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. Author manuscript; available in PMC: 2008 Sep 17.
Published in final edited form as: Org Lett. 2006 Oct 12;8(21):4711–4714. doi: 10.1021/ol061727g

Stereochemical control in the reduction of 2-Chromanols

Kelin Li 1,2, Kumar Vanka 1, Ward H Thompson 1, Jon A Tunge 1,2
PMCID: PMC2538801  NIHMSID: NIHMS63818  PMID: 17020284

Abstract

graphic file with name nihms63818f8.jpg

Reduction of C5-substituted 2-hydroxychromans selectively provides 2,4-cis-chromans using large silane reductants and 2,4-trans-chromans using the smaller silane PhSiH3. The stereochemical outcome has been rationalized based on a Curtin-Hammett kinetic situation arising from hydride delivery to two different conformations of an intermediate oxocarbenium ion. This method provides a powerful way to control the relative stereochemistry of these substructures which are prevalent in bioactive natural products.

Substituted chromans are a class of compounds that are found widely in bioactive natural products. The broad range of bioactivities exhibited by molecules containing this core element has led to their description as “privileged structures.”1 Given that the key scaffold in these compounds remains constant, one can attribute their biological selectivity to the nature, pattern, and stereochemistry of substitutents that adorn the chroman core.

For example, the stereochemistry of the myristinin flavanoids has been shown to affect their bioactivities, with myristinin A being a more potent polymerase β-inhibitor and the atropisomeric myristinins B/C being more potent COX-2 inhibitors (Figure 1).2 Thus, the control of stereochemistry in the formation of natural and synthetic flavanoids is of considerable interest.

Figure 1.

Figure 1

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Herein we report a stereoselective reduction of 2-chromanols to provide molecules that contain the core structure of the myristinins.3 In some cases the choice of reductant allows selective synthesis of either the cis-2,4 or trans-2,4 diastereomers.

To begin, we were interested in examining the stereochemistry of reduction of oxocarbenium ions derived from 2-chromanols using silane reductants (Scheme 1).3 It was expected that the desired 2-chromanols would be accessible via the addition of organometallic reagents to dihydrocoumarins. We have recently reported a simple, atom-economical procedure for the synthesis of dihydrocoumarins based on acid-catalyzed hydroarylation of cinnamic acids.4 While treatment of dihydrocoumarins with PhMgBr did not lead to any addition product,5 their reaction with 0.9 equiv. of PhLi selectively provided mixtures of the two possible monoaddition products in good yields (Scheme 2).6,7 The lactol (2)/ketone (3) ratio of the product proved to be highly variable (Table 1). While we do not have a definitive explanation for the variability, it appears that R5-alkyl substitution favors lactol (2) formation and R5+R8 alkyl substitution provides the highest ratios of lactol.

Scheme 1.

Scheme 1

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Scheme 2.

Scheme 2

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Table 1.

PhLi additions to dihydrocoumarins (Scheme 3).

reactant R5 R6 R7 R8 yield lactol/ketone
1a OMe H OMe H 75a 0.54:1
1b H t-Bu H H 97 0.69:1
1c H OCH2O H 74 0.64:1
1d Me Cl Me H 95 6.4:1
1e Me H H i-Pr 60a 18.5:1
1f H OMe H H 81 0.48:1
1g H H OMe H 95 0.47:1
1h Me H Me H 73a 2.4:1
1i OMe OMe OMe H 61a 0.52:1
1j Me H H Me 82a 13.5:1
1k i-Pr H H Me 62a 15.7:1
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a)

the mass balance is recovered starting material

Treatment of the lactol/ketone mixture 2a/3a with BF3-Et2O and Et3SiH at −78 °C for 1h resulted in complete conversion to the product chroman 4a as a 1.7:1 cis:trans mixture of diastereomers (Scheme 3). In an attempt to improve this ratio, i-Pr3SiH was used as the reductant which indeed provided the cis-product in 20:1 dr as determined by 1H NMR spectroscopy. Interestingly, use of PhSiH3 as the reductant afforded the trans-product selectively (1:11 cis:trans). It is important to note that the cis- and trans-chromans are both configurationally stable under the reaction conditions.

Scheme 3.

Scheme 3

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The observed products could possibly arise from one of two mechanisms. First, hydrosilylation of the ketone followed by intramolecular substitution could produce the chroman.5 Alternatively, formation of an oxocarbenium ion from the lactol followed by addition of hydride is a possibility (Scheme 1).8 Since the observed stereochemical dependence on the nature of the silane is inconsistent with an intramolecular SN1 reaction, we favor the latter mechanism.

Given the silane-dependent reversal of stereochemical outcome, experiments aimed at determining the origin of stereoselectivity were conducted. To begin, a variety of lactol/chalcone mixtures that differ only in the substitution of the arene ring of the chroman were prepared. These substrates were subjected to reductions with i-Pr3SiH, Et3SiH, or PhSiH3. While PhSiH3 always gave more trans product than Et3SiH or i-Pr3SiH did, it is clear from the data in Table 2 that a substituent in the 5-position is required for high trans-selectivity.

