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Organocatalytic and Late-Stage CH-Functionalization Enabled Asymmetric Synthesis of Communesin F and Putative Communesins Jisook Park, Alexandre Jean, and David Y.-K. Chen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02426 • Publication Date (Web): 01 Nov 2017 Downloaded from http://pubs.acs.org on November 2, 2017

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The Journal of Organic Chemistry

Organocatalytic and Late-Stage CH-Functionalization Enabled Asymmetric Synthesis of Communesin F and Putative Communesins Jisook Park, Alexandre Jean, and David Y.-K. Chen* Department of Chemistry, Seoul National University, Gwanak-1 Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea ABSTRACT: Herein we report the total syntheses of communesin F and putative members of the communesin family of polycyclic bis-aminal alkaloids. The successful strategy featured a novel organocatalytic reaction between two oxindole subunits to cast, after extensive optimization, the all-carbon vicinal quaternary stereocenters of the target molecule with high enantiocontrol. The resulting bis-oxindole intermediate further underwent a Ti(OiPr)4-mediated dehydrative skeletal rearrangement to furnish the communesin core structure. Consider the ready availability and low-cost of unsubstituted isatin, and the inferior organocatalytic reaction employing a bromo-substituted substrate, a Pd(OAc)2-catalyzed and oxalamide-directed aryl CH-alkenylation reaction was implemented to assemble the complete skeletal backbone of the target molecule. Collectively, the synthetic technologies disclosed herein constitute the first asymmetric organocatalytic approach to the communesins, together with a highly effective late-stage CHfunctionalization in stark contrast to the bromoarene substrates employed in all of the past synthetic work.

INTRODUCTION Advent of new synthetic methods is pivotal to the evolving efficiency, practicality and creativity of target-oriented organic synthesis. Moreover, generalized reaction protocols can profoundly influence the mindset behind synthetic design, as evident by the wide-spread application of Diels-Alder reaction,1 stereocontrolled aldol reactions,2 metal-mediated cross-coupling reactions3 and asymmetric oxidation/reduction protocols,4 just to name a few well-recognized examples. Today, in view of the rich repertoire of synthetic methods already at our disposal, practitioners of targetoriented synthesis are motivated or compelled to employ new reactions primarily based on: i) “novelty or popularity” - when the newly developed and existing methods are comparably competent; ii) “efficiency or practicality” - when the newly

developed method is synthetically superior than the existing methods; or iii) “necessity” - when there are no existing methods available. The “necessity” to apply or develop new synthetic method naturally bestows a greater scientific merit, which may be forecasted either at the outset of the synthetic campaign, or as the result of an unanticipated reactivity (or lack of) uncovered during the synthetic studies. Over the course of our chemical investigations towards the bis-aminal alkaloids communesins, the initial objective was to develop a catalytic asymmetric transformation to cast the signature all-carbon vicinal quaternary stereocenters of the target molecule(s). As we shall see, the successful realization of this primary objective was further complemented with the discovery, development and implementation of a late-stage CHfunctionalization process to render greater practicality and costeffectiveness for the entire synthetic sequence.

Figure 1. a. Chemical Structures of the Reported Communesin Bis-Aminal Alkaloids; b. Key Synthetic Strategies Featured in the Reported Chemical Syntheses of Communesins

a

Identified through biogenetic experiments.8c Boc = tert-butoxycarbonyl; nPr = n-propyl; TBS = tert-butyldimethyl silyl.

ACS Paragon Plus Environment


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Before delving into our synthetic endeavor, a cursory overview of the communesin family of bis-aminal alkaloids will be an instructive entry point. To date, eleven structurally characterized communesins (A to K) have been reported and featured in numerous biological, chemical, and biosynthetic investigations (Figure 1a). Specifically, the cytotoxic and insecticidal properties of the communesins have been documented,5 together with chemical synthesis of communesins A (1), B (2), and F (6) in both racemic and optically active forms,6,7 and identification of the communesin biosynthetic gene cluster (cns).8 Recently, the Movassaghi group elegantly amalgamated the chemical and biosynthetic findings of the communesins and culminated in a biomimetic asymmetric synthesis of communesin F (6) that featured a highly complex late-stage radical heterodimerization and a series of programmed aminal exchange reactions.7h On close inspection (Figure 1b), each of the successful communesin synthesis featured an unique and ingenious solution to address the all-carbon quaternary stereocenter(s) of the target molecule. Qin’s intramolecular cyclopropanation-fragmentation,7a Weinreb’s intramolecular Heck cyclization,7b,c Ma’s intramolecular oxidative indole-enolate coupling,7d Funk’s cycloaddition-fragmentation,7e Stoltz’s malonate alkylation,7f,g Movassaghi’s radical heterodimerization,7h and Yang’s Ir-catalyzed asymmetric indole allylation7i each represented a monumental achievement in the communesin field. However, among these only Movassaghi’s approach delivered both quaternary stereocenters simultaneously, while the first catalytic asymmetric solution devised by Yang only fashioned one of the two quaternary centers during the asymmetry inducing step. It is with these opportunities in mind, together with the recent surge of activities in the organocatalytic synthesis of spirooxindoles,9 we set out to develop a novel transformation catered for the communesin synthesis. After an extensive literature survey of the relevant organocatalytic processes, we were inspired by the studies from Zhang10a,b and Hayashi10c laboratories who demonstrated the utility of oxindole enal 9 in highly enantioselective silyl-prolinol catalyzed carbon-carbon bond forming reactions (Scheme 1a). Therefore, in connection with the proposed installation of the all-carbon vicinal quaternary stereocenters for the communesins, enal 10 together with nucleophilic oxindoles 11 and 12 were judiciously selected for our preliminary investigations (Scheme 1b).11 At this juncture we also became aware, and cautiously concerned, with the independent reports from Wang12a and Funk12b laboratories on closely related bond constructions that afforded predominantly the undesired diastereochemical outcome for the communesin synthesis (Scheme 1c).

RESULTS AND DISCUSSION With all facts considered, we proceeded to examine the proposed organocatalytic reaction and the results are summarized in Scheme 2 and 3. Under the originally reported conditions,10a,b reaction between enal 10 and oxindole 11 in an ethanolic media in the presence of catalytic amounts of TMS-prolinol 28 and benzoic acid, followed by in-situ reduction (NaBH4), smoothly delivered two bis-oxindole primary alcohols (29/29a) in ~1:0.4 diastereoselectivity based on 1H NMR analysis. Inspired by the detailed mechanistic study by Hayashi and co-workers,10c we further established that methoxy oxindole aldehyde 26 was an equally competent coupling partner with no discernable differences in the reaction yield and diastereoselectivity compared to enal oxindole 10. At this juncture, although the targeted all-carbon vicinal quaternary stereocenters had been realized, the direction of diastereopreference and the degree of asymmetric induction were unknown. Much to our delight, NMR spectroscopic correlation with a previously reported intermediate readily validated the major diastereoisomer 29 as required for the communesin synthesis.13 However, chiral HPLC analysis of alcohol 29 revealed a dismal

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30% e.e. that left much room for improvements. Extensive optimization of the reaction conditions was carried out (for details, see Supporting Information) and soon revealed the reaction temperature and the organocatalyst as the most critical enantioselectivity determining parameters. Ultimately, performing the reaction at −20 °C with organocatalyst 28b provided the most optimal balance between reaction rate and enantioselectivity (90% e.e.), but the diastereoselectivity was notably compromised (29:29a~1:0.9). We speculated at elevated temperature (23 °C), equilibration took place and resulted the preferential formation of the thermodynamically more stable diastereoisomer at the expense of reduced enantioselectivity, and this equilibration was not operative at low temperature. Indeed, the temperature-dependent equilibration was verified when aldehyde 29a’ was re-subjected to the established organocatalytic conditions (Scheme 3b) to afford 29/29a (after NaBH4 reduction) at a compromised enantioselectivity. Under the optimized conditions oxindole 12 and aldehyde 26 also coupled to deliver bis-oxindole 30 (81% e.e., after NaBH4 reduction), and as we shall see, bis-oxindole 30 proved to be a preferred substrate for our ensuing synthetic investigations.

Scheme 1. a. Reported Organocatalytic Reactions Employing Enal 9; b. Proposed Organocatalytic Reactions Between Enal 10 and Oxindoles 11 and 12; c. Reported OneStep Synthesis of Related Bis-Oxindole Systems a. CHO O N Bn 9 b.

H N CO2Me NO2 CO Me 2 OHC OHC OHC O O O N N N Bn Bn Bn (81%, 93% ee)[10a] (60%, 91% ee)[10b] (72%, 93% ee)[10c] R

CHO O

R1 H

3 Me R

O

N Me

Me

N H

R3 Br

R1 O

R2

N N H R2 communesins

11: R = CH=CH2; 12: R = CH2N3

10 c.

N

N

N H

a. 15: R3 = OTIPS N b. 16: R3 = N 3 H a. Funk: 13, 15, Cs2CO3

N

R1

O N H

R3 R2 a. 18: R1 = N3, R2 = Br, OMe R3 = OTIPS OMe (89%, 95:5 dr) N H b. 19: R1 = phthalyl, 17 (20 mol%) R2 = H, R3 = N3 Ni(OAc)2 (20 mol%), 14, 16, K3PO4 (2 equiv) (94%, 10:1 dr, 92% ee) R1 R3

b. W ang: a. 13: R1 = N3, R2 = Br 1 2 b. 14: R = phthalyl, R = H

H N

O N

R2 20

N H 15, 16

Having established a reliable and practical entry to the optically active bis-oxindoles 29 and 30, further elaboration to the communesin core structure required the introduction of an additional nitrogen atom(s) and a skeletal reorganization (Scheme 2). In this context, while both 29 and 30 were feasible synthetic intermediates, azide containing oxindole 30 proved synthetically more attractive and was readily elaborated to amino-alcohol 32 through hydrogenation (Pd/C, H2) followed by reductive amination with pnitrobenzaldehyde.14 The latter event was carefully optimized to circumvent any unwanted double reductive amination in the presence of excess p-nitrobenzaldehyde.


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Scheme 2. Preparation of Azido Amidines 36 and 37a/ba

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a

Reagents and Conditions: a) For 22: allylmagnesium bromide (3.0 equiv), THF/Et2O (1.6:1), −78 to 23 °C, 16 h, 75%, For 24: allylmagnesium bromide (1.3 equiv), THF/Et2O (1.9:1), −78 to 23 °C, 1 h, 80%; b) For 23: NaH (3.0 equiv), MeI (3.0 equiv), THF, 0 to 23 °C, 11 h, 83%; For 25: NaH (1.5 equiv), MeI (1.3 equiv), THF, 0 to 23 °C, 4.5 h, 97%; c) For 26: O3, CH2Cl2/MeOH (1:1), −78 °C, 70 min; then DMS (5.0 equiv), 16 h, 98%; For 27: O3, CH2Cl2/MeOH (1:1), −78 °C, 90 min; then DMS (5.0 equiv), 12 h, 94%; d) pTsOH•H2O (1.0 equiv), toluene, 100 °C, 45 min, 92%; e) For 29/29a: 26 (1.0 equiv), 11 (1.1 equiv), 28b (0.2 equiv), benzoic acid (0.2 equiv), H2O (1.3 equiv), EtOH, −20 °C, 180 h; then NaBH4 (5.0 equiv), EtOH, −20 °C, 2.5 h, 56% (29:29a~1:0.9, 29: 90% e.e., 29a: 95% e.e.) for two steps; For 30/30a: 26 (1.0 equiv), 12 (1.1 equiv), 28b (0.2 equiv), benzoic acid (0.2 equiv), H2O (1.3 equiv), EtOH, −20 °C, 180 h; then NaBH4 (5.0 equiv), EtOH, −20 °C, 12.5 h, 58% (30:30a~1:0.5, 30: 81% e.e., 30a: 90% e.e.) for two steps; For 31/31a: 27 (1.0 equiv), 12 (1.1 equiv), 28b (0.2 equiv), benzoic acid (0.2 equiv), H2O (1.3 equiv), EtOH, −20 °C, 180 h; then NaBH4 (5.0 equiv), EtOH, −20 °C, 12.5 h, 55% (31:31a~1:0.8, 31: 86% e.e., 31a: 90% e.e.) for two steps; f) From 30: Pd/C (10% wt/wt, 0.1 equiv), H2 (1 atm), MeOH, 23 °C, 12 h, 77%; From 31: Pd/C (10% wt/wt, 0.1 equiv), H2 (1 atm), MeOH, 23 °C, 12 h; g) For 32: p-NO2C6H4CHO (3.0 equiv), MeOH/THF (3:1), 23 °C, 12 h; then NaBH4 (5.0 equiv), 0 to 23 °C, 6 h, 60%; For 33: p-NO2C6H4CHO (2.6 equiv), MeOH/THF (3:1), 23 °C, 3 h; then NaBH4 (5.2 equiv), 0 to 23 °C, 1 h, 66%; h) For 34: Ti(OiPr)4 (10.0 equiv), THF, 130 °C, 16 h, 71%; For 35a/35b: Ti(OiPr)4 (10.0 equiv), THF, 130 °C, 22 h, 35a+35b: 89%; i) From 34: TsCl (2.5 equiv), DMAP (1.0 equiv), Et3N (2.5 equiv), CH2Cl2, 0 to 23 °C, 15.5 h, 93%; From 35a/b: TsCl (3.0 equiv), DMAP (1.0 equiv), Et3N (3.0 equiv), CH2Cl2, 0 to 23 °C, 15/2 h, Ts-35a: 55%, Ts-35b: 98%; j) For 36: NaN3 (10.0 equiv), DMF, 50 °C, 12 h, 97%; For 37a/b: NaN3 (10.0 equiv), DMF, 50 °C, 4.5/11.5 h, 37a: 86%, 37b: 97%. DMAP = N,N'-dimethylaminopyridine; DMF = N,N'-dimethylformamide; DMS = dimethyl sulfide; MOM = methoxymethyl; p-TsOH•H2O = p-toluenesulfonic acid monohydrate; Ts = p-toluenesulfonyl; TsCl = p-toluenesulfonyl chloride.

Scheme 3. Optimization Summary of Organocatalytic Coupling Reaction Between Oxindole 11 and Aldehyde 26 a. Original condition: 28, H2O, C6H5CO2H, EtOH, 25 °C, 20 h; HO then NaBH4 (1:0.4 dr, 30% ee)

CHO

MeO

H

N Me

O + O

O

O N Me

N H

26 (1.0 equiv)

NH

Optimized condition: 28b, H2O, C6H5CO2H, 11 (1.1 equiv) EtOH, 20 °C, 180 h; then NaBH4 (1:0.9 dr, 90% ee)

29

catalyst: Ph Ph OSiMe3

N H 28

N H 28a

Ph Ph OTES

Solvent: EtOH, MeOH, iPrOH

Ph Ph OTBS

Ar Ar N N OSiMe3 H H 28c 28b (20 mol%) Ar = 3,5-(CF3)2C6H3 Temperature (°C): 25, 0, 20, 40

Additive: H2O (1.3 equiv), C6H 5CO2H (20 mol%), p-NO2-C6H4CO2H, NaOAc b. O

NH

R O N Me 29a: R = CH2OH 29a': R = CHO

28b, 11 (1.1 equiv), H2O, C6H5CO2H, EtOH, 20 to 23 °C; then NaBH4 (1:1 dr, 61% ee) ( 20 to 0 °C: No equilibration) Dess-Martin Periodinane

HO

O

NH O N Me 29

+ 29a

Next, skeletal rearrangement of bis-oxindole 32 leading to the polycyclic framework resembling the partial structure of the communesins required extensive reaction scouting, and the success of this transformation represented one of the highlights of the entire synthesis. Ultimately, we resorted to the dehydrative action of Ti(OiPr)415 under thermal condition to furnish pyrrolidinone amidine 34 in 71% yield. Consider the multitude of possible skeletal rearrangement pathways engaging the three nucleophilic nitrogens and two electrophilic carbonyl groups in bis-oxindole 32, the exclusive formation of amidine 34 was remarkable (desired cyclizations illustrated in structure 32, Scheme 2). Finally, the remaining nitrogen atom required for the communesins was introduced through tosylation of primary alcohol 34 followed by azide displacement to furnish pentacyclic azide 36 (90% yield over two steps). The structural similarity between pentacyclic amidine 36 and the previously reported communesin intermediates was apparent, with the most significant difference being the bromo-substituted arene intermediates prepared by Qin,7a Weinreb,7b,c Funk,7d Stoltz7f,g and Yang (Figure 1b).7i In this context, with the aforementioned organocatalytic transformation and skeletal rearrangement in mind, we postulated an analogous synthetic sequence starting from 4-bromoisatin (38) should readily afford the bromoarene analogue of 36 (Br-36, Scheme 4a). When this proposal was put to practice, we immediately became concerned with the high-priced 4-bromoisatin (38) compared to unsubstituted isatin.16 More disturbingly, the organocatalytic reaction between bromooxindole aldehyde 40 and allyl oxindole 11 under the optimized



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conditions afforded bis-oxindole 41 possessing the communesin relative stereochemistry as the minor constituent (41:41a ~ 0.6:1), together with a notably diminished enantioselectivity (41: 76% e.e., 41a: 93% e.e.) and yield (41: 11%, 41a: 19%). The structure of 41 was confirmed based on NMR spectroscopic comparison with reported data,7g and its characteristic 1H NMR signature analogous to bis-oxindoles 29/30 described in Scheme 2.17 While contemplating a mechanistic rationale for the observed substrateimplicated reactivity and stereoselectivity, we became aware of a report from Hayashi laboratory documented a substituentdependent reversal in absolute stereochemistry in a silyl-prolinol catalyzed asymmetric aldol reaction with isatin (Scheme 4b).18a Hence, to affirm the absolute stereochemical relationship between bis-oxindoles 29 and 41, optical rotation correlation was performed on debrominated 41 (tBuLi) and validated the reversal in absolute stereochemistry was not operative in our developed organocatalytic reaction (Scheme 4c).

Scheme 4. a. Organocatalytic Coupling Reaction Between Oxindole 11 and Bromo-Oxindole Aldehyde 40; b. Substituent-Dependent Reversal of Absolute Stereochemistry Observed by Hayashi and Co-workers; c. Absolute Stereochemistry Correlation via [α α]D Comparisona a. TMS Br

O

Br MeO

a. Hg(OTf)2 O b. MeI, NaH

N H

Br MeO CHO

c. O3

O

O

N Me 40

N Me

38 39 - substantially more expensive - prepared with chloral hydrate (restricted chemical)

or its unsubstituted variant (29 or 30), we decided to embark on the latter journey mindful of both the risks and rewards. Specifically, an aryl CH-functionalization was deemed necessary,19 and after contemplating several possible reaction manifolds we opted to explore the relatively well-documented yet still evolving Pd(OAc)2-catalyzed directed CH-functionalization.20 Model study for this unprecedented process in the context of communesin synthesis was pursued in earnest, and the results are summarized in Table 1. Under the standard reaction conditions,20 the nature of directing group played a commanding role and Zhao’s diisopropyl oxalamide proved uniquely effective for the proposed CHfunctionalization reaction.20e As stated in Zhao’s seminal publication, the oxalamide directed CH-activation represents a rare example of a directing-group capable of operating through a sevenmembered palladacycle intermediate (e.g. 47), a crucial requirement for our proposed transformation. Next, implementation of the newly developed CH-functionalization was systematically examined with oxalamide 48, a substrate readily obtained from azide 36 which also delivered a crystalline material 51 (see Supporting Information) amenable for X-ray structural analysis (Scheme 5).21 The result of our optimization study proved highly rewarding, where the CH-alkenylation product 50 could be reproducibly prepared in synthetically useful yields and quantity after a single recycling. The necessity to employ methyl acrylate 49c instead of our originally preferred alkenyl tertiary alcohol 49a was a minor setback, but readily rectified in our ensuing synthetic studies (vide infra).

Table 1. Summary of Directed CH-Activation/Alkenylation Model Studiesa Me

O

d. 11, 28b; then NaBH4

O p-NO2C6H4 N3

O

N

HO Br

O Br N N Me b. R

O

O

NH

HO + Br

O N Me 41a : 41 = 1 : 0.6 41

i. CH3MgBr,

DG

Ar Ar OSiMe3

O

DG

NH

R = H, 73%, 85% ee (R configuration) OTIPS R = Br, 86%, 82% ee (S configuration)

R HO

HO

O

Ph

41

O N Me 29

[ ]D comparison: From 41: "+" enantiomer From 23 + 11: "+" enantiomer

a

Reagents and Conditions: a) Hg(OTf)2 (0.02 equiv), allyltrimethylsilane (2.0 equiv), CH2Cl2, 23 °C, 4 h, 92%; b) NaH (3.0 equiv), MeI (3.0 equiv), THF, 0 to 23 °C, 16 h, 99%; c) O3, CH2Cl2/MeOH (1:1), −78 °C, 15 min; then DMS (5.0 equiv), 16 h, 99%; d) 11 (1.1 equiv), 28b (0.2 equiv), benzoic acid (0.2 equiv), H2O (1.3 equiv), EtOH, −20 °C, 180 h; then NaBH4 (3.8 equiv), EtOH, −20 °C, 12.5 h, 30% (41:41a~0.6:1, 41: 76% e.e., 41a: 93% e.e.) for two steps; e) tBuLi (1.7 M in pentane, 5.0 equiv), THF, −78 °C, 30 min, 95%. Hg(OTf)2 = mercury(II) trifluromethanesulfonate. Confronted with the options to utilize the poorly accessible but synthetically more predictable bromo-substituted bis-oxindole 41,

Ph

C: R =

O

O

i

NH N N N R

O

e. tBuLi N Me

Me O OMe

Me

NH

O

O

O

OTIPS R

NH

B: R =

42 to 46

c. O

Me OH Me

Me N Me

NHTf

HO Br

A: R = NH

N Me

O

Mod-3: R = CH2CN Mod-4: R = (CH2)2NH2 42, 43, 44, 45, 46

DG = directing group

O

O

R

Directed CH activation

Me

OH

* N

NaBH4, CoCl2• 6H2O

NaH, MeI

R N Me

N Me

Mod-2

21: R = H Mod-1: R = Me

Me NaH, ClCH2CN

O

ii. SnCl2

N R

H

N H , Me H Ar = 3,5-(CF3)2-C6H3 ; then NaBH4

O

N

O N Me 41a

Br-36 HO

NH

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Pr2N

A: 41%b (54%)c B: 39%b (52%)c C: 45%b (53%)c Me

NH OR

Me

N Me

O

O

N Me

N Me 43: R = H (N.R.)a

42: R = H (N.R.)a O

i

O NH

NH

NR

Me

O N Me 44: R = H (N.R.)a

Pr2N O

NR Me

46: R = H, 46a: R = A 46b: R = B, 46c: R = C

Pd

O N 7

Me

O

O

N Me 45: R = H (N.R.)a

47

N Me

a Standard reaction condition: Pd(OAc)2 (10 mol%), Ag2CO3 (2.0 equiv), 1,2-dichloroethane, 120 °C. a. N.R. = No Reaction based on 1H NMR analysis of the crude reaction mixture; b. isolated yield; c. recovered starting material.


