Diversity-Oriented Approach to N-Heterocyclic Compounds from Î±

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Diversity-oriented approach to N-heterocyclic compounds from #phenyl-#-enamino ester via a Mitsunobu-Michael reaction sequence Hina P. A. Khan, and Tushar Kanti Chakraborty J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02962 • Publication Date (Web): 15 Jan 2018 Downloaded from http://pubs.acs.org on January 16, 2018

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The Journal of Organic Chemistry

Diversity-oriented approach to N-heterocyclic compounds from αphenyl-β-enamino ester via a Mitsunobu-Michael reaction sequence Hina P. A. Khan and Tushar Kanti Chakraborty* Department of Organic Chemistry, Indian Institute of Science, Bengaluru - 560012, India

ABSTRACT: Herein we delineate a novel route for the diastereoselective construction of diversely substituted N-heterocyclic ring systems as valuable scaffolds for natural products and pharmaceuticals, starting from easily accessible prochiral α-phenyl-β-enamino ester. The reaction sequence relies on the unexplored reactivity of α-phenyl-β-enamino ester as a nucleophilic partner in Mitsunobu reaction to forge the N-tethered alkene-alcohol/thiol/amine intermediate which was subjected to intramolecular hetero-Michael addition reaction under mild conditions to furnish the respective N-heterocyclic compounds embedded with an exocyclic chiral center in high yields and excellent diastereoselectivities. The methodology is amenable for a broad range of substrates based on a metal free approach.

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INTRODUCTION Diversity-oriented approach, in contrast to the targeted chemistry, is fascinating as it enables the construction of unique and biologically relevant molecular frameworks starting from a single material. In this regard, there has been a resurgence of interest in the development of processes to afford a single potential route for the synthesis of diverse five/six-membered 1,3-X,Nheterocyclic ring systems (X = S, O, N), because they are privileged structural scaffolds that exist in many bioactive compounds (Figure 1). For example, 1,3-thiazolidine (1) and 1,3-thiazinane (2) structural motives are found in the penicillin1 and cephalosporin2 family of β-lactam antibiotics, respectively.

H N

Ph O

H N

H S

S

O

N O

H

O

H

N

OH

H N N

N

O

Cef alotin (2)

O

N

N

O

N

COOH

N

OH H

O

Penicillin G (1)

HO

O S

O

OMe

Quinocarcin (3) O

H

H

N

N

O

Cl

O

F F

F

C5H11

H

O

Chaetominine (4)

Efavirenz (5)

Tetraponerine-8 (6)

Figure 1. Examples of bioactive 1,3-X,N-heterocyclic natural products and drugs.

Quinocarcin (3) and its analogue terazomine are oxazolidine containing compounds that show potent antitumor activities.3 Similarly, chaetominine (4), a cytotoxic alkaloid produced by endophytic Chaetomium sp. and having an imidazolidine scaffold is highly potent against human leukemia K562 and colon cancer SW1116 cell lines.4 Efavirenz (5) containing the 1,3-oxazinane moiety is an antiretroviral drug.5 Tetraponerine-8 (6) with hexahydropyrimidine unit acts as an


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efficient inhibitor of a range of nAChRs (nicotinic acetylcholine receptors).6 1,3-X,Nheterocyclic systems (X = S, O, N) are also broadly employed in asymmetric synthesis as chiral auxiliaries or as chiral ligands for transition-metal catalysts.7 The classical approach to the aforementioned ring systems involves condensation of an aldehyde with cysteine8 (for thiazolidine), 3-amino propanethiol9a (for thiazinane), an amino alcohol7c,9b,c (for oxazolidine and oxazinane) and diamines9d,e (for imidazolidine and hexahydropyrimidine). Alternatively, thiazolidines are synthesized by the Asinger method10 while the syntheses of oxazolidine and imidazoline include the carbon-heteroatom bond forming cycloaddition,11 conjugate addition,12 and aza-Wacker type reactions13 which are mainly based on the use of transition-metal complexes (Pd, Rh, Ni, Fe) and metal salts (Cu, Ag). Despite this progress, most of the reported methods suffer from the use of toxic or expensive chiral reagents and catalysts in high loading and the use of additives. Moreover, their recovery and reuse are often impossible. These shortcomings posed the requirement of developing new, efficient and cheaper methods to construct such moieties. β-Enamino esters have wide applications in synthetic organic chemistry to furnish pyrrole,14a pyrolinone,14b pyridine,14c and indole derivatives.14d Despite their wide-ranging uses, so far there has been no synthetic endeavour available where α-phenyl-β-enamino ester served as a nucleophilic donor (in Mitsunobu reaction)15 and an electrophile (in intramolecular heteroMichael reaction) in a sequence to construct 1,3-X,N-heterocyclic ring systems (X = S, O, N). The major drawbacks of hetero-Michael addition (typically, oxa-Michael) are due to the relatively poor nucleophilicity of the employed alcohols as well as the reversibility issues.16 This renders hetero-Michael addition reactions challenging which prompted us to re-evaluate 3 ACS Paragon Plus Environment


synthetic strategies and enable connections/disconnections that would not involve the use of traditional synthetic equivalents or metal catalysts. Concealed -amino acid TM

CO2Et TsHN

Ph 7a

Mitsunobu-Michael sequence Ts N XPG

Ph Metal-free approach

nX

9

CO2Et

Ph

Mild reaction conditions High diastereoselectivity

CO2Et

R n

NTs

R

Broad substrate scope

8

n = 1, 2; X = O, S, N; PG = TBS, Trt, Ts; R = H, Me, Ph

Scheme 1. Generalized scheme of our approach.

Herein, we disclose the ability of α-phenyl-β-enamino ester 7a to serve as a valuable nucleophilic synthon for Mitsunobu alkylation of wide-ranging diols, amino-alcohols, and mercapto-alkanols which bodes well for its adoption for the synthesis of diverse saturated Nheterocycles 9 by further utilizing intramolecular hetero-Michael addition, via 8, under mild and atom economical conditions (Scheme 1). Taken as a whole, the designed strategy represents a general, potential and transition-metal free approach for the assembly of a large panel of very useful N-heterocyclic scaffolds, embedded with an exocyclic chiral centre, of biological and medicinal relevance. RESULTS AND DISCUSSION To evaluate the potentiality of α-phenyl-β-enamino esters 7a and 7b, we embarked towards their synthesis following the procedure documented in the literature.17a,b Scheme 2 outlines the reactions used for converting N-tosyldiazoketamine 10 into the corresponding E/Z-α-phenyl-βenamino ester via decomposition of 10 through 1,2-phenyl migration under two different catalytic conditions, Rh2(OAc)4 and p-TsOH. For the reaction catalyzed by Rh2(OAc)4,17a E4 ACS Paragon Plus Environment

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isomer 7b was found to be the major product along with the formation of minute quantities of the Z-isomer of 1,2-phenyl migration product 7a and 1,2-hydride migration product 7c. The ratio of 7a:7b:7c was found to be 5:91:4. In contrast, the 1,2-hydride migration product 7c could not be detected in reactions catalyzed by p-TsOH.17b Moreover, in later case, the Z-α-phenyl-β-enamino ester 7a was formed as the major product (7a:7b = 95:5).

Scheme 2. Synthesis of α-phenyl-β-enamino ester.