Table 2.

Selective reductions of lactol/chalcone mixtures.

prod R5 R6 R7 R8 X-H yield (dr)a
4a OMe H OMe H i-Pr3Si 56 (20:1)
Et3Si 65 (1.7:1)
PhH2Si 94 (1:11)
4b H t-Bu H H Et3Si 90 (>20:1)
PhH2Si 72 (2.7:1)
4c H OCH2O H Et3Si 82 (>20:1)
PhH2Si 50 (7.3:1)
4d Me Cl Me H i-Pr3Si 76 (11:1)
PhH2Si 99 (1:10)
4e Me H H i-Pr i-Pr3Si 99 (9.1:1)
Et3Si 99 (1.6:1)
PhH2Si 99 (1:17)
4f H OMe H H Et3Si 89 (14:1)
PhH2Si 49 (2.6:1)
4g H H OMe H Et3Si 68 (>20:1)
PhH2Si 63 (5:1)
4h Me H Me H i-Pr3Si 56 (11:1)
PhH2Si 95 (1:12)
4i OMe OMe OMe H i-Pr3Si 62 (13:1)
PhH2Si 82 (1:4)
4j Me H H Me i-Pr3Si 55 (4:1)
PhH2Si 96 (1:14)
4k i-Pr H H Me i-Pr3Si 86 (14:1)
PhH2Si 99 (1:11)
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a)

yield and cis:trans ratio of isolated product

The stereochemical outcome of the reduction can be explained if one considers the delivery of hydride to the hypothetical oxocarbenium ion intermediate. Geometry optimizations at the B3LYP/6-31G* level of theory, using the Gaussian program,9 show that a simple 2,4-phenyl substituted oxocarbenium ion intermediate adopts a half-chair structure where the 4-aryl group can occupy either a pseudo-axial or a pseudo-equatorial position. When R5=H, the calculations show that the C4-phenyl group prefers to occupy the equatorial position by 0.4 kcal/mol (Fig. 2). However, if R5=Me, then the C4-phenyl group prefers the axial position by 3.2 kcal/mol.10

Figure 2.

Figure 2

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Most stable conformations of oxocarbenium ions

Further calculations show that the barrier for interconversion of the axial and equatorial conformers is 3.8 kcal/mol for R5=H and 4.8 kcal/mol for R5=Me. Therefore, the conformational equilibrium is rapidly maintained at −78 °C and reduction of the oxocarbenium is expected to follow Curtin-Hammett kinetics.11 In the case of a Curtin-Hammett kinetic situation, the cis/trans ratio equals the product of Keq and the ratio of rate constants for hydride delivery (Scheme 4).

Scheme 4.

Scheme 4

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With large hydride sources such as i-Pr3SiH, axial delivery of the hydride is expected to occur preferentially on the equatorial conformer so as to minimize the incipient 1,3-diaxial interaction (kcis>>ktrans).3c,12 In this case, the reaction product is primarily controlled by the rates of hydride delivery (kcis/ktrans>>Keq); thus the cis-product is favored regardless of the conformational equilibrium.

If the hydride source is small (i.e. PhSiH3), then hydride can be delivered axially to either conformer (kcis~ktrans). In this case, the product ratio will have a large dependence on population of conformers as given by Keq.13 Thus, when R5=H and the there is a small preference for the equatorial conformer, PhSiH3 provides low cis-selectivity. However, the trans-chroman is selectively produced from substrates where R5≠H and the axial conformer is preferred.

In summary, we have developed a convenient, stereoselective procedure for the reduction of 2-chromanols. The reduction is the key step in a convenient 3-step procedure for the formation of diarylchromans from phenols and cinnamic acids (Scheme 5). Furthermore, the stereochemistry of the reduction can be predicted based on a simple Curtin-Hammett kinetic model for hydride delivery to an intermediate oxocarbenium ion. Finally, the ability to selectively access either cis- or trans-chromans is expected to facilitate production of stereochemically diverse chemical libraries.

Scheme 5.

Scheme 5

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Supplementary Material

1si20060816_03. Supporting Information Available.

Experimental procedures and spectroscopic data of all compounds. Cartesian coordinates of the DFT-optimized structures. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgment

We acknowledge support of this work by the National Institutes of Health (KU Chemical Methodologies and Library Development Center of Excellence, P50 GM069663).

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1si20060816_03. Supporting Information Available.

Experimental procedures and spectroscopic data of all compounds. Cartesian coordinates of the DFT-optimized structures. This material is available free of charge via the Internet at http://pubs.acs.org.

NIHMS63818-supplement-1si20060816_03.pdf (5.2MB, pdf)

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