Four Routes to 3-(3-Methoxy-1,3-dioxopropyl)pyrrole, a Core Motif of Rings C and E in Photosynthetic Tetrapyrroles

The photosynthetic tetrapyrroles share a common structural feature comprised of a β-ketoester motif embedded in an exocyclic ring (ring E). As part of a total synthesis program aimed at preparing native structures and analogues, 3-(3-methoxy-1,3-dioxopropyl)pyrrole was sought. The pyrrole is a precursor to analogues of ring C and the external framework of ring E. Four routes were developed. Routes 1–3 entail a Pd-mediated coupling process of a 3-iodopyrrole with potassium methyl malonate, whereas route 4 relies on electrophilic substitution of TIPS-pyrrole with methyl malonyl chloride. Together, the four routes afford considerable latitude. A long-term objective is to gain the capacity to create chlorophylls and bacteriochlorophylls and analogues thereof by facile de novo means for diverse studies across the photosynthetic sciences.


Introduction
Photosynthetic tetrapyrroles harvest sunlight and thereby channel the energy that drives the biosphere, yet the chemical synthesis of such molecules-an enabling methodology for diverse studies-has largely been neglected [1]. While the structures within the family of bacteriochlorophylls and chlorophylls vary in terms of the extent of saturation and nature of peripheral substituents [2], selected structural motifs are constant across the family. One example in this regard is the fifth ring, known equivalently as ring E, the exocyclic ring, or the isocyclic ring. The structures of bacteriochlorophyll a and chlorophyll a, the chief pigments of anoxygenic and oxygenic photosynthesis, respectively, are shown in Chart 1.
We are working toward synthetic strategies that provide access to the entire suite of native photosynthetic tetrapyrroles as well as synthetic analogues [3][4][5][6][7][8]. The general route under development is shown in Scheme 1 panel a. An AD-half and a BC-half undergo Knoevenagel condensation [9] to form the corresponding Knoevenagel enone. The enone then undergoes a double-ring closure process via Nazarov cyclization [10] (forming ring E), electrophilic aromatic substitution (S E Ar, forming the macrocycle), and elimination of methanol, giving the aromatic macrocycle. The conditions for the Knoevenagel condensation entail 40 mM reactants (AD-half, BC-half) in acetonitrile containing piperidine, acetic acid, and molecular sieves at room temperature (overnight). The recently optimized conditions [7] for the one-flask, double-ring closure entail 0.20 mM reactant (Knoevenagel enone) in acetonitrile containing Yb(OTf) 3 at 80 • C (4 h). The Knoevenagel condensation and the double-ring closure process each affords a yield of ≈50%. To date, eight bacteriochlorophyll analogues have been prepared in this general manner, as shown in Scheme 1 panel b [3,[5][6][7]. Three chlorophyll analogues also have been prepared by employing a dipyrromethane BC-half (not shown) [4]. manner, as shown in Scheme 1 panel b [3,[5][6][7]. Three chlorophyll analogues also have been prepared by employing a dipyrromethane BC-half (not shown) [4]. Chart 1. Representative photosynthetic tetrapyrroles (a) and pyrrole-β-ketoesters (b). Scheme 1. Retrosynthesis for bacteriochlorophylls and analogues (a), with omission of substituents for clarity. Macrocycles prepared in this manner (b).
In early synthetic routes toward native photosynthetic tetrapyrroles and analogues thereof, formation of ring E presented a challenge that was met by annulation of an intact macrocycle [11]. In the route shown in Scheme 1, ring E is formed in a process integral to macrocycle formation. The nascent ring E is the nexus for macrocycle formation, and the β-ketoester attached to ring C is the linchpin. The β-ketoester motif at the 3-position Chart 1. Representative photosynthetic tetrapyrroles (a) and pyrrole-β-ketoesters (b).
Scheme 1. Retrosynthesis for bacteriochlorophylls and analogues (a), with omission of substituents for clarity. Macrocycles prepared in this manner (b).
In early synthetic routes toward native photosynthetic tetrapyrroles and analogues thereof, formation of ring E presented a challenge that was met by annulation of an intact macrocycle [11]. In the route shown in Scheme 1, ring E is formed in a process integral to macrocycle formation. The nascent ring E is the nexus for macrocycle formation, and the β-ketoester attached to ring C is the linchpin. The β-ketoester motif at the 3-position In early synthetic routes toward native photosynthetic tetrapyrroles and analogues thereof, formation of ring E presented a challenge that was met by annulation of an intact macrocycle [11]. In the route shown in Scheme 1, ring E is formed in a process integral to macrocycle formation. The nascent ring E is the nexus for macrocycle formation, and the β-ketoester attached to ring C is the linchpin. The β-ketoester motif at the 3-position participates in both Knoevenagel and Nazarov reactions to form ring E in a double-ring closure process [3,[5][6][7][8]. Hence, access to diverse β-ketoester-bearing ring C precursors is an important sub-objective of the overall synthesis program.
Molecules 2023, 28, 1323 3 of 16 We recently described the synthesis of 3-(3-methoxy-1,3-dioxopropyl)-4-methylpyrrole (I) [4], a precursor to native ring C that bears the requisite β-ketoester motif (Chart 1). For fundamental studies of the core chromophores undecorated with peripheral substituents [11], we sought the analogue of I that lacks the 4-methyl substituent (3). A single methyl group can increase the reactivity of a pyrrole toward electrophiles by ≈30fold [12,13]. On the other hand, sparsely substituted tetrapyrroles often exhibit spectral features altered from those of the native macrocycles (vide infra), and the open β-pyrrole positions provide sites for unwanted reactivity [14].
Inspection of the macrocycles that we have prepared to date shows some control over the presence of the substituent at the 12-position (Scheme 1, panel b) and might suggest the issue of the 12-H or 12-Me group is a settled matter. The development of the route initially employed a gem-dimethyl group in each pyrroline ring in lieu of the nativetrans-dialkyl group (Scheme 1, panel b). Each BC-half bearing a gem-dimethyl group was synthesized by installation of the β-ketoester motif in a fairly late-stage, Pd-mediated coupling process [3,4,8]. In contrast, the presently envisaged synthesis of a BC-half bearing a native-trans-dialkyl group requires early installation of the β-ketoester motif.
In this paper, we report four routes to 3. Routes 1-3 entail a Pd-mediated coupling process of a 3-iodopyrrole with potassium methyl malonate, whereas route 4 relies on electrophilic substitution of TIPS-pyrrole with methyl malonyl chloride. The various routes afford considerable latitude depending on available starting materials, desired yield, and other constraints. As part of this Special Issue on Macrocycles, we also outline some of the motivations for the preparation of tailored bacteriochlorophylls and chlorophylls, particularly sparsely substituted macrocycles that would make use of pyrrole 3.

