Cascading Auto-oxidative Biproline Guanylations Form Optically

Apr 30, 2018 - Cascading Auto-oxidative Biproline Guanylations Form Optically Active Dispacamide Dimers and Permit an Eight-Step Synthesis of (−)- ...
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Cascading auto-oxidative biproline guanylations form optically active dispacamide dimers and permit an eight-step synthesis of (-)-ageliferin Hui Ding, Andrew G. Roberts, Rocky Chiang, and Patrick G Harran J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00631 • Publication Date (Web): 30 Apr 2018 Downloaded from http://pubs.acs.org on May 1, 2018

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The Journal of Organic Chemistry

Cascading auto-oxidative biproline guanylations form optically active dispacamide dimers and permit an eight-step synthesis of (−)-ageliferin Hui Ding, Andrew G. Roberts†, Rocky Chiang and Patrick G. Harran* Department of Chemistry & Biochemistry, University of California, Los Angeles, CA 90095 ABSTRACT: A nickel catalyzed synthesis of isomeric 3, 3’-biproline esters is described. When those materials are doubly acylated with the acid chloride of pyrrole-2-carboxylic acid, they become susceptible to auto-oxidation in the presence of guanidine. Through proper staging of reaction conditions, it is possible to initiate two consecutive oxidative guanylations prior to in situ cycloisomerization to afford spirocyclic bis-glycocyamidines. This unique outcome reflects a cascade of no fewer than ten reactions occurring sequentially in one flask. The chemistry provides rapid access to advanced intermediates useful for the preparation of complex, optically-active pyrrole/imidazole alkaloids.

Introduction

Figure 1. Relating lignan precursors to dispacamide dimers Polycyclic bis-guanidines in the palau’amine family possess a range of biological activities and have fasci1 nated synthetic chemists for more than two decades. Seminal work by Baran, Chen, Tanino and others, has contributed greatly to an understanding of their chemistry and provided laboratory access to the group. In Nature the2 se structures arise as dimeric composites of oroidin-type alkaloids. Synthetic experiments of our own were deACS Paragon Plus Environment

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signed with this in mind and drew upon a simple analogy to lignans. In one branch of lignan biosynthesis, coniferyl 3 alcohol is oxidatively dimerized to pinoresinol by way of tethered bis-parabenzoquinonemethide (2, Fig. 1). Dis4 pacamide is an oxygenation product of oroidin. We felt that a one-electron oxidation product of that molecule (namely 3), could dimerize in a manner related to that seen for 1. The resultant tethered bisalkylidene 4 could then be desymmetrized via electrophilic halogenation to afford a core spirocycle (5) from which several members of the palau’amine family could derive. In the laboratory, controlled generation of radical 3 proved a challenge. Instead, we built molecules of type 4 by dimerizing protected dispacamidyl synthons via heterocyclic enolate oxidations. We 2c were then able to demonstrate the key halogenative desymmetrization. Unfortunately, the protection scheme in that case was not suited to completing the natural products. Notably, in all subsequent variations, species 4 were 2b, 2d found labile and readily cycloisomerized to spiro bisglycocyamidines 6. The original hypothesis was clearly valid. In fact, bisalkylidenes 4 were so prone to form a palau’amine type core, they slipped by without opportunity to halogenate. As we considered alternatives, the cycloisomerization reaction was useful in other settings. For example, it was employed during the conversion of C2 symmetric polyheterocycle 6 to the microbial biofilm inhibitor 5, 6 ageliferin (8, Fig. 2). Cycloisomerization, thermodynamic equilibration and subsequent ring-expanding rear2a rangement (vide infra) were highlights of that synthesis. However, the drawback was the intermediacy of 7. This protected, conformationally constrained molecule had been designed to tame reactivity of its alkylidenes in hopes of chlorinating the structure. Ageliferin was not chlorinated and those attributes now seemed unnecessary.

Figure 2. Al-Mourabit auto-oxidation as means to streamline access to polycyclic pyrrole/imidazole alkaloids.

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The Journal of Organic Chemistry

The question was how best to prepare an unconstrained, fully unprotected form of 4. A strong hint came 7 from chemistry reported in 2004 by Al-Mourabit et al. They had discovered that partially oxidized proline dimers (e.g. 10) in the presence of guanidine salts would auto-oxidize in air to afford mixtures of desbromodispacamide (11) and its spirocyclic tautomer 12. This implied to us that a C2-symmetric 3, 3’-biproline homolog (i.e. 13) might undergo two such oxidations in sequence. The linked bis-alkylidene anticipated from that cascade (namely, 4 in Fig. 1), 2d given previous observations, would likely cycloisomerize in situ to afford spirocycles 6. Here we describe experiments that led to this remarkable transformation being realized and that have enabled access to optically active advanced intermediates useful for the synthesis of dimeric oroidin alkaloids.

Results and discussion

8

Isomeric 2,2’-biprolines and 2,3’-biprolines were known. To our knowledge, the corresponding 3,3’-linked variants were not. Commercial Z-L-hydroxyl proline ethyl ester was brominated (with inversion of configuration) to 9 10 give 14 and then reductively dimerized using low valent nickel catalysis (Scheme 1). As was recently noted, stere3 ocontrolled homodimerization of sp -hybridized precursors is a perennial challenge. In our case, while the radical 11 character of organonickel species propagating the catalysis minimized premature reduction, it did generate three 12 diastereoisomeric products. Fortunately, that limitation was offset by the practicality of the method. Fifty gram batches of bromide 14 could be dimerized using 5 mol % of a readily available nickel complex. The mixture of diastereomers formed was treated with HBr in AcOH and the resultant diamine salts 16 were precipitated with Et2O. Diastereomer 16c could then be largely (>90%) removed by crystallization from aqueous i-PrOH. The structure of 16c was confirmed by X-ray diffraction analysis of a single crystal grown in i-PrOH. When the remaining isomers

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(16a/b, ~6:1) were dissolved in CH2Cl2 and treated with acid chloride 17, doubly acylated species 18a/b were formed. These unstable molecules degraded on silica gel, although we were able to secure the structure of 18b by growing single crystals of small amounts of HPLC purified material. The stereochemistry of 18a was then assignable by inference.

