Synthesis of Diaryl Hydroxyl Dicarboxylic Acids from Amino Acids

Herein we report a unique method for preparing diaryl hydroxyl dicarboxylic acids in a diastereospecific manner. The three-component reaction occurs between amino acid, aromatic aldehyde, and primary alcohol in alkaline solutions under microwave-assisted conditions. The dicarboxylic acids are isolated as sodium salts in high yields (up to 77%) by direct precipitation from the reaction solution. The experimental results suggest that the diastereospecificity originates from a [3,3]-sigmatropic rearrangement followed by a sodium-assisted hydride transfer. As further shown, the previously unreported dicarboxylic acids are easily turned into corresponding δ-lactones.


Optimization
Method 1 and 2 were optimized to reach the maximum yield and purity of diacid 1. In the graphs, lighter blue refers to pure product and darker blue to product containing impurities. All of the 13 diacids were synthesized with both of the reported methods. When using tert-butanol as a co-solvent, more product 1 was isolated (Method 2).

Optimization of Method 1
Optimized conditions for Method 1 (M1) Amino acid (3 mmol) was dissolved into NaOH solution (4.5 mmol, 0.9 ml, 5M) and the solution was placed at microwave vial (10 ml). Next, the corresponding primary alcohol (4.1 ml) was added together with aromatic aldehyde (6 mmol) to the same microwave vial. After stirrer insertion, the vial was capped. The reaction mixture was heated as follows: Heat as fast as possible to 135 °C and maintain heat for 90 minutes. Stirring speed was 600 rpm during the reaction. Pressure typically stays within 3 to 10 bars during the reaction (See Fig. S2). After the reaction, vial is cooled to 50 °C with compressed air. Crystals forms typically within couple of days. If crystals do not form, an addition of EtOH (2 to 3 ml) initiates the crystallization. The colorless crystals were filtered and washed with EtOH and air-dried. If needed, the products were recrystallized with a minimal amount of water and EtOH as an anti-solvent. Impurities, which do not dissolve to water, are filtered out before recrystallization. (Note: Products 3, 7 and 11 require different purification method. For more details, see manuscript experimental section).

S4
Alternative workup: After completion of the reaction, evaporate all solvent in vacuum and wash with EtOH until only crude product is left. Recrystallize from water ethanol mixture.      Note: Optimal amount of benzaldehyde is two equivalents (compared to amino acid).

Optimization of Method 2
Optimized conditions for Method 2 (M2) Amino acid (2 mmol), NaOH solution (10 mmol, 1.0 ml, 10M) and tert-butanol/corresponding alcohol mixture (4.0 ml, 75%/25% v/v%) was added into microwave vial (10 ml) equipped with stirrer. Finally, aromatic aldehyde (10 mmol) is added to the same vial. (Note: After all reagents are added, the reaction mixture often becomes solid.) Fast heating during the microwave reaction may cause high pressure spikes when solids are turning into liquids. To avoid the pressure problems slow temperature build up is necessary. After capping the microwave vial it is heated to 135 °C in 5 minutes and maintained for 90 minutes. Stirring speed is 600 rpm during the reaction. Pressure typically stays within 3 to 10 bars during the reaction (See Fig. S8). Afterwards, the vial is cooled to 50 °C with compressed air. Isopropanol (2 ml) is added into the vial to initiate the crystallization. Typically powder like substance is observed after few hours. Next day the solid powder is filtered and washed with EtOH (expect the product 3, 7 and 11, see manuscript experimental section for more details). If needed recrystallize the product from small amount of water using ethanol as antisolvent. Equivalents of Benzaldehyde and NaOH at Tert-butanol vs. the Yield of 1

Equivalents of Benzaldehyde and NaOH
Yield of 1 (%) Figure S10: Benefits of additional benzaldehyde and NaOH for yield of 1 at 75% tert-butanol reaction solution. Optimal amount was 5 eq. for both reagents.

S9
3 Yields of the products

Single crystal growing
Single crystals were grown by dissolving the products 1 and 2 to water. Ethanol was added as antisolvent until the point of precipitation was reached. Couple extra drops of water were added and solutions were kept in closed vials at RT. After three months, the single crystals were collected and crystal structure was determined by X-ray diffraction. (Note: the products are easy to crystallize from water-ethanol solution, but growth of single crystals demands a slow growing process). S11   Proton H3 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C2 and C4. The group has connectivity to aromatic carbon C5 and weaker C6. The group also sees inside the phenyl ring of C5, suggesting a neighboring position.