Stability of the Z-isomer 7a is greater than the corresponding E-isomer 7b mainly because of the intramolecular H-bonding in the former.17b Since the E/Z-isomerisation of α-phenyl-β-enamino ester was observed during the silica gel column chromatographic separation, the mixture was used directly in the next step without further purification. At the outset, we decided to use the Z-isomer 7a (prepared via p-TsOH route, Scheme 2) to delve into its reliability as a nucleophilic partner for the Mitsunobu alkylation and chose monoprotected ethylene glycol 11a18 as an alkylating source. After an extensive survey of reaction parameters,19 to our delight, Mitsunobu adduct 8a was detected in 84% yield (Table 1, entry 1) by premixing DEAD and PPh3 at 0 °C for 20 min followed by sequential addition of Zα-phenyl-β-enamino ester 7a and alcohol 11a. Then the reaction mixture was heated at 37 °C



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(oil-bath temperature) for 1 h. Only E-isomer having olefinic proton at δ 8.06 ppm was formed in the reaction as evident from the 1H-NMR spectrum of the product 8a. Table 1. Mitsunobu alkylation of 7a to deliver N-tethered alkene-alcohol/thiol/amine.a

Entry

ROH

b

Procedure

Solvent

Temp. (°C)

Time (h)

1

A

THF

37

1

84

2

A

THF

37

1

Quant

3

D

THF

40

4

71

4

A

THF

37

1

89

5

A

THF

37

1

Quant

6

D

THF

40

4

75

7

B

THF

37

5

77

8

C

toluene/THF

37

6

81

9

B/C

Toluene

65

1.5

86

10

A

THF

37

1

86

11

A

THF

37

1

83


Product

Yield (%)

c

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a

Unless otherwise stated, all reactions were carried out using 1.0 equiv of 11a-k (0.10 mmol), 2.0 equiv of 7a (0.20 mmol), 4.0 equiv of DEAD (0.40 mmol) and 4.0 equiv of PPh3 (0.40 mmol) in 1.0 mL of solvent. b Procedure A: DEAD was added to a solution of PPh3 in THF at 0 °C. After 20 min β-enamino ester 7a was added and again after 15 min, a solution of alcohol in THF was cannulated into the reaction mixture and stirred at 37 °C (oil bath) until the reaction was complete; Procedure B: DEAD was added to a solution of alcohol and PPh3 in toluene/THF at 0 °C. After 20 min, β-enamino ester 7a was added and the reaction mixture was then heated at 37 °C/65 °C (oil bath) until the reaction was complete; Procedure C: DEAD was added to a solution of alcohol, β-enamino ester 7a and PPh3 in toluene-THF (3:2) or toluene (3mL/mmol) at 0 °C. After stirring for 5 min at 0 °C, the reaction mixture was stirred at 37 °C/65 °C (oil bath); Procedure D: DEAD was added to a solution of β-enamino ester 7a and PPh3 in THF (3mL/mmol) at 0 °C. After 10 min the temperature was raised to 40 °C (oil bath) and then alcohol was added after 15 min. c Yields of isolated products after purification by silica gel column chromatography.

Notably, the foremost requirement of 37 °C was realized because the temperature lower than that resulted in a mixture of E/Z-isomer of the alkylated product with olefinic proton at δ 8.06 and 6.61 ppm. It was witnessed that when the reaction mixture was placed at room temperature (below 37 °C), the rate of conversion of the Z-α-phenyl-β-enamino ester 7a into its E-isomer 7b was slow-going that led to a mixture of E/Z-isomer of the alkylated product. Whereas, complete conversion of Z-isomer into E-isomer was realized within 10 min when the reaction mixture was placed at 37 °C as primarily evident from the TLC. Independent experiments in which 7a in THF was treated with Ph3P alone and, in the 2nd, with Ph3P plus DEAD, both at 37 °C, confirmed that in the former, there was no change in 7a, but in the latter reaction within 10-15 min 7a was fully converted into 7b as seen in TLC. The mechanism of Z to E isomerization is shown in Scheme 3. With an aim to establish an alternate method devoid of isomerisation, normal alkylation of 7a was attempted by treating it with NaH or KH. But, it was observed that while the enolate of Zisomer was formed because of the chelation (7a"), it failed to give the desired alkylated product. However, use of organic bases like DIPEA, tetramethylammonium hydroxide exclusively gave the E-alkylated product. As a conclusion, it is surmised that, unless prevented by chelation, the



isomer 7b' that has the lowest net dipole moment is likely to be the most favourable intermediate and explain the selective formation of the E-product.

Scheme 3. Rationalization for the conversion of Z-isomer into E-isomer and formation of the E-products.

The full conversion of Z-isomer 7a into E-isomer 7b at 37 °C prompted us to carry out the Mitsunobu reaction at that temperature to furnish the alkylated product with exclusively Estereochemistry. This observation also drove us to set up the same reaction with the enamino ester prepared via Rh2(OAc)4 route (Scheme 2) containing mainly (>90%) the E-isomer 7b. Surprisingly 1H-NMR of one and the other were truly found to be the exact blueprint of what was observed with 7a. The E-stereochemistry of all the products 8a-k were confirmed by 1HNMR analysis which was also unambiguously supported by single crystal X-ray crystallographic analysis of 8j (Figure 2). Based on these observations, and in order to keep our approach metalfree, we decided to continue our synthetic endeavours with the Z-isomer 7a obtained from diazo decomposition of 10 with p-TsOH (Scheme 2).


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In a similar manner, S-trityl-2-mercaptoethanol 11b20 and N-Boc-ethanolamine 11j21 (Table 1, entries 2, 10) effortlessly furnished the anticipated products, 8b in quantitative yield and 8j in 86% yield. We next explored the use of homologous alkylating agents 11d,22 11e23 and 11k24 (Table 1, entries 4, 5, 11) and were pleased to find that our designed protocol worked very well to deliver the Mitsunobu products 8d, 8e and 8k respectively, without compromising the yields.

Figure 2. X-ray crystal structure of 8j.

Over and above, we also investigated the suitability of the method with the substituted chiral alcohols (Table 1, entries 7-9) to examine the influence of the substitution on diastereoselectivity in

the

subsequent

intramolecular

cyclization

stage

(Table

4).

When

(R)-1-(tert-

butyldimethylsilyloxy)propan-2-ol 11g25 was subjected to the optimized reaction condition, it failed to provide the desired product. Gratifyingly, altering the addition sequences furnished the alkylated product 8g by following the procedure B (Table 1, entry 7), where the THF solution of alcohol (11g), PPh3 and DEAD was stirred for 20 min at 0 °C followed by treatment of the mixture with 7a and then heating the reaction at 37 °C for 5 h. But this modified procedure B failed in the Mitsunobu reaction with (R)-2-(tert-butyldimethylsilyloxy)-1-phenylethan-1-ol 11h26 having a reactive benzyl alcohol prompting us for further manipulations of the reaction protocol by changing the order of adding the components and screening the solvents. Indeed, 9 ACS Paragon Plus Environment


when a toluene/THF (3:2) solution of β-enamino ester 7a, benzyl alcohol 11h and PPh3 were treated with DEAD at 0 °C and stirred at 37 °C for 6 h, it resulted in the desired product 8h (procedure C, Table 1, entry 8). Further to create the structural diversity, we selected alcohol 11i27,28 to carry out Mitsunobu alkylation with the primary hydroxyl group and more importantly to forge the oxazolidine ring (with substitution at C-5 instead of C-4) by intramolecular Michael addition at the later stage. Alcohol 11i worked well under both conditions, B and C, at 65 °C (Table 1, entry 9). During the course of optimization, it was observed that temperatures lower than 65 °C slowed down the reaction providing a mixture of the alkylated products 8h and 8i resulting from both the primary and secondary hydroxyl groups due to an in situ migration of the silyl group during the course of the reaction. Unlike N-Boc-ethanolamine 11j and N-Boc-propanolamine 11k which underwent Mitsunobu reactions under condition A, alkylation with N-tosyl-ethanolamine 11c29 and N-tosylpropanolamine 11f30 were found to be more challenging which failed to work in any of the optimized conditions A, B or C. The reaction was particularly precarious because both 11c and 11f themselves hold the nucleophilic component which could undergo self-Mitsunobu alkylation. On that account, we had to explore a new protocol to avoid the formation of any self-alkylated product. Notably, when a toluene solution of β-enamino ester 7a, PPh3 and DEAD was stirred at 0 °C for 10 min and then at 37 °C for 15 min followed by the addition of alcohol 11c or 11f, the emergence of the expected product was found to be fruitful (procedure D, Table 1, entries 3 and 6). It is worth mentioning here that, to the best of our knowledge, this is the first example of alkylation of E/Z-α-phenyl-β-enamino esters 7a and 7b via a Mitsunobu procedure. The 10 ACS Paragon Plus Environment

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rationally designed N-tethered alkene-alcohol/thiol/amines were now ready for final ring closure under intramolecular hetero-Michael addition reaction to layout the target N-heterocyclic compounds. Compound 8a was chosen as the first substrate to establish an optimized reaction condition for the intramolecular cyclization to furnish the target oxazolidine framework. The results are summarized in Table 2. To begin with, when alkenol 8a was treated with HF/Py in THF for 2 h, it led solely to the TBSdeprotected product 12a (Table 2, entry 1) failing to provide the desired cyclized product 9a. Use of camphorsulfonic acid (CSA) led to the same result (Table 2, entry 2). Treatment with KF failed to give any reaction leading to the recovery of starting material (Table 2, entry 3). Table 2. Optimizations for intramolecular cyclization.a

a b

Entry

Reagent (eq.)

