Phenolate-induced intramolecular ring-opening cyclization of: N -tosylaziridines: Access to functionalized benzoxacycles

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ARTICLE

Phenolate-induced intramolecular ring-opening cyclization of N-

tosylaziridines: access to functionalized benzoxacycles

Runjun Devi,^aJonali Das,^aBipul Sarma^aand Sajal Kumar Das*^a

Received 00th April 2018,

Accepted 00th xxxx 2018

DOI: 10.1039/x0xx00000x

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Phenolate-induced, diastereo- and regioselective intramolecular Intermolecular ring-opening reactions of aziridines by

exo-tet ring-opening cyclization of N-tosylaziridines has been phenols/phenolates often suffer from disadvantages such as

achieved for the first time. The N-tosylaziridine substrates bearing long reaction times, low yields, poor regio- and

a

tethered (ortho-(tert-butyldimethylsiloxy))aryl substituent, stereoselectivity, use of expensive reagents and tedious

prepared directly from the corresponding olefins under Sharpless operations. These shortcomings have been critical obstructions

aziridination conditions, furnished functionalized 2,3- for further advances in the aziridine ring-opening chemistry.

dihydrobenzofuran, chroman, and 1-benzoxepane derivatives in While some of these problems have on rare occasions been

excellent yields when treated with tetrabutylammonium fluoride resolved by fine tuning of the steric and electronic effects on

(TBAF) at room temperature. Our ability to synthesize the two aziridine-carbon atoms (Scheme 1, upper panel),³

benzoxacycle-based N-tosyl-protected amino alcohols, that are more often than not they remain unsettled.

otherwise difficult to obtain by traditional synthetic routes, has

On the other hand, benzo-fused oxygen heterocycles such

opened the door to diversify the chemistry of β-amino alcohols. as 2,3-dihydrobenzofuran, chroman, 1,4-benzodioxane, and 1-

We also succesfully performed the Baeyer-Villiger oxidation of a benzoxepane ring systems are integral parts of a large number

salicylaldehyde ether bearing a tethered N-tosylaziridine moiety of biologically important natural and synthetic compounds.⁴A

with m-CPBA followed by tandem saponification and 6-exo-tet plethora of methods is available for the stereo- and

aziridine ring-opening cyclization, furnishing the corresponding regioselective synthesis of these privileged heterocyclic

trans-3,4-disubstituted-1,4-benzodioxane derivative. Overall, the systems, but the most commonly reported methods are

study has unveiled a new entry to the synthesis benzoxacycles and intramolecular S_NAr reaction, transition-metal-catalyzed C-O

has also broadened the impact of aziridines as synthetic building bond formation reaction, and Mitsunobu reaction, with each

blocks.

approach has its own advantages and disadvantages.⁴The

development of new approaches for their synthesis involving

various advantageous features, such as complete atom-

economy, transition-metal-free conditions, shorter reaction

time, ambient temperature, operational simplicity, and high

yields are still in high demand.

Introduction

N-Activated aziridines serve as versatile building blocks to

We recognized

a base-mediated intramolecular ring-

generate

(N-derivatized)aminoethyl

fragment-bearing

opening cyclization of an N-activated aziridine such as N-tosyl

aziridine with a tethered phenol would satisfy such synthetic

features (Scheme 1, lower panel). Driven by the entropy factor

and guided by the Baldwin's rules, phenolate-induced

intramolecular aziridine ring-opening reactions should be more

synthetically useful (than the intermolecular ones), and would

not only unveil a new entry to the synthesis benzoxacycles but

also broaden the impact of aziridines as synthetic building

blocks. In this paper, we describe new synthesis of 2,3-

dihydrobenzofuran, chroman, 1,4-benzodioxane, and 1-

benzoxepane derivatives based on the above-mentioned

envisioned approach. Surprisingly, however, to the best of our

knowledge, such a process has heretofore not been reported,

compounds via inter- and intramolecular nucleophilic ring-

opening reactions.¹Today, the portfolio of nucleophiles that

are widely used in the manipulations of aziridine ring-opening

chemistry includes diverse carbon- and hetero-nucleophiles.

Along this line, phenols are notable exceptions as they are

scarcely found in the gamut of main line nucleophiles used in

the aziridine ring-opening chemistry.²This dearth is apparently

due to the poor nucleophilicity of phenols/phenolates.

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although De Kimpe et al. elegantly showcased the potential of

To start with, we subjected compounds 1a

,b

to

intramolecular ring-opening of aziridine by phenolate on a dihydroxylation reaction under Upjohn conditions (OsO₄and

transient aziridine bearing intermediate in the synthesis of a NMO) to afford diols 2a,b in excellent yields (Scheme 2, upper

2,3-dihydrobenzo[b][1,4]oxathiine derivative from cis-1-tosyl- panel). Next, oxidative cleavage of 2a,b with NaIO₄and

2-tosyloxymethyl-3-(trifluoromethyl)

aziridine

and

2- subsequent Wittig olefination of the resulting crude aldehydes

with triphenylcarbethoxymethylenephosphorane

(Ph₃P=CHCO₂Et) afforded (E)-α,β-unsaturated esters 3a,b

mercaptophenol (Scheme 1, middle panel).^3b

.

DIBAL-H reduction of compounds 3a,b gave the corresponding

E-allylic alcohols 4a,b in high yields.

For the synthesis of homologues 7a-c, first hydroboration

(9-BBN) ─ oxidaꢀon (H₂O₂, NaOH) of 1a, 1c and 1

d was

performed to obtain primary alcohols 5a, 5b and 5c

,

respectively (Scheme 2, middle panel). PCC oxidation of 5a-c

followed by Wittig olefination of the resulting crude aldehydes

with Ph₃P=CHCO₂Et afforded (E)-α,β-unsaturated esters 6a-c

which were then reduced by DIBAL-H to obtain E-allylic

alcohols 7a-c

On the other hand, hydrogenation (Pd-C, H₂) of 4a furnished

saturated alcohol which was then converted to E-allylic

.

8

alcohols 10 in a similar fashion to the synthesized homologues

7a-c (Scheme 2, lower panel). Noteworthy is that in all of these

cases, frequently used benzyl group was not chosen as the

phenolic-OH protecting group since aziridine ring of the

corresponding N-tosylaziridine substrates would be prone to

hydrogenolysis during the debenzylation process.⁵

Scheme 1. Inter- vs intramolecular aziridine ring-opening by tethered phenols

Results and Discussion

In order to utilize N-tosylaziridines for the synthesis of

benzoxacycles, first synthesis of a set of substituted olefins

ortho-tethered to a protected phenol component by different

lengths was necessary. As shown in Scheme 2, following

(directly or after procedural modifications) well-established

Scheme 2. Preparation of olefin substrates.

protocols,^17-20we synthesized E-allylic alcohols 4a-b

, 7a-c, and

We then opted for the aziridination of terminal alkenes

1a,b and E-allylic alcohols 4a-b, 7a-c, and 10 to synthesize the

10 as olefin substrates in multistep but high overall yielding

corresponding N-tosylaziridines using the standard Sharpless

reaction sequences.

2 | Org. Biomol. Chem., 2018, 00, xx-xx

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aziridination conditions.⁶Thus, aziridination of these olefins conditions which involved treatment of 11a-h with

with 1.1 equiv of chloramine-T trihydrate (TsNClNa·3H₂O) in tetrabutylammonium fluoride (TBAF) in THF. In this way, we

the presence of 10 mol % of phenyltrimethylammonium were delighted to see very rapid and clean reaction of

tribromide (PTAB) in acetonitrile gave aziridines 11a-h (Table aziridines 11a-h, providing the corresponding benzoxacycles

1, third column). Noticeably, the yields of 11c-h were much 12a-h in very high yields within 10 min (Table 1, fourth

higher than 11a,b under Sharpless aziridination conditions ─ column). The aziridine ring-opening cyclizations were so fast

possibly due to the important roles played by the proximate that in none of these cases we could detect the corresponding

hydroxyl group in the allylic alcohol substrates.⁶Also, as intermediate phenolic derivative. The reactions clearly

expected, N-tosyl-2,3-aziridino alcohols 11c-h were formed in involved a tandem TBS-deprotection ─ exo-tet ring opening of

completely diastereoselective fashion.

aziridine ring by the in situ generated phenolate anion. This

mode of cyclization, obeying the Baldwin rules, is consistent

Table 1 Two-step synthesis (Sharpless aziridination followed by with previous findings on the cyclization reactions of similar

intramolecular ring-opening ─ cyclizaꢀon of N-tosylaziridines) of 2,3- epoxide-bearing substrates.⁷However, the very short reaction

dihydrobenzofuran, chroman, and 1-benzoxepane derivatives^a

time in the present scenario further supports the fact that N-

tosylaziridines are more reactive than epoxides towards ring-

opening process.¹Additionally, the annulation reaction in the

last step involved a relatively uncommon 7-exo-tet cyclization.

The structures of benzoxacycles 12a-h were assigned by

NMR spectroscopy, mass spectrometry and elemental analysis,

and further unambiguously verified by single crystal X-ray

diffraction analysis of 12e (Figure 1). The X-ray structure

showed that the intramolecular nucleophilic attack of

phenolate ion onto the aziridine ring had occurred anti to the

C3─NTs bond in a typical S_N2 fashion to provide the expected

relative stereochemistry between the two adjacent

stereocenters.

Chloramine-T

trihydrate

OTBS

( )_n

OTBS

NHTs

R

O

TBAF, THF

rt, 10 min

Ar

NTs

R

PTAB, MeCN

rt, 15 h

( )_n

11a-h

12a-h

4a,b, 7a-c, and 10

benzoxacycle

O

N-tosylaziridine

olefin

OTBS

NTs

1a

1b

NHTs

11a (62%)

12a (96%)

OTBS

O

NTs

NHTs

F

11b (65%)

12b (95%)

OTBS

NHTs

OH

O

NTs

4a

4b

OH

11c (92%)

12c (95%)

NHTs

OH

O

OTBS

NTs

F

OH

12d (93%)

11d (90%)

NHTs

O

OH

OTBS

TsN

7a

OH

12e (94%)

11e (90%)

Figure 1. ORTEP of compound 12e with 35% probability ellipsoid [only one asymmetric

NHTs

OMe

molecule is displayed for clarity]

OTBS

TsN

O

OH

7b

7c

OH

β-Amino alcohol, also known as vicinal amino alcohol or 1,2-

amino alcohol, is privileged motif that serve as an

12f (96%)

11f (87%)

NHTs

a

OTBS

O

OH

indispensable structural unit in a very large number of

bioactive compounds, clinical drugs, agrochemicals, and

TsN

OH

MeO

natural products.⁸However,

β-amino alcohols or their

11g (89%)

12g (95%)

TsHN

derivatives of type 12c-h are yet to be reported. Nonetheless,

introduction of a nitrogen functionality, like an azido group, on

the secondary carbon adjacent to a pre-formed benzoxacycle

ring can appear as a quite simple task by an S_N2 reaction; but it

is actually far from being so trivial. For examples, our attempt

to synthesize 14 by azidation of 13 (synthesized via phenolate

induced diastereo- and regioselective intramolecular epoxide

ring-opening)⁹under Mitsunobu conditions ((PhO)₂P(O)N₃,

DEAD, Ph₃P) was met with complete failure (Scheme 3). S_N2

reactions of tosylate/nosylate/triflate derivatives of 13 with

NaN₃were also disappointing (not shown here), resulting in

either recovery or decomposition of the starting material.