Table 1. Survey of conditions for the oxidative guanylation cascade. Entry

a.

b.

a

Oxidants

% yield

b

c

19

22

23

9

20

25

1

Air

2

Air

32

36

4

3

H2O2-urea (2.5 eq)

36

3

18

4

Davis oxaziridine (2.5 eq)

25

11

0

5

O2 (2.1 eq)

37

12

2

6

O2 (4.2 eq)

43

11

6

7

O2 (balloon)

50

17

2

8

TBHP

-

-

-

d

Except for entry 1, the reactions were run as a two-stage, one-pot procedure using free guanidine as the base. This involved pre-mixing 18a and free guanidine at room temperature, followed by exposure to the oxidant and brief heating o at 90 C. The reaction was run as a single-stage, one pot procedure using guanidine carbonate as the base.

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The Journal of Organic Chemistry c. d.

Yields quoted reflect HPLC (Waters XSELECT Fluoro-phenyl column, eluted with CH3CN/H2O containing 0.1% TFA) peak integrals monitored at 280 nm. None detected by HPLC.

Figure 3. Re-examining the Al-Mourabit oxidation via in situ monitoring. A. Plausible intermediates during the conversion of 24 to 11. B: 1H NMR (top) and 13C NMR (bottom) spectra of predominate species present (labeled) for the following progression (from bottom to top): a) t = 0 min, under argon. b) guanidine free base for 15 min under argon. c) 3 min, under 1 atm oxygen gas. d) 48h, under 1 atm oxygen gas. All measurements recorded at 25 oC.

The key auto-oxidative guanylation cascade was then tested on 18a. Initially, conditions paralleling those de7 scribed by Al-Mourabit were explored. This involved pre-mixing 18a and guanidine carbonate in DMF solution over 4A molecular sieves and heating (flask open to air) at 90˚C for 1 h (Scheme 2). Only small amounts of target 19 were formed in that experiment. Instead, the major products isolated were the unique azabicyclooctane carboxylate 22 and mono-alkylidene 23 (~40% total mass recovery). Compound 22 was rationalized in terms of incomplete oxidation, wherein an enolized precursor to 22 (namely 20) was instead internally trapped by an imino tautomer of its tethered alkylidene glycocyamidine as drawn. The formation of 23 was consistent with the intermediacy and subse7b quent degradation of dioxetanone 21, a species also invoked in Al-Mourabit’s studies. Interestingly, replacing guanidine carbonate with guanidine acetate or guanidine hydrochloride in the same procedure left 18a largely unchanged. Amongst those three salts, only guanidine carbonate would likely generate appreciable amounts of it’s 14 free-base under the reaction conditions. We therefore examined whether pure guanidine base would provide an 15 improvement. In fact, when freshly prepared guanidine free-base was used in place of guanidine carbonate, spirocycles 19 became a major product. Moreover, we discovered that separating the reaction into two stages was optimal, wherein 18a was first stirred with guanindine free-base (an excess was used to minimize formation of 21) at room temperature under anaerobic conditions, prior to opening the flask to air wherein auto-oxidation rapidly ensued at room temperature. Brief heating at 90˚C then formed 19 (Table 1, entry 2). We next screened alternate oxidants and, while some success was had (Table 1, entry 2), molecular oxygen remained the reagent of choice, especially when present as a pure atmosphere (Table 1, entry 7). In that case proper reaction times and temperatures were critical to avoid over-oxidation. In total, the findings allowed us to design a one-flask procedure to convert diamine hydrobromides 16a/b directly into spirocyclic bis-glycocyamidines 19 (vide infra). This outcome was the result of no fewer than ten reactions occurring sequentially in the flask! While this complexity made detailed mechanistic studies a challenge, we were able to gain some insight by revisiting the Al-Mourabit system. When acylpyr-

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13

rolidine 24 was treated with guanidine in DMSO-d6 under argon, in situ monitoring by H and C NMR showed 7a rapid formation of ethanol (Fig. 3). Signals for the product formed were not consistent with diketopiperazine 27 , which we had made independently. Actually, when 27 was treated with guanidine in DMSO-d6, it rapidly converted to the same product formed from 24, which we thus assigned as enolized (C10H not observed, C10 δ = 97.2 ppm) acyl guanidine species 25. When that molecule was exposed to oxygen, it was consumed within minutes and re16 placed by a compound having data consistent with angular peroxide 26. This molecule then slowly converted to 7a desbromodispacamide (11) upon standing at rt for 48 h. Relating this data to the conversion of 18 to 19, we presumed that a similar progression had occurred at each end of the symmetric dimer, and that heating the resultant bis-alkylidene (or partially hydrated variants thereof) initiated a thermodynamically driven spirocycloisomerization to complete the process. We next turned attention to applying an optimal procedure to total synthesis (Scheme 3). On gram scales, hydrobromides 16a/b were dissolved in DMF containing K2CO3 and 4 Å MS under argon and then treated with a DMF solution of acid chloride 17 containing 2 mol % DMAP. The resultant mixture of 18a/b was treated with a DMF solution (4.4 M) of guanidine free-base at room temperature. The reaction was stirred under argon for 20 minutes, then under a balloon of oxygen for 20 min, and finally heated at 90˚C under argon for 10 minutes to afford spirocycles 19. These isomeric molecules were isolated in 31% overall yield following purification via preparative mPLC (MeOH / H2O containing 0.1% TFA) using C18 cartridges. Spirocycles 19 showed limited solubility in organic solvents which made advancing the material further a challenge. Brominating the pyrrole rings improved solubility although rea17 gents such as Br2 and NBS caused uncontrolled polyhalogenation. Snyder’s bromosulfonium salt provided a useful alternative, wherein tetrabrominated products 28 could be isolated in 50% yield. Notably, racemic 28 was a key in2a termediate in our previous synthesis of ageliferin. NH O

a) K2CO3

HN H2N

N

EtO2C NH

NH

NH

EtO2C H N

ClOC

H N

NH2

14

O

HN

b)

NH

NH

1 atm O2 RT to 90 oC

17

O

EtO2C

16a 16b (3R, 3'R)

NH

N H HN

H N

NH

H N

NH

Br

O O

NH

Br

O

NH

EtO2C NH

NH

NH

O

N

3

14

O

Br

3'

HN

[SbCl5Br] a S

NH

N H

DMF

O

O

Br

N H Br

19a 19b epi C14

18a 18b (3R, 3'R)

28a 28b epi C14

c)

[NH2BH]Li

Ref. 2a NH

NH

.