ESI-TOF-MS parameters
Proton H4 is attached to carbon C2 forming CH group. This group is connected strongly to carbon C1, C3 and weakly to C4. The group has strong connectivity to aromatic carbon C6 and weaker to C5. This group also see inside the phenyl ring C6, suggesting a neighboring position. The group has weak connectivity to acid carbon C8.
Proton H5 is attached to Carbon C4 forming CH group. The group has connectivity to aliphatic carbons C3 and weaker to C2. The group has connectivity to aromatic carbon C5. The group is only one with connectivity to acid carbon C7.

S29
2D NMR Explanations: Protons H1 and H2 are attached to carbon C1 forming CH 2 group. The group has connectivity to aliphatic carbons C2 and C3. The group has connectivity to aromatic carbon C6. The group has strong connectivity to acid carbon C8.
Proton H3 is attached to carbon C2 forming CH group. Due to the carbons C2 and C3 being so close each other it is hard to tell them apart, nevertheless very accurate analysis of HSQC spectrum suggests proton H3 is attach to carbon C2. The group has connectivity at aliphatic region to C3, C1 and weakly to C4. The group has connectivity to aromatic carbon C5 and stronger to C6 carbon. The group sees inside the phenyl of aromatic carbon of C6, suggesting a neighboring position. The group has also connections to acid carbon C8.
Proton H4 is attached to carbon C3 forming CH group. The group has connectivity at aliphatic region to C2 and weak connectivity to C4. Group has strong connectivity to aromatic carbon C5 and has connections to inside of the indole group suggesting it being neighboring group. The CH group has weak connectivity to the aromatic carbon C6.
Proton H5 is attached to carbon C4 forming CH group. The group has connectivity at aliphatic region to C3. The group has connectivity to indole carbon C5 suggesting it to be nearby. The CH group is the only group having connectivity with acid carbon C7 suggesting it being the neighboring group of it.

S37
2D NMR explanation: Protons H1 and H2 are attached to C1 forming CH 2 group. The group has connectivity to aliphatic carbons C2 and C3. The group also has connectivity to aromatic carbon C7. The group has strong connectivity to acid carbon C10. Suggesting the group being next to the acid group.
Proton H3 is attached to carbon C3 forming CH group. The CH group has connectivity to aliphatic carbons C2 and C4. The group has strong connectivity to aromatic carbon C6 of phenol group, suggesting neighboring position of phenol group. The group has no connectivity to acid carbons.
Proton H4 is attached to carbon C2 forming CH group. The group has connectivity to aliphatic carbons C1 and C3 and weak connectivity to C4. The group has strong connectivity to aromatic carbon C7 and sees inside of it, suggesting the group being next to the phenyl group. The group has weak connectivity to acid carbon C10.
Proton H5 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbon C3. The group has also connectivity aromatic carbon C6 of the phenol group. The group is only one with connectivity to acid carbon C9, suggesting it being neighboring group.
Aromatic carbon H6 is attached to aromatic carbon C5 forming aromatic CH groups. The group has connectivity at aromatic region to C8 and C6. This group is part of the phenolic aromatic group.  Protons H2 and H3 are attached to carbon C2 forming CH 2 group. The group has connectivity to aliphatic carbons C3 and C4. The group has also connectivity to aromatic carbon C8. The group has strong connectivity to acid carbon C10 suggesting it to be next to it.
Proton H4 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbons C3 and C5. The group has also connectivity to aromatic carbon C7 and inside the phenyl group suggesting it to be next to the phenyl group.
Proton H5 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C2, C4 and C5. The group has strong connectivity to aromatic carbon C8 and inside to the phenyl group similar to the methyl group (C1/H1), suggesting the group to be next to the methylated phenyl group. The group has also connectivity to acid carbon C10.
Proton H6 is attached to carbon C5 forming CH group. The group has connectivity to aliphatic carbons C3 and C4. The group has also connectivity to aromatic carbon C7. The group is the only one with connectivity to acid carbon C9, suggesting it to be next to it.

