^12,13cand (Z)-6/(E)-6⁰, the geometry of 3b and 16

could be assigned.

Scheme 3. Synthesis of the amido hydroquinone precursor 3b.

We demonstrated transformation of the acetamide analogue of

15 into the corresponding 1,4-benzoquinone by cleavage of the

PMB ether and 2,6-DCPFC oxidation of the resultant 3-

amidophenol.⁶Attempts at similar transformations from 15 and

18 met low yields (20e60%) of the desired 1,4-benzoquinones and

poor reproducibility of the results. For facilitating the oxidation

step, we synthesized the 1,4-dimethoxy-substituted analogue 21 as

shown in Scheme 4. The anti-selective aldol reaction of 7b¹⁶with

(1R,2S)-8 gave the aldol product 19 in 92% yield and in a 96:4 ratio

of diastereomers. The ortho-OMe group in the aldehyde 7b was

found not interfering with asymmetric induction of the aldol re-

action. After protection of the hydroxy group in 19 as the TBS ether

(99% yield), the chiral auxiliary was removed by DIBAL-H reduction

to afford the primary alcohol 20 in 98% yield. It was found that the

free hydroxy group in 20 did not affect the subsequent amidation.

Thus, the CuI-catalyzed amidation of 20 with CF₃CONH₂at 100 ^ꢀC

for 45 h furnished the anilide 21 in 83% yield. Oxidation of 21 using

DMP produced the aldehyde 22 (95% yield), which was subjected to

Scheme 2. Synthesis of the amido hydroquinone precursor 16.

4782

G. Zhao et al. / Tetrahedron 71 (2015) 4779e4787

CAN oxidation^9aecat 0 ^ꢀC for 15 min to furnish the 2-amido-1,4-

benzoquinone 23 in 92% yield. These results demonstrated that

oxidation of 1,4-dimethoxybenzenes to form the corresponding

1,4-benzoquinones is much more easy than phenols. Therefore, it

could be considered as an alternative for total synthesis of diver-

golide A and its congeners.

4. Experimental

4.1. General methods

¹H and ¹³C NMR spectra were recorded in CDCl₃or DMSO-d₆

(400 or 500 MHz for ¹H and 100 or 125 MHz for ¹³C, respectively).

Residual solvent peaks are used as the internal reference; the sig-

nals at 7.26 and 77.00 ppm are set for ¹H and ¹³C NMR spectra,

respectively, taken in CDCl₃while the signals at 2.50 and 40.45 ppm

are set for ¹H and ¹³C NMR spectra, respectively, taken in DMSO-d₆.

IR spectra were taken on an FTIR spectrophotometer. High resolu-

tion mass spectra (HRMS) were measured by TOF MS under the þEI

conditions. Silica gel plates pre-coated on glass were used for thin-

layer chromatography using UV light, or 7% ethanolic phospho-

molybdic acid and heating as the visualizing methods. Silica gel was

used for ﬂash column chromatography. Yields refer to chromato-

graphically and spectroscopically (¹H NMR) homogeneous mate-

rials. Petroleum ether (PE) of bp 60e90 ^ꢀC was used. Reagents were

obtained commercially and used as received.

4.2. Sodio-1,1,3,3-tetracarboethoxypropene (9)^12,13c

To a solution of NaOEt (9.20 g,135.00 mmol) in dry EtOH (80 mL)

were added dropwise diethyl malonate (12.10 g, 11.5 mL,

76.00 mmol) and chloroform (3.05 mL, 38.00 mmol). The resultant

mixture was heated at reﬂux for 30 min. The hot yellow-colored

reaction mixture was ﬁltered off with washing by warm EtOH.

The combined ﬁltrate was cooled to room temperature and evap-

orated under reduced pressure. The residue was recrystallized from

EtOH (60 mL) at 0 ^ꢀC to give 9 (12.80 g, 95%) as a yellow solid. Mp

268e270 ^ꢀC (EtOH); ¹H NMR (400 MHz, DMSO-d₆)

3.94 (q, J¼7.2 Hz, 8H), 1.15 (t, J¼7.2 Hz, 12H).

d 7.99 (s, 1H),

4.3. 1,1,3,3-Tetracarboethoxybutene (10)^12,13c

To a solution of 9 (12.80 g, 36.00 mmol) in dry DMF (25 mL) was

added MeI (25.80 g, 11.5 mL, 180.00 mmol) dropwise over 15 min.

The resultant mixture was stirred at room temperature overnight.

The reaction mixture was diluted with water (100 mL) and

extracted with Et₂O (150 mLꢁ3). The combined organic layer was

washed with brine, dried over anhydrous Na₂SO₄, and evaporated

under reduced pressure to give 10 (12.10 g, 98%) as a pale yellow oil.