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Scheme 5. a. Oxalamide Directed CH-Functionalization of Methyl Amidine 48; b. Oxalamide Directed CHFunctionalization of MOM Amidine 52aa

a

Reagents and Conditions: a) PPh3 (2.0 equiv), THF/H2O (10:1), 50 °C, 12 h, 92%; b) N,N'-diisopropyloxamoyl chloride (1.5 equiv), Et3N (1.0 equiv), CH2Cl2, 0 to 23 °C, 12 h, 97%; c) see text and Supporting Information. PivOH = 2,2-dimethylpropionic acid; TFA = trifluoroacetic acid, NBS = N-bromosuccinimide, Pd(OAc)2 = palladium(II) acetate, Selectfluor® = 1-chloromethyl-4-fluoro-1,4diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate). While the highly functionalized pentacyclic methyl amidine 50 represented a possible synthetic precursor towards the communesins, independent studies in amidine reduction to afford the corresponding aminal (e.g. 55 to 56, Scheme 6, vide infra) suggested a related substrate was more suitable. In this instance, a synthetic pathway in accordance to our developed technologies was readily applied to MOM-oxindole aldehyde 27 (Scheme 2), to afford bis-oxindole 31 (86% e.e.), amidine 35a and its isopropyl derivative 35b (35a:35b ~ 0.55:1), and oxalamides 52a and 52b (Scheme 5 and 6). Much to our delight and for reasons yet to be fully elucidated, under the optimized CH-alkenylation reaction conditions oxalamides 52a and 52b displayed notably enhanced reactivity with full conversion after a single recycling in stark contrast to methyl amidine 48 (Scheme 5 and 6). Furthermore, the serendipitously synthesized isopropyloxy substrate 52b originated from the action of Ti(OiPr)4 during the amidine formation (33 to 35a/b, Scheme 2) proved superior than the parent MOM substrate 52a, where 52a routinely afforded a trace but notable amount of a speculated double-CH alkenylation product (53a’, Scheme 5b). This latter observation, although undesirable for our ensuing synthetic investigations, suggested MOM ether or hemiaminal methyl ether could be a competent and readily removable CH-activation directing group that warrants further investigations. With 53b (and 53a) in hand and in preparation for reduction of its amidine, the isopropoxymethyl group of 53b (or methoxymethyl group of 53a) was exchanged to a Boc carbamate (55, HCl; then Boc2O) and on further treatment with NaCNBH3 afforded aminal 56 in 50% yield (plus 28% of Boc-deprotected 55 generated during the reaction).

(Scheme 6). Therefore, we initially aimed to prepare a tertiary alcohol intermediate directly from the CH-activation/alkenylation process, similar to that demonstrated in the model studies (46a, Table 1). Furthermore, we recognized the Weinreb group had prepared tertiary alcohol 65 via a MeLi addition to the enone precursor 62,7b,c which implied an enone CH-activation/alkenylation product could be equally valuable. However, the CH-activation reaction scope displayed by simplified model system 46 did not fully translate to the highly functionalized CH-activation precursors 48 and 52a/b,22 thus the attention was turned to the readily accessible enoate 53a/b and its elaboration to enone 61 and tertiary alcohol 63. In this venture, conversion of the enoate appendage in 56 to the corresponding enone was realized through oxidative cleavage (OsO4, NaIO4) and hydrolytic removal of the oxalamide and p-nitrobenzyl groups (LiOOH, then NaOH),23 followed by treatment of the resulting aldehyde (57) with alkynyl Grignard 59 and an Au-catalyzed Meyer-Schuster rearrangement24 of the alkynyl benzyl alcohol intermediate 58. Alternatively, enone 61 could also be accessed via a Wittig reaction (with ylide 60) of the aforementioned aldehyde intermediate (57), but required more extensive chromatographic purifications to remove the ylide derived triphenylphosphoryl byproducts. Enone 61 was subsequently treated with MeLi and the resulting tertiary alcohol 63 was subjected to PPTS to furnish the hexacylic intermediate 66 uneventfully. Similar to the reaction sequence developed by Qin and Weinreb,7a-c intramolecular cyclization of 66 via its imidate (Meerwein salt, BF4•OEt3) provided heptacyclic imine 67 as a potential synthetic precursor to a number of reported communesins shown in Figure 1.

Advancing pentacyclic aminal 56 required two intramolecular cyclizations to cast the remaining ring framework of the communesin core structure. In this context, the works of Qin,7a Weinreb,7b,c Funk,7e Movassaghi,7h and Yang7i each featured a tertiary alcohol containing substrate (e.g. advanced intermediates 64 and 65 synthesized by Qin and Weinreb, respectively, Scheme 6) as the most effective cyclization precursor for the formation of the nitrogen-containing 7-membered ring in communesin

Inspired by the recent biosynthetic studies by Tang and Garg,8c we first demonstrated the utility heptacyclic imine intermediate 67 with the preparation of “putative” commnesins 68 and 68a. In this context, communesins lacking the N15-methyl and the C21−C22 epoxide are missing from the current collection of isolated natural products (Table 2), and furthermore, the common biosynthetic precursor 68a (core) was reported to be too unstable to be characterized spectroscopically. With imine 67 in hand, compound 68



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Scheme 6. Synthesis of “Putative” Communesin 68, Postulated Common Biosynthetic Precursor 68a, and Total Synthesis of Communesin F (6)a

a

Reagents and Conditions: a) PPh3 (2.0 equiv), THF/H2O (10:1), 50 °C, 16 h, 98%; b) N,N'-diisopropyloxamoyl chloride (1.25 equiv), Et3N (1.0 equiv), CH2Cl2, 0 to 23 °C, 8.5 h, 82%; c) Pd(OAc)2 (0.1 equiv), Ag2CO3 (2.0 equiv), 49c (5.0 equiv), 1,2-dichloroethane, 120 °C, 43 h; then Pd(OAc)2 (0.1 equiv), Ag2CO3 (2.0 equiv), 49c (5.0 equiv), 1,2-dichloroethane, 120 °C, 39 h, 93%; d) HCl (10 M aq.)/MeOH (1:6), 100 °C, 16 h; e) Boc2O (5.0 equiv), DMAP (0.5 equiv), CH3CN, 23 °C, 13 h, 75% for two steps; f) NaCNBH3 (30 equiv), AcOH (30 equiv), THF, 0 to 23 °C, 6 h, 50% (+ 28% mono-Boc of 54); g) 2,6-lutidine (2.0 equiv), OsO4 (4 wt/wt% in H2O, 0.2 equiv), NaIO4 (2.0 equiv), 23 °C, 65 h, 83%; h) LiOH (10.0 equiv), H2O2 (10.0 equiv), THF/H2O (4:1), 23 to 50 °C, 3 h; then NaOH (20% aq.)/MeOH (1:3), 23 to 75 °C, 4.5 h, 74%; i) 59 (13.5 equiv), THF, −78 to 0 °C, 3 h, 47%; then [(IPr)AuCl] (0.3 equiv), AgSbF6 (0.3 equiv), MeOH/H2O (60:1), 23 °C, 1 h, 62%; or 60 (2.0 equiv), toluene, 23 to 120 °C, 85 h, 80%; j) MeLi (3.0 M in Et2O, 10.0 equiv), THF, −78 °C, 30 min, 64%; k) PPTS (0.1 equiv), CHCl3, 23 °C, 4 h, 52%; l) Et3OBF4 (5.1 equiv), iPr2NEt (10.0 equiv), CH2Cl2, 0 °C, 50 min; m) TFA (5 wt% in CH2Cl2), 23 °C, 2 h, then silica-gel, MeOH/CH2Cl2 (1:1), 50 °C, 20 h, 30% for two steps; n) AcOH/Ac2O (1:1), NaBH4 (excess), 0 °C, 10 min; then TFA/CH2Cl2 (1:2), 23 °C, 2 h; 36%; o) NaBH4 (excess), AcOH, 0 °C, 25 min; then TFA/CH2Cl2 (1:2), 23 °C, 2 h, 49%; p) NaBH4 (excess), AcOH, 0 °C, 25 min; then LiAlH4 (excess), THF, 80 °C, 2.5 h; then AcOH/Ac2O (1:1), 0 °C, 20 min, 67%. AcOH = acetic acid; Boc2O = di-tert-butyl dicarbonate, [(IPr)AuCl] = chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2ylidene]gold(I), PPTS = pyridinium p-toluenesulfonate.

Table 2. Chemical Structures of Reported and “Putative” Communesins

was readily synthesized through C9−N16 imine reduction with insitu N16 acylation followed by N15-Boc carbamate removal (TFA). The preparation of the speculated common biosynthetic precursor 68a was also carried out through C9−N16 imine reduction followed by N15-Boc carbamate removal. In contrary to the reported stability profile,8c compound 68a could be isolated and spectroscopically characterized for the first time (see Supporting Information for details). Finally, the total synthesis of communesin F (6) was also accomplished through sequential imine and Boc-carbamate reductions of common precursor 67 (in doing so intercepted communesin K, 6b), followed by N-16 acetylation.

CONCLUSIONS In conclusion, the total syntheses of communesin F (6) and two putative communesins (68 and 68a) have been accomplished. Our journey began with the pursuit of an asymmetric organocatalytic process to address the all-carbon vicinal quaternary stereocenters in the target molecule(s), and later motivated the development of a late-stage, directed aryl CH-alkenylation which was extensively optimized to deliver high synthetic efficiency and practicality.


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The success of this CH-alkenylation reaction represented one of the most elaborated examples of late-stage CH-activation to date. Collectively, the synthetic methods disclosed herein not only served to advance the chemical synthesis of the communesins, but also aid to more in depth understanding of the communesin biosynthetic network.

EXPERIMENTAL SECTION General Procedures. Reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF), diethyl ether (Et2O), methylene chloride (CH2Cl2), toluene and 1,2-dichloroethane (DCE) were dried and distilled from calcium hydride. Methanol (MeOH), ethanol (EtOH), N,N'-dimethylformamide (DMF), 1,4dioxane, chloroform (CHCl3), and acetonitrile (CH3CN) were purchased in anhydrous form and used without further purification. Acetone, ethyl acetate (EtOAc), Et2O, CH2Cl2, hexanes, MeOH and water were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reactions were monitored by thin-layers chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F−254) using UV light as visualizing agent and an ethanolic solution of ammonium molybdate, anisaldehyde or potassium permanganate, and heat as developing agents. E. Merck silica gel (60, particle size 0.040−0.063 mm) was used for flash column chromatography. NMR spectra were recorded on an Agilent 400-MR DD2 Magnetic Resonance System or Varian/Oxford As-500 instrument and calibrated using residue undeuterated solvent as internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra were recorded on a Thermo Scientific Nicolet 6700 spectrometer and IRTracer-100 spectrometer. High-resolution mass spectra (HRMS) were recorded on a Bruker (compact) Ultra High Resolution ESI Q-TOF mass spectrometer. Optical rotation ([α]D25) was recorded on a Jasco P-1030 polarimeter. Alcohol 22: To a stirred solution of isatin (21, 12.0 g, 81.6 mmol) in THF (400 mL) at −78 °C was added allylmagnesium bromide (1.0 M in Et2O, 245 mL, 245 mmol). The resulting mixture was warmed to room temperature and stirred for 16 h before it was quenched with NH4Cl (300 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 250 mL), the combined organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1 → 1:1) to afford alcohol 22 (11.5 g, 75%) as a yellow amorphous solid. 22: Rf = 0.30 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3326, 3055, 2985, 1724, 1625, 1355, 1263, 748 cm−1; 1H NMR (499 MHz, CDCl3): δ 8.69 (br s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.72−5.60 (m, 1H), 5.14−5.03 (m, 2H), 3.74 (s, 1H), 2.77 (dd, J = 13.5, 6.4 Hz, 1H), 2.63 ppm (dd, J = 13.5, 8.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 180.5, 140.3, 130.3, 130.2, 129.6, 124.4, 123.0, 120.4, 110.4, 76.4, 42.7 ppm; HRMS calcd. For C11H11NO2Na+ [M + Na]+ 212.0682, found 212.0685. Methyl Ether 23: To a stirred solution of alcohol 22 (5.01 g, 26.5 mmol) in THF (178 mL) at 0 °C was added NaH (60% in mineral oil, 3.18 g, 79.4 mmol) in portions. The resulting mixture was stirred for 55 min before MeI (5.00 mL, 79.4 mmol) was added.

The resulting mixture was warmed to room temperature and stirred for 11 h before it was quenched with NH4Cl (150 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 300 mL), the combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1 → 2:1) to afford methyl ether 23 (4.80 g, 83%) as a yellow thick oil. 23: Rf = 0.69 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3059, 2933, 2248, 1716, 1468, 1249, 1117, 1023, 728 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.35−7.24 (m, 2H), 7.08 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.57−5.44 (m, 1H), 5.02−4.91 (m, 2H), 3.18 (s, 3H), 3.00 (s, 3H), 2.71 (dd, J = 13.5, 6.5 Hz, 1H), 2.57 ppm (dd, J = 13.5, 8.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 175.3, 143.6, 130.3, 129.5, 126.3, 124.1, 122.6, 119.3, 108.0, 82.2, 52.7, 41.6, 25.7 ppm; HRMS calcd. For C13H15NO2Na+ [M + Na]+ 240.0995, found 240.0994. Aldehyde 26: To a stirred solution of alkene 23 (11.9 g, 54.8 mmol) in CH2Cl2/MeOH (1:1, 280 mL) at −78 °C was purged with a stream of ozone for 70 min before it was quenched with dimethyl sulfide (20.0 mL, 274 mmol). The resulting mixture was warmed to room temperature and stirred for 16 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford aldehyde 26 (11.8 g, 98%) as a red amorphous solid. 26: Rf = 0.37 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3058, 2985, 2305, 1723, 1470, 1264, 1023, 737 cm−1; 1 H NMR (400 MHz, CDCl3): δ 9.71 (t, J = 2.3 Hz, 1H), 7.20 (td, J = 7.7, 1.3 Hz, 1H), 7.12 (dd, J = 7.4, 1.2 Hz, 1H), 6.94 (td, J = 7.5, 1.0 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 3.05 (s, 3H), 2.82 (s, 3H), 2.69 ppm (s, 2H); 13C NMR (101 MHz, CDCl3): δ 198.5, 174.0, 143.4, 130.0, 125.1, 123.7, 122.7, 108.3, 79.1, 52.0, 49.4, 25.7 ppm; HRMS calcd. For C12H13NO3Na+ [M + Na]+ 242.0788, found 242.0787. Enal 10: To a stirred solution of aldehyde 26 (268 mg, 1.22 mmol) in toluene (12.0 mL) at room temperature was added ptoluenesulfonic acid monohydrate (233 mg, 1.22 mmol). The resulting mixture was warmed to 100 °C and stirred for 45 min before it was cooled to room temperature and quenched with NaHCO3 (15 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 25 mL), the combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to afford enal 10 (210 mg, 92%) as a red powder. 1H NMR analysis indicated a mixture of alkene geometric isomers in 2:1 ratio. 10: Rf = 0.75, 0.65 (silica gel, CH2Cl2:Et2O 9:1); IR (film) νmax 3005, 2988, 1710, 1669, 1611, 1471, 1258, 1042, 731 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.09 (dd, J = 7.7, 0.7 Hz, 0.6H), 10.53 (dd, J = 6.3, 0.7 Hz, 0.4H), 8.00 (d, J = 7.7 Hz, 0.4H), 7.49−7.37 (m, 1.6H), 7.10−7.03 (m, 1H), 6.98 (d, J = 6.1 Hz, 0.4H), 6.86−6.79 (m, 1H), 6.67 (d, J = 7.7 Hz, 0.6H), 3.25 (s, 1H), 3.24 ppm (s, 2H); 13C NMR (101 MHz, CDCl3) δ 191.9, 189.7, 167.2, 165.7, 146.0, 145.1, 139.4, 138.6, 133.2, 132.9, 128.8, 127.3, 126.9, 122.8, 122.7, 122.2, 120.8, 119.5, 108.8, 108.7, 26.1, 25.8 ppm. N-MOM Isatin MOM-21: Method 1: To a stirred solution of isatin (21, 5.00 g, 34.0 mmol) in THF (170 mL) at 0 °C was added NaH (60% in mineral oil, 1.63 g, 40.8 mmol) in portions. The resulting mixture was stirred for 40 min before MOMCl (3.10 mL, 40.8 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 1.5 h before it was quenched with NH4Cl (100 mL, sat. aq.) and water (50 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL), the combined organic layer was washed with brine (300 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The re-



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sulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to afford N-MOM isatin MOM21 (5.88 g, 91%) as an orange powder. MOM-21: Rf = 0.37 (silica gel, hexanes:EtOAc 2:1); IR (film) νmax 3053, 2986, 2254, 1744, 1612, 911, 743 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.68−7.60 (m, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.12 (dd, J = 8.0, 0.7 Hz, 1H), 5.16 (s, 2H), 3.38 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): δ 182.6, 158.1, 149.8, 138.4, 125.0, 124.0, 117.1, 111.3, 71.3, 56.3 ppm; HRMS calcd. For C10H9NO3Na+ [M + Na]+ 214.0475, found 214.0477. Method 2: To a stirred solution of isatin (21, 5.00 g, 34.1 mmol) in dimethoxymethane (60.0 mL, 0.68 mol) at room temperature was added boron trifluoride diethyl etherate complex (5.10 mL, 40.9 mmol). The resulting mixture was warmed to 70 °C and stirred for 2.5 h before it was cooled to room temperature and quenched with NaHCO3 (100 mL. sat. aq.). The resulting mixture was extracted with EtOAc (3 × 150 mL), the combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 2:1) to afford MOM isatin MOM-21 (5.41 g, 83%) as an orange powder. All physical data of MOM isatin MOM-21 are identical to those obtained from Method 1. Alcohol 24: To a stirred solution of MOM isatin (MOM-21, 20.1 g, 105 mmol) in THF (260 mL) at −78 °C was added allyl magnesium bromide (0.9 M in Et2O, 126 mL, 140 mmol). The resulting mixture was warmed to room temperature and stirred for 1 h before it was quenched with NH4Cl (200 mL, sat. aq.) and water (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 300 mL), the combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to afford alcohol 24 (19.7 g, 80%) as a yellow powder. 24: Rf = 0.36 (silica gel, hexanes:EtOAc 2:1); IR (film) νmax 3155, 2253, 1729, 1469, 910, 736 cm−1; 1H NMR (499 MHz, CDCl3): δ 7.41 (d, J = 7.5 Hz, 1H), 7.33 (td, J = 7.7, 1.1 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 5.65−5.55 (m, 1H), 5.15−5.07 (m, 3H), 5.04 (d, J = 11.0 Hz, 1H), 3.31 (s, 3H), 3.08 (br, 1H), 2.78 (dd, J = 13.3, 6.2 Hz, 1H), 2.66 ppm (dd, J = 13.3, 4.9 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 178.5, 141.3, 130.3, 129.6, 129.2, 124.1, 123.4, 120.1, 109.7, 76.4, 71.3, 56.1, 42.7 ppm; HRMS calcd. For C13H15NO3Na+ [M + Na]+ 256.0944, found 256.0946. Methyl Ether 25: To a stirred solution of alcohol 24 (24.1 g, 103 mmol) in THF (250 mL) at 0 °C was added NaH (60% in mineral oil, 6.20 g, 155 mmol) in portions. The resulting mixture was stirred for 30 min before MeI (8.40 mL, 134 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 4.5 h before it was quenched with NH4Cl (200 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 300 mL), the combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to afford methyl ether 25 (24.8 g, 97%) as a yellow thick oil. 25: Rf = 0.55 (silica gel, hexanes:EtOAc 2:1); IR (film) νmax 3054, 2986, 2305, 1731, 1264, 745 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.37−7.31 (m, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.57−5.44 (m, 1H), 5.11 (q, J = 10.9 Hz, 2H), 5.06−4.97 (m, 2H), 3.31 (s, 3H), 3.05 (s, 3H), 2.76 (dd, J = 13.3, 6.2 Hz, 1H), 2.64 ppm (dd, J = 13.3, 8.4 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 175.9, 142.0, 130.3, 129.8, 125.9, 124.4, 123.2, 119.7, 109.6, 82.6, 71.1, 56.1, 52.8, 41.2 ppm; HRMS calcd. For C14H17NO3Na+ [M + Na]+ 270.1101, found 270.1100. Aldehyde 27: To a stirred solution of alkene 25 (22.1 g, 89.4 mmol) in CH2Cl2/MeOH (1:1, 200 mL) at −78 °C was purged

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with a stream of ozone for 1.5 h before it was quenched with dimethyl sulfide (33.0 mL, 447 mmol). The resulting mixture was warmed to room temperature and stirred for 12 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford aldehyde 27 (20.9 g, 94%) as a red thick oil. 27: Rf = 0.47 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3054, 2986, 2305, 1727, 1264, 737 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 7.37 (dd, J = 11.6, 3.9 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H), 7.16 (dd, J = 11.0, 3.9 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 5.15 (s, 2H), 3.35 (s, 3H), 3.05 (s, 3H), 2.97 ppm (s, 2H); 13C NMR (101 MHz, CDCl3): δ 198.4, 175.0, 142.2, 130.4, 125.0, 124.1, 123.6, 110.0, 79.6, 71.3, 56.2, 52.4, 50.1 ppm; HRMS calcd. For C13H15NO4Na+ [M + Na]+ 272.0893, found 272.0891. Allyl Oxindole 11: To a stirred solution of alcohol 22 (8.00 g, 42.3 mmol) in CH2Cl2 (200 mL) at 0 °C was added boron trifluoride diethyl etherate complex (16.0 mL, 127 mmol) and triethylsilane (20.3 mL, 127 mmol). The resulting mixture was warmed to 85 °C and stirred for 22 h before it was cooled to room temperature and quenched with NaHCO3 (200 mL. sat. aq.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 400 mL), the combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 6:1) to afford allyl oxindole 11 (5.61 g, 77%) as a yellow amorphous solid. 11: Rf = 0.54 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3429, 3057, 2988, 2304, 1707, 1470, 709 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.53 (br s, 1H), 7.25 (d, J = 7.4 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 5.83−5.70 (m, 1H), 5.12 (d, J = 17.8 Hz, 1H), 5.05 (d, J = 10.0 Hz, 1H), 3.58−3.52 (m, 1H), 2.88−2.78 (m, 1H), 2.64−2.53 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 180.5, 141.7, 133.8, 129.1, 127.8, 124.2, 122.0, 117.9, 109.9, 45.7, 34.6 ppm; HRMS calcd. For C11H11NONa+ [M + Na]+ 196.0733, found 196.0735. Azide 16: (i) To a stirred solution of tryptophol (12.7 g, 79.0 mmol) in CH2Cl2 (400 mL) at 0 °C was added imidazole (10.7 g, 0.16 mol), triphenylphosphine (22.8 g, 86.9 mmol) and iodine (22.1 g, 86.9 mmol). The resulting mixture was warmed to room temperature and stirred for 4 h before it was quenched with sodium thiosulfate (200 mL. sat. aq.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 500 mL), the combined organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford the corresponding iodide (13.2 g, 62%) as a white powder. (ii) To a stirred solution of iodide (obtained above, 14.0 g, 51.6 mmol) in DMF (103 mL) at room temperature was added sodium azide (10.1 g, 155 mmol). The resulting mixture was warmed to 50 °C and stirred for 4 h before it was cooled to room temterature and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL), the combined organic layer was washed with water (4 × 500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 3:1) to afford azide 16 (9.51 g, 99%) as a brown oil. Azido Oxindole 12: To a stirred solution of indole 16 (2.92 g, 15.7 mmol) in THF (110 mL) at −18 °C was added H2O (0.30 mL, 15.7 mmol) and N-chlorosuccinimide (2.21 g, 16.5 mmol) in portions for 5 min. The resulting mixture was stirred for 2.5 h at −18 °C before it was warmed to room temperature and stirred for 3 h. The resulting mixture was concentrated under reduced pressure, and the resulting residue was purified by flash column