Solvent

Temp. (°C)

Time (h)

Product

Yield b (%)

1

HF/Py

THF

RT

2

12a

93

2

CSA (2.5)

DCM/EtOH (2:1)

37

3

12a

90

3

KF (3.0)

EtOH

RT

12

-

-

4

BF3 OEt2 (1.2)

CH2Cl2

RT

0.5

9a e (dr = 1:1)

92

5

BF3 OEt2 (1.2)

CH2Cl2

0

0.5

12a

94

6

TFA

CH2Cl2

0

12

13a & 9a (1.5:1) e (9a: dr = 1.1:1)

87

7

TBAF (1.1)

THF

0

1

13a

90

c

.

.

f

d

Unless otherwise stated, all reactions were carried out using 1.0 equivalent of 8a (0.10 mmol) in 1.5 mL of solvent. Yields of isolated products after purification by silica-gel column chromatography. c The reaction was carried out



using HF.Py/Py/THF (1:1:3). d No reaction; starting material was recovered. e The ratio was determined by 1H-NMR spectroscopy of the crude mixture. f The reaction was carried out using TFA/CH2Cl2 (1:6).

Gratifyingly, the reaction occurred to produce the desired oxazolidine 9a in 92% yield when alkenol 8a was stirred with 1.2 equiv of BF3.OEt2 at room temperature for 30 min albeit with no diastereoselectivity (Table 2, entry 4). Lowering the reaction temperature resulted in the formation of only 12a (Table 2, entry 5). Reaction with trifluoroacetic acid (TFA) at 0 °C for 12 h gave a (1.5:1) mixture of 13a and oxazolidine 9a (dr = 1.1:1) (Table 2, entry 6). The reaction with 1.1 equiv of tetrabutylammonium fluoride (TBAF) furnished the O-tethered alkenylamine 13a, presumably via 9a, in 90% yield in 1 h (Table 2, entry 7). The stereostructure of 13a was confirmed from the NOESY experiment. NOE crosspeak between olefinic proton and methylene proton of ester indicated that these two were syn to each other (see supporting information).

Despite extensive efforts, we have so far been unable to deliver the oxazolidine in a single step with better diastereoselectivity, which prompted us to look for an alternate way to achieve the cyclization. With this objective in mind, it was planned to attempt cyclization on 12a and 13a discretely under basic conditions. A brief screening of bases was performed for the intramolecular cyclization. It was observed that 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or K2CO3 did not lead to the cyclized product. Subsequently, intramolecular hetero-Michael addition was performed on 12a in THF at 0 °C using 0.5M toluene solutions of LiHMDS, NaHMDS and KHMDS.31 We were pleased to observe the formation of the desired oxazolidine with good to moderate diastereoselectivity. During the course of the reaction, we observed that conversion of 12a into 13a preceded the cyclization as evident from TLC and was confirmed by 1H-NMR. The best selectivity was obtained with KHMDS (Table 3, entry 3). In due course, both the substrates 12a and 13a, 12 ACS Paragon Plus Environment

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separately, were made to react with KHMDS in THF at -5 °C (Table 3, entries 4-5). Distinctly, the O-tethered alkenol 13a when subjected to cyclization produced the cyclized product in high yield with much better diastereoselectivity. Further lowering of the reaction temperature to -15 °C showed marked boost in diastereoselectivity (Table 3, entry 7). Table 3. Optimizations for oxa-/aza-Michael addition.a

c

Entry

Substrate

Reagent (eq.)

Temp. (°C)

Time (h)

Yield b (%)

dr

1

12a

LiHMDS (1.0)

0

15

88

6.7:1

2

12a

NaHMDS (1.0)

0

17

87

7.4:1

3

12a

KHMDS (1.0)

0

20

81

8.5:1

4

12a

KHMDS (1.0)

-5

21

82

10:1

5

13a

KHMDS (1.0)

-5

17

87

13:1

6

13a

KHMDS (0.9)

-10

15

92

15:1

7

13a

KHMDS (0.9)

-15

18

91

35:1

a

All reactions were carried out using 1.0 equiv of 12a or 13a (0.10 mmol) and 0.5 M toluene solution of the reagent in 2 mL of THF. b Yields refer to pure isolated products. c Diastereomeric ratios were determined by 1H-NMR analysis of the chromatographically purified material.

Next, to further investigate the scope of these reactions in one pot, the reaction from 8a to 13a was performed using first TBAF in THF at 0 °C. Once the reaction gave rise to 13a as evident from TLC, the temperature was lowered to -15 °C and KHMDS solution was added to provide the cyclized product 9a. The reaction was found to be comparatively slower and led to reduced diastereoselectivity.



Although, the one pot strategy was found to be effective in all cases, but to achieve better diastereoselectivities it was decided to opt for the two-step strategy for all the N-tethered alkenylalcohol Mitsunobu products. Compounds 8d, 8g-i were thus converted first to their Otethered alkenylamines 13d, 13g-i respectively in good yields (91-83%) following the best deprotection condition (Table 2, entry 7) using TBAF at 0 °C (Scheme 4).

Scheme 4. Preparation of the O-tethered alkenylamines.

Further, alkenylamines were subjected to intramolecular cyclization following the optimum condition developed for 13a (Table 3, entry 7) to deliver the target N-heterocycles 9d, 9g-i (Table 4, entries 2-5). Efficient cyclization was observed for the substrates with substituents (Table 4, especially entries 3 and 5). For example, 13i delivered 9i in 87% yield and with complete diastereoselectivity. We were also delighted to see that both 5-membered and 6-membered rings were formed with equal ease. The 1,3-oxazinane ring was obtained under optimized conditions at 32 °C in 81% yield and 91:9 dr (Table 4, entry 2).


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Table 4. Synthesis of N-heterocycles via intramolecular aza-Michael addition from O-tethered alkenylamines.a

Entry

Substrate

Reagent

Solvent

Temp. (°C)

Time (h)

1

KHMDS

THF

-15

2

KHMDS

THF

3

KHMDS

4

5

Product

b

c

Yield (%)

dr

18

91

>97:3

32

30

81

91:9

THF

-15

14

92

>98:2

KHMDS

THF

-15

15

83

93:7

KHMDS

THF

-15

12

87

single Isomer

a

All reactions were carried out using 1.0 equiv of starting substrate (0.10 mmol), KHMDS (0.5 M in toluene, 0.9 equiv) in 2 mL of solvent. b Yields refer to pure isolated products. c Diastereomeric ratios were determined by 1HNMR analysis of the pure, isolated material.

While the N-tethered alkenylalcohols needed two steps to furnish the target N-heterocyclic products, both N-tethered alkenylamines (8c and 8f) and alkenylthiols (8b and 8e) underwent cyclizations in a single step. Following the same cyclization conditions developed for 13a (Table 3, entry 7), N-tethered alkenylamines 8c and 8f also delivered imidazolidine 9c and hexahydropyrimidine 9f as single compounds in 83% and 77% yields, respectively (Table 5, entries 2 and 4). Similarly, the construction of 1,3-thiazolidine 9b and 1,3-thiazinane 9e also required only one step after the Mitsunobu reaction. The cyclised products 9b and 9e were



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obtained from the N-tethered tritylated-alkenylthiols 8b and 8e in one pot using TFA in good yields and diastereoselectivities (Table 5, entries 1 and 3). A conclusive verification of the stereochemical outcome of the hetero-Michael addition reaction was obtained by X-ray crystallographic analysis of 9b, 9c, 9f and 9i (Figure 3). Molecular framework of the compounds revealed that the C2-substituent and the tosyl group are antiperiplanar to each other. Stereochemical assignments of other variants were assigned by analogy. Table 5. Synthesis of N-heterocycles via intramolecular hetero-Michael addition from N-tethered alkenylthiols and alkenylamines.

Entry

Substrate

Reagent

a

1

TFA

2

KHMDS

3

TFA

b

a

Product

Yield (%)

b

KHMDS

d

Temp. (°C)

Time (h)

CH2Cl2

-10

12

75

>96:4 (>95:5)

THF

-15

20

83

single Isomer

CH2Cl2

0

15

79

86:14 (>85:15)

77

single Isomer

NTs

4

c

Solvent

toluene

Reflux

12

N Ts

Ph H CO2Et

dr

9f

a

The reaction was carried out using TFA/DCM (1:20). b The reaction was carried out using 1.0 equiv of starting substrate (0.10 mmol), KHMDS (0.5 M in toluene, 0.9 equiv) in 2 mL of solvent. c Yields refer to pure isolated products. d Diastereomeric ratios were determined by 1H-NMR analysis of the pure, isolated material. Numbers in parentheses are diastereomeric ratios observed by NMR analysis of the crude reaction mixtures.