OH

OTBS

O

NTs

10

OH

11h (90%)

12h (89%)

^aReaction conditions: olefin (1.0 equiv), TsNClNa·3H₂O (1.1 equiv),

PTAB (0.1 equiv) for the aziridination step; N-tosylaziridine (1.0 equiv),

TBAF (1.1 equiv) for the ring-opening/cyclization step.

With N-tosylaziridines 11a-h in hand, we were now ready to

study their intramolecular aziridine ring-opening reaction. Our

protocol involved

a typical TBS deprotection reaction

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1

In the H NMR spectrum of 18, while the C2-H appeared as

Moreover, attempted conversion of substrate 15 to compound

16 via protection of the primary –OH group and functional a doublet of doublets of doublets (ddd) at

group interconversion of the secondary –OH group was also 5.0 Hz), the two protons attached to C-3 appeared as doublet

unsuccessful (Scheme 3; details not shown here). Thus, of doublets (dd) at 3.23 (dd, J = 16.5, 9.6 Hz, 1H) and 2.99 (J =

epoxide-ring opening chemistry could not be utilized for the 16.5, 7.0 Hz, 1H) (Figure 2).

synthesis of -amino alcohols or their derivatives of type 12c-

δ 4.82 (J = 9.6, 7.3,

δ

β

h.

N₃

OH

(PhO)₂P(O)N₃

DEAD, Ph₃P

O

CO₂Et

X

THF, 0 ^oC - rt, 12 h

F

13

14 (not formed)

(synthesized via phenolate induced

intramolecular epoxide ring-opening)

OH

N₃

O

OH

O

OP

Figure 2. Structure confirmation of 18 by ¹H NMR.

X

F

P = protecting group

16 (could not be synthesized)

15

(synthesized via phenolate induced

intramolecular epoxide ring-opening)

Had the cyclic product been chroman derivative 18a, the

Scheme 3. Difficulty in the late-stage introduction of nitrogen functionality adjacent to protons attached to C-2, C-3 and C-4 in 18a would have

the chroman ring.

appeared with different chemical shifts and/or different

splitting patterns in the ¹H NMR spectrum. Thus, the

In contrast, the presented phenolate induced diastereo- and

regioselective intramolecular ring-opening of N-tosylaziridines

(Table 1) represents an efficient pathway to access 2-(N-

tosylamido)-2-(benzoxacycle-2-yl)ethanols 12c-h as a new class

of amino alcohol derivatives. For installation of the nitrogen

preferential formation of 2,3-dihydrobenzofuran derivative 18

over chroman derivative 18a was confirmed.

Our final effort was to apply the intramolecular aziridine

ring-opening methodology for the construction of 1,4-

benzodioxane ring. Schemes 5 and 6 summarize our effort

along this direction. First, we attempted NaH-mediated

alkylation of TBS-monoprotected catechol 20¹⁰with known

aziridine derivative 19¹¹(Scheme 5). Unfortunately, the

reaction resulted in complete decomposition of electron rich

20, resulting in inaccessibility of compound 21 which was

supposed to provide 1,4-benzodioxane derivative 22 in the

next planned step of tandem TBS-deprotection and 6-exo-tet

ring opening of epoxide ring by the in situ generated phenolate

anion. Attempts of alkylating 20 with 19 under other reaction

conditions were also met with failure. Given this experimental

outcome, an alternative synthetic approach was necessitated

functionality in the synthesis of

β-amino alcohols or their

derivatives of type 12c-h, our method (Table 1) should be

appealing and practical (compared to other methods like those

mentioned in Scheme 3) as cyclic nature of the aziridine

moiety

renders

competing

elimination

processes

stereoelectronically unfavourable.

Meanwhile, nucleophilic ring opening of vinyl aziridines

have been known to take place at both the two aziridine-

carbon atoms (S_N2 attack), in addition to the double bonded

remote carbon atom (S_N2′ attack).^1dHard nucleophiles

normally provide the S_N2 process whereas soft nucleophiles

often prefer S_N2’ route. We were very much curious about the

possible outcome of the intramolecular nucleophilic attack of

phenolate anion on a vinyl aziridine system. As shown in

Scheme 4, vinyl aziridine derivative 17, prepared by a two-step

reaction sequence^1dinvolving Dess-Martin oxidation of 11d

and Wittig olefination of the resulting crude aldehyde,

underwent phenolate-ion induced smooth intramolecular

aziridine 5-exo-tet ring-opening cyclization to provide 18 as a

sole product in high yield (93%).

for obtaining 22

.

1. Dess–Martin periodinane

OTBS

TBAF, THF, rt

10 min

CH₂Cl₂, rt, 3 h

11d

NTs

CO₂Et

NHTs

2. Ph₃P=CHCO₂Et, CH₂Cl₂

rt, 6 h

F

Scheme 5. Unsuccessful approach to 1,4-benzodioxane derivatives by intramolecular

aziridine ring-opening.

(65% over two steps)

17

CO₂Et

O

x

Ultimately, we decided to alkylate relatively less electron-

rich 2-hydroxy-4-methoxybenzaldehyde 23 with 20 (Scheme

6). This choice was based on a well-established approach of

exploiting aromatic aldehyde/ketone group as a masked

phenolic hydroxyl group.¹²However, reaction between 20 (1

equiv.) and 23 (1 equiv.) mediated by NaH was complex in

O

NTs

F

CO₂Et

(93%)

18

Scheme 4. Synthesis of 2,3-dihydrobenzofuran derivative 18 by intramolecular ring-

opening of vinylaziridine 17.

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nature and we could isolate only aziridine derivative 24 in 34% methodology should be useful in the field of heterocycles.

yield. Clearly, tosylate 20 underwent an S_N2 ring-opening at

the benzylic position of the aziridine ring by the in situ

generated phenolate to yield an intermediate which, in turn,

suffered aziridination via intramolecular S_N2 to produce 24 ¹¹

Experimental section

General information

.

Aziridine derivative 25 might have been produced, but we

could not isolate it in the pure form from the complex reaction

mixture. Nonetheless, compound 24 on Baeyer-Villiger

oxidation with m-CPBA followed by tandem saponification and

6-exo-tet aziridine ring-opening cyclization furnished trans-3,4-

disubstituted-1,4-benzodioxane derivative 26 in high yield. The

trans relationship between the 2-tosylamidomethyl and 3-

phenyl groups was established by the large coupling constant

between the two protons attached to C-2 and C-3 (the proton

All dry reactions were carried out under nitrogen in oven-dried

glassware using standard gas-light syringes, cannulas, and

septa. Commercial reagents were used without further

purification unless otherwise stated. Progress of reactions was

monitored by TLC on precoated Merck silica gel plates (60F-

254). Visualization of reactants and products was

accomplished with UV light. Column chromatography was

performed over silica gel (60–120 mesh) procured from Merck

using freshly distilled solvents. Melting points were

determined with a Buchi-535 apparatus and are not corrected.

Perkin Elmer 20 analyser was utilized for elemental analysis of

attached to C-3 appeared as a doublet with J = 9.1 Hz at

δ

4.80), consistent with that in other trans-2,3-disubstituted-1,4-

benzodioxane derivatives.¹³Such use of a salicyaldehyde

derivative as a surrogate for an unsymmetrically substituted

catechol moiety should allow the stereo- and regioselective

synthesis of diverse 3,4-disubstituted-1,4-benzodioxanes.

1

all compounds. H NMR and ¹³C NMR spectra were run on a

JEOL 400 MHz spectrometer in CDCl₃as solvent. Residual

chloroform (7.27 ppm) served as an internal standard in 1H

NMR and CDCl₃(77.0 ppm) in ¹³C NMR. All spectra were

recorded at 25 °C. Coupling constants (J values) are given in

hertz (Hz). Chemical shifts are expressed in parts per million

(ppm).

OHC

NTs

O

OMe

25 (could not be isolated)

CHO

OH

CHO

O

MeO

O

OTs

MeO

23

NaH, DMF, 0 ^oC - rt, 2h

Preparation of compounds

19

Compounds 1a-d have been prepared following literature

procedures.^14-17

NTs

24 (34%)

N

Ts

1

1. m-CPBA, CH₂Cl₂

3-(2-((tert Butyldimethylsilyl)oxy)phenyl)propane-1,2-diol

(2a). To a stirred mixture of olefin 1a (4.0 g, 16.10 mmol) and

NMO (3.77 g, 32.20 mmol) in acetone (70 mL) and water (10

mL) was added OsO₄(4% w/w in H₂O, 5.6 mL, 0.84 mmol) at

0°C. The reaction mixture was allowed to come to room

temperature and stirred for 6 h. An aqueous saturated NaHSO₃

solution (30 mL) was added to it, and the stirring was

continued for an additional 15 min. Acetone was removed

under reduced pressure and the resulting suspension was then

extracted with EtOAc (50 x 2 mL). The combined organic layers

were washed with brine (50 mL), dried over Na₂SO₄, filtered,

and concentrated under reduced pressure. The resulting crude

product was purified by a silica gel column chromatography

(10-40% EtOAc in hexanes) to obtain diol 2a as a colorless

2

O

0 ^oC - rt, 12 h

NHTs

3

MeO

O

4

2. NaOH, H₂O, THF

0 ^oC - rt, 2h

26 (80% over two steps)

Scheme 6. Studies on the synthesis of 1,4-benzodioxane derivatives by intramolecular

aziridine ring-opening.