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chromatography (silica gel, hexanes:EtOAc 5:1) to afford azido oxindole 12 (3.09 g, 98%) as a yellow amorphous solid. 12: Rf = 0.53 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3426, 3198, 3054, 2986, 2102, 1708, 1471, 1333, 738 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.44 (br s, 1H), 7.25−7.19 (m, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 3.59 (t, J = 6.5 Hz, 1H), 3.57−3.43 (m, 2H), 2.29−2.18 ppm (m, 2H); 13C NMR (101 MHz, CDCl3): δ 180.3, 141.6, 128.2, 128.0, 123.7, 122.2, 110.1, 47.9, 43.2, 29.4 ppm; HRMS calcd. For C10H10N4ONa+ [M + Na]+ 225.0747, found 225.0745. Bis-Oxindole Alcohols 29 and 29a: (i) To a stirred solution of aldehyde 26 (150 mg, 0.68 mmol) and allyl oxindole 11 (130 mg, 0.75 mmol) in EtOH (7.0 mL) at room temperature was added organocatalyst 28 (50.4 mg, 0.14 mmol), benzoic acid (16.7 mg, 0.14 mmol) and water (0.02 mL, 0.89 mmol). The resulting mixture was stirred for 23 h before it was subjected directly to the following step. A small quantity of chromatographically purified material was obtained for characterization. 29’: Rf = 0.40 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3423, 3053, 2985, 2305, 1708, 1471, 1353, 1184, 895, 694 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1H), 8.15 (br, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.03 (dt, J = 13.4, 6.9 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H), 6.84 (t, J = 7.7 Hz, 2H), 6.50 (t, J = 7.4 Hz, 2H), 5.15−4.97 (m, 2H), 4.82−4.75 (m, 1H), 4.25 (d, J = 17.8 Hz, 1H), 3.56 (dd, J = 13.2, 5.7 Hz, 1H), 3.44 (d, J = 17.8 Hz, 1H), 3.17 (s, 3H), 2.88 ppm (dd, J = 13.2, 6.7 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 198.4, 179.0, 176.5, 143.4, 140.4, 131.7, 128.6, 128.4, 127.5, 127.4, 123.7, 122.7, 122.1, 121.6, 119.3, 109.3, 107.6, 56.4, 51.1, 43.4, 33.5, 25.9 ppm; HRMS calcd. For C22H20N2O3Na+ [M + Na]+ 383.1366, found 383.1366. 29a’: Rf = 0.19 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 2359, 1712, 1613, 1376, 1473, 751 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1H), 7.74 (br, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.04−6.93 (m, 2H), 6.75 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 7.6 Hz, 1H), 6.07 (s, 1H), 5.14 (td, J = 16.7, 7.2 Hz, 1H), 4.97 (d, J = 16.8 Hz, 1H), 4.83 (d, J = 9.9 Hz, 1H), 4.23 (d, J = 17.8 Hz, 1H), 3.36 (d, J = 17.8 Hz, 1H), 3.19 (dd, J = 12.6, 7.5 Hz, 1H), 2.89 (s, 3H), 2.79 ppm (dd, J = 12.7, 6.5 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 198.1, 177.4, 175.9, 144.9, 141.5, 131.1, 129.2, 128.7, 127.8, 127.6, 123.9, 123.8, 122.0, 121.3, 119.8, 109.8, 108.4, 55.9, 52.9, 44.1, 35.6, 25.9 ppm; HRMS calcd. For C22H20N2O3Na+ [M + Na]+ 383.1366, found 383.1369. (ii) To a stirred solution of the organocatalytic reaction mixture (obtained above) at 0 °C was added NaBH4 (190 mg, 5.00 mmol). The resulting mixture was warmed to room temperature and stirred for 12 h before it was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford bis-oxindole alcohol 29 (156 mg, 63% over two steps) as a white foam and bisoxindole alcohol 29a (64.0 mg, 26% over two steps) as a white foam. 29: Rf = 0.38 (silica gel, hexanes:EtOAc 1:4); IR (film) νmax 3425, 3049, 2988, 2305, 1702, 1612, 1421, 1352, 1272, 895, 696 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.35 (br s, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.05−6.98 (m, 2H), 6.93 (t, J = 7.7 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 5.13−4.99 (m, 1H), 4.93 (d, J = 17.0 Hz, 1H), 4.72 (dd, J = 9.9, 2.3 Hz, 1H), 3.56 (dd, J = 13.4, 6.5 Hz, 1H), 3.44−3.31 (m, 1H), 3.28−3.15 (m, 1H), 3.08 (s, 3H), 2.95 (dd, J = 13.5, 7.5 Hz, 1H), 2.69−2.53 ppm (m, 2H); 13C NMR (101 MHz, CDCl3:CD3OD 4:1): δ 179.1, 177.9, 142.8, 140.6, 131.9, 128.1, 128.0, 127.9, 127.1, 123.3, 123.1, 121.9, 121.1, 118.5, 108.9, 107.4, 58.4, 56.4, 53.4, 33.1, 31.0, 25.4 ppm; HRMS calcd. For C22H22N2O3Na+ [M + Na]+ 385.1523, found 385.1522. 29a: Rf = 0.19 (silica gel, hexanes:EtOAc 1:4); IR

(film) νmax 3212, 2370, 1709, 1613, 1473, 1350, 753 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.28 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.88 (t, J = 7.5 Hz, 2H), 6.73 (t, J = 8.8 Hz, 2H), 6.65 (br, 1H), 6.58 (br, 1H), 5.17 (td, J = 16.9, 7.3 Hz, 1H), 4.98 (d, J = 16.9 Hz, 1H), 4.82 (d, J = 10.0 Hz, 1H), 3.45 (dd, J = 12.9, 7.6 Hz, 1H), 3.23 (br, 2H), 3.06−2.95 (m, 4H), 2.84 (dd, J = 13.1, 6.7 Hz, 1H), 2.51−2.43 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 177.9, 177.2, 144.3, 141.8, 131.8, 128.7, 128.6, 128.0, 124.5, 124.0, 121.8, 121.5, 119.3, 109.8, 108.2, 58.9, 57.5, 54.3, 34.6, 33.4, 26.0 ppm; HRMS calcd. For C22H22N2O3Na+ [M + Na]+ 385.1523, found 385.1523. Bis-Oxindole Alcohols 29 and 29a: (i) To a stirred solution of aldehyde 26 (150 mg, 0.68 mmol) and allyl oxindole 11 (130 mg, 0.75 mmol) in EtOH (7.0 mL) at −20 °C was added organocatalyst 28b (50.4 mg, 0.14 mmol), benzoic acid (16.7 mg, 0.14 mmol) and water (0.02 mL, 0.89 mmol). The resulting mixture was stirred for 180 h before it was subjected directly to the following step. (ii) To a stirred solution of the organocatalytic reaction mixture (obtained above) at −20 °C was added NaBH4 (190 mg, 5.00 mmol). The resulting mixture was stirred for 12.5 h before it was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford bis-oxindole alcohol 29 (75.4 mg, 30% over two steps) as a white foam and bis-oxindole alcohol 29a (64.5 mg, 26% over two steps) as a white foam. 29: [α]D25 +131.7 (c = 1.51, CHCl3); 29a: [α]D25 +44.8 (c = 1.49, CHCl3). Recycling of Bis-Oxindole Alcohol 29a: (i) To a stirred solution of bis-oxindole alcohol 29a (112 mg, 0.31 mmol) in CH2Cl2 (5.0 mL) at 0 °C was added Dess-Martin periodinane (263 mg, 0.62 mmol). The resulting mixture was warmed to room temperature and stirred for 2.5 h before it was quenched with sodium thiosulfate (5 mL, sat. aq.). The resulting mixture was extracted with CH2Cl2 (3 × 10 mL), and the combined organic layer was washed with NaHCO3 (20 mL, sat. aq.), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford aldehyde 29a’ (57.4 mg, 52%) as a white foam. All physical data of aldehyde 29a’ are identical to those obtained from organocatalytic reaction between aldehyde 26 and allyl oxindole 11. (ii) To a stirred solution of aldehyde 29a’ (obtained above, 48.6 mg, 0.14 mmol) and allyl oxindole 11 (25.7 mg, 0.15 mmol) in EtOH (3.00 mL) at −20 °C was added organocatalyst 28b (10.0 mg, 0.03 mmol), benzoic acid (3.30 mg, 0.03 mmol) and water (325 µL, 0.18 mmol). The resulting mixture was stirred for 165 h, then warmed to 0° C and stirred for 98 h, then warmed to room temperature and stirred for 7 h while the reaction was monitored by thin layer chromatography analysis. (iii) To a stirred solution of the organocatalytic reaction mixture (obtained above) at 0 °C was added NaBH4 (27 mg, 0.70 mmol). The resulting mixture was stirred for 4 h before it was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford bis-oxindole alcohol 29 (15.1 mg, 31% over two steps) as a white foam and bisoxindole alcohol 29a (15.3 mg, 31% over two steps) as a white foam. Bis-Oxindole Alcohols 30 and 30a: (i) To a stirred solution of aldehyde 26 (150 mg, 0.68 mmol) and azide oxindole 12 (152 mg, 0.75 mmol) in EtOH (7.0 mL) at −20 °C was added organocatalyst 28b (50.4 mg, 0.14 mmol), benzoic acid (16.7 mg, 0.14 mmol) and water (0.02 mL, 0.89 mmol). The resulting mixture was



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stirred for 180 h before it was subjected directly to the following step. A small quantity of chromatographically purified material was obtained for characterization. 30’: Rf = 0.37 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3054, 2986, 2305, 2102, 1708, 1613, 1421, 1264, 895, 734 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.26 (br s, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.10−6.97 (m, 3H), 6.90−6.80 (m, 2H), 6.56 (d, J = 7.7 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.22 (d, J = 17.9 Hz, 1H), 3.38 (d, J = 17.9 Hz, 1H), 3.28−3.18 (m, 1H), 3.15 (s, 3H), 3.10−3.00 (m, 1H), 2.77 (dt, J = 12.1, 8.0 Hz, 1H), 2.47 ppm (dt, J = 13.7, 8.0 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 198.1, 179.1, 176.4, 143.4, 140.6, 129.0, 128.8, 126.7, 126.0, 123.6, 122.7, 122.1, 121.8, 109.8, 107.6, 54.6, 51.4, 47.9, 43.1, 27.9, 25.9 ppm; HRMS calcd. For C21H19N5O3Na+ [M + Na]+ 412.1380, found 412.1382. 30a’: Rf = 0.22 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 2359, 2107, 1712, 1607, 1468, 1376, 753 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1H), 8.84 (s, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.06−6.96 (m, 2H), 6.84 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 2H), 4.21 (d, J = 17.9 Hz, 1H), 3.36 (d, J = 17.7 Hz, 1H), 3.09−3.01 (m, 1H), 2.85 (s, 3H), 2.80−2.64 (m, 2H), 2.36−2.27 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 197.8, 177.2, 175.6, 144.9, 141.5, 129.4, 129.2, 127.5, 126.5, 123.8, 123.6, 122.2, 121.6, 110.3, 108.5, 54.2, 53.2, 47.2, 43.9, 30.5, 25.9 ppm; HRMS calcd. For C21H19N5O3Na+ [M + Na]+ 412.1380, found 412.1380. (ii) To a stirred solution of the organocatalytic reaction mixture (obtained above) at −20 °C was added NaBH4 (190 mg, 5.00 mmol). The resulting mixture was stirred for 12.5 h before it was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford bis-oxindole alcohol 30 (105 mg, 39% over two steps) as a white powder and bis-oxindole alcohol 30a (51.7 mg, 19% over two steps) as a white foam. 30: Rf = 0.45 (silica gel, hexanes:EtOAc 1:4); [α]D25 +141.3 (c = 1.53, CHCl3); IR (film) νmax 3423, 3047, 2985, 2305, 1708, 1612, 1422, 1256, 894, 743 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.15 (br s, 1H), 7.24 (d, J = 12.3 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 7.03−6.96 (m, 2H), 6.90 (t, J = 7.5 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 3.47−3.37 (m, 1H), 3.32−3.22 (m, 1H), 3.21−3.12 (m, 2H), 3.08 (s, 3H), 3.05−2.95 (m, 1H), 2.79 (dt, J = 12.2, 8.0 Hz, 1H), 2.63−2.49 ppm (m, 2H); 13 C NMR (101 MHz, CDCl3:CD3OD 1:1): δ 178.6, 177.4, 142.6, 140.7, 128.1, 127.9, 126.5, 126.2, 123.0, 122.7, 121.5, 120.8, 109.0, 107.1, 57.8, 54.3, 53.4, 47.3, 30.4, 27.2, 24.9 ppm; HRMS calcd. For C21H21N5O3Na+ [M + Na]+ 414.1537, found 414.1536. 30a: Rf = 0.25 (silica gel, hexanes:EtOAc 1:4); [α]D25 +47.7 (c = 1.48, CHCl3); IR (film) νmax 3276, 2943, 2107, 1712, 1610, 1473, 753 cm−1; 1H NMR (499 MHz, CDCl3): δ 7.80 (br, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.94−6.85 (m, 2H), 6.80 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.67 (br, 1H), 6.50 (br, 1H), 3.21 (dd, J = 12.6, 6.1 Hz, 2H), 3.13−3.06 (m, 1H), 3.06−3.00 (m, 1H), 3.00−2.90 (m, 4H), 2.79−2.71 (m, 1H), 2.43 (dd, J = 12.8, 6.5 Hz, 1H), 2.40−2.31 (m, 1H), 1.53 ppm (br, 1H); 13 C NMR (126 MHz, CDCl3:MeOD 1:1): δ 177.6, 176.3, 143.5, 141.9, 128.6, 128.3, 127.3, 127.0, 123.9, 123.2, 121.5, 121.2, 109.6, 107.7, 57.4, 55.6, 53.8, 46.9, 32.4, 28.5, 25.0 ppm; HRMS calcd. For C21H21N5O3Na+ [M + Na]+ 414.1537, found 414.1542. Recycling of Bis-Oxindole Alcohol 30a: (i) To a stirred solution of bis-oxindole alcohol 30a (500 mg, 1.28 mmol) in CH2Cl2 (13.0 mL) at 0 °C was added Dess-Martin periodinane (1.10 g, 2.56 mmol). The resulting mixture was warmed to room temperature and stirred for 20 min before it was quenched with sodium thiosulfate (15 mL, sat. aq.). The resulting mixture was extracted with

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CH2Cl2 (3 × 30mL), and the combined organic layer was washed with NaHCO3 (50 mL, sat. aq.), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford aldehyde 30a’ (387 mg, 84%) as a white foam. All physical data of aldehyde 30a’ are identical to those obtained from organocatalytic reaction between aldehyde 26 and allyl oxindole 12. (ii) To a stirred solution of aldehyde 30a’ (obtained above, 52.6 mg, 0.14 mmol) and azide oxindole 12 (29.9 mg, 0.15 mmol) in EtOH (3.00 mL) at −20 °C was added organocatalyst 28b (10.0 mg, 0.03 mmol), benzoic acid (3.30 mg, 0.03 mmol) and water (325 µL, 0.18 mmol). The resulting mixture was stirred for 165 h, then warmed to 0° C and stirred for 98 h, then warmed to room temperature and stirred for 7 h while the reaction was monitored by thin layer chromatography analysis. (iii) To a stirred solution of the organocatalytic reaction mixture (obtained above) at 0 °C was added NaBH4 (27 mg, 0.70 mmol). The resulting mixture was stirred for 4 h before it was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford bis-oxindole alcohol 30 (25.0 mg, 47% over two steps) as a white foam and bisoxindole alcohol 30a (14.0 mg, 27% over two steps) as a white powder. Bis-Oxindole Alcohols 31 and 31a: (i) To a stirred solution of aldehyde 27 (150 mg, 0.60 mmol) and azide oxindole 12 (134 mg, 0.66 mmol) in EtOH (6.0 mL) at −20 °C was added organocatalyst 28b (44.1 mg, 0.12 mmol), benzoic acid (14.7 mg, 0.12 mmol) and water (0.02 mL, 0.78 mmol). The resulting mixture was stirred for 180 h before it was subjected to the following step. A small quantity of chromatographically purified material was obtained for characterization. 31’: Rf = 0.46 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3254, 2107, 1718, 1613, 1470, 756 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.42 (s, 1H), 8.73 (s, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.09−6.96 (m, 3H), 6.86 (q, J = 7.3 Hz, 2H), 6.71 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 5.22 (d, J = 10.8 Hz, 1H), 4.86 (d, J = 10.8 Hz, 1H), 4.31 (d, J = 18.1 Hz, 1H), 3.43 (d, J = 18.4 Hz, 1H), 3.42 (s, 3H), 3.16 (dd, J = 12.8, 6.1 Hz, 1H), 3.05 (dd, J = 11.8, 6.2 Hz, 1H), 2.80−2.71 (m, 1H), 2.54−2.43 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 197.8, 178.9, 177.3, 142.2, 140.5, 129.1, 128.9, 126.3, 125.7, 123.9, 122.7, 122.5, 121.9, 109.8, 109.2, 71.8, 56.9, 54.7, 51.5, 47.8, 43.4, 28.0 ppm; HRMS calcd. For C22H21N5O4Na+ [M + Na]+ 442.1487, found 442.1486. 31a’: Rf = 0.27 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3292, 2101, 1723, 1701, 1613, 1470, 751 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H), 8.88 (br, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.19−7.06 (m, 3H), 6.98 (d, J = 7.8 Hz, 1H), 6.84 (t, J = 7.8 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 5.91 (s, 1H), 4.78 (s, 2H), 4.39 (d, J = 18.4 Hz, 1H), 3.43 (d, J = 18.6 Hz, 1H), 3.10−1.97 (m, 1H), 2.86 (s, 3H), 2.77−2.63 (m, 2H), 2.42−2.33 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 197.6, 177.4, 176.5, 143.7, 141.5, 129.6, 129.4, 127.3, 126.4, 123.9, 123.8, 122.7, 122.0, 110.4, 110.0, 71.9, 56.0, 53.9, 53.5, 47.0, 44.3, 31.00 ppm; HRMS calcd. For C22H21N5O4Na+ [M + Na]+ 442.1487, found 442.1486. (ii) To a stirred solution of the organocatalytic reaction mixture (obtained above) at −20 °C was added NaBH4 (190 mg, 5.00 mmol). The resulting mixture was stirred for 12.5 h before it was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford bis-oxindole alcohol 31 (77.4 mg, 31% over two steps) as a white powder and bis-oxindole alcohol 31a


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(60.2 mg, 24% over two steps) as a white foam. 31: Rf = 0.40 (silica gel, hexanes:EtOAc 1:2); [α]D25 +102.6 (c = 1.51, CHCl3); IR (film) νmax 3690, 3054, 2986, 2305, 1717, 1264, 735 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.35 (br, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.27−7.14 (m, 3H), 7.09 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 5.32 (d, J = 10.8 Hz, 1H), 4.97 (d, J = 10.8 Hz, 1H), 3.66−3.58 (m, 1H), 3.49 (s, 3H), 3.42−3.32 (m, 2H), 3.32−3.24 (m, 1H), 3.15 (dd, J = 12.1, 7.6 Hz, 1H), 2.92 (dt, J = 12.2, 7.9 Hz, 1H), 2.83−2.68 (m, 2H), 2.43 ppm (br, 1H); 13C NMR (101 MHz, CDCl3): δ 179.3, 178.8, 142.1, 140.7, 128.8, 128.7, 126.7, 126.1, 123.8, 123.8, 122.4, 121.7, 109.8, 109.0, 71.8, 59.2, 56.8, 54.9, 54.2, 47.8, 31.5, 27.9 ppm; HRMS calcd. For C22H23N5O4Na+ [M + Na]+ 444.1642, found 444.1644. 31a: Rf = 0.34 (silica gel, hexanes:EtOAc 1:4); [α]D25 +16.3 (c = 1.56, CHCl3); IR (film) νmax 3276, 2938, 2096, 1715, 1607, 1427, 1350, 756 cm−1; 1H NMR (499 MHz, CDCl3): δ 8.11 (br, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.04−6.93 (m, 2H), 6.87 (br, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.73 (br, 1H), 6.49 (br, 1H), 4.86 (s, 2H), 3.33−3.26 (m, 1H), 3.25−3.17 (m, 1H), 3.11−2.93 (m, 6H), 2.78−2.68 (m, 1H), 2.47−2.34 (m, 2H), 1.59 ppm (br, 1H); 13C NMR (126 MHz, CDCl3): δ 177.9, 177.6, 143.0, 141.8, 129.2, 129.1, 127.5, 127.1, 124.2, 122.5, 122.0, 110.0, 109.7, 71.7, 58.7, 56.1, 55.2, 47.3, 33.3, 29.8 ppm; HRMS calcd. For C22H23N5O4Na+ [M + Na]+ 444.1642, found 444.1643. Recycling of Bis-Oxindole Alcohol 31a: (i) To a stirred solution of bis-oxindole alcohol 31a (500 mg, 1.19 mmol) in CH2Cl2 (12.0 mL) at 0 °C was added Dess-Martin periodinane (1.00 g, 2.37 mmol). The resulting mixture was warmed to room temperature and stirred for 20 min before it was quenched with sodium thiosulfate (10 mL, sat. aq.). The resulting mixture was extracted with CH2Cl2 (3 × 30 mL), and the combined organic layer was washed with NaHCO3 (50 mL, sat. aq.), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford aldehyde 31a’ (396 mg, 80%) as a white foam. All physical data of aldehyde 31a’ are identical to those obtained from organocatalytic reaction between aldehyde 27 and allyl oxindole 12. (ii) To a stirred solution of aldehyde 31a’ (obtained above, 56.6 mg, 0.14 mmol) and azide oxindole 12 (29.9 mg, 0.15 mmol) in EtOH (3.00 mL) at −20 °C was added organocatalyst 28b (10.0 mg, 0.03 mmol), benzoic acid (3.30 mg, 0.03 mmol) and water (325 µL, 0.18 mmol). The resulting mixture was stirred for 165 h, then warmed to 0° C and stirred for 98 h, then warmed to room temperature and stirred for 7 h while the reaction was monitored by thin layer chromatography analysis. (iii) To a stirred solution of the organocatalytic reaction mixture (obtained above) at 0 °C was added NaBH4 (27 mg, 0.70 mmol). The resulting mixture was stirred for 4 h before it was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford bis-oxindole alcohol 31 (24.0 mg, 42% over two steps) as a white powder and bisoxindole alcohol 31a (18.3 mg, 32% over two steps) as a white powder. Alcohol 38a: To a stirred solution of 4-bromoisatin 38 (2.00 g, 8.85 mmol) in CH2Cl2 (90.0 mL) at room temperature was added allyltrimethylsilane (2.80 mL, 17.7 mmol) and mercury(II) trifluoromethanesulfonate (89.8 mg, 0.18 mmol). The resulting mixture was stirred for 4 h before it was diluted with EtOAc (50 mL) and quenched with HCl (10 M, aq., approx. 20 drops). The resulting mixture was extracted with EtOAc (3 × 150 mL), the combined organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under re-

