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Enantioselectivity of Isomerization of n-Humulone to Trans- and Cis-n-Isohumulones

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06 July 2026

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07 July 2026

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Abstract
The enantiomeric composition of products obtained from isomerization of n-humulone 1a to trans- and cis-n-isohumulones 2a and 3a, respectively, was determined by chiral HPLC analysis of the isolated trans and cis isomers. Enantiomers of humulones 1 were readily resolved on a Whelk-O1 chiral stationary phase (CSP), whereas the isomeric isohumulones 2 and 3 were separated on a carbohydrate based IC-3 CSP. Magnesium catalyzed isomerization of n-humulone under basic conditions gave mixtures or trans- and cis-n-isohumulones exhibiting an increasing preference for the cis isomer at lower temperatures. At either 10 oC in CH2Cl2/H2O or reflux in methanol-water, the trans-(-) (4S,5S)-2a isomer was obtained in greater than 95% ee, while cis-3a exhibited 88% ee of the (+)-(4S,5R) enantiomer. Precision continuous flow photochemical isomerization using 395 nm LEDs provided trans-(-)-2a in greater than 95% ee in an isolated yield of 93%. However, photochemical isomerization with 365 nm LEDs gave a mixture of isomers consisting of 46% ee for the trans-(-)-2a and greater than 95% ee for the cis-(-)-(4R,5S)-3a enantiomer. The photochemically obtained (-)-3a isomer has the opposite absolute configuration compared to thermal isomerization. An oxadi-π-methane rearrangement is proposed to account for the formation of isohumulone isomers under photochemical conditions.
Keywords: 
humulone
;  
isohumulone
;  
photochemistry
;  
continuous flow synthesis
;  
chiral HPLC
;  
precision photochemistry
;  
oxadi-π-methane rearrangement
;  
ODPM
Subject: 
Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

The hops plant (Humulus lupus L.) is primarily known for the use of the flowering inflorescence or strobile as one of the major components, along with malts, water and yeast, in the production of beer [1,2,3,4,5]. Hops in brewing gives desirable bitter and aroma flavors to the final product and has the added benefit of acting as a preservative, helping prevent infection by undesirable bacteria such as lactobacillus or pediococcus [6,7,8]. Recently hops have found use as a flavoring agent and desirable component of non-alcoholic beverages such as hop teas and relaxation drinks [9,10,11]. Perhaps less known is the use of hop extracts for over-the-counter nutritional supplements purporting a wide range of potential benefits including treatment of anxiety, insomnia, symptoms of menopause, inflammation and an extended list of other maladies [12,13,14]. Hops extracts have been evaluated for alleviation of early menopausal symptoms in randomized placebo-controlled trials [15]. In a recent clinical trial, hop extracts have been shown to modulate gut peptide hormone secretion in healthy-weight men [16].
Hops have also proven to be an excellent source of isolated biologically active compounds [17,18,19] (Figure 1). The harvested strobiles of the hops plant contain between 2 and 15% amount by weight of humulone, a mixture of prenylated oxidized phloroglucinols [20]. The major homologs of humulone differ in the alkyl ketone substitution of the cyclohexadienone ring with over 95% of the content represented by isobutyl (n-), isopropyl (co-) and sec-butyl (ad-) ketones. The homolog n-humulone has been evaluated for it sleep-promoting activity [21] and shown to inhibit cell growth of lung and bonecancer cells [22]. Humulones can be isomerized to isohumulones by both thermal and photochemical methods [23]. Isohumulones have been evaluted for medical nutrition therapy to treat or prevent metabolic syndrome and related disorders such as diabetes, inflammation and impaired glucose tolerance [24]. In a study with pre-diabetic patients, daily administration of capsules containing 48 mg of isohumulones over a 12 week period led to a significant reduction in body weight and BMI [25]. The brewing industry has developed reduced isohumulones for providing light stable bittering agents for beer. Unlike isohumulones which are readily oxidized and sensitive to light, the reduced isohumulones have improved stability and provide bitter flavors that do not degrade in the final beverage [26]. META060 is a reduced tetrahydro-isohumulone product that consists of a mixture of the cis and trans isomers of the n-, co- and ad-homologs. Notably, a single oral dose of 940 mg of META060 in human trials was found to provide plasma levels sufficient to inhibit LPS-stimulation of TNFα and IL-6 suggesting its potential for treatment of chronic inflammatory disease [27]. Further development of reduced isohumulone derivatives led to the identification of KDT-501, which has been in phase 2 clinical trials for control of metabolic disease in insulin resistant patients [28]. KDT-501 is also being considered for control of polycystic ovarian syndrome and non-fatty acid liver disease [29,30]. Xanthohumol, a prenylated chalcone found in hops, has been shown to have significant antioxidant, anti-inflammatory, anti-cancer and antimicrobial activity in a number of in vitro and in vivo studies [31,32]. However, it suffers from low bioavailabilty and short half-life [33]. Ring closure of xanthohumol followed by demethylation affords the prenylated flavonoid 8-prenylnaringenin (8-PN), which has been reported as potent phytoestrogen and a selective ERα agonist [34]. A daily dietary supplement of a hop extract containing a standardized 100 ug of 8-PN was evaluated in a 16-week trial for alleviation of menopausal discomfort. The trial showed some improvement over placebo and the authors suggest that standardized hop extracts may provide an alternative for women seeking relief of mild vasomotor symptoms [35]. The full range of beneficial and potential undesirable health consequences of exposure to 8-PN have yet to be evaluated [36,37].
Our interest in the natural products obtained from hops began with the introduction of a special topics course on brewing science for non-science major undergraduate students [38]. During the development of this course, we explored analytical methods for the analysis of humulone and isohumulone in hops and beer [39,40]. Isotopically labeled isohumulones were prepared for use in stable isotope dilution assays and potential analysis of degradation products [41]. A continuous flow photochemical method was developed for stereoselective formation of gram quantities of trans-iso-humulones in nearly quantitative yield [42]. The absolute configuration of (-)-n-humulone and (+)-cis-n-isohumulone have been established by x-ray crystallography of their chiral salts [43]. Nevertheless, the enantiomeric purity of humulones and derivatives present in beverages and evaluated in biological studies is only infrequently considered. In this report, we investigate the resolution and enantiomeric purity of isohumulones obtained from both thermal and photochemical processes.