Conclusions

In summary, we have developed a new method for the

assembly

of

2,3-dihydrobenzofuran,

chroman,

1,4-

benzodioxane, and 1-benzoxepine skeletons via phenolate-

induced intramolecular ring-opening cyclization of N-

tosylaziridines involving ArO─C bond-forming cyclization under

metal-free conditions. The exo-tet nucleophilic cyclizations

were shown to proceed very rapidly in a completely regio- and

diastereoselective fashion. The ability to synthesize 2-(N-

gum. Yield: 92% (4.18 g); R_f: 0.33 (silica gel, 40% EtOAc in

1

hexanes); H NMR (400 MHz, CDCl₃):

δ 7.18-7.11 (m, 2H), 6.92

(t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 3.98-3.92 (m, 1H),

3.64 (dd, J = 11.4, 3.2 Hz, 1H), 3.48 (dd, J = 11.4, 6.4 Hz, 1H),

2.85-2.74 (m, 2H), 2.51 (brs, 2H), 1.03 (s, 9H), ), 0.26 (s, 6H);

¹³C NMR (100 MHz, CDCl₃):

δ 153.7, 131.5, 128.3, 127.7, 121.4,

118.7, 72.3, 66.1, 34.6, 25.8, 18.2, –4.1; This is a known

compound.¹⁸

tosylamido)-2-(benzoxacycle-2-yl)ethanols

that

are

troublesome, if not impossible, to access by traditional

synthetic routes, is one of the best opportunities now available

to diversify the chemistry of β-amino alcohols. Given the vast

chemistry associated with synthetic applications of

3-(2-((tert-Butyldimethylsilyl)oxy)-5-fluorophenyl)propane

1,2-diol (2b). Olefin 1b (2.0 g, 7.50 mmol) was dihydroxylated

essentially in the same manner as described for the

functionalized benzoxacycles, we anticipate that this

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dihydroxylation of 1a. The crude product was purified by a 23.0 Hz), 113.8 (d, J = 23.0 Hz), 60.2, 32.9, 25.7, 18.2, 14.2, -

silica gel column chromatography (10-40% EtOAc in hexanes) 4.2.

to obtain diol 2b as a colorless gum. Yield: 90% (2.03 g); R_f:

0.29 (silica gel, 40% EtOAc in hexanes); ¹H NMR (400 MHz,

(E)-4-(2-((tert-Butyldimethylsilyl)oxy)phenyl)but-2-en-1-ol

CDCl₃):

δ 6.90 (dd, J = 8.7, 3.2 Hz, 1H), 6.81 (td, J = 8.3, 3.2 Hz, (4a). To a stirred solution of compounds 3a and its cis isomer

1H), 6.74 (dd, J = 8.7, 4.6 Hz, 1H), 3.96–3.90 (m, 1H), 3.63 (dd, J (as obtained from the Wittig olefination reaction; 1.0 g, 3.12

= 11.4, 3.2, 1H), 3.47 (dd, J = 11.4, 6.9, 1H), 2.80-2.71 (m, 3H), mmol) in dry CH₂Cl₂(20 mL) at 0 °C under nitrogen was added

2.49 (br. s, 1H), 1.01 (s, 9H), 0.23 (s, 6H); ¹³C NMR (100 MHz, DIBAL-H (7.8 mL, 1.0 M in CH₂Cl₂, 7.8 mmol). The solution was

CDCl₃): δ 157.2 (d, J = 239.6 Hz), 149.6, 130.1 (d, J = 7.7 Hz), stirred at this temperature for 2 h. The reaction was quenched

119.3 (d, J = 8.6 Hz), 117.7 (d, J = 22.0 Hz), 113.8 (d, J = 23.0 by careful addition of methanol (2 mL) and then allowed to

Hz), 72.1, 66.0, 34.5, 25.7, 18.2, −4.2; Anal. Calcd for warm to room temperature. Saturated aq. potassium sodium

C₁₅H₂₅FO₃Si: C, 59.97; H, 8.39, found: C, 59.89; H, 8.36.

tartrate (15 mL) and EtOAc (80 mL) were added and the

mixture was stirred vigorously for 1 hour. The phases were

(E)-Ethyl 4-(2-((tert-butyldimethylsilyl)oxy)phenyl)but-2- then separated and the aqueous phase was extracted with

enoate (3a). To an ice-cooled solution of diol 2a (4.0 g, 14.16 EtOAc (25 x 2 mL). The combined organic layers were washed

mmol) in methanol (50 mL) was added a solution of NaIO₄with brine (50 mL), dried over Na₂SO₄, filtered, and

(4.54 g, 21.24 mmol) in water (25 mL). After stirring the concentrated under reduced pressure. The resulting crude

reaction mixture at 0 °C for 2 h, methanol was evaporated product was purified by a silica gel column chromatography (5-

under reduced pressure. The resulting suspension was 15% EtOAc in hexanes) to afford an inseparable mixture of

extracted with CH₂Cl₂(50 x 2 mL). The combined organic layers trans-α,β-unsaturated alcohol 4a and its cis isomer as a

were washed with brine (50 mL), dried over Na₂SO₄, filtered, colorless gum (trans : cis = 4.2 : 1). Yield: 95% (825 mg); R_f:

and concentrated under reduced pressure to obtain the 0.37 (silica gel, 20 % EtOAc in hexanes); ¹H NMR (400MHz,

corresponding crude aldehyde (3.35 g) as a colorless gum CDCl₃, only peaks for the trans isomer are reported): δ 7.16-

which was used for the next step without further purification. 7.09 (m, 2H), 6.92 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H),

To a stirred solution of the above crude aldehyde in 5.91-5.84 (m, 1H), 5.72-5.65 (m, 1H), 4.11 (d, J = 5.5 Hz, 2H),

dichloromethane (50 mL), was added (carbethoxymethylene) 3.39 (d, J = 6.9 Hz, 2H), 1.76 (br. s, 1H), 1.05 (s, 9H), 0.26 (s,

triphenylphosphorane (6.17 g, 17.70 mmol) and the reaction 6H); ¹³C NMR (100 MHz, CDCl₃, only peaks for the trans isomer

was further stirred for an additional 2 h. Removal of the are reported):

δ 153.2, 131.2, 130.6, 130.1, 129.9, 127.1,

solvent under reduced pressure gave the crude product which 121.1, 118.4, 63.5, 32.9, 25.7, - 4.2.

was purified by silica gel column chromatography (0-5% ethyl

acetate in hexanes) to afford an inseparable mixture of trans-

(E)-4-(2-((tert-Butyldimethylsilyl)oxy)-5-fluorophenyl)but-2-

α,β-unsaturated ester 3a and its cis isomer as a colorless oil en-1-ol (4b). A mixture of esters 3b and its cis isomer (as

(trans : cis = 4.2 : 1). Yield (over two steps): 80% (3.62 g); R_f: obtained from the Wittig olefination reaction; 1.0 g, 2.95

0.52 (silica gel, 15% EtOAc in hexanes); ¹H NMR (only peaks for mmol) were subjected to DIBAL-H reduction essentially in the

the trans isomer are reported, 400MHz, CDCl₃): δ 7.15- 7.10 same manner as described for the synthesis of 4a. The crude

(m, 3H), 6.90 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.77 (d, product was purified by silica gel column chromatography (5-

J = 15.6 1H), 4.17 (q, J = 7.3 Hz, 2H), 3.51 (d, J = 5.9 Hz, 2H), 15% ethyl acetate in hexanes) to afford an inseparable mixture

1.27 (t, J = 7.3 Hz, 3H), 1.01 (s, 9H), 0.25 (s, 6H); ¹³C NMR (only of trans-

peaks for the trans isomer are reported, 100 MHz, CDCl₃):

166.6, 153.5, 147.3, 130.5, 128.4, 127.7, 121.9, 121.2, 118.4, 0.32 (silica gel, 20% EtOAc in hexanes); ¹H NMR (only peaks for

60.1, 33.0, 25.7, 18.2, 14.2, - 4.2. the trans isomer are reported, 400MHz, CDCl₃): 6.85- 6.70

α

,

β

-unsaturated alcohol 4b and its cis isomer as a

δ

colorless gum (trans : cis = 4.1 : 1). Yield: 94% (828 mg); R_f:

δ

(E)-Ethyl 4-(2-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl) (m, 3H), 5.86-5.77 (m, 1H), 5.72-5.66 (m, 1H), 4.12 (dd, J = 5.0

but-2-enoate (3b). Diol 2b (4.0 g, 13.31 mmol) was subjected Hz, 2H), 3.34 (d, J = 6.4 Hz, 2H), 1.65 (br. s, 1H), 1.01 (s, 9H),

to NaIO₄oxidation─Wiꢁg oleﬁnaꢀon reacꢀon sequence 0.22 (s, 6H); ¹³C NMR (only peaks for the trans isomer are

essentially in the same manner as described for the synthesis reported, 100 MHz, CDCl₃):

δ 157.3 (d, J = 238.7 Hz), 149.2,

of 3a. The crude product was purified by silica gel column 132.2 (d, J = 7.7 Hz), 130.7, 130.2, 119.0 (d, J = 7.7 Hz), 116.3

chromatography (0-5% ethyl acetate in hexanes) to afford an (d, J = 23.0 Hz), 113.1 (d, J = 23.0 Hz), 63.5, 32.8, 25.7, -4.2.

inseparable mixture of trans-α,β-unsaturated ester 3b and its

cis isomer as a colorless oil (trans : cis = 4.1 : 1). Yield (over the 3-(2-((tert-Butyldimethylsilyl)oxy)phenyl)propan-1-ol (5a). To

two steps): 82% (3.69 g); R_f: 0.47 (silica gel, 15% EtOAc in stirred solution of 1a (1.5 g, 6.04 mmol) in anhydrous THF (30

hexanes); ¹H NMR (only peaks for the trans isomer are mL) was added 9-BBN (0.5 M solution in THF, 25.0 mL, 12.5

reported, 400 MHz, CDCl₃):

δ 7.10- 7.03 (m, 1H), 6.82-6.72 (m, mmol) dropwise under a nitrogen atmosphere at 0 °C. The

3H), 5.77 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.3 Hz, 2H), 3.47 (d, J mixture was then stirred at room temperature for 6 h. The

= 5.5 Hz, 2H), 1.27 (t, J = 7.3 Hz, 3H), 0.99 (s, 9H), 0.22 (s, 6H); reaction was carefully terminated by the addition of H₂O (2

¹³C NMR (only peaks for the trans isomer are reported, 100 mL) at 0 °C. Next, 1 M NaOH solution (15 mL) and 30% H₂O₂

MHz, CDCl₃): δ 166.4, 157.1 (d, J = 239.6 Hz), 149.4, 146.2, (10 mL) were added to it sequentially and the reaction mixture

129.8 (d, J = 6.7 Hz), 122.5, 119.0 (d, J = 8.6 Hz), 116.8 (d, J = was stirred for an additional 12 h at rt. The reaction mixture

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was then partitioned between brine (40 mL) and EtOAc (40 the resultant crude product was subjected to further

mL). The layers were separated and the aqueous phase was purification involving a silica gel column chromatography (0-

extracted with EtOAc (20 mL). The combined organic extracts 5% ethyl acetate in hexanes) to afford trans-α,β-unsaturated

were washed with brine, dried over anhydrous Na₂SO₄, ester 6a as a colorless oil. Yield (over the two steps): 74% (929

filtered, and concentrated under reduced pressure. The crude mg); R_f: 0.49 (silica gel, 15% EtOAc in hexanes); ¹H NMR (400

product was purified by silica gel column chromatography (5- MHz, CDCl₃):

δ 7.00 (dt, J = 15.9, 7.2 Hz, 1H), 6.71-6.60 (m, 3

15% ethyl acetate in hexanes) to afford the title compound 5a H), 5.83 (d, J = 15.9 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.73 (s,

as a colorless oil. Yield: 93% (1.49 g); R_f: 0.39 (silica gel, 25% 3H), 2.70 (t, J = 7.2 Hz, 2H), 2.48 (td, J = 7.9, 7.0 Hz, 2H), 1.27 (t,

EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

δ

7.4, 1.7 Hz, 1H), 7.08 (td, J = 7.8, 1.8 Hz, 1H), 6.89 (td, J = 7.4, CDCl₃):

7.15 (dd, J = J = 7.2 Hz, 3H), 1.01 (s, 9H), 0.21 (s, 6H); ¹³C NMR (100 MHz,

166.8, 154.0, 149.8, 132.2, 130.5, 127.7, 121.5, 118.7,

δ

1.1 Hz, 1H), 6.80 (dd, J = 8.1, 1.0 Hz, 1H), 3.62 (t, J = 6.1 Hz, 60.2, 33.0, 29.5, 26.2, 18.5, 14.5, −4.1; Spectroscopic data