S53
2D NMR explanation: Protons H1 and H2 are attached to carbon C1 forming CH 2 group. The group has connectivity to aliphatic carbons C2 and C3. The group have connectivity to aromatic carbon C7. The group has strong connectivity to acid carbon C11, suggesting it to be next to it.
Proton H3 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C2 or/and C1 (heavy overlapping, hard to tell) and C5. The group has connectivity to aromatic carbon C8 and weakly C7. The group has connectivity to inside of the phenyl, suggesting neighboring position.
Proton H4 is attached to carbon C2 forming CH group. The group has connectivity to aliphatic carbons C1, C3 and C5. The group has connectivity to aromatic carbons C7 and weak connectivity to C8, suggesting group to be next to phenyl group. Group has weak connectivity to acid carbon C11.
Protons H5 are attached to carbon C4 forming CH 3 group. The group has no aliphatic connections. The group is connected to aromatic carbon C9, suggesting it being part of the anisaldehyde methoxy group.
Proton H6 is attached to carbon C5 forming CH group. The group has connectivity to aliphatic carbons C2 and C3. The group has connectivity to aromatic carbon C8. The group is the only one with connectivity to acid carbon C10, suggesting neighboring position of it.
Proton H7 is attached to carbon C6 forming two aromatic CH groups. The groups have connectivity to aromatic carbons C7, C9. Group is part of the methoxy benzaldehyde group.

S61
2D NMR explanation: Protons H1 and H2 are attached to carbon C1 forming CH 2 group. The group has connectivity with aliphatic carbons C2 and C3. The group has connectivity with aromatic carbon C6. The group has connectivity with acid carbon C8.
Proton H3 is attached to carbon C3 forming CH group. The group has connectivity at aliphatic region to C2 and C4. The group has connections to aromatic carbon C5 and weaker to C6, also the group has connectivity to inside the non-substituted phenyl group suggesting it being the neighboring group of it.
Proton H4 is attached to carbon C2 forming CH group. It has connectivity at aliphatic region to C1, C3 and weak connectivity to C4. The group has strong connectivity to aromatic carbon C6 and sees inside of the substituted aromatic group, suggesting it being neighbor of it. The group also has also weak connectivity to aromatic carbon C5. The HC group has also weak connectivity to C8 acid carbon.
Proton H5 is attached to carbon C4 forming CH group. The group has connectivity at aliphatic region to C3 and C2. The group has connectivity to non-substituted aromatic carbon C5, suggesting it to be nearby. The group is the only one with connectivity to acid carbon C7, suggesting it being the neighboring group of it.

S70
2D NMR explanation: Protons H1 and H2 are attached to carbon C1 forming CH 2 group. The group has connectivity to aliphatic carbons C2 and C3. The group has connectivity to aromatic carbon C11. The group has also connectivity to acid carbon C14.
Proton H3 is attached to carbon C3 forming CH group. The group has connectivity at aliphatic region to carbon C2 and very weak C4. The group has connectivity to aromatic carbon C10 and C8, thus suggesting it neighboring the non-substituted phenyl. The group has no connectivity to acid carbons.
Proton H4 is attached to carbon C2 forming CH group. The group has connectivity to aliphatic carbons C1, C3 and weak C4. The group has connectivity to aromatic carbons C11 and C9, suggesting the group being neighbor of the substituted phenyl group. The group has also connectivity to acid carbon C14.
Proton H5 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbons C3 and weak C2. The group has connectivity to aromatic carbon C10. The group is only one with connectivity to acid carbon C13.

S78
2D NMR explanation: Protons H1 are attached to carbon C1 forming CH 3 group. The group has no connectivity at aliphatic region. The group has connectivity at aromatic region to carbons C7 and has connectivity inside the substituted aromatic phenyl group.
Protons H2 and H3 are attached to carbon C2 forming CH 2 group. The group has connectivity at aliphatic region to carbons C3 and C4. The group has also connectivity to aromatic carbon C9. The group has connectivity to acid carbon C11, suggesting it being next to it.
Proton H4 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbons C3 and C5. The group has also connectivity to aromatic carbon C8 and weaker to C9, the group has connectivity inside the aromatic ring, suggesting it being next to that group.
Proton H5 is attached to C3 forming CH group. The group has connectivity at aliphatic region to carbons C2, C4 and weak C5. The group has also connectivity to aromatic carbons C9 and weaker C8, the group also has connectivity to inside the aromatic group suggesting it being next to it. The group also has weak connectivity to acid carbon C11.
Proton H6 is attached to carbon C5 forming CH group. The group has connectivity to aliphatic carbons C4 and C3. The group has also connectivity to aromatic carbon C8. The group is only one with connectivity to acid carbon C10, suggesting it being next to it.