Reconnaissance
Pyrrole 3 has been employed in studies of Knoevenagel condensation and subsequent Nazarov reaction, but without experimental procedures, characterization data, or information about scale. Two routes have been alluded to for the preparation of 3 (Scheme 2) [15,16].
participates in both Knoevenagel and Nazarov reactions to form ring E in a double-ring closure process [3,[5][6][7][8]. Hence, access to diverse β-ketoester-bearing ring C precursors is an important sub-objective of the overall synthesis program.
We recently described the synthesis of 3-(3-methoxy-1,3-dioxopropyl)-4methylpyrrole (I) [4], a precursor to native ring C that bears the requisite β-ketoester motif (Chart 1). For fundamental studies of the core chromophores undecorated with peripheral substituents [11], we sought the analogue of I that lacks the 4-methyl substituent (3). A single methyl group can increase the reactivity of a pyrrole toward electrophiles by ≈30fold [12,13]. On the other hand, sparsely substituted tetrapyrroles often exhibit spectral features altered from those of the native macrocycles (vide infra), and the open β-pyrrole positions provide sites for unwanted reactivity [14].
Inspection of the macrocycles that we have prepared to date shows some control over the presence of the substituent at the 12-position (Scheme 1, panel b) and might suggest the issue of the 12-H or 12-Me group is a settled matter. The development of the route initially employed a gem-dimethyl group in each pyrroline ring in lieu of the native transdialkyl group (Scheme 1, panel b). Each BC-half bearing a gem-dimethyl group was synthesized by installation of the β-ketoester motif in a fairly late-stage, Pd-mediated coupling process [3,4,8]. In contrast, the presently envisaged synthesis of a BC-half bearing a native-trans-dialkyl group requires early installation of the β-ketoester motif.
In this paper, we report four routes to 3. Routes 1-3 entail a Pd-mediated coupling process of a 3-iodopyrrole with potassium methyl malonate, whereas route 4 relies on electrophilic substitution of TIPS-pyrrole with methyl malonyl chloride. The various routes afford considerable latitude depending on available starting materials, desired yield, and other constraints. As part of this Special Issue on Macrocycles, we also outline some of the motivations for the preparation of tailored bacteriochlorophylls and chlorophylls, particularly sparsely substituted macrocycles that would make use of pyrrole 3.

Reconnaissance
Pyrrole 3 has been employed in studies of Knoevenagel condensation and subsequent Nazarov reaction, but without experimental procedures, characterization data, or information about scale. Two routes have been alluded to for the preparation of 3 (Scheme 2) [15,16]. Malona et al., referring to general procedures of others [17,18], indicated that pyrrole-3-carboxylic acid (II) was converted to the acid chloride, which upon reaction with the Malona et al., referring to general procedures of others [17,18], indicated that pyrrole-3carboxylic acid (II) was converted to the acid chloride, which upon reaction with the enolate of methyl acetate affords 3 (Scheme 2) [15]. Subsequent Knoevenagel condensation [19] with butanal gave III. Fujiwara et al. reported a specific procedure for 2-acetylpyrrole, which was then employed for reaction of 3-acetylpyrrole (IV) [16]. Thus, the enolate of 3-acetylpyrrole (IV) was reacted with dimethyl carbonate to obtain 3 [16], which upon subsequent Knoevenagel condensation with benzaldehyde gave V [16]. The overall yield in the two-step process was 35%. In neither case were specific experimental procedures, yield values, or characterization data provided for 3. The chief focus of the two research groups was to probe the Nazarov reactions with a variety of heterocycles [15] or to examine diverse catalysts [16]; in each case, extensive studies were reported with 2-substituted pyrroles, whereas 3 was used in only a single instance. The 3-substituted pyrroles II and IV are ≈30 and ≈300 times more expensive than the 2-substituted pyrroles, respectively, which may have influenced the choice of substrates for investigation.

