SULFONAMIDE-BASED ORGANOCATALYSTS AND METHOD FOR THEIR USE

CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of the earlier filing date of U.S.

Provisional Application No. 60/994,199, filed on September 17, 2007, which is incorporated herein by reference.

FIELD The present disclosure concerns a novel organo catalyst, more particularly a proline mimetic organocatalyst, that is particularly useful for facilitating asymmetric syntheses, particularly enantioselective and diastereoselective reactions.

ACKNOWLEDGMENT OF GOVERNMENT SUPPORT This invention was made with government support under grant No.

GM63723 awarded by National Institutes of Health. The government has certain rights in the invention.

BACKGROUND Since the early days of enantioselective Robinson annulations facilitated by proline, organocatalysis has garnered the attention of the synthetic community. Organocatalysis typically employs mild conditions, are relatively easy to execute, and can be used for a wide variety of chemical transformations. Much of the key reactivity in organocatalysis concerns activating carbonyl moieties via formation of a chiral iminium ion, which resembles nature's method for forming alkaloid natural products. Despite this similarity, relatively little attention has been focused on the application of organocatalysis to alkaloid synthesis. Furthermore, while an intramolecular conjugate addition is often a key ring forming strategy in the synthesis of polycyclic natural products, only limited examples of organocatalyzed, intramolecular Michael addition have been reported.

Certain proline sulfonamides are known. For example, the following proline sulfonamides have been disclosed in the literature.

Proline and Select Proline Mimetics

1 2 3 R = Me 6 R = OTBDPS

4 R = Ph 7 R = 4-f-Bu-C ₆ H ₄

5 R = p-tol 8 R = C(O)alkyl

The solubility for compounds 1-5 is quite poor (<5 mg/mL of dichloromethane). These poor solubilities substantially limit the usefulness of such compounds both for research purposes, and more importantly for catalytic reactions used to make commercial chemicals. Compounds 6-8 are substantially more expensive to make and use than are catalyst embodiments disclosed in the present application. Furthermore, only one enantiomer is available for making each of compounds 6-8.

SUMMARY

Accordingly, new organo catalysts are needed to supplement such known compounds, and which improve on both there usefulness, particularly for commercial applications, and effectiveness, particularly for performing enantioselective or diastereoselective reactions. Thus, certain embodiments of the present invention concern organocatalysts, particularly pro line sulfonamide organocatalysts, having a first general formula as follows.

With reference to this first general formula, R ₁ -Rs are independently selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, formyl, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded together to form a ring. At least one of such substituents typically comprises 4 or more carbon atoms, generally carbon

atoms in an aliphatic chain. At least one OfR ₁ and R ₅ is hydrogen or halogen. This contributes substantially to the organic solvent solubility of such compounds, and provides a substantial benefit relative to known compounds. This is evidenced by the generally increased reactivity and enantioselectivity of disclosed embodiments of the organocatalyst. IfR ₁ -R ₅ is aryl, the aryl group is directly bonded to one OfR ₁ -R ₅ and the compound is other than (S)-N-(I -napthylsulfonyl)-2- pyrrolidinecarboxamide, a known compound. More typically, R ₁ -R ₅ are independently selected from aliphatic groups having 4 or more carbon atoms, hydrogen or halogen, including chlorine, fluorine, bromine and iodine. The aliphatic group also can be halogenated. Fluorinated compounds do provide some known benefits relative to the other halogens. For example, such compounds generally are easier to purify and recover the catalyst using, for example, chromatography.

In certain embodiments, one OfR ₂ -R ₄ is aliphatic or substituted aliphatic, often alkyl, having 4 or more carbon atoms, and most typically having a chain length of from 4 to 24 carbon atoms. Again, for these embodiments, at least one OfR ₁ -R ₂ and R ₄ -R ₅ typically is a hydrogen or halogen, and at least one OfR ₂ -R ₄ also may be a halogenated alkyl, such as a fluorinated alkyl.

R ₆ -R ₁₁ independently are selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, azides, cyclic, substituted cyclic, ester, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, thiol, thiol ether, thiol ester, silyl, silyl ether, silyl ester, or are bonded together to form a ring. R ₁₂ -R ₁₄ are independently selected from hydrogen and lower alkyl. For certain disclosed embodiments, R ₆ -R ₁₁ are independently selected from aliphatic, carbonyl, ether, hydrogen, hydroxyl, nitro, nitroso, or are atoms in an aryl, heteroaryl, cyclic, or heterocyclic ring, and even more typically are independently selected from hydrogen, lower alkyl, hydroxyl, nitro, nitrso, ether, carbonyl, cyclohexyl or phenyl. R ₁₂ and R ₁₃ are independently selected from aliphatic, most typically alkyl, and hydrogen.

A person of ordinary skill in the art will appreciate that the first general formula is stereoambiguous. That is, it does not indicate the relative or absolute stereochemistry of the potential stereoisomers. This is to indicate that all such stereoisomers are within the scope of the disclosed organocatalysts. Particular stereoisomers are more likely to be used than others, based on certain criteria, such as commercial availability of starting materials, or effectiveness as a catalyst. For example, certain disclosed catalysts have a formula

or

Embodiments of a method for using these organocatalysts also are disclosed. The method comprises providing a disclosed organocatalyst, and performing a reaction, often an enantioselective or diastereoselective reaction, using the organocatalyst. A person of ordinary skill in the art will appreciate that a wide variety of different reactions can be performed using such catalysts. However, solely by way of example, disclosed catalysts can be used to perform aldol reactions, conjugate additions, such as Michael additions, Robinson annulations, Mannich reactions, α-aminooxylations, α-hydroxyaminations, α-aminations and alkylation reactions. Certain of such reactions are intramolecular cyclizations used to form cyclic compounds, such as 5- or 6-membered rings, having one or more chiral centers.

The effectiveness of disclosed catalysts can be described in several different ways. First, disclosed organocatalysts generally are much more soluble in typical

solvents used for organic synthesis than are known compounds. Moreover, the reaction yield is generally quite good with disclosed compounds, and most typically is greater than 50%, and more typically is 60% or greater. The reactions often also are used to produce compounds having new chiral centers. The enantioselective and diastereoselective effectiveness of such catalysts to perform these reactions also is very high. For example, for certain embodiments, the enantioselective reaction provides an enantiomeric excess of at least about 70%, such as greater than 80%, or greater than 90%, and in some cases up to at least 99%. Similarly, the dr typically is greater than 10:1, such as 20:1, often as high as 50:1 and can be as high as 99:1 or greater.

The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.

DETAILED DESCRIPTION

I. Terms

The following term definitions are provided to aid the reader, and should not be considered to provide a definition different from that known by a person of ordinary skill in the art. And, unless otherwise noted, technical terms are used according to conventional usage.

As used herein, the singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Also, as used herein, the term "comprises" means "includes." Hence "comprising A or B" means including A, B, or A and B. It is further to be understood that all nucleotide sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides or other compounds are approximate, and are provided for description.

Aldehyde: Is a carbonyl -bearing functional group having a formula

where the line drawn through the bond indicates that the functional group can be attached to any other moiety, but that such moiety simply is not indicated.

Aldol Reaction: A carbon-carbon bond forming reaction that involves the nucleiphilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals. Sometimes, the aldol addition product loses water to form an α,β-unsaturated ketone in an aldol condensation.

Aliphatic: A substantially hydrocarbon-based compound, or a radical thereof (e.g., C ₆ Hn, for a hexane radical), including alkanes, alkenes, alkynes, including cyclic version thereof, and further including straight- and branched-chain arrangements, and all stereo and position isomers as well.

Amide: An organic functional group characterized by a carbonyl group (C=O) linked to a nitrogen atom and having the following general formula, where R, R' and R" are the same or different, and typically are selected from hydrogen, aliphatic, and aryl.

Analog, Derivative or Mimetic: An analog is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure, such as a difference in the length of an alkyl chain), a molecular fragment, a structure that differs by one or more functional groups, a change in ionization. Structural analogs are often found using quantitative structure activity relationships (QSAR), with techniques such as those disclosed in Remington (The Science and Practice of Pharmacology, 19th Edition (1995), chapter 28). A derivative is a biologically active molecule derived from the base structure. A mimetic is a molecule that mimics the activity of another molecule, such as a biologically active molecule. Biologically active molecules can include chemical structures that mimic the biological activities of a compound.

Aryl: A substantially hydrocarbon-based aromatic compound, or a radical thereof (e.g. C ₆ H ₅ ) as a substituent bonded to another group, particularly other

organic groups, having a ring structure as exemplified by benzene, naphthalene, phenanthrene, anthracene, etc.

Arylalkyl: A compound, or a radical thereof (C ₇ H ₇ for toluene) as a substituent bonded to another group, particularly other organic groups, containing both aliphatic and aromatic structures.

Carbonyl: Refers to a functional group comprising a carbon-oxygen double bond, where the carbon atom also has two additional bonds to a variety of groups, including hydrogen, aliphatic, such as alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and the like. Carboxylic Acid: Refers to a carbonyl-b earing functional group having a formula

Cyclic: Designates a substantially hydrocarbon, closed-ring compound, or a radical thereof. Cyclic compounds or substituents also can include one or more sites of unsaturation, but does not include aromatic compounds. One example of such a cyclic compound is cyclopentadienone.

Enantiomer: One of two stereoisomers that are not superimposable mirror images.

Enantiomeric Excess: Refers to chemical mixtures where one enantiomer is present more than the other. Enantiomeric excess is defined as the absolute difference between the mole fraction of each enantiomer. ee = \ F ₊ — F - \ where

F ₊ + F - = 100% Enantiomeric excess is most often expressed as a percent enantiomeric excess.

Enantiomeric excess is used to indicate the success of an asymmetric synthesis. For mixtures of diastereomers, analogous definitions are used for diastereomeric excess and percent diastereomeric excess. As an example, a sample with 70% of R isomer and 30% of S will have an enantiomeric excess of 40%. This can also be thought of as a mixture of 40% pure R with 60% of a racemic mixture (which contributes 30%

R and 30% S to the overall composition). The use of enantiomeric excess has established itself because of its historic ties with optical rotation. These concepts of ee and de may be replaced by enantiomeric ratio or er (S :R) or q (S/R) and diastereomeric ratio (dr).

Ester: A carbonyl-bearing substituent having a formula

where R is virtually any group, including aliphatic, substituted aliphatic, aryl, arylalkyl, heteroaryl, etc.

Ether: A class of organic compounds containing an ether group, that is an oxygen atom connected to two aliphatic and/or aryl groups, and having a general formula R-O-R', where R and R may be the same or different.

Heteroaryl: Refers to an aromatic, closed-ring compound, or radical thereof as a substituent bonded to another group, particularly other organic groups, where at least one atom in the ring structure is other than carbon, and typically is oxygen, sulfur and/or nitrogen.

Heterocyclic: Refers to a closed-ring compound, or radical thereof as a substituent bonded to another group, particularly other organic groups, where at least one atom in the ring structure is other than carbon, and typically is oxygen, sulfur and/or nitrogen. Ketone: A carbonyl-bearing substituent having a formula

where R is virtually any group, including aliphatic, substituted aliphatic, aryl, arylalkyl, heteroaryl, etc.

Lower: Refers to organic compounds having 10 or fewer carbon atoms in a chain, including all branched and stereochemical variations, particularly including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

Michael addition: Refers generally to addition of a compound containing an electron withdrawing group, Z, which, in the presence of a base, add to olefins of the form C=C-Z, as indicated below.

Z-CH ₂ -Z' + — C=C-Z" Z-CH-C-C-Z"

Z ¹ H

Z can be a variety of groups, including C=C, CHO, COR (including quinones), COOR, CONH ₂ , CN, NO ₂ , SOR SO ₂ R, etc. With reference to addition using a nucleophile Y ^" , the mechanism is believed to be as follows.

Y H I I -C-C-C=O

Protecting or Protective Group: To synthesize organic compounds, often some specific functional group cannot survive the required reagents or chemical environments. These groups must be protected. A protecting group, or protective group, is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. Various exemplary protecting or protective groups are disclosed in Greene's Protective Groups in Organic Synthesis, by Peter G. M. Wuts and Theodora W. Greene (October 30, 2006), which is incorporated herein by reference.