2H), 2.74–2.64 (m, 2H), 1.92–1.80 (m, 2H), 1.58 (t, J = 5.3 Hz, were consistent with those previously reported.²¹

1H), 1.02 (s, 9H), 0.24 (s, 6H); Spectroscopic data were

consistent with those previously reported.¹⁹

(

E)-Ethyl

5-(2-((tert-Butyldimethylsilyl)oxy)-5-

methoxyphenyl)pent-2-enoate (6b). Compound 5b (1.0 g, 3.37

mmol) was subjected to sequential PCC oxidation─Wiꢁg

3-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxyphenyl)propan-

1-ol (5b). Compound 1c (1.5 g, 5.38 mmol) was subjected to olefination essentially in the same manner as described for the

hydroboration (9-BBN)─oxidaꢀon (H₂O₂, NaOH) essentially in synthesis of 6a. The crude product was purified by silica gel

the same manner as described for the synthesis of 5a. The column chromatography (0-8% ethyl acetate in hexanes) to

crude product was purified by silica gel column afford trans-

chromatography (5-15% ethyl acetate in hexanes) to afford the (over the two steps): 73% (897 mg); R_f: 0.41 (silica gel, 15%

title compound 5b as a colorless oil. Yield: 94% (1.49 g); R_f: EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

7.02 (dt, J =

0.37 (silica gel, 25% EtOAc in hexanes); ¹H NMR (400 MHz, 16.0, 6.4 Hz, 1H), 6.84 (dd, J = 8.7, 7.3 Hz, 1H), 6.74 (d, J = 7.8

CDCl₃): 6.86 (t, J = 7.8 Hz, 1H), 6.77 (dd, J = 7.8, 1.8 Hz, 1H), Hz, 1H), 5.86 (d, J = 16.0 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.79

6.73 (dd, J = 7.8, 1.4 Hz, 1H), 3.79 (s, 3H), 3.61 (t, J = 6.4 Hz, (s, 3H), 2.79 (t, J = 7.3 Hz, 2H), 2.52-2.47 (m, 2H), 1.30 (t, J = 7.2

2H), 2.74 (t, J = 7.3 Hz, 2H), 1.90–1.83 (m, 3H), 1.02 (s, 9H), Hz, 3H), 1.01 (s, 9H), 0.20 (s, 6H); ¹³C NMR (100 MHz, CDCl₃):

0.20 (s, 6H); ¹³C NMR (100 MHz, CDCl₃):

149.8, 142.7, 132.9, 166.7, 149.8, 148.6, 142.7, 132.1, 121.7, 121.4, 120.7, 109.5,

α,β-unsaturated ester 6b as a colorless oil. Yield

δ

121.9, 120.9, 109.1, 62.1, 54.6, 32.9, 26.3, 26.1, 18.9, −3.9; 60.1, 54.7, 32.6, 29.1, 26.1, 18.8, 14.2, -3.8; Anal. Calcd. for

Anal. Calcd. for C₁₆H₂₈O₃Si: C, 64.82; H, 9.52, found: C, 64.96; C₂₀H₃₂O₄Si: C, 65.89; H, 8.85, found: C, 65.76; H, 8.89.

H, 9.61.

(E)-Ethyl

5-(2-((tert-Butyldimethylsilyl)oxy)-5-

3-(2-((tert-Butyldimethylsilyl)oxy)-5-methoxyphenyl)propan-

methoxyphenyl)pent-2-enoate (6c). Compound 5c (1.0 g, 3.37

1-ol (5c). Compound 1d (1.5 g, 5.38 mmol) was subjected to mmol) was subjected to sequential PCC oxidation─Wiꢁg

hydroboration (9-BBN)─oxidaꢀon (H₂O₂, NaOH) essentially in olefination essentially in the same manner as described for the

the same manner as described for the synthesis of 5a. The synthesis of 6a. The crude product was purified by silica gel

crude product was purified by silica gel column column chromatography (0-8% ethyl acetate in hexanes) to

chromatography (5-15% ethyl acetate in hexanes) to afford the afford trans-

title compound 5c as a colorless oil. Yield: 91% (1.45 g); R_f: 0.35 (over the two steps): 72% (885 mg); R_f: 0.41 (silica gel, 15%

(silica gel, 25% EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃): EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

7.00 (dt, J =

α,β-unsaturated ester 6c as a colorless oil. Yield

δ

6.72-6.58 (m, 3H), 3.72 (s, 3H), 3.60 (t, J = 6.3 Hz, 2H), 2.66 (t, J 15.9, 7.2 Hz, 1H), 6.71-6.60 (m, 3 H), 5.83 (d, J = 15.9 Hz, 1H),

= 7.4 Hz, 2H), 1.90–1.85 (m, 2H), 1.71 (s, 1ꢂH), 1.02 (s, 9H), 0.21 4.17 (q, J = 7.2 Hz, 2H), 3.73 (s, 3H), 2.70 (t, J = 7.2 Hz, 2H), 2.48

(s, 6H); ¹³C NMR (100 MHz, CDCl₃):

δ

154.3, 147.7, 133.5, (td, J = 7.9, 7.0 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.01 (s, 9H),

119.5, 116.2, 111.9, 62.5, 56.0, 33.4, 27.1, 26.2, 18.6, −3.8; 0.21 (s, 6H); ¹³C NMR (100 MHz, CDCl₃):

δ

Spectroscopic data were consistent with those previously 147.8, 132.6, 122.0, 119.3, 116.1, 112.2, 60.5, 56.0, 33.0, 29.9,

167.1, 154.2, 148.8,

reported.^17,20

26.2, 18.6, 14.7, −3.8; Spectroscopic data were consistent with

those previously reported.²⁰

(E)-Ethyl

5-(2-((tert-Butyldimethylsilyl)oxy)phenyl)pent-2-

enoate (6a). To an ice-cooled mixture of 5a (1.0 g, 3.75 mmol) (E)-5-(2-((tert-Butyldimethylsilyl)oxy)phenyl)pent-2-en-1-ol

and Celite® (500 mg) in anhydrous CH₂Cl₂(20 mL) was added (7a). Compound 6a (500 mg, 1.49 mmol) was subjected to

PCC (1.21 g, 5.63 mmol) under an atmosphere of nitrogen. The DIBAL-H reduction essentially in the same manner as described

reaction was stirred vigorously for 4h at rt. for the synthesis of 4a. The resulting crude product was

(Carbethoxymethylene)triphenylphosphorane (1.74 g, 5.0 purified by silica gel column chromatography (5-15% EtOAc in

mmol) was then added and the reaction was further stirred for hexanes) to obtain the title compound 7a as a colorless oil.

6h at rt. The reaction mixture was concentrated under reduced Yield: (415 mg, 95%); R_f: 0.44 (silica gel, 25% EtOAc in

pressure. The resulting residue was suspended in hexanes); ¹H NMR (400 MHz, CDCl₃):

δ 7.15 (dd, J = 7.4 and 1.6

EtOAc/hexanes (1:1, 50 mL), stirred vigorously for 10 min and Hz, 1H), 7.09 (td, J = 7.8, 1.8 Hz, 1H), 6.89 (td, J = 7.4 and 1.1

filtered. Filtrate was concentrated under reduced pressure and Hz, 1H), 6.80 (dd, J = 8.1, 1.0 Hz, 1H), 5.81-5.56 (m, 2H), 4.06

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(d, J = 5.6 Hz, 2H), 2.67 (t, J = 7.9 Hz, 2H), 2.36-2.30 (m, 2H), to sequential PCC oxidation─Wiꢁg oleﬁnaꢀon essenꢀally in

1.43 (br s, 1H), 1.04 (s, 9H), 0.24 (s, 6H); ¹³C NMR (100 MHz, the same manner as described for the synthesis of 6a. The

CDCl₃):

63.6, 32.5, 30.2, 25.7, 18.1, -3.9; Spectroscopic data were chromatography (0-5% ethyl acetate in hexanes) to afford

consistent with those previously reported.²¹

trans- -unsaturated ester as a colorless semi-solid. Yield

(over the two steps): 74% (460 mg); R_f: 0.52 (silica gel, 15%

δ 153.4, 132.7, 132.1, 130.1, 129.2, 126.8, 119.9, 118.2, crude product was purified by silica gel column

α

,β

9

1

(E)-5-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxyphenyl)pent- EtOAc in hexanes); H NMR (400 MHz, CDCl₃):

δ 7.12-7.06 (m,

2-en-1-ol (7b). Compound 6b (500 mg, 1.37 mmol) was 2H), 7.03-6.95 (m, 1H), 6.88 (t, J = 7.3 Hz, 1H), 6.79 (d, J = 7.8

subjected to DIBAL-H reduction essentially in the same manner Hz, 1H), 5.83 (d, J = 15.6 Hz, 1H), 4.19 (q, J = 7.3 Hz, 2H), 2.62

as described for the synthesis of 4a. The resulting crude (t, J = 7.3 Hz, 2H), 2.23 (q, J = 7.3 Hz, 2H), 1.79-1.72 (m, 2H),

product was purified by silica gel column chromatography (5- 1.29 (t, J = 7.2 Hz, 3H), 1.02 (s, 9H), 0.24 (s, 6H); ¹³C NMR (100

15% EtOAc in hexanes) to obtain the title compound 7b as a MHz, CDCl₃):

colorless oil. Yield: (419 mg, 95%); R_f: 0.35 (silica gel, 25% 120.9, 118.4, 60.1, 32.0, 30.1, 28.3, 25.8, 18.2, 14.3, −4.2; Anal.

EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

6.84 (t, J = 7.8 Calcd for C₂₀H₃₂O₃Si: C, 68.92; H, 9.25, found C, 68.81; H, 9.31.

δ 166.7, 153.5, 149.1, 132.3, 130.1, 126.9, 121.5,

δ

Hz, 1H), 6.75-6.72 (m, 2H), 5.79-5.62 (m, 2H), 4.08 (d, J = 5.5

Hz, 2H), 3.77 (s, 3H), 2.72 (t, J = 8.0 Hz, 2H), 2.37-2.31 (m, 2H), (E)-6-(2-((tert-Butyldimethylsilyl)oxy)phenyl)hex-2-en-1-ol

1.35 (br s, 1H), 1.01 (s, 9H), 0.19 (s, 6H); ¹³C NMR (100 MHz, (10). Compound

9

(401 mg, 1.15 mmol) was subjected to

149.9, 142.7, 133.0, 129.9, 129.2, 121.9, 120.6, 109.2, DIBAL-H reduction essentially in the same manner as described

63.8, 54.7, 32.7, 30.2, 26.1, 18.9, -3.8; Anal. Calcd. for for the synthesis of 4a. The resulting crude product was

CDCl₃):

δ

C₁₈H₃₀O₃Si: C, 67.03; H, 9.38, found: C, 67.21; H, 9.34.

purified by silica gel column chromatography (5-10% EtOAc in

hexanes) to obtain the title compound 10 as a colorless semi-

(E)-5-(2-((tert-Butyldimethylsilyl)oxy)-5-methoxyphenyl)pent- solid. Yield: (331 mg, 94%); R_f: 0.52 (silica gel, 25% EtOAc in

1

2-en-1-ol (7c). Compound 6c (500 mg, 1.37 mmol) was hexanes); H NMR (400 MHz, CDCl₃):

δ 7.14-7.06 (m, 2H), 6.88

subjected to DIBAL-H reduction essentially in the same manner (t, J = 7.3 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 5.76-5.60 (m, 2H),

as described for the synthesis of 4a. The resulting crude 4.09 (d, J = 5.5 Hz, 2H), 2.60 (t, J = 7.8 Hz, 2H), 2.10 (q, J = 7.3

product was purified by silica gel column chromatography (5- Hz, 2H), 1.72-1.64 (m, 2H), 1.26 (t, J = 7.6 Hz, 1 H); 1.03 (s, 9H),

15% EtOAc in hexanes) to obtain the title compound 7c as a 0.24 (s, 6H); ¹³C NMR (100 MHz, CDCl₃):

colorless oil. Yield: (416 mg, 94%); R_f: 0.32 (silica gel, 25% 130.1, 129.1, 126.7, 120.9, 118.3, 63.8, 32.2, 30.1, 29.4, 25.8,

EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

6.72-6.59 (m, 18.2, -4.2; Anal. Calcd for C₁₈H₃₀O₂Si: C, 70.53; H, 9.87, found C,

δ 153.5, 133.2, 132.9,

δ

3H), 5.75-5.62 (m, 2H), 4.08 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H), 70.68; H, 9.93.