2. Results

In 1965, Clarke and Hildebrand reported the isolation of trans-n-isohumulone 2a from photochemical isomerization of n-humulone 1a [44]. Their crystalline product had a specific rotation of -7.60 (methanol) and stereochemistry consistent with the isolated trans product 2a (-) obtained by base catalyzed isomerization of 1a. In our studies, the trans isomer 2a obtained by continuous flow photochemistry had a specific rotation of -90 (ethanol) [42] which within experimental error and slight solvent differences agrees with previous reports [45]. Considering the modest specific rotation of this compound, it would be difficult to ascertain the enantiomeric purity from rotation data alone. Thermal or base-catalyzed isomerization results in a mixture of cis and trans isomers, in which the optical purity of the isomers also indicates remarkable enantioselectivity resulting in the trans-2a (-) and cis-3a (+) enantiomers (Scheme 1) [23,41]. Based on x-ray crystallographic data, the absolute configuration has been assigned as 4S,5S for (-)-2a and 4S,5R for (+) 3a [43]. Although these are considered as enantiomerically pure products of these reactions, it has been suggested that as much as 15% racemization might occur in the thermal process [46].
To evaluate the enantioselectivity of photochemical isomerization of 1 to 2, we prepared authentic samples of racemic 1a and 1b. Racemization of 1a was first reported by Anteunis and Verzele [47] and has been achieved in various non-polar solvents at elevated temperatures [22,23,43]. We found it convenient to conduct the racemization in isooctane under an argon atmosphere in the pressure tube at 130 oC. The course of the reaction was determined by chiral HPLC analysis of aliquots taken at various time points. Enantiomers of 1a were readily separated by chiral HPLC using a (R,R)-Whelk-O1 chiral stationary phase (figure 2) [48]. Humulones are weak acids with a reported pKa of 5.0 [49]. As a result, an acid modifier was required in the chromatographic analysis to obtain reasonable peak shape. Isocratic conditions of 2% isopropyl alcohol in hexanes with 0.1% trifluoroacetic acid provided baseline separation of the enantiomers of 1a. Nearly complete racemization was achieved in 9 h with the unnatural R-(+) enantiomer eluting first. A plot of the natural log of the enantiomeric excess (ln %ee) vs time in minutes resulted in a straight line indicating first order kinetics for the racemization process (figure 3). The rate constant determined from linear regression of this plot is krac = 0.359h−1, which corresponds to a half-life of 116 min.
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Figure 2. HPLC resolution of humulone 1a enantiomers during thermal racemization. Pirkle Covalent (R,R)-WhelkO1 chiral stationary phase; 2% isopropanol/hexane/0.1% TFA mobile phase.
Figure 2. HPLC resolution of humulone 1a enantiomers during thermal racemization. Pirkle Covalent (R,R)-WhelkO1 chiral stationary phase; 2% isopropanol/hexane/0.1% TFA mobile phase.
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Figure 3. Changes in ln of the percent enantiomer excess (%ee) vs time for the racemization of 1a in isooctane at 130 oC.
Figure 3. Changes in ln of the percent enantiomer excess (%ee) vs time for the racemization of 1a in isooctane at 130 oC.
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The homolog cohumulone 1b was racemized by the same process as 1a. Some decomposition was also observed during the racemization resulting in lower yields of the desired racemic products (+/-) 1a and 1b. The humulones are very sensitive to light and oxidation resulting is losses during purification and handling. Isolated yields after reverse phase HPLC purification of 1a and 1b were between 36 and 39%.