We next sought to prepare another imidazolidine 9j and hexahydropyrimidine 9k scaffolds having either one of the N-atoms free from any protecting group or orthogonally protected Natoms for a facile β-lactam synthesis. They were initially planned to be synthesized from 8j and 16 ACS Paragon Plus Environment

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8k, respectively, in one step. With an aim to attempt one pot cyclization, the substrates 8j and 8k when treated with KHMDS resulted in no cyclization and reaction with TFA, unfortunately, provided only the Boc-deprotected compounds 14j and 14k (Scheme 5). Further efforts towards cyclization of free amines with KHMDS delivered the E/Z-mixture of 15j-16j and 15k-16k, but again failed to provide any cyclized product under various reaction conditions. Next, we transformed the free amine substrates 14j and 14k into their corresponding N-tosyl-derivatives 8c and 8f (Scheme 5). The spectroscopic data of the products obtained from

Figure 3. X-ray crystal structures of 9b, 9c, 9f and 9i. this approach were in full accord with the previous ones, cyclizations of which have already been discussed in Table 5 (entries 2 and 4).



Scheme 5. Attempted cyclization of differentially protected N-tethered amines 8j and 8k.

A model that accounts for the stereochemical outcome of the hetero-Michael addition products is illustrated in Figure 4. Transformations of substrates 13a, 13g-i proceeds via transition state 14, in which the O-tethered alkene is oriented in equatorial position anti to tosyl group to avoid steric strain that would be present in the transition state 15. Substrates 8b-c undergo cyclization via transition state 16, in which N-tethered alkene is oriented in equatorial position anti to tosyl group to minimize A1,3-strain present in an alternative transition state 17. Cyclization of 13d moves along with transition state 18, in which O-tethered alkene is oriented in axial position anti to tosyl group to avoid steric strain encountered in 19, while substrates 8e-f follow cyclization through the transition state 20 to minimize A1,3-strain present in transition state 21. The high diastereoselectivity observed in the protonation of the intermediate ester enolate arises due to the presence of an adjacent chiral centre and in all the cases, it is observed that the protonation occurred very selectively antiperiplanar to the α-NTs substituent probably through a transition state like 22 (Figure 4) in which there also exists the possibility of a chelation between the ester enolate and NTs.32


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Figure 4. Proposed stereochemical models for hetero-Michael addition reactions.

The carefully designed 1,3-X,N-heterocyclic scaffolds synthesized here also represent masked αsubstituted-β-amino acids (highlighted in Scheme 1), similar to extensively studied conformationally constrained β2,3- and β3-homoprolines and can have great potential utility in peptidomimetic studies due to the roles played by them in biology as isosteres of α-amino acids.33-35



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CONCLUSION Driven by the ever-increasing demands for small functionalized bioactive scaffolds and the need of broadening the toolbox of unexplored chemical space, we have demonstrated for the first time the ability of α-phenyl-β-enamino ester to serve both as a nucleophilic and an electrophilic component under two sets of circumstances. In the first instance, the employment of α-phenyl-βenamino ester in Mitsunobu reaction proved to be beneficial to accomplish N-tethered alkeneanalogues which would serve as a valuable modular synthon for any later stage functionalization. In the second instance, we extended the synthetic utility of the Mitsunobu adduct as a key to intramolecular Michael-addition under mildly basic and/or acidic conditions to rapidly construct the

unique

five/six-membered

1,3-

oxazolidine/thiazolidine/imidazolidine/oxazinane/thiazinane/hexahydropyrimidine ring systems with two contiguous stereocenters in a single step with high yield and excellent diastereoselectivities. The strategy presented herein is flexible and can be adopted for a limitless array of possibilities to obtain other enticing heterocyclic variants of biological importance. In the light of importance, the wide substrate scope, excellent diastereoselectivity, mild reaction condition and ease of operation make this strategy highly beneficial to produce complex heterocyclic molecules. Further exploration of its synthetic utility is currently underway and will be reported in due course. EXPERIMENTAL SECTION General Experimental Details: All the reactions were carried out under an inert atmosphere in oven-dried glassware using dry solvents, unless otherwise stated. All chemicals purchased from commercial suppliers were used as received unless otherwise stated. Reactions and chromatography fractions were monitored by 20 ACS Paragon Plus Environment

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Merck silica gel 60 F-254 glass TLC plates and visualized using UV light, 7% ethanolic phosphomolybdic acid-heat or 2.5% ethanolic anisaldehyde (with 1% AcOH and 3.3% conc. H2SO4)-heat, or 1.5% n-butanolic ninhydrin (with 3% AcOH)-heat as developing agents. Flash column chromatography was performed with 100-200 mesh silica gel and yields refer to chromatographically and spectroscopically pure compounds.

Instrumentation: All NMR spectra were recorded in CDCl3 on a 400 MHz instruments at 300 K and are calibrated to residual solvent peaks (CHCl3 7.26 ppm and 77.0 ppm). For 1H-NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = double of doublet, ddd = doublet of doublet of doublet, t = triplet, q = quartet, dq = doublet of duartet, quint = quintet, sext = sextet, m = multiplet), coupling constants (Hz) andintegration. Infrared (FT-IR) spectra were recorded on PerkinElmer Spectrum BX spectrophotometer, νmax in cm-1. High resolution mass spectrometry (HRMS) was performed onMicromass Q-TOF Micro instrument. Optical rotations were measured on JASCO P-2000 polarimeter. Melting point is uncorrected and was determined in capillary tube on Buchi melting point M-560 apparatus. XRay crystallographic structure were collected on a Bruker D8 Quest diffractometer (for 9b, 9c, 9i) and Xcalibur, Eos, Nova diffractometer (for 8j, 9f). Experimental Procedures and Characterization Data: General procedure for the Mitsunobu alkylation: Procedure A: To an oven-dried round-bottom flask was added triphenylphosphine (4.0 equiv) in THF (3mL/mmol) and the mixture was cooled to 0 °C (ice bath). The solution was then treated with DEAD (4.0 equiv) and the mixture was stirred for 20 min resulting in the precipitation of the phosphine-DEAD adduct. To the slurry was then added β-enamino ester 7a (2.0 equiv) and the resultant mixture was stirred at 0 °C. After 15 min, a solution consisting of alcohol 11 in THF was added and the reaction mixture was then stirred at 37 °C (oil bath) until complete. After that it was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc and the combined organic extracts were washed with water, brine, dried over Na2SO4. Solvent was concentrated in vacuo and the residue was purified by flash column chromatography using neutral alumina. 21 ACS Paragon Plus Environment


Procedure B: To an oven-dried round bottom flask was added the alcohol 11, PPh3 (4.0 equiv) in toluene/THF (3mL/mmol). The mixture was cooled to 0 °C (ice bath) and treated with DEAD (4.0 equiv) to give a bright yellow solution. After 20 min, the β-enamino ester 7a (2.0 equiv) was added and the reaction mixture was then heated at 37 °C/65 °C (oil bath) until complete. After that it was quenched with saturated aqueous NH4Cl solution. The mixture was then extracted with EtOAc and the combined organic extracts were washed with water, brine, dried over Na2SO4. Solvent was concentrated in vacuo and the residue was purified by flash column chromatography using neutral alumina. Procedure C: To an oven-dried round bottom flask was added the alcohol 11, β-enamino ester 7a (2.0 equiv), PPh3 (4.0 equiv) in toluene-THF (3:2) or toluene (3mL/mmol). The mixture was cooled to 0 °C (ice bath) and treated with DEAD (4.0 equiv) to give a bright yellow solution. After stirring for 5 min at 0 °C, the reaction mixture was stirred at 37 °C/65 °C (oil bath). The reaction was continued until TLC revealed a complete consumption of the alcohol substrate. After that it was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc and the combined organic extracts were washed with water, brine, dried over Na2SO4. Solvent was concentrated in vacuo and the residue was purified by flash column chromatography using neutral alumina. Procedure D: To an oven-dried round bottom flask was added β-enamino ester 7a (2.0 equiv), PPh3 (4.0 equiv) in THF (3mL/mmol). The mixture was cooled to 0 °C (ice bath) and treated with DEAD (4.0 equiv) to give a bright yellow solution. After stirring for 10 min at 0 °C the reaction mixture was stirred at 40 °C (oil bath) for further 15 min. Then the alcohol 11 was added and stirring was continued until TLC revealed the complete consumption of alcohol substrate. After that it was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc and the combined organic extracts were washed with water, brine, dried over Na2SO4. Solvent was concentrated in vacuo and the residue was purified by flash column chromatography using neutral alumina. Data for 8a: Prepared following the procedure A; scale of reaction 100 mg, 0.57 mmol; yield 240 mg, 84% as colorless oil. Rf = 0.6 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.777.73 (m, 2H), 7.39-7.34 (m, 2H), 7.26-7.21 (m, 3H), 6.96-6.89 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.32-3.26 (m, 2H), 3.10-3.04 (m, 2H), 2.46 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 0.77 (s, 9H), -0.09 22 ACS Paragon Plus Environment

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(s, 6H); 13C NMR (100 MHz, CDCl3): δ 167.4, 144.4, 137.0, 135.9, 133.7, 130.2, 130.0, 128.1, 127.9, 127.2, 116.8, 60.9, 60.1, 47.8, 25.7, 18.1, 14.3, -5.5; IR νmax (neat, cm–1): 3403, 2922, 2852, 1637, 1454, 1362, 1220, 1017; HRMS (ESI): calcd for C26H37NO5SSiNa: 526.2059 ([M+Na]+), found 526.2059. Data for 8b: Prepared following the procedure A; scale of reaction 150 mg, 0.47 mmol; yield 302 mg, quantitative yield as colorless oil. Rf = 0.6 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.597.55 (m, 2H), 7.30-7.18 (m, 20H), 6.84-6.79 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.93-2.87 (m, 2H), 2.43 (s, 3H), 1.94-1.89 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.4, 144.5, 135.9, 135.4, 133.2, 130.2, 129.9, 128.14, 128.09, 127.2, 126.6, 115.9, 66.4, 60.9, 44.7, 29.4, 21.6, 14.3; IR νmax (neat, cm–1): 3435, 2921, 2855, 1705, 1617, 1445, 1360, 1255, 1162, 1019; HRMS (ESI): calcd for C39H37NO4S2Na: 670.2062 ([M+Na]+), found 670.2064. Data for 8c: Prepared following the procedure D; scale of reaction 100 mg, 0.46 mmol; yield 179 mg, 71% as colorless oil. Rf = 0.3 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 7.737.68 (m, 2H), 7.67-7.60 (m, 2H), 7.40-7.35 (m, 2H), 7.34-7.21 (m, 5H), 6.97-6.89 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.92 (dd, J = 12.6, 6.2 Hz, 1H), 3.03 (t, J = 6.7 Hz, 2H), 2.63 (q, J = 6.7 Hz, 2H), 2.47 (s, 3H), 2.45 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.2, 145.1, 143.6, 136.4, 135.9, 134.5, 133.6, 130.5, 130.2, 129.7, 128.26, 128.21, 127.3, 127.1, 114.7, 61.1, 45.4, 40.8, 21.7, 21.5, 14.2; IR νmax (neat, cm–1): 3397, 2920, 1703, 1647, 1420, 1362, 1160, 1019; HRMS (ESI): calcd for C27H30N2O6S2K: 581.1182 ([M+K]+), found 581.1183. Data for 8d: Prepared following the procedure A; scale of reaction 100 mg, 0.52 mmol; yield 242 mg, 89% as light yellow oil. Rf = 0.7 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.777.72 (m, 2H), 7.37-7.33 (m, 2H), 7.29-7.22 (m, 3H), 7.04-6.99 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.09-3.03 (m, 2H), 2.95 (t, J = 6.0 Hz, 2H), 2.46 (s, 3H), 1.31-1.23 (m, 5H), 0.80 (s, 9H), -0.10 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 167.7, 144.5, 136.6, 135.7, 133.9, 130.6, 130.0, 127.9, 127.3, 114.9, 60.9, 59.9, 43.9, 30.6, 25.8, 21.6, 18.1, 14.3, -5.5; IR νmax (neat, cm–1): 3404, 2928, 2854, 1702, 1652, 1466, 1362, 1256, 1017; HRMS (ESI): calcd for C27H39NO5SSiNa: 540.2216 ([M+Na]+), found 540.2219. 23 ACS Paragon Plus Environment


Data for 8e: Prepared following the procedure A; scale of reaction 150 mg, 0.45 mmol; yield 297 mg, quantitative yield as colorless oil. Rf = 0.6 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.727.66 (m, 2H), 7.35-7.10 (m, 20H), 6.93-6.87 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.90-2.82 (m, 2H), 2.45 (s, 3H), 1.45 (t, J = 7.3 Hz, 2H), 1.27-1.16 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 167.5, 144.6, 144.5, 136.2, 135.7, 133.7, 130.4, 130.0, 129.4, 127.93, 127.89, 127.8, 127.2, 126.6, 115.2, 66.4, 60.9, 45.4, 28.3, 26.7, 21.6, 14.3; IR νmax (neat, cm–1): 3451, 2923, 2852, 1743, 1651, 1575, 1458, 1353, 1280, 1167, 1021; HRMS (ESI): calcd for C40H39NO4S2Na: 684.2218 ([M+Na]+), found 684.2221. Data for 8f: Prepared following the procedure D; scale of reaction 100 mg, 0.43 mmol; yield 179 mg, 75% as colorless oil. Rf = 0.3 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.747.67 (m, 2H), 7.67-7.60 (m, 2H), 7.41-7.35 (m, 2H), 7.31-7.19 (m, 5H), 6.98-6.88 (m, 2H), 4.25 (br s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.00 (t, J = 7.1 Hz, 2H), 2.55-2.46 (m, 5H), 2.42 (s, 3H), 1.31-1.21 (m, 5H);

13

C NMR (100 MHz, CDCl3): δ 167.5, 144.8, 143.4, 136.7, 135.7, 135.2,

133.8, 130.5, 130.2, 129.7, 128.2, 128.0, 127.1, 126.9, 115.4, 61.1, 43.2, 39.4, 27.7, 21.6, 21.5, 14.2; IR νmax (neat, cm–1): 3400, 2921, 2858, 2362, 1602, 1442, 1359, 1219, 1160, 1021; HRMS (ESI): calcd for C28H32N2O6S2Na: 579.1599 ([M+Na]+), found 579.1602. Data for 8g: Prepared following the procedure B in THF at 37 °C; scale of reaction 100 mg, 0.52 mmol; yield 207 mg, 77% as light yellow oil. Rf = 0.8 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.73-7.67 (m, 2H), 7.66 (s, 1H), 7.35-7.30 (m, 2H), 7.29-7.26 (m, 3H), 7.14-7.06 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.63-3.52 (m, 2H), 3.22 (dd, J = 9.64, 5.88 Hz, 1H), 2.45 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 0.820.76 (s, 12H), -0.06 (s, 3H), -0.07 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.1, 143.9, 138.7, 136.8, 134.1, 130.1, 129.8, 128.1, 128.0, 127.4, 125.4, 65.4, 61.0, 60.6, 25.7, 21.6, 18.0, 14.9, 14.2, -.5.5, -5.6; IR νmax (neat, cm–1): 3400, 2923, 2853, 1712, 1637, 1459, 1357, 1259, 1166, 1019; HRMS (ESI): calcd for C27H39NO5SSiNa: 540.2216([M+Na]+), found 540.2213; optical rotation [α]D22 +72.1 (c 0.81, CHCl3). Data for 8h: Prepared following the procedure C in toluene-THF (3:2) at 37 °C; scale of reaction 100 mg, 0.40 mmol; yield 187 mg, 81% as colorless oil.