2.73 (t, J = 7.8 Hz, 2H), 2.36-2.29 (m, 2H), 1.38 (br s, 1H), 1.03 General Procedure A: Aziridination of alkenes by Sharpless

(s, 9H), 0.22 (s, 6H); ¹³C NMR (100 MHz, CDCl₃):

δ 153.4, 147.1, aziridination method. To a stirred mixture of chloramine-T

133.0, 132.3, 129.1, 118.0, 115.6, 111.1, 63.4, 55.4, 32.3, 30.3, trihydrate (1.1 equiv) and an appropriate alkene (1.0 equiv) in

25.6, 18.0, -4.2; Spectroscopic data were consistent with those CH₃CN (5 mL/mmol) was added phenyltrimethylammonium

previously reported.²⁰

tribromide (PTAB) (0.1 equiv) at room temperature. The

reaction was stirred vigorously for 15 h and then concentrated

under reduced pressure. The resulting residue was dissolved in

CH2Cl2 and filtered through a short column of silica gel (eluted

with 30% EtOAc in hexanes). After removal of the solvent, the

resultant crude product was subjected to further purification

involving a silica gel column chromatography (EtOAc/hexanes)

to give the corresponding aziridine product.

4-(2-((tert-Butyldimethylsilyl)oxy)phenyl)butan-1-ol (8).

A

mixture of 4a (600 mg, 2.15 mmol) and 10% Pd-C (75 mg) in

EtOAc (15 mL) was stirred for 12 h at room temperature under

pressure of a hydrogen balloon. The reaction mixture was

filtered through a pad of Celite® and the filter pad was well-

washed with EtOAc. The filtrates were combined and

concentrated under reduced pressure. The resulting crude

product was purified by silica gel column chromatography (5-

2-(2-((tert-Butyldimethylsilyl)oxy)benzyl)-1-tosylaziridine

(11a). Following the General Procedure A, compound 1a (745

mg, 3.0 mmol) was subjected to the Sharpless aziridination

reaction. The resulting crude product was purified by silica gel

column chromatography (2-12% EtOAc in hexanes) to obtain

15% ethyl acetate in hexanes) to afford the title compound

8

as a colorless oil. Yield (over two steps): 93% (562 mg); R_f: 0.42

(silica gel, 25% EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

δ

7.14 (dd, J = 7.3, 1.7 Hz, 1H), 7.07 (td, J = 8.2, 1.8 Hz, 1H),

the title compound 11a as a light yellow gum

62%); R_f: 0.49 (silica gel, 20% EtOAc in hexanes); H NMR (400

MHz, CDCl₃): 7.68 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H),

. Yield: (777 mg,

6.88 (t, J = 7.3 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 3.66 (t, J = 6.4

Hz, 2H), 2.63 (t, J = 6.9 Hz, 2H), 1.68-1.62 (m, 4H), 1.35 (br s,

1H), 1.03 (s, 9H), 0.24 (s, 6H); ¹³C NMR (100 MHz, CDCl₃):

1

δ

7.04 (td, J = 7.8, 1.8 Hz, 1H), 6.93 (dd, J = 7.8, 1.8 Hz, 1H), 6.72-

6.68 (m, 2H), 3.04-2.98 (m, 1H), 2.81 (dd, J = 14.2, 5.5 Hz, 1H),

2.70 (d, J = 6.9 Hz, 1H), 2.63 (dd, J = 14.2, 6.9 Hz, 1H), 2.41 (s,

3H), 2.16 (d, J = 4.6 Hz, 1H), 1.01 (s, 9H), 0.24 (s, 3H), 0.23 (s,

δ

153.5, 132.8, 130.1, 126.7, 120.9, 118.4, 63.0, 32.7, 30.3,

26.2, 25.8, 18.2, -4.2. Anal. Calcd for C₁₆H₂₈O₂Si: C, 68.52; H,

10.06, found C, 68.59; H, 10.09.

3H); ¹³C NMR (100 MHz, CDCl₃):

δ 153.4, 144.1, 130.7, 129.5,

127.7, 127.62, 127.57, 121.0, 118.1, 40.3, 32.9, 32.4, 25.8,

(E)-Ethyl

6-(2-((tert-butyldimethylsilyl)oxy)phenyl)hex-2-

(500 mg, 1.78 mmol) was subjected

enoate (9). Compound

8

8 | Org. Biomol. Chem., 2018, 00, xx-xx

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21.6, -4.1; Anal. Calcd. for C₂₂H₃₁NO₃SSi: C, 63.27; H, 7.48; N, CDCl₃):

δ 156.8 (d, J = 239.6 Hz), 149.4 (d, J = 1.9 Hz), 144.2,

3.35, found: C, 63.38; H, 7.52; N, 3.31.

136.5, 129.5, 129.4 (d, J = 7.7 Hz), 127.2, 118.7 (d, J = 8.6 Hz),

117.0 (d, J = 23.0 Hz), 113.9 (d, J = 23.0 Hz), 60.7, 51.7, 45.5,

32.0, 25.7, 21.5, 18.2, -4.2, -4.3; Anal. Calcd. for C₂₃H₃₂FNO₄SSi:

2-(2-((tert-Butyldimethylsilyl)oxy)-5-fluorobenzyl)-1-

tosylaziridine (11b). Following the General Procedure A, C, 59.32; H, 6.93; N, 3.01, found: C, 59.19; H, 6.86; N, 3.07.

compound 1b (799 mg, 3.0 mmol) was subjected to the

Sharpless aziridination reaction. The resulting crude product ((2R*,3S*)-3-(2-((tert-Butyldimethylsilyl)oxy)phenethyl)-1-

was purified by silica gel column chromatography (2-12% tosylaziridin-2-yl)methanol (11e). Following the General

EtOAc in hexanes) to obtain the title compound 11b as a light Procedure A, compound 7a (293 mg, 1.0 mmol) was subjected

yellow gum

.

Yield: (850 mg, 65%); R_f: 0.45 (silica gel, 20% to the Sharpless aziridination reaction. The resulting crude

7.64 (d, J = 8.2 product was purified by silica gel column chromatography (5-

EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

δ

Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.69 (td, J = 8.7, 3.2 Hz, 1H), 15% EtOAc in hexanes) to obtain the title compound 11e as a

6.61 (dd, J = 9.1, 5.0 Hz, 1H), 6.52 (dd, J = 8.7, 3.2 Hz, 1H), 2.95- colorless gum. Yield: (416 mg, 90%); R_f: 0.43 (silica gel, 30%

2.89 (m, 2H), 2.77 (d, J = 6.4 Hz, 1H), 2.41 (s, 3H), 2.36 (dd, J = EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

δ

7.85 (d, J = 8.2

15.1, 9.2 Hz, 1H), 2.17 (d, J = 4.1 Hz, 1H), 1.00 (s, 9H), 0.23 (s, Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.10-7.04 (m, 2H), 6.87 (t, J =

3H), 0.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

156.6 (d, J_C-F7.8 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 3.92-3.73 (m, 2H), 2.96-

δ

=

239.6 Hz), 149.2 (d, J_C-F= 1.9 Hz), 144.3, 134.5, 129.5, 129.3 (d, 2.92 (m, 1H), 2.81-2.71 (m, 1H), 2.68-2.53 (m, 3H), 2.44 (s, 3H),

J_C-F= 6.7 Hz), 127.6, 118.5 (d, J_C-F= 8.6 Hz), 117.1 (d, J_C-F= 23.0 2.01-1.85 (m, 2H), 0.99 (s, 9H), 0.22 (s, 3H), 0.21 (s, 3H); ¹³C

Hz), 113.6 (d, J_C-F= 23.0 Hz), 40.2, 32.4 (d, J_C-F= 7.7 Hz), 25.8, NMR (100 MHz, CDCl₃): δ 153.5, 144.2, 137.3, 130.9, 130.3,

21.5, 18.2, -4.2; Anal. Calcd. for C₂₂H₃₀FNO₃SSi: C, 60.66; H, 129.6, 127.4, 127.3, 121.2, 118.6, 61.0, 51.6, 46.2, 30.3, 28.3,

6.94; N, 3.22, found: C, 60.78; H, 6.99; N, 3.15.

25.8, 21.6, 18.2, -4.2; Anal. Calcd. for C₂₄H₃₅NO₄SSi: C, 62.44; H,

7.64; N, 3.03, found: C, 62.56; H, 7.69; N, 3.07.

((2R*,3S*)-3-(2-((tert-Butyldimethylsilyl)oxy)benzyl)-1-

tosylaziridin-2-yl)methanol (11c). Following the General

Procedure A, a mixture of compound 4a and its cis isomer (as ((2R*,3S*)-3-(2-((tert-Butyldimethylsilyl)oxy)-3-

obtained from the DIBAL-H reduction; 557 mg, 2.0 mmol) was methoxyphenethyl)-1-tosylaziridin-2-yl)methanol

(11f).

subjected to the Sharpless aziridination reaction. The resulting Following the General Procedure A, compound 7b (323 mg, 1.0

crude product was purified by silica gel column mmol) was subjected to the Sharpless aziridination reaction.

chromatography (5-15% EtOAc in hexanes) to obtain the title The resulting crude product was purified by silica gel column

compound 11c as a colorless gum

. Yield: (665 mg, 92%; chromatography (5-15% EtOAc in hexanes) to obtain the title

calculated with respect to the starting E-isomer); R_f: 0.41 (silica compound 11f as a colorless gum. Yield: (428 mg, 87%); R_f:

7.62 0.35 (silica gel, 30% EtOAc in hexanes); ¹H NMR (400 MHz,

7.85 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 6.83 (t,

1

gel, 30% EtOAc in hexanes); H NMR (400 MHz, CDCl₃):

δ

(d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.09 (td, J = 8.2, 1.8 CDCl₃):

δ

Hz, 1H), 6.85 (d, J = 6.4 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.70 (t, J = 7.8 Hz, 1H), 6.72 (d, J = 6.8 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H),

J = 7.3 Hz, 1H), 4.13-4.08 (m, 1H), 3.98-3.89 (m, 1H), 3.31-3.27 3.91-3.77 (m, 5H), 2.96-2.91 (m, 1H), 2.79-2.75 (m, 1H), 2.69-

(m, 1H), 3.06-3.02 (m, 1H), 2.94 (dd, J = 14.2, 5.5 Hz, 1H), 2.83- 2.62 (m, 3H), 2.43 (s, 3H), 2.05-1.83 (m, 2H), 0.98 (s, 9H), 0.17

2.82 (m, 1H), 2.70 (dd, J = 14.2, 7.3 Hz, 1H), 2.43 (s, 3H), 1.01 (s, 3H), 0.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

(s, 9H), 0.25 (s, 3H), 0.24 (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

142.6, 137.2, 131.6, 129.6, 127.2, 121.9, 120.9, 109.6, 61.0,

δ 144.9, 144.1,

δ

153.5, 143.9, 136.9, 130.6, 129.5, 127.8, 127.7, 127.2, 121.1, 54.6, 51.4, 46.3, 30.4, 28.0, 26.1, 21.5, 18.8, -3.9; Anal. Calcd.