Photochemical isomerization of racemic (+/-) 1a and 1b using a continuous flow apparatus resulted in the expected trans isomers 2a and 2b. The enantiomers were not separable using the Whelk-O1 CSP. Chromatographic resolution was investigated on several available CSPs to find a suitable alternative (Table 1). Resolution of the parent humulone 1a was readily achievable on a variety of carbohydrate based CSPs (IA3, IB3, IC3, ADH) in addition to the Whelk-O1 bonded phase. The IC3 CSP provided an improvement in separation factor α of 2.85, however peak resolution was significantly less due to the lower resolution performance of the column. In fact, all the carbohydrate CSPs had lower resolving power and fewer observed theoretical plates compared to the Whelk-O1 bonded phase. Surprisingly, the separation of cohumulone1b on either the Whelko-1A or the IC3 (a = 1.11 and 1.25, respectively) was significantly less than observed for 1a. For all these cases, the unnatural (+) enantiomer of humulones 1 was eluted first from the CSP. We did not observe resolution of the isohumulones 2 or 3 on the Whelko-1A CSP. However, we were able to obtain greater than baseline resolution of enantiomers of trans-isohumulones 2a and 2b on the IC3 CSP with the (+) enantiomer eluting first.
The racemic cis-isohumulones 3a and 3b were obtained by magnesium catalyzed thermal isomerization at 10 oC [50]. Under these conditions, a mixture of the cis and trans isomers is obtained in an 83:17 ratio. The minor trans isomer can be removed by selective fractional crystallization with dicyclohexylamine. Separation factors for the cis isomers were less than the values observed for the trans isomers. However, separation of the purified cis-isohumulones, 3a and 3b, on an IC3 CSP provided sufficient resolution with the (-) enantiomers eluting first.
With the analytical chiral chromatography method in hand, we turned our attention to analysis of isomerization of naturally occurring (S)-(-)-humulone 1a to the trans- and cis-isohumulones 2a and 3a (Table 2). Although the IC3 CSP was effective for the separation of the isohumulone enantiomers, it did not provide separation of the cis and trans diastereomers. The trans-cis ratios of products from the isomerization reactions were determined by comparison of 1H NMR and reverse phase C18 HPLC with authentic samples. Magnesium catalyzed isomerization under basic conditions afforded mixtures of the cis and trans isomers in which the cis isomer was the major component. The reaction at 10 oC required 5 days for completion and gave an 83:17 mixture of 3a and 2a, respectively. At reflux in methanol-water, the reaction gave a 57:43 mixture of isomers. In both cases, we observed enantiospecific formation of the trans isomers in greater than 95% ee as determined by chiral HPLC. Isolation of the cis isomer, however, resulted in a mixture of enantiomers having an 88% enantiomer excess of the positive 4S,5R isomer. This led us to consider the potential for parital racemization of isohumulones during food processing such as encountered in preparation of beer, hop tea and other products. Acetate buffer conditions at pH 5.5 were investigated to provide a suitable comparison for isomerization encountered during beer brewing [51]. Under these weakly acidic conditions, we obtained a 27:71 mixture of trans and cis isomers, respectively. Separation of the two diastereomers followed by chiral HPLC analysis indicated stereospecific isomerization in the formation of both (-)-2a and (+)-3a.
The photochemical continuous flow reaction using a 395 nm LED light source gave stereo and enantiospecific formation of the (4S,5S)-(-)-2a product which, based on the limits of detection of the minor enantiomer, is greater than 95% ee. The photoflow reaction carried out with higher energy 365 nm LEDs gave significantly different results providing an 80:20 mixture of trans-2a and cis-3a. Analysis of the reaction mixture by chiral HPLC showed two peaks but did not provide separation of the diastereomers (figure 4a). To determine enantioselectivity of the individual products, it was necessary to separate the cis and trans diastereomers by semi-preparative reverse phase C18 chromatography. Purified cis-3a isomer proved to be at least 95% enantiomerically pure based on the levels of detection provided by HPLC analysis. While thermal isomerization provides enantioselective formation of the (+)-(4S, 5S)-3a enantiomer, photochemical isomerization at 365 nm gave stereospecific formation of the opposite enantiomer (-)-(4R,5S)-3a (figure 4b). Surprisingly, chiral HPLC of the purified trans isomer gave a 73:27 mixture of enantiomers resulting in 46% ee of (-)-2a (figure 4c).