2 CF3CO2 H2N

NH2 NH

NH

HO

HN NH

HN

HN

HN

Br

N

N H

e) TFAA /TFA then 2 M HCl HN

O

NH

HN NH

[ ] D 24

NH

N H HN

H N

aq. THF

N H

N H

NH

(-)-ageliferin

NH2

H N

Br

O NH

O

O Br

Br Br

O

16.0 o (c 0.03, MeOH)

N

d) SmI2

O Br

NH

O NH2

Br

Br

30

[ ] D 20

25.6 o (c 0.18, H2O)

29

Scheme 3. Reagents and conditions: a) K2CO3 (5 eq.), DMAP (cat.), 17 (2.1 eq.), DMF, 80 min; guanidine (7.5 eq.), 10 min; O2, 30 min; 90oC, 11 min; 31% . b) BDSB (8 eq.), ACN, RT, 80 min, 47%. c) excess Li(NH2BH3), THF, 60 oC, 10 h; TFA/H2O (1:9), 60 oC, 4 h. d) major isomer, excess SmI2, THF/H2O. e). TFAA/TFA, THF, 70 oC; aq. 1 M HCl.

Following procedures and separation schemes used in that work, optically active isomers of 28 were advanced via chemoselective lithium amidotrihydroborate deoxygenation, SmI2 mediated partial reduction of the C1 carbonyl and TFAA/TFA mediated ring expansion initiated via ionization of the resultant hemiaminal 30. This provided (-)-ageliferin (8) in a total of eight steps beginning with commercial Z-L-hydroxyl proline ethyl ester. Because the diastereomeric ratio of bis-pyrrolidines 16a/b translates to the enantiomeric ratio of auto-oxidation products 19, the corresponding enantiomeric excess of synthetic ageliferin would be maximally 72% in the current sequence. 20 The [α]D measured for our synthetic material was -16˚ (c=0.03, MeOH), which compares to a literature value of 10˚ (c=0.03, MeOH) for this antipode of the natural product. We are activing seeking to improve stereocontrol in

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The Journal of Organic Chemistry

the homodimerization of 14, which would permit access to this series of compounds in greater optical purity. The 6a, 6d assignment of absolute stereochemistry to ageliferin has been studied carefully, and we look forward to exploring the properties of both enantiomers of the natural product in the future.

Conclusion We have described the first synthesis of 3, 3’-biproline esters via a 3 step sequence featuring nickel catalyzed reductive dimerization of a hydroxy proline derivative. In one flask, these amino esters can be doubly acylated with the acid chloride of pyrrole-2-carboxylic acid and subjected to a cascading auto-oxidation in the presence of guanidine free base. This provides an optically active spirocyclic core structure from which numerous polycyclic pyrrole imidazole alkaloids can potentially derive. Biological activities including antibacterial, antifungal, antiviral, antimalarial and immunosuppression have been attributed to this class of structures. As we refine stereoselectivity in the constructions above, the route promises to drive biochemical and pharmacological research in many new directions. Studies along these lines are ongoing as our collection of synthetic analogs expands.