118.2, 60.9, 51.6, 46.0, 31.7, 25.8, 21.6, 18.2, -4.2; HRMS for C₂₅H₃₇NO₅SSi: C, 61.07; H, 7.58; N, 2.85, found: C, 61.22; H,

(ESI/[M+H]⁺) Calcd. for C₂₃H₃₄NO₄SSi: 448.1978, found 7.52; N, 2.81.

448.1982.

((2R*,3S*)-3-(2-((tert-Butyldimethylsilyl)oxy)-5-

((2R*,3S*)-3-(2-((tert-Butyldimethylsilyl)oxy)-5-fluorobenzyl)- methoxyphenethyl)-1-tosylaziridin-2-yl)methanol

(11g).

1-tosylaziridin-2-yl)methanol (11d). Following the General Following the General Procedure A, compound 7c (323 mg, 1.0

Procedure A, a mixture of compound 4b and its cis isomer (as mmol) was subjected to the Sharpless aziridination reaction.

obtained from the DIBAL-H reduction; 593 mg, 2.0 mmol) was The resulting crude product was purified by silica gel column

subjected to the Sharpless aziridination reaction. The resulting chromatography (5-15% EtOAc in hexanes) to obtain the title

crude product was purified by silica gel column compound 11g as a colorless gum. Yield: (437 mg, 89%); R_f:

chromatography (5-15% EtOAc in hexanes) to obtain the title 0.32 (silica gel, 30% EtOAc in hexanes); ¹H NMR (400 MHz,

compound 11d as a colorless semi-solid. Yield: (674 mg, 90%; CDCl₃): δ 7.84 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 6.69-

calculated with respect to the starting E-isomer); R_f: 0.38 (silica 6.60 (m, 3H), 3.93-3.88 (m, 1H), 3.79-3.73 (m, 4H), 2.96-2.92

1

gel, 20% EtOAc in hexanes); H NMR (400 MHz, CDCl₃):

(d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 6.74 (td, J = 8.7, 3.2 1.99-1.81 (m, 2H), 0.97 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H); ¹³C

Hz, 1H), 6.67 (dd, J = 8.7, 5.5 Hz, 1H), 6.42 (dd, J = 8.7, 5.5 Hz, NMR (100 MHz, CDCl₃): 153.8, 147.2, 144.2, 137.3, 131.8,

δ 7.58 (m, 1H), 2.81-2.78 (m, 1H), 2.63-2.51 (m, 3H), 2.43 (s, 3H),

δ

1H), 4.18-4.11 (m, 1H), 4.01-3.94 (m, 1H), 3.27-3.23 (m, 1H), 129.6, 127.3, 119.1, 115.8, 112.0, 61.0, 55.6, 51.6, 46.1, 30.4,

3.05-3.00 (m, 2H), 2.88 (dd, J = 9.6, 4.6 Hz, 1H), 2.45-2.42 (m, 28.5, 25.8, 21.6, 18.1, -4.2; Anal. Calcd. for C₂₅H₃₇NO₅SSi: C,

4H), 1.00 (s, 9H), 0.25 (s, 3H), 0.22 (s, 3H); ¹³C NMR (100 MHz, 61.07; H, 7.58; N, 2.85, found: C, 61.17; H, 7.63; N, 2.89.

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mg, 95%); mp: 145–147 °C; R_f: 0.32 (silica gel, 40% EtOAc in

1

hexanes); H NMR (400 MHz, CDCl₃):

δ 7.74 (d, J = 8.2 Hz, 2H),

((2R*,3S*)-3-(3-(2-((tert-

7.31 (d, J = 7.8 Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.77 (t, J = 8.7

Hz, 1H), 6.60 (dd, J = 8.2, 3.7 Hz, 1H), 4.89-4.82 (m, 2H), 3.32-

3.10 (m, 3H), 2.98 (dd, J = 16.0, 6.9 Hz, 1H), 2.43 (s, 3H); ¹³C

Butyldimethylsilyl)oxy)phenyl)propyl)-1-tosylaziridin-2-

yl)methanol (11h). Following the General Procedure A,

compound 10 (306 mg, 1.0 mmol) was subjected to the

Sharpless aziridination reaction. The resulting crude product

was purified by silica gel column chromatography (5-15%

EtOAc in hexanes) to obtain the title compound 2h as a

colorless gum. Yield: (428 mg, 90%); R_f: 0.48 (silica gel, 30%

NMR (100 MHz, CDCl₃): δ 157.6 (d, J_C-F= 237.7 Hz), 154.6 (d, J_C-

= 1.9 Hz), 143.7, 136.7, 129.8, 127.4 (d, J_C-F= 9.6 Hz), 127.0,

F

114.3 (d, J_C-F= 23.9 Hz), 112.2 (d, J_C-F= 24.9 Hz), 109.5 (d, J_C-F

=

8.6 Hz), 81.3, 46.7, 32.7 (d, J_C-F= 1.9 Hz), 21.5; MS (ESI) m/z:

322 (M + H)⁺; Anal. Calcd. for C₁₆H₁₆FNO₃S: C, 59.80; H, 5.02; N,

4.36, found: C, 59.95; H, 5.09; N, 4.33.

EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

δ 7.84 (d, J = 8.2

Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.09-7.05 (m, 1H), 6.98-6.97

(m, 1H), 6.85 (t, J = 6.9 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 4.14-

4.08 (m, 1H), 3.93-3.98 (m, 1H), 2.95-2.93 (m, 2H), 2.73 (br s,

1H), 2.53 (t, J = 6.9 Hz, 2H), 2.43 (s, 3H), 1.67-1.46 (m, 4H), 0.99

N-((S*)-1-((R*)-2,3-Dihydrobenzofuran-2-yl)-2-hydroxyethyl)-

4-methylbenzenesulfonamide (12c). Following the General

Procedure C, compound 11c (448 mg, 1.0 mmol) was subjected

to the intramolecular aziridine ring-opening reaction. The

resulting crude product was purified by silica gel column

chromatography (10-30% EtOAc in hexanes) to obtain the title

(s, 9H), 0.22 (s, 3H), 0.21 (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

δ

153.4, 144.2, 137.1, 132.0, 129.9, 129.6, 127.3, 126.9, 120.9,

118.4, 60.9, 51.9, 46.2, 30.1, 29.8, 27.3, 25.7, 21.6, 18.2, -4.2;

Anal. Calcd. for C₂₅H₃₇NO₄SSi: C, 63.12; H, 7.84; N, 2.94, found:

C, 63.29; H, 7.89; N, 2.96.

compound 12c as a white crystalline solid

. Yield: (317 mg,

95%); mp: 110–112 °C; R_f: 0.36 (silica gel, 50% EtOAc in

1

hexanes); H NMR (400MHz, CDCl₃):

δ 7.76 (d, J = 7.8 Hz, 2H),

General Procedure B: Intramolecular aziridine ring-opening

To a stirred solution of appropriate N-tosylaziridine derivative

(1 equiv) in anhydrous THF (5 mL/mml) was added TBAF (1.1

equiv) dropwise under a nitrogen atmosphere at 0 °C. The

reaction mixture was stirred at room temperature for 10 min.

The reaction mixture was then diluted with ethyl acetate and

water. The phases were separated, the organic layer was

washed with brine, dried over anhydrous Na₂SO₄, filtered, and

concentrated under reduced pressure. The resulting residue

was purified by silica gel column chromatography to obtain the

7.29 (d, J = 7.8 Hz, 2H), 7.13-7.07 (m, 2H), 6.86 (t, J = 7.3 Hz,

1H), 6.67 (d, J = 7.8 Hz, 1H), 5.56 (d, J = 8.7 Hz, 1H), 4.79-4.73

(m, 1H), 3.83 (dd, J = 11.0, 2.7 Hz, 1H), 3.45-3.37 (m, 2H), 3.23

(dd, J = 16.5, 9.6 Hz, 1H), 2.13 (dd, J = 16.0, 6.8 Hz, 1H), 2.43 (s,

3H), 2.18 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃):

δ 158.6, 143.7,

137.5, 129.8, 128.0, 127.0, 125.9, 125.2, 121.0, 109.3, 80.9,

60.7, 57.7, 32.4, 21.5; MS (ESI) m/z: 334 (M + H)⁺; Anal. Calcd

for C₁₇H₁₉NO₄S: C, 61.24; H, 5.74; N, 4.20, found: C, 61.39; H,

5.79; N, 4.11.

N-((S*)-1-((R*)-5-Fluoro-2,3-dihydrobenzofuran-2-yl)-2-

hydroxyethyl)-4-methylbenzenesulfonamide (12d). Following

the General Procedure C, compound 11d (65 mg, 0.14 mmol)

was subjected to the intramolecular aziridine ring-opening

reaction. The resulting crude product was purified by silica gel

column chromatography (10-30% EtOAc in hexanes) to obtain

corresponding benzo-fused oxygen heterocycles

.