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Figure 4. Chiral HPLC resolution of the products obtained from flow photochemical isomerization of 1a at 365 nm. a) reaction mixture; b) isolated cis isomer 3a; c) isolated trans isomer 2a.
Figure 4. Chiral HPLC resolution of the products obtained from flow photochemical isomerization of 1a at 365 nm. a) reaction mixture; b) isolated cis isomer 3a; c) isolated trans isomer 2a.
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The significantly different product mixtures obtained from the 395 nm and 365 nm LED light sources demonstrate the importance of precision photochemistry for optimization of desired compounds [52]. These results can be rationalized in terms of an initial oxadi-π-methane (OPDM) rearrangement to give diastereomeric bicyclic cyclopropanols 5 and 6 [53,54] (scheme 2). Ring opening of the cyclopropanol results in isohumulones 2aand 3a [55]. The OPDM cycloaddition between the sigma 3-4 bond and the p 5-6 bond can occur from either face of the cyclohexanone ring. Based on the product results, at 395 nm the cycloaddition can be rationalized as stereospecific resulting in bicyclic intermediate 5. Ring opening of the cyclopropanol by proton transfer results in a single product (-)-(4S,5S)-2a. We propose that at the lower wavelength of 365 nm, a mixture of bicyclic intermediates 5 and 6 is obtained. A similar mixture of isomeric products has been reported for the photochemical OPDM rearrangement of 2,5-cyclohexadien-1-one and steroid intermediates [56,57]. The cyclopropanol ring opening of intermediate 6 is not stereospecific and results in a mixture of trans and cis isomers (+)-2a and (-)-3a, respectively.
The absolute configuration of (-)-(S)-1a and the cis isomer (+)-(4S,5R)-3a have been previously established by x-ray crystallography of suitable salts with chiral amines [43]. Absolute configuration of the trans isohumulone (-)-2a was inferred based on analysis of the hydrogenated derivative tetrahydro-n-isohumulone. To further establish the absolute configuration of (-)-2a, we evaluated a set of salts prepared from seven chiral amines for potential direct x-ray analysis. Four of the salt pairs resulted in isolated solids, however in all but one case the solids were amorphous and not amenable to x-ray analysis. The crystallization of (-)-2a with (S)-2-benzylamino-2-phenylethanol afforded a highly crystalline salt suitable for X-Ray analysis (scheme 1). The hydroxyl hydrogen atom at C3 position dissociated the trans-n-isohumulone and protonated at the amino N-atom of the 2-benzylamino-2-phenylethanol molecule. The absolute configuration of the humulone molecule is mainly determined by collecting the X-Ray intensity data using Cu-Kα radiation, which triggers the anomalous dispersion effect in the crystal. The trans-n-isohumulone:(S)-2-benzylamino-2-phenylethanol salt crystallizes in non-centrosymmetric P212121spacegroup, with a refined flack parameter of 0.14(9) which confirms the compound is enantiopure in nature. The molecular structure of trans-n-isohumulone anion is shown in Figure 5. It is observed that both the chiral ring carbon atoms C4 and C5 of the humulone molecule exhibit S-configuration, as observed in the previous reported structures [43,58]. Similarly, the lone chiral carbon atom of (S)-2-benzylamino-2-phenylethanol labelled as C28 exhibits the expected S-configuration. The central five-membered ring of the isohumulone molecule exhibit chair conformation with a calculated puckering parameters of q2 = 0.174(4)Å and ϕ2 = 265.8(3)°[59,60]. The substituted moiety at C4 atom lies in the axial position form the five membered Cramer &Pople plane with an angle of 19.9(3)°, the oxygen atom O3 at C1 and the substitution at C2 atom lies in the equatorial position from the five membered plane with an angle of 83.7(3)°, whereas the substitution at C5 atom lies between the axial and equatorial (bisextional) position from the five membered plane with an angle of 56.6(3)° respectively. These deviation of substitution moieties from the five membered Cramer &Pople plane shows that the molecule exhibits trans-conformation.