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Rf = 0.6 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.317.26 (m, 5H), 7.20-7.09 (m, 7H), 6.91-6.86 (m, 2H), 4.87 (t, J = 7.1 Hz, 1H), 4.26-4.17 (m, 2H), 4.04-3.96 (m, 2H), 2.41 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.8 (s, 9H), -0.01 (s, 3H), -0.05 (s, 3H); 13

C NMR (100 MHz, CDCl3): δ 167.5, 143.7, 138.3, 136.4, 135.2, 133.8, 130.3, 129.4, 128.7,

128.2, 128.0, 127.8, 127.6, 127.3, 64.2, 63.1, 61.0, 25.7, 21.5, 18.1, 14.2, -5.4, -5.6; IR νmax (neat, cm–1): 3397, 2924, 2857, 1709, 1647, 1420, 1363, 1250, 1161, 1019; HRMS (ESI): calcd for C32H41NO5SSiNa: 602.2372 ([M+Na]+), found 602.2371; optical rotation [α]D22 +86.6 (c 0.61, CHCl3). Data for 8i: Prepared following the procedure B/C in toluene at 65 °C; scale of reaction 100 mg, 0.4 mmol; yield 199 mg, 86% as light yellow oil. Rf = 0.6 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.737.69 (m, 2H), 7.37-7.33 (m, 2H), 7.22-7.15 (m, 6H), 6.95-6.90 (m, 2H), 6.80-6.75 (m, 2H), 4.70 (dd, J = 9.4, 3.4 Hz, 1H), 4.26-4.18 (m, 2H), 3.21 (dd, J = 14.8, 9.4 Hz, 1H), 2.85 (dd, J = 14.8, 3.4 Hz, 1H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.84 (s, 9H), 0.07 (s, 3H), -0.21 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.4, 144.2, 141.6, 137.5, 136.3, 134.0, 130.4, 129.9, 128.1, 128.0, 127.6, 126.9, 126.2, 117.8, 73.7, 60.9, 53.5, 25.8, 21.6, 17.9, 14.3, -4.9; IR νmax (neat, cm–1): 3400, 2926, 2855, 1708, 1607, 1455, 1359, 1252, 1163, 1020 ; HRMS (ESI): calcd for C32H41NO5SSiNa: 602.2372 ([M+Na]+), found 602.2375; optical rotation [α]D22 -53.8 (c 0.53, CHCl3). Data for 8j: Prepared following the procedure A; scale of reaction 100 mg, 0.62 mmol; yield 260 mg, 86%. Solid was crystallized to get colorless crystal plates suitable for X-ray crystallographic analysis from EtOAc/n-Hexane = 1:5 at 25 °C [m.p. = 88.6-91.4 ºC, see ORTEP presentation, Figure 2]. Rf = 0.4 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.767.72 (m, 2H), 7.40-7.36 (m, 2H), 7.31-7.22 (m, 3H), 6.99-6.90 (m, 2H), 4.27 (br s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.06 (t, J = 6.0 Hz, 2H), 2.81 (q, J = 6.0 Hz, 2H), 2.47 (s, 3H), 1.40 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H);

13

C NMR (100 MHz, CDCl3): δ 167.3, 155.7, 144.7, 136.1, 135.4, 133.7,

130.4, 130.1, 128.1, 127.2, 116.6, 79.3, 61.0, 45.5, 38.3, 28.3, 21.6, 14.2; IR νmax (neat, cm–1): 3400, 2978, 2928, 1708, 1615, 1449, 1361, 1247, 1166, 1019; HRMS (ESI): calcd for C25H32N2O6SNa: 511.1879 ([M+Na]+), found 511.1878.



Page 26 of 36

Data for 8k: Prepared following the procedure A; scale of reaction 100 mg, 0.57 mmol; yield 237 mg, 83% as colorless oil. Rf = 0.4 (silica gel, 20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.757.71 (m, 2H), 7.39-7.35 (m, 2H), 7.29-7.23 (m, 3H), 7.00-6.96 (m, 2H), 4.22-4.16 (m, 3H), 3.042.97 (m, 2H), 2.76-2.61 (m, 2H), 2.47 (s, 3H), 1.40 (s, 9H), 1.35-1.23 (m, 5H);

13

C NMR (100

MHz, CDCl3): δ 167.5, 155.7, 144.6, 136.1, 135.6, 133.9, 130.6, 130.1, 128.2, 128.0, 127.1, 115.5, 61.0, 43.8, 37.0, 28.4, 27.9, 21.6, 14.3; IR νmax (neat, cm–1): 3399, 2923, 2852, 1706, 1600, 1450, 1360, 1255, 1164, 1020; HRMS (ESI): calcd for C26H34N2O6SNa: 525.2035 ([M+Na]+), found 525.2037. Preparation of 12a: To a stirred solution of 8a (100 mg, 0.2 mmol, 1.0 equiv) in CH2Cl2-EtOH (2:1, 3 mL) at 0 ºC, CSA (116 mg, 0.50 mmol, 2.5 equiv) was added. After stirring for 3 h at 37 ºC, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate. After filtration and concentration in vacuo, the resulting residue was purified by flash column chromatography (silica gel, 20%EtOAc in hexane) to afford 12a (70 mg, 90% yield) as colorless liquid. Data for 12a: Scale of reaction 100 mg, 0.20 mmol; yield 70 mg, 90% as light yellow oil. Rf = 0.5 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.807.72 (m, 2H), 7.40-7.36 (m, 2H), 7.32-7.27 (m, 3H), 7.05-6.98 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.28-3.21 (m, 2H), 3.15-3.09 (m, 2H), 2.47 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H);

13

C NMR (100

MHz, CDCl3): δ 167.4, 144.8, 136.4, 135.1, 133.8, 130.4, 130.1, 128.2, 127.3, 115.6, 61.1, 59.7, 48.1, 21.6, 14.2; IR νmax (neat, cm–1): 3399, 2923, 2853, 1704, 1620, 1452, 1356, 1260, 1161, 1018; HRMS (ESI): calcd for C20H23NO5SNa: 412.1195 ([M+Na]+), found 412.1198. General procedure for silyl deprotection (13a, 13d, 13g-i): TBAF (1 M in THF, 0.22 mmol, 1.1 equiv) was added to a solution of compound (8a/8d/8g-i) (0.2 mmol, 1.0 equiv) in THF (0.6 mL) at 0 ºC. The solution was stirred at 0 ºC until TLC revealed the complete consumption of the starting substrate and after that it was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water, brine, dried over sodium sulfate. Solvent was concentrated in vacuo and the residue was purified by silica gel (100-200 mesh) flash column chromatography. 26 ACS Paragon Plus Environment

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Data for 13a: Scale of reaction 100 mg, 0.20 mmol; yield 70 mg, 90% as colorless oil. Rf = 0.45 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.74-7.62 (m, 2H), 7.46 (s, 1H), 7.37-7.26 (m, 7H), 4.71 (t, J = 5.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.03 (t, J = 5.3 Hz, 2H), 3.23-3.15 (m, 2H), 2.42 (s, 3H), 1.29-1.24 (m, 3H);

13

C NMR (100 MHz, CDCl3): δ

167.3, 157.0, 143.7, 136.7, 132.3, 130.0, 129.8, 127.8, 127.2, 126.9, 112.9, 72.9, 60.5, 42.6, 21.5, 14.2; IR νmax (neat, cm–1): 3298, 3275, 2920, 2854, 1683, 1629, 1447, 1331, 1273, 1157, 1018; HRMS (ESI): calcd for C20H23NO5SNa: 412.1195 ([M+Na]+), found 412.1198. Data for 13d: Scale of reaction 103 mg, 0.20 mmol; yield 73 mg, 91% as light yellow oil. Rf = 0.4 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.65-7.59 (m, 2H), 7.51 (s, 1H), 7.37-7.24 (m, 7H), 4.66 (t, J = 5.6 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.04 (t, J = 5.9 Hz, 2H), 3.02-2.96 (m, 2H), 2.41 (s, 3H), 1.86-1.78 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.5, 157.5, 143.4, 136.7, 132.5, 129.9, 129.7, 127.9, 127.1, 126.9, 112.3, 72.5, 60.4, 40.3, 29.5, 21.5, 14.3; IR νmax (neat, cm–1): 3405, 2922, 2854, 1651, 1379, 1266, 1120, 1017; HRMS (ESI): calcd for C21H25NO5SNa: 426.1351 ([M+Na]+), found 426.1354. Data for 13g: Scale of reaction 103 mg, 0.20 mmol; yield 71 mg, 88% as colorless oil. Rf = 0.45 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.72-7.66 (m, 2H), 7.45 (s, 1H), 7.36-7.25 (m, 7H), 4.66 (d, J = 7.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.91 (dd, J = 10.3, 4.5 Hz, 1H), 3.85 (dd, J = 10.3, 4.9 Hz, 1H), 3.57-3.46 (m, 1H), 2.41 (s, 3H), 1.28 (t, J =7.1 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.4, 157.4, 143.6, 137.4, 132.3, 130.0, 129.8, 127.7, 127.1, 126.9, 112.6, 77.3, 60.4, 49.1, 21.5, 18.0, 14.3; IR νmax (neat, cm–1): 3397, 3275, 3044, 2861, 1701, 1629, 1425, 1336, 1226, 1161, 1019; HRMS (ESI): calcd for C21H25NO5SNa: 426.1351 ([M+Na]+), found 426.1347; optical rotation [α]D22 -58.0 (c 0.61, CHCl3). Data for 13h: Scale of reaction 116 mg, 0.20 mmol; yield 82 mg, 88% as colorless oil. Rf = 0.48 (silica gel, 30% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.56-7.45 (m, 2H), 7.38 (s, 1H), 7.36-7.26 (m, 3H), 7.25-7.15 (m, 5H), 7.14-7.10 (m, 2H), 7.04-6.99 (m, 2H), 5.11 (d, J = 6.3 Hz, 1H), 4.52-4.46 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.14 (d, J = 5.5 Hz, 2H), 2.36 (s, 3H), 1.25 (t, J =7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.2, 156.8, 143.5, 136.8, 136.5, 132.2, 130.1, 129.5, 128.6, 128.2, 127.7, 127.2, 127.0, 113.0, 76.7, 60.4, 57.1, 21.5, 14.3; IR νmax (neat, cm–1): 3426, 2922, 2854, 1697, 1627, 1455, 1329, 1219, 1156; HRMS (ESI): Calcd 27 ACS Paragon Plus Environment


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for C26H27NO5SNa: 488.1508 ([M+Na]+), found 488.1509; optical rotation [α]D22 +28.9 (c 0.83, CHCl3). Data for 13i: Scale of reaction 116 mg, 0.20 mmol; yield 77 mg, 83% as light yellow oil. Rf = 0.45 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.69-7.61 (m, 2H), 7.41-7.27 (m, 11H), 7.20-7.16 (m, 2H), 4.95 (dd, J = 8.8, 3.8 Hz, 1H), 4.69 (dd, J = 8.5, 4.4 Hz, 1H), 4.22-4.09 (m, 2H), 3.31-3.24 (m, 1H), 3.16-3.07 (m, 1H), 2.42 (s, 3H), 1.22 (t, J =7.1 Hz, 3H);

13

C NMR (100 MHz, CDCl3): δ 167.2, 155.7, 143.7, 136.9, 136.7, 132.6, 130.1, 129.8,

129.2, 129.0, 127.9, 127.2, 126.9, 126.4, 113.9, 84.8, 60.4, 48.7, 21.5, 14.3; IR νmax (neat, cm– 1

): 3402, 3301, 2921, 1650, 1579, 1447, 1376, 1219, 1126, 1020; HRMS (ESI): Calcd for

C26H27NO5SNa: 488.1508 ([M+Na]+), found 488.1509; optical rotation [α]D22 +21.8 (c 0.68, CHCl3). General procedure for aza-Michael addition: To a stirred solution of (13a/8c/13d/8f/13g-i) (0.15 mmol, 1.0 equiv) in THF (3 mL) at -15 ºC (0 ºC in case of 13d and 8f) was added KHMDS (0.5 M in toluene, 0.135 mmol, 0.9 equiv). Stirring was continued at the temperatures mentioned in Tables 4 and 5, until TLC revealed the complete consumption of starting substrate. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. After washing with water, brine, the solvent was dried over sodium sulfate. The combined organic phases were concentrated in vacuo and the resulting residue was purified by silica gel (100-200 mesh) flash column chromatography. Data for 9a: Scale of reaction 58 mg, 0.15 mmol; yield 53 mg, 91% as colorless oil. Rf = 0.55 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.54-7.49 (m, 2H), 7.42-7.38 (m, 2H), 7.37-7.31 (m, 3H), 7.25-7.19 (m, 2H), 5.87 (d, J = 7.7 Hz, 1H), 4.21 (dq, J = 10.8, 7.1 Hz, 1H), 4.14 (dq, J = 10.8, 7.1 Hz, 1H), 3.97-3.89 (m, 1H), 3.80 (d, J = 7.5 Hz, 1H), 3.72-3.62 (m, 1H), 3.39-3.29 (m, 2H), 2.40 (s, 3H), 1.24 (t, J =7.1 Hz, 3H);

13

C NMR (100

MHz, CDCl3): δ 170.4, 144.1, 134.9, 133.7, 129.8, 129.3, 128.5, 127.9, 127.7, 92.2, 65.6, 61.2, 56.7, 46.1, 21.5, 14.0; IR νmax (neat, cm–1): 3399, 2923, 2854, 1728, 1663, 1359, 1209, 1164, 1020; HRMS (ESI): calcd for C20H23NO5SNa: 412.1195 ([M+Na]+), found 412.1194. Data for 9c: Scale of reaction 81 mg, 0.15 mmol; yield 67 mg, 83%. Solid was crystallized to get colorless crystal plates suitable for X-ray crystallographic analysis from EtOAc/n-hexane = 1:5 at 25 °C [m.p. = 128.2-131.1 ºC, see ORTEP presentation, Figure 3].


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Rf = 0.35 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.71-7.66 (m, 2H), 7.50-7.45 (m, 2H), 7.39-7.36 (m, 2H), 7.34-7.29 (m, 5H), 7.16-7.11 (m, 2H), 6.02 (d, J = 4.2 Hz, 1H), 4.33 (d, J = 4.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.20-3.10 (m, 2H), 3.02-2.93 (m, 2H), 2.53-2.46 (m, 4H), 2.39 (s, 3H), 1.33 (t, J =7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.9, 144.3, 143.9, 134.9, 133.4, 132.8, 130.9, 129.8, 129.6, 128.15, 128.08, 127.8, 127.7, 75.5, 61.4, 57.5, 46.7, 46.3, 21.7, 21.6, 14.1; IR νmax (neat, cm–1): 3403, 2921, 2854, 1738, 1592, 1452, 1354, 1219, 1162, 1021; HRMS (ESI): calcd for C27H30N2O6S2Na: 565.1443 ([M+Na]+), found 565.1441. Data for 9d: Scale of reaction 60 mg, 0.15 mmol; yield 49 mg, 81% as colorless oil. Rf = 0.53 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.47-7.41 (m, 2H), 7.37-7.31 (m, 3H), 7.28-7.24 (m, 2H), 7.15-7.05 (m, 2H), 6.23 (d, J = 10.8 Hz, 1H), 4.57 (d, J = 10.8 Hz, 1H), 4.29-4.10 (m, 3H), 3.81-3.75 (m, 1H), 3.55-3.46 (m, 1H), 3.33-3.23 (m, 1H), 2.37 (s, 3H), 1.77-1.64 (m, 1H), 1.31-1.25 (m, 4H);

13

C NMR (100 MHz, CDCl3): δ 170.4, 143.3,

136.9, 133.8, 129.4, 128.85, 128.78, 128.1, 127.7, 83.4, 61.3, 59.9, 51.3, 38.9, 23.0, 21.5, 14.0; IR νmax (neat, cm–1): 3403, 2921, 2851, 1733, 1642, 1453, 1215, 1158, 1019; HRMS (ESI): calcd for C21H25NO5SNa: 426.1351 ([M+Na]+), found 426.1352. Data for 9f: Scale of reaction 83 mg, 0.15 mmol; yield 64 mg, 77%. Solid was crystallized to get light yellow crystal flakes suitable for X-ray crystallographic analysis from EtOAc/n-hexane = 1:5 at 25 °C [m.p. = 217.2-220.7 ºC, see ORTEP presentation, Figure 3]. Rf = 0.3 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.94-7.83 (m, 2H), 7.57-7.49 (m, 2H), 7.39-7.29 (m, 5H), 7.01-6.86 (m, 5H), 4.39 (d, J = 11.1 Hz, 1H), 4.15-4.07 (m, 2H), 3.79-3.71 (m, 1H), 3.59-3.50 (m, 1H), 3.32-3.24 (m, 1H), 3.13-3.03 (m, 1H), 2.42 (m, 3H), 2.31 (s, 3H), 1.33-1.21 (m, 5H);

13

C NMR (100 MHz, CDCl3): δ 169.5, 143.6, 143.1,

137.1, 136.2, 133.8, 129.5, 129.2, 128.9, 128.3, 128.2, 127.6, 66.7, 61.7, 53.1, 39.6, 39.1, 22.7, 21.6, 21.4, 13.9; IR νmax (neat, cm–1): 3413, 2923, 2854, 1733, 1639, 1598, 1454, 1336, 1217, 1160, 1026; HRMS (ESI): calcd for C28H32N2O6S2Na: 579.1600 ([M+Na]+), found 579.1597. Data for 9g: Scale of reaction 60 mg, 0.15 mmol; yield 54 mg, 92% as light yellow oil. Rf = 0.53 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.59-7.52 (m, 2H), 7.49-7.42 (m, 2H), 7.39-7.31 (m, 3H), 7.27-7.22 (m, 2H), 5.72 (d, J = 7.5 Hz, 1H), 4.26-4.10 (m, 2H), 3.97 (d, J = 7.5 Hz, 1H), 3.83 (sext, J = 6.4 Hz, 1H), 3.78-3.71 (m, 1H), 3.66 (dd, J = 8.6, 5.7 Hz, 1H), 2.40 (s, 3H), 1.28-1.23 (m, 6H);

13

C NMR (100 MHz, CDCl3): δ 170.5, 144.0,



Page 30 of 36

134.3, 133.4, 129.75, 129.71, 128.4, 127.95, 127.89, 93.2, 71.9, 61.1, 56.8, 55.1, 21.5, 20.6, 14.0; IR νmax (neat, cm–1): 3403, 2923, 2854, 1731, 1650, 1449, 1355, 1204, 1163, 1019; HRMS (ESI): calcd for C21H25NO5SNa: 426.1351 ([M+Na]+), found 426.1355; optical rotation [α]D22 -12.3 (c 0.9, CHCl3). Data for 9h: Scale of reaction 70 mg, 0.15 mmol; yield 58 mg, 83% as light yellow oil. Rf = 0.6 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.44-7.40 (m, 2H), 7.37-7.28 (m, 8H), 7.25-7.21 (m, 2H), 7.19-7.15 (m, 2H), 6.14 (d, J = 8.8 Hz, 1H), 4.97 (t, J = 7.1 Hz, 1H), 4.18-4.05 (m, 4H), 3.76 (d, J = 8.8 Hz, 1H), 2.39 (s, 3H), 1.18 (t, J =7.1 Hz, 3H); 13

C NMR (100 MHz, CDCl3): δ 170.6, 144.1, 138.3, 134.5, 133.3, 129.7, 129.6, 128.5, 128.4,

128.0, 127.99, 127.88, 126.5, 93.6, 71.6, 61.9, 61.1, 56.2, 21.5, 13.9; IR νmax (neat, cm–1): 3399, 2922, 2855, 1732, 1592, 1452, 1359, 1217, 1163, 1020; HRMS (ESI): calcd for C26H27NO5SNa: 488.1508, found 488.1505; optical rotation [α]D22 +85.9 (c 0.93, CHCl3). Data for 9i: Scale of reaction 70 mg, 0.15 mmol; yield 61 mg, 87%. Solid was crystallized to get colorless crystal plates suitable for X-ray crystallographic analysis from EtOAc/n-hexane = 1:5 at 25 °C [m.p. = 140.2-142.5 ºC, see ORTEP presentation, Figure 3]. Rf = 0.7 (silica gel, 40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.57-7.52 (m, 2H), 7.48-7.43 (m, 2H), 7.35-7.28 (m, 6H), 7.27-7.22 (m, 4H), 5.96 (d, J = 6.8 Hz, 1H), 4.35 (dd, J = 10.4, 5.6 Hz, 1H), 4.28 (dq, J = 10.8, 7.1 Hz, 1H), 4.16 (dq, J = 10.8, 7.1 Hz, 1H), 4.01-3.94 (m, 2H), 3.11 (dd, J = 12.4, 10.4 Hz, 1H), 2.40 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H);

13

C NMR (100

MHz, CDCl3): δ 170.3, 144.3, 137.2, 135.3, 133.8, 129.9, 129.6, 128.54, 128.47, 128.4, 127.9, 127.8, 126.1, 92.3, 79.6, 61.6, 57.8, 53.6, 21.5, 14.1; IR νmax (neat, cm–1): 3399, 2921, 2858, 1732, 1595, 1451, 1363, 1219, 1160, 1021; HRMS (ESI): calcd for C26H27NO5SNa: 488.1508 ([M+Na]+), found 488.1509; optical rotation [α]D22-0.7 (c 0.63, CHCl3). General procedure for thia-Michael addition: To the compound (8b or 8e) (0.15 mmol, 1 equiv) in CH2Cl2 (6 mL) at -10 °C (in case of 8b) and 0 °C (in case of 8e), was added trifluoroacetic acid (TFA; 0.3 mL) and stirring was continued at the temperatures shown in Table 5, until TLC revealed the complete consumption of starting material. The reaction mixture was then concentrated in vacuo, followed by azeotroping with CH2Cl2 for 3 times to obtain the crude mixture which was purified by silica gel (100-200 mesh) flash column chromatography.


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Data for 9b: Scale of reaction 97 mg, 0.15 mmol; yield 46 mg, 75%. Solid was crystallized to get light yellow needle suitable for X-ray crystallographic analysis from EtOAc/n-hexane = 1:10 at 25 °C [m.p. = 82.4-85.7 ºC, see ORTEP presentation, Figure 3]. Rf = 0.4 (silica gel, 25% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.36-7.30 (m, 7H), 7.16-7.11 (m, 2H), 5.94 (d, J = 10.5 Hz, 1H), 4.26-4.04 (m, 3H), 3.73 (d, J = 10.5 Hz, 1H), 3.27 (ddd, J = 10.9, 13.5, 6.6 Hz, 1H), 2.89 (ddd, J = 10.2, 6.6, 1.4 Hz, 1H), 2.65-2.56 (m, 1H), 2.38 (s, 3H), 1.23 (t, J =7.1 Hz, 3H);

13

C NMR (100 MHz, CDCl3): δ 171.0, 143.9, 135.6, 135.5,

129.5, 128.7, 128.7, 128.1, 127.7, 67.2, 61.4, 60.9, 49.8, 31.8, 21.5, 14.0; IR νmax (neat, cm–1): 3421, 2923, 1727, 1596, 1444, 1368, 1219, 1161, 1027; HRMS (ESI): calcd forC20H23NO4S2Na: 428.0966 ([M+Na]+), found 428.0963. Data for 9e: Scale of reaction 99 mg, 0.15 mmol; yield 50 mg, 79% as light yellow semisolid. Rf = 0.45 (silica gel, 25% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.48-7.44 (m, 2H), 7.38-7.25 (m, 5H), 7.13-7.07 (m, 2H), 5.91 (d, J = 11.8 Hz, 1H), 4.47 (d, J = 11.8 Hz, 1H), 4.264.08 (m, 2H), 3.47-3.39 (m, 1H), 3.27-3.17 (m, 1H), 3.07-2.97 (m, 1H), 2.63-2.53 (m, 1H), 2.36 (s, 3H), 1.76-1.57 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H);

13

C NMR (100 MHz, CDCl3): δ 170.6,

143.3, 136.7, 134.9, 129.3, 128.8, 128.5, 128.2, 127.9, 61.4, 56.5, 54.8, 40.5, 23.3, 22.8, 21.5, 13.9; IR νmax (neat, cm–1): 3399, 2923, 2853, 1730, 1593, 1404, 1364, 1278, 1159, 1019; HRMS (ESI): calcd for C21H25NO4S2Na: 442.1123 ([M+Na]+), found 442.1126. General procedure for deprotection of N-Boc group (14j, 14k): To the compound in CH2Cl2 (3 mL/mmol) at 0 °C, was added trifluoroacetic acid (TFA; 1 mL/mmol) and the mixture was stirred for 30 min at room temperature. The reaction mixture was then concentrated in vacuo, followed by azeotroping with CH2Cl2 for 3 times to obtain the trifluoroacetate salt which was directly used in the next step. General procedure for N-tosyl protection (8c, 8f): To a stirred solution of (14j or 14k) (0.2 mmol, 1.0 equiv) in CH2Cl2 (1 mL) at 0 ºC, NEt3 (0.8 mmol, 4.0 equiv) and TsCl (0.22 mmol, 1.1 equiv) were added sequentially. After stirring for 4 h at room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate. After filtration and concentration in vacuo, the resulting residue was purified by silica gel (100-200 mesh) flash column chromatography.



ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org; copies of 1H,

13

C NMR and NOESY spectra of products and X-ray

crystallographic data (ORTEP) of 8j, 9b, 9c, 9f, 9i; CIF data for 8j, 9b, 9c, 9f, 9i.

Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT Authors gratefully acknowledge the financial support by SERB, New Delhi, India for JC Bose Fellowship (T.K.C., SERB No.: SR/S2/JCB-30/2007) and IISc, Bangalore for research fellowship to H. P. A. K. The authors are also thankful to Department of Organic Chemistry, IISc for providing the spectroscopic and analytical data.

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