S80
Mass spectrometry for product 8:

S86
2D NMR explanation: Protons H1 is attached to carbon C1 forming CH 3 group. The group has no connectivity at aliphatic region. The group has connectivity at aromatic region to carbon C8 and inside the aromatic ring, suggesting it being attached to the aromatic ring from ortho position.
Protons H2 and H3 are attached to carbon C3 forming CH 2 group. The group has connectivity to aliphatic carbons C2 and C4. The group has also connectivity to aromatic carbon C8. The group has connectivity to acid carbon C10.
Proton H4 is attached to carbon C4 forming CH group. The group has connectivity at aliphatic region to carbon C2. The group has connectivity to aromatic carbon C7 and inside the phenyl group, suggesting it being neighbor of the group.
Proton H5 is attached to carbon C2 forming CH group. The group has connectivity to aliphatic region carbons C3 and C4. The group has connectivity to aromatic carbon C8 and inside the substituted phenyl group, suggesting it being neighbor of it. The group has weak connectivity to acid carbon C10.
Proton H6 is attached to carbon C5 forming CH group. The group has connectivity to aliphatic carbons C4 and weak connectivity to C2. The group has connectivity to aromatic carbon C7. The group is only one with connectivity to acid carbon C9. S88 HRMS spectra of 9:

S94
2D NMR explanation: Protons H1 are attached to carbon C1 forming CH 3 group. The group has connectivity to carbons C2, C3 and weaker C4. The group has connectivity to acid carbon C9.
Proton H2 is attached to carbon C2 forming CH group. The group has connectivity at aliphatic region to C1 and C3. Group has connection to aromatic carbon C7. The group has connectivity to acid carbon C9.
Proton H3 is attached to carbon C4 forming CH group. The group has connectivity at aliphatic region to C2, C3 and weak connectivity to C5. The group has strong connectivity to aromatic carbon C6 and has connections to inside of the substituted aromatic group suggesting it being neighbor of it.
Proton H4 is attached to carbon C3 forming CH group. The group has connectivity at aliphatic region to C1, C2, C4 and C5. The group has connectivity to aromatic carbon C7 suggesting it to be nearby, the group has also weaker connectivity to carbon C6. The CH group has connectivity with acid carbon C9.
Proton H5 is attached to carbon C5 forming CH group. The group has connectivity to carbon C4 at aliphatic region. It has connectivity to C6 at aromatic region. The group is the only one with connectivity to acid carbon C8.

S102
2D NMR explanation: Protons H1 are attached to carbon C1 forming CH 3 group. This group has connectivity with aliphatic carbons C2 and C5.
Protons H2 and H3 are attached to carbon C2 forming CH 2 group. The group has connectivity to aliphatic carbons C1, C5 and weak connectivity to C3. The group has also connectivity to acid carbon C10.
Proton H4 is attached to carbon C5 forming CH group. The group has connectivity to aliphatic carbons C1, C2, and C3 and weak connectivity to C4. The group also has connectivity to aromatic carbon C8. The group has also connectivity to acid carbon C10.
Protons H5 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbons C3, C6 and weak one to C5. The group has connectivity to aromatic carbon C7, suggesting neighboring position. Group has no connections to any acid groups.
Proton H6 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C2, C4 and C5. The group has connectivity to aromatic carbon C8 and weak C7, which suggesting the group to be next to phenyl group of C8. The group has also connectivity to acid carbon C10.
Proton H7 is attached to carbon C6 forming CH group. The group has connectivity to aliphatic carbons C4 and weaker to C3. The group has also connectivity to aromatic carbon C7. The group is only one with connectivity to acid carbon C9.

S110
2D NMR explanation: Proton H1 is attached to carbon C2 and forms CH group. This group has connectivity with aliphatic carbons C1 and C4 and weak one to C3. Group has strong connectivity to aromatic carbons C5 and weaker to C7. The group is neighboring phenyl group which C5 belongs to.
Proton H2 is attached to carbon C3 forming CH group. The group has connectivity with aliphatic carbons C1 and C2. The group also has connectivity to aromatic carbon C6, which suggest neighboring position to the mentioned phenyl group. The group has also connectivity to acid carbon C9, suggesting nearby location.
Proton H3 is attached to carbon C1 forming CH group. The group has connectivity with aliphatic carbons C2 and C3. The group has connectivity to aromatic carbon C7 and weak one to C5, suggesting nearby location of phenyl group of C7. The group has very weak connectivity to acid carbon C9.
Proton H4 is attached to carbon C4 forming CH group. The group has connectivity with aliphatic carbons C2 and C1. The group has connectivity with aromatic carbon C5. The group is only with connectivity to acid carbon C8, suggesting nearby location.

S118
2D NMR explanation: Protons H1 and H2 are attached to carbons C1 or C2 (too close to tell) forming two -CH 3 groups. The groups have connectivity to aliphatic carbons C3 and C6 and each other.
Proton H3 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C1, C2, C6, C7 and C5.
Proton H4 is attached to carbon C6 forming CH group. The group has connectivity to aliphatic carbons C3, C1, C2, C5, C4 and C7. The group has connectivity to aromatic carbon C9. The group has also weak connectivity to acid carbon C11.
Protons H5 and H6 are attached to carbon C4 forming -CH 2 -group. The group has connectivity to aliphatic carbons C5 and C6. The group has also connectivity to aromatic carbon C9. The group has connectivity to acid carbon C10, suggesting neighboring location.
Proton H7 is attached to carbon C5 forming CH group. The group has connectivity to aliphatic carbons C4, C6 C7 and weaker C3. The group has connectivity to aromatic carbon C9 and sees inside the phenyl ring, suggesting neighboring location. The group has weak connectivity to acid carbon C10.
Proton H8 is attached to carbon C7 forming CH group. The group has connectivity to aliphatic carbons C6, C5 and C3. The group has strong connectivity to acid carbon C11, suggesting neighboring location.

S126
2D NMR explanation: Protons H1 and H2 are attached to carbon C1 forming -CH 2 -group. The group has connectivity at aliphatic region to carbons C2 and C3. The group has connectivity to aromatic carbon C6. The group has also connectivity to carbonyl carbon C7/C8 (too close to tell apart).
Proton H3 is attached to carbon C2 forming -CH group. The group has connectivity to aliphatic carbons C1, C3 and weak C4. The group has connectivity to aromatic carbons C6 and weaker C5, the group sees inside phenyl group of C6, thus suggesting neighboring position. The group has only weak connectivity to carbonyl carbon(s).
Proton H4 is attached to carbon C3 forming -CH group. The group has connectivity to aliphatic carbons C4, C2 and C1. The group has connectivity to aromatic carbons C5 and weaker C6, the group sees inside the phenyl group of C5, thus it is neighbor. The group has strong connectivity to carbonyl carbons C7/C8.
Proton H5 is attached to carbon C4 forming -CH group. The group has connectivity to aliphatic carbons C3, C2. The group has also connectivity to aromatic carbon C5. The group has strong connectivity to carbonyl carbons C7/C8.  Proton H3 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C1, C2 and weak C4. The group has connectivity to aromatic carbon C7 and weaker C5. The group sees inside the phenyl group, suggesting neighboring position to it. The group has weak connectivity to carbonyl carbon C8.
Proton H4 is attached to carbon C2 forming CH group. The group has connectivity to aliphatic carbons C3, C1 and C4. The group has connectivity to aromatic carbon C5 and weaker C7. The group sees inside the indole group, thus suggesting neighboring position to it. The group has connectivity to acid carbon C9.
Proton H5 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbons C3 and C2. The group has connectivity to aromatic carbon C5. The group has connectivity to both acid and carbonyl carbons C9 and C8, this proofs directly the cyclic nature of the compound.  Protons H2 and H3 are attached to carbon C2 forming -CH 2 group. The group has connectivity to aliphatic carbons C3 and C4. The group has also connectivity to aromatic carbon C8. The group has connectivity to carbonyl carbon C10.
Proton H4 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C2, C4 and weak C5. The group has strong connectivity to aromatic carbons C8 and weaker C7. The group sees inside the methylated phenyl group, thus suggesting neighboring position. The group has only weak connectivity to carbonyl carbon C10.
Proton H5 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbons C3, C2 and C5. The group has connectivity to aromatic carbons C7 and weaker C8. The group sees inside the phenyl group, suggesting neighboring position. The group has connectivity to acid carbon C9.
Proton H6 is attached to carbon C5 forming CH group. The group has connectivity to aliphatic carbons C4 and C3. The group has connectivity to aromatic carbon C7. The group has connectivity to at least acid carbon C9 and maybe carbonyl carbon C10. The resolution isn't good enough to tell for sure.

S150
2D NMR explanation: Protons H1 are attached to carbon C1 forming -CH 3 group. The group has connectivity to aliphatic carbons C2 and C4. The group has weak connectivity to aromatic carbon C7. The group has connectivity to ester carbon C9.
Proton H2 is attached to carbon C2 forming -CH group. The group has connectivity to aliphatic carbons C1, C4. The group sees aromatic carbon C7. The group has connectivity to ester carbon C9.
Proton H3 is attached to carbon C4 forming -CH group. The group has connectivity to aliphatic carbons C2, C1, C3 and very weak C5. The group has connectivity to aromatic carbons C7 and weaker C6. The group sees inside phenyl group C7, thus being neighboring group. The group has no connectivity on carbonyl carbons.
Proton H4 is attached to carbon C3 forming -CH group. The group has connectivity to aliphatic carbons C5, C4 and C2. The group has connectivity to aromatic carbons C6 and weaker C7. The group sees inside the phenyl group of C6, thus being neighbor of the group. The group sees acid carbon C8.
Proton H5 is attached to carbon C5 forming -CH group. The group has connectivity to aliphatic carbons C3 and maybe C4 (the connectivity is spread between these two carbons). The group has connectivity to aromatic carbon C6. The group has connectivity to both acid carbon C8 and ester carbon C9. This proofs directly the cyclic nature of the compound.

S158
2D NMR explanation: Protons H1 and H2 are attached to carbon C1 forming -CH 2 group. This group has connectivity at aliphatic region to carbons C2 and C3. The group has also connectivity to aromatic carbon C6. The group has also connectivity to acid carbon C7.
Proton H3 is attached to carbon C3 forming -CH group. The group has connectivity at aliphatic area to carbons C2, C4 and weak C1. The group has connectivity at aromatic region to carbons C5 and C6. The C5 carbon is stronger, which suggests the group being its neighbor. The group has no connectivity to acid carbons.
Proton H4 is attached to carbon C2 forming -CH group. The group has connectivity at aliphatic region to carbons C1, C3 and C4. The group has connectivity at aromatic region to carbons C6 and C5, C6 being the stronger suggesting it being neighbor of it. The group has also weak connectivity to acid carbon C7.
Proton H5 is attached to carbon C4 forming CH group. The group has connectivity at aliphatic region to carbons C2 and C3. The group has connectivity to aromatic carbon C5. The group is only one with connectivity to acid carbon C8.

S166
2D NMR explanation: Protons H1 and H2 are attached to carbon C1 forming -CH 2 group. The group has connectivity to aliphatic carbons C3 and C2. The group has connectivity to aromatic carbon C7. The group has connectivity to acid carbon C8.
Proton H3 is attached to carbon C3 forming -CH group. The group has connectivity to aliphatic carbons C1, C2 and C4. The group has also connectivity to aromatic carbons C7 and C5. The group sees inside phenyl group thus, it is at neighboring position. The group has connectivity to acid carbon C8.
Proton H4 is attached to carbon C2 forming -CH group. The group has connectivity to aliphatic carbons C3, C4 and C1. The groups has connectivity to aromatic carbons C5 and C7, the group sees inside the indole group suggesting a neighboring position. The group has no connectivity to acid carbons.
Protons H5 is attached to carbon C4 forming -CH group. The group has connectivity to aliphatic carbon C2. The group has connectivity to aromatic carbon C5. The group is only one with connectivity to acid carbon C9.

S173
2D NMR explanation: Protons H1 are attached to carbon C1 forming CH 3 group. The group has connectivity to aromatic carbons C6 and weak C8. Methyl group is clearly attached to the phenyl ring. The group has also connectivity inside the phenyl ring. The group has no other connectivity.
Protons H2 and H3 are attached to carbon C2 forming CH 2 group. The group has connectivity to aliphatic carbons C3 and C4. The group has connectivity to aromatic carbon C8. The group has connectivity to acid carbon C9.
Proton H4 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbons C3, C5 and C2. The group has connectivity to aromatic carbon C7 and sees inside the phenyl group, suggesting neighboring position. The group has no connectivity to acid carbons.
Proton H5 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C2, C4 and weak C5. The group has connectivity to aromatic carbon C8 and sees inside of the group similarly to the methyl group H1, C1, suggesting that the group is next to the methylated phenyl ring. The group has connectivity to acid carbon C9.
Proton H6 is attached to Carbon C5 forming CH group. The group has connectivity to aliphatic carbons C4 and C3. The group has connectivity to aromatic carbon C7. The group is the only one with connectivity to acid carbon C10, suggesting neighboring position. 2D NMR explanation: Protons H1 and H2 are attached to carbon C1 forming -CH 2 -group. The group has connectivity to aliphatic carbons C2 and C3. The group have connectivity to aromatic carbon C10. The group has also connectivity to acid carbon C13.
Proton H3 is attached to carbon C3 forming -CH group. The group has connectivity to aliphatic carbons C2, C4 and C1. The group has also connectivity to aromatic carbon C11 and C8, suggesting neighboring location to the non-substituted phenyl group. The group has no connectivity to acid carbons.
Proton H4 is attached to carbon C2 forming -CH group. The group has connectivity to aliphatic carbons C1, C3 and C4. The group has also connectivity to aromatic carbons C10 and C9, suggesting neighboring position to the substituted phenyl ring. The group has also connectivity to acid carbon C13.
Proton H5 is attached to carbon C4 forming -CH group. The group has connectivity to aliphatic carbons C3 and C2. The group has connectivity to aromatic carbon C11. The group is only one with connectivity to acid carbon C14. 2D NMR explanation: Protons H1 are attached to carbon C1 forming -CH3 group. The group has connectivity to aliphatic carbons C2 and C3. The group has no connectivity to aromatic carbons. The group has also connectivity to acid carbon C9.
Proton H2 is attached to carbon C2 forming CH group. The group has connectivity to aliphatic carbons C1, C3 and C4. The group has connectivity to aromatic carbon C7. The group has connectivity to acid carbon C9.
Proton H3 is attached to carbon C4 forming CH group. The group has connectivity to aliphatic carbons C5, C3 and C2. The group has connectivity to aromatic carbon C6 and sees inside the phenyl group, suggesting nearby location. The group has no connectivity to acid carbons.
Protons H4 is attached to carbon C3 forming CH group. The group has connectivity to aliphatic carbons C2, C1, C4 and C5. The group has connectivity to aromatic carbon C7 and sees inside the phenyl group, suggesting neighboring location. The group has connectivity to acid carbon C9.
Proton H5 is attached to carbon C5 forming CH group. The group has connectivity to aliphatic carbons C4 and C3. The group has connectivity to aromatic carbon C6. The group is only one with connectivity to acid carbon C8. Diacid salts are formed in a three component reaction between amino acid (R 1 ), aromatic aldehyde (R 2 ) and primary alcohol (R 3 ) in alkaline conditions (Fig. S238). Amino acid and aromatic aldehyde react into phenylpyruvic acid I (Fig. S239) and aromatic aldehyde reacts with primary alcohol into cinnamaldehyde IV (Fig. S241). These two in situ formed species react further to the final diacid salt product (Fig. S243).
According to the solid-state structures of 1 and 2, the compounds are generated as stereoisomer (RRR) or its enantiomer (SSS). The formation of these stereocenters is described in detail in section 9. The reaction begins with a condensation reaction between amino acid and aromatic aldehyde (Fig.  S239). The formed imine compound undergoes isomerization reaction, which is most likely catalyzed by either base or alcohols in the solution and is mediated by forming a six-membered ring. Oxygen atom of the catalyst extracts a proton from the α-carbon and donates another proton to the double bond of imine functionality (see details in Fig. S240). After isomerization, the compound undergoes hydrolysis to phenylpyruvic acid salt I and benzyl amine II. The benzyl amine further reacts with benzaldehyde or with itself to generate observed side-product benzylidenebenzylamine III. Mass spectrum and 1 H NMR spectrum were recorded from the reaction solution and benzylidenebenzylamine III and its chloro derivative were confirmed (Fig. S259S264). In method 1, the isomerization is either catalyzed by a base or ethanol. In method 2 also tert-butanol can act as the catalyst. As method 2 results in higher yields of 1, tert-butanol is proposed to affect the rate of isomerization. It is also possible that tert-butoxide, which is a highly powerful base for extracting the α-proton, forms in the applied reaction conditions. In the reaction, aromatic aldehyde undergoes Meerwein-Pondorf-Verley (MPV) reaction with primary alcohol. As a result, primary alcohol turns into aldehyde and aromatic aldehyde turns into aromatic alcohol (Fig. S241). The formed aldehyde undergoes keto-enol tautomerization. Then the enol reacts with another aromatic aldehyde molecule by the Aldol condensation reaction and generates cinnamaldehyde IV.  Figure S241: The formation of cinnamaldehyde or its derivatives.
Based on GC-MS measured from the reaction, a high reactivity of IV is suggested, as IV is not observed experimentally (Figs. S259S267). However, IV formation was tested in a reaction between ethanol and benzaldehyde at the applied microwave conditions, and the generation of an alcohol analogue of IV was observed. With IV derivatives either alcohol or aldehyde analogues were observed (Fig. S242). The composition of alcohol/aldehyde is dependent on the length of the side chain; shorter side chain produces alcohol and longer chains produces aldehyde (Fig. S242). The phenomena is probably related S192 to Cannizzaro or MPV reaction as sterically hindered aldehydes seem to be less likely to undergo the transformation to alcohol. The chiral hemiacetal i is formed by enolate of I (E or Z) attacking the cinnamaldehyde IV from either re or si face (See Fig. S245). Additionally, IV has cis or trans isomers which both can appear at different angle (m1 or m2) at hemiacetal i structure. Thus, the amount of possible reaction combinations are limited to 16, but only 8 of those can proceed to ii (see Fig. S248  In Fig. S247 is illustrated the hemiacetal formation from I and IV. The left hand side, the reaction does not proceed due the phenyl repulsion. On the right hand side, the reaction proceeds further as the phenyl groups are pointing at different directions.  Fig. S248). RS or SR combinations are impossible, as these would require phenyl groups to be at unfavorable position. The [3,3]sigmatropic rearrangement is the underlying reason why this reaction produces only enantiomer pair SSS(S) / RRR(R) as a final product. Interestingly, IV configuration has no effect on formed stereocenters at ii. S196 trans or cis (m1 or m2) Hydroxide attacks to the carbonyl group in the aldehyde, followed by Na + -ion assisted hydride transfer reaction. Reaction only happens in chair conformation, where the phenyl groups are in equatorial position. The hydride transfer from ε-carbon to α-carbon was confirmed with ethanol-d 6 labeling studies (Section 9.2). Hydride transfer Figure S252: Similarly as above, the equatorial position is most favored for the hydride transfer. Due the fact that extra phenyl group changes priorities for naming some of the RR centers turn SS. Therefor stereocenters at final product are enantiomers RRSS and SSRR.

Labeling studies
Product 1 was synthesized from ethanol in NaOD/D 2 O solution. The areas of signals belonging to protons at β and δ carbons dropped in the 1 H NMR spectrum indicating the replacement of protons by deuterium. As was suggested in Section 9, these positions undergo keto-enol tautomerization.  When product 1 synthesized in deuterated ethanol (DO-CD 2 -CD 3 ), similarly, proton integral values dropped at β and δ position as ethanol-d 6 exchanges deuterium to protons from water. The proton of α carbon disappeared from the 1 H NMR spectrum (Fig. S256). This is explained by hydride transfer from ε carbon to α carbon.  Figure S255: Synthesis of 1 from deuterated ethanol. Deuterium is replacing protons at β and δ carbons but also at α carbon. This is a direct proof of hydride transfer from ε to α carbon. Figure S256: 1 H NMR spectrum of 1 when synthesized from ethanol-d 6 in NaOH/H 2 O solution. Proton H5 has turned into deuterium 100%. Figure S257: Comparing product 1 made from ethanol-d 6 and regular 1. The peak from α carbon position has totally disappeared from the proton spectrum.

Synthesis of 1 from commercial I and IV
Phenylpyruvic acid I (3 mmol) was placed into a microwave vial together with cinnamaldehyde IV (3 mmol). NaOH (4.5 mmol, 5M, 0.9 ml) and EtOH (4.1 ml) were added. Reaction was conducted in microwave at 135 °C for 90 min. Similar to synthesis of 1, white crystals were formed. Yield: 56 % (602 mg). Product was same as 1 (see Fig.  S258 for NMR comparison). This experiment proofs that I and IV are related intermediate species for the synthesis of 1. Figure S258: 1 H NMR spectra of 1 prepared with different approaches.

GC-MS data
Reaction solutions were studied by GC-MS after filtering the product out. Few drops of the remaining reaction solution was diluted with ethyl acetate and the sample was filtered prior to the measurement.
The chromatogram contained small peaks belonging to unreacted benzaldehyde and a side-product benzyl alcohol. The most intensive signal belonged to benzylidenebenzylamine III (Fig. S259). Signals related to III were also found in 1 H NMR spectrum measured from the reaction solution (Fig. S261). When benzaldehyde was replaced by 4-cholorbenzaldehyde, the mass peak of III-Cl 2 was observed in GC-MS (Figs. S262-S264).  S207 Figure S264: 1 H NMR spectrum of dichloro-benzylidenebenzylamine III-Cl 2 (chloroform-d).
Cinnamaldehyde IV formation was tested with ethanol and benzaldehyde at applied reaction conditions (method 1). A sample for GC-MS was taken from the reaction solution and diluted with ethyl acetate.  When 1-propanol and benzaldehyde were reacted similarly, the reaction produces alcohol and aldehyde analogues (Fig. S268).