duced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford alcohol 38a (2.18 g, 92%) as a white powder. 38a: Rf = 0.34 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3352, 2947, 2515, 2045, 1726, 1616, 1451, 1025, 740 cm−1; 1H NMR (400 MHz, CDCl3:CD3OD 4:1): δ 6.94 (d, J = 8.1 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.58 (d, J = 7.5 Hz, 1H), 5.19−5.03 (m, 1H), 4.85 (d, J = 16.9 Hz, 1H), 4.70 (d, J = 10.4 Hz, 1H), 3.05 (dd, J = 12.9, 7.1 Hz, 1H), 2.51 ppm (dd, J = 12.9, 7.7 Hz, 1H); 13C NMR (101 MHz, CDCl3:CD3OD 4:1): δ 178.6, 142.8, 130.0, 129.5, 127.8, 125.8, 118.6, 118.3, 108.4, 77.4, 38.2 ppm; HRMS calcd. For C11H10BrNO2Na+ [M + Na]+ 289.9787, found 289.9784. Methyl Ether 39: To a stirred solution of alcohol 38a (2.06 g, 7.68 mmol) in THF (77.0 mL) at 0 °C was added NaH (60% in mineral oil, 922 mg, 23.0 mmol) in portions. The resulting mixture was stirred for 0.5 h before MeI (1.43 mL, 23.0 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 16 h before it was quenched with NH4Cl (50 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 100 mL), the combined organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to afford methyl ether 39 (2.25 g, 99%) as a yellow thick oil. 39: Rf = 0.66 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3058, 2986, 2827, 2305, 1724, 1604, 1457, 1225, 1028, 893, 649 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.21−7.12 (m, 2H), 6.80−6.69 (m, 1H), 5.29−5.14 (m, 1H), 4.97 (d, J = 10.4 Hz, 1H), 4.83 (d, J = 10.2 Hz, 1H), 3.15 (s, 3H), 3.15−3.07 (m, 1H), 3.02 (s, 3H), 2.74 ppm (dd, J = 12.9, 7.8 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 174.0, 145.4, 130.8, 129.3, 126.4, 123.5, 119.2, 119.1, 106.9, 83.8, 52.5, 38.3, 25.5 ppm; HRMS calcd. For C13H14BrNO2Na+ [M + Na]+ 318.0100, found 318.0100. Aldehyde 40: To a stirred solution of alkene 39 (2.31 g, 7.81 mmol) in CH2Cl2/MeOH (1:1, 80.0 mL) at −78 °C was purged with a stream of ozone for 15 min before it was quenched with dimethyl sulfide (2.90 mL, 39.1 mmol). The resulting mixture was warmed to room temperature and stirred for 16 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford aldehyde 40 (2.30 g, 99%) as a yellow amorphous solid. 40: Rf = 0.42 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3054, 2929, 2306, 1722, 1603, 1456, 1273, 1025, 722 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.77 (s, 1H), 7.25−7.16 (m, 2H), 6.82 (d, J = 7.2 Hz, 1H), 3.36 (d, J = 17.1 Hz, 1H), 3.22 (s, 3H), 3.23−3.14 (m, 1H), 3.04 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): δ 198.3, 173.9, 145.9, 131.7, 127.0, 123.1, 119.4, 107.6, 80.5, 52.4, 47.6, 26.2 ppm; HRMS calcd. For C12H12BrNO3Na+ [M + Na]+ 319.9893, found 319.9895. Bis-Oxindole Alcohols 41 and 41a: (i) To a stirred solution of aldehyde 40 (150 mg, 0.50 mmol) and allyl oxindole 11 (95.8 mg, 0.55 mmol) in EtOH (5.00 mL) at −20 °C was added organocatalyst 28b (37.1 mg, 0.10 mmol), benzoic acid (12.3 mg, 0.10 mmol) and water (0.01 mL, 0.65 mmol). The resulting mixture was stirred for 180 h before it was subjected to the following step. (ii) To a stirred solution of the organocatalytic reaction mixture (obtained above) at −20 °C was added NaBH4 (140 mg, 3.68 mmol). The resulting mixture was stirred for 12.5 h before it was diluted with water (10 mL). The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 2:1 → 1:1) to afford alcohol 41 (25 mg, 11% over two steps) and 41a (42.0 mg, 19% over two steps) as white amorphous solids. 41: Rf = 0.40 (silica gel, hexanes:EtOAc



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1:2); [α]D25 +10.7 (c = 1.49, MeOH); IR (film) νmax 3054, 2986, 2305, 1725, 1605, 1421, 1263, 1156, 895 cm−1; 1H NMR (499 MHz, DMSO): δ 10.31 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.89 (dd, J = 15.7, 7.8 Hz, 2H), 6.70 (dt, J = 14.6, 7.2 Hz, 2H), 6.56 (d, J = 7.6 Hz, 1H), 6.43 (d, J = 7.7 Hz, 1H), 4.94 (td, J = 16.7, 6.9 Hz, 1H), 4.84 (d, J = 16.8 Hz, 1H), 4.72 (d, J = 9.9 Hz, 1H), 4.37 (t, J = 4.9 Hz, 1H), 3.38−3.31 (m, 2H), 3.16 (dt, J = 13.7, 4.4 Hz, 1H), 3.01 (s, 3H), 2.84 (dt, J = 15.6, 7.9 Hz, 1H), 2.74 (dd, J = 13.4, 6.8 Hz, 1H), 2.26−2.18 ppm (m, 1H); 13C NMR (101 MHz, DMSO): 177.4, 175.8, 146.5, 142.7, 133.4, 130.2, 128.5, 128.1, 126.9, 126.8, 123.5, 120.4, 119.2, 118.9, 108.8, 107.4, 58.4, 57.2, 56.0, 33.5, 28.9, 26.3 ppm; HRMS calcd. For C22H21BrN2O3Na+ [M + Na]+ 463.0628, found 463.0621. 41a: Rf = 0.12 (silica gel, hexanes:EtOAc 1:2); [α]D25 −32.7 (c = 1.45, MeOH); IR (film) νmax 3047, 2985, 2304, 1603, 1421, 1258, 1156, 895 cm−1; 1H NMR (499 MHz, DMSO): δ 10.25 (s, 1H), 7.25 (dd, J = 15.6, 7.7 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.64 (d, J = 7.7 Hz, 1H), 6.58 (t, J = 7.5 Hz, 1H), 5.95 (d, J = 7.4 Hz, 1H), 4.98−4.89 (m, 1H), 4.80 (d, J = 16.5 Hz, 1H), 4.73 (d, J = 9.9 Hz, 1H), 4.40 (t, J = 4.8 Hz, 1H), 3.16−3.06 (m, 2H), 2.89−2.79 (m, 3H), 2.78−2.70 (m, 1H), 2.57 ppm (s, 3H); 13C NMR (101 MHz, DMSO): δ 176.6, 175.5, 147.8, 142.9, 132.7, 131.1, 128.9, 128.5, 127.5, 126.6, 123.9, 120.54, 119.9, 119.6, 109.4, 108.4, 58.2, 58.1, 58.0, 38.4, 29.4, 26.1 ppm; HRMS calcd. For C22H21BrN2O3Na+ [M + Na]+ 463.0628, found 463.0623. Preparation of Bis-Oxindole Alcohols 29 from Bromo BisOxindole 41: To a stirred solution of the alcohol 41 (8.3 mg, 0.02 mmol) in THF (1.0 mL) at −78 °C was added tBuLi (1.7 M in pentane, 0.06 mL, 0.10 mmol) dropwise. The resulting mixture was stirred for 30 min before it was quenched with water (5 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford alcohol 29 (6.5 mg, 95%) as white foam. All physical data of alcohol 29 are identical to those obtained from organocatalytic reaction between oxindole 26 and allyl oxindole 11 followed by NaBH4 reduction. 29: [α]D25 +151.5 (c = 0.98, CHCl3). Preparation of Bis-Oxindole Alcohols 29a from Bromo BisOxindole 41a: To a stirred solution of the alcohol 41a (21.1 mg, 0.05 mmol) in THF (1.00 mL) at −78 °C was added tBuLi (1.7 M in pentane, 0.15 mL, 0.25 mmol) dropwise. The resulting mixture was stirred for 30 min before it was quenched with water (5 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1.5:1) to afford alcohol 29a (11.9 mg, 69%) as white foam. All physical data of alcohol 29a are identical to those obtained from organocatalytic reaction between oxindole 26 and allyl oxindole 11 followed by NaBH4 reduction. 29a: [α]D25 +20.4 (c = 1.36, CHCl3). Amine 30-NH2: To a stirred solution of azide 30 (1.45 g, 3.70 mmol) in MeOH (40.0 mL) at room temperature was added Pd/C (10% wt/wt, 392 mg, 0.37 mmol). The resulting mixture was purged with a stream of hydrogen (bubbling with a hydrogen filled balloon) for 0.5 h and stirred for further 12 h before it was filtered through a pad of Celite® and eluted with EtOAc (100 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel, CH2Cl2:MeOH 4:1) to afford amine 30-NH2 (1.04 g, 77%) as a white amorphous solid. 30-NH2: Rf = 0.20 (silica gel, CH2Cl2:MeOH 4:1); IR (film) νmax 3425, 3062, 2685, 2410, 1716, 1612, 1550, 1263, 894, 649 cm−1; 1H NMR (400 MHz, CD3OD): δ 7.17 (d, J = 7.6 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.96−6.90 (m,

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2H), 6.87 (t, J = 7.6 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H), 6.46 (d, J = 7.3 Hz, 1H), 3.12−2.97 (m, 3H), 3.04 (s, 3H), 2.97−2.87 (m, 1H), 2.49 (dt, J = 13.0, 8.0 Hz, 1H), 2.36 (td, J = 12.1, 4.7 Hz, 1H), 2.17 (td, J = 12.0, 4.7 Hz, 1H), 1.93 ppm (td, J = 11.7, 5.1 Hz, 1H); 13C NMR (101 MHz, CD3OD): δ 179.7, 179.0, 144.7, 142.7, 130.0, 129.8, 128.5, 128.0, 124.7, 124.4, 123.2, 122.9, 110.8, 109.2, 59.3, 56.1, 55.0, 37.5, 32.2, 28.8, 26.3 ppm; HRMS calcd. For C21H24N3O3 [M + H]+ 366.1812, found 366.1813. p-Nitrobenzylamine 32: To a stirred solution of amine 30-NH2 (1.03 g, 2.82 mmol) in MeOH/THF (3:1, 28.0 mL) at room temperature was added p-nitrobenzylaldehyde (1.28 g, 8.46 mmol). The resulting mixture was stirred for 12 h before it was cooled to 0 °C followed by the addition of NaBH4 (534 mg, 14.1 mmol). The resulting mixture was stirred for 6 h before it was quenched with water (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 50 mL), the combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, EtOAc) to afford p-nitrobenzylamine 32 (847 mg, 60%) as a orange amorphous solid. 32: Rf = 0.35 (silica gel, CH2Cl2:MeOH 9:1); IR (film) νmax 3054, 3004, 2987, 2305, 1705, 1521, 1347, 1261, 896, 734 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.9 Hz, 2H), 7.96 (br s, 1H), 7.25−7.18 (m, 3H), 7.05 (td, J = 7.7, 1.2 Hz, 1H), 7.00−6.94 (m, 2H), 6.88 (td, J = 7.6, 1.1 Hz, 1H), 6.79 (td, J = 7.6, 1.1 Hz, 1H), 6.49 (d, J = 7.4 Hz, 1H), 6.44 (d, J = 7.9 Hz, 1H), 3.73 (d, J = 14.5 Hz, 1H), 3.57 (d, J = 14.5 Hz, 1H), 3.42−3.33 (m, 1H), 3.24−3.07 (m, 3H), 3.06 (s, 3H), 2.66−2.57 (m, 1H), 2.49 (dt, J = 13.7, 7.8 Hz, 1H), 2.29−2.18 ppm (m, 2H); 13C NMR (101 MHz, CDCl3): δ 179.8, 178.0, 147.7, 146.7, 143.2, 140.7, 128.4, 128.3, 128.3, 128.1, 127.0, 123.7, 123.6, 123.3, 121.9, 121.4, 109.2, 107.5, 59.2, 55.5, 54.2, 52.5, 45.3, 31.5, 28.4, 25.8 ppm; HRMS calcd. For C28H29N4O5+ [M + H]+ 501.2132, found 501.2128. Amidine 34: To a stirred solution of p-nitrobenzylamine 32 (216 mg, 0.43 mmol) in THF (40.0 mL) at room temperature was added titanium(IV) isopropoxide (1.23 g, 4.32 mmol). The resulting mixture was warmed to 130 °C and stirred for 16 h before it was cooled to room temperature and quenched with water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 100 mL), the combined organic layer was washed with water (400 mL) and brine (400 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexaned:EtOAc 1:2) to afford amidine 34 (147 mg, 71%) as a yellow foam. 34: Rf = 0.21 (silica gel, EtOAc); IR (film) νmax 3055, 2986, 2305, 1689, 1524, 1493, 1347, 895, 715 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.8 Hz, 2H), 7.37 (td, J = 7.7, 1.1 Hz, 1H), 7.30 (dd, J = 7.5, 1.1 Hz, 1H), 7.25−7.21 (m, 2H), 7.11 (d, J = 7.7 Hz, 1H), 7.01−6.95 (m, 2H), 6.94−6.87 (m, 3H), 4.54 (d, J = 15.6 Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H), 3.62 (q, J = 9.0 Hz, 1H), 3.43 (s, 3H), 3.43−3.36 (m, 2H), 3.23−3.14 (m, 1H), 3.09−2.96 (m, 1H), 2.77 (dd, J = 14.1, 7.4 Hz, 1H), 2.40−2.28 (m, 1H), 1.92−1.79 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 172.9, 169.4, 147.5, 147.2, 145.9, 143.5, 129.5, 129.3, 129.2, 128.2, 125.6, 125.0, 124.3, 123.7, 122.9, 121.1, 108.3, 58.3, 53.5, 47.2, 45.6, 44.5, 35.5, 28.0, 26.7 ppm; HRMS calcd. For C28H27N4O4+ [M + H]+ 483.2027, found 483.2042. Tosylate Ts-34: To a stirred solution of alcohol 34 (1.55 g, 3.21 mmol) in CH2Cl2 (35.0 mL) at 0 °C was added p-toluenesulfonyl chloride (1.53 g, 8.03 mmol), N,N'-dimethylaminopyridine (392 mg, 3.21 mmol), and triethylamine (1.10 mL, 8.03 mmol). The resulting mixture was warmed to room temperature and stirred for 15.5 h before it was quenched with water (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2


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(3 × 100 mL), the combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:2) to afford tosylate Ts-34 (1.90 g, 93%) as a yellow foam. Ts-34: Rf = 0.30 (silica gel, hexanes:EtOAc 1:4); IR (film) νmax 2990, 2305, 1799, 1654, 1101, 897, 741 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.32−7.19 (m, 5H), 7.07 (d, J = 7.8 Hz, 1H), 7.03−6.93 (m, 2H), 6.90 (d, J = 7.9 Hz, 2H), 6.84 (d, J = 7.9 Hz, 1H), 4.52 (d, J = 15.5 Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H), 3.84−3.74 (m, 1H), 3.68−3.52 (m, 2H), 3.42−3.34 (m, 1H), 3.37 (s, 3H), 3.00−2.88 (m, 1H), 2.71 (dd, J = 14.3, 8.0 Hz, 1H), 2.42 (s, 3H), 2.42−2.33 (m, 1H), 1.97−1.87 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 172.4, 167.7, 147.4, 147.0, 145.7, 144.6, 143.4, 132.3, 129.6, 129.4, 129.3, 128.1, 128.1, 127.5, 125.2, 125.0, 124.3, 123.7, 123.5, 122.9, 121.1, 108.4, 66.1, 53.2, 46.5, 45.4, 44.2, 31.7, 27.8, 26.4, 21.5 ppm; HRMS calcd. For C35H33N4O6S+ [M + H]+ 637.2115, found 637.2113. Azide 36: To a stirred solution of tosylate Ts-34 (1.20 g, 1.89 mmol) in DMF (20.0 mL) at room temperature was added sodium azide (1.23 g, 18.9 mmol). The resulting mixture was warmed to 50 °C and stirred for 12 h before it was cooled to room temperature and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL), the combined organic layer was washed with water (4 × 200 mL) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 2:1) to afford azide 36 (931 mg, 97%) as a yellow foam. 36: Rf = 0.47 (silica gel, hexanes:EtOAc 1:4); IR (film) νmax 3050, 2989, 2305, 2098, 1691, 1652, 1263, 895, 703 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.3 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.33−7.23 (m, 3H), 7.11 (d, J = 8.0 Hz, 1H), 7.04−6.95 (m, 2H), 6.95−6.87 (m, 3H), 4.54 (d, J = 15.6 Hz, 1H), 4.05 (d, J = 15.6 Hz, 1H), 3.62 (q, J = 8.9 Hz, 1H), 3.46 (s, 3H), 3.41 (t, J = 9.9 Hz, 1H), 3.10−2.94 (m, 2H), 2.83−2.72 (m, 2H), 2.39−2.24 (m, 1H), 1.83–1.73 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 172.5, 168.1, 147.6, 147.1, 145.9, 143.5, 129.4, 128.5, 128.1, 125.3, 125.2, 124.3, 123.7, 123.5, 122.7, 121.1, 108.3, 53.4, 47.1, 46.8, 45.5, 44.3, 31.7, 27.9, 26.5 ppm; HRMS calcd. For C28H26N7O3+ [M + H]+ 508.2092, found 508.2090. p-Nitrobenzylamine 33: (i) To a stirred solution of azide 31 (29.6 g, 70.6 mmol) in MeOH (450 mL) at room temperature was added Pd/C (10% wt/wt, 5.98 g). The resulting mixture was purged with a stream of hydrogen (bubbling with a hydrogen filled balloon) for 1 h and stirred for further 12 h before it was filtered through a pad of Celite® and eluted with EtOAc (500 mL). The filtrate was concentrated under reduced pressure. The resulting crude residue was used directly in the next step without further purification. (ii) To a stirred solution of crude amine 31-NH2 (obtained above, 30.0 g, 77.8 mmol) in MeOH/THF (3:1, 240 mL) at room temperature was added p-nitrobenzylaldehyde (30.4 g, 201 mmol). The resulting mixture was stirred for 3 h before it was cooled to 0 °C followed by the addition of NaBH4 (15.2 g, 402 mmol). The resulting mixture was stirred for 1 h before it was quenched with water (250 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 300 mL), the combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1→ EtOAc) to afford p-nitrobenzylamine 33 (24.5 g, 66% over two steps) as a yellow foam. 33: Rf = 0.30 (silica gel, CH2Cl2:MeOH 4:1); [α]D25 +100 (c = 1.51, CHCl3); IR (film) νmax 3053, 3005, 2987, 2305, 1421, 1274, 896 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.77 (br, 1H), 7.98 (d, J = 8.5 Hz,

2H), 7.23 (d, J = 7.4 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.05−6.91 (m, 3H), 6.87 (t, J = 7.5 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 5.11 (d, J = 10.8 Hz, 1H), 4.76 (d, J = 10.8 Hz, 1H), 3.66 (d, J = 14.6 Hz, 1H), 3.52 (d, J = 14.6 Hz, 1H), 3.42−3.34 (m, 1H), 3.28 (s, 3H), 3.21−3.04 (m, 3H), 2.68−2.56 (m, 1H), 2.53−2.41 (m, 1H), 2.18 (t, J = 7.0 Hz, 2H) ppm; 13C NMR (101 MHz, CDCl3): δ 179.7, 178.7, 147.8, 146.5, 142.0, 140.7, 128.4, 128.3, 128.2, 127.7, 126.4, 123.8, 123.7, 123.2, 122.2, 121.4, 109.2, 108.9, 71.7, 59.0, 56.6, 55.4, 54.2, 52.5, 45.1, 31.6, 28.4 ppm; HRMS calcd. For C29H31N4O6+ [M + H]+ 531.2238, found 531.2236. Amidines 35a and 35b: To a stirred solution of pnitrobenzylamine 33 (9.24 g, 17.4 mmol) in THF (175 mL) at room temperature was added titanium(IV) isopropoxide (52.0 mL, 174 mmol). The resulting mixture was warmed to 130 °C and stirred for 22 h before it was cooled to room temperature and quenched with sodium potassium tartrate (50 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 200 mL), the combined organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexaned:EtOAc 1:2) to afford an inconsequential mixture of amidine 35a and 35b (35a:35b ~ 0.6:1, 8.23 g, 89%) as a yellow foam. Small amount of analytically pure amidines 35a and 35b were obtained through column chromatography. 35a: Rf = 0.31 (silica gel, hexanes:EtOAc 1:4); [α]D25 −71.9 (c = 1.60, CHCl3); IR (film) νmax 3060, 2931, 2855, 1682, 1346, 737 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 9.8 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.25−7.21 (m, 2H), 7.11 (dd, J = 15.1, 7.7 Hz, 2H), 7.03−6.96 (m, 2H), 6.94 (d, J = 8.5 Hz, 2H), 5.50 (d, J = 10.7 Hz, 1H), 5.23 (d, J = 10.7 Hz, 1H), 4.53 (d, J = 15.5 Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H), 3.62 (dd, J = 17.7, 8.8 Hz, 1H), 3.53 (s, 3H), 3.48−3.35 (m, 2H), 3.25−3.15 (m, 1H), 3.03 (dt, J = 13.9, 9.6 Hz, 1H), 2.76 (dd, J = 14.0, 7.7 Hz, 1H), 2.39−2.28 (m, 1H), 1.89−1.79 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 172.8, 168.5, 147.3, 146.3, 145.6, 143.6, 129.4, 129.1, 128.3, 126.0, 125.8, 124.3, 124.2, 123.7, 122.9, 122.8, 121.6, 109.6, 73.2, 58.6, 56.8, 53.5, 47.4, 45.7, 44.4, 35.9, 26.7 ppm; HRMS calcd. For C29H28N4O5Na+ [M + Na]+ 535.1952, found 535.1954. 35b: Rf = 0.49 (silica gel, hexanes:EtOAc 1:4); [α]D25 −60.7 (c = 1.60, CHCl3); IR (film) νmax 3051, 2940, 2887, 2304, 1684, 1264, 733 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.21−7.14 (m, 2H), 7.10 (t, J = 7.5 Hz, 2H), 6.95 (q, J = 7.7 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.58 (d, J = 10.9 Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H), 4.49 (d, J = 15.6 Hz, 1H), 4.05−3.91 (m, 2H), 3.59 (q, J = 8.7 Hz, 1H), 3.44−3.28 (m, 2H), 3.11 (td, J = 9.9, 5.5 Hz, 1H), 2.98 (dt, J = 13.6, 9.5 Hz, 1H), 2.72 (dd, J = 14.0, 7.6 Hz, 1H), 2.33−2.20 (m, 2H), 1.85−1.72 (m, 1H), 1.19 ppm (dd, J = 11.7, 6.1 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 172.6, 168.3, 147.0, 146.4, 145.5, 143.6, 129.1, 129.1, 129.0, 128.2, 125.9, 125.4, 124.2, 124.0, 123.5, 122.7, 121.4, 109.6, 69.6, 69.3, 58.1, 53.4, 47.3, 45.5, 44.3, 35.7, 26.4, 22.2, 21.9 ppm; HRMS calcd. For C31H33N4O5+ [M + H]+ 541.2445, found 541.2440. Tosylate Ts-35a: To a stirred solution of alcohols 35a (2.53 g, 4.93 mmol) in CH2Cl2 (80.0 mL) at 0 °C was added ptoluenesulfonyl chloride (2.82 g, 14.8 mmol), N,N'dimethylaminopyridine (603 mg, 4.93 mmol), and triethylamine (2.00 mL, 14.8 mmol). The resulting mixture was warmed to room temperature and stirred for 15 h before it was quenched with water (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford



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tosylates Ts-35a (1.81 g, 55%) as a brown foam. Ts-35a: Rf = 0.40 (silica gel, hexanes:EtOAc 1:2); [α]D25 −81.0 (c = 1.48, CHCl3); IR (film) νmax 3054, 2984, 2305, 1689, 1347, 742 cm−1; 1 H NMR (499 MHz, CDCl3) δ 8.00 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.7 Hz, 1H), 7.29−7.20 (m, 5H), 7.08 (dd, J = 14.4, 7.7 Hz, 2H), 7.00 (dt, J = 10.6, 7.8 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 5.39 (d, J = 10.9 Hz, 1H), 5.32−5.22 (br, 1H), 4.51 (d, J = 15.6 Hz, 1H), 4.05 (d, J = 15.6 Hz, 1H), 3.85−3.77 (m, 1H), 3.64−3.56 (m, 2H), 3.48 (s, 3H), 3.40 (t, J = 9.8 Hz, 1H), 3.03−2.91 (m, 1H), 2.72 (dd, J = 14.0, 7.6 Hz, 1H), 2.42 (s, 3H), 2.41−2.34 (m, 1H), 2.00−1.91 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 172.3, 167.2, 147.2, 146.2, 145.3, 144.7, 143.5, 132.5, 129.7, 129.6, 129.4, 128.2, 127.8, 127.6, 125.9, 125.5, 124.4, 124.3, 123.7, 123.0, 121.7, 109.8, 73.2, 66.1, 56.8, 53.3, 46.8, 45.6, 44.3, 32.2, 26.6, 21.6 ppm; HRMS calcd. For C36H35N4O7S+ [M + H]+ 667.2221, found 667.2220. Tosylate Ts-35b: To a stirred solution of alcohols 35b (3.35 g, 6.20 mmol) in CH2Cl2 (60.0 mL) at 0 °C was added ptoluenesulfonyl chloride (3.60 g, 18.6 mmol), N,N'dimethylaminopyridine (758 mg, 6.20 mmol), and triethylamine (2.50 mL, 6.20 mmol). The resulting mixture was warmed to room temperature and stirred for 2 h before it was quenched with water (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford tosylates Ts-35b (4.22 g, 98%) as a brown foam. Ts-35b: Rf = 0.60 (silica gel, hexanes:EtOAc 1:2); [α]D25 −105 (c = 1.48, CHCl3); IR (film) νmax 3060, 2971, 2931, 1655, 1347, 759 cm−1; 1 H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.33 (t, J = 7.7 Hz, 1H), 7.25−7.13 (m, 5H), 7.09 (d, J = 8.2 Hz, 2H), 7.01−6.91 (m, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.56 (d, J = 11.1 Hz, 1H), 5.17 (d, J = 11.1 Hz, 1H), 4.46 (d, J = 15.6 Hz, 1H), 4.01−3.91 (m, 2H), 3.86−3.77 (m, 1H), 3.61−3.48 (m, 2H), 3.37 (t, J = 9.7 Hz, 1H), 2.97−2.86 (dt, J = 13.6, 9.5 Hz, 1H), 2.66 (dd, J = 13.8, 7.6 Hz, 1H), 2.38 (s, 3H), 2.36−2.27 (m, 1H), 1.96−1.84 (m, 1H), 1.21 (d, J = 6.0 Hz, 3H), 1.16 ppm (d, J = 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 172.2, 166.9, 146.9, 146.3, 145.3, 144.6, 143.4, 132.3, 129.5, 129.3, 129.1, 128.1, 127.7, 127.4, 125.6, 125.3, 124.2, 124.1, 123.4, 122.8, 121.4, 109.8, 69.7, 69.0, 66.0, 53.2, 46.5, 45.4, 44.1, 32.0, 26.2, 22.2, 21.7, 21.4 ppm; HRMS calcd. For C38H39N4O7S+ [M + H]+ 695.2534, found 695.2537. Azide 37a: To a stirred solution of tosylates Ts-35a (695 mg, 1.04 mmol) in DMF (10.0 mL) at room temperature was added sodium azide (678 mg, 10.4 mmol). The resulting mixture was warmed to 50 °C and stirred for 4.5 h before it was cooled to room temperature and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL), the combined organic layer was washed with brine (5 × 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 2:1) to afford azide 37a (484 mg, 86%) as a yellow foam. 37a: Rf = 0.39 (silica gel, hexanes:EtOAc 1:1); [α]D25 −99.9 (c = 1.54, CHCl3); IR (film) νmax 3054, 2934, 2099, 1655, 1344, 739 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.6 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.27−7.24 (m, 1H), 7.12 (t, J = 6.8 Hz, 2H), 7.02 (t, J = 7.7 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 5.50 (d, J = 10.8 Hz, 1H), 5.29 (d, J = 10.8 Hz, 1H), 4.53 (d, J = 15.5 Hz, 1H), 4.06 (d, J = 15.5 Hz, 1H), 3.63 (dd, J = 17.8, 8.8 Hz, 1H), 3.57 (s, 3H), 3.42 (t, J = 9.8 Hz, 1H), 3.13−2.96 (m, 2H), 2.87−2.71 (m, 2H), 2.39−2.27 (m, 1H), 1.88−1.72 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 172.6, 167.6, 147.3, 146.5, 145.5, 143.6, 129.6, 129.5, 128.3, 128.2,

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126.0, 125.7, 124.4, 124.3, 123.8, 122.8, 121.8, 109.8, 73.4, 57.0, 53.6, 47.4, 46.8, 45.7, 44.4, 32.1, 26.7 ppm; HRMS calcd. For C29H28N7O4+ [M + H]+ 538.2197, found 538.2195. Azide 37b: To a stirred solution of tosylates Ts-35b (4.22 g, 6.07 mmol) in DMF (60.0 mL) at room temperature was added sodium azide (4.00 g, 60.7 mmol). The resulting mixture was warmed to 50 °C and stirred for 11.5 h before it was cooled to room temperature and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL), the combined organic layer was washed with brine (5 × 200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 4:1) to afford azide 37b (3.33 g, 97%) as a yellow foam. 37b: Rf = 0.52 (silica gel, hexanes:EtOAc 1:1); [α]D25 −134.4 (c = 1.52, CHCl3); IR (film) νmax 3052, 2984, 2305, 2100, 1689, 1265, 738 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.6 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.24 (d, J = 4.0 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.04−6.96 (m, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.66 (d, J = 11.0 Hz, 1H), 5.22 (d, J = 11.0 Hz, 1H), 4.51 (d, J = 15.6 Hz, 1H), 4.07 (dt, J = 12.2, 6.1 Hz, 1H), 3.99 (d, J = 15.6 Hz, 1H), 3.61 (dd, J = 17.7, 8.7 Hz, 1H), 3.41 (t, J = 9.7 Hz, 1H), 3.12−2.94 (m, 2H), 2.87−2.69 (m, 2H), 2.36−2.25 (m, 1H), 1.86−1.74 (m, 1H), 1.27 (d, J = 6.1 Hz, 3H), 1.25 ppm (d, J = 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 173.2, 167.3, 147.0, 146.6, 145.5, 143.5, 129.4, 129.2, 128.1, 128.0, 125.6, 125.5, 124.2, 124.0, 123.5, 122.6, 121.5, 109.8, 69.8, 69.2, 53.3, 47.2, 46.6, 45.5, 44.2, 31.8, 26.4, 22.2, 21.8 ppm; HRMS calcd. For C31H32N7O4+ [M + H]+ 566.2510, found 566.2514. Methyl isatin Mod-1: To a stirred solution of isatin (5.00 g, 34.0 mmol) in DMF (136 mL) at 0 °C was added NaH (60% in mineral oil, 1.63 g, 40.8 mmol) in portions. The resulting mixture was stirred for 0.5 h before MeI (7.24 g, 51.0 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 16 h before it was quenched with NH4Cl (50 mL, sat. aq.) and water (50 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL), the combined organic layer was washed with water (3 × 500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 2:1) to afford methyl isatin Mod-1 (3.40 g, 62%) as an orange powder. Oxindole Mod-2: (i) To a stirred solution of methyl isatin Mod-1 (5.00 g, 31.0 mmol) in THF (124 mL) at −78 °C was added methylmagnesium bromide (3.0 M in Et2O, 11.4 mL, 34.1 mmol). The resulting mixture was warmed to room temperature and stirred for 16 h before it was quenched with NH4Cl (100 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 200 mL), the combined organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. (ii) To a stirred solution of the residue (obtained above) in AcOH (glacial)/HCl (10 M, aq.) (15:1, 120 mL) was added SnCl2 (anhydrous, 8.23 g, 43.4 mmol). The resulting mixture was warmed to 80 °C and stirred for 1.5 h before it was cooled to room temperature and quenched with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3 × 200 mL), the combined organic layer was washed with NaOH (1.0 M aq., 100 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 9:1) to afford oxindole Mod-2 (2.44 g, 49%) as a yellow oil. Mod-2: Rf = 0.56 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 3052, 2987, 2935, 2305, 1699, 1471, 1376, 895, 698 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.31−7.21 (m, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 3.43 (q, J = 7.6 Hz, 1H), 3.21 (s,


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3H), 1.48 ppm (d, J = 7.7 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 178.1, 143.5, 130.2, 127.5, 123.0, 121.9, 107.5, 40.1, 25.7, 15.0 ppm; HRMS calcd. For C10H11NONa+ [M + Na]+ 184.0733, found 184.0732. Nitrile Mod-3: To a stirred solution of oxindole Mod-2 (2.44 g, 15.1 mmol) in DMF (75.7 mL) at 0 °C was added NaH (60% in mineral oil, 787 mg, 19.7 mmol) in portions. The resulting mixture was warmed to room temperature and stirred for 1 h before it was cooled to 0 °C followed by the addition of chloroacetonitrile (1.71 g, 22.7 mmol). The resulting mixture was warmed to room temperature and stirred for 1 h before it was quenched with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 × 150 mL), the combined organic layer was washed with water (3 × 500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to afford nitrile Mod-3 (2.74 g, 90%) as a green oil. Mod-3: Rf = 0.44 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax 2981, 2831, 2685, 2305, 2250, 1709, 1259, 896, 696 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.4 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 3.24 (s, 3H), 2.85 (d, J = 16.6 Hz, 1H), 2.56 (d, J = 16.6 Hz, 1H), 1.53 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): δ 177.0, 142.3, 130.6, 128.8, 122.7, 122.6, 116.3, 108.3, 44.4, 26.1, 25.7, 21.8 ppm; HRMS calcd. For C12H12N2ONa [M + Na]+ 223.0842, found 223.0842. Amine Mod-4: To a stirred solution of nitrile Mod-3 (3.81 g, 19.0 mmol) in MeOH (137 mL) at room temperature was added CoCl2 hexahydrate (9.74 g, 40.9 mmol) followed by NaBH4 (7.75 g, 205 mmol) in portions over 45 min. The resulting mixture was stirred for 1.5 h before it was quenched with water (150 mL). The resulting mixture was extracted with EtOAc (3 × 250 mL), the combined organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, MeOH:CH2Cl2 1:4) to afford amine Mod-4 (2.04 g, 53%) as a yellow oil. Mod-4: Rf = 0.23 (silica gel, MeOH:CH2Cl2 1:4); IR (film) νmax 3381, 3038, 2305, 2124, 1824, 1255, 765, 694 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.25 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 7.3 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 7.7 Hz, 1H), 4.38 (br s, 2H), 3.19 (s, 3H), 2.66−2.38 (m, 2H), 2.23−1.98 (m, 2H), 1.35 ppm (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 180.0, 142.6, 132.9, 127.8, 122.6, 122.4, 108.0, 46.8, 38.7, 36.9, 26.0, 23.8 ppm; HRMS calcd. For C12H17N2O+ [M + H]+ 205.1335, found 205.1336. Trifluoromethanesulfonamide 42: To a stirred solution of amine Mod-4 (522 mg, 2.56 mmol) in CH2Cl2 (12.8 mL) at −78 °C was added triethylamine (0.35 mL, 2.56 mmol). The resulting mixture was stirred for 5 min before trifluoromethanesulfonic anhydride (1.0 M in CH2Cl2, 2.69 mL, 2.69 mmol) was added. The resulting mixture was stirred for 1 h before it was quenched with ice water (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL), the combined organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 6:1) to afford trifluoromethanesulfonamide 42 (444 mg, 52%) as a colorless oil. 42: Rf = 0.57 (silica gel, hexanes:EtOAc 2:1); IR (film) νmax 3058, 2975, 2306, 1703, 1260, 859, 717 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 3.85−3.68 (m, 2H), 3.23 (s, 3H), 2.40 (td, J = 12.2, 5.3 Hz, 1H), 2.18 (td, J = 12.4, 5.1 Hz, 1H), 1.41 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): δ 178.4, 142.7, 131.7, 128.6, 123.1, 122.5, 120.4 (q, JC-F = 327.0 Hz), 108.5, 49.8, 46.2,

36.9, 26.3, 23.4 ppm; HRMS calcd. For C13H15F3N2O3SNa+ [M + Na]+ 359.0648, found 359.0647. Triazole-Amide 43: To a stirred solution of amine Mod-4 (192 mg, 0.94 mmol) in CH2Cl2 (20.0 mL) at room temperature was added 1-benzyl-5-phenyl-1H-1,2,3-triazole-4-carboxylic acid (289 mg, 1.04 mmol), EDC hydrochloride (198 mg, 1.04 mmol), HOBt monohydrate (140 mg, 1.04 mmol) and diisopropylethylamine (0.50 mL, 2.82 mmol). The resulting mixture was stirred for 15 h before it was quenched with water (20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL), the combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to afford triazole-amide 43 (354 mg, 81%) as a white foam. 43: Rf = 0.40 (silica gel, hexanes:EtOAc 1:2); IR (film) νmax 3420, 3341, 3049, 2685, 2410, 2305, 1673, 1257, 897, 715 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.49−7.34 (m, 3H), 7.30−7.15 (m, 7H), 7.11 (br s, 1H), 7.05−6.94 (m, 3H), 6.80 (d, J = 7.6 Hz, 1H), 5.39 (s, 2H), 3.26−3.13 (m, 1H), 3.17 (s, 3H), 3.08−2.98 (m, 1H), 2.28−2.18 (m, 1H), 2.13−2.03 (m, 1H), 1.37 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): δ 179.7, 159.7, 142.6, 138.7, 138.5, 134.6, 132.8, 129.6, 129.5, 128.4, 128.1, 128.0, 127.6, 127.1, 125.7, 122.4, 122.4, 107.9, 51.6, 46.7, 36.9, 35.0, 25.9, 23.7 ppm; HRMS calcd. For C28H27N5O2Na+ [M + Na]+ 488.2057, found 488.2057. Quinoline-2-Carboxamide 44: To a stirred solution of amine Mod-4 (500 mg, 2.45 mmol) in CH2Cl2 (25.0 mL) at room temperature was added quinoline-2-carboxylic acid (550 mg, 3.18 mmol), EDC hydrochloride (517 mg, 2.70 mmol), HOBt monohydrate (364 mg, 2.70 mmol) and diisopropylethylamine (1.25 mL, 7.35 mmol). The resulting mixture was stirred for 14 h before it was quenched with water (25 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL), the combined organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 2:1) to afford quinoline-2-carboxamide 44 (194 mg, 22%) as a yellow oil. 44: Rf = 0.45 (silica gel, hexanes:EtOAc 1:2); IR (film) νmax 3389, 3054, 2986, 2305, 1707, 1676, 1613, 1350, 896, 721 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.19−8.14 (m, 2H), 8.07 (br s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.16 (td, J = 7.7, 1.3 Hz, 1H), 6.98 (td, J = 7.5, 1.1 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 3.33−3.22 (m, 1H), 3.22−3.12 (m, 1H), 3.10 (s, 3H), 2.38−2.27 (m, 1H), 2.21−2.10 (m, 1H), 1.37 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): δ 179.9, 163.8, 149.2, 146.1, 142.8, 137.1, 132.8, 129.8, 129.4, 128.9, 127.8, 127.5, 127.4, 122.6, 122.4, 118.3, 108.0, 46.9, 37.1, 35.6, 26.0, 24.1 ppm; HRMS calcd. For C22H21N3O2Na+ [M + Na]+ 382.1526, found 382.1526. Picolinamide 45: To a stirred solution of amine Mod-4 (470 mg, 2.30 mmol) in CH2Cl2 (23.0 mL) at room temperature was added picolinic acid (308 mg, 2.50 mmol), EDC hydrochloride (479 mg, 2.50 mmol), HOBt monohydrate (338 mg, 2.50 mmol) and diisopropylethylamine (0.17 mL, 6.90 mmol). The resulting mixture was stirred for 12 h before it was quenched with water (20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 40 mL), the combined organic layer was washed with water (150 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford picolinamide 45 (490 mg, 69%) as a yellow oil. 45: Rf = 0.26 (silica gel, hexanes:EtOAc 1:2); IR (film) νmax 3399, 3043, 2685, 2523, 2410, 2305, 1865, 1277, 894, 695 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.48 (dd, J = 4.8, 1.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.87 (br s, 1H), 7.78 (td, J = 7.8, 1.7



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Hz, 1H), 7.39−7.35 (m, 1H), 7.26−7.20 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 3.29−3.19 (m, 1H), 3.18−3.08 (m, 1H), 3.17 (s, 3H), 2.34−2.24 (m, 1H), 2.18−2.09 (m, 1H), 1.39 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): δ 179.5, 163.5, 149.2, 147.5, 142.6, 136.7, 132.6, 127.5, 125.6, 122.3, 122.2, 121.4, 107.8, 46.6, 36.9, 35.3, 25.7, 23.8 ppm; HRMS calcd. For C18H19N3O2Na+ [M + Na]+ 332.1369, found 332.1371. Oxalamide 46: To a stirred solution of N,N'-diisopropyloxamoyl chloride (680 mg, 3.60 mmol) in CH2Cl2 (7.20 mL) at 0 °C was added a solution of amine Mod-4 (589 mg, 2.88 mmol) in CH2Cl2 (5.80 mL). The resulting mixture was stirred for 5 min before triethylamine (0.42 mL, 3.02 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 16 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford oxalamide 46 (821 mg, 79%) as a pale yellow foam. 46: Rf = 0.42 (silica gel, hexanes:EtOAc 1:2); IR (film) νmax 3413, 3046, 2989, 2830, 2305, 1712, 1635, 1519, 1348, 896, 716 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.31−7.23 (m, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.89−6.79 (m, 2H), 4.72−4.62 (m, 1H), 3.53−3.39 (m, 1H), 3.21 (s, 3H), 3.11−3.00 (m, 1H), 3.00−2.86 (m, 1H), 2.26−2.13 (m, 1H), 2.04−1.93 (m, 1H), 1.39−1.37 (m, 9H), 1.19 (d, J = 5.4 Hz, 3H), 1.18 ppm (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 179.8, 163.0, 162.9, 142.7, 132.7, 127.8, 122.6, 122.4, 108.0, 49.3, 46.7, 46.0, 36.4, 35.3, 26.0, 23.7, 20.6, 20.5, 19.8, 19.8 ppm; HRMS calcd. For C20H29N3O3Na+ [M + Na]+ 382.2101, found 382.2102. Oxindole 46a: To a stirred solution of oxalamide 46 (60.7 mg, 0.17 mmol) in 1,2-dichloroethane (2.00 mL) was at room temperature added 2-methyl-but-3-en-2-ol (0.09 mL, 0.85 mmol), Pd(OAc)2 (3.80 mg, 0.02 mmol), Ag2CO3 (93.8 mg, 0.34 mmol), pivalic acid (3.50 mg, 0.03 mmol). The resulting mixture was warmed to 120 °C and stirred for 22 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, CH2Cl2:Et2O 4:1) to afford CH-activation product 46a (30.6 mg, 41%) as a pale yellow oil, and recovered starting material 46 (32.8 mg, 54%) as a yellow oil. 46a: Rf = 0.27 (silica gel, hexanes:EtOAc 1:2); IR (film) νmax 3413, 3056, 2984, 2831, 2305, 1707, 1634, 1519, 1371, 1345, 896, 710 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.26−7.18 (m, 2H), 6.90 (d, J = 15.9 Hz, 1H), 6.84 (br s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 6.40 (d, J = 15.8 Hz, 1H), 4.70−4.52 (m, 1H), 3.56−3.39 (m, 1H), 3.22 (s, 3H), 3.05−2.92 (m, 1H), 2.68−2.52 (m, 1H), 2.44−2.23 (m, 2H), 1.60 (s, 3H), 1.44 (s, 3H), 1.43 (s, 3H), 1.39 (d, J = 6.9 Hz, 3H), 1.37 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 7.4 Hz, 3H), 1.17 ppm (d, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 180.0, 163.1, 162.8, 143.2, 141.6, 134.4, 128.6, 128.1, 121.4, 119.9, 106.9, 70.5, 49.6, 47.9, 46.4, 36.1, 35.6, 30.1, 29.0, 26.4, 24.0, 20.8, 20.0, 19.9 ppm; HRMS calcd. For C25H37N3O4Na+ [M + Na]+ 466.2676, found 466.2678. Oxindole 46b: To a stirred solution of oxalamide 46 (61.4 mg, 0.17 mmol) in 1,2-dichloroethane (2.00 mL) was at room temperature added methyl vinyl ketone (0.07 mL, 0.85 mmol), Pd(OAc)2 (3.80 mg, 0.02 mmol), Ag2CO3 (93.8 mg, 0.34 mmol), pivalic acid (3.50 mg, 0.03 mmol). The resulting mixture was warmed to 120 °C and stirred for 22 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to afford CH-activation product 46b (27.2 mg, 39%) as a pale yellow oil, and recovered starting material 46 (31.6 mg, 52%) as a