3. Materials and Methods

3.1. General Methods

Commercial reagents of high purity were purchased (Millipore Sigma, St. Louis, MO, USA and Fisher Scientific, Hampton, NH, USA) and used without further purification.

3.2. Synthesis of Racemic-n-Humulone (1a)

A solution of 241 mg (0.512 mmole) of n-humulone phenylenediamine salt in 25 mL of CH2Cl2 was treated with 3N HCl to afford the free acid. The organic layer was washed with H2O, dried with Na2SO4 and concd in vacuo to afford 187 mg of the free acid as a semi-solid. Without further purification, the free acid was dissolved in 6 mL of isooctane, transferred to a pressure tube and flushed with Ar gas for 5 min. The sealed tube was heated to 130 oC using an oil bath for 12 hrs. The reaction mixture was allowed to cool and concd in vacuo to give a viscous reddish-yellow oil. Purification by preparative reverse phase chromatography (60% MeOH/40% H2O/0.1% TFA) afforded 60 mg (36%) of a yellow oil. Analytical characterization data (Supplementary Material) is consistent with the reported values for the naturally occurring (-)-1a.

3.3. Synthesis of Racemic Trans-n-Isohumulone (2a)

A solution of 77 mg (0.21 mmole) of racemic n-humulone in 15 mL ethanol was prepared. The resultant 0.014 M solution was introduced to the continuous flow photoreactor (395 nm, 42 W) at a flow rate of 1.0 mL/min. The dual flow syringe pump was programmed to follow the introduction of the 0.014 M stock solution with a flush of 125 mL reagent alcohol. Collection of product was initiated after the first 50 mL of void volume. Following the void volume, 90 mL of eluant was collected and concd in vacuo. The crude semi-solid was dissolved in 2.5 mL ethanol, treated with 2.5 mL water and placed in a freezer overnight. The product was collected and washed with a minimum amount of ethanol-water to afford 32 mg (41.6%) of a crystalline white-yellow solid. Analytical characterization data (Supplementary Material) is consistent with the reported values for (-)-2a.

4. Conclusions

In summary, we have developed useful methods for the analysis of enantiomeric composition of humulones and isohumulones. Knowledge of the enantiomeric composition of isohumulones is important for evaluating the bioactivity and pharmacokinetics of these compounds. It is also relevant for understanding taste profile of these compounds as bittering agents in food and drinks. Preparation of racemic n- and co-humulone was readily achieved at elevated temperatures in isooctane exhibiting first order kinetics for racemization and a half-life for (S)-(-)-1a of 116 m at 130 oC. Enantiomers of humulone 1a were readily separated on five different CSPs, with Whelk-O1 showing the best resolution and overall performance. Isohumulone 2a was not resolvable on the Whelko-O1 bonded phase, but the enantiomers were resolved on the carbohydrate IC-3 CSP. The carbohydrate-based IC-3 CSP was employed for resolution enantiomers of 2 and 3. Basic, magnesium catalyzed isomerization of 1a resulted in partial racemization of the cis-3a isomer resulting in 88%ee. However, the trans-2a isomer was obtained in greater than 95% ee or enantiomerically pure within the limits of detection by chiral HPLC. Surprisingly, isomerization of 1a in refluxing aqueous acetate buffer and pH of 5.5, a system chosen to mimic the pH and conditions of wort in beer brewing, resulted in both 2a and 3a in greater than 95% ee. The continuous photoflow isomerization of 1a using a 395 nm LED light source resulted in exclusive formation of the trans-(-)-4S,5S)-2a isomer in greater than 95% ee. X-ray crystallography of the salt obtained from (-)-2a and (S)-2-benzylamino-2-phenylethanol allowed confirmation of the absolute configuration as 4S,5S. Surprisingly, continuous photoflow isomerization using a 365 nm LED light source resulted in a mixture of three isomers; (-)-2a, (+)-2a and (-)-3a. This mixture consists of an 80:20 ratio of the trans and cis isomers in which the trans-(-)-2a isomer is obtained in 46% ee and (-)-3a is obtained in 95% ee. The cis-(-)-3a isomer thus obtained has the opposite absolute configuration compared to thermal aqueous isomerization in either basic or buffered solution. This is the first report of a synthetic method for preparation of cis-(-) (4R,5S)-3a. Composition of the isomeric isohumulone products can be controlled by precision photochemistry. These methods can be applied for understanding the relevance of enantiomeric purity to biological evaluation of humulone and isohumulone derived products.