Synthetic Routes to a Pyrrole-β-Ketoester
Route 1 begins with commercially available 1-(triisopropylsilyl)pyrrole (1-TIPS) [20], which upon treatment with N-iodosuccinimide (NIS) in anhydrous CHCl 3 afforded βiodopyrrole 2-TIPS in 80% yield (Scheme 3, blue arrow). The compound 2-TIPS has been prepared previously from 1-TIPS at large scale by bromo-lithium exchange [20], use of I 2 [21], and use of NIS in acetone [22]. Our prior studies [4] showed that a Bocprotected halopyrrole is superior to a TIPS-protected halopyrrole in carbonylation to install the β-ketoester group. Thus, treatment of 2-TIPS with tetra-n-butylammonium fluoride (TBAF) followed by tert-butoxycarbonyl anhydride [(Boc) 2 O] and a catalytic amount of 4-dimethylaminopyridine (DMAP) gave the known [23,24] Boc-protected analogue 2-Boc in 75% yield. Note that the unmasked 3-iodopyrrole was quite unstable (toward light, air, moisture, and acid) and began to decompose shortly after purification, consistent with the general sensitivity of halopyrroles [25]. The TIPS/Boc protecting group not only afforded excellent selectivity of halogenation and carbonylation but also increased the stability and scalability for manipulation of this type of compound. enolate of methyl acetate affords 3 (Scheme 2) [15]. Subsequent Knoevenagel condensation [19] with butanal gave III. Fujiwara et al. reported a specific procedure for 2-acetylpyrrole, which was then employed for reaction of 3-acetylpyrrole (IV) [16]. Thus, the enolate of 3acetylpyrrole (IV) was reacted with dimethyl carbonate to obtain 3 [16], which upon subsequent Knoevenagel condensation with benzaldehyde gave V [16]. The overall yield in the two-step process was 35%. In neither case were specific experimental procedures, yield values, or characterization data provided for 3. The chief focus of the two research groups was to probe the Nazarov reactions with a variety of heterocycles [15] or to examine diverse catalysts [16]; in each case, extensive studies were reported with 2substituted pyrroles, whereas 3 was used in only a single instance. The 3-substituted pyrroles II and IV are ≈30 and ≈300 times more expensive than the 2-substituted pyrroles, respectively, which may have influenced the choice of substrates for investigation.

Synthetic Routes to a Pyrrole-β-Ketoester
Route 1 begins with commercially available 1-(triisopropylsilyl)pyrrole (1-TIPS) [20], which upon treatment with N-iodosuccinimide (NIS) in anhydrous CHCl3 afforded βiodopyrrole 2-TIPS in 80% yield (Scheme 3, blue arrow). The compound 2-TIPS has been prepared previously from 1-TIPS at large scale by bromo-lithium exchange [20], use of I2 [21], and use of NIS in acetone [22]. Our prior studies [4] showed that a Boc-protected halopyrrole is superior to a TIPS-protected halopyrrole in carbonylation to install the βketoester group. Thus, treatment of 2-TIPS with tetra-n-butylammonium fluoride (TBAF) followed by tert-butoxycarbonyl anhydride [(Boc)2O] and a catalytic amount of 4dimethylaminopyridine (DMAP) gave the known [23,24] Boc-protected analogue 2-Boc in 75% yield. Note that the unmasked 3-iodopyrrole was quite unstable (toward light, air, moisture, and acid) and began to decompose shortly after purification, consistent with the general sensitivity of halopyrroles [25]. The TIPS/Boc protecting group not only afforded excellent selectivity of halogenation and carbonylation but also increased the stability and scalability for manipulation of this type of compound. The installation of the β-ketoester relies on a known reaction of an aryl halide and potassium monomethyl malonate [26] that we have used previously with other pyrroles [3][4][5]8].
Route 2 employs the palladium-mediated carbonylation of 2-TIPS to install the βketoester motif. Following workup, cleavage of the TIPS group by treatment with TBAF afforded the desired compound 3 in 29% yield (Scheme 3, red arrow).
Route 3 affords a simplification of route 2. Routes 1 and 2 both employed Co 2 (CO) 8 as a source of carbon monoxide. Carbon monoxide is essential as the carbon constitutes the carbonyl that is attached to the pyrrole 3-position [26]. Upon use of CO gas instead of Co 2 (CO) 8 under the same conditions for carbonylative coupling of 2-TIPS with potassium monomethyl malonate [26], we were surprised to find that the target compound 3 formed directly in 43% yield. We have no explanation for this observation, but the higher yield, avoidance of the costly reagents Co 2 (CO) 8 and TBAF, and lack of a second workup procedure collectively comprise a serendipitous finding.
Route 4 arose from a desire for even greater simplicity. Friedel-Crafts acylation [27] of pyrrole 1-TIPS was carried out with methyl malonyl chloride in 1,2-dichloroethane containing AlCl 3 (Scheme 4). The conditions are very similar to those of Bray et al. [21], who reported the Friedel-Crafts acylation of pyrrole 1-TIPS with a variety of acylating agents. Subsequent treatment to TBAF in refluxing THF gave the desired pyrrole 3 along with the 2-substituted isomer 4, a known [15,16,28] compound. In one preparation (12 mmol of 1-TIPS), the respective yields were 15% and 14%. In a second preparation (100 mmol of 1-TIPS), the respective yields were 7% (1.10 g) and 36% (6.16 g). The two isomers were readily separable by column chromatography, evidenced by the clean separation on thin layer chromatography (TLC) (R f = 0.21 and 0.42 with hexanes/ethyl acetate (1:1) on silica). The latter preparation was repeated once, with identical results.
Route 2 employs the palladium-mediated carbonylation of 2-TIPS to install the βketoester motif. Following workup, cleavage of the TIPS group by treatment with TBAF afforded the desired compound 3 in 29% yield (Scheme 3, red arrow).
Route 3 affords a simplification of route 2. Routes 1 and 2 both employed Co2(CO)8 as a source of carbon monoxide. Carbon monoxide is essential as the carbon constitutes the carbonyl that is attached to the pyrrole 3-position [26]. Upon use of CO gas instead of Co2(CO)8 under the same conditions for carbonylative coupling of 2-TIPS with potassium monomethyl malonate [26], we were surprised to find that the target compound 3 formed directly in 43% yield. We have no explanation for this observation, but the higher yield, avoidance of the costly reagents Co2(CO)8 and TBAF, and lack of a second workup procedure collectively comprise a serendipitous finding.
Route 4 arose from a desire for even greater simplicity. Friedel-Crafts acylation [27] of pyrrole 1-TIPS was carried out with methyl malonyl chloride in 1,2-dichloroethane containing AlCl3 (Scheme 4). The conditions are very similar to those of Bray et al. [21], who reported the Friedel-Crafts acylation of pyrrole 1-TIPS with a variety of acylating agents. Subsequent treatment to TBAF in refluxing THF gave the desired pyrrole 3 along with the 2-substituted isomer 4, a known [15,16,28] compound. In one preparation (12 mmol of 1-TIPS), the respective yields were 15% and 14%. In a second preparation (100 mmol of 1-TIPS), the respective yields were 7% (1.10 g) and 36% (6.16 g). The two isomers were readily separable by column chromatography, evidenced by the clean separation on thin layer chromatography (TLC) (Rf = 0.21 and 0.42 with hexanes/ethyl acetate (1:1) on silica). The latter preparation was repeated once, with identical results. The formation of the 2-substituted isomer (4) was surprising because the TIPS group is designed to block reaction by steric hindrance at the 2-position, causing reaction to proceed preferentially at the 3-position. Several experiments were carried out to explore this result.


First, treatment of pyrrole with methyl malonyl chloride in the presence of AlCl3 in 1,2-dichloroethane at 0 °C to room temperature for 3 h gave the 2-substituted isomer (4) in 30% isolated yield.  Second, Bray and coworkers [21] reported that TIPS-pyrrole would react with potent acyl electrophiles in the absence of a Lewis acid. In our hands, the reaction of 1-TIPS with methyl malonyl chloride in 1,2-dichloroethane containing pyridine at 0 °C to reflux for 24 h gave two unknown products. The formation of the 2-substituted isomer (4) was surprising because the TIPS group is designed to block reaction by steric hindrance at the 2-position, causing reaction to proceed preferentially at the 3-position. Several experiments were carried out to explore this result.

•
First, treatment of pyrrole with methyl malonyl chloride in the presence of AlCl 3 in 1,2-dichloroethane at 0 • C to room temperature for 3 h gave the 2-substituted isomer (4) in 30% isolated yield. • Second, Bray and coworkers [21] reported that TIPS-pyrrole would react with potent acyl electrophiles in the absence of a Lewis acid. In our hands, the reaction of 1-TIPS with methyl malonyl chloride in 1,2-dichloroethane containing pyridine at 0 • C to reflux for 24 h gave two unknown products. • Third, the same reaction of 1-TIPS with methyl malonyl chloride in nitromethane containing one of several Lewis acids also afforded 4 as the only product detectable by 1 H-NMR spectroscopy. The Lewis acids were those identified in reactions of heterocycles [29], namely, Ga(OTf) 3 , Yb(OTf) 3 , and Hf(OTf) 3 . The results indicated that the TIPS group had been removed during the course of the reaction, without any treatment with a fluoride reagent, stemming most likely from chloride liberated during the course of the reaction.
• Fourth, we again treated 1-TIPS with methyl malonyl chloride in 1,2-dichloroethane containing AlCl 3 (Scheme 5). The two products isolated were 3-TIPS and 4; thus, 3acylation occurred with the TIPS group intact, whereas it is most likely that 2-acylation occurred following the adventitious loss of the TIPS group. The subsequent treatment with TBAF, as shown in Scheme 4, then is only required for the conversion of 3-TIPS to the pyrrole 3. To achieve a higher yield in the acylation of 3-TIPS will require identification of reaction conditions wherein the TIPS group remains intact, thereby thwarting 2-acylation. Regardless, route 4 as is remains the most expeditious among the four routes examined. The synthesis of 3-TIPS was achieved by independent means, as described in the next section.
 Third, the same reaction of 1-TIPS with methyl malonyl chloride in nitromethane containing one of several Lewis acids also afforded 4 as the only product detectable by 1 H-NMR spectroscopy. The Lewis acids were those identified in reactions of heterocycles [29], namely, Ga(OTf)3, Yb(OTf)3, and Hf(OTf)3. The results indicated that the TIPS group had been removed during the course of the reaction, without any treatment with a fluoride reagent, stemming most likely from chloride liberated during the course of the reaction.  Fourth, we again treated 1-TIPS with methyl malonyl chloride in 1,2-dichloroethane containing AlCl3 (Scheme 5). The two products isolated were 3-TIPS and 4; thus, 3acylation occurred with the TIPS group intact, whereas it is most likely that 2acylation occurred following the adventitious loss of the TIPS group. The subsequent treatment with TBAF, as shown in Scheme 4, then is only required for the conversion of 3-TIPS to the pyrrole 3. To achieve a higher yield in the acylation of 3-TIPS will require identification of reaction conditions wherein the TIPS group remains intact, thereby thwarting 2-acylation. Regardless, route 4 as is remains the most expeditious among the four routes examined. The synthesis of 3-TIPS was achieved by independent means, as described in the next section.

Structural Studies
The identities of 3 and 4 are readily distinguished by 1 H-NMR spectroscopy. The 1 H-NMR spectra in CDCl3 are shown in Figure 1.

Structural Studies
The identities of 3 and 4 are readily distinguished by 1 H-NMR spectroscopy. The 1 H-NMR spectra in CDCl 3 are shown in Figure 1.
by H-NMR spectroscopy. The Lewis acids were those identified in reactions of heterocycles [29], namely, Ga(OTf)3, Yb(OTf)3, and Hf(OTf)3. The results indicated that the TIPS group had been removed during the course of the reaction, without any treatment with a fluoride reagent, stemming most likely from chloride liberated during the course of the reaction.  Fourth, we again treated 1-TIPS with methyl malonyl chloride in 1,2-dichloroethane containing AlCl3 (Scheme 5). The two products isolated were 3-TIPS and 4; thus, 3acylation occurred with the TIPS group intact, whereas it is most likely that 2acylation occurred following the adventitious loss of the TIPS group. The subsequent treatment with TBAF, as shown in Scheme 4, then is only required for the conversion of 3-TIPS to the pyrrole 3. To achieve a higher yield in the acylation of 3-TIPS will require identification of reaction conditions wherein the TIPS group remains intact, thereby thwarting 2-acylation. Regardless, route 4 as is remains the most expeditious among the four routes examined. The synthesis of 3-TIPS was achieved by independent means, as described in the next section.

Structural Studies
The identities of 3 and 4 are readily distinguished by 1 H-NMR spectroscopy. The 1 H-NMR spectra in CDCl3 are shown in Figure 1.  Each pyrrole contains three C-H bonds and shows three multiplets (Figure 1). The wide chemical shifts of three protons provide a clear distinction and basis for structural assignment. The assignments for 4 were based on COSY measurements (H 4 ) and NOESY measurements (H 3 interaction with the ketoester methylene moiety). The assignments for 3 were based exclusively on NOESY measurements for H 2 (interaction with the ketoester methylene moiety and with the N-H proton) and H 5 (interaction with the N-H proton), with H 4 assigned by difference. The chemical shift of the N-H proton, while less reliable, was at 8.7, 9.0, or 9.1 ppm for 3 (three samples) versus ≈9.8 ppm for 4. The clear distinctions in spectra make disambiguation of the two isomers clear.
The target compound 3 is an oil at room temperature. The Pd-mediated carbonylation of 2-TIPS was carried out using Co 2 (CO) 8 but without subsequent treatment with TBAF ( Figure 2). The TIPS derivative 3-TIPS was isolated as a solid at room temperature (m.p. 76-78 • C). A single-crystal X-ray crystallographic structure was obtained, verifying formation of the β-ketoester scaffold (Figure 2). The size of the TIPS group is comparable to that of the pyrrole-β-ketoester. The structure clearly shows the hindrance by the TIPS group imparted to the 2,5-positions versus the 3,4-positions of the pyrrole molecule. Additional X-ray crystallographic data are provided in the Supplementary Materials. wide chemical shifts of three protons provide a clear distinction and basis for structural assignment. The assignments for 4 were based on COSY measurements (H 4 ) and NOESY measurements (H 3 interaction with the ketoester methylene moiety). The assignments for 3 were based exclusively on NOESY measurements for H 2 (interaction with the ketoester methylene moiety and with the N-H proton) and H 5 (interaction with the N-H proton), with H 4 assigned by difference. The chemical shift of the N-H proton, while less reliable, was at 8.7, 9.0, or 9.1 ppm for 3 (three samples) versus ≈9.8 ppm for 4. The clear distinctions in spectra make disambiguation of the two isomers clear.
The target compound 3 is an oil at room temperature. The Pd-mediated carbonylation of 2-TIPS was carried out using Co2(CO)8 but without subsequent treatment with TBAF ( Figure 2). The TIPS derivative 3-TIPS was isolated as a solid at room temperature (m.p. 76-78 °C). A single-crystal X-ray crystallographic structure was obtained, verifying formation of the β-ketoester scaffold (Figure 2). The size of the TIPS group is comparable to that of the pyrrole-β-ketoester. The structure clearly shows the hindrance by the TIPS group imparted to the 2,5-positions versus the 3,4-positions of the pyrrole molecule. Additional X-ray crystallographic data are provided in the Supplementary Materials.

Discussion
In this section, we first compare the four routes explored herein for the synthesis of 3. We then turn to consider part of the rationale for the de novo synthesis of analogues of native bacteriochlorophylls and chlorophylls.

Comparison of Routes
A long-term objective is to establish synthetic methodology that enables access to native photosynthetic macrocycles and analogues. Such syntheses present a significant number of challenges beyond obvious issues of achieving the desired patterns of substituents, stereochemistry, and pyrrole versus pyrroline rings. One challenge is scale: we seek ≥ 5 mmol of each precursor to rings A-D, 0.5 mmol of each AD-half and BC-half,

Discussion
In this section, we first compare the four routes explored herein for the synthesis of 3. We then turn to consider part of the rationale for the de novo synthesis of analogues of native bacteriochlorophylls and chlorophylls.

Comparison of Routes
A long-term objective is to establish synthetic methodology that enables access to native photosynthetic macrocycles and analogues. Such syntheses present a significant number of challenges beyond obvious issues of achieving the desired patterns of substituents, stereochemistry, and pyrrole versus pyrroline rings. One challenge is scale: we seek ≥ 5 mmol of each precursor to rings A-D, 0.5 mmol of each AD-half and BC-half, and 0.05 mmol of each target macrocycle. A second challenge is efficacy: we seek procedures such that a skilled investigator, with individual A-D ring precursors in hand, can create one macrocycle in one month.
The four routes described here afford considerable latitude in choice of synthetic approach to a precursor to an analogue of ring C. Conversion of pyrrole 1-TIPS to 3 could be achieved in four steps in 42% yield (route 1), in three steps in 23% yield (route 2), and in two steps via the intermediacy of 2-TIPS in 34% yield (route 3). Routes 1-3 rely on the intermediacy of 2-TIPS. The conversion of pyrrole 1-TIPS to 3 was obtained in two steps in 7 or 15% yield (route 4) without the intermediacy of 2-TIPS and the use of a Pd-mediated coupling reaction. Route 4 places expediency over elegance yet readily afforded 1.1 g (6.6 mmol) of 3. The use of Friedel-Crafts acylation in route 4 harkens back to an era of organic chemistry that long predates the use of Pd-mediated coupling reactions, but is attractive in its simplicity and efficacy. Facile access to >5 mmol of 3 satisfies the objective for extension to the synthesis of native photosynthetic tetrapyrroles and analogues.

Perspective on Design
The proper functioning of bacteriochlorophylls and chlorophylls in native photosynthetic machinery requires appropriate energetic features of each macrocycle. The energetics comes in two flavors: (1) An appropriate position of the long-wavelength absorption band of each macrocycle, which in large part determines the excited-state energy level. Control of the latter parameter is essential for flow of excited-state energy in the antennas and from the antenna to the reaction centers. (2) An appropriate level of the highest-occupied molecular orbital (HOMO) and lowest-unoccupied molecular orbital (LUMO) for those molecules to facilitate, or preclude, electron-transfer processes. The electron transfer from one photosynthetic pigment to another generates a hole in the HOMO of the donor and single occupancy of the former LUMO of the acceptor. Control over redox potentials is essential for efficient charge-separation processes.
The absorption spectra of two native photosynthetic tetrapyrrole macrocycles, bacteriopheophytin a and pheophytin a (where "pheo" implies the free base macrocycle), are shown in Figure 3. The spectra are compared with those of core macrocycles that lack any substituents other than a gem-dimethyl group in each pyrroline ring, namely, the chlorin H 2 C [30] and the bacteriochlorin H 2 BC [31]. The structures of the four macrocycles are shown in Chart 2. The core macrocycles lack ring E. The parameters corresponding to the spectra are listed in Table 1. The parameters for each band include the position of wavelength maximum (λ abs , in nm), the full-width-at-half-maximum (fwhm, in nm), and molar absorption coefficient (ε, in M −1 cm −1 ). The spectra were obtained from the literature [30][31][32][33]. The spectra of additional native and synthetic macrocycles are available in PhotochemCAD [33][34][35]. and 0.05 mmol of each target macrocycle. A second challenge is efficacy: we seek procedures such that a skilled investigator, with individual A-D ring precursors in hand, can create one macrocycle in one month.
The four routes described here afford considerable latitude in choice of synthetic approach to a precursor to an analogue of ring C. Conversion of pyrrole 1-TIPS to 3 could be achieved in four steps in 42% yield (route 1), in three steps in 23% yield (route 2), and in two steps via the intermediacy of 2-TIPS in 34% yield (route 3). Routes 1-3 rely on the intermediacy of 2-TIPS. The conversion of pyrrole 1-TIPS to 3 was obtained in two steps in 7 or 15% yield (route 4) without the intermediacy of 2-TIPS and the use of a Pdmediated coupling reaction. Route 4 places expediency over elegance yet readily afforded 1.1 g (6.6 mmol) of 3. The use of Friedel-Crafts acylation in route 4 harkens back to an era of organic chemistry that long predates the use of Pd-mediated coupling reactions, but is attractive in its simplicity and efficacy. Facile access to >5 mmol of 3 satisfies the objective for extension to the synthesis of native photosynthetic tetrapyrroles and analogues.

Perspective on Design
The proper functioning of bacteriochlorophylls and chlorophylls in native photosynthetic machinery requires appropriate energetic features of each macrocycle. The energetics comes in two flavors: (1) An appropriate position of the long-wavelength absorption band of each macrocycle, which in large part determines the excited-state energy level. Control of the latter parameter is essential for flow of excited-state energy in the antennas and from the antenna to the reaction centers. (2) An appropriate level of the highest-occupied molecular orbital (HOMO) and lowest-unoccupied molecular orbital (LUMO) for those molecules to facilitate, or preclude, electron-transfer processes. The electron transfer from one photosynthetic pigment to another generates a hole in the HOMO of the donor and single occupancy of the former LUMO of the acceptor. Control over redox potentials is essential for efficient charge-separation processes.
The absorption spectra of two native photosynthetic tetrapyrrole macrocycles, bacteriopheophytin a and pheophytin a (where "pheo" implies the free base macrocycle), are shown in Figure 3. The spectra are compared with those of core macrocycles that lack any substituents other than a gem-dimethyl group in each pyrroline ring, namely, the chlorin H2C [30] and the bacteriochlorin H2BC [31]. The structures of the four macrocycles are shown in Chart 2. The core macrocycles lack ring E. The parameters corresponding to the spectra are listed in Table 1. The parameters for each band include the position of wavelength maximum (λabs, in nm), the full-width-at-half-maximum (fwhm, in nm), and molar absorption coefficient (ε, in M −1 cm −1 ). The spectra were obtained from the literature [30][31][32][33]. The spectra of additional native and synthetic macrocycles are available in PhotochemCAD [33][34][35].  [30,33] and pheophytin a (in Et2O, green) [32]. (b) H2BC (in toluene, orange) [31] and bacteriopheophytin a (in benzene, red) [32]. individual methyl groups. Moreover, while prediction of spectral properties is a matter under active investigation by calculation [38][39][40], much less is known about electrochemical properties [41]. Both spectra, which reflect the difference in energy of ground and excited-states, and energies of anion radicals and cation radicals in solution (for which calculated HOMO and LUMO energies provide only an estimate), bear critically on photosynthetic function. The ability to synthesize analogues of the native macrocycles would enable a variety of fundamental studies in this regard.    The substituents arrayed about the perimeter of the native macrocycles serve as auxochromes [36]. The spectra of the native macrocycles can be compared with those of the naked synthetic counterparts. Painting with a broad brush, the net effect of the substituents for each macrocycle causes oscillator strength to be shifted from the near-ultraviolet (B) band to the long-wavelength Q y band. The effects of the potent auxochromes such as vinyl, acetyl, and the keto group of ring E are reasonably well known (as such groups are readily modifiable) [37], but much less is known about the effects of individual methyl groups. Moreover, while prediction of spectral properties is a matter under active investigation by calculation [38][39][40], much less is known about electrochemical properties [41]. Both spectra, which reflect the difference in energy of ground and excited-states, and energies of anion radicals and cation radicals in solution (for which calculated HOMO and LUMO energies provide only an estimate), bear critically on photosynthetic function. The ability to synthesize analogues of the native macrocycles would enable a variety of fundamental studies in this regard.

General Methods
1 H-NMR and 13 C{ 1 H}-NMR spectra were collected at room temperature in CDCl 3 unless noted otherwise. The recorded NMR spectra of the compounds can be found in the Supplementary Materials. Electrospray ionization mass spectrometry (ESI-MS) data are reported for the molecular ion or protonated molecular ion. Silica gel (40 µm average particle size) was used for column chromatography. THF used in all reactions was freshly distilled from Na/benzophenone ketyl unless noted. All commercially available compounds were used as received. The Co 2 (CO) 8 was received as a solid stabilized with hexane, whereupon the content of the cobalt complex was 95% by mass. The number of mmol employed in each reaction has been corrected accordingly from the weighed quantity.

Route 4
3-(3-Methoxy-1,3-dioxopropyl)pyrrole (3). Example A: Following a reported procedure [21] with modification [4], methyl malonyl chloride (2.0 mL, 19 mmol) was added slowly to a stirred slurry of AlCl 3 (2.4 g, 18 mmol) in 1,2-dichloroethane (25 mL) at 0 • C. After 20 min, 1-TIPS (2.7 g, 12 mmol) was added dropwise. The mixture was stirred at 0 • C for 15 min, then for 3 h at room temperature. The mixture was poured into an ice-water mixture, which was then acidified by the addition of aqueous HCl solution (2 M). The resulting organic phase was separated and extracted with dichloromethane. The organic extract was washed with saturated aqueous NaHCO 3 solution and brine, dried (Na 2 SO 4 ), and concentrated. The resulting residue was treated with TBAF solution (1.0 M in THF, 12 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous NaHCO 3 solution and brine. The organic phase was dried (Na 2 SO 4 ) and concentrated. Column chromatography (silica, hexanes/ethyl acetate (1:1)) gave the unwanted 2-substituted pyrrole isomer (275 mg, 14%) and the desired 3-substituted pyrrole title compound as a brown oil (309 mg, 15%): 1  Example B: Following a reported procedure [21] with modification [4], methyl malonyl chloride (16.0 mL, 150 mmol) was added dropwise to a suspension of AlCl 3 (20.0 g, 150 mmol) in anhydrous 1,2-dichloroethane (200 mL) at 0 • C. After 15 min, 1-TIPS (22.34 g, 100 mmol) was added dropwise to the reaction mixture at 0 • C. The resulting mixture was stirred for 3 h at room temperature, then quenched by pouring the reaction contents into a beaker containing ice water. The mixture was then concentrated under reduced pressure to remove 1,2-dichloroethane (which otherwise gave an emulsion upon addition of ethyl acetate and attempted aqueous extraction) followed by treatment with aqueous HCl solution (2 M, 200 mL). The resulting mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic extract was washed with saturated aqueous NaHCO 3 (2 × 200 mL) and saturated brine (1 × 100 mL), dried (Na 2 SO 4 ), and concentrated. The resulting brown oil was then treated with TBAF solution (1.0 M in THF, 150 mL) and stirred for 1 h at room temperature. The reaction mixture was treated with saturated aqueous NaHCO 3 (200 mL). The aqueous layer was extracted with CH 2 Cl 2 (3 × 150 mL). The combined organic extract was washed with brine (1 × 100 mL), dried (Na 2 SO 4 ), and concentrated. The crude product was purified by column chromatography (silica, column size 8 cm × 20 cm), hexanes/ethyl acetate (1:1)) to obtain the unwanted isomer (4) followed by the title compound (3).
Survey of Lewis acids: Following a reported procedure [29], a sample of a Lewis acid (0.1 mmol) was added to a stirred solution of 1-TIPS (240 µL, 1.0 mmol) and methyl malonyl chloride (160 µL, 1.5 mmol) in nitromethane (1.0 mL). The reaction was monitored by TLC analysis. After stirring for 5 h at room temperature, the reaction was quenched by treatment with saturated aqueous NaHCO 3 (5.0 mL). The aqueous layer was extracted with CH 2 Cl 2 (3 × 5 mL). The combined organic extract was dried (Na 2 SO 4 ) and concentrated to obtain a viscous dark crude oil. The 1 H-NMR spectrum was identical with that of the 2-acylated product 4 reported above.
Example using AlCl 3 : Following a reported procedure [21] with modification [4], methyl malonyl chloride (800 µL, 7.5 mmol) was added dropwise to a suspension of AlCl 3 (1.0 g, 7.5 mmol) in anhydrous 1,2-dichloroethane (10 mL) at 0 • C. After 10 min, 1-TIPS (1.2 mL, 4.9 mmol) was added dropwise to the reaction mixture at 0 • C. The resulting mixture was stirred for 3 h at room temperature, then quenched by pouring the reaction contents into a beaker containing ice water. The mixture was then concentrated under reduced pressure to remove 1,2-dichloroethane (which otherwise gave an emulsion upon addition of ethyl acetate and attempted aqueous extraction) followed by treatment with aqueous HCl solution (2 M, 50 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extract was washed with saturated aqueous NaHCO 3 (2 × 100 mL) and saturated brine (1 × 50 mL), dried (Na 2 SO 4 ), and concentrated. The crude product was purified by column chromatography (silica, hexanes/ethyl acetate (30:1 then 5:1 then 1:1)) to obtain 3-TIPS (157 mg, 10% as a black solid) followed by 4 (143 mg, 17% as a black oil). The 1 H and 13 C{ 1 H}-NMR data were consistent with those reported above for each compound.

XRD Analysis
A sample of 3-TIPS was crystallized by slow evaporation of a solution of CDCl 3 from an NMR tube over some days. A resulting colorless block-like specimen of C 17 H 29 NO 3 Si, approximate dimensions 0.154 × 0.204 × 0.254 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured on a Bruker-Nonius X8 Kappa APEX II system equipped with a fine-focus sealed tube (MoKα, λ = 0.71073 Å) and a graphite monochromator. The total exposure time was 3.88 h. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 64,836 reflections to a maximum θ angle of 30.99 • (0.69 Å resolution), of which 5920 were independent (average redundancy 10.952, completeness = 100.0%, R int = 6.33%, R sig = 3.14%) and 4552 (76.89%) were greater than 2σ(F 2 ). The final cell constants of a = 7.9903(3) Å, b = 14.9649(7) Å, c = 31.0291(13) Å, volume = 3710.3(3) Å 3 are based upon the refinement of the XYZ-centroids of 2055 reflections above 20 σ(I) with 5.222 • < 2θ < 68.33 • . Data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.952. The calculated minimum and maximum transmission coefficients (based on crystal size) were 0.9660 and 0.9790.
The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P b c a, with Z = 8 for the formula unit, C 17 H 29 NO 3 Si. The final anisotropic full-matrix least-squares refinement on F 2 with 206 variables converged at R 1 = 3.73% for the observed data and wR 2 = 9.99% for all data. The goodness-of-fit was 1.030. The largest peak in the final difference electron density synthesis was 0.456 e -/Å 3 , and the largest hole was -0.221 e -/Å 3 with an RMS deviation of 0.053 e -/Å 3 . On the basis of the final model, the calculated density was 1.158 g/cm 3 and F(000), 1408 e − . These structural data for 3-TIPS (CCDC 2226334) can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/Search?Ccdcid=2226334&DatabaseToSearch= Published (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk), accessed on 28 January 2023.

Outlook
The full synthesis of any native bacteriochlorophylls or chlorophylls has not yet been achieved [1]. The syntheses reported herein provide straightforward access to a precursor of an analogue of native ring C. The scope (>5 mmol) and efficacy (one day at most) from commercially available TIPS-pyrrole (1-TIPS) via route 4 are suitable to meet the stated objectives for incorporation in a planned program for the synthesis of photosynthetic tetrapyrrole macrocycles and analogues. Still, improved reaction conditions remain an important focus to streamline synthetic access more fully in this domain, illustrated by the multiple products (and the unexplained, variable ratios in batch-to-batch runs) obtained in the Friedel-Crafts acylation of 1-TIPS. Access to precursors to ring C and analogues may also prove useful in the synthesis of phyllobilins [42,43]-catabolic products of chlorophyll that contain an intact ring E-for which general syntheses also remain to be developed.
Author Contributions: Investigation, all authors. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the NSF (CHE-1760839, CHE-2054497). Mass spectrometry measurements were carried out in the Molecular Education, Technology, and Research Innovation Center (METRIC) at NC State University.
Data Availability Statement: X-ray crystal data are deposited at CCDC for 3-TIPS (2226334). All other data are contained within the paper and Supplementary Materials.