N-((2,3-Dihydrobenzofuran-2-yl)methyl)-4-

methylbenzenesulfonamide (12a). Following the General

Procedure B, compound 11a (418 mg, 1.0 mmol) was

subjected to the intramolecular aziridine ring-opening

reaction. The resulting crude product was purified by silica gel

column chromatography (10-25% EtOAc in hexanes) to obtain

the title compound 12d as a white crystalline solid

. Yield: (46

mg, 93%); mp: 125–127 °C; R_f: 0.32 (silica gel, 50% EtOAc in

1

hexanes); H NMR (400MHz, CDCl₃):

δ 7.76 (d, J = 8.2 Hz, 2H),

the title compound 12a as a white crystalline solid

. Yield: (291

7.31 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 7.3 Hz, 1H), 6.78 (t, J = 8.7

Hz, 1H), 6.59 (dd, J = 8.7, 4.1 Hz, 1H), 5.24 (d, J = 8.7 Hz, 1H),

4.81-4.75 (m, 1H), 3.83 (d, J = 11.0 Hz, 1H), 3.44-3.16 (m, 4H),

3.23 (d 2.13 (dd, J = 16.0, 6.8 Hz, 1H), 2.44 (s, 3H), 1.87 (br s,

1H); MS (ESI) m/z: 352 (M + H)⁺; Anal. Calcd for C₁₇H₁₈FNO₄S: C,

58.11; H, 5.16; N, 3.99, found: C, 58.26; H, 5.07; N, 4.08.

mg, 96%); mp: 160–162 °C; R_f: 0.34 (silica gel, 40% EtOAc in

1

hexanes); H NMR (400MHz, CDCl₃):

δ 7.75 (d, J = 8.2 Hz, 2H),

7.32 (d, J = 8.2 Hz, 2H), 7.11 (dd, J = 17.4, 7.8 Hz, 2H), 6.85 (t, J

= 7.3 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 4.88-4.79 (m, 2H), 3.35-

3.22 (m, 2H), 3.17-3.11 (m, 1H), 2.96 (dd, J = 15.6, 7.3 Hz, 1H),

2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

δ 158.6, 143.6, 136.8,

129.8, 128.2, 127.0, 126.0, 125.1, 120.9, 109.5, 80.7, 46.9,

32.5, 21.5; MS (ESI) m/z: 304 (M + H)⁺; Anal. Calcd for

C₁₆H₁₇NO₃S: C, 63.34; H, 5.65; N, 4.62, found: C, 63.27; H, 5.63;

N, 4.67.

N-((S*)-1-((R*)-Chroman-2-yl)-2-hydroxyethyl)-4-

methylbenzenesulfonamide (12e). Following the General

Procedure C, compound 11e (231 mg, 0.5 mmol) was

subjected to the intramolecular aziridine ring-opening

reaction. The resulting crude product was purified by silica gel

column chromatography (10-30% EtOAc in hexanes) to obtain

N-((5-Fluoro-2,3-dihydrobenzofuran-2-yl)methyl)-4-

methylbenzenesulfonamide (12b). Following the General

Procedure B, compound 11b (436 mg, 1.0 mmol) was

subjected to the intramolecular aziridine ring-opening

reaction. The resulting crude product was purified by silica gel

column chromatography (10-25% EtOAc in hexanes) to obtain

the title compound 12b as a white crystalline solid. Yield: (305

the title compound 12e as a white crystalline solid

. Yield: (163

mg, 94%); mp: 135–138 °C; R_f: 0.34 (silica gel, 50% EtOAc in

1

hexanes); H NMR (400MHz, CDCl₃):

δ 7.80 (d, J = 8.2 Hz, 2H),

7.31 (d, J = 8.2 Hz, 2H), 7.09-7.03 (m, 2H), 6.86 (t, J = 6.87, 1H),

6.72 (d, J = 8.2 Hz, 1H), 5.35 (d, J = 8.2 Hz, 1H), 4.05 (ddd, J =

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10.5, 5.9, 1.8 Hz, 1H), 3.93 (dd, J = 10.5, 2.7 Hz, 1H), 3.47-3.41 NMR (100 MHz, CDCl₃): δ 158.5, 143.6, 137.7, 135.2, 130.3,

(m, 2H), 2.81-2.77 (m, 2H), 2.44 (s, 3H), 2.15-2.08 (m, 1H), 2.02 129.7, 127.5, 127.0, 124.1, 120.8, 85.0, 61.1, 58.0, 33.9, 33.6,

(br s, 1H), 1.85-1.75 (m, 1H); ¹³C NMR (100 MHz, CDCl₃):

δ

25.6, 21.5; HRMS (ESI) m/z calcd for C₁₉H₂₄NO₄S [M + H]⁺:

153.7, 143.7, 137.7, 129.8, 129.6, 127.3, 127.0, 121.9, 120.9, 362.1426, found: 362.1392. MS (ESI) m/z: 362 (M + H)⁺; Anal.

116.6, 75.9, 60.8, 57.2, 24.3, 24.0, 21.5; HRMS (ESI) m/z calcd Calcd. for C₁₉H₂₃NO₄S: C, 63.13; H, 6.41; N, 3.88, found: C,

for C₁₈H₂₂NO₄S [M + H]⁺: 348.1270, found: 348.1284.

63.31; H, 6.48; N, 3.95.

N-((S*)-2-Hydroxy-1-((R*)-8-methoxychroman-2-yl)ethyl)-4-

(E)-Ethyl 3-((2R*,3R*)-3-(2-((tert-butyldimethylsilyl)oxy)-5-

methylbenzenesulfonamide (12f). Following the General fluorobenzyl)-1-tosylaziridin-2-yl)acrylate (17). To a stirred

Procedure C, compound 11f (246 mg, 0.5 mmol) was subjected solution of 11d (104 mg, 0.223 mmol) in CH₂Cl₂(5 mL) was

to the intramolecular aziridine ring-opening reaction. The added sodium bicarbonate (25 mg, 0.3 mmol) and Dess-Martin

resulting crude product was purified by silica gel column periodinane (119 mg, 0.28 mmol) at 0 °C. The reaction mixture

chromatography (10-30% EtOAc in hexanes) to obtain the title was stirred for 3 h at rt and then quenched with saturated

compound 12f as a white crystalline solid

96%); mp: 90–92 °C; R_f: 0.30 (silica gel, 50% EtOAc in hexanes); mixture was diluted with CH₂Cl₂(10 mL), filtered through a pad

¹H NMR (400MHz, CDCl₃):

7.79 (d, J = 8.2 Hz, 2H), 7.30 (d, J = of Celite and phases were separated. The combined organic

. Yield: (181 mg, solutions of Na₂SO₃(5 mL) and NaHCO₃(5 mL). The reaction

δ

8.2 Hz, 2H), 6.80 (t, J = 7.8 Hz, 1H), 6.70-6.65 (m, 2H), 5.63 (br phase was dried over anhydrous Na₂SO₄and concentrated

s, 1H), 4.14 (t, J = 7.3 Hz, 1H), 3.88 (dd, J = 11.4, 2.3 Hz, 1H), under reduced pressure to obtain the corresponding crude

3.80 (s, 3H), 3.44-3.34 (m, 2H), 2.78-2.77 (m, 2H), 2.43 (s, 3H), aldehyde as a colorless gum.

2.14-2.11 (m, 1H), 1.86-1.76 (m, 1H); ¹³C NMR (100 MHz,

CDCl₃): 148.2, 143.6, 142.9, 137.8, 129.8, 127.0, 122.7, 121.4, dichloromethane

To a stirred solution of the above crude aldehyde in

δ

120.2, 109.2, 61.1, 56.7, 55.7, 24.0, 23.9, 21.5; HRMS (ESI) m/z (carbethoxymethylene)triphenylphosphoraneafforded

(5

mL)

was

added

(116

calcd for C₁₉H₂₄NO₅S [M + H]⁺: 378.1375, found: 378.1370.

mg, 0.335 mmol) and the reaction mixture was further stirred

for an additional 6 h. Removal of the solvent under reduced

pressure gave the crude product which was purified by silica

N-((S*)-2-Hydroxy-1-((R*)-6-methoxychroman-2-yl)ethyl)-4-

methylbenzenesulfonamide (12g). Following the General gel column (2-10% ethyl acetate in hexanes) to afford

Procedure C, compound 11g (246 mg, 0.5 mmol) was compound 17 as a white solid compound Yield: (78 mg, 65%

subjected to the intramolecular aziridine ring-opening over two steps); mp: 100–102 °C; R_f: 0.46 (silica gel, 20% EtOAc

;

1

reaction. The resulting crude product was purified by silica gel in hexanes); H NMR (400 MHz, CDCl₃):

column chromatography (10-30% EtOAc in hexanes) to obtain 2H), 7.20 (d, J = 7.8 Hz, 2H), 7.03 (dd, J = 15.6, 9.1 Hz, 1H), 6.74

the title compound 12g as a white crystalline solid Yield: (179 (td, J = 8.7, 3.2 Hz, 1H), 6.67 (dd, J = 9.1, 5.0 Hz, 1H), 6.47 (dd, J

mg, 95%); mp: 111–113 °C; Rf: 0.28 (silica gel, 50% EtOAc in = 8.70, 3.2 Hz, 1H), 6.16 (d, J = 15.1 Hz, 1H), 4.28-4.15 (m, 2H),

δ 7.63 (d, J = 8.2 Hz,

.

1

hexanes); H NMR (400MHz, CDCl₃):

7.31 (d, J = 7.8 Hz, 2H), 6.65-6.64 (m, 2H), 6.58-6.57 (m, 1H), 13.7, 6.4 Hz, 1H), 2.42 (s, 3H), 1.30 (t, J =7.3 Hz, 3H), 1.00 (s,

5.36 (d, J = 8.7 Hz, 1H), 3.99 (ddd, J = 10.5, 5.9, 1.8 Hz, 1H), 9H), 0.25 (s, 6H), 0.23 (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

δ 7.79 (d, J = 8.2 Hz, 2H), 3.31-3.24 (m, 2H), 3.03 (dd, J = 14.2, 5.0 Hz, 1H), 2.63 (dd, J =

δ

3.91 (dd, J = 10.5, 2.7 Hz, 1H), 3.74 (s, 3H), 3.44-3.37 (m, 2H), 165.0, 156.8 (d, J = 239.6 Hz), 149.4 (d, J = 1.9 Hz), 144.4,

2.79-2.75 (m, 2H), 2.43 (s, 3H), 2.11-2.06 (m, 2H), 1.83-1.73 (m, 140.3, 136.0, 129.5, 129.4 (d, J = 7.7 Hz), 127.4, 126.9, 118.7

1H); ¹³C NMR (100 MHz, CDCl₃):

δ 153.8, 147.9, 143.8, 137.8, (d, J = 7.7 Hz), 117.0 (d, J = 23.0 Hz), 114.0 (d, J = 23.0 Hz), 60.7,

129.9, 127.2, 122.6, 117.3, 114.1, 113.5, 76.1, 61.0, 57.2, 55.8, 48.7, 48.4, 31.8, 25.8, 21.6, 18.2, 14.2, -4.1, -4.3; Anal. Calcd

24.7, 24.1, 21.6; MS (ESI) m/z: 378 (M + H)⁺; Anal. Calcd for for C₂₇H₃₆FNO₅SSi: C, 60.76; H, 6.80; N, 2.62, found C, 60.90; H,

C₁₉H₂₃NO₅S: C, 60.46; H, 6.14; N, 3.71, found: C, 60.34; H, 6.18; 6.91; N, 2.69.

N, 3.67.

N-((S*)-2-Hydroxy-1-((R*)-2,3,4,5-tetrahydrobenzo[b]oxepin-

(R*,E)-Ethyl

4-((S*)-2,3-dihydrobenzofuran-2-yl)-4-(4-

2-yl)ethyl)-4-methylbenzenesulfonamide (12h). Following the methylphenylsulfonamido)but-2-enoate (18). Following the

General Procedure C, compound 11h (238 mg, 0.5 mmol) was General Procedure C, compound 17 (50 mg, 0.094 mmol) was

subjected to the intramolecular aziridine ring-opening subjected to the intramolecular aziridine ring-opening

reaction. The resulting crude product was purified by silica gel reaction. The resulting crude product was purified by silica gel

column chromatography (10-30% EtOAc in hexanes) to obtain column chromatography (10-25% EtOAc in hexanes) to obtain

the title compound 12h as a white crystalline solid

(

.

Yield: (161 the title compound 18 as a white crystalline solid. Yield: (37

mg, 89%); mp: 105–107 °C; R_f: 0.35

1

hexanes); H NMR (400MHz, CDCl₃):

silica gel, 50% EtOAc in mg, 93%); mp: 110–112 °C; R_f: 0.38 (silica gel, 40% EtOAc in

1

δ 7.77 (d, J = 8.2 Hz, 2H), hexanes); H NMR (400MHz, CDCl₃): δ 7.71 (d, J = 8.2 Hz, 2H),

7.25 (d, J = 7.8 Hz, 2H), 7.12-7.08 (m, 2H), 6.98 (t, J = 7.4 Hz, 7.28 (d, J = 8.2 Hz, 2H), 6.81-6.74 (m, 2H), 6.59-6.53 (m, 2H),

1H), 6.93 (d, J = 7.8 Hz, 1H), 5.69 (d, J = 8.7 Hz, 1H), 4.01 (dd, J 5.78 (d, J = 16.0 Hz, 1H), 5.14 (d, J = 8.7 Hz, 1H), 4.84-4.79 (m,

= 11.4, 3.2 Hz, 1H), 3.64 (dd, J =10.9, 4.1 Hz, 1H), 3.45 (dd, J = 1H), 4.16-4.07 (m, 3H), 3.23 (dd, J = 16.5, 9.6 Hz, 1H), 2.99 (dd,

11.4, 3.6 Hz, 1H), 3.34-3.30 (m, 1H), 2.80 (t, J = 13.0 Hz, 1H), J = 16.5, 7.0 Hz, 1H), 2.42 (s, 3H), 1.22 (t, J = 7.3 Hz, 3H); ¹³C

2.66 (dd, J = 14.6, 5.5 Hz, 1H), 2.39 (s, 4H), 2.01-1.95 (m, 2H), NMR (100 MHz, CDCl₃): δ 165.1, 157.6 (d, J = 238.6 Hz), 154.7

1.81-1.70 (m, 1H), 1.43-1.32 (m, 1H), 1.31-1.26 (m,1H); ¹³C (d, J = 1.9 Hz), 143.8, 140.4, 137.3, 129.7, 127.2, 126.8 (d, J =

Org. Biomol. Chem., 2018, 00, xx-xx | 11

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Organic & Biomolecular Chemistry

9.6 Hz), 125.0, 114.5 (d, J = 23.9 Hz), 112.1 (d, J = 24.9 Hz), 1H), 4.92 (d, J = 8.7 Hz, 1H), 4.81 (d, J = 9.2 Hz, 1H), 4.59 (dd, J

109.5 (d, J = 8.6 Hz), 83.6, 60.6, 57.8, 32.1 (d, J = 1.9 Hz),, 21.5, = 12.8, 2.7 Hz, 1H), ), 4.29 (d, J = 12.4 Hz, 1H), 3.95-3.91 (m,

14.0; MS (ESI) m/z: 420 (M + H)⁺; Anal. Calcd for C₂₁H₂₂FNO₅S: 1H), 3.68 (s, 3H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

δ

155.1, 149.0, 143.8, 143.2, 137.3, 136.5, 129.5, 128.54, 128.47,

C, 60.13; H, 5.29; N, 3.34, found C, 60.28; H, 5.21; N, 3.37.

127.1, 126.8, 120.5, 109.5, 106.1, 84.6, 74.0, 59.5, 55.6, 21.5.

MS (ESI) m/z: 426 (M + H)⁺; Anal. Calcd. for C₂₃H₂₃NO₅S: C,

4-Methoxy-2-((R*)-phenyl((S*)-1-tosylaziridin-2-

yl)methoxy)benzaldehyde (24). To a stirred suspension of 64.92; H, 5.45; N, 3.29, found: C, 65.11; H, 5.52; N, 3.32.

sodium hydride (96 mg, 4.0 mmol) in DMF (10 mL), was added

a solution of 2-hydroxy-4-methoxybenzaldehyde (0.5 g, 3.28

mmol) in dry DMF (10 mL) dropwise at 0 °C under N₂

Acknowledgements

atmosphere. The resulting mixture was stirred for 5 min, and

then a solution of 19 (1.5 g, 3.28 mmol, compound 19 was

prepared following literature procedure¹¹) in DMF (15 mL) was

We acknowledge the financial supports provided by the

Department of Science and Technology [(DST), SB/FT/CS-

added dropwise. The solution was stirred for an additional 2 h

073/2013], and University Grant Commission [F30-

at 0 °C. Saturated aqueous NH₄Cl (15 mL) and Et₂O (80 mL)

33/2014(BSR)], New Delhi, India.

were added and the mixture was stirred vigorously for 10 min.

The phases were then separated and the aqueous phase was

extracted with Et₂O (25 x 2 mL). The combined organic layers

Notes and references

were washed with brine, dried over Na₂SO₄, filtered, and

concentrated under reduced pressure. The resulting crude

product was purified by silica gel column chromatography (5-

15% EtOAc in hexanes) to obtain the title compound 24 as a

1

2

For recent reviews, see: (a) X.-E. Hu, Tetrahedron, 2004, 60

2701-2743; (b) P.-F. Lu, Tetrahedron, 2010, 66, 2549-2560;

(c) P.-A. Wang, Beilstein J. Org. Chem., 2013, , 1677–1695;

(d) C.-Y. D. Huang and A. G. Doyle, Chem. Rev., 2014, 114

8153–8198; (e) G. Callebaut, T. Meiresonne, N. De Kimpe,

and S. Mangelinckx, Chem. Rev., 2014, 114, 7954–8015; (f) H.

Ohno, Chem. Rev., 2014, 114, 7784–7814.

,

9

1

,

colorless semi-solid. Yield: (488 mg, 34%); H NMR (400 MHz,

CDCl₃):

δ 10.08 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.2

Hz, 2H), 7.27-7.23 (m, 7H), 6.49 (dd, J = 8.7, 1.8 Hz, 1H), 6.20

(d, J = 2.3 Hz, 1H), 5.17 (d, J = 4.6 Hz, 1H), 3.69 (s, 3H), 3.26-

3.22 (m, 1H), 2.78 (d, J = 7.3 Hz, 1H), 2.45 (s, 3H), 2.37 (d, J =

For selected recent examples of intermolecular aziridine

ring-opening by phenols/phenolates, see: (a) C. K. Shahi, A.

Bhattacharyya, Y. Nanaji, and M. K. Ghorai J. Org. Chem.,

2017, 82, 37–47; (b) S. J. Bailey, S. M. Wales, A. C. Willis, and

P. A. Keller, Org. Lett., 2014, 16, 4344–4347; (c) F. Ji, M. F. Lv,

W. B. Yi and C. Cai, Adv. Synth. Catal., 2013, 355, 3401–3406;

(d) Y. Takehiroa, K. Hirotakia, C. Takeshitaa, H. Furunob and

T. Hanamotoa, Tetrahedron, 2013, 69, 7448–7454; (e) G.

Chouhan and H. Alper, Org. Lett., 2010, 12, 192–195; (f) L. K.

Ottesen, J. W. Jaroszewski and H. Franzyk, J. Org. Chem.,

2010, 75, 4983–4991; (g) R. K. Rao, A. B. Naidu and G. Sekar,

Org. Lett., 2009, 11, 1923–1926.

For regioselective intermolecular ring-opening of di- and tri-

substituted aziridines by phenols/phenolates, see: (a) B. T.

Kelley, P. Carroll, and M. M. Joullié, J. Org. Chem., 2014, 79,

5121–5133; (b) S. Kenis, M. D'Hooghe, G. Verniest, M.

Reybroeck, T. A. Dang Thi, C. Pham The, T. Thi Pham, K. W.

Törnroos, N. Van Tuyen and N. De Kimpe, Chem. – Eur. J.,

2013, 19, 5966–5971; (c) E. M. Forbeck, C. D. Evans, J. A.

Gilleran, P. Li and M. M. Joullié, J. Am. Chem. Soc., 2007, 129,

14463–14469; (d) P. Li, E. M. Forbeck, C. D. Evans and M. M.

Joullié, Org. Lett., 2006, 8, 5105–5107.

4.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃):

δ 187.8, 165.6, 161.2,

144.9, 136.1, 134.1, 130.4, 129.7, 128.8, 128.7, 127.9, 126.4,

119.4, 106.9, 100.5, 78.7, 55.5, 42.6, 30.3, 21.7; Anal. Calcd.

for C₂₄H₂₃NO₅S: C, 65.89; H, 5.30; N, 3.20, found: C, 65.77; H,

5.36; N, 3.28.

N-(((2R*,3R*)-6-Methoxy-3-phenyl-2,3-

dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-

methylbenzenesulfonamide (26). To a solution of compound

24 (400 mg, 0.914 mmol) in CH₂Cl₂(10 mL) was added m-CPBA

(77% purity, 338 mg, 1.37 mmol) at 0 °C and the mixture was

stirred overnight at rt. The mixture was diluted with CH₂Cl₂(20

mL) and washed successively with aq solutions of Na₂SO₃(10

mL) and NaHCO₃(10 mL). The combined organic layers were

washed with brine, dried over Na₂SO₄, filtered, and

concentrated under reduced pressure.

3

To a stirred solution of the above crude product in THF (5

mL) was added saturated 10% NaOH solution (4 mL) at 0 ^oC

and the resulting solution was stirred vigorously for 2 h. Water

(10 mL) was added to the resulting residue. The mixture was

extracted with EtOAc (20 mL) washed with brine, dried over

Na₂SO₄, filtered, and concentrated under reduced pressure.

The resulting crude product was purified by silica gel column

chromatography (5-15% EtOAc in hexanes) to obtain the title

compound 26 as a colorless crystalline solid. Yield: (311 mg,

80% over two steps); mp: 160–162 °C; R_f: 0.29 (silica gel, 40%

4

For reviews, see: (a) R. Pratap and V. J. Ram, Chem. Rev.,

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2011, 35, 377–385; (c) H. C. Shen, Tetrahedron, 2009, 65

,

3931–3952.; (d) N. L. Snyder, H. M. Haines and M. W.

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5

6

7

EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃):

δ 7.36 (d, J = 8.2

Hz, 2H), 7.30-7.25 (m, 1H; overlapped with the peak for

residual CHCl₃, resulting in higher integrated area of 3 instead

of 1), 7.21 (d, J = 4.6 Hz, 4H), 7.06 (d, J = 8.2 Hz, 2H), 6.87 (d, J =

8.7 Hz, 1H), 6.50 (dd, J = 8.7, 2.7 Hz, 1H), 6.44 (d, J = 3.2 Hz,

8

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8579-8629; (c) F.-X. Felpin and J. Lebreton, Eur. J. Org.

,

12 | Org. Biomol. Chem., 2018, 00, xx-xx

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Org. Biomol. Chem.

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Org. Biomol. Chem., 2018, 00, xx-xx | 13

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Article Doi

Phenolate-induced intramolecular ring-opening cyclization of: N -tosylaziridines: Access to functionalized benzoxacycles

DOI: 10.1039/c8ob01143e

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