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org, Details for synthesis of all compounds, chromatographic resolution of enantiomers and x-ray crystallographic data can be found online.

Author Contributions

B.C.H., G.G., R. J. and T.S. conducted the experiments. B.C.H. and G.G. collected spectral data. T.S. collected mass spectral data. R. J. provided the x-ray crystallographic data. B.C.H. supervised the project and prepared the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

Not applicable.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Natural products and derivatives obtained from humulus lupus L. (hops).
Figure 1. Natural products and derivatives obtained from humulus lupus L. (hops).
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Scheme 1. Isomerization of humulones1 to trans/cis isohumulones 2 and 3.
Scheme 1. Isomerization of humulones1 to trans/cis isohumulones 2 and 3.
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Scheme 2. Precision photochemical isomerization of humulone 1a to isohumulones 2a and 3a. Photochemistry at 365 nm provided 2a (46% ee of (-)-2a) and 3a (>95%ee). .
Scheme 2. Precision photochemical isomerization of humulone 1a to isohumulones 2a and 3a. Photochemistry at 365 nm provided 2a (46% ee of (-)-2a) and 3a (>95%ee). .
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Figure 5. Molecular structure of trans-n-isohumulone showing displacement ellipsoids anion drawn at 50% probability level.
Figure 5. Molecular structure of trans-n-isohumulone showing displacement ellipsoids anion drawn at 50% probability level.
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Table 1. HPLC separations factors (α) and resolution (R) of humulones 1 and isohumulones 2 and 3 on selected chiral stationary phases (CSP).
Table 1. HPLC separations factors (α) and resolution (R) of humulones 1 and isohumulones 2 and 3 on selected chiral stationary phases (CSP).
Compound CSP Mobile Phase*
(% IPA) 		Capacity factor (k’) Alpha (α) Resolution (R)
1a Whelk-O1 2 0.49 (+) 1.73 5.0
IA3 5 0.92 (+) 1.30 2.5
IB3 2 1.20 (+) 1.62 4.0
IC3 2 0.37 (+) 2.85 2.6
ADH 5 1.27 (+) 1.27 1.6
1b Whelk-O1 1 1.55 (+) 1.11 1.6
IC3 1 1.70 (+) 1.25 0.5
2a Whelk-O1 1 2.0 NS
IC3 1 1.56 (+) 1.72 2.3
2b IC3 1 1.60 1.55 3.0
3a IC3 1 2.20 (-) 1.32 3.8
3b IC3 1 2.10 (-) 1.24 2.1
*Mobile phase consists of hexane/isopropanol (IPA) with added 0.1 % TFA. Capacity factor indicates the retention of the first eluted enantiomer with its sign of rotation listed in parenthesis. NS indicates no separation. Details for HPLC conditions and description of CSPs in Supplementary Material.
Table 2. Enantiomeric composition of isohumulones obtained from isomerization reactions under thermal or photochemical conditions.
Table 2. Enantiomeric composition of isohumulones obtained from isomerization reactions under thermal or photochemical conditions.
Conditions Trans:cis ratio
(isolated yield) 		trans-2a%ee (rotation) cis-3a%ee (rotation)
5 eq MgSO4/2 eq NaOH (CH2Cl2/H2O), 10C, 5 d 17:83 (86%) >95% (-) 88% (+)
5 eq MgSO4/2 eq NaOH (MeOH/H2O), heat, 15 m 43:57 (72%) >95% (-) 88% (+)
Acetate buffer, pH = 5.5,
Heat, 4h		 27:71 >95% (-) >95% (+)
Photoflow, 395 nm >95% trans (93%) >95% (-) 2-3%
Photoflow, 365 nm 80:20 (53%) 46% (-) >95% (-)
* Reaction details given in the Supplementary Material.
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