R_f¼0.34 (2.4% EtOAc in PE); ¹H NMR (400 MHz, CDCl₃)

4.26e4.16 (m, 8H), 1.64 (s, 3H), 1.32e1.22 (m, 12H).

d 7.55 (s, 1H),

4.4. (E)-g

-Methylglutaconic acid [(E)-11]^12,13c

Scheme 4. Synthesis and CAN oxidation of the 2,5-dimethoxyanilide 22.

To an aqueous solution of KOH (2.5 M, 120 mL) was added neat

10 (12.10 g, 35.00 mmol) dropwise followed by heating at reﬂux for

3 h. The reaction mixture was cooled to room temperature and

acidiﬁed with 1 M aqueous HCl solution to pH 3. The resultant

mixture was extracted with EtOAc (200 mLꢁ3). The combined or-

ganic layer was washed with brine, dried over anhydrous Na₂SO₄

and evaporated under reduced pressure. The residue was recrys-

tallized in MeCN (30 mL) at ꢂ10 ^ꢀC to give (E)-11 (3.10 g, 62%) as

a white solid. Mp 139e141 ^ꢀC (MeCN); IR (ﬁlm): 3000e2800 (br),

3. Conclusion

In summary, we have established an improved synthesis of

methylglutaconic anhydride (12)¹²and two methods for in-

stallation of (E)- and (Z)- -methylglutaconic acids onto a model 3-

aminophenol core of divergolide A and EeH. Amidation of the aryl

bromide 14 with methyl (Z)-4-carbamoyl-2-methylbut-2-enoate

(6) under Cu(I) catalysis using N,N⁰-dimethylethylenediamine as

the ligand and K₂CO₃as the base gave the (E)-anilide 16 as the

major product. On the other hand, aminolysis of the anhydride 12

with the aniline derivative 17 afforded exclusively the (Z)-anilide

3b. Moreover, the 1,4-dimethoxy-substituted anilide 22 has been

synthesized and transformed into the 1,4-benzoquinone 23 in ex-

cellent yield upon CAN oxidation. Our results on these model

1678, 1274, 1223 cm^ꢂ1; ¹H NMR (400 MHz, DMSO-d₆)

2H), 6.78e6.75 (m, 1H), 3.20 (dd, J¼7.2, 1.2 Hz, 2H),1.72 (d, J¼1.2 Hz,

d 12.39 (br s,

3H); ¹³C NMR (100 MHz, DMSO-d₆)

d 172.8, 169.5, 134.9, 130.7, 34.7,

13.5; HRMS (þEI) calcd for C₆H₈O₄144.0423 (M^þ), found 144.0425.

4.5. (Z)-g

-Methylglutaconic acid [(Z)-11]^12,13c

studies reveal the lability of the (Z)-conﬁguration in

g-methyl-

glutaconic acid and its derivatives toward both acidic and basic

conditions, which should be of reference value for total synthesis of

divergolide A and EeH.

A solution of (E)-11 (300.0 mg, 2.10 mmol) in triﬂic acid (2 mL)

was heated at 120 ^ꢀC for 2 h. The hot deep brown oil was quenched

with ice water. The mixture was cooled to room temperature and

G. Zhao et al. / Tetrahedron 71 (2015) 4779e4787

4783

extracted with EtOAc (5 mLꢁ3). The combined organic layer was

washed with brine, dried over anhydrous Na₂SO₄, and evaporated

under reduced pressure to give a 9:1 mixture of (Z)-11 and (E)-11

(204.0 mg, 68%) as a yellow solid. Mp 119e121 ^ꢀC (MeCN); ¹H NMR

ꢂ95 ^ꢀC under N₂was added n-BuLi (0.8 mL, 1.30 mmol, 1.6 M in

hexanes) dropwise in 5 min followed by stirring at same temper-

ature for 1 h. To the resultant mixture was added anhydrous DMF

(0.9 mL,12.00 mmol). The reaction mixture was allowed to warm to

room temperature, quenched with saturated aqueous NH₄Cl, and

extracted with EtOAc (15 mLꢁ3). The combined organic layer was

washed with brine, dried over anhydrous Na₂SO₄, and evaporated

under reduced pressure. The residue was puriﬁed by column

chromatography (silica gel, 4.8% EtOAc in PE) to give the aldehyde

7a (321.2 mg, 85%) as a colorless oil. R_f¼0.40 (4.8% EtOAc in PE); IR

(400 MHz, DMSO-d₆)

3.45 (dd, J¼7.2, 1.2 Hz, 2H), 1.85 (d, J¼1.2 Hz, 3H).

12.4 (br s, 2H), 6.11 (td, J¼7.2, 1.6 Hz, 1H),

4.6.

-Methylglutaconic anhydride (12)¹²

4.6.1. Method A. A 10-mL pressurized process vial was charged

with (E)-11 (212.4 mg, 1.47 mmol) and 2,2,2-triﬂuoroacetic anhy-

dride (1 mL). The vial was sealed with a cap containing a silicon

septum. The vial was heated in an oil bath at 80 ^ꢀC for 4 h. The

reaction mixture was cooled to room temperature and evaporated

under reduced pressure. The residue was puriﬁed by column

chromatography (silica gel, CH₂Cl₂) to give 12 (168.7 mg, 91%) as

a pale yellow solid. Mp 74e75 ^ꢀC (CH₂Cl₂); R_f¼0.42 (25% EtOAc in

(ﬁlm): 1699, 1244, 1027 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃)

d 9.87 (d,

J¼2.0 Hz, 1H), 7.56 (br s, 1H), 7.38e7.32 (m, 4H), 6.95e6.90 (m, 2H),

5.02 (s, 2H), 3.81 (d, J¼0.8 Hz 3H); ¹³C NMR (100 MHz, CDCl₃)

190.4, 159.9, 159.6, 138.6, 129.3 (ꢁ2), 127.6, 125.7, 124.5, 123.4,

114.0 (ꢁ2), 113.0, 70.3, 55.2; HRMS (þEI) calcd for C₁₅H₁₃BrO₃

320.0048 (M^þ), found 320.0047.

PE); IR (ﬁlm): 1801, 1743, 1270, 1041 cm^ꢂ1

;

¹H NMR (400 MHz,

4.9. (1R,2S)-2-{N-Benzyl-N-[(2⁰,4⁰,6⁰-trimethylbenzene)-sulfo-

nyl]amino}-1-phenylpropyl (2R,3S)-3-{3⁰-bromo-5⁰-[(4⁰⁰-me-

thoxybenzyl)oxy]phenyl}-3-hydroxy-2-methylpropionate (13)

CDCl₃)

d 6.64e6.61 (m, 1H), 3.54e3.52 (m, 2H), 2.04e2.02 (m, 3H);

¹³C NMR (100 MHz, CDCl₃)

d 165.0, 161.1, 136.9, 126.6, 32.3, 16.6;

HRMS (þEI) calcd for C₆H₆O₃126.0317 (M^þ), found 126.0315.

To a solution of the chiral propionate (1R,2S)-8 (950.3 mg,

2.00 mmol) in anhydrous CH₂Cl₂(150 mL) cooled at ꢂ78 ^ꢀC was

added Et₃N (0.70 mL, 5.00 mmol) under a nitrogen atmosphere.

After stirring at the same temperature for 5 min, a solution of c-

Hex₂BOTf (1.0 M in hexane, 6.00 mL, 6.00 mmol) was added

dropwise over 20 min. The resultant mixture was stirred at the

same temperature for 2 h. A solution of the aldehyde 7a (803.2 mg,

2.50 mmol) in anhydrous CH₂Cl₂(3 mL) was added dropwise fol-

lowed by stirring at the same temperature for 1 h. The mixture was

allowed to warm to ꢂ50 ^ꢀC over 1 h and the reaction was quenched

by addition of a mixture of pH 7 buffer and MeOH (1/1, v/v, 20 mL).

The reaction mixture was diluted with MeOH to make a homoge-

neous solution. After careful addition of 30% H₂O₂(8 mL), the

mixture was stirred at room temperature for 6 h and then evapo-

rated under reduced pressure. The residue was extracted with

CH₂Cl₂(100 mLꢁ3). The combined organic layer was washed with

brine, dried over anhydrous Na₂SO₄, and evaporated under reduced

pressure. The residue was puriﬁed by column chromatography

(silica gel, 14.3% EtOAc in PE) to give the anti-aldol product 13

(1.400 g, 88%, dr¼91:9) as a colorless viscous oil. R_f¼0.32 (14.3%

4.6.2. Method B. A solution of (Z)-11 (138.3 mg, 0.96 mmol) in

acetic anhydride (3 mL) was heated at 70 ^ꢀC for 30 min. The dark

brown reaction mixture was cooled to room temperature and

evaporated under reduced pressure. The residue was puriﬁed by

column chromatography (silica gel, CH₂Cl₂) to give 12 (117.3 mg,

97%) as a pale yellow solid.

4.7. Methyl (Z)-4-carbamoyl-2-methylbut-2-enoate (6)

A mixture of 12 (208.2 mg,1.65 mmol) and concentrated aqueous

NH₄OH (4 mL) in EtOH (95%, 7 mL) was heated at reﬂux for 4 h. The

reaction mixture was cooled to ꢂ10 ^ꢀC and acidiﬁed with diluted

aqueous HCl to pH 4. The resultant mixture was extracted with EtOAc

(10 mLꢁ3). The combined organic layer was washed with brine, dried

overanhydrous Na₂SO₄, and evaporated under reduced pressure. The

residue was puriﬁed by column chromatography (silica gel, 50%

EtOAc in PE) to give an 82:18 mixture of (Z)-4-carbamoyl-2-

methylbut-2-enoic acid (198.5 mg, 84%) as a pale yellow solid. Mp

98e100 ^ꢀC (MeOH); R_f¼0.38 (50% EOAc in PE); IR (ﬁlm): 3418 (br),

1662,1000 cm^ꢂ1; ¹H NMR (400 MHz, DMSO-d₆)

12.4 (br s, 3H), 6.77

EtOAc in PE); ½a ²_D⁰

ꢃ

ꢂ8.3 (c 0.32, CHCl₃); IR (ﬁlm): 3408 (br), 1727,

(td, J¼7.2,1.6 Hz, 0.18H) [for (E)-isomer], 6.11 (td, J¼7.2,1.6 Hz, 0.82H)

[for (Z)-isomer], 3.45 (dd, J¼7.2, 1.2 Hz, 1.64H) [for (Z)-isomer], 3.20

(dd, J¼7.2,1.2 Hz, 0.36H) [for (E)-isomer],1.85 (d, J¼1.2 Hz, 2.46H) [for

(Z)-isomer], 1.73 (d, J¼1.2 Hz, 0.54H) [for (E)-isomer]; ¹³C NMR

1600, 1493, 1314, 1149 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃)

d 7.34e7.16

(m, 10H), 7.09 (br s, 1H), 7.04 (t, J¼2.0 Hz, 1H), 6.93e6.89 (m, 2H),

6.89 (s, 2H), 6.86 (dd, J¼2.0, 1.6 Hz, 1H) 6.84 (d, J¼1.6 Hz, 1H), 6.82

(d, J¼2.0 Hz, 1H), 5.83 (d, J¼4.0 Hz, 1H), 4.93 (s, 2H), 4.71 and 4.49

(ABq, J¼16.8 Hz, 2H), 4.61 (dd, J¼8.0, 4.8 Hz, 1H), 4.10e4.04 (m, 1H),

3.82 (s, 3H), 3.16 (d, J¼4.8 Hz, 1H, OH), 2.72e2.65 (m, 1H), 2.50 (s,

6H), 2.29 (s, 3H), 1.12 (d, J¼6.8 Hz, 3H), 0.97 (d, J¼7.6 Hz, 3H); ¹³C

(100 MHz, DMSO-d₆)

d 173.3, 169.5, 134.8 [for (E)-isomer], 134.5,

130.3, 35.3, 34.6 [for (E)-isomer], 21.4, 13.5 [for (E)-isomer]; HRMS

(þEI) calcd for C₆H₉NO₃143.0582 (M^þ), found 143.0583.

To a solution of the above monoacid (54.4 mg, 0.38 mmol) in

benzene (4 mL) and MeOH (1 mL) was added a solution of TMSCHN₂

(0.38 mL, 2.0 M in hexane, 0.76 mmol) dropwise. The resultant yellow

solutionwas allowed to stir at room temperature for 2 h. The reaction

mixture was evaporated under reduced pressure and the residue was

puriﬁed by column chromatography (silica gel, 10% EtOAcePE) to

give 6 (56.7 mg, 95%) as a pale yellow oil. R_f¼0.44 (10% EtOAc in PE);

NMR (100 MHz, CDCl₃)

174.3, 159.6, 159.6, 144.8, 142.6, 140.3 (ꢁ2),

138.6, 138.1, 133.4, 132.1 (ꢁ2), 129.3 (ꢁ2), 128.5 (ꢁ2), 128.4 (ꢁ2),

128.1, 128.0, 127.6 (ꢁ2), 127.2, 125.7 (ꢁ2), 122.9, 122.1, 117.4, 114.0

(ꢁ2), 112.6, 78.6, 75.6, 70.1, 56.8, 55.3, 48.2, 46.9, 22.9 (ꢁ2), 20.9,

14.5, 13.1; HRMS (þEI) calcd for C₄₃H₄₆BrNO₇S 799.2178 (M^þ),

found 799.2175.

IR (ﬁlm): 3428, 3348, 3201, 1704, 1664, 1228, 1134 cm^ꢂ1

;

¹H NMR

4.10. (1R,2S)-2-{N-Benzyl-N-[(2⁰,4⁰,6⁰-trimethylbenzene)-sul-

fonyl]amino}-1-phenylpropyl (2R,3S)-3-{3⁰-bromo-5⁰-[(4⁰⁰-

methoxybenzyl)oxy]phenyl}-3-[(tert-butyldimethylsilyl)oxy]-

2-methylpropionate

(400 MHz, CDCl₃) d 6.22 (br s,1H, CONH₂), 6.24e6.20 (m,1H), 5.77 (br

s,1H, CONH₂), 3.74 (s, 3H), 3.40 (dd, J¼7.6, 0.8 Hz, 2H),1.94 (s, 3H); ¹³

NMR (100 MHz, CDCl₃)

d 172.9, 168.3, 135.3, 130.0, 51.7, 37.0, 20.3;

HRMS (þEI) calcd for C₇H₁₁NO₃157.0739 (M^þ), found 157.0738.

To a solution of the alcohol 13 (880.8 mg, 1.10 mmol) in anhy-

drous CH₂Cl₂(10 mL) cooled at 0 ^ꢀC was sequentially added 2,6-

lutidine (0.25 mL, 2.20 mmol) and TBSOTf (0.4 mL, 1.60 mmol)

under a nitrogen atmosphere. After stirring at 0 ^ꢀC for 1 h, the re-

action was quenched by addition of saturated aqueous NaHCO₃at

4.8. 3-Bromo-5-((p-methoxybenzyl)oxy)benzaldehyde (7a)

To a solution of 1,3-dibromo-5-((4-methoxybenzyl)oxy)-ben-

zene¹⁷(440.3 mg, 1.20 mmol) in anhydrous THF (15 mL) cooled at

4784

G. Zhao et al. / Tetrahedron 71 (2015) 4779e4787

^ꢀC. The reaction mixture was then extracted with CH₂Cl₂

1H), 6.99 (t, J¼2.0 Hz, 1H), 6.92e6.89 (m, 2H), 6.84 (s, 1H), 4.96 and

4.93 (ABq, J¼10.8 Hz, 2H), 4.56 (d, J¼7.2 Hz, 1H), 3.82 (s, 3H), 3.57

and 3.47 (ABqd, J¼10.0, 5.6 Hz, 2H), 1.91e1.84 (m, 1H), 1.56 (s, 3H),

0.91 (s, 9H), 0.85 (s, 9H), 0.65 (d, J¼6.8 Hz, 3H), 0.05 (s, 3H), 0.04 (s,

(15 mLꢁ3). The combined organic layer was washed with brine,

dried over anhydrous Na₂SO₄, and evaporated under reduced

pressure. The residue was puriﬁed by column chromatography

(silica gel, 9.1% EtOAc in PE) to give the corresponding TBS ether

(911.6 mg, 98%) as a colorless viscous oil. R_f¼0.35 (9.1% EtOAc in PE);

3H), 0.01 (s, 3H), ꢂ0.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 159.5,

159.1, 146.8, 129.2 (ꢁ2), 128.5, 122.7, 122.0, 116.7, 114.0 (ꢁ2), 112.6,

75.1, 70.0, 64.4, 55.3, 43.8, 26.0 (ꢁ3), 25.8 (ꢁ3), 18.3, 18.1, 12.5, ꢂ4.6,

ꢂ5.1, ꢂ5.3, ꢂ5.4; HRMS (þEI) calcd for C₃₀H₄₉BrO₄Si₂608.2353

(M^þ), found 608.2359.

a ²_D⁰

ꢃ

ꢂ21.4 (c 0.40, CHCl₃); IR (ﬁlm): 2938, 1741, 1602, 1450, 1319,

1249, 1154, 103 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃)

7.42 (d, J¼7.2 Hz,

2H), 7.33e7.23 (m, 5H), 7.16 (t, J¼7.2 Hz, 1H), 7.08 (t, J¼7.2 Hz, 2H),

7.01 (s, 2H), 6.93e6.87 (m, 2H), 6.88 (s, 2H), 6.73 (t, J¼1.6 Hz, 1H),

6.70 (s, 1H), 6.68 (s, 1H), 5.73 (d, J¼5.6 Hz, 1H), 4.89 and 4.82 (ABq,

J¼11.2 Hz, 2H), 4.86 and 4.46 (ABq, J¼16.4 Hz, 2H), 4.67 (d, J¼8.8 Hz,

1H), 4.04e4.01 (m, 1H), 3.81 (s, 3H), 2.68e2.61 (m, 1H), 2.44 (s, 6H),

2.31 (s, 3H), 1.15 (d, J¼7.2 Hz, 3H), 0.79 (s, 9H), 0.72 (d, J¼7.2 Hz, 3H),

4.13. N-(1⁰S,2⁰S)-3-{1⁰,3⁰-Bis[(tert-butyldimethylsilyl)oxy]-2⁰-

methylporpyl}-5-[(4⁰⁰-methoxybenzyl)oxy]phenyl 2,2,2-

triﬂuoroacetamide (15)

ꢂ0.05 (s, 3H), ꢂ0.21 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

172.9,

An over-dried Schlenk tube was charged with CuI (10.0 mg,

5.0ꢁ10^ꢂ2mmol), K₂CO₃(276.4 mg, 2.00 mmol) and 4 A MS

ꢀ

159.5, 159.2, 145.3, 142.4, 140.4 (ꢁ2), 138.6, 138.1, 133.0, 132.1 (ꢁ2),

129.2 (ꢁ2), 128.4 (ꢁ2), 128.2 (ꢁ2), 128.2, 128.2 (ꢁ2), 127.8, 127.4,

126.2 (ꢁ2), 122.6, 122.5, 117.4, 114.0 (ꢁ2), 112.8, 77.9, 76.1, 70.0, 56.7,

55.3, 48.6, 48.2, 25.8 (ꢁ3), 22.9 (ꢁ2), 20.9, 18.1, 14.3, 13.4, ꢂ4.7,

ꢂ5.0; HRMS (þEI) calcd for C₄₉H₆₀BrNO₇SSi 913.3043 (M^þ), found

913.3049.

(500 mg). The tube was evacuated and backﬁlled with nitrogen

several times. Then, a solution of the aryl bromide 14 (609.9 mg,

1.00 mmol), 2,2,2-triﬂuoroacetamide (170.2 mg, 1.50 mmol), and

N,N⁰-dimethylethylenediamine (12

mL, 0.10 mmol) in degassed an-

hydrous 1,4-dioxane (3.0 mL) was added under nitrogen through

a syringe. The tube was heated at 100 ^ꢀC for 18 h. The reaction

mixture was cooled to room temperature and extracted with EtOAc

(7 mLꢁ3). The combined organic layer was washed with brine,

dried over anhydrous Na₂SO₄, and evaporated under reduced

pressure. The residue was puriﬁed by column chromatography

(silica gel, 4.8% EtOAc in PE) to give 15 (603.5 mg, 94%) as a pale

4.11. (2S,3S)-3-{3⁰-Bromo-5⁰-[(4⁰⁰-methoxybenzyl)oxy]-phe-

nyl}-3-[(tert-butyldimethylsilyl)oxy]-2-methylpropan-1-ol

To a solution of the above TBS ether (1.522 g, 1.80 mmol) in

anhydrous CH₂Cl₂(20 mL) cooled at ꢂ78 ^ꢀC was added DIBAL-H

(1.0 M in hexane, 3.60 mL, 3.60 mmol) followed by stirring at the

same temperature for 45 min. The reaction was quenched by

careful addition of MeOH (5 mL) at ꢂ78 ^ꢀC and the reaction mixture

was allowed to warm to room temperature. A saturated aqueous

solution of sodium potassium tartrate (20 mL) was added and the

resultant mixture was stirred at room temperature for about 1 h.

The mixture was extracted with CH₂Cl₂(20 mLꢁ3). The combined

organic layer was washed with brine, dried over anhydrous Na₂SO₄,

and evaporated under reduced pressure. The residue was puriﬁed

by column chromatography (silica gel, 7.7% EtOAc in PE) to give the

primary alcohol (856.2 mg, 96%) as a colorless oil. R_f¼0.30 (7.7%

yellow oil. R_f¼0.36 (4.8% EtOAc in PE); ½a _D²⁰

ꢂ30.0 (c 0.52, CHCl₃); IR

ꢃ

(ﬁlm): 3306 (br), 2936, 1715, 1611, 1462, 1249, 1170, 1080 cm^ꢂ1; ¹H

NMR (400 MHz, CDCl₃) d 7.83 (br s, 1H, NH), 7.37e7.34 (m, 2H), 7.33

(t, J¼2.0 Hz, 1H), 6.93e6.90 (m, 2H), 6.91 (s, 1H), 6.81 (s, 1H), 5.01

and 4.97 (ABq, J¼11.2 Hz, 2H), 4.57 (d, J¼6.8 Hz, 1H), 3.82 (s, 3H),

3.60 and 3.52 (ABqd, J¼10.0, 6.0 Hz, 2H), 1.91e1.84 (m, 1H), 0.92 (s,

9H), 0.87 (s, 9H), 0.66 (d, J¼6.8 Hz, 3H), 0.05 (s, 6H), 0.02 (s, 3H),

ꢂ0.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 159.5, 159.1, 154.4

(²J_C,F¼37.2 Hz), 146.4, 135.5, 129.2 (ꢁ2), 128.6, 115.7

(¹J_C,F¼288.9 Hz), 114.0 (ꢁ2), 111.7, 111.3, 105.8, 75.4, 69.9, 64.4, 55.3,

43.9, 25.9 (ꢁ3), 25.8 (ꢁ3), 18.3, 18.1, 12.7, ꢂ4.6, ꢂ5.2, ꢂ5.3, ꢂ5.5;

EtOAc in PE); ½a ²_D⁰

ꢃ

ꢂ12.2 (c 0.47, CHCl₃); IR (ﬁlm): 3448 (br), 2933,

HRMS (þEI) calcd for

₃₂H₅₀F₃NO₅Si₂641.3180 (M^þ), found

1601, 1575, 1515, 1446, 1249, 1031 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃)

641.3185.

7.36e7.32 (m, 2H), 7.03 (br s, 2H), 6.93e6.90 (m, 2H), 6.84 (br s,

1H), 4.98 and 4.94 (ABq, J¼11.2 Hz, 2H), 4.49 (d, J¼6.8 Hz, 1H), 3.82

(s, 3H), 3.66e3.53 (m, 2H), 2.65 (br s, 1H, OH), 1.90e1.84 (m, 1H),

0.89 (s, 9H), 0.85 (d, J¼6.8 Hz, 3H), 0.05 (s, 3H), ꢂ0.20 (s, 3H); ¹³C

4.14. Methyl (2E,1⁰⁰S,2⁰⁰S)-4-{3⁰-[1⁰⁰,3⁰⁰-bis((tert-butyldi-methyl-

silyl)oxy)-2⁰⁰-methylporpyl]-5⁰-[(4⁰⁰⁰-methoxybenzyl)-oxy]phe-

nylcarbomoyl}-2-methylbut-2-enoate (16) and methyl

(2Z,1⁰⁰S,2⁰⁰S)-4-{3⁰-[1⁰⁰,3⁰⁰-bis((tert-butyldimethylsilyl)oxy)-2⁰⁰-

methylporpyl]-5⁰-[(4⁰⁰⁰-methoxybenzyl)oxy]-phenyl-

carbomoyl}-2-methylbut-2-enoate (3b)

NMR (100 MHz, CDCl₃)

159.6,159.3,146.9,129.3 (ꢁ2),128.3,122.4,

122.3, 117.0, 114.0 (ꢁ2), 112.2, 79.7, 70.1, 65.8, 55.3, 43.0, 25.8 (ꢁ3),

18.1, 14.2, ꢂ4.5, ꢂ5.2; HRMS (þEI) calcd for C₂₄H₃₅BrO₄Si 494.1488

(M^þ), found 494.1485.

An over-dried Schlenk tube was charged with CuI (3.0 mg,

4.12. (1⁰S,2⁰S)-1-Bromo-3-{1⁰,3⁰-bis[(tert-butyldimethylsilyl)-

oxy]-2⁰-methylporpyl}-5-[(4⁰⁰-methoxybenzyl)oxy]benzene

(14)

1.5ꢁ10^ꢂ2mmol), K₂CO₃(82.9 mg, 0.60 mmol) and 4 A MS (150 mg).

ꢀ

The tube was evacuated and backﬁlled with nitrogen several times.

Then, a solution of the aryl bromide 14 (183.0 mg, 0.30 mmol), 6

(70.8 mg, 0.45 mmol), and N,N⁰-dimethylethylenediamine (3.6

mL,

To a solution of the above primary alcohol (743.3 mg,1.50 mmol)

in anhydrous CH₂Cl₂(15 mL) cooled at 0 ^ꢀC was sequentially added

2,6-lutidine (0.34 mL, 3.00 mmol) and TBSOTf (0.55 mL, 2.20 mmol)

under a nitrogen atmosphere followed by stirring at same tem-

perature for 1 h. The reaction was quenched by addition of satu-

rated aqueous NaHCO₃at 0 ^ꢀC and the reaction mixture was

extracted with CH₂Cl₂(15 mLꢁ3). The combined organic layer was

washed with brine, dried over anhydrous Na₂SO₄, and evaporated

under reduced pressure. The residue was puriﬁed by column

chromatography (silica gel, 1.2% EtOAc in PE) to give 14 (905.6 mg,

3.0ꢁ10^ꢂ2mmol) in degassed anhydrous 1,4-dioxane (1.0 mL) was

added under nitrogen through a syringe. The tube was heated at

100 ^ꢀC for 18 h. The reaction mixture was cooled to room tem-

perature and extracted with EtOAc (5 mLꢁ3). The combined or-

ganic layer was washed with brine, dried over anhydrous Na₂SO₄,

and evaporated under reduced pressure. The residue was puriﬁed

by column chromatography (silica gel, 6.3% EtOAc in PE) to give an

88:12 mixture of 16 and 3b (189.4 mg, 92% combined yield).

Compound 16: a pale yellow oil; R_f¼0.48 (6.3% EtOAc in PE); ½a _D²⁰

ꢃ

ꢂ27.5 (c 0.36, CHCl₃); IR (ﬁlm): 3337, 2933, 1705, 1605, 1463, 1249,

99%) as a colorless oil. R_f¼0.30 (1.2% EtOAc in PE); ½a _D²⁰

ꢃ

ꢂ39.2 (c

1078 cm^ꢂ1; ¹H NMR (500 MHz, CDCl₃)

d 7.37e7.34 (m, 3H), 7.12 (s,

0.84, CHCl₃); IR (ﬁlm): 2933, 1601, 1576, 1515, 1462, 1250,

1H), 7.00 (td, J¼8.0, 0.5 Hz, 1H), 6.90e6.89 (m, 2H), 6.78 (s, 1H), 6.70

1082 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃)

d 7.35e7.32 (m, 2H), 7.02 (s,

(s, 1H), 4.99 and 4.96 (ABq, J¼11.0 Hz, 2H), 4.50 (d, J¼7.0 Hz, 1H),

G. Zhao et al. / Tetrahedron 71 (2015) 4779e4787

4785

3.81 (s, 3H), 3.77 (s, 3H), 3.58 (ABqd, J¼10.0, 6.5 Hz, 1H), 3.55 (ABqd,

J¼10.0, 5.5 Hz, 1H), 3.30 (d, J¼7.0 Hz, 2H), 1.923 (s, 3H), 1.89e1.83

(m, 1H), 0.91 (s, 9H), 0.86 (s, 9H), 0.66 (d, J¼7.0 Hz, 3H), 0.04 (s, 3H),

0.04 (s, 3H), 0.01 (s, 3H), ꢂ0.21 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

3H) (The proton signal for CO₂H is not observed.); ¹³C NMR

(100 MHz, CDCl₃) 172.0, 168.6, 159.3, 158.9, 145.9, 138.4, 136.2,

130.5, 129.3 (ꢁ2), 128.9, 113.9 (ꢁ2), 110.7, 109.8, 105.1, 75.8, 69.8,

64.6, 55.3, 43.9, 39.0, 26.0 (ꢁ3), 25.7 (ꢁ3), 20.4, 18.3, 18.1, 13.0, ꢂ4.6,

ꢂ5.2, ꢂ5.3, ꢂ5.4; HRMS (þEI) calcd for C₃₆H₅₇NO₇Si₂671.3674

(M^þ), found 671.3676.

167.8, 167.1, 159.4, 159.0, 145.9, 138.0, 132.9, 131.8, 129.2 (ꢁ2),

129.0, 113.9 (ꢁ2), 110.7, 110.2, 105.2, 75.7, 69.8, 64.6, 55.3, 52.0, 43.9,

37.4, 26.0 (ꢁ3), 25.8 (ꢁ3), 18.3, 18.1, 12.9, 12.9, ꢂ4.6, ꢂ5.1, ꢂ5.3,

ꢂ5.4; HRMS (þEI) calcd for C₃₇H₅₉NO₇Si₂685.3830 (M^þ), found

685.3833. Compound 3b: a pale yellow oil; R_f¼0.46 (6.3% EtOAc in

4.17. Formation of methyl ester 3b from 18

PE); ½a ²_D⁰

ꢃ

ꢂ18.1 (c 0.27, CHCl₃); IR (ﬁlm): 3312, 2950, 2858, 1710,

To a solution of 18 (10.1 mg, 1.5ꢁ10^ꢂ2mmol) PhH (1 mL) and

1609, 1463, 1437, 1248, 1080 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃)

8.65

MeOH (0.3 mL) was added TMSCHN₂(15 mL, 2.0 M in hexane,

(s, 1H, NH), 7.37 (s, 1H), 7.37e7.34 (m, 2H), 6.91e6.89 (m, 2H), 6.81

(s, 1H), 6.65 (s, 1H), 6.27 (t, J¼8.0 Hz, 1H), 4.99 and 4.95 (ABq,

J¼11.2 Hz, 2H), 4.50 (d, J¼7.2 Hz, 1H), 3.81 (s, 3H), 3.81 (s, 3H), 3.57

(d, J¼5.6 Hz, 2H), 3.52e3.40 (m, 2H), 1.97 (s, 3H), 1.90e1.83 (m, 1H),

0.90 (s, 9H), 0.86 (s, 9H), 0.68 (d, J¼6.8 Hz, 3H), 0.03 (s, 6H), 0.00 (s,

3.0ꢁ10^ꢂ2mmol) dropwise. The resultant yellow solution was

allowed to stir at room temperature for 2 h. The reaction mixture

was evaporated under reduced pressure and the residue was pu-

riﬁed by column chromatography (silica gel, 6.3% EtOAc in PE) to

give 3b (9.9 mg, 96%) as a pale yellow oil.

3H), ꢂ0.21 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 169.0, 168.2, 159.3,

158.8, 145.7, 138.8, 135.4, 130.4, 129.2 (ꢁ2), 129.1, 113.9 (ꢁ2), 110.5,

109.4, 104.8, 75.7, 69.7, 64.6, 55.3, 52.0, 43.9, 39.5, 26.0 (ꢁ3), 25.8

(ꢁ3), 20.4, 18.3, 18.1, 13.0, ꢂ4.6, ꢂ5.2, ꢂ5.3, ꢂ5.4; HRMS (þEI) calcd

for C₃₇H₅₉NO₇Si₂685.3830 (M^þ), found 685.3833.

4.18. (1R,2S)-2-{N-Benzyl-N-[(2⁰,4⁰,6⁰-trimethylbenzene)-sul-

fonyl]amino}-1-phenylpropyl (2R,3S)-3-(3⁰-bromo-2⁰,5⁰-dime-

thoxyphenyl)-3-hydroxy-2-methylpropionate (19)

To a solution of the chiral propionate (1R,2S)-8 (950.3 mg,

2.00 mmol) in anhydrous CH₂Cl₂(150 mL) cooled at ꢂ78 ^ꢀC was

added Et₃N (0.70 mL, 5.00 mmol) under a nitrogen atmosphere.

After stirring at the same temperature for 5 min, a solution of c-

Hex₂BOTf (1.0 M in hexane, 6.00 mL, 6.00 mmol) was added

dropwise over 20 min. The resultant mixture was stirred at the

same temperature for 2 h. A solution of the aldehyde 7b (612.7 mg,