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yellow oil. 46b: Rf = 0.35 (silica gel, hexanes:EtOAc 1:2); IR (film) νmax 3412, 3056, 2979, 2305, 1715, 1516, 1449, 1347, 895, 695 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 16.0 Hz, 1H), 7.35−7.27 (m, 2H), 6.88 (d, J = 5.9 Hz, 1H), 6.76 (br s, 1H), 6.72 (d, J = 16.0 Hz, 1H), 4.74 (m, 1H), 3.47 (m, 1H), 3.23 (s, 3H), 3.03−2.92 (m, 1H), 2.86−2.74 (m, 1H), 2.46−2.34 (m, 1H), 2.41 (s, 3H), 2.30−2.18 (m, 1H), 1.50 (s, 3H), 1.38 (d, J = 6.2 Hz, 3H), 1.36 (d, J = 6.2 Hz, 3H) 1.19 (d, J = 6.6 Hz, 3H), 1.17 ppm (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 197.7, 179.4, 162.7, 162.2, 143.7, 137.8, 131.4, 131.3, 129.4, 128.6, 120.3, 109.6, 49.4, 47.9, 46.4, 36.4, 35.8, 28.0, 26.5, 24.2, 20.7, 19.9, 19.9 ppm; HRMS calcd. For C24H33N3O4Na+ [M + Na]+ 450.2363, found 450.2362. Oxindole 46c: To a stirred solution of oxalamide 46 (60.9 mg, 0.17 mmol) in 1,2-dichloroethane (2.00 mL) was at room temperature added methyl acrylate (0.08 mL, 0.85 mmol), Pd(OAc)2 (3.80 mg, 0.02 mmol), Ag2CO3 (93.8 mg, 0.34 mmol), pivalic acid (3.50 mg, 0.03 mmol). The resulting mixture was warmed to 120 °C and stirred for 22 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 5:1) to afford CH-activation product 46c (34.0 mg, 45%) as a pale yellow oil, and recovered starting material 46 (32.0 mg, 53%) as a yellow oil. 46c: Rf = 0.41 (silica gel, hexanes:EtOAc 1:2); IR (film) νmax = 3053, 2985, 2305, 1714, 1635, 1516, 1372, 1344, 895, 738 cm−1; 1 H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 15.9 Hz, 1H), 7.31– 7.21 (m, 2H), 6.84 (d, J = 7.0 Hz, 1H), 6.73 (br s, 1H), 6.41 (d, J = 15.8 Hz, 1H), 4.74−4.63 (m, 1H), 3.79 (s, 3H), 3.49−3.37 (m, 1H), 3.19 (s, 3H), 2.97−2.86 (m, 1H), 2.86−2.73 (m, 1H), 2.43−2.31 (m, 1H), 2.24−2.14 (m, 1H), 1.47 (s, 3H), 1.34 (d, J = 4.7 Hz, 3H), 1.33 (d, J = 4.6 Hz, 3H), 1.16 (d, J = 7.0 Hz, 3H), 1.14 ppm (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 179.5, 166.7, 162.5, 162.1, 143.7, 139.4, 131.2, 131.0, 128.6, 120.8, 120.3, 109.5, 51.9, 49.3, 47.9, 46.5, 36.4, 35.8, 26.5, 23.9, 20.7, 19.9, 19.9 ppm; HRMS calcd. For C24H33N3O5Na+ [M + Na]+ 466.2312, found 466.2311. Amine 36-NH2: To a stirred solution of azide 36 (930 mg, 1.83 mmol) in THF/H2O (10:1, 22.0 mL) at room temperature was added triphenylphosphine (960 mg, 3.66 mmol). The resulting mixture was warmed to 50 °C and stirred for 12 h before it was cooled to room temperature, diluted with acetonitrile (40 mL) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, MeOH:CH2Cl2 1:4) to afford amine 36-NH2 (810 mg, 92%) as a yellow foam. 36-NH2: Rf = 0.10 (silica gel, CH2Cl2:MeOH 9:1); IR (film) νmax = 3756, 3690, 3051, 2989, 2305, 1688, 1649, 1607, 1588, 1550, 1347, 895, 699 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.7 Hz, 2H), 7.35 (t, J = 7.7 Hz, 1H), 7.31−7.20 (m, 3H), 7.11 (d, J = 7.6 Hz, 1H), 7.02−6.89 (m, 4H), 6.87 (d, J = 8.2 Hz, 1H), 4.55 (d, J = 15.5 Hz, 1H), 4.03 (d, J = 15.6 Hz, 1H), 3.61 (q, J = 8.9 Hz, 1H), 3.44 (s, 3H), 3.39 (t, J = 9.9 Hz, 1H), 3.01 (dt, J = 13.8, 9.5 Hz, 1H), 2.75 (dd, J = 14.0, 7.7 Hz, 1H), 2.57−2.47 (m, 1H), 2.23−2.07 (m, 2H), 1.77−1.67 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 173.0, 169.2, 147.7, 147.2, 146.2, 143.6, 129.7, 129.3, 129.1, 128.2, 125.7, 125.3, 124.3, 123.7, 123.6, 122.8, 121.0, 108.2, 53.6, 47.8, 45.6, 44.5, 37.2, 36.4, 27.9, 26.7 ppm; HRMS calcd. For C28H28N5O3+ [M + H]+ 482.2187, found 482.2185. Oxalamide 48: To a stirred solution of amine 36-NH2 (1.13 g, 2.35 mmol) in CH2Cl2 (24.0 mL) at 0 °C was added a solution of N,N'-diisopropyloxamoyl chloride (677 mg, 3.53 mmol) in CH2Cl2 (9.00 mL). The resulting mixture was stirred for 5 min before triethylamine (0.32 mL, 2.35 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 12 h


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before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 1:2) to afford oxalamide 48 (1.45 g, 97%) as a yellow foam. 48: Rf = 0.41 (silica gel, EtOAc); IR (film) νmax = 3412, 2986, 2830, 2685, 2305, 1685, 1638, 1568, 1436, 1347, 896, 691 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.28−7.21 (m, 2H), 7.10 (d, J = 6.8 Hz, 1H), 7.02−6.94 (m, 2H), 6.90 (t, J = 9.2 Hz, 3H), 6.54 (br s, 1H), 4.68−4.59 (m, 1H), 4.54 (d, J = 15.6 Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H), 3.61 (q, J = 9.0 Hz, 1H), 3.46 (s, 3H), 3.44−3.35 (m, 2H), 3.05−2.96 (m, 1H), 2.96−2.87 (m, 2H), 2.74 (dd, J = 14.1, 7.8 Hz, 1H), 2.27−2.18 (m, 1H), 1.92−1.81 (m, 1H), 1.34 (d, J = 6.9 Hz, 6H), 1.14 ppm (t, J = 6.5 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 172.8, 168.6, 162.7, 162.3, 147.7, 147.3, 146.1, 143.6, 129.6, 129.5, 128.9, 128.3, 125.5, 125.4, 124.3, 123.8, 123.8, 123.0, 121.3, 108.5, 53.5, 49.4, 47.5, 46.5, 45.7, 44.5, 35.0, 32.0, 28.1, 26.8, 20.8, 20.8, 19.9, 19.9 ppm; HRMS calcd. For C36H41N6O5+ [M + H]+ 637.3133, found 637.3130. Isopropenyl Oxalamide 51: The amine 36-NH2 was purified by flash column chromatography (silica gel, acetone), and to a stirred solution of the purified product (143 mg, 0.27 mmol) in CH2Cl2 (3.00 mL) at 0 °C was added a solution of N,N'diisopropyloxamoyl chloride (78.2 mg, 0.41 mmol) in CH2Cl2 (1.00mL). The resulting mixture was stirred for 5 min before triethylamine (0.04 mL, 0.27 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 12 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, CH2Cl2:Et2O 6:1) to afford oxalamide 51 (60 mg, 32%) as a yellow oil. 51: Rf = 0.25 (silica gel, CH2Cl2:Et2O 2:3); IR (film) νmax = 3053, 2985, 2305, 1649, 1421, 1263, 723 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.6 Hz, 2H), 7.36 (dd, J = 7.7, 3.3 Hz, 2H), 7.24 (d, J = 3.9 Hz, 2H), 7.09 (d, J = 7.7 Hz, 1H), 7.03−6.94 (m, 2H), 6.90 (t, J = 8.8 Hz, 3H), 4.71 (s, 1H), 4.59 (s, 1H), 4.52 (d, J = 15.6 Hz, 1H), 4.06 (d, J = 15.6 Hz, 1H), 3.71−3.63 (m, 1H), 3.62−3.55 (m, 1H), 3.46 (s, 3H), 3.41−3.28 (m, 2H), 3.19−3.10 (m, 1H), 3.06−2.91 (m, 2H), 2.75 (dd, J = 13.9, 7.6 Hz, 1H), 2.20 (td, J = 12.3, 4.3 Hz, 1H), 1.98 (td, J = 12.3, 5.3 Hz, 1H), 1.67 (s, 3H), 1.32 (m, 6H), 1.13 ppm (m, 6H); 13C NMR (101 MHz, CDCl3): δ 172.9, 168.6, 164.1, 163.9, 147.7, 147.3, 146.2, 143.6, 143.5, 129.5 129.4, 128.9, 128.3, 125.6, 125.3, 124.4, 123.8, 123.2, 121.4, 112.8, 108.3, 53.6, 50.3, 47.4, 45.7, 45.6, 44.6, 40.0, 29.7, 28.1, 26.7, 20.5, 20.3, 19.8, 19.8, 19.7, −0.02 ppm; HRMS calcd. For C39H45N6O5+ [M + H]+ 677.3446, found 677.3443. Enoate 50: To a stirred solution of oxalamide 48 (134 mg, 0.21 mmol) in 1,2-dichloroethane (2.00 mL) at room temperature were added methyl acrylate (0.10 mL, 1.05 mmol), Pd(OAc)2 (4.71 mg, 0.02 mmol), and Ag2CO3 (116 mg, 0.42 mmol). The resulting mixture was warmed to 120 °C and stirred for 38 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:5) to afford enoate 50 as an inseparable mixture with starting material 48 (50:48 ~0.9:1 based on 1H NMR analysis, 134 mg) as a yellow foam. The inseparable mixture of oxalamide 48 and enoate 50 was resubjected to the CH-functionalization condition as follows: To a stirred solution of oxalamide 48 and enoate 50 (50:48 ~0.9:1, 134 mg) in 1,2-dichloroethane (2.00 mL) at room temperature were added methyl acrylate (0.10 mL, 1.05 mmol), Pd(OAc)2 (4.71 mg, 0.02 mmol), and Ag2CO3 (116 mg, 0.42 mmol). The resulting mixture was warmed to 120 °C and stirred for 38 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (10 mL), and the filtrate was concentrated under re-

duced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:5) to afford enoate 50 as an inseparable mixture with starting material 48 (50:48 ~3.6:1 based on 1H NMR analysis, 136 mg, ~72% of 50 based on NMR calculation) as a yellow foam. 50: Rf = 0.41 (silica gel, EtOAc); IR (film) νmax 3941, 3069, 2684, 2303, 1601, 1418, 896 cm−1; HRMS calcd. For C40H45N6O7+ [M + H]+ 721.3344, found 721.3346. Amine 37a-NH2: To a stirred solution of azide 37a (2.12 g, 3.95 mmol) in THF/H2O (10:1, 44.0 mL) at room temperature was added triphenylphosphine (2.10 g, 7.90 mmol). The resulting mixture was warmed to 50 °C and stirred for 16 h before it was cooled to room temperature, diluted with acetonitrile (50 × 3 mL) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, MeOH:CH2Cl2 1:4) to afford amine 37a-NH2 (1.93 g, 96%) as a yellow foam. 37a-NH2: Rf = 0.27 (silica gel, CH2Cl2:MeOH 4:1); [α]D25 −160.4 (c = 1.45, CHCl3); IR (film) νmax 3944, 3053, 2305, 1688, 1265, 745 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.6 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 6.1 Hz, 1H), 7.23 (d, J = 5.4 Hz, 2H), 7.10 (dd, J = 15.4, 7.7 Hz, 2H), 7.03−6.96 (m, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.51 (d, J = 10.8 Hz, 1H), 5.24 (d, J = 10.8 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H), 3.60 (dt, J = 13.2, 6.7 Hz, 1H), 3.54 (s, 3H), 3.40 (t, J = 9.7 Hz, 1H), 3.09−2.97 (m, 1H), 2.75 (dd, J = 14.0, 7.5 Hz, 1H), 2.62−2.52 (m, 1H), 2.23−2.11 (m, 2H), 1.77−1.65 (m, 1H), 1.39 ppm (br, 2H); 13C NMR (101MHz, CDCl3): δ 172.8, 168.6, 147.3, 146.4, 145.7, 143.6, 129.4, 129.3, 129.2, 128.3, 126.2, 125.8, 124.3, 124.1, 123.7, 122.8, 121.5, 109.5, 73.3, 56.8, 53.6, 48.0, 45.7, 44.5, 37.2, 36.8, 26.7 ppm; HRMS calcd. For C29H30N5O4+ [M + H]+ 512.2292, found 512.2295. Amine 37b-NH2: To a stirred solution of azide 37b (7.60 g, 12.4 mmol) in THF/H2O (10:1, 132 mL) at room temperature was added triphenylphosphine (6.50 g, 24.8 mmol). The resulting mixture was warmed to 50 °C and stirred for 16 h before it was cooled to room temperature, diluted with acetonitrile (150 × 3 mL) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, MeOH:CH2Cl2 1:4) to afford amine 37b-NH2 (7.10 g, 98%) as a yellow foam. 37b-NH2: Rf = 0.35 (silica gel, CH2Cl2:MeOH 4:1); [α]D25 −103.8 (c = 1.45, CHCl3); IR (film) νmax 3943, 3053, 2988, 2305, 1688, 1266, 733 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.7 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.30−7.19 (m, 3H), 7.16−7.08 (m, 2H), 6.96−6.89 (m, 4H), 5.67 (d, J = 11.0 Hz, 1H), 5.20 (d, J = 11.0 Hz, 1H), 4.55 (d, J = 15.5 Hz, 1H), 4.08−3.98 (m, 2H), 3.60 (dd, J = 17.7, 8.8 Hz, 1H), 3.39 (t, J = 9.8 Hz, 1H), 3.02 (dt, J = 13.7, 9.5 Hz, 1H), 2.75 (dd, J = 14.0, 7.6 Hz, 1H), 2.55 (t, J = 11.2 Hz, 1H), 2.23−2.12 (m, 2H), 1.70 (t, J = 7.9 Hz, 1H), 1.27 (d, J = 6.1 Hz, 3H), 1.24 ppm (d, J = 6.1 Hz, 3H); 13C NMR (101 MHz,CDCl3): δ 172.7, 168.4, 147.1, 146.7, 145.8, 143.6, 129.2, 129.1, 129.0, 128.2, 126.0, 125.6, 124.2, 123.8, 123.6, 122.7, 121.3, 109.6, 69.9, 69.1, 53.5, 47.8, 45.5, 44.3, 37.1, 36.6, 26.5, 22.4, 21.8 ppm; HRMS calcd. For C31H34N5O4+ [M + H]+ 540.2605, found 540.2607. Oxalamide 52a: To a stirred solution of N,N'-diisopropyloxamoyl chloride (903 mg, 4.71 mmol) in CH2Cl2 (10.0 mL) at 0 °C was added a solution of amine 37a-NH2 (1.93 g, 3.77 mmol) in CH2Cl2 (13.0 mL). The resulting mixture was stirred for 5 min before triethylamine (0.60 mL, 3.96 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 9 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford oxalamide 52a (2.12 g, 84%) as a yellow foam. 52a: Rf = 0.19 (silica gel, hexanes:EtOAc 1:2); [α]D25 −104.4 (c = 1.43, CHCl3); IR (film) νmax 3944, 3053, 2305, 1608, 1263, 753 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J =



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8.6 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.29−7.21 (m, 2H), 7.14−7.06 (m, 2H), 7.06−6.98 (m, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.61 (br, 1H), 5.52 (d, J = 10.7 Hz, 1H), 5.28 (d, J = 10.6 Hz, 1H), 4.59 (dd, J = 13.3, 6.7 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 4.07 (d, J = 15.6 Hz, 1H), 3.67−3.59 (m, 1H), 3.57 (s, 3H), 3.42 (td, J = 14.0, 8.0 Hz, 2H), 3.07−2.98 (m, 1H), 2.98−2.88 (m, 2H), 2.74 (dd, J = 14.0, 7.7 Hz, 1H), 2.32−2.18 (m, 1H), 1.91−1.79 (m, 1H), 1.34 (dd, J = 6.7, 2.8 Hz, 6H), 1.15 ppm (dd, J = 9.3, 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 172.6, 167.8, 162.9, 162.5, 147.2, 146.2, 145.4, 143.5, 129.4, 129.3, 128.4, 128.2, 125.9, 125.8, 124.3, 124.2, 123.6, 123.0, 121.8, 109.6, 73.1, 56.8, 53.4, 49.3, 47.7, 46.3, 45.6, 44.4, 34.8, 32.3, 26.6, 20.7, 20.6, 19.8, 19.7 ppm; HRMS calcd. For C37H43N6O6+ [M + H]+ 667.3239, found 667.3242. Oxalamide 52b: To a stirred solution of N,N'-diisopropyloxamoyl chloride (3.18 g, 16.6 mmol) in CH2Cl2 (35.0 mL) at 0 °C was added a solution of amine 37b-NH2 (7.15 g, 13.3 mmol) in CH2Cl2 (45.0 mL). The resulting mixture was stirred for 5 min before triethylamine (1.90 mL, 13.9 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 8.5 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford oxalamide 52b (7.52 g, 82%) as a yellow foam. 52b: Rf = 0.30 (silica gel, hexanes:EtOAc 1:2); [α]D25 −62.7 (c = 1.46, CHCl3); IR (film) νmax 3154, 2980, 2253, 1793, 1659, 887 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.5 Hz, 2H), 7.36 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.28−7.20 (m, 2H), 7.14 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.99 (t, J = 7.3 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.60 (br, 1H), 5.67 (d, J = 10.9 Hz, 1H), 5.23 (d, J = 10.9 Hz, 1H), 4.64−4.49 (m, 2H), 4.11−3.99 (m, 2H), 3.60 (dd, J = 17.7, 8.8 Hz, 1H), 3.42 (dt, J = 15.3, 8.0 Hz, 2H), 3.06−2.97 (m, 1H), 2.93 (dd, J = 14.3, 7.4 Hz, 2H), 2.74 (dd, J = 14.0, 7.6 Hz, 1H), 2.29−2.17 (m, 1H), 1.90−1.80 (m, 1H), 1.34 (d, J = 6.9 Hz, 6H), 1.26 (t, J = 6.5 Hz, 6H), 1.14 ppm (t, J = 7.4 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 172.7, 167.8, 162.8, 162.4, 147.3, 146.6, 145.7, 143.6, 129.5, 129.4, 128.6, 128.3, 125.9, 125.8 124.3, 124.2, 123.7, 122.9, 121.7, 110.0, 69.9, 69.5, 53.5, 49.4, 47.7, 46.5, 45.7, 44.5, 34.9, 32.5, 30.3, 26.6, 22.4, 22.0, 20.8, 19.9 ppm; HRMS calcd. For C39H47N6O6+ [M + H]+ 695.3552, found 695.3555. Enoate 53a: To a stirred solution of oxalamide 52a (477 mg, 0.72 mmol) in 1,2-dichloroethane (2.00 mL) at room temperature were added methyl acrylate (0.32 mL, 3.58 mmol), Pd(OAc)2 (16.2 mg, 0.07 mmol), and Ag2CO3 (397 mg, 1.44 mmol). The resulting mixture was warmed to 120 °C and stirred for 51 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford enoate 53a as an inseparable mixture with starting material 52a (52a:53a ~1:1 based on 1H NMR analysis, 523mg) as a yellow foam. The inseparable mixture of oxalamide 52a and enoate 53a was resubjected to the CHfunctionalization condition as follows: To a stirred solution of oxalamide 52a and enoate 53a (52a:53a ~1:1, 523 mg) in 1,2dichloroethane (2.00 mL) at room temperature were added methyl acrylate (0.32 mL, 3.58 mmol), Pd(OAc)2 (16.2 mg, 0.07 mmol), and Ag2CO3 (397 mg, 1.44 mmol). The resulting mixture was warmed to 120 °C and stirred for 22 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford mixture of enoate 53a (505mg, 94%) and suspected double CH-functionalization product 53a' (53a:53a' ~1:0.05 based on 1H NMR analysis) as a yellow foam. 53a: Rf =

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0.35 (silica gel, hexanes:EtOAc 1:2); [α]D25 −213.2 (c = 1.57, CHCl3); IR (film) νmax 3944, 3055, 2685, 2304, 1717, 1422, 895 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 15.2 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 7.6 Hz, 2H), 7.17−7.07 (m, 2H), 7.02 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 6.71 (br, 1H), 6.00 (d, J = 15.6 Hz, 1H), 5.54 (d, J = 10.8 Hz, 1H), 5.31 (d, J = 10.5 Hz, 1H), 4.75−4.65 (m, 1H), 4.46 (d, J = 15.3 Hz, 1H), 4.05 (d, J = 15.5 Hz, 1H), 3.77 (s, 3H), 3.56 (s, 3H), 3.54−3.48 (m, 1H), 3.48−3.41 (m, 1H), 3.21−3.13 (m, 2H), 3.09−2.90 (m, 2H), 2.76−2.65 (m, 1H), 2.36−2.25 (m, 1H), 2.21−2.10 (m, 1H), 1.36 (d, J = 6.4 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.14 ppm (d, J = 6.6 Hz, 3H); 13C NMR (126 MHz, CDCl3): δ 172.1, 166.8, 166.2, 162.6, 162.2, 147.1, 147.0, 144.8, 143.6, 143.3, 132.9, 129.6, 129.2, 128.1, 125.6, 125.4, 125.2, 124.5, 124.1, 123.4, 122.1, 120.7, 110.3, 73.2, 56.7, 53.7, 51.6, 50.8, 49.1, 46.1, 45.5, 43.7, 35.0, 29.5, 26.3, 20.5, 20.4, 19.7, 19.6 ppm; HRMS calcd. For C41H46N6O8Na+ [M + Na]+ 773.3269, found 773.3271. Enoate 53b: To a stirred solution of oxalamide 52b (5.52 g, 7.94 mmol) in 1,2-dichloroethane (50.0 mL) at room temperature were added methyl acrylate (3.60 mL, 39.7 mmol), Pd(OAc)2 (178 mg, 0.79 mmol), and Ag2CO3 (4.38 g, 15.9 mmol). The resulting mixture was warmed to 120 °C and stirred for 43 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (100 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford enoate 53b as an inseparable mixture with starting material 52b (52b:53b ~0.7:1 based on 1H NMR analysis, 6.34 g) as a yellow foam. The inseparable mixture of oxalamide 52b and enoate 53b was resubjected to the CHfunctionalization condition as follows: To a stirred solution of oxalamide 52b and enoate 53b (52b:53b ~0.7:1, 6.34 g) in 1,2dichloroethane (50.0 mL) at room temperature were added methyl acrylate (3.60 mL, 39.7 mmol), Pd(OAc)2 (178 mg, 0.79 mmol), and Ag2CO3 (4.38 g, 15.9 mmol). The resulting mixture was warmed to 120 °C and stirred for 39 h before it was cooled to room temperature. The resulting mixture was filtered through a pad of Celite® and eluted with EtOAc (100 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:1) to afford enoate 53b (5.78 g, 93%) as a yellow foam. 53b: Rf = 0.56 (silica gel, hexanes:EtOAc 1:2); [α]D25 −168.1 (c = 1.44, CHCl3); IR (film) νmax 3943, 3053, 2305, 1717, 1265, 751 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.05−7.97 (m, 3H), 7.38 (t, J = 7.8 Hz, 1H), 7.28−7.23 (m, 1H), 7.20 (dd, J = 7.3, 4.4 Hz, 2H), 7.09 (d, J = 7.7 Hz, 1H), 7.00 (dd, J = 11.6, 7.6 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.70 (br, 1H), 5.98 (d, J = 15.6 Hz, 1H), 5.69 (d, J = 11.0 Hz, 1H), 5.25 (d, J = 11.0 Hz, 1H), 4.71 (dt, J = 13.4, 6.7 Hz, 1H), 4.46 (d, J = 15.4 Hz, 1H), 4.10−3.99 (m, 2H), 3.76 (s, 3H), 3.53−3.39 (m, 2H), 3.20−3.08 (m, 2H), 3.07−2.97 (m, 1H), 2.97−2.87 (m, 1H), 2.76−2.65 (m, 1H), 2.33−2.23 (m, 1H), 2.21−2.12 (m, 1H), 1.35 (t, J = 6.2 Hz, 6H), 1.28 (d, J = 6.0 Hz, 3H), 1.25 (d, J = 6.1 Hz, 3H), 1.17 (d, J = 6.7 Hz, 3H), 1.14 ppm (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 172.3, 167.0, 166.5, 162.6, 162.1, 147.7, 147.3, 145.2, 143.9, 143.5, 133.0, 129.9, 129.4, 128.3, 125.6, 125.6, 125.5, 124.6, 124.3, 123.7, 122.2, 120.8, 110.9, 70.3, 69.5, 54.0, 51.9, 50.9, 49.3, 46.5, 45.7, 44.0, 35.2, 29.7, 26.4, 22.4, 22.0, 20.8, 20.7, 19.9, 19.8 ppm; HRMS calcd. For C43H50N6O8Na+ [M + Na]+ 801.3582, found 801.3583. Boc-Amidine 55: (i) To a stirred solution of amidine 53b (661 mg, 0.85 mmol) in MeOH (25.0 mL) at room temperature was added HCl (10 M aq., 4.40 mL). The resulting mixture was warmed to 100 °C and stirred for 16 h before it was cooled to room temperature and quenched with NaHCO3 (100 mL, sat. aq.). The resulting


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mixture was extracted with CH2Cl2 (3 × 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was used directly in the next step without further purification. (ii) To a stirred solution of crude amidine 54 (obtained above, 641 mg, 0.91 mmol) in acetonitrile (12.0 mL) at room temperature was added di-tert-butyl dicarbonate (990 mg, 4.54 mmol) and N,N'-dimethylaminopyridine (55.5 mg, 0.45 mmol). The resulting mixture was stirred for 13 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:Et2O 1:1) to afford Boc-amidine 55 (580 mg, 75% over two steps) as a yellow foam. 55: Rf = 0.30 (silica gel, hexanes:EtOAc 1:1); [α]D25 −82.0 (c = 1.52, CHCl3); IR (film) νmax 3941, 3053, 2987, 2305, 1741, 1720, 721 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.13−8.05 (m, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.33−7.26 (m, 2H), 7.18−7.06 (m, 3H), 6.87 (d, J = 8.5 Hz, 2H), 5.93 (d, J = 15.7 Hz, 1H), 4.51 (d, J = 15.4 Hz, 1H), 3.97 (d, J = 15.4 Hz, 1H), 3.74 (s, 3H), 3.48 (dd, J = 15.6, 7.7 Hz, 1H), 3.42−3.28 (m, 4H), 3.25−3.16 (m, 1H), 3.12 (dd, J = 17.0, 7.5 Hz, 1H), 2.68 (dd, J = 13.7, 8.1 Hz, 1H), 2.33−2.22 (m, 1H), 2.16−2.05 (m, 1H), 1.68 (s, 9H), 1.44−1.34 (m, 15H), 1.11 ppm (dd, J = 6.0, 4.3 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 172.0, 166.3, 163.3, 162.7, 151.3, 149.6, 147.3, 144.3, 144.2, 143.9, 143.5, 133.3, 129.6, 129.2, 128.3, 126.7, 126.4, 126.0, 125.2, 124.7, 124.5, 123.7, 120.9, 116.2, 84.1, 83.9, 53.9, 51.9, 50.6, 50.5, 45.7, 45.4, 43.8, 39.3, 28.5, 28.2, 27.9, 26.4, 20.1, 19.8, 19.5 ppm; HRMS calcd. For C49H58N6O11Na+ [M + Na]+ 929.4056, found 929.4059. Boc-Amidine 55 from 53a: (i) To a stirred solution of amidines 53a and 53a' (1.52 g, 2.03 mmol) in MeOH (51.0 mL) at room temperature was added HCl (10 M aq., 10.3 mL). The resulting mixture was warmed to 100 °C and stirred for 19 h before it was cooled to room temperature and quenched with NaHCO3 (100 mL, sat. aq.). The resulting mixture was extracted with CH2Cl2 (3 × 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was used directly in the next step without further purification. (ii) To a stirred solution of crude amidine 54 (obtained above, 1.29 g, 1.83 mmol) in acetonitrile (20.0 mL) at room temperature was added di-tert-butyl dicarbonate (1.99 g, 9.13 mmol) and N,N'-dimethylaminopyridine (112 mg, 0.92 mmol). The resulting mixture was stirred for 40 min before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 2:1) to afford Boc-amidine 55 (1.30 g, 71% over two steps) as a yellow foam. All physical data of Bocamidine 55 are identical to those obtained from acid-mediated hydrolysis of amidine 53b followed by Boc protection. Aminal 56: To a stirred solution of amidine 55 (420 mg, 0.46 mmol) in THF (16.0 mL) at 0 °C was added acetic acid (0.80 mL, 13.9 mmol) and sodium cyanoborohydride (876 mg, 13.9 mmol). The resulting mixture was warm to room temperature and stirred for 6 h before it was quenched with NaHCO3 (50 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:Et2O 1:1) to afford aminal 56 (210 mg, 50%) and amidine Boc-54 (103 mg, 28%) as yellow foams. Amidine Boc-54 was readily recycled to Boc-amidine 55 (Boc2O, DMAP, MeCN, 23 °C). 56: Rf = 0.57 (silica gel, hexanes:EtOAc 1:1); [α]D25 −54.8 (c = 1.48, CHCl3); IR (film) νmax 3943, 3054, 2986, 2304, 1740, 1688, 1264, 740 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 13.9 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.55 (br, 1H), 7.30−7.22 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.7 Hz, 2H), 7.00 (d, J = 7.9 Hz, 2H), 6.72 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 7.4 Hz, 1H), 6.27 (d, J = 15.7 Hz, 1H), 5.75 (d, J = 3.3 Hz, 1H), 4.38 (br, 1H), 4.33 (d, J =

15.5 Hz, 1H), 3.80 (s, 3H), 3.65 (br, 1H), 3.51−3.32 (m, 3H), 3.31−3.15 (m, 3H), 2.47 (br, 1H), 2.29 (br, 1H), 2.15 (br, 1H), 1.61 (s, 9H), 1.46 (s, 9H), 1.43 (d, J = 6.7 Hz, 6H), 1.16 ppm (d, J = 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 171.9, 166.8, 166.3, 163.2, 151.3, 147.1, 144.1, 143.4, 141.5, 133.5, 129.3, 128.3, 127.4, 125.3, 125.2, 123.6, 121.1, 119.9, 115.3, 84.3, 82.4, 75.7, 54.4, 51.6, 50.6, 46.0, 45.4, 43.9, 39.6, 32.3, 30.2, 28.8, 28.3, 27.9, 27.8, 27.6, 19.9, 19.8, 19.7, 19.6 ppm; HRMS calcd. For C49H60N6O11Na+ [M + Na]+ 931.4212, found 931.4216. Aldehyde 56a: Method 1: To a stirred solution of enoate 56 (288 mg, 0.32 mmol) in 1,4-dioxane/H2O (3:1, 12.0 mL) at room temperature were added 2,6-lutidine (0.08 mL, 0.64 mmol), osmium tetroxide (4 wt.% in H2O, 0.41 mL, 0.06 mmol) and sodium periodate (141 mg, 0.64 mmol). The resulting mixture was stirred for 65 h before it was quenched with sodium thiosulfate (10 mL, sat. aq.). The resulting mixture was extracted with EtOAc (3 × 20 mL), the combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 3:1) to afford aldehyde 56a (225 mg, 83%) as a white foam. 56a: Rf = 0.68 (silica gel, hexanes:EtOAc 1:1); [α]D25 +13.7 (c = 1.48, CHCl3); IR (film) νmax 3943, 3053, 2984, 2305, 1741, 1265, 745 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.89 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.86 (br, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.99 (dd, J = 11.8, 7.6 Hz, 2H), 6.65 (dd, J = 14.7, 7.5 Hz, 2H), 5.77 (s, 1H), 4.72 (d, J = 15.1 Hz, 1H), 4.46 (d, J = 15.2 Hz, 1H), 3.41 (dd, J = 15.8, 8.4 Hz, 4H), 3.35–3.23 (m, 2H), 3.11 (t, J = 9.0 Hz, 2H), 2.27 (br s, 1H), 1.93 (br s, 1H), 1.59 (s, 9H), 1.49 (s, 9H), 1.47 (d, J = 6.6 Hz, 6H), 1.13 ppm (d, J = 6.4 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 189.8, 172.3, 166.3, 163.4, 151.5, 147.3, 143.6, 142.1, 137.3, 131.6, 128.8, 127.5, 125.5, 124.3, 123.8, 120.9, 118.0, 116.5, 84.3, 82.3, 79.2, 53.6, 50.6, 46.6, 45.4, 44.5, 39.9, 34.5, 31.3, 28.2, 27.8, 19.8, 19.7, 19.5 ppm; HRMS calcd. For C46H56N6O10Na+ [M + Na]+ 875.3950, found 875.3953. Method 2: (i) To a stirred solution of enoate 56 (1.95 g, 2.15 mmol) in acetone/H2O (3:1, 24.0 mL) at room temperature was added osmium tetroxide (4 wt.% in H2O, 2.93 mL, 0.43 mmol) and N−methylmorpholine N−oxide monohydrate (872 mg, 6.45 mmol). The resulting mixture was stirred for 16 h before it was quenched with sodium thiosulfate (30 mL, sat. aq.). The resulting mixture was extracted with EtOAc (3 × 50 mL), washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was used directly in the next step without further purification. (ii) To a stirred solution of crude residue (obtained above, 2.13 g, 2.26 mmol) in MeOH (25.0 mL) at room temperature was added sodium periodate (1.45 g, 6.78 mmol). The resulting mixture was stirred for 12 h before it was quenched with sodium thiosulfate (30 mL, sat. aq.). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL), the combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 1:1) to afford aldehyde 56a (1.50 g, 82%) as a white foam. Pyrrolidinone 57: (i) To a stirred solution of aldehyde 56a (1.10 g, 1.29 mmol) in THF/H2O (4:1, 25.0 mL) at 0 °C was added lithium hydroxide monohydrate (541 mg, 12.9 mmol) and hydrogen peroxide (34.5 w/w%, 1.30 mL, 12.9 mmol). The resulting mixture was warmed to 50 °C and stirred for 3 h before it was cooled to room temperature and quenched with sodium sulfite (30 mL, sat. aq.). The resulting mixture was extracted with EtOAc (3 × 50 mL), washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 3:1) to afford aldehyde 57a (805 mg, 89%) as a pale yellow foam. (ii) To a stirred solution of aldehyde 57a (854



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mg, 0.85 mmol) in MeOH (31.0 mL) at room temperature was added NaOH (20% aq., 9.80 mL). The resulting mixture was warmed to 75 °C and stirred for 4.5 h before it was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 1:1) to afford pyrrolidinone 57 (568 mg, 83%) as a yellow foam. 57: Rf = 0.39 (silica gel, hexanes:EtOAc 1:2); [α]D25 −11.3 (c = 1.53, CHCl3); IR (film) νmax 3370, 2977, 1684, 1455, 1250, 755 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ 10.21 (s, 0.6H), 10.16 (s, 0.4H), 8.19 (s, 0.4H), 7.96 (s, 0.6H), 7.46 (t, J = 8.7 Hz, 1H), 7.17 (d, J = 7.2 Hz, 2H), 7.01 (t, J = 7.5 Hz, 1H), 6.70 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 5.62 (s, 1.6H), 5.09 (s, 0.4H), 4.87 (s, 1H), 3.69−3.51 (m, 2H), 3.30 (t, J = 9.4 Hz, 1H), 3.15 (br, 2H), 2.64 (br, 2H), 2.11−1.95 (m, 2H), 1.61 (s, 9H), 1.40 ppm (s, 9H); 13C NMR (101 MHz, CDCl3, mixture of rotamers): δ 190.4, 177.0, 176.9, 152.0, 151.0, 144.6, 143.5, 142.3, 137.0, 132.5, 132.5, 128.7, 127.4, 125.7, 122.6, 122.3, 121.2, 117.9, 116.6, 82.7, 79.7, 79.2, 60.3, 59.3, 53.7, 53.5, 40.4, 40.3, 37.5, 36.5, 34.4, 28.4 ppm; HRMS calcd. For C31H38N4O6Na+ [M + Na]+ 585.2684, found 585.2686. Enone 61: Method 1: (i) To a stirred solution of aldehyde 57 (10.0 mg, 0.02 mmol) in THF (1.00 mL) at −78 °C was added 1propynylmagnesium bromide (59, 0.5 M in THF, 0.54 mL, 0.27 mmol). The resulting mixture was warmed to 0 °C and stirred for 3 h before it was quenched with NH4Cl (1 mL). The resulting mixture was extracted with EtOAc (3 × 5 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 2:1) to afford alkynyl alcohol 58 (5.0 mg, 47%) as a yellow oil. (ii) To a stirred solution of alkynyl alcohol 58 (5.0 mg, 0.01 mmol) in MeOH/H2O (60:1, 1.22 mL) at room temperature was added 1,3bis(2,6-di-isopropylphenyl)imidazol-2-ylidene gold(I) chloride (1.9 mg, 3.00 µmol) and silver hexafluoroantimonate (1.1 mg, 3.00 µmol). The resulting mixture was stirred for 1 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 1:2) to afford alcohol enone 61 (3.1 mg, 62%) as a yellow oil. Method 2: To a stirred solution of aldehyde 57 (568 mg, 1.01 mmol) in toluene (10.0 mL) at room temperature was added phosphonium ylide 60 (643 mg, 2.02 mmol). The resulting mixture was warmed to 120 °C and stirred for 85 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 1.5:1) to afford enone 61 (489 mg, 80%) as a white foam. 61: Rf = 0.20 (silica gel, hexanes:EtOAc 1:3); [α]D25 −20.4 (c = 1.20, CHCl3); IR (film) νmax 3370, 2982, 1696, 1568, 1366, 749 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ 8.05 (d, J = 15.4 Hz, 1H), 7.54 (br, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.16 (t, J = 5.1 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 6.98 (br, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 15.6 Hz, 1H), 5.90 (br s, 1H), 5.52 (s, 1H), 4.50 (br s, 1H), 3.36 (br s, 3H), 3.00 (br s, 1H), 2.82 (br s, 1H), 2.52−2.29 (m, 5H), 2.14 (s, 1H), 1.60 (s, 9H), 1.39 ppm (s, 9H); 13C NMR (101 MHz, CDCl3, mixture of rotamers): δ 198.4, 175.4, 155.6, 154.7, 151.7, 143.5, 142.0, 133.7, 129.4, 128.5, 128.0, 125.6, 121.6, 117.7, 116.0, 83.0, 79.6, 56.6, 53.7, 39.7, 37.1, 35.1, 31.4, 28.9, 28.4, 28.3 ppm; HRMS calcd. For C34H42N4O6Na+ [M + Na]+ 625.2997, found 625.3001. Tertiary alcohol 63: To a stirred solution of enone 61 (114 mg, 0.19 mmol) in THF (32.0 mL) at −78 °C was added MeLi (1.6 M in Et2O, 1.19 mL, 1.90 mmol). The resulting mixture was for 30 min before it was quenched with NaHCO3 (20 mL) and concentrated under reduced pressure. The resulting mixture was diluted water and extracted with EtOAc (3 × 10 mL), the combined or-

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ganic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The inseparable mixture of enone 61 and tertiary alcohol 63 was resubjected to the same condition as follows: To a stirred solution of crude mixture of enone 61 and tertiary alcohol 63 in THF (32.0 mL) at −78 °C was added MeLi (1.6 M in Et2O, 0.60 mL, 0.95 mmol). The resulting mixture was for 30 min before it was quenched with NaHCO3 (20 mL) and concentrated under reduced pressure. The resulting mixture was diluted water and extracted with EtOAc (3 × 10 mL), the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexane:EtOAc 1:1) to afford alcohol tertiary 63 (74.5 mg, 64%) as a yellow amorphous solid. 63: Rf = 0.58 (silica gel, hexanes:EtOAc 1:4); [α]D25 −46.0 (c = 1.27, CHCl3); IR (film) νmax 3321, 2979, 2362, 1696, 1367, 1172, 743 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ 7.50 (br, 0.5H), 7.32 (d, J = 15.5 Hz, 1.5H), 7.17 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H), 6.64 (d, J = 7.4 Hz, 1H), 6.35 (d, J = 15.6 Hz, 1H), 5.74 (s, 0.5H), 5.44 (s, 1.5H), 4.68 (s, 1H), 4.13 (s, 1H), 3.43−3.27 (m, 3H), 3.22 (br, 1H), 2.78 (t, J = 12.9 Hz, 1H), 2.60 (t, J = 10.8 Hz, 1H), 2.52−2.42 (m, 1H), 1.77−1.66 (m, 2H), 1.59 (s, 8H), 1.42 (s, 3H), 1.40 ppm (s, 12H); 13C NMR (101 MHz, CDCl3, mixture of rotamers): δ 175.6, 156.0, 143.2, 141.6, 140.0, 136.4, 132.0, 129.0, 128.0, 125.5, 125.4, 125.1, 124.2, 120.0, 119.0, 115.0, 112.6, 82.1, 79.9, 75.4, 70.7, 54.3, 53.9, 39.4, 37.3, 34.1, 30.9, 30.4, 29.7, 29.2, 28.5, 28.4 ppm; HRMS calcd. For C35H46N4O6Na+ [M + Na]+ 641.3310, found 641.3310. Hexacycle 66: To a stirred solution of tertiary alcohol 63 (64.2 mg, 0.11 mmol) in CHCl3 (11.6 mL) at room temperature was added pyridinium p-toluenesulfonate (2.61 mg, 10.4 µmol). The resulting mixture was for 4 h before it was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:acetone 6:1) to afford hexacycle 66 (32.0 mg, 52%) as a yellow oil. 66: Rf = 0.56 (silica gel, hexanes:EtOAc 1:2); [α]D25 −147.0 (c = 1.10, CHCl3); IR (film) νmax 2975, 1696, 1506, 1447, 1365, 1166 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ 7.42 (br, 1H), 7.14 (dd, J = 14.3, 7.2 Hz, 3H), 6.80–6.59 (m, 3H), 6.21 (br, 0.8H), 5.75 (br, 0.2H), 5.32 (s, 1H), 5.20 (s, 1H), 4.92 (s, 1H), 3.71 (br, 1H), 3.32 (s, 1H), 3.23 (t, J = 13.3 Hz, 1H), 3.12 (s, 1H), 2.74 (s, 1H), 2.57 (s, 1H), 1.95 (s, 3H), 1.74 (s, 3H), 1.61 (s, 9H), 1.57 (s, 3H), 1.49 ppm (s, 9H); 13C NMR (101 MHz, CDCl3, mixture of rotamers): δ 175.3, 155.6, 154.4, 143.7, 141.7, 139.3, 133.8, 129.2, 128.8, 128.4, 128.1, 125.9, 125.3, 124.9, 122.7, 117.7, 114.2, 112.4, 80.2, 58.3, 54.9, 53.9, 40.7, 38.9, 28.6, 28.6, 28.3, 25.7, 18.8 ppm; HRMS calcd. For C35H44N4O5Na+ [M + Na]+ 623.3204, found 623.3205. Heptacyclic Imine 67: (i) To a stirred solution of hexacycle 66 (116 mg, 0.19 mmol) in CH2Cl2 (47.5 mL) at 0 °C was added diisopropylethyl amine (0.33 mL, 1.90 mmol) and a solution of triethoxonium tetrafluoroborate (freshly prepared, 0.5 M in CH2Cl2, 1.93 mL, 0.97 mmol) dropwise. The resulting mixture was stirred for 50 min at 0 °C before it was quenched with NaHCO3 (50 mL), warmed up to room temperature and extracted with CH2Cl2 (3 × 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was semi-purified by flash column chromatography (silica gel, hexanes:EtOAc 5:1) to afford imidate 66a (94.8 mg) as a pale yellow oil, which was directly used in the subsequent step. A small quantity of chromatographically purified material was obtained for characterization. 66a: Rf = 0.50 (silica gel, hexanes:EtOAc 1:1); [α]D25 −158.8 (c = 0.98, CHCl3); IR (film) νmax 2979, 1688, 1440, 1305, 1105, 749 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ 7.15 (t, J = 7.5 Hz, 3H), 7.09 (t, J = 6.8 Hz, 1H), 6.68 (d, J = 7.5 Hz, 2H), 6.60 (s,


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1H), 6.12 (br, 1H), 5.22 (s, 1H), 5.18 (d, J = 7.1 Hz, 1H), 3.74 (dd, J = 15.6, 8.3 Hz, 2H), 3.65 (d, J = 7.3 Hz, 2H), 3.48 (br, 1H), 3.30−3.09 (m, 2H), 2.64 (s, 2H), 2.10 (br, 1H), 1.93 (s, 3H), 1.76 (s, 3H), 1.61 (s, 9H), 1.49 (s, 9H), 1.05 ppm (t, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl3, mixture of rotamers): δ 171.9, 155.6, 154.3, 143.7, 142.2, 141.6, 139.3, 133.9, 128.8, 128.0, 127.6, 125.7, 125.1, 123.1, 121.6, 117.4, 113.2, 111.7, 82.0, 79.4, 63.8, 59.9, 51.2, 40.5, 37.4, 34.7, 32.8, 29.7, 28.6, 28.4, 25.7, 18.9, 18.6, 13.9 ppm; HRMS calcd. For C37H49N4O5+ [M + H]+ 629.3697, found 629.3699. (ii) To a flask containing imidate 66a (semi-purified, obtained above) at room temperature was added a solution of trifluoroacetic acid (freshely prepared, 5 wt% in CH2Cl2, 38.0 mL). The resulting mixture was stirred for 2 h before it was quenched with NaHCO3 (40 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was dissolved in CH2Cl2/MeOH (1:1, 10.0 mL) and treated with silica gel (1.0 g) at room temperature. The resulting mixture was warmed to 50 °C and stirred for 20 h before it was filtered and filterate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc = 1:1) to afford heptacyclic imine 67 (26.4 mg, 36% over 2 steps) as a pale yellow foam. 67: Rf = 0.48 (silica gel, hexanes:EtOAc 1:2); [α]D25 +55.4 (c = 1.47, CHCl3); IR (film) νmax 2976, 1693, 1640, 1435, 1379, 1251, 750 cm−1; 1H NMR (400 MHz, CDCl3 mixture of rotamers): δ 7.55 (br, 0.4H), 7.18 (br, 0.6H), 7.00 (d, J = 7.2 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 6.61 (t, J = 7.3 Hz, 1H), 6.48 (d, J = 7.7 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H), 5.46 (br, 0.4H), 5.34 (d, J = 8.8 Hz, 1H), 5.11 (br, 0.2H), 4.92 (d, J = 8.9 Hz, 1H), 4.71 (br, 0.2H), 4.36 (br, 0.2H), 3.84 (dd, J = 14.6, 7.7 Hz, 1H), 3.78−3.69 (m, 1H), 3.31−3.17 (m, 2H), 2.90 (td, J = 11.4, 7.8 Hz, 1H), 2.23 (dt, J = 12.6, 8.6 Hz, 1H), 2.18−2.10 (m, 1H), 1.89−1.84 (m, 1H), 1.81 (s, 3H), 1.71 (s, 3H), 1.64 ppm (s, 9H); 13C NMR (101 MHz, CDCl3) δ 179.9, 142.8, 134.2, 128.3, 128.2, 127.5, 123.8, 122.2, 122.0, 118.8, 115.0, 113.3, 75.1, 59.8, 57.6, 54.8, 45.5, 39.1, 31.9, 29.7, 29.3, 28.5, 27.5, 27.2, 25.7, 25.5, 22.7, 18.5, 14.1 ppm; HRMS calcd. For C30H35N4O2+ [M + H]+ 483.2755, found 483.2759. “Putative” Communesin 68: (i) To a stirred solution of Boccarbamate 67 (5.7 mg, 11.8 µmol) in AcOH/Ac2O (1:1, 1.2 mL) at 0 °C was added sodium borohydride (38.0 mg, 1.00 mmol). The resulting mixture was stirred for 10 min before it was quenched with sodium carbonate (5 mL, sat. aq.) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was used directly in the next step without further purification. (ii) To a stirred solution of crude residue (obtained above) in CH2Cl2 (2.5 mL) at room temperature was added trifluoroacetic acid (1.0 mL). The resulting mixture was stirred for 1 h before it was quenched with sodium carbonate (5 mL, sat. aq.) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:acetone 4:1) to afford “putative” communesin 68 (1.8 mg, 36% over 2 steps) as a pale yellow foam. 68: Rf = 0.43 (silica gel, hexanes:EtOAc 1:2); [α]D25 −205.7 (c = 0.23, CHCl3); IR (film) νmax 3738, 1746, 1651, 1507, 1318, 749 cm−1; 1H NMR (400 MHz, CDCl3 mixture of rotamers): δ 7.02 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.7 Hz, 1H), 6.70 (t, J = 8.0 Hz, 3H), 6.25 (d, J = 7.6 Hz, 0.3H), 6.19 (d, J = 7.7 Hz, 0.7H), 6.12 (d, J = 7.5 Hz, 1H), 5.48 (s, 0.4H), 5.38 (d, J = 8.4 Hz, 0.4H), 5.22 (d, J = 8.4 Hz, 0.6H), 5.11 (s, 0.6H), 5.07 (d, J = 8.8 Hz, 1H), 4.99 (s, 2H), 4.15 (br, 1H), 3.85 (dd, J = 11.4, 9.2 Hz, 0.8H), 3.69 (t, J = 9.4 Hz, 0.2H), 3.41−3.37 (m, 0.2H), 3.34 (dd, J = 15.4, 9.4 Hz, 0.8H), 3.18−3.09 (m, 2H), 3.05 (td, J = 11.5, 7.7

Hz, 1H), 2.90 (dd, J = 21.5, 11.4 Hz, 0.2H), 2.74 (dd, J = 21.6, 11.9 Hz, 0.8H), 2.41 (s, 1.8H), 2.36−2.20 (m, 2H), 2.12 (s, 1.2H), 1.97 (s, 1.2H), 1.95–1.91 (m, 1H), 1.86 (s, 1.8H), 1.79 (s, 1.8H), 1.76 ppm (s, 1.2H); 1H NMR (499 MHz, 5% CF3COOH in CDCl3): δ 7.11 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 7.7 Hz, 1H), 6.83−6.77 (m, 2H), 6.54 (d, J = 7.6 Hz, 1H), 6.28 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 7.5 Hz, 1H), 5.92 (d, J = 8.5 Hz, 1H), 5.76 (s, 1H), 5.14−5.07 (m, 2H), 4.16 (br, 1H), 4.07 (br, 1H), 3.72 (br, 1H), 3.65 (br, 1H), 3.28 (m, 1H), 2.98 (m, 1H), 2.59 (br, 1H), 2.42 (br, 1H), 2.24−2.21 (m, 1H), 2.20 (s, 3H), 2.08 (s, 3H), 2.05−1.98 (m, 1H), 1.86 ppm (s, 3H); 13C NMR (100 MHz, CDCl3, mixture of rotamers) δ 172.7, 171.5, 149.1, 142.4, 141.3, 136.1, 135.8, 132.0, 131.8, 128.2, 127.2, 124.6, 123.1, 120.5, 117.0, 116.9, 105.2, 100.2, 79.7, 64.4, 52.2, 44.2, 37.9, 36.1, 33.9, 31.9, 30.7, 29.7, 26.0, 22.6, 18.4 ppm; HRMS calcd. For C27H30N4ONa+ [M + Na]+ 449.2312, found 449.2314. “Putative” Communesin Common Biosynthetic Precursor 68a: (i) To a stirred solution of Boc-carbamate 67 (5.7 mg, 11.8 µmol) in AcOH (0.6 mL) at 0 °C was added sodium borohydride (38.0 mg, 1.00 mmol). The resulting mixture was stirred for 25 min before it was quenched with NaHCO3 (5 mL, sat. aq.) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was used directly in the next step without further purification. (ii) To a stirred solution of crude residue (obtained above) in CH2Cl2 (3.0 mL) at room temperature was added trifluoroacetic acid (1.20 mL). The resulting mixture was stirred for 2 h before it was quenched with NaHCO3 (5 mL, sat. aq.) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, EtOAc) to afford “putative” communesin common biosynthetic precursor 68a (2.2 mg, 49% over 2 steps) as a pale yellow oil. 68a: Rf = 0.39 (silica gel, EtOAc); [α]D25 −132.6 (c = 0.28, CHCl3); IR (film) νmax 2922, 1734, 1604, 1457, 1247, 747 cm−1; 1H NMR (400 MHz, CDCl3, mixture of isomeric forms): δ 7.38 (d, J = 7.9 Hz, 0.2H), 7.08 (d, J = 7.7 Hz, 0.2H), 7.03 (d, J = 7.4 Hz, 0.6H), 6.99−6.92 (m, 1H), 6.78 (t, J = 7.9 Hz, 0.2H), 6.76 (t, J = 7.7 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.6 Hz, 0.8H), 6.47 (d, J = 7.4 Hz, 0.2H), 6.39 (d, J = 7.3 Hz, 0.2H), 6.18 (dd, J = 7.6, 2.2 Hz, 1.6H), 5.37 (d, J = 9.2 Hz, 0.2H), 5.30 (d, J = 8.9 Hz, 0.8H), 5.01 (s, 1H), 4.96 (d, J = 9.0 Hz, 1H), 4.90 (d, J = 9.1 Hz, 0.2H), 4.89 (s, 1H), 4.55 (s, 0.2H), 4.53 (s, 0.2H), 4.19 (s, 0.2H), 3.91 (br, 0.2H), 3.60 (td, J = 11.9, 3.9 Hz, 0.2H), 3.49−3.39 (m, 0.8H), 3.25−3.13 (m, 2H), 2.99−2.81 (m, 0.2H), 2.76−2.59 (m, 2.2H), 2.39−2.29 (m, 0.8H), 2.14−2.06 (m, 0.8H), 2.05−2.01 (m, 0.8H), 1.89 (s, 0.6H), 1.81 (s, 2.4H), 1.77 (s, 2.4H), 1.71 (s, 0.6H), 1.62 ppm (dd, J = 12.2, 11.8 Hz, 0.2H); 13C NMR (100 MHz, CDCl3, mixture of isomeric forms) δ 148.7, 143.2, 140.7, 135.8, 133.0, 132.3, 127.8, 127.1, 126.6, 125.0, 123.7, 119.6, 117.3, 116.0, 112.9, 105.6, 80.4, 67.0, 64.2, 53.5, 52.2, 50.9, 43.8, 43.3, 38.1, 35.2, 35.0, 34.0, 29.7, 25.9, 18.6 ppm; HRMS calcd. For C25H29N4+ [M + H]+ 385.2387, found 385.2389. Bis-Acetate Ac-68: To a stirred solution of amine 68a (2.2 mg, 6.0 µmol) in AcOH (0.30 mL) at 0 °C was added acetic anhydride (0.30 mL). The resulting mixture was stirred for 15 min before it was quenched with NaHCO3 (5 mL, sat. aq.) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:Acetone 3:1) to afford bis-acetate Ac-68 (2.2 mg, 82%) as a pale yellow oil. Ac-68: Rf = 0.23 (silica gel, hexanes:EtOAc 1:3); [α]D25 −6.80 (c = 0.28, CHCl3); IR (film) νmax 2928, 1643, 1386, 1460, 1250, 752 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 6.96 (dt, J = 11.0, 5.4 Hz, 2H),



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6.71−6.59 (m, 4H), 6.56 (d, J = 7.7 Hz, 1H), 5.53 (d, J = 11.6 Hz, 1H), 5.48 (s, 0.3H), 5.43 (d, J = 11.3 Hz, 1H), 5.13 (s, 1.2H), 5.07 (s, 0.5H), 3.85 (t, J = 9.2 Hz, 0.7H), 3.68 (t, J = 9.2 Hz, 0.3H), 3.44−3.27 (m, 1.4H), 3.22−3.08 (m, 1.5H), 3.01 (dd, J = 19.1, 11.3 Hz, 0.7H), 2.91 (dd, J = 22.8, 10.3 Hz, 0.7H), 2.74 (dd, J = 21.8, 11.7 Hz, 0.7H), 2.39 (s, 2H), 2.37 (s, 3H), 2.29−2.19 (m, 1.3H), 2.11 (s, 1H), 2.05−1.99 (m, 0.7H), 1.96 (s, 1H), 1.85 (s, 2H), 1.78 (s, 2H), 1.74 ppm (s, 1H); 13C NMR (100 MHz, CDCl3, mixture of rotamers) δ 171.4, 170.8, 169.6, 169.5, 143.4, 142.4, 142.0, 141.8, 140.3, 138.7, 135.2, 135.1, 131.1, 128.0, 127.9, 127.6, 127.4, 124.1, 124.0, 123.2, 122.9, 122.8, 122.4, 120.6, 120.4, 116.8, 110.2, 109.9, 79.2, 79.1, 78.9, 64.3, 64.2, 51.5, 49.6, 48.8, 48.7, 45.8, 44.1, 37.6, 37.4, 36.5, 36.0, 32.2, 30.7, 29.7, 26.0, 25.8, 25.4, 25.3, 23.0, 22.6, 18.5, 18.4 ppm; HRMS calcd. For C29H32N4O2Na+ [M + Na]+ 491.2417, found 491.2417. Bis-Acetate Ac-68 from Mono-Acetate 68: To a stirred solution of mono-acetate 68 (1.8 mg, 4.1 µmol) in AcOH (0.20 mL) at 0 °C was added acetic anhydride (0.20 mL). The resulting mixture was stirred for 20 min before it was quenched with NaHCO3 (5 mL, sat. aq.) and extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:Acetone 3:1) to afford afford bis-acetate Ac-68 (1.6 mg, 83%) as a pale yellow oil. All physical properties of bis-acetate Ac-68 are identical to those obtained from double acetylation of bis-aminal 68a. Communesin F (6): (i) To a stirred solution of Boc-carbamate 67 (5.7 mg, 12.0 µmol) in AcOH (0.6 mL) at 0 °C was added sodium borohydride (38.0 mg, 1.0 mmol). The resulting mixture was stirred for 25 min before it was quenched with NaHCO3 (10 mL, sat. aq.) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was used directly in the next step without further purification. (ii) To a stirred solution of crude residue (obtained above) in dry THF (1.0 mL) at room temperature was added lithium aluminium hydride (12.3 mg, 0.33 mmol). The resulting mixture was warmed to 80 °C and stirred for 2.5 h before it was cooled to room temperature, quenched with NaHCO3 (5 mL, sat. aq.) and extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue (communesin K, 6b) was used directly in the next step without further purification. (iii) To a stirred solution of crude residue (communesin K, 6b, obtained above) in AcOH (0.3 mL) at 0 °C was added acetic anhydride (0.3 mL). The resulting mixture was stirred for 20 min before it was quenched with NaHCO3 (10 mL, sat. aq.) and extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 2:1) to afford communesin F (6, 3.5 mg, 67% over 3 steps) as a white pale yellow oil. 6: Rf = 0.30 (silica gel, hexanes:EtOAc 1:3); [α]D25 −224.6 (c = 0.23, CHCl3, 86% ee), Literature: [α]D25 −264.0 (c = 0.34, CHCl3); IR (film) νmax 2873, 1646, 1596, 1491, 1397, 1278, 744 cm−1; 1H NMR (400 MHz, CDCl3, mixture of rotamers): δ 7.00 (td, J = 7.4 Hz, 1H), 6.82 (t, J = 7.7 Hz, 1H), 6.76−6.61 (m, 3H), 6.14 (d, J = 7.6 Hz, 0.4H), 6.08 (d, J = 7.6 Hz, 0.6H), 5.86 (d, J = 7.6 Hz, 1H), 5.48 (s, 0.4H), 5.35 (d, J = 9.0 Hz, 0.4H), 5.23 (d, J = 8.7 Hz, 1H), 5.11 (s, 0.6H), 5.05 (d, J = 8.8 Hz, 0.6H), 4.67 (s, 0.6H), 4.63 (s, 0.4H), 4.55 (br, 1H), 3.85 (dd, J = 11.6, 9.2 Hz, 0.6H), 3.67 (d, J = 9.4 Hz, 0.4H), 3.41 (br, 0.4H), 3.34 (dd, J = 15.2, 9.2 Hz, 0.6H), 3.21–3.09 (m, 1H), 3.04 (dd, J = 19.0, 11.6 Hz, 0.6H), 2.97−2.88 (m, 0.4H), 2.82 (s, 1.8H), 2.80 (s, 1.2H), 2.78−2.70 (m, 1H), 2.40 (s, 1.8H), 2.34−2.19 (m, 2H), 2.11 (m, 1.2H), 2.06−2.01 (m, 0.4), 2.00−1.93 (m, 1.8H), 1.85 (s, 1.8H), 1.79 (s, 1.8H), 1.76 ppm (s,

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1.2H); 13C NMR (100 MHz, CDCl3, major rotamer) δ 171.6, 150.1, 142.7, 140.6, 136.0, 132.7, 131.3, 128.4, 127.3, 124.6, 123.2, 120.6, 117.0, 114.7, 100.8, 82.7, 79.6, 64.4, 51.8, 51.2, 44.3, 37.8, 36.3, 30.8, 29.7, 26.0, 22.6, 18.5 ppm; HRMS calcd. For C28H33N4O+ [M + H]+ 441.2649, found 441.2649. Allyl Lactone 69:13To a stirred solution of lactone 69a (610 mg, 1.73 mmol) in DMF (20.0 mL) at 0 °C was added NaH (60% in mineral oil, 138 mg, 3.46 mmol) in one portion. The resulting mixture was stirred for 10 min before allyl bromide (0.40 mL, 4.33 mmol) was added. The resulting mixture was warmed to 100 °C and stirred 5 h before it was quenched with water (20 mL). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL), the combined organic layer was washed with water (3 × 200 mL) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 2:1) to afford allyl lactone 69 (505 mg, 74%) as a white amorphous solid. 69: Rf = 0.45 (silica gel, hexanes:EtOAc 1:1); IR (film) νmax = 3005, 2987, 2253, 1707, 1535, 1472, 1358, 1258, 1201, 727 cm−1; 1 H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 7.9 Hz, 1H), 7.21−7.10 (m, 2H), 7.07 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.63 (t, J = 7.6 Hz, 1H), 5.62−5.46 (m, 1H), 5.41−5.25 (m, 1H), 5.01 (d, J = 17.2 Hz, 1H), 4.92 (d, J = 10.2 Hz, 1H), 4.71−4.61 (m, 1H), 3.44 (dd, J =16.0, 7.1 Hz, 1H), 3.26 (s, 3H), 2.98 (dd, J = 15.4, 6.8 Hz, 1H), 2.93−2.78 (m, 1H), 2.27−2.18 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): δ 177.2, 168.6, 149.7, 142.1, 133.8, 133.1, 131.1, 130.4, 128.6, 127.9, 125.6, 124.7, 122.2, 118.9, 107.7, 64.8, 54.1, 53.9, 43.6, 30.7, 26.5 ppm; HRMS calcd. For C22H20N2O5Na+ [M + Na]+ 415.1264, found 415.1262. Bis-Oxindole 29:13 To a stirred solution of allyl lactone 69 (505 mg, 1.29 mmol) in MeOH/H2O (2:1, 49.2 mL) at room temperature was added titanium(III) chloride (10% wt. HCl, 8.00 mL, 5.00 mmol) and ammonium acetate (4.96 g, 64.6 mmol). The resulting mixture was stirred for 12 h before it was quenched with brine (10 mL). The resulting mixture was extracted with EtOAc (4 × 50 mL), the combined organic layer was washed with brine (2 × 150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 1:3) to afford bis-oxindole 29 (380 mg, 82%) as a yellow foam. All physical data of bis-oxindole 29 are identical to those obtained for the major diastereoisomer from the organocatalytic coupling reaction between aldehyde 26 and oxindole 11 followed by reductive workup.

ASSOCIATED CONTENT Supporting Information Tables of reaction optimization studies, chiral HPLC analysis, selected NMR comparisons, 1H and 13C spectral data of all compounds, and single X-ray analysis. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported by Seoul National University Foreign Faculty Fund, New Faculty Resettlement Fund, National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (Nos. 2012R1A2A2A01002895,


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2013R1A1A2057837, and 2014-011165, Center for New Directions in Organic Synthesis), and Novartis. Alexandre Jean and Jisook Park were supported by the BK21Plus Program, Ministry of Education. We thank Suyong Goh and Rosa Youn for preliminary asymmetric organocatalysis studies. We thank Professor Mohammad Movassaghi (MIT) for valuable discussions on the stability of late-stage polycyclic bis-aminal intermediates.

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Nicolaou, K. C., Snyder, S. A., Motagnon, T., Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668. (a) Heathcock, C. H. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 133-238. (b) Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 239-275. (c) Paterson, I. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 301-319. (a) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062. (b) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6723. (c) Negishi, E. Angew. Chem., Int. Ed. 2011, 50, 6738. (d) Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3740. (e) Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748. (f) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760. (a) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998. (b) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (c) Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (a) Numata, A.; Takahashi, Ch.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M. Tetrahedron Lett. 1993, 34, 2355. (b) Andersen, B.; Smedsgaard, J.; Frisvad, J. C. J. Agric. Food Chem. 2004, 52, 2421. (c) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V. J. Nat. Prod. 2004, 67, 78. (d) Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci. Biotechnol. Biohem. 2004, 68, 753. (e) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad, J. C.; Christophersen, C. J. Nat. Prod. 2005, 68, 258. (f) Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561. (g) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26. For a recent review on the synthetic studies of the communesin alkaloids and perophoramidine, see: Trost, B. M.; Osipov, M. Chem. Eur. J. 2015, 21, 16318. (a) Yang, J.; Wu, H.; Shen, Y.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794. (b) Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000. (c) Seo, J. H.; Liu, P.; Weinreb, S. M. J. Org. Chem. 2010, 75, 2667. (d) Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226. (e) Belmar, J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134, 16941. (f) Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316. (g) Han, S.-J.; Vogt, F.; May, J. A.; Krishnan, S.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. J. Org. Chem. 2015, 80, 528. (h) Lathrop, S. P.; Pompeo, M.; Chang, W.-T. W.; Movassaghi, M. J. Am. Chem. Soc. 2016, 138, 7763. (i) Liang, X.; Zhang, T.-Y.; Zeng, X.-Y.; Zheng, Yu.; Wei, K.; Yang, Y.-R. J. Am. Chem. Soc. 2017, 139, 3364. (j) Park, J.; Jean, A.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2017, 56, DOI: 10.1002/anie.201707806. For biosynthetic and computational studies of the communesins, see: (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203. (b) May, J. A.; Stoltz, B. M. Tetrahedron 2006, 62, 5262. (c) Lin, H.-C.; Chiou, G.; Chooi, Y.-H.; McMahon, T. C.; Xu, W.; Garg, N. K.; Tang, Y. Angew. Chem. Int. Ed. 2015, 54, 3004. (d) Lin, H.-C.; McMahon, T. C.; Patel, A.; Corsello, M.; Simon, A.; Xu, W.; Zhao, M.; Houk, K. N.; Garg, N. K.; Tang, Y. J. Am. Chem. Soc. 2016, 138, 4002. For a recent review on the synthesis of spirooxindoles via organocatalytic strategies, see: Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F. III. ACS Catal. 2014, 4, 743.

(10) For examples of organocatalytic reaction involving oxindole enals, see: (a) Liu, R.; Zhang, J. Chem. Eur. J. 2013, 19, 7319. (b) Liu, R.; Zhang, J. Org. Lett. 2013, 15, 2266. (c) Mukaiyama, T.; Ogata, K.; Sato, I.; Hayashi, Y. Chem. Eur. J. 2014, 20, 13583. (11) For preparation of oxindole 11, see: (a) Badiola, E.; Fiser, B.; Gómez-Bengoa, E.; Mielgo, A.; Olaizola, I.; Urruzuno, I.; García, J. M.; Odriozola, J. M.; Razkin, J.; Oiarbide, M.; Palomo, C. J. Am. Chem. Soc., 2014, 136, 17869. For preparation of oxindole 12, see: (b) Menozzi, C.; Dalko, P. I.; Cossy, J. Chem. Comm. 2006, 4638 and Supporting Information (12) (a) Zhang, H.; Hong, L.; Kang, H.; Wang, R. J. Am. Chem. Soc. 2013, 135, 14098. (b) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068. (13) Stoltz and co-workers reported the preparation of lactone 69 with the desired relative stereochemistry for the communesins (ref 7g). We independently synthesized compound 69 and performed reductive skeletal rearrangement to afford bis-oxindole 29 with 1H and 13C NMR signatures identical to our organocatalytic process. For details, see Supporting Information. (14) Amino-alcohol 32 could also be accessed through an analogous reductive amination sequence using bis-oxindole 29 derived aldehyde (O3) but required the significantly more costly pnitrobenzyl amine. (15) For related dehydrative amidine formation, see: (a) Trost, B. M.; Zhang, Y. Chem. Eur. J. 2011, 17, 2916. (b) Evans, M. A.; Sacher, J. R.; Weinreb, S. M. Tetrahedron 2009, 65, 6712. (16) To date, The preparation of substituted-isatin from chloral hydrate and substituted-aniline is still the most practical approach. However, chloral hydrate is a highly toxic and a restricted substance. For a representative synthesis of 4-bromoisatin 38 from chloral hydrate and 2-bromoaniline, see: Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A.-L.; Myrianthopoulos, V.; Mikros, E.; Tarricone, A.; Musacchio, A.; Roe, S. M.; Pearl, L.; Leost, M.; Greengard, P.; Meijer, L. J. Med. Chem. 2004, 47, 935. (17) We noticed the structure of the two diastereoisomeric oxindole primary alcohols (29/29a, 30/30a, 31/31a, and 41/41a) could be easily distinguished based on characteristics of their 1H NMR signature. The desired diastereoisomer for the communesin synthesis (29, 30, 31 and 41) displayed sharp and clearly defined aromatic signals, whereas the undesired diastereoisomer (29a, 30a, 31a and 41a) exhibited significantly broadened aromatic signals. We also noticed the same 1H NMR behavior in the work reported by Stoltz (ref 7g). For illustrative 1H NMR comparisons, see Supporting Information. (18) (a) Itoh, T.; Ihikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854. For a computational study, see: (b) Correa, R. J.; Garden, S. J.; Angelici, G.; Tomasini, C. Eur. J. Org. Chem. 2008, 736. (19) For selected recent reviews on CH-functionalization in targetoriented synthesis, see: (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (b) Chen, D. Y. K.; Youn, S. W. Chem. Eur. J. 2012, 18, 9452. (c) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. (d) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976. (20) For selected examples of directing groups in Pd(OAc)2 catalyzed CH-functionalization, see: -NHTf: (a) Li, J.-J.; Mei, T.S.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 6452. Picolinamide: (b) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124. Quinolinamide: (c) Huang, L.; Li, Q.; Wang, C.; Qi, C. J. Org. Chem., 2013, 78, 3030. 1,2,3-triazole: (d) Ye, X.; Shi, X. Org. Lett., 2014, 16, 4448. Oxalylamide: (e) Wang, Q. Han, J.; Wang, C.; Zhang, J.; Huang, Z.; Shi, D.; Zhao, Y. Chem. Sci. 2014, 5, 4962. (21) CCDC-1525169 contains the supplementary crystallographic data for compound 51. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.



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(22) Under the optimized reaction conditions we could not detect any corresponding CH-activation/alkenylation products derived from oxalamides 48, 52a and 52b with alkenyl tertiary alcohol 49a, while CH-activation/alkenylation with enone 49b displayed significantly lower conversion compared to enoate 49c together with a much more complex crude reaction mixture based on 1H NMR analysis. (23) Han, S.-J.; de Melo, G. F.; Stoltz, B. M. Tetrahedron Lett. 2014, 55, 6467. (24) Ramon, R. S.; Marion, N.; Nolan, S. P. Tetrahedron 2009, 65, 1767.


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