Experimental Section Materials and Methods. Unless otherwise specified, reactions were performed in flame-dried glassware under an atmosphere of argon. Dichloromethane (CH2Cl2) and acetonitrile (CH3CN) were passed through Glass Contour solvent drying systems. N,N-dimethylformamide (DMF) and ethanol (EtOH) was distilled and dried over 4 Å molecular sieves prior to use. N,N-dimethylacetamide (DMA) was dried over 4 Å molecular sieves for at least 48 hours before use. Chemicals obtained from commercial sources were used as received with no further purification. Thinlayer chromatography (TLC) was conducted on pre-coated plates (Sorbent Technologies, silica gel 60 PF254, 0.25 mm) visualized with UV 245 nm or basic potassium permanganate stain. Column chromatography was performed on silica gel 60 (SiliCycle, 240-400 mesh). Purification of intermediates (19, 28 and 29) were performed with an Intershim automated chromatography system equipped with a Biotage 60-g C18 cartridge. Purification of compound 30 and ageliferin were performed with an Agilent 1200 HPLC system equipped with G1361A preparative pumps, a G1314A autosampler, a G1314A VWD, a G1364B automated fraction collector, and Waters Sunfire C18 column (5μm, 19x250 mm), unless otherwise noted. Analytical HPLC was performed using the same system, but with a G1312A binary pump. Mass spectra were recorded using Agilent 6130 LC/MS system equipped with an ESI source. High resolution mass spectra were recorded using Thermo Fisher Scientific Exactive Plus with IonSense ID-CUBE DART source and Orbitrap analyzer. NMR spectra were recorded on Bruker Avance spectrometers (400 or 500 MHz), DRX (500 MHz). Synthesis of Bromide 14. To a flask charged with (2S,4R)-1-benzyl-2-ethyl-4-hydroxypyrrolidine-1,2-dicarboxylate (222.4 g, 0.758 mol; commercially available but was also prepared from trans-4-hydroxy-L-proline as reported (Wieland, T.; Schermer, D.; Rohr, G.; Faulstich, H. Liebigs Ann. Chem. 1977, 806-810)) and CBr4 (277 g, 0.834 mol, 1.1 o equiv) was added CH2Cl2 (1.5 L). The mixture was cooled to 0 C. PPh3 (240 g, 0.910 mol, 1.2 equiv) was added in portions (4 x 60 g) over an hour. The reaction was warmed to rt and stirred for 16 h. It was concentrated to about 0.5 L and filtered. The filtrate was concentrated in vacuo to give the crude, which was separated into 3 equal batches and purified by flash chromatography (SiO2, 4 : 1 hexanes/EtOAc) to give 14 as clear yellow oil (208.3 g, 77% yield). 1 H NMR (500 MHz, CDCl3): δ (ppm) 7.39-7.28 (m, 5H), 5.22-5.05 (m, 2H), 4.51-4.05 (m, 5H), 3.87-3.76 (m, 1H), 2.9113 2.78 (m, 1H), 2.52-2.41 (m, 1H), 1.32-1.13 (m, 3H); C NMR (125 MHz, CDCl3): δ (ppm) 171.4, 171.1, 154.4, 154.0, 136.4, 136.3, 128.7, 128.6, 128.3, 128.25, 128.18, 128.1, 67.6, 67.5, 61.7, 58.6, 58.3, 56.0, 55.6, 42.1, 41.5, 41.1, 40.1, 14.2, 14.1; HRMS + 20 (DART-Orbitrap) m/z: [M+H] Calcd for C15H19BrNO4: 356.0492; Found 356.0476; [α]D –29.5 (c 1.0, CHCl3). Bi-proline dimers 15 from [Ni] catalyzed homocoupling of 14. A solution of 14 (50.6 g, 142 mmol) in DMA (65 mL) was degassed by sparging for 15 min with Ar (Vessel 1). In a second reaction vessel, NiCl2(glyme) (1.53 g, 7.08 mmol, 5 mol%) and the sec-Bu-PyBOX ligand (2.9 g, 8.84 mmol, 6.25 mol%) was dissolved in degassed DMA (65 mL) and stirred at rt for 15 min. The solution in Vessel 1 was added to Vessel 2 via cannulation. The mixture was o cooled to 0 C. The reaction was initiated by the addition of activated Mn (15.6 g, 284 mmol) in one portion and o stirred at 0 C for 16 h. The reaction was then warmed to rtstirred until judged complete by TLC or LCMS analysis. It was warmed to rt and stirred for 3 h, filtered through a short SiO2 plug to remove any inorganic material and washed with EtOAc (4x). The combined organic layers were washed with 1 M HCl (2x), water, brine, dried over

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Na2SO4, and concentrated in vacuo to give a crude yellow oil that was purified by flash chromatography (SiO2, 4:1 to 1:1 hexanes/EtOAc) to give 14 as an inseparable mixture of three diastereomers (15a-c, 26.2 g, 60%; d.r.: 5.4:1:2.3, as 1 inferred by ratio of 18). H NMR (500 MHz, CDCl3): δ (ppm) 7.39-7.26 (m, 10H), 5.21-5.01 (m, 4H), 4.46-4.24 (m, 2H), 4.24-4.15 (m, 2H), 4.11-3.97 (m, 2H), 3.89-3.70 (m, 2H), 3.19-3.02 (m, 2H), 2.47-2.35 (m, 0.6H), 2.32-2.14 (m, 1.4H), 13 2.14-1.97 (m, 2H), 1.97-1.82 (m, 1.4H), 1.72-1.58 (m, 0.6H), 1.31-1.21 (m, 3H), 1.20-1.07 (m, 3H); C NMR (125 MHz, CDCl3): δ (ppm) 172.5, 172.4, 154.8, 154.6, 154.2, 136.6, 128.7, 128.5, 128.3, 128.2, 128.1, 128.1, 127.9, 67.4, 67.3, 61.5, 61.4, 61.3, 59.5, 59.4, 59.3, 59.2, 59.1, 58.9, 51.5, 51.2, 51.0, 51.0, 50.9, 50.6, 42.1, 41.5, 40.8, 40.7, 40.6, 39.9, 39.7, 36.2, 35.9, + + 35.5, 35.5, 35.1, 34.9, 34.6, 14.3, 14.2, 14.1; LRMS (ESI-quadrupole) m/z: [M+H] Calcd for C30H37N2O8 : 553.3; Found: + 553.3. HRMS (ESI-TOF) m/z: [M+H] Calcd for C30H37N2O8: 553.2544; Found: 553.2512.

5, 5’-Diethyl-[3, 3’-bipyrrolidine]-5, 5’-dicarboxylate 2-HBr salt 16. Purified 15 (19.8 g, 35.9 mmol) was dissolved o in conc. acetic acid (20 mL) and cooled to 0 C. HBr (33 wt% in acetic acid, 90 mL, 367 mmol) was added in one portion. The reaction mixture was warmed to rt. After stirred for 1 h, white precipitate began to form. The mixture o o was cooled to 0 C and stirred for 15 min. Cold Et2O (50 mL) was added and the mixture was stored at –20 C for 16 h. The solvent was decanted and the solid was washed with Et2O (2 x 100 mL) to give crude 16(16a-c, 13.8 g, 86%, crude yield) as an off-white solid. It was recrystallized from iPrOH-H2O to give a colorless crystalline solid (16c, 4.8 o 1 g). 16c: mp 228-230 C; H NMR (500 MHz, MeOH-d4): δ (ppm) 4.61 (dd, J = 9.5, 4.5 Hz, 1H), 4.50 (dd, J = 10.5, 7.6 Hz, 1H), 4.34-4.28 (m, 2H), 3.66-3.59 (m, 2H), 3.20-3.11 (m, 2H), 2.66 (ddd, J = 13.9, 7.1, 7.1 Hz, 1H), 2.61-2.51 (m, 1H), 13 2.47-2.36 (m, 2H), 2.25-2.16 (m, 1H), 1.84 (ddd, J = 10.5, 10.5, 2.8 Hz, 1H), 1.32 (t, J = 7.2 Hz, 6H); C NMR (125 MHz, MeOH-d4): δ (ppm) 168.5, 168.1, 62.8, 62.7, 59.5, 59.2, 49.1, 48.9, 40.7, 39.6, 32.9, 32.4, 12.94, 12.92; HRMS (DART+ Orbitrap) m/z: [M+H] Calcd for C14H25N2O4: 285.1809; Found: 285.1795. The mother liquor was concentrated to 1 give a pale yellow powder (16a/b, 8.2 g, ~6:1 dr). H NMR (500 MHz, MeOH-d4): δ (ppm) 9.92-9.58 (bs, 2H), 9.248.93 (bs, 2H), 4.63-4.35 (m, 2H), 4.26-4.19 (m, 4H), 3.07-2.86 (m, 2H), 2.49-2.20 (m, 6H), 2.12-1.98 (m, 1.5H), 1.78-1.64 13 (m, 0.5H), 1.29-1.20 (m, 6H); C NMR (125 MHz, MeOH-d4): δ (ppm) 168.7, 168.3, 62.24, 62.18, 58.7, 58.5, 58.4, 58.3, + 48.70, 48.67, 48.5, 32.4, 32.1, 32.0, 13.9; HRMS (DART-Orbitrap) m/z: [M+H] Calcd for C14H25N2O4: 285.1809; Found: 285.1799. (5S, 5’S)-Diethyl 1, 1’-di(1H-pyrrole-2-carbonyl)-[3,3’-bipyrrolidine]-5,5’-dicarboxylate (18, mixture of diastereomers). To a flask charged with 16 (mixture of 16a-c, 9.4 g, 21. 3 mmol) and 17 (6.9 g, 53.0 mmol) in CH2Cl2 (210 mL) was added pyridine (20.5 mL) and DMAP (50 mg). The reaction mixture was stirred for 12 h, then quenched with 1 M HCl (1.0 mL). It was diluted with CHCl3 and separated. The organic layer was washed with water, saturated aqueous NaHCO3 and brine, dried over Na2SO4, concentrated in vacuo to give 18 as a tan solid (10.9 g, d.r.(18a:18b:18c) = 5.4 : 1 : 2.3) as determined by HPLC. The crude mixture was dried under high-vacuum (3 h) and suspended in anhydrous CHCl3 (50 mL). The precipitous mixture was cooled to −20 °C and stored overnight (12 h). The precipitate was separated by filtration to give approximately 1.8 g of 18c (18%, >90% purity) and an enriched filtrate containing 18a/18b/18c (5.3: 1:0.5). Concentration and drying of this filtrate provided the enriched mixture as a tan foam (8.8 g). While flash chromatography (SiO2, 99:1 to 49:1 CHCl3/MeOH) can provide pure 18a, 18b and 18c are always co-eluted. Moreover, the recovery is quite low (~20%), probably due to oxidative decomposition of the material on silica gel. For analytical purpose, part of the mixture was purified by preparative HPLC to give pure 18a, 18b and 18c. (3S,3’S,5S,5’S)-diethyl 1,1’-di(1H-pyrrole-2-carbonyl)-[3,3’-bipyrrolidine]-5,5’-dicarboxylate (18a): 1 H NMR (500 MHz, DMSO-d6): δ (ppm) 11.47 (bs, 2H), 6.93 (bs, 2H), 6.76 (bs, 2H), 6.18 (bs, 2H), 4.46-4.37 (m, 2H), 4.14-4.03 (m, 6H), 3.52-3.43 (m, 2H), 2.47-2.37 (m, 2H), 2.32-2.21 (m, 2H), 1.58-1.46 (m, 2H), 1.80 (t, J = 7.0 Hz, 6H); 13 C NMR (125 MHz, DMSO-d6): δ (ppm) 172.0, 159.9, 124.8, 122.0, 113.0, 109.0, 60.2, 59.8, 52.7, 42.0, 33.2, 14.1; LRMS + + (ESI-quadrupole) m/z: [M+H] Calcd for C24H31N4O6+H: 471.2; Found: 471.3. HRMS (DART-Orbitrap) m/z: [M+H] Calcd for C24H31N4O6: 471.2238; Found: 471.2227. (3R,3'R,5S,5'S)-diethyl 1,1'-di(1H-pyrrole-2-carbonyl)-[3,3'o 1 bipyrrolidine]-5,5'-dicarboxylate (18b): mp 126-129 C; H NMR (500 MHz, DMSO-d6): δ (ppm) 11.50 (bs, 2H), 6.93 (bs, 2H), 6.82 (bs, 2H), 6.18 (bs, 2H), 4.50 (d, J = 8.3 Hz, 2H), 4.16-4.04 (m, 6H), 3.57-3.49 (m, 2H), 2.41-2.32 (m, 2H), 13 2.06-1.94 (m, 4H), 1.20 (t, J = 7.1 Hz, 6H); C NMR (125 MHz, DMSO-d6): δ (ppm) 172.1, 159.7, 124.8, 122.0, 113.0, 109.1, + 60.3, 59.5, 51.9, 40.9, 32.3, 14.1; LRMS (ESI-quadrupole) m/z: [M+H] Calcd for C24H31N4O6 471.2; Found: 471.3. HRMS + (DART-Orbitrap) m/z: [M+H] Calcd for C24H31N4O6: 471.2238; Found: 471.2214. (3S,3'R,5S,5'S)-diethyl 1,1'-di(1H1 pyrrole-2-carbonyl)-[3,3'-bipyrrolidine]-5,5'-dicarboxylate (18c): H NMR (500 MHz, DMSO-d6): δ (ppm) 11.49 (bs, 1H), 11.46 (bs, 1H), 6.93 (bs, 2H), 6.77 (bs, 2H), 6.17 (bs, 2H), 4.52 (d, J = 9.1 Hz, 1H), 4.45-4.39 (m, 1H), 4.18-3.98 (m, 6H), 3.56-3.44 (m, 2H), 2.52-2.32 (m, 2H), 2.32-2.19 (m, 1H), 2.18-2.07 (m, 1H), 2.06-1.93 (m, 1H), 1.61-1.51 (m, 1H), 13 1.26-1.12 (m, 6H); C NMR (125 MHz, DMSO-d6): δ (ppm); 172.1, 171.9, 159.9, 159.7, 124.8 (2C), 122.0 (2C), 113.1, 112.9,

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109.1, 109.0, 60.3, 60.2, 60.0, 59.8, 52.5, 52.0, 42.2, 40.9, 33.3, 32.5, 14.1 (2C); HRMS (DART-Orbitrap) m/z: [M+H] Calcd for C24H31N4O6: 471.2238; Found: 471.2216.

+

One-pot procedure for autoxidation of 16. A flask was charged with 16 (6:1 mixture of 16a/16b, 1.5 g, 3.36 mmol) in dry DMF (18 mL), anhydrous K2CO3 (2.32 g, 16.8 mmol), and 4 Å MS powder (6.4 g) under argon. After 30 min, a solution of 17 (3.0 mL, 2.46 M in DMF, 7.38 mmol) was added dropwise at rt. The mixture was stirred for 80 min and HPLC analysis showed full conversion to N-acylpyrrole dimers 18a/b. A solution of guanidine (5.5 mL, 4.42 M in DMF, 24.3 mmol) was added and the mixture was stirred at rt for 20 min. The flask was then evacuated and an O2 ballon was attached. After stirred at rt for 30 min, the flask was evacuated and refilled with argon. The mixture was o o placed in a pre-heated oil-bath (90 C) and stirred for 11 min. It was cooled to 0 C and filtered through Celite to remove any inorganics. The filter cake was washed with DMF (2x) and the combined filtrate was concentrated in vacuo. The residue was redissolved in MeOH-10% TFA in water and purified by chromatography on C18. mPLC Conditions: Biotage Snap Ultra C18 column (60 g); solution A: H2O w/ 0.1% TFA and solution B: MeOH w/ 0.1% TFA; increase gradient of solution B from 0%, 0-3 min; 0-80%, 3-28 min. Flow rate 30 mL/min. The fractions containing the desired were combined, concentrated and lyophilized to give 19 as a yellow powder (mixture of diastereomers, 743 mg, 31% yield). For analytical purpose, part of the mixture was purified by preparative HPLC to give 1 20 pure 19a. [α]D + 4.8 (c 0.08, MeOH). H NMR (500 MHz,MeOH-d4): δ (ppm) 6.92 (s, 1H), 6.85 (s, 1H), 6.72 (d, J = 2.8 Hz, 1 H), 6.65 (d, J = 2.6 Hz, 1 H), 6.15 (dd, J = 3.0, 3.0 Hz, 1 H), 6.07(d, J = 3.1, 3.1 Hz, 1 H), 3.76 (dd, J = 14.1, 5.8 13 Hz, 1 H), 3.58 (dd, J = 14.0, 7.3Hz, 1 H), 3.35-3.30 (m, 1H), 3.18-3.12 (m, 1H), 2.65-2.54 (m, 2H), 2.45-2.35 (m, 1H); C NMR (125 MHz,MeOH-d4): 175.3, 163.1, 162.6, 158.2, 125.1, 124.6, 122.2, 121.6, 111.1, 110.4, 109.2, 108.8, 68.8, 49.1, 42.6, + 42.4, 42.3, 41.8; LRMS (ESI-quadrupole) m/z: [M+H] Calcd for C22H25N10O4: 493.2; Found: 493.0. HRMS (ESI-TOF) + m/z: [M+H] Calcd for C22H25N10O4: 493.2060; Found: 493.2047. Bromination of spirocycle 19: Spirocycle 19 (580 mg, mixture of diastereomers, 0.81 mmol) and bromodiethylsulfonium bromopentachloroantimonate (BDSB, 3.5 g, 6.4 mmol) was dissolved in CH3CN (48 mL). The mixture was stirred at rt for 1 h and judged complete by LCMS analysis. The reaction was quenched with aqueous Na2SO3 solution (50 mL, 1.4 w%) and stirred for 30 min. A saturated solution of NaHCO3 (50 mL) was added slowly. When bubbling ceased, the mixture was concentrated and lyophilized. The residue was mixed with MeOH-10% TFA in o water (1:1, 50 mL), sonicated for 10 min, and then stirred at 60 C for 30 min. The warm mixture was filtered. The solid was transferred to a flask and the above sonication-extraction process was repeated two more times. The combined filtrates were concentrated, dissolved in warm MeOH-20% TFA in water (1:3, 8 mL) and purified by chromatography on C18. LC Conditions: Biotage Snap Ultra C18 column (60 g); solution A: H2O w/ 0.1% TFA and solution B: MeOH w/ 0.1% TFA; increase of B from 0-30%, 0-3 min; 30-90%, 3-28 min. Flow rate 30 mL/min. The fractions containing the desired were combined, concentrated and lyophilized to give 28 as a yellow powder (mixture of diastereomers, 392 mg, 47% yield). Spectroscopic data of 28 is in agreement with those previously reported for the racemic compound (ref. 2b). 2b

Synthesis of aminoimidazole 29 from spirocycle 28: Following our previous procedure for preparing racemic 29, from spirocycle 28 (mixture of diatereomers, 590 mg, 0.57 mmmol) was obtained 29a (54 mg, 9.6%) and a mix2a ture of its diastereomers (epi-C10-, epi-C14, and epi-C10, C14- isomers that can be isomerized to 29a , 193 mg, 33%) after purification by chromatography on C18. LC Conditions: Biotage Snap Ultra C18 column (60 g); solution A: H2O w/ 0.1% TFA and solution B: MeOH w/ 0.1% TFA; increase of B from 0-10%, 2-3 min; 10-70%, 3-28 min. Flow rate 30 mL/min. The fractions containing the desired were combined, concentrated and purified again on the Biotage C18 column using the same gradient (solution B from 10-70%, 3-28 min). An analytical sample of 29a was obtained after purification by preparative HPLC. HPLC Conditions: Waters Xbridge RP18 column (5 μm, 19x250 mm) with UV detection at 280 nm; Solution A: H2O w/ 0.1% TFA and Solution B: CH3CN w/ 0.1% TFA; increase gradient of Solution 20 B from 10-12%, 0.5-2 min; 12-25%, 2-13min. Flow rate 20 mL/min. 29a: [α]D –25.6 (c 0.18, H2O). Spectroscopic data 2b of 29a is in agreement with those previously reported for the racemic compound . 2a

Synthesis of ageliferin from spirocycle 29a: Following our previous procedure for preparing racemic ageliferin , from spirocycle 29a (54 mg, 0.053 mmmol) was obtained 30 (23 mg, 0.026 mmol), which was submitted to TFAA/TFA to give (-)-ageliferin (1.5 mg) after HCl work up and purification by HPLC on C18 (twice). Spectroscopic 24 data of (-)-ageliferin is in agreement with those previously reported. (-)-Ageliferin: [α]D –16.0 (c 0.03, MeOH, 6b 25 TFA salt). Literature values: (-)-ageliferin: [α]D –10.0 (c 0.03, MeOH, TFA salt) ; (+)-ageliferin: [α]D + 4.1 (c 5d 33 5c 0.146, MeOH, HOAc salt) ; (+)-ageliferin: [α]D + 15.5 (c 0.11, MeOH, HCl salt) . ASSOCIATED CONTENT

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Supporting Information. Experimental procedures, X-ray crystallographic data including CIF files for 16c and 18b, and NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author * Email: [email protected] Present Addresses †Department of Chemistry, University of Utah, 315 S1400E, HEB 2020, Salt Lake City, UT 84112-0850. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work is supported by the Donald J. & Jane M. Cram Endowment, the Foote Family Endowment (fellowship to A.G.R.), and a major instrumentation grant from the National Science Foundation (CHE-1048804). We are grateful to Dr. Saeed Khan (UCLA) for X-ray crystallographic analyses. We thank Wenjing Wei and Linh Truong for experimental assistance. REFERENCES (1) (a) Ma, Z.; Wang, X.; Wang, X.; Rodriguez, R. A.; Moore, C. E.; Gao, S.; Tan, X.; Ma, Y.; Rheingold, A. L.; Baran, P. S.; Chen, C. Asymmetric Syntheses of Sceptrin and Massadine and Evidence for Biosynthetic Enantiodivergence. Science, 2014, 346, 219-224. (b) Seiple, I. B.; Su, S.; Young, I. S.; Nakamura, A.; Yamaguchi, J.; Jørgensen, L.; Rodriguez, R. A.; O’Malley, D. P.; Gaich, T.; Köck, M.; Baran, P. S. Enantioselective Total Syntheses of (−)-Palau’amine, (−)Axinellamines, and (−)-Massadines. J. Am. Chem. Soc. 2011, 133, 14710-14726 and references therein. (c) Ma, Z.; Wang, X.; Ma, Y.; Chen, C. Asymmetric Synthesis of Axinellamines A and B. Angew. Chem., Int. Ed. 2016, 55, 4763-4766. (d) Wang, X.; Ma, Z.; Wang, X.; De, S.; Ma, Y.; Chen, C. Dimeric Pyrrole–imidazole Alkaloids: Synthetic Approaches and Biosynthetic Hypotheses. Chem. Commun. 2014, 50, 8628-8639 and references therein. (e) Namba, K.; Takeuchi, K.; Kaihara, Y.; Oda, M.; Nakayama, A.; Nakayama, A.; Yoshida, M.; Tanino, K. Total Synthesis of Palau’amine. Nature Commun. 2015, 6, 9731/1-9731/9. (f ) Zancanella, M. A.; Romo, D. Facile Synthesis of the Trans-Fused Azabicyclo[3.3.0]octane Core of the Palau’amines and the Tricyclic Core of the Axinellamines from a Common Intermediate. Org. Lett. 2008, 10, 3685–3688. (g) Sivappa, R.; Hernandez, N. M.; He, Y.; Lovely, C. J. Studies toward the Total Synthesis of Axinellamine and Massadine. Org. Lett. 2007, 9, 3861–3864. (2) (a) Ding, H.; Roberts, A. G.; Harran, P. G. .Total Synthesis of Ageliferin via Acyl N-Amidinyliminium Ion Rearrangement. Chem. Sci. 2013, 4, 303-306. (b) Ding, H.; Roberts, A. G.; Harran, P. G. Synthetic (±)-Axinellamines Deficient in Halogen. Angew. Chem. Int. Ed. 2012, 51, 4340-4343. (c) Li, Q.; Hurley, P.; Ding, H.; Roberts, A. G.; Akella, R.; Harran, P. G. Exploring Symmetry-Based Logic for a Synthesis of Palau’amine. J. Org. Chem. 2009, 74, 5909-5919. (d) Garrido-Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li, Q.; Doundoulakis, T.; Harran, P. G. Spirocycloisomerization of Tethered Alkylidene Glycocyamidines: Synthesis of a Base Template Common to Palau’amine Family Alkaloids. Angew. Chem., Int. Ed. 2005, 44, 765-769. (3) Davin, L. B.; Wang, H.-B.; Crowell, A. L.; Bedgar, D. L.; Martin, D. M.; Sarkanen, S.; Lewis, N. G. Stereoselective Bimolecular Phenoxy Radical Coupling by an Auxiliary (dirigent) Protein Without an Active Center. Science, 1997, 275, 362-366. (4) Cafieri,F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. Dispacamides, Anti-histamine Alkaloids from Caribbean Agelas Sponges. Tetrahedron Lett. 1996, 37, 3587-3590. (5) Isolation of ageliferin: (a) Rinehart, K. L. Bioactive Metabolites from the Caribbean Sponge Agelas coniferin. US Pat., 4737510, April 12, 1988. (b)Rinehart, K. L. Biologically Active Marine Natural Products. Pure Appl. Chem., 1989, 61, 525-528. (c) Kobayashi, J.; Tsuda, H.; Murayama, T.; Nakamura, H.; Ohizumi, Y.; Ishibashi, M.; Iwamura, M. Ageliferins, Potent Actomyosin Atpase Activators from the Okinawan Marine Sponge Agelas sp. Tetrahedron, 1990, 46, 5579-5586. (d) Keifer, P. A.; Schwartz, R. E.; S. Koker, M. E.; Hughes, Jr.; Rittschof , R. G. D.; Rinehart, K. L. Bioactive Bromopyrrole Metabolites from the Caribbean Sponge Agelas conifer. J. Org. Chem., 1991, 56, 2965-2975. (6) Synthesis of ageliferin: (a) Wang X.; Ma, Z.; Lu, J.; Tan, X.; Chen, C. Asymmetric Synthesis of Ageliferin. J. Am. Chem. Soc. 2011, 133, 15350−15353. (b). Baran, P. S.; Li, K.; O’Malley, D. P.; Christos Mitsos, C. Short, Enantioselective Total Synthesis of Sceptrin and Ageliferin by Programmed Oxaquadricyclane Fragmentation. Angew. Chem. Int. Ed. 2006, 45, 249 –252. (c) Baran, P. S.; O’Malley, D. P.; Zografos, A. L. Sceptrin as a Potential Biosynthetic Precursor to Complex Pyrrole–Imidazole Alkaloids: The Total Synthesis of Ageliferin. Angew. Chem. Int. Ed. 2004, 43, 2674–2677. (d) Northrop, B. H.; O’Malley, D. P.; Zografos, A. L.; Baran, P. S.; Houk, K. N. Mechanism of the Vinylcyclobutane Rearrangement of Sceptrin to Ageliferin and Nagelamide E. Angew. Chem., Int. Ed. 2006, 45, 4126–4130.

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(7) (a) Vergne, C.; Appenzeller, J.; Ratinaud, C.; Martin, M.; Debitus, C.; Zaparucha, A.; Ali Al-Mourabit, A. Debromodispacamides B and D:  Isolation from the Marine Sponge Agelas mauritiana and Stereoselective Synthesis Using a Biomimetic Proline Route. Org. Lett. 2008, 10, 493-496; (b) Travert N.; Al-Mourabit, A. A Likely Biogenetic Gateway Linking 2-Aminoimidazolinone Metabolites of Sponges to Proline:  Spontaneous Oxidative Conversion of the Pyrrole-Proline-Guanidine Pseudo-peptide to Dispacamide A. J. Am. Chem. Soc. 2004, 126, 10252-10253. (8) Franca, Z.; Andrea, S.; Claudio, C.; Lucia, B.; Gloria, R.; Giuseppe, N.; Giovanni, C. Diastereoselective Synthesis of 4,5‘-Bis-proline Compounds via Reductive Dimerization of N-Acyloxyiminium Ions. J. Org. Chem. 2007, 72, 18141817. (9) (a) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides. Org. Lett. 2011, 13, 2138-2141; (b) Prinsell, M. R.; Everson, D. A.; Weix, D. J. Nickel-catalyzed, sodium iodidepromoted reductive dimerization of alkyl halides, alkyl pseudohalides, and allylic acetates. Chem. Comm. 2010, 46, 5743-5745; (c) Goldup, S. M.; Leigh, D. A.; McBurney, R. T.; McGonigal, P. R.; Plant, A. Ligand-assisted Nickelcatalysed sp3–sp3 Homocoupling of Unactivated Alkyl Bromides and Its Application to the Active Template Synthesis of Rotaxanes. Chem. Sci. 2010, 1, 383-386. (10) Eswar Bhimireddy, E.; Corey, E. J. Method for Highly Enantioselective Ligation of Two Chiral C(sp3) Stereocenters. J. Am. Chem. Soc. 2017, 139, 11044–11047. (11) When 14 was treated with Zn / CuI in phosphate buffer, dimers 15 were obtained in ~20% yield along with 50% yield of N-Z-L-proline ethyl ester. For Zn-mediated dimerization of alkyl bromides, see: De Sá, A. C. P. F.; Pontes, G. M. A.; dos Anjos, J. A. L.; Santana, S. A.; Bieber, L. W.; Malvestiti, I. Reductive coupling reaction of benzyl, allyl and alkyl halides in aqueous medium promoted by zinc. J. Braz. Chem. Soc. 2003, 14, 429-434. For a review see: Lucas, E. L.; Jarvo, E. R. Stereospecific and Stereoconvergent Cross-couplings between Alkyl electrophiles. Nat. Rev. Chem. 2017, 1, 0065/1-7. (12) The PyBOX ligand sphere was important in this chemistry, while the chirality of the ligand was not. We Found no set of conditions where the asymmetry of the ligand governed relative diastereoselectivity observed in the reactions. See Table S1 in SI for a survey of attempts. (13) Boatman, R. J.; Whitlock, H. W. Some Novel Reactions of Pyrrolecarboxylic Acid Chlorides. J. Org. Chem., 1976, 41, 3050–3051. (14) Seipp, C. A.; Williams, N.; Kidder, M. K.; Custelcean, R. CO2 Capture from Ambient Air by Crystallization with a Guanidine Sorbent. Angew. Chem., Int. Ed. 2017, 56, 1042-1045. (15) Yamada, T.; Liu, X.; Englert, U.; Yamane, H.; Dronskowski, R. Solid-State Structure of Free Base Guanidine Achieved at Last. Chem. Eur. J. 2009, 15, 5651 – 5655. (16) Ginanneschi, M.; Chelli, M.; Rapi, G. Action of Hydrogen Peroxide on Some 2-Aminooxazoles and Imidazolin2-ones. Isolation of Hydroperoxyimidazolidin-2-ones. J. Heterocyclic Chem. 1985, 22, 1675-1678. (17) Snyder S. A.; Treitler, D. S. Et2SBr⋅SbCl5Br: An Effective Reagent for Direct Bromonium-Induced Polyene Cyclizations. Angew. Chem., Int. Ed. 2009, 48, 7899-7903.

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TOC: Cascading auto-oxidative biproline guanylations form optically active dispacamide dimers

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