Silyl: A functional group comprising a silicon atom bonded to different functional groups, and typically having a formula

Where R ₁ -R ₃ independently are selected from various groups, including by way of example aliphatic, substituted aliphatic, cyclic aliphatic, substituted cyclic aliphatic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

Substituted: A fundamental compound, such as an aryl or aliphatic compound, or a radical thereof, having coupled thereto, typically in place of a hydrogen atom, a second substituent. For example, substituted aryl compounds or substituents may have an aliphatic group coupled to the closed ring of the aryl base, such as with toluene. Again solely by way of example and without limitation, a long-chain hydrocarbon may have a substituent bonded thereto, such as one or more halogens, an aryl group, a cyclic group, a heteroaryl group or a heterocyclic group.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety, unless the context clearly indicates otherwise.

II. Proline-Based Organocatalysts

The present invention is directed to organocatalysts, particularly proline sulfonamide organoscatalysts. Particular disclosed embodiments of the catalyst have a formula

where R1-R5 are independently selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded

together to form a ring. Each of such substituents typically comprises 4 or more carbon atoms, generally carbon atoms in an aliphatic chain. At least one OfR ₁ and R ₅ is hydrogen or halogen. This contributes substantially to the organic solvent solubility of such compounds, and provides a substantial benefit relative to known compounds. This is evidenced by the generally increased reactivity and enantioselectivity of disclosed embodiments of the organocatalyst. IfR ₁ -R ₅ is aryl, the aryl group is directly bonded to one OfR ₁ -R ₅ and the compound is other than (S)-N-(I -napthylsulfonyl)-2-pyrrolidinecarboxamide, a known compound. More typically, R ₁ -R ₅ are independently selected from aliphatic groups having 4 or more carbon atoms, hydrogen or halogen, including chlorine, fluorine, bromine and iodine, and generally fluorine. The aliphatic group also can be halogenated.

In certain embodiments, one OfR ₂ -R ₄ is aliphatic or substituted aliphatic, often alkyl, having 4 or more carbon atoms, and most typically having a chain length of from 4 to 24 carbon atoms. Again, for these embodiments, at least one OfR ₁ -R ₂ and R ₄ -R ₅ typically is a hydrogen or halogen, and at least one OfR ₂ -R ₄ also may be a halogenated alkyl, such as a fluorinated alkyl.

R ₆ -R ₁₁ independently are selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, azides, cyclic, substituted cyclic, ester, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded together to form a ring. R ₁₂ -R ₁₄ are independently selected from hydrogen and lower alkyl. For certain disclosed embodiments, R ₆ -R ₁₁ are independently selected from aliphatic, carbonyl, ether, hydrogen, hydroxyl, nitro, nitroso, or are atoms in an aryl, heteroaryl, cyclic, or heterocyclic ring, and even more typically are independently selected from hydrogen, lower alkyl, hydroxyl, nitro, nitrso, ether, carbonyl, cyclohexyl or phenyl.

A person of ordinary skill in the art will appreciate that the first general formula is stereoambiguous. That is, it does not indicate the relative or absolute stereochemistry of all potential stereoisomers. This is to indicate that all such stereoisomers are within the scope of the disclosed organocatalysts. Particular

stereoisomers are more likely to be used than others, based on certain criteria, such as commercial availability of starting materials, or effectiveness as a catalyst. For example, certain disclosed catalysts have a formula

or

R ₁ -R ₅ often are alkyl. Thus, second general formulas that describes disclosed embodiments are provided below.

or

With reference to these formulas, n is from 1-5. Each of the alkyl substituents has 4 or more, typically from 4 to about 24, carbon atoms. These substituents may be in any position on the phenyl ring, including the ortho, meta and para positions relative to the sulfonamide functional group. Thus, certain disclosed compounds have a formula

or

where n is from 4 to about 24, more typically from about 8 to about 20, carbon atoms. One particular working embodiment is provided below, having a dodecyl substituent in the para position.

or

Certain disclosed embodiments are directed to amine compounds. For example, certain disclosed embodiments have a formula

or

With reference to these amine-type compounds, n is from 1 to 5. Moreover, the amine typically has at least one substituent comprising at least 4 carbon atoms. Again, the amine substituents may be in any position on the phenyl ring, including the ortho, meta and para positions relative to the sulfonamide functional group, and hence further general formulas include

or

Ris and R ₁₆ generally are independently selected from hydrogen and aliphatic substituents. Moreover, at least one OfR _1S and R ₁₆ typically comprises 4 or more carbon atoms. For certain embodiments, R _1S and R ₁₆ are alkyl groups having from 4

to 24 carbon atoms, and also may be dialkyl amine, again where at least one amine substituent typically has 4 or more carbon atoms.

Certain disclosed embodiments are directed to ester-type compounds. For example, certain disclosed embodiments have a formula where at least one OfR ₁ -Rs is an ester. Thus, a first general formula useful for describing such ester compounds is as provided below.

(Ester) _n

With reference to this general formula, n typically is from 1 to 5. Particular disclosed ester compounds have a structure

With reference to this formula, R ₁₅ typically is an aliphatic group comprising 4 or more carbon atoms. Particular esters are alkyl esters having from 4 to 24 carbon atoms.

Still other disclosed compounds are aryl compounds. Such compounds may have a formula

With reference to this general formula, n is from 1 to 5. Particular aryl compounds are based on general biaryl structures, as provided below.

or

With reference to these general biaryl compounds, R21-R25 typically are independently selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded together to form a ring. More typically, R ₂₁ -R ₂₅ are independently selected from aliphatic, substituted aliphatic, halogen, or hydrogen.

Aryl compounds may be fused ring systems, such as the naphthalene and anthracene-type compounds. For example, certain aryl compounds have a structure

or

With reference to these formulas, R ₁₇ -R _2O typically are independently selected from aliphatic, substituted aliphatic, alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, cyclic, substituted cyclic, ester, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, nitro, nitroso, or are bonded together to form a ring, and where at least one OfR ₁ -R _2O is other than hydrogen.

Still other disclosed compounds are ether compounds. For example, a first general formula useful for describing such ether compounds is as follows.

With reference to this general formula, n is from 1 to 5. Moreover, and at least one of the ether functional groups typically comprises 4 or more carbon atoms. Particular disclosed ether compounds have a formula

With reference to these formulas, R ₁₅ typically comprises 4 or more carbon atoms and is aliphatic, substituted aliphatic, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, heterocyclic and substituted hetereocyclic.

Still other disclosed compounds are amide -type compounds. A first general formula useful for describing such amide-type compounds is provided below.

With reference to this formula, n is from 1 to 5. Moreover, the amide typically includes a substituent having 4 or more carbon atoms, most typically from 4 to about 24 carbon atoms. Particular embodiments of amide-type compounds have the following formulas.

With reference to these formulas, R ₁₅ typically comprises 4 or more carbon atoms and is aliphatic, substituted aliphatic, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, heterocyclic and substituted hetereocyclic. R ₁₆ most typically is hydrogen or lower alkyl. These first amide compounds have the phenyl ring directed bonded to a carbonyl functional group. A person of ordinary skill in the art will recognize that other amide compounds are possible where the nitrogen atom is directly bonded to the phenyl ring. Such compounds typically have formulas as follows.

With reference to these formulas, R ₁₅ typically comprises 4 or more carbon atoms and is aliphatic, substituted aliphatic, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, heterocyclic and substituted hetereocyclic. And, again, R ₁₆ typically is hydrogen or lower alkyl.

Halogenated aryl compounds also are disclosed. For example, a first general formula useful for describing such compounds has the following formulas.

or

With reference to these general formulas, X is a halogen, and n is from 1 to 5. If n is less than 5, any remaining R ₁ -Rs groups are independently selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded together to form a ring. Each of such substituents comprises 4 or more carbon atoms, typically carbon atoms in an aliphatic chain. Particular halogenated compounds have the following general formulas.

or

or

With reference to these formulas, X is a halogen, typically fluorine, n is from 1 to 5. R ₃ , R ₄ and R ₅ are independently selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl,

substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded together to form a ring. Each of such substituents comprises 4 or more carbon atoms, typically carbon atoms in an aliphatic chain.

In addition to halogenated aromatic rings, substituents also may be halogenated. For example, such compounds may have the following first general formulas.

or

With reference to these formulas, n is 4 or greater; m is the number of halogen atoms and is from 1 to 2n + 1; and o is from 1 to 5. If o is less than 5, any remaining R ₁ -Rs is/are selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded together to form a ring. Each of such substituents comprises 4 or more carbon atoms, typically carbon atoms in an aliphatic chain. Particular embodiments of such halogenated compounds have the following formulas.

Cn ^X mH[(2n ₊ 1)- ^■ ,m]

or

With reference to these formulas, n is 4 or greater,; m is the number of halogen atoms and is from 1 to 2n + 1. R ₁ -R ₄ are independently selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone,

nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded together to form a ring. Each of such substituents comprises 4 or more carbon atoms, typically carbon atoms in an aliphatic chain.

Still additional embodiments of the presently disclosed organocatalysts are ketone-based catalysts. Such compounds typically have a formula

With reference to this formula, n is from 1 to 5. The ketone typically includes a substituent, often an aliphatic substituent, having 4 or more carbon atoms, and most typically from 4 to about 24 carbon atoms.

A person of ordinary skill in the art also will appreciate that the pro line ring also can be substituted with various substituents. For example, certain such compounds can be described using the following general formulas

or

With reference to these formulas R _1S is hydrogen, aliphatic, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, cyclic, substituted cyclic, heterocyclic, substituted heterocyclic, or silyl. Particular embodiments include

10

or

Additional particular examples of organocatalysts also are disclosed. For these compounds, any R groups present are as disclosed for the first general formula provided above. These particular compounds include:

and

One issue associated with the present compounds is their solubility in organic solvents, such as chlorinated solvents. Proline mimetic organo catalysts have been developed that exhibit improved solubility in less polar organic solvents compared to known catalysts. This solubility profile has added industrial advantages by utilizing solvents that provide good phase splits with water and are more easily recycled on increased commercial scales.

Disclosed proline mimetic organocatalysts can be utilized for unprecedented enantioselective, intramolecular Michael addition of keto sulfones to enones with high enantioselectivity and diasteroselectivity. Furthermore, the flexibility of disclosed proline mimetic organocatalysts to facilitate enantioselective aldol reactions in more non-polar solvents has been accomplished - including highly enantioselective anti aldol reactions between cyclohexanones and aldehydes, including the unexpected syn aldol adduct with cyclopentanones. Finally, the enantioselective keto sulfone Michael addition has been applied to a second generation strategy toward lycopodine.

In order to explore the effects of solvent polarity, the solubility of certain catalysts in methylene chloride was screened. Disclosed catalysts typically have a solubility of at least 10 milligrams/milliliter in dichloromethane, and typically at least 50 milligrams/milliliter in dichloromethane. In comparison, the solubility properties for each of the known compounds listed below were quite poor (<5 mg / mL).

Proline and Select Proline Mimetics.

^- N ^N N' ^N ^N HN-SO ₂ R N OH

H H H H H

1 2 3 R = Me 6 R = OTBDPS

4 R = Ph 7 R = 4-J-Bu-C ₆ H ₄

5 R = p-tol 8 R = C(O)alkyl

The absence of a significant non-polar region to the molecule may be the origin of this poor solubility. Consequently, certain disclosed sulfonamide catalysts possess a group, such as a sizable hydrocarbon chain connected to the aromatic ring, that enhances solubility in organic catalysts. Sulfonamides are ideal choices for proline mimetics as their pKa has been documented to nicely match that of proline. In contrast to catalysts 1-5, the exemplary sulfonamide below displays impressive solubility in methylene chloride (300 mg/mL dichloromethane).

Ester-based catalysts according to the present disclosure also have markedly better solubilities than previously known compounds. For example, the compound below had a solubility of 60 mg/mL in dichloromethane.

III. Method for Making Disclosed Catalyst Embodiments

Disclosed embodiments of the present catalyst can be made by any currently known or future developed methods. Solely to illustrate certain particular embodiments, the following schemes provide methodologies for making disclosed catalysts.

A first class of catalysts include an aliphatic group, such as an alkyl group, on the phenyl ring. Although the alkyl group can be ain various ring positions, Scheme 1 illustrates making para substituted compounds. Certain /?αrα-substituted alkyl phenyl suolfonamides are known, and hence can be used to make the corresponding organocatalysts. Alternatively, the sulfonamide itself can be made, again as indicated generally in Scheme 1.

A. Synthesis of p-A\ky\ Series

CISO ₃ H, H ₂ , Pd / C | r—— PP P === CU CbZ 10 CH ₂ CI ₂ NH ₄ OH MeOH I→ P = H 12

R = C ₄ or greater

Precedent for synthesis of p-alkyl sulfonyl chloirdes

Scheme 1

With reference to Scheme 1, a phenyl ring substituted with a desired aliphatic substituent, as exemplified by forming compounds substituted with alkyl groups at the para position, such as compound 2. Compound 2 is treated with sulfonyl chloride to form the/?αrα-substituted derivative 4. Amide 6 is then formed by treating 4 with ammonium hydroxide. Combining sulfonamide 6 with Cbz- protected pro line compound 8 produces the Cbz-protedcted catalylst 10. The Cbz protecting group is then removed as desired, such as by the illustrated palladium- mediated hydrogenation. Scheme 2 illustrates synthesis of a particular working embodiment according to this general procedure. According to Scheme 2,

= CbZ I— 11 P = H

Scheme 2

B. Synthesis of /)-Ester Series

R KOUHM |— K = H 2 H ₂ , Pd / C |— PP == CCbbZz 8

EDCI, DMAP L-^ R = C ₄ or greater 4 MeOH L-^ P = H 10

Est

"-C ₁₂ H ₂₅ r— R = H H ₂ , Pd / C I — P P == C Cbt Z EDCI, DMAP I— - R = C ₁₂ H ₂₅ MeOH ^L →- P = H DMF, 53% 86%

R = H commercially available CAS 138-41-0 Alrich Cat # C11804

Scheme 3

With reference to Scheme 3, a phenyl ring substituted with a desired ester, as exemplified by forming compounds substituted with ester groups at the para position. Sulfonamide carboxylic acid 2 may be converted to a desired ester by treating 2 with the appropriate alcohol. Thus, treating compound 2 with an alcohol in EDCl and DMAP produces corresponding ester 4. Combining ester 4 with Cbz- protected proline compound 6, again using EDCl and DMAP, produces protected catalyst 8. Removal of the protecting group, such as by palladium mediated hydrogenation to remove the Cbz protecting group, produces catalysts having esters in the position para to the sulfonamide.

C. Synthesis of Alkyl Amino Series

R ₁ and / or R ₂ = C ₄ or greater H ₂ , Pd / C I I —— P P P === C C Cbz 6 R ₁ does not have to equal R ₂ M MePOOHH L→-. P = H 8 Should also include cylic examples . see below

Dialkyl amine Precedent #1

Use R-I instead of MeI for alkylation Alrich Cat # S9251

Dialkyl a

Use R instead of

Me for transformation

X = OH

PCI ₅₁ CH ₂ CI ₂ F _y - H

9922%% ^ ^x : Cl -η NH ₄ OH

Ref: Eur. JJ.. MMeed. Chem ^{x ~ NH} 2 -— ' CHCI ₃

2001 , 36, 809-28

Scheme 4

Scheme 4 illustrates one method for making compounds substituted with an amino group, particularly mono-substituted amines, where one OfR ₁ and R ₂ are other than hydrogen, or di-substituted amines, where both R ₁ and R ₂ are other than hydrogen, and typically are aliphatic or aryl groups having more than 4 total carbon atoms. For di-substituted compounds, R ₁ and R ₂ can be the same or different. While the amine may be in various positions on the phenyl ring, Scheme 4 illustrates making amines

in the para position. According to Scheme 4, phenyl sulfonamide 2 is combined with nitrogen-protected pro line compound 4. Combining 2 with 4 in the presence of EDCl and DMAP produces protected catalyst 6. Removal of the protecting group, such as by palladium-mediated hydrogenation to remove the Cbz protecting group, produces catalysts having esters in the position para to the sulfonamide.

D. Synthesis of Napthalene Derivative Series

2-Naphthalene de

Commercially available H ₂ , Pd / C |— P = Cbz 6 Aid rich Cat 634077 MPOH ! — + ^■ P = H R CAS 1576-47-2

1 -naphthalene derivative could be made using identical pathway as the 1- naphthalene sulfonamide is available

Scheme 5

The present invention also includes aryl compounds other than phenyl -based compounds. For example, Scheme 5 illustrates one method suitable for making both 1- and 2-substituted naphthalene derivatives. Commercially available naphthalene sulfonamide 2 is coupled with protected proline compound 4 in the presence of EDCl and DMAP to produce protected catalyst 6. Removal of the protecting group, such as by palladium-mediated hydrogenation to remove the Cbz protecting group, produces catalysts 8.

E. Synthesis of Biphenyl Derivative Series

NH ₄ OH H ₂ , Pd / C | ^~ P = Cbz 8 CHCI ₃ , 99% r X ^{X =} = NH ₂ 4 MeOH ^ P = H 10

(R = H) sulfonyl chloride is commercially avaiable ^Note - R = H, C, OR, NR ₂ etc Aldrich Cat 536938 CAS 1623-93-4

Scheme 6

The present invention also includes bi-phenyl-based compounds. For example, Scheme 6 illustrates one method suitable for making substituted biphenyl derivatives. Compound 2, commercially available biphenyl sulfonyl chloride, is converted to the amide 4 using ammonium hydroxide. Amide 4 is coupled with protected proline compound 6 in the presence of EDCl and DMAP to produce protected catalysts 8. Removal of the protecting group, such as by palladium- mediated hydrogenation to remove the Cbz protecting group, produces catalysts 10.

F. Synthesis of Derivatives in the Ortho Position

Many of the representative catalysts disclosed herein have aryl substitutions in the para position relative to the sulfonamide functional group. Substitution patterns other than para also produce suitable catalysts. For example, Scheme 7 below illustrates one method for making ortho substituted catalysts.

para product _O rtho product

4 6

Overall Yield Ratio para:ortho

Data from'

C ₈ H ₁₇ 98% 81 15 J Org Chem 1961 , 26, 209-12 C ₁₀ H ₂ I 99% 80.15 C ₁₂ H ₂ 5 98% 81.14

Ci -| H ₂ 3 99% 86.7

Ci ₃ H ₂₇ 98% 91 6 C15H31 98% 907 C17H35 98% 897

C Cbz 12

R = C ₄ or greater Scheme 7

As indicated in Scheme 7, various substituted phenyl compounds can be obtained commercially, such as from Aldrich. Such aliphatic-substituted phenyl compounds 2 can be converted to the corresponding sulfonic acids 4 and 6 by treatment with fuming sulfuric acid (oleum). These compounds, including ortho substituted derivative 6, is then converted to the sulfonamide 8 by treatment with ammonium hydroxide. Sulfonamide 8 is coupled with protected proline compound 10 in the presence of EDCl and DMAP to produce protected catalyst 12. Removal of the protecting group, such as by palladium-mediated hydrogenation to remove the Cbz protecting group, produces catalysts 14.

G. Synthesis of Halogenated Derivatives

Catalysts according to the present disclosure can include additional substitutions, such as substituting one or more hydrogen atoms on either the aryl ring, or rings, the aliphatic substituents, or both. For example, as indicated below in Scheme 8, an aryl ring, or rings, can be substituted with one or more halogen atoms, such as one or more fluorine atoms.

CA 12r -S 8

Scheme 8

With reference to Scheme 8, starting fluorinated phenyl compound 2 is treated with a desired lithiated aliphatic compound, such as an alkyl lithium reagent, to form the corresponding substituted phenyl compound 4. Silylated compound 4 is then converted to the corresponding sulfonyl chloride by treatment with SO ₃ and PCI ₅ . The resulting sulfonyl chloride is then converted to the sulfonamide 6 using ammonium hydroxide. Sulfonamide 6 is coupled with protected proline compound 8 in the presence of EDCl and DMAP to produce protected catalysts 12. Removal

of the protecting group, such as by palladium-mediated hydrogenation to remove the Cbz protecting group, produces catalysts 12. This reaction sequence is indicated generally in Scheme 8 too, with the production of compound 22. H. Synthesis of Halogenated Aliphatic Derivatives

Substituents other than the aryl substituent also can be halogenated. For example, aliphatic substituents, such as alkyl substituents, also can be halogenated. Embodiments of a method for making such compounds is illustrated below in Scheme 9.

P 10 Aldirch Cat # 93037

Precedent for synthesis of Fluornated aromatics

commercially available CAS 673-40-5 Aldirch Cat # 280895

commercially available CAS 307-60-8 Matrix Cat # 003153

commercially SE-090820

Scheme 9

With reference to Scheme 9, /?αra-substituted compound 2 is first treated with BuLi and SO ₂ followed by SO ₂ Cl ₂ to form the sulfonyl chloride 4. The acid chloride is then converted into the corresponding sulfonamide 6 using ammonium hydroxide. Sulfonamide 6 is coupled with protected proline compound 8 in the presence of

EDCl and DMAP to produce protected catalysts 10. Removal of the protecting group, such as by palladium-mediated hydrogenation to remove the Cbz protecting group, produces catalysts 12.

This reaction sequence is indicated generally in Scheme 9 too, with the production of compound 22. Any of the potential halogenated compounds can be made by the illustrated process. The halogenated side chain has a formula C _m X[(2 _{m +} i ₎ _ _n] H _n , where m typically is 4 or greater, and up to at least 24, n is the number of hydrogen atoms present, and is decreased by the number of any additional halogen atoms present, and X is a halogen, such as chlorine, fluorine, bromine and iodine, and most typically fluorine. Compounds having combinations of halogen atoms also can be produced.

A person of ordinary skill in the art will appreciate that compounds having a substitution pattern other than the /?αrα-substituted compounds illustrated in Scheme 9 also can be produced. For example, meto-substituted compounds also are within the scope of disclosed catalysts according to the present invention. One embodiment of a method for making such compounds is illustrated below in Scheme 10.

δOH ^ I— X X == C CII ₂ 2 ≡ ^?TPh''. ^D " ^M ' ^AP C >V ^H f ^N - ^S X° ^{2 C7F11} L- X = NH _{2 4} CH ₂ CI ₂

H ₂ , Pd / C I — P P == C Cbz 8 MeOH L- P = H 10

Precedent for synthesis of Fluornated aromatics

Scheme 10

With reference to Scheme 10, meto-substituted sulfonyl chloride compound 2 is converted into the corresponding sulfonamide 4 using ammonium hydroxide. Sulfonamide 4 is coupled with protected proline compound 6 in the presence of EDCl and DMAP to produce protected catalysts 8. Removal of the protecting group, such as by palladium-mediated hydrogenation to remove the Cbz protecting group, produces catalysts 10. This reaction sequence is indicated generally in Scheme 10 too, with the production of compound 18. Any of the potential halogenated compounds can be made by the illustrated process. The halogenated side chain has a formula C _m X[(2 _{m +} i)-n]H _n , where m typically is 4 or greater, and up

to at least 24, n is the number of hydrogen atoms present, and is decreased by the number of any additional halogen atoms present, and X is a halogen, such as chlorine, fluorine, bromine and iodine, and most typically fluorine. Compounds also can be produced having combinations of halogen atoms.

I. Synthesis of /)αrø-Acylated Anilino Derivatives

Presently disclosed catalysts also can be amide-substituted catalysts. Such compounds can be made as generally illustrated below in Scheme 11.

X = H commercially available CAS 637-54-7

20

R ₁ and / or R ₂ = C ₄ or greater R ₁ or R ₂ can equal H or C

Scheme 11

With reference to Scheme 1 l,/?αra-substituted compound amide 2 is first treated with chlorosulfonic acid to form the sulfonyl chloride 4, which is converted to sulfonamide 6 using ammonium hydroxide. Sulfonamide 6 is coupled with protected proline compound 8 in the presence of EDCl and DMAP to produce protected catalysts 10. Removal of the protecting group, such as by palladium- mediated hydrogenation to remove the Cbz protecting group, produces catalysts 12.

This reaction sequence is indicated generally in Scheme 11 too, with the production of catalysts 22.

J. Synthesis of ortho-Alkyl Phenolic Anilino Derivatives Presently disclosed catalysts also can be ether-substituted catalysts too. Such compounds can be made as generally illustrated below in Scheme 12.

BuLi, TMEDA; I — X = H 2 H ₂ , Pd / C I — P = CbZ 10

SO ₂ ; SO ₂ CI ₂ L→ x = SO ₂ CI 4 — . _K|U _ _u MeOH L-- P = H ₁₂ X = SO ₂ NH _{2 6} -_l ^NH 4<JH

X = H commcerically available CAS 35021-68-2 SALOR Cat S347949

Prep: Tetrahedron 19

BuLi, TMEDA; p X = H 14 H H ₂₂ ,, P Pdd / / C |— ^{P = Cbz 20}

SO ₂ ; SO ₂ CI ₂ L- X = SO ₂ CHe π _{NH OH} M MReOOHH ! — *- P = H 22 λ ^{λ λ} X = SO ₂ NH ₂ 18-« — I ^NH 4 ^UH

Ref : Angew. Chem. Int. Ed. 2004, 43, 892-894

R = C ₄ or greater Scheme 12 With reference to Scheme 12, o/t/zo-substituted compound ether 2 is first treated with sulfuryl chloride to form the sulfonyl chloride 4, which is converted to sulfonamide 6 using ammonium hydroxide. Sulfonamide 6 is coupled with protected proline compound 8 in the presence of EDCl and DMAP to produce protected catalysts 10. Removal of the protecting group, such as by palladium- mediated hydrogenation to remove the Cbz protecting group, produces catalysts 12. This reaction sequence is indicated generally in Scheme 12 too, with the production of catalysts 22.

IV. Reactions Catalyzed by Disclosed Catalysts

Disclosed embodiments of the present catalyst can be used to catalyze a variety of different types of reactions. Other catalysts are known, and have been reviewed in the technical literature. For example, (S)- and (R)-5-pyrrolidin-2-yl-lH- tetrazole catalysts, formulas provided below, have been reviewed for their catalytic behavior in "Practical Organocatalysis with (S)- and (R)-5-pyrrolidin-2-yl-lH- tetrazoles," J. Aldrichchimica ACTA, 41, 3-11 (2008), which is incorporated herein by reference.

(S)-5-pyrrolidin-2-yl-lH-tetrazole

(R)-5 -pyrrolidin-2-yl- 1 H-tetrazole Each of the reactions reviewed in this article also can be conducted using the catalysts disclosed herein. Particular reactions are discussed in more detail below. However, solely by way of example, disclosed catalysts can be used to perform aldol reactions, conjugate additions, such as Michael additions, Robinson annulations, Mannich reactions, α-aminooxylations, α-hydroxyaminations, α-aminations and alkylation reactions. The aldol reaction usually involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol). The aldol addition product may loses a molecule of water during the reaction to form an α,β-unsaturated ketone. This is called an aldol condensation. A Michael addition reaction is a nucleophilic addition of a carbanion to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds. The Mannich reaction is an organic reaction that involves amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde,

ammonia or any primary or secondary amine. The final product is a β-amino- carbonyl compound.

A. Enantioselective Michael Addition for Lycopodine Synthesis

One proposed synthesis of the alkaloid lycopodine (1), involved using an enantioselective, intramolecular cyclization of a C ₈ keto sulfone 5 onto the internal C ₇ Michael acceptor (Scheme 13).

Scheme 13 - Retrosynthetic Strategy for Lycopodine (1)

No organocatalyzed protocols were known for accomplishing this reaction. Consequently, a viable enantioselective, intramolecular Michael addition of keto sulfones was developed using organo catalysis.

B. Racemic Intramolecular Keto Sulfone Michael Addition

Prior to investigating the enantioselective Michael cyclization, a racemic protocol was developed, as indicated below in Scheme 14.

CH ₂ CI ₂ rt dr

Scheme 14 - Racemic Protocol for Intramolecular, Keto Sulfone Michael

Addition

With reference to Scheme 14, enone 5 was prepared in two steps from the known sulfone 6. Hydride (e.g. NaH, PhH) and alkoxide (e.g. Cs ₂ CO ₃ , EtOH) conditions were first tested for the conjugate addition of 5. These conditions had proven effective in prior intramolecular Michael additions with the desired relative configuration by Stork and Evans. In both cases, overreaction appeared to occur to provide a product derived from attack of the resultant methyl ketone (after conjugate addition) by an enolate at C ₁₄ . Furthermore, cyclization occurred with the undesired C _7,8 cis relationship in the initial Michael addition. Fortunately, treatment of the keto sulfone 5 with diisopropylamine [IPA / CH ₂ Cl ₂ (1 : 1), rt, 76 h, 84%] cleanly induced Michael addition to generate the desired C ₇ ,8 trans diastereomer 4 (Table 1, Entry 1). The stereochemical outcome of this transformation was confirmed by X- ray crystallo graphic analysis. The nature of the enolate geometry is likely the culprit in controlling the stereochemical outcome of the Michael addition.

C. Enantioselective Intramolecular Keto Sulfone Michael Addition

With a working route to a diastereoselective, intramolecular Michael addition, an enantioselective variant was developed (Table 1). Optimum levels of enantioselectivity would be best obtained in non-polar, chlorinated solvents. Pro line was initially screened (10) but no reaction in CHCl ₃ (Entry 1) was observed. Tetrazole catalyst 11, which has also shown enhanced activity compared to pro line (10) - particularly in CHCl ₃ , was screened next Interestingly, no reaction was observed after 3 days at room temperature (Entry 2). Ley and co-workers have

recently shown that the addition of a stoichiometric secondary amine base can impact the rate and enantioselectivity. Addition of piperidine (Entry 3) facilitated the desired transformation with a reasonable rate (16 hours) - albeit with a modest enantioselectivity (33% ee). The background reaction (piperidine, CHCI3, rt) gave no product formation - even after prolonged exposure to the reaction conditions. Using ClCH ₂ CH ₂ Cl as a solvent led decreased the reaction rate but afforded an increase in enantiomeric excess (Entry 4). Using CHCI3 was quite fortuitous as 1% EtOH is typically added commercially as a stabilizing agent for this solvent. This additive turned out to useful, as using 1% EtOH in ClCH ₂ CH ₂ Cl gave a dramatic increase in rate and enantioselectivity (Entry 5).

Proline sulfonamides were tried next as potential organocatalysts. While these ligands have shown promise in certain organocatalyzed reactions, they previously have proven problematic in facilitating Michael addition processes. Proline sulfonamides performed well, providing improved enantiomeric excess (e.e.) at room temperature (Entries 6-8). While the sulfonamide tested, 12-14, proved more soluble than the analogous tetrazole 11, solubility at lower temperatures continued to be problematic. Ultimately, the previously unknown sulfonamide derivative 15 gave greatly improved solubility properties and continued high levels of enantiomeric excess. This sulfonamide 15 is readily accessible from the commercially available /?αrα-dodecylsulfonylchloride (16) and Cbz-protected proline 18 in 3 steps (Scheme 15).

NH ₄ OH I — 16 X = CI H ₂ Pd / C r~ 19 P = Cbz

CHCI ₃ , 99% L- ^» 17 _X = NH _{2 Mθ} θH, 91% *→ 15 P = H

Scheme 15 - Synthesis of Novel Sulfonamide 15

Cooling the reaction to -20 ⁰ C with 10 mol% catalyst loading gave the optimum results (Table 1, Entry 10). The absolute configuration of keto sulfone 4 was conclusively established via X-ray crystallographic analysis.

Table 1

Optimization of Conditions for Enantioselective, Organocatalyzed Intramolecular Michael Addition

[a] The reaction was performed at 0.1 M concentration of substrate unless otherwise noted, [b] The enantiomeric excess was determined by chiral shift NMR [50% Eu(hfc) ₃ , C ₆ D ₆ ]. [c] Commercial CHCI3 stabilized with 1% EtOH was used without further purification.

The scope of the novel organocatalyzed, intramolecular Michael reaction (Table 2) was then explored. This intramolecular, keto sulfone Michael addition has not been reported previously reported using organocatalysis (Entry 1). A great number of different moieties are tolerated on the keto sulfone side arm. The level of diastereoselectivity in each case was excellent (20: 1 dr). Additionally, reasonable enantioselectivities were observed (81-88% ee). Finally, the cyclization could be extended to the analogous 5-membered series (Entry 5) with good success (58% yield, 84% ee).

Table 2

Exploration of Scope for Enantioselective, Organocatalyzed Intramolecular Michael Addition

(reaction time) (% yield,

CH ₂ CH ₂ CH ₂ N ₃ 88% ee (72 h) (75%, 20:1 dr)

Me 83% ee (5 d) (80%, 20:1 dr)

CH ₂ CH ₂ OTBS 83% ee

(72 h) (76%, 20:1 dr)

CH ₂ Ph 81% ee

(72 h) (89%, 20:1 dr) 1 MMee 84% ee (6 d) (58%, 20:1 dr) [a] The enantiomeric excess was determined by chiral shift NMR [50% Eu(hfc)3,

C ₆ D ₆ ].

D. Enantioselective Synthesis of Lycopodine Tricyclic Core

Application of this technology to a second generation approach toward lycopodine is shown in Scheme 16.

Scheme 16 - Enantioselective Synthesis of the Lycopodine Tricyclic Core 2

Using the enantiomeric catalyst ent-15 gave comparable results (71% yield, 88% ee). A single recrystallization provided material that was enantiomerically pure (>95% ee, 60-65% yield). This series was required for the synthesis of the correct enantiomer of lycopodine. Subsequent Staudinger reduction with in situ imine generation followed by silyl enol ether formation provided the cyclization precursor 3. The key tandem 1,3-sulfone shift/Mannich cyclization proceeded in accord with our prior work in the area to yield the tricycle 2. This compound is ideally suited for subsequent functionalization to incorporate the C ₁₅ methyl moiety and complete a second generation synthesis of lycopodine.

E. Sulfonamide Catalyst for Additional Organocatalyzed Processes

Sulfonamide catalyst 15 can be used for additional organocatalyzed processes. Certain exemplary such processes are illustrated below in Scheme 17.

22 87% θθ) 83% θθ)

77% θθ) antι-28 (26%, 80% θθ)

97% θθ)

Scheme 17 - Preliminary Application of Sulfonamide 15 in Additional Organocatalytic Processes

Aldol reaction of acetone (22) with benzaldehyde (23a) and/?-nitro- benzaldehyde (23b) proceeded in good yields (76-80%) and enantioselectivities (83- 87% ee). The analogous transformation in ClCH ₂ CH ₂ Cl / EtOH (99: 1) with L- proline (10) gave essentially no reaction (<5%) after 3 days. Barbas and Arvidsson

have shown that proline (10) and the tetrazole 11 can affect this transformation in a more polar solvent (DMSO); however, the levels of enantioselectivity and yields using the sulfonamide catalyst compare favorably with their results.

The reactivity of cyclopentanone (27) and cyclohexanone (29) with aldehyde 23b also was explored. Cyclopentanone (27) nicely provided the aldol adducts syn- 28 and anti-28 (2.7:1 syn:anti) in good enantioselectivity (77-80% ee). Once again, this result compared favorably with other catalyst systems- including Ley's elegant work with sulfonamides 12 and 13. This reaction showed an unusual preference for the adduct, notably syn-2% in this transformation. Typically, the adduct anti-2% is the predominant product. Finally, cyclohexanone (29) yielded the anti aldol adduct 30 in excellent diastereoselectivity and enantioselectivity (14.4:1 anti:syn, 97% ee, 96% yield).

With reference to Table 3, below, aldol reaction between cyclohexanone (9) and p-nitrobenzaldehyde (10) in methylene chloride using sulfonamide 11 provided the desired product 12 in reasonable ee and dr (Entry 1); however, the yield of this transformation was somewhat disappointing (51%). Use of dichloroethylene (DCE) led to an appreciable rate increase (Entry 2). Further improvement was found using a DCE / EtOH mixed solvent system (99: 1) (Entry 3). Alternatively, a single equivalent of water had a similar rate accelerating effect, and with the added benefit of increased diastereoselectivity (Entry 4). The optimum reaction conditions included cooling of the reaction to 4°C with a 30 h reaction time (Entry 5).

Table 3 - Optimization of Reaction Conditions with Sulfonamide 11

Entry Conditions ^a Additive %Yield %ee ^c

(dr ^b )

1 CH ₂ Cl ₂ , rt, 36 - 51% 97% h (15:1)

2 ClCH ₂ CH ₂ Cl, - 92% 95% rt, (12:1)

46 h

ClCH ₂ CH ₂ Cl, EtOH 96% 97% rt, (1%) (14:1)

36 h

ClCH ₂ CH ₂ Cl, H ₂ O 96% 97% rt, (1 equiv.) (36:1)

36 h

ClCH ₂ CH ₂ Cl, H ₂ O 95% 99%

4°C, 3O h (1 equiv.) (>99:1)

^a All reactions were performed at 1 M. dr was determined by IH NMR. ^c ee was determined by chiral HPLC using Daicel AD column.

A direct comparison between sulfonamide 11 and a series of commonly used organocatalysts is provided in Table 4 below. Each of the known catalysts 1-5 facilitated the transformation with good enantioselectivity (98-99% ee); however, only the tetrazole 2 is able to provide a reasonable yield (91%) for this transformation (Entry 2). Unfortunately, the diastereoselectivity with the tetrazole catalyst 2 (7.2:1 dr) is significantly below the sulfonamides (Entries 3-6). In contrast, /?-dodecylphenylsulfonamide catalyst 11 provided excellent diastereoselectivity, enantioselectivity and chemical yield for this transformation

(Entry 6). It is important to note that the standard proline-based conditions for this transformation (DMSO, rt) have been shown to perform less effectively [65%, 1.7:1 dr, 67% ee (syή), 89% ee (anti)].

Table 4

Comparison of Select Proline Mimetics

(5 equiv )

Entry Catalyst % dr

Yield ee

1 1 22% 98% 13:1

2 2 91% 98% 7:1

3 3 42% 99% 65:1

4 4 49% 98% 83:1

5 5 52% 99% 92:1

6 11 95% 99% >99:1 a dr was determined by H NMR. ee was determined by chiral HPLC using Daicel AD column.

Sulfonamide catalyst 11 was screened for facilitating aldol reactions across a range of substrates (Scheme 18).

Exploration of Substrate Scope with Sulfonamide Catalyst ll ^a

(91%, >99 1 dr, 99% ee) (52%, >99 1 dr, 97% ee) >99 1 dr, 98% ee) 20 R = 4-CI-C ₆ H ₄ (68%, >99 1 dr, 99% ee) 21 R = 2,6-CI-C ₆ H ₃ (94%, >99 1 dr, 99% ee) 22 R = C ₆ F ₅ (91 %, >99 1 dr, >99% ee) 23 R = 4-pyrιdyl (98%, 29 1 dr, 99% ee) 24 R = Ph (60%, >99 1 dr, >99% ee) 25 R = 2-naphthyl (63%, >99 1 dr, 99% ee) 26 R = 4-OMe-C ₆ H ₄ (16%, 80 1 dr, 98% ee) 27 R = CH ₂ CH ₂ Ph (32%, 29 1 dr, 59% ee) ^{b c}

ee

ee

94% ee) 5 1 dr, 96% ee) >99 1 dr, 97% ee)

11 (20 mol %) o RCHO O OH

A, CICH ₂ CH ₂ CI

H ₂ O 37 R = Ph (42%, 87% ee)

36 (1 equiv) 38 R = 4-NO ₂ -C ₆ H ₄ (64%, 83% ee) 4 "C, 72 h a The ratio of ketone to aldehyde was 5: 1. ^b This reaction was conducted at room temperature. ^c This reaction was performed in without the addition OfH ₂ O.

Scheme 18

Both aromatic and aliphatic aldol adducts 17-27 derived from their corresponding aldehydes were made. Additionally, 4-methylcyclohexanone (28) proved to be a competent substrate for these conditions. Ketones containing α-heteroatoms [the dihydroxyacetone equivalent 30 and pyran-4-one (32)] also were effective in this transformation to provide aldol adducts 33 and 33-35. This transformation is effective with acetone (36) to provide adducts 37-38 in reasonable enantioselectivities.

Extension to cyclopentanone (39) revealed some interesting results (Scheme

19).

Select Examples with Cyclopentanone

(

Scheme 19

Optimized one equivalent of water conditions gave poor diasteroselectivity in the transformation [94%, 1.35:1 (40:41), 87-95% ee]. In contrast, the DCE / EtOH (99:1) solvent system gave improved levels of diastereoselectivity favoring the syn product 40. Limited prior examples of syn selective aldol reactions with cyclopentanone have been reported. Interestingly, slightly improved levels of syn selectivity are observed at room temperature (syn-40: 71%, 77% ee; anti-41 : 26%, 80% ee), but with reduced enantioselectivity.

Aldol reactions with catalyst loading as low as 2 mol % have been performed if the reaction is performed neat (Scheme 20).

Select Aldol Reactions using Low Catalyst Loading ^a

(96%, >99 1 dr, 96% ee) >99 1 dr, 99% ee) >99 1 dr, 92% ee) 1 dr, 91% ee) 99% ee)

¹ The ratio of ketone to aldehyde was 2: 1.

Scheme 20

Under these conditions, a single equivalent of water is added for improved reaction rate and selectivity. As seen in the previous examples, these transformations generally proceeded in good to excellent diastereoselectivity and enantioselectivity.

The practicality of this process has been demonstrated by preparing one mole of the aldol adduct 12 (Scheme 21) using a 500 mL round bottom flask in excellent diastereoselectivity and enantioselectivity (88% yield, 97% ee, 98:1 dr). Over 50% of the catalyst 11 was also recovered via a single crystallization.

Large Scale Example of Enantioselective Aldol Reaction.

9 (235 g, 10 (181 g, _rt , 48 h 263 grams (1 06 mole) prepared i n 2 equiv ) 1 equiv ) 88% yield, 97% ee, 98 1 dr

Scheme 21

Based on this disclosure, highly practical and readily available proline mimetic catalysts have been developed. The sulfonamides can be prepared from commercially available and inexpensive D- or L-proline. This important attribute is 15 not shared by 4-trans-hydroxyproline derivatives where only one of the two enantiomers is commercially available at a reasonable price. Disclosed catalysts have been shown to be effective at facilitating a range of aldol reactions with some of the highest levels diastereoselectivity and enantioselectivity reported for many of these transformations. 0 Mannich reactions also can be accomplished using disclosed embodiments of the present invention. In general, a Mannich reaction is a reaction between a carbonyl-bearing compound and a nitrogen bearing compound, particularly imines. The final product is a β-amino-carbonyl compound. Reactions between aldimines and α-methylene carbonyls also are considered Mannich reactions because amines 5 and aldehydes form imines. Various exemplary Mannich reactions that can be catalyzed using disclosed embodiments of the present catalyst are provided below in Scheme 22.

Scheme 22

V. Amino Acid Derivatives

The preceding portions of this disclosure focused on sulfonamide catalysts based on the proline amino acid. However, a person of ordinary skill in the art will appreciate that amino acids other than proline also can be used to make sulfonamide-

based catalysts within the scope of the present invention. All prior statements concerning the exemplary proline -based sulfonamide organocatalysts apply to other amino acid sulfonamides as well, to the extent such statements are not contradictory to express statements made in this section. Such amino acid organocatalysts typically have a formula

or

With reference to these general formulas, R1-R5 are independently selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, formyl, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are bonded together to form a ring, at least one of such substituents comprises 4 or more carbon atoms, at least one OfR ₁ and R ₅ is hydrogen or halogen, and if R ₁ -Rs is aryl, the aryl group is directly bonded to one of R ₁ -R ₅ . R ₆ -R ₇ independently are selected from aliphatic and hydrogen. R ₈ is selected from substituents defining naturally occurring amino acids or their derivatives. Rp-R _1O are independently aliphatic or hydrogen. R ₁₁ and R ₁₂ are independently selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, cyclic, substituted cyclic, ester, ether, formyl, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl,

hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thiol ether, thiol ester, or are atoms in a ring.

The following Scheme 23 illustrates that alpha amino acids generally can be used to make sulfonamide-based catalysts according to the present invention.

Generalized example for using alpha-amino acid derivatives:

NH ₄ OH X = CI 2 h H ₂ , Pd / C I — P = Cbz 8 CHCI ₃ XX == NNHH ₂₂ 4 4 MeOH ^ P = H 10

Ry = ^: H, lower alkyl

Scheme 23

With reference to Scheme 23, compound 4 can be formed by treating compound 2 with ammonium hydroxide. A protected alpha-amino acid 6, generally commercially available, is then coupled to compound 4 to form protected sulfonamide 8. Deprotection of sulfonamide 8 produces catalysts 10. With reference to this Scheme 23, the R groups are as stated above for the general formulas.

Beta amino acids also can be used to form sulfonamide-based catalysts according to the present invention. This approach is illustrated in Scheme 24. Generalized example for using beta-amino acid derivaties:

Ry = H, lower alkyl

Scheme 24

With reference to Scheme 24, compound 4 can be formed by treating compound 2 with ammonium hydroxide. A protected beta-amino acid 6, generally commercially

available, is then coupled to compound 4 to form protected sulfonamide 8. Deprotection of sulfonamide 8 produces catalysts 10. Again, With reference to this Scheme 24, the R groups are as stated above for the general formulas.

Particular examples of amino-acid-based sulfonamide catalysts according to the present invention are provided below. Selected sulfonamide examples include:

R = H, lower alkyl, R = H, acyl, lower R = H, acyl, lower carbamate alkyl, silyl alkyl, silyl

R = H, acyl, lower alkyl, silyl

R = H, lower alkyl, carbamate

VI. Examples

The following examples are provided to illustrate certain features of working embodiments of the present invention. A person of ordinary skill in the art will appreciate that the scope of the invention is not limited to the particular feature exemplified by these examples.

General. Infrared spectra were recorded neat unless otherwise indicated and are reported in cm ^"1 . ¹ H NMR spectra were recorded in deuterated solvents and are reported in ppm relative to tetramethylsilane and referenced internally to the residually protonated solvent. ¹³ C NMR spectra were recorded in deuterated solvents and are reported in ppm relative to tetramethylsilane and referenced internally to the residually protonated solvent.

Routine monitoring of reactions was performed using EM Science DC- Alufolien silica gel, aluminum-backed TLC plates. Flash chromatography was performed with the indicated eluents on EM Science Gedurian 230-400 mesh silica gel.

Air and/or moisture sensitive reactions were performed under usual inert atmosphere conditions. Reactions requiring anhydrous conditions were performed under a blanket of argon, in glassware dried in an oven at 120 ⁰ C or by flame, then cooled under argon. Dry THF and DCM were obtained via a solvent purification system. All other solvents and commercially available reagents were either purified via literature procedures or used without further purification.

Example 1

6 7 31 Keto sulfone 31 : To a stirred solution of 6 (1.0 g, 4.18 mmol) in THF (40 mL) at -78°C was added lithium 2,2,6,6-tetramethylpiperidine (8.36 mL, 8.36 mmol, 1.0 M in THF) dropwise. After 5 min, a solution of ester 7 (1.07 g, 8.36 mmol) in pre-cooled THF (5.0 mL) was added via cannula to the sulfone solution. After 30 min, the reaction was warmed up to -10 ⁰ C over 1 h and quenched with sat. aq. NH ₄ Cl (15 mL) and extracted with ether (3 x 20 mL). The dried (Na ₂ SO ₄ )

extract was concentrated in vacuo and purified chromatography over silica gel, eluting with 5-20% EtOAc / hexanes, to give 31 (1.02 g, 3.04 mmol, 73%) as a colorless oil. IR: (neat) 2933, 2095, 1716, 1316, 1308, 1144, 1080, 684 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72-7.81 (m, 3H), 7.59-7.63 (m, 2H), 5.74-5.84 (m, IH), 5.02-5.08 (m, 2H), 4.15-4.17 (m, IH), 3.25-3.32 (m, 2H), 2.91-2.99 (m, IH), 2.57-2.66 (m, IH), 2.08-2.13 (m, 2H), 1.92-2.00 (m, 2H), 1.67-1.76 (m, 2H), 1.48- 1.55 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 202.0, 137.6, 136.1, 134.5, 129.4, 129.2, 115.6, 74.5, 50.8, 44.4, 32.7, 26.3, 24.6, 22.3; HRMS (EI+) calcd. for Ci ₆ H ₂₂ N ₃ O ₃ S (M+H) 336.1382, found 336.1399.

Example 2

Enone 5: To a solution of 31 (252 mg, 0.752 mmol) and 2-pentenone (94 mg, 1.11 mmol) in CH ₂ Cl ₂ (3.7 mL) was added 2 ^nd Gen. Hoveyda-Grubbs catalyst (23.3 mg, 37.3 μmol) at room temperature. After 3.5 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give 5 (178 mg, 0.472 mmol, 63%) as colorless oil as well as recovered 31 (75 mg, 0.224 mmol, 30%): IR (neat) 2929, 2095, 1712, 1665, 1449, 1308, 1252, 1144, 1075 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.73-7.81 (m, 3H), 7.60- 7.68 (m, 2H), 6.78 (dt, J= 16.0, 6.8 Hz, IH), 6.13 (d, J= 16.0 Hz, IH), 4.16 (t, J= 7.6 Hz, IH), 3.27 (t, J= 6.3 Hz, 2H), 2.99-3.07 (m, IH), 2.53-2.68 (m, IH), 2.16-2.31 (m, 5H), 1.95 (q, J= 7.6 Hz, 2H), 1.64-1.86 (m, 2H), 1.47-1.54 (m, 2H); ¹³ C NMR (IOO MHZ, CDCl ₃ ) δ 201.4, 198.5, 146.6, 136.1, 134.6, 131.9, 129.4, 129.3, 74.5, 50.8, 44.3, 31.3, 27.1, 26.3, 24.6, 21.6; HRMS (FAB+) calcd. for Ci ₈ H ₂₄ N ₃ O ₄ S (M+H) 378.1488, found 378.1489.

Example 3

Cyclohexanone 4: Racemic Protocol - To a solution of 5 (8.0 mg, 0.0212 mmol) in CH ₂ Cl ₂ / Isopropanol (1 :1, 0.2 niL) was added diisopropylamine (2.2 mg, 3.0 μL, 0.0212 mmol) at room temperature. After 76 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the product 4 (6.7 mg, 0.0178 mmol, 84%) as a white solid. Enantios elective Protocol - To a solution of 5 (82.0 mg, 0.217 mmol) in EtOH/DCE (1 :99, 1.1 mL) was added 15 (9.2 mg, 0.0217 mmol) and piperidine (18.5 mg, 21 μL, 0.217 mmol) at -20 ⁰ C. After stirring at same temperature for 72 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the product 4 (58 mg, 0.154 mmol, 71%, 88% ee) as a white solid. Mp 95-96 ⁰ C; [α] _D ²³ = +101° (c = 0.78, CHCl ₃ ); IR (neat) 2925, 2099, 1716, 1699, 1445, 1355, 1303, 1140, 1088, 723, 688 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82-7.84 (m, 2H), 7.69-7.72 (m, IH), 7.56-7.60 (m, 2H), 3.48 (tq, J= 10.8, 2.0 Hz, IH), 3.20-3.40 (m, 3H), 2.89 (dt, J = 15.2, 7.2 Hz, IH), 2.53 (dd, J= 17.6, 10.8 Hz, IH), 2.41 (dt, J= 15.2, 7.2 Hz, IH), 2.26 (s, 3H), 1.85-2.18 (m, 5H), 1.57-1.69 (m, 2H), 1.38-1.47 (m, IH); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 206.0, 205.8, 135.9, 134.3, 130.6, 128.8, 78.9, 51.5, 44.6, 39.4, 35.0, 30.5, 27.6, 27.1, 24.5, 21.5; HRMS (F AB+) calcd. for Ci ₈ H ₂₄ N ₃ O ₄ S (M+H) 378.1488, found 378.1497.

Determination of the enantiomeric excess: Product 4 (3 mg) in C ₆ D ₆ (0.55 ml) with 40 mol% (+) Eu(hfc) ₃ (3.8 mg) at 400 MHz. ¹ H NMR difference of α- methylene protons (doublet at 3.31 ppm) on C ₆ for two enantiomers is 18.8 Hz. The enantiomeric excess can be obtained based on the calculation of ratio for two sets of doublets.

Example 4 enM8 17 ^{enM 9}

Cbz sulfonamide ent-19: To a solution of Z-D-proline ent-lS (3.16 g, 12.7 mmol) in CH ₂ Cl ₂ (127 niL) was added sulfonamide 17 (4.13 g, 12.7 mmol), DMAP (0.248 g, 2.03 mmol) and EDCI (2.44 g, 12.7 mmol) respectively. The reaction mixture was stirred at room temperature for 72 hours before being partitioned between EtOAc (180 mL) and aq. HCl (120 mL, 1 N). The organic layer was washed with half-saturated brine. The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 10% EtOAc/CH ₂ Cl ₂ , to give ent-19 (5.85 g, 10.5 mmol, 83%) as a colorless liquid. [α] _D ²³ = +90° (c = 2.2, CHCl ₃ ). IR (neat) 3148, 2955, 2925, 2856, 1720, 1677, 1449, 1411, 1355, 1174, 1131, 1088, 826, 692 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 10.4 (br s, IH), 7.93-7.95 (m, 2H), 7.26-7.40 (m, 7H), 5.23 (s, 2H), 4.31 (br s, IH), 3.42 (m, 2H), 2.45-2.57 (m, IH), 0.85-1.87 (m, 28H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 169.0, 157.2, 135.9, 128.6, 128.4, 128.3, 128.1, 127.5, 68.1, 60.8, 47.2, 46.2, 38.8, 38.1, 36.6, 31.8, 29.6, 29.3, 27.5, 27.2, 26.7, 24.3, 22.7, 14.1; HRMS (EI+) calcd. for C _3I H ₄₅ N ₂ O ₅ S (M+l), 557.3049 found 557.3067.

Example 5 e" ^M9 en ⁽ -15

Sulfonamide ent-15: To a solution of Z-D-sulfamide (4.99 g, 8.97 mmol) in MeOH (178 mL) was added 10% Pd/C (536 mg). The mixture was stirred at rt for under an atmosphere of hydrogen. After 24 hours, the reaction was filtered through Celite and silica gel pad, and the filtrate was concentrated in vacuo to give white solid. The crude product was purified by chromatography over silica gel, eluting with 10% MeOH / CH ₂ Cl ₂ , to give the product ent-15 (3.26 g, 7.73 mmol, 86%) as a white solid. Mp: 184-186 ⁰ C; [α] _D ²³ = +94° (c = 0.95, CHCl ₃ ). IR (neat) 3135, 2955, 2920, 2852, 1626, 1458, 1372, 1308, 1144, 1084, 843 cm ^"1 ; ¹ H NMR (400 MHz,

CDCl ₃ ) 8.73 (br s, IH), 8.06 (br s, IH), 7.85 (d, J= 8.0 Hz, 2H), 122-126 (m, 2H), 4.33 (t, J= 8.0 Hz, IH), 3.23-3.43 (m, 2H), 2.33-2.40 (m, IH), 0.82-2.05 (m, 28H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 173.8, 140.4, 127.8, 127.2, 126.4, 62.8, 47.8, 39.9, 38.2, 36.8, 31.9, 31.8, 30.1, 29.7, 29.6, 29.3, 29.2, 27.6, 27.2, 24.5, 22.7, 14.1; HRMS (EI+) calcd. for C ₂₂ H ₃₉ N ₂ O ₃ S (M+l), 423.2681 found 423.2701.

Imine 3: To a solution of 4 (0.132 g, 0.350 mmol) in THF (13 rnL) was added PPh ₃ (91.8 mg, 0.350 mmol). The reaction mixture was heated to reflux.

After 5 hours, the reaction was cooled to rt and the solvent was removed in vacuo to give crude imine. The crude imine was used next step immediately. To a stirred solution of crude imine (0.35 mmol) in CH ₂ Cl ₂ (3.5 mL) at 0 ⁰ C was added /-Pr ₂ NEt (0.203 g, 0.27 mL, 1.57 mmol). After 1 min, TBSOTf (0.166 g, 0.14 mL, 0.628 mmol) was added dropwise. After 5 hours, the reaction was removed from the cooling bath, quenched with sat. aq. NaHCO ₃ (5 mL) and extracted with CH ₂ Cl ₂ (3 x 10 mL). The dried (K ₂ CO ₃ ) extract was concentrated in vacuo purified by chromatography over alumina, eluting with 2-10% EtOAc / hexanes, to give 3 (0.125 g, 0.279 mmol, 80%) as a colorless oil: [α] _D ²³ = +48° (c = 1.3, CHCl ₃ ); IR (neat) 2951, 2933, 2852, 1652, 1630, 1445, 1299, 1256, 1140, 1024, 830, 692, 606 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86-7.88 (m, 2H), 7.66-7.70 (m, IH), 7.55- 7.59 (m 2H), 4.13 (s, IH), 4.07 (s, IH), 3.65 (d, J= 15.6 Hz, IH), 3.36-3.43 (m, IH), 2.88-2.92 (m, IH), 2.67-2.73 (m, IH), 2.46-2.53 (m, 2H), 2.15-2.27 (m, 2H), 2.02 (t, J= 12.4 Hz, 2H), 1.59-1.90 (m, 3H), 1.27-1.32 (m, 2H), 0.94 (s, 9H), 0.21 (s, 3H), 0.19 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.4, 156.2, 137.1, 133.7, 130.0, 129.0, 91.9, 70.1, 48.2, 38.9, 37.2, 36.5, 28.5, 25.7, 23.2, 21.1, 20.7, 18.0, - 4.7, -4.8; HRMS (CI+) calcd. for C ₂₄ H ₃₈ NO ₃ SSi (M+l) 448.2342, found 448.2339.

Example 7

Tricyclic amine 2: To a solution of 3 (68 mg, 0.152 mmol) in dry DCE (3 rnL) was added Zn(OTf) ₂ (166 mg, 0.455 mmol). The reaction mixture was heated in sealed tube at 96 ⁰ C. After 9 h, the solvent was then removed in vacuo. The residue was diluted with 1 N HCl (1 mL) and washed with Et ₂ O (2 x 5 mL). The aqueous phase was neutralized by solid K ₂ Cθ ₃ and extracted with CH ₂ Cl ₂ (3 x 5 mL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo purified by chromatography over alumina, eluting with 30-50% EtOAc / hexanes, to give 2 (38 mg, 0.114 mmol, 75%) as a white solid. [α] _D ²³ = +6° (c = 0.9, CHCl ₃ ); Mp 134-136 ⁰ C; IR (neat) 3359, 2925, 1703, 1295, 1144, 1080, 714, 688 cm ^"1 ; ¹ H NMR (SOO MHz, CDCl ₃ ) δ 7.91-7.93 (m, 2H), 7.64-7.69 (m, IH), 7.54-7.59 (m, 2H), 3.65 (s br, IH), 3.13-3.22 (m, 2H), 2.88-3.01 (m, 2H), 2.53 (dd, J= 17.1, 6.6 Hz, IH), 2.22 (d, J= 17.1 Hz, IH), 2.05-2.07 (m, IH), 1.64-1.89 (m, 10H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 210.7, 139.4, 133.7, 129.1, 128.5, 72.9, 59.7, 44.4, 41.1, 40.9, 40.3, 34.4, 32.0, 25.6, 25.5, 21.6; HRMS (EI+) calcd. for Ci ₈ H ₂₃ NO ₃ S (M+) 333.1399, found 333.1405.

Example 8

Keto sulfone 34: To a stirred solution of 32 (0.68 g, 4.0 mmol) in THF (40 mL) at -78°C was added LDA (5.3 mL, 8.0 mmol, 1.5 M in THF) dropwise. After 20 minutes, a solution of ester 7 (1.025 g, 8.0 mmol) in pre-cooled THF (2 mL) was added via cannula to the sulfone solution. The reaction was stirred at -78°C for 2 hours and quenched with sat. aq. NH ₄ Cl (15 mL) and extracted with ether (3 x 15 mL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified chromatography over silica gel, eluting with 2-15% EtOAc / hexanes, to give 34 (1.013 g, 3.80 mmol, 95%) as a colorless oil: IR: (neat) 2976, 2938, 1713, 1582, 1369, 1152, 1081, 994, 912, 765, 732, 689 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ

7.82-7.67 (m, 3H), 7.57 (t, J= 7.2 Hz, 2H), 5.70-5.83 (m, IH), 4.97-5.06 (m, 2H), 4.18 (q, J= 7.2 Hz, IH), 2.91 (dt, J= 18.3, 7.2 Hz, IH), 2.65 (dt, J= 18.6, 6.9 Hz, IH), 2.03-2.10 (m, 2H), 1.69 (p, J= 7.2 Hz, 2H), 1.40 (d, J= 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) 5 202.2, 137.7, 136.3, 134.3, 129.4, 129.1, 115.5, 70.0, 43.1, 32.7, 22.3, 12.0; HRMS (EI+) calcd. for C ₁₆ Hi ₉ O ₃ S (M+H) 267.1055, found 267.1060.

Example 9

34 35 Enone 35: To 34 (110 mg, 0.414 mmol) was added 2 ^nd Gen. Grubbs catalyst

(17.5 mg, 37.3 μmol) in CH ₂ Cl ₂ (4 niL) and methylvinylketone (87 mg, 0.102 mL, 1.242 mmol) at room temperature. After 24 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give 35 (89 mg, 0.289 mmol, 70%) as colorless oil as well as recovered 34 (20 mg, 0.0752 mmol, 18%): IR (neat) 2943, 1718, 1664, 1631, 1582, 1315, 1250, 1108, 759, 738, 694, 585 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60-7.70 (m, 3H), 7.55-7.58 (m, 2H), 6.76 (dt, J= 15.9, 6.9 Hz, IH), 6.09 (dt, J= 15.9, 1.5 Hz, IH), 4.17 (q, J= 7.2 Hz, IH), 2.99 (dt, J= 18.9, 7.2 Hz, IH), 2.70 (dt, J= 18.6, 6.9 Hz, IH), 2.21-2.29 (m, 5H), 1.79 (p, J= 7.2 Hz, 2H), 1.38 (t, J= 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 201.6, 198.5, 146.8, 136.2, 134.4, 131.8, 129.3, 129.2, 70.0, 43.0, 31.3, 27.0, 21.6, 12.0; HRMS (F AB+) calcd. for Ci ₆ H ₂₁ O ₄ S (M+H) 309.1161, found 309.1150.

Example 10

36

Cyclohexanone 36: To a solution of 35 (25 mg, 0.0812 mmol) in EtOH/DCE (1 :99, 0.4 mL) was added sulfonamide 15 (3.4 mg, 0.00812 mmol) and piperidine (6.9 mg, 8 μL, 0.0812 mmol) at -20 ⁰ C. After stirring at same

temperature for 72 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the product 36 (20 mg, 0.0649 mmol, 80%, 82% ee) as colorless oil. [α] _D ²³ = +63.3° (c = 1.3, CHCl ₃ ); IR (neat) 2949, 2884, 1713, 1446, 1375, 1310, 1364, 1141, 1108, 1075, 972, 754, 721, 629 cm ^"1 ; ¹ H NMR (400 MHz, C ₆ D ₆ ) δ 7.84-7.86 (m, 2H), 7.00-7.09 (m, 3H), 3.84-3.90 (m, IH), 3.15 (dt, J= 14.4, 9.6 Hz, IH), 2.87 (dd, J = 17.2, 3.2 Hz, IH), 2.18-2.32 (m, 2H), 1.34-1.87 (m, 6H), 2.15 (s, 3H), 0.94-1.02 (m, IH); ¹³ C NMR (100 MHz, C ₆ D ₆ ) δ 205.1, 204.2, 136.4, 133.5, 130.4, 128.4, 75.9, 44.7, 38.2, 34.8, 29.4, 26.0, 20.9, 15.2; HRMS (EI+) calcd. for Ci ₆ H ₂₀ O ₄ S (M+) 308.1082, found 308.1078.

Example 11

33 37

Sulfone 37: To a solution of 33 (2.306 g, 9.11 mmol) in DMF (36 mL) was added NaSO ₂ Ph (2.24 g, 13.67 mmol). After stirring for 5 hours, the reaction mixture was poured into ice water (20 mL). The resulting solution was extracted with diethyl ether (3 x 40 mL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 2-20% EtOAc / hexanes, to give 37 (2.403 g, 7.65 mmol, 84%) as a colorless oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.28-7.95 (m, 5H), 3.66 (t, J= 5.7 Hz, 2H), 3.20-3.25 (m, 2H), 1.87- 1.96 (m, 2H), 0.86 (s, 9H), 0.016 (s, 3H), 0.015 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 139.2, 133.6, 129.3, 128.0, 60.7, 53.3, 26.2, 25.8, 18.2, -5.46.

Example 12

PhO ₂ S

TBSO^ ^X/ ^SO ₂ Ph ^^^^^^Y ^^^OTBS

O 37 38

Keto sulfone 38: To a stirred solution of 37 (0.408 g, 1.30 mmol) in THF (13 mL) at -78°C was added LDA (2.6 mL, 2.6 mmol, 1.0 M in THF) dropwise. After 20 minutes, a solution of ester 7 (0.333 g, 2.60 mmol) in pre-cooled THF (1.5 mL) was added via cannula to the sulfone solution. The reaction was stirred at - 78°C for 1.5 hours and quenched with sat. aq. NH ₄ Cl (15 mL) and extracted with

ether (3 x 20 rnL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified chromatography over silica gel, eluting with 5-15% EtOAc / hexanes, to give 38 (0.469 g, 1.144 mmol, 88%) as a colorless oil. IR: (neat) 2927, 2862, 1718, 1467, 1315, 1369, 1146, 1092, 1005, 836, 776, 683, 591 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J= 7.2 Hz, 2H), 7.70 (t, J= 7.2 Hz, IH), 7.58 (t, J= 7.6 Hz, 2H), 5.73-5.83 (m, IH), 4.99-5.07 (m, 2H), 4.40 (dd, J = 8.8, 4.8 Hz, IH), 3.43-3.66 (m, 2H), 2.91 (dt, J= 18.4, 7.6 Hz, IH), 2.64 (dt, J= 18.4, 7.2 Hz, IH), 2.04-2.11 (m, 4H), 1.67 (p, J= 7.6 Hz, 2H), 0.85 (s, 9H), -0.003 (s, 3H), -0.009 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 202.0, 137.7, 136.6, 134.2, 129.4, 129.0, 115.4, 72.1, 59.8, 44.5, 32.8, 30.4, 25.8, 22.2, 18.2, -5.56, -5.60; HRMS (EI+) calcd. for C ₂ iH ₃₄ O ₄ SSi (M+H) 411.2025, found 411.2035.

Example 13

Enone 39: To 38 (133 mg, 0.324 mmol) was added 2 ^nd Gen. Grubbs catalyst

(14 mg, 16.2 μmol) in CH ₂ Cl ₂ (3.3 mL) and methylvinylketone (114 mg, 0.133 mL, 1.62 mmol) at room temperature. After 24 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-15% EtOAc / hexanes, to give 39 (84 mg, 0.186 mmol, 57%) as light yellow oil as well as recovered (45 mg, 0.110 mmol, 34%): IR (neat) 2954, 2927, 2856, 1718, 1674, 1446, 1315, 1261, 1152, 1086, 972, 830, 781, 694, 585 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J= 7.2 Hz, 2H), 7.70 (t, J= 7.6 Hz, IH), 7.58 (t, J= 7.6 Hz, 2H), 6.78 (dt, J= 16, 6.8 Hz, IH), 6.1 (d, J= 16 Hz, IH), 4.34-4.38 (m, IH), 3.62 (p, J = 5.2 Hz, 2H), 3.43-3.49 (m, IH), 2.97 (dt, J= 18.4, 8.0 Hz, IH), 2.65 (dt, J= 18.8, 7.6 Hz, IH), 2.22-2.31 (m, 5H), 2.04-2.10 (m, 2H), 1.78-1.83 (m, 2H), 0.83 (s, 9H), -0.023 (s, 3H), -0.027 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 201.3, 198.5, 146.9, 136.5, 134.3, 131.8, 129.4, 129.1, 72.2, 59.9, 44.2, 31.4, 30.4, 27.0, 25.8, 21.5, 18.2, -5.57, -5.60; HRMS (EI+) calcd. for C ₂₃ H ₃₆ O ₅ SSi (M+) 452.2053, found 452.2066.

Example 14

Cyclohexanone 40: To a solution of 39 (35 mg, 0.077 mmol) in EtOH/DCE (1 :99, 0.39 niL) was added sulfonamide 15 (3.3 mg, 0.0077 mmol) and piperidine (6.6 mg, 7.7 μL, 0.077 mmol) at -20 ⁰ C. After stirring at same temperature for 5 days, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-20% EtOAc / hexanes, to give the product 40 (26.6 mg, 0.0588 mmol, 76%, 83% ee) as colorless oil. [α] _D ²³ = +35° (c = 0.8, CHCl ₃ ); IR (neat) 2922, 2851, 1718, 1364, 1299, 1255, 1075, 836, 716, 689 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (d, J= 7.2 Hz, 2H), 7.67 (t, J= 7.2 Hz, IH), 7.55 (t, J= 7.6 Hz, 2H), 3.74 (t, J= 6.4 Hz, IH), 3.46 (d, J= 17.6 Hz, IH), 3.37 (t, J= 7.6 Hz, IH), 2.45-2.72 (m, 4H), 2.18-2.32 (m, 5H), 1.74-1.96 (m, 3H), 1.40-1.50 (m, IH), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 206.3, 205.4, 136.3, 134.0, 131.0, 128.6, 78.5, 59.3, 45.3, 39.6, 35.3, 32.9, 30.5, 29.7, 27.7, 25.9, 21.9, 18.3, -5.51; HRMS (ES+) calcd. for C ₂₃ H ₃₆ O ₅ NaSSi (M+Na) 475.1950, found 475.1959.

Example 15

PhO ₂ S r^> PhO ₂ S r*^ π

4 ⁴ 1 ¹ 4 °2 Keto sulfone 42: To a stirred solution of 41 (0.394 g, 1.602 mmol) in THF

(16 mL) at -78°C was added LDA (3.2 mL, 3.2 mmol, 1.0 M in THF) dropwise. After 5 minutes, a solution of ester 7 (0.411 g, 3.204 mmol) in pre-cooled THF (2.0 mL) was added via cannula to the sulfone solution. The reaction was stirred at - 78°C for 1.5 hours and quenched with sat. aq. NH ₄ Cl (15 mL) and extracted with ether (3 x 20 mL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified chromatography over silica gel, eluting with 5-15% EtOAc / hexanes, to give 42 (0.499 g, 1.46 mmol, 91%) as a colorless oil: IR: (neat) 2922, 2851, 1723, 1636, 1457, 1320, 1152, 923, 754, 689 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-

7.88 (m, 2H), 7.61-7.77 (m, 3H), 7.04-7.29 (m, 5H), 5.58-5.63 (m, IH), 4.85-4.93 (m, 2H), 4.41 (dd, J= 12, 2.8 Hz, IH), 3.27 (dd, J= 13.2, 2.8 Hz, IH), 3.10 (t, J = 18 Hz, IH), 2.68 (dt, J= 18, 6.4 Hz, IH), 2.15 (dt, J= 18.4, 6.4 Hz, IH), 1.82-1.89 (m, 2H), 1.43-1.50 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 201.8, 137.5, 136.4, 135.7, 134.5, 129.6, 129.2, 128.89, 128.86, 127.3, 115.3, 76.0, 45.2, 33.3, 32.4, 21.9; HRMS (EI+) calcd. for C ₂₀ H ₂₂ O ₃ S (M+) 342.1290, found 341.9227.

Example 16

Enone 43: To 42 (0.121 g, 0.354 mmol) was added 2 ^nd Gen. Grubbs catalyst

(15 mg, 17.7 μmol) in CH ₂ Cl ₂ (3.5 rnL) and methylvinylketone (74 mg, 87 μL, 1.062 mmol) at room temperature. After 24 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give 43 (88 mg, 0.229 mmol, 65%) as colorless oil as well as recovered 42 (35 mg, 0.102 mmol, 29%): IR (neat) 2927, 2851, 1718, 1669, 1451, 1359, 1310, 1255, 1146, 1075, 972, 743, 694, 596 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.61-7.87 (m, 5H), 7.03- 7.27 (m, 5H), 6.61 (dt, J= 16.4, 6.8 Hz, IH), 5.94 (d, J= 15.6 Hz, IH), 4.41 (dd, J= 12, 3.2 Hz, IH), 3.24 (dd, J= 13.2, 3.2 Hz, IH), 3.10 (t, J= 12 Hz, IH), 2.72 (dt, J= 18.4, 6.8 Hz, IH), 2.22 (s, 3H), 1.97-2.19 (m, 3H), 1.55-1.60 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 201.3, 198.4, 146.7, 136.3, 135.6, 134.6, 131.7, 129.6, 129.2, 128.9, 128.8, 127.3, 76.0, 45.0, 33.4, 31.0, 27.0, 21.2; HRMS (EI+) calcd. for C ₂₂ H ₂₄ O ₄ S (M+) 384.1395, found 384.1389.

Example 17

44

Cyclohexanone 44: To a solution of 43 (32 mg, 0.0833 mmol) in EtOH/DCE (1 :99, 0.4 mL) was added sulfonamide 15 (3.5 mg, 8.33 μmol) and

piperidine (7.1 mg, 8.2 μL, 0.0833 mmol) at -20 ⁰ C. After stirring at same temperature for 72 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the product 44 (28.6 mg, 0.0745 mmol, 89%, 81% ee) as colorless oil. [α] _D ²³ = +44.4° (c = 1.1, CHCl ₃ ); IR (neat) 2922, 1718, 1696, 1304, 1141, 689 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.84 (m, 5H), 7.14-7.29 (m, 5H), 3.63-3.77 (m, 3H), 3.20 (d, J = 13.6 Hz, IH), 2.72 (dt, J= 15.6, 8.8 Hz, IH), 2.58-2.65 (m, IH), 2.18-2.26 (m, 4H), 1.72-1.81 (m, IH), 1.53-1.61 (m, IH), 1.41-1.49 (m, IH), 0.56-0.61 (m, IH); ¹³ C NMR (IOO MHZ, CDCl ₃ ) 5 207.1, 206.2, 135.5, 135.2, 134.2, 131.2, 130.5, 128.68, 128.65, 127.5, 79.9, 45.6, 39.1, 35.7, 33.2, 30.3, 26.5, 19.3; HRMS (ES+) calcd. for C ₂₂ H ₂₄ O ₄ SNa (M+) 407.1293, found 407.1288.

Example 18

PhOoS OMe (^ PhO ₂ S

\ O ^'

32 45 O

46 Keto sulfone 46 : To a stirred solution of 32 (0.186 g, 1.10 mmol) in THF

(11 mL) at -78°C was added LDA (2.2 mL, 2.2 mmol, 1.0 M in THF) dropwise. After 20 minutes, a solution of ester 45 (0.25 g, 2.2 mmol) in pre-cooled THF (1.5 mL) was added via cannula to the sulfone solution. The reaction was stirred at - 78°C for 90 minutes and quenched with sat. aq. NH ₄ Cl (15 mL) and extracted with ether (3 x 15 mL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified chromatography over silica gel, eluting with 2-15% EtOAc / hexanes, to give 46 (0.278 g, 1.10 mmol, 100%) as a colorless oil. IR: (neat) 2987, 2938, 1718, 1642, 1576, 1440, 1353, 1222, 1141, 1086, 999, 917, 787, 759, 689 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.83 (m, 5H), 5.76-5.86 (m, IH), 5.01-5.10 (m, 2H), 4.18 (q, J= 7.2 Hz, IH), 2.91 (dt, J= 18.4, 7.6 Hz, IH), 2.65 (dt, J= 18.4, 6.8 Hz, IH), 2.36 (q, J= 6.8 Hz, 2H), 1.41 (d, J= 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 201.5, 136.4, 136.1, 134.3, 129.4, 129.1, 115.8, 70.0, 43.0, 27.3, 12.0; HRMS (EI+) calcd. for C ₁₃ Hi ₆ O ₃ S (M+) 252.0820, found 252.0815.

Example 19

PhO ₂ S O PhO ₂ S

O O

46 47

Enone 47: To 46 (0.123 g, 0.488 mmol) was added 2 ^nd Gen. Grubbs catalyst (41.4 mg, 48.8 μmol) in CH ₂ Cl ₂ (2.4 niL) and methylvinylketone (0.102 g, 0.12 niL, 1.464 mmol) at room temperature. After 24 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give 47 (89 mg, 0.304 mmol, 62%) as colorless oil as well as recovered 46 (30 mg, 0.119 mmol, 24%): IR (neat) 2998, 2927, 1718, 1669, 1625, 1446, 1369, 1310, 1255, 1152, 1086, 983, 765, 732, 689 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.57-7.80 (m, 5H), 6.78 (dt, J= 16, 6.4 Hz, IH), 6.12 (d, J= 16 Hz, IH), 4.20 (q, J = 7.2 Hz, IH), 3.19 (dt, J= 18.8, 7.2 Hz, IH), 2.83 (dt, J= 19.2, 6.8 Hz, IH), 2.53 (q, J= 7.2 Hz, 2H), 2.25 (s, 3H), 1.41 (d, J= 7.2 Hz, 3H); ¹³ C NMR (IOO MHZ ₅ CDCI ₃ ) δ 200.6, 198.3, 145.4, 136.0, 134.5, 134.3, 132.0, 129.3, 129.2, 70.0, 41.9, 27.1, 25.9, 12.0; HRMS (F AB+) calcd. for C ₁₅ Hi ₈ O ₄ S (M+) 294.0926, found 294.0917.

Example 20

PhO ₂ S \

^/""SO ₂ Ph

O

O

47

48

Cyclohexanone 48: To a solution of 47 (40 mg, 0.137 mmol) in EtOH/DCE (1 :99, 0.68 mL) was added sulfonamide 15 (5.7 mg, 0.0137 mmol) and piperidine (11.6 mg, 13 μL, 0.137 mmol) at -20 ⁰ C. After stirring at same temperature for 6 days, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the product 48 (23.2 mg, 0.0792 mmol, 58%, 84% ee) as colorless oil. [α] _D ²³ = -22° (c = 0.3, CHCl ₃ ); IR (neat) 2960, 2916, 2845, 1745, 1713, 1446, 1299, 1146, 1130, 1086, 759, 721, 689 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.86 (m, 5H), 3.49-3.56 (m, IH), 3.08 (dd, J= 17.2, 2.0 Hz, IH), 2.30-2.49 (m, 4H), 2.22 (s, 3H), 1.24-1.45 (m, 4H); ¹³ C NMR (100 MHz, CCl ₃ ) δ 210.1, 206.0, 135.3, 134.3, 130.8, 128.8, 72.5, 44.9, 38.6, 36.3,

30.3, 25.6, 14.1; HRMS (ES+) calcd. for Ci ₅ H ₁₈ O ₄ NaS (M+Na) 317.0824, found 317.0834.

Example 21

Aldol 24a: To a solution of 23a (53 mg, 0.5 mmol) in EtOH/DCE (1 :99, 0.6 rnL) was added sulfonamide 15 (42.2 mg, 0.1 mmol) and acetone (22, 0.29 g, 0.36 mL, 5 mmol) at room temperature. After stirring at same temperature for 72 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the known product 24a (62 mg, 0.378 mmol, 76%, 87% ee) as colorless oil. [α] _D ²³ = +52° (c = 0.7, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29-7.39 (m, 5H), 5.18 (d, J= 9.2 Hz, IH), 3.30 (s, IH), 2.83-2.95 (m, 2H), 2.22 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 209.1, 142.7, 128.6, 127.7, 125.6, 69.9, 52.0, 30.8; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 1 mL min ^"1 , 257 min: t _R (major) = 10.6 min; t _R (minor) = 11.4 min.

Aldol 24b: To a solution of 23b (75 mg, 0.5 mmol) in EtOH/DCE (1 :99, 0.64 mL) was added sulfonamide 15 (42.2 mg, 0.1 mmol) and acetone (22, 0.29 g, 0.36 mL, 5 mmol) at room temperature. After stirring at same temperature for 48 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the product 24b (88 mg, 0.421 mmol, 84%, 83% ee) as yellow solids. [α] _D ²³ = +54° (c = 0.55, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J= 8.8 Hz, 2H), 7.56 (d, J= 8.8 Hz, 2H), 5.27-5.31 (m, IH), 3.60 (d, J= 3.6 Hz, IH), 2.82-2.92 (m, 2H), 2.25 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 208.5, 149.9, 147.4, 126.4, 123.8, 68.9, 51.5, 30.7; HPLC: Daicel Chiralpak OJ. Hexanes-z-PrOH, 90:10, 1 mL min ^"1 , 254 min: t _R (major) = 35.5 min; fo (minor) = 40.8 min.

Example 23

Aldol 28: To a solution of 23b (75 mg, 0.5 mmol) in EtOH/DCE (1 :99, 0.6 niL) was added sulfonamide 15 (42.2 mg, 0.1 mmol) and cyclopentanone (27) (0.42 g, 0.44 mL, 5 mmol) at room temperature. After stirring at same temperature for 15 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with CH ₂ Cl ₂ , to give the known products αnti-28 (31 mg, 0.132 mmol, 26%, 80% ee) and syn-28 (84 mg, 0.357 mmol, 71%, 77% ee) as white solids, αnti-28: [α] _D ²³ = -77° (c = 0.5, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J= 8.8 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 4.86 (d, J= 9.2 Hz, IH), 4.77 (s, IH), 2.23-2.52 (m, 3H), 2.00-2.07 (m, IH), 1.54-1.83 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 222.2, 148.7, 147.7, 127.4, 123.7, 74.4, 55.1, 38.6, 26.8, 20.4; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 0.75 mL min ^"1 , 254 min: t _R (major) = 40.7 min; t _R (minor) = 38.2 min. syn-28: [α] _D ²³ =+183° (c=0.6, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (d, J= 8.7 Hz, 2H), 7.54 (d, J= 8.7 Hz, 2H), 5.44 (t, J = 3.3 Hz, IH), 2.37-2.65 (m, 3H), 1.70-2.23 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 219.8, 150.3, 147.1, 126.4, 123.6, 70.4, 56.1, 39.0, 22.4, 20.3; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 1 mL min ^"1 , 254 min: t _R (major) = 21.5min; t _R (minor) = 16.1 min.

Example 24 29 23b antι-30

Aldol 30: To a solution of 23b (75 mg, 0.5 mmol) in EtOH/DCE (1 :99, 0.5 mL) was added sulfonamide 15 (42.2 mg, 0.1 mmol) and cyclohexanone (29) (0.49 g, 0.52 mL, 5 mmol) at room temperature. After stirring at same temperature for 36 hours, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 5-20% EtOAc / hexanes, to give the known product αnti-30 (119 mg, 0.478 mmol, 96%, 97% ee) as white solids. [α] _D ²³ = +8.0° (c = 1.2,

CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J= 8.7 Hz, 2H), 7.53 (d, J= 8.7 Hz, 2H), 4.92 (dd, J= 8.4, 3.2 Hz, IH), 4.10 (d, J= 3.2 Hz, IH), 2.38-2.62 (m, 3H), 2.11-2.16 (m, IH), 1.38-1.87 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 214.8, 148.4, 147.6, 127.9, 123.6, 74.0, 57.2, 42.7, 30.8, 27.7, 24.7; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 1 niL min ^"1 , 254 min: t _R (major) = 41.1 min; t _R (minor) = 32.7 min.

Example 25

Sulfonamide 17, Scheme 3: To a solution ofp-dodecylbenzenesulfonyl chloride (16) (1.25 g, 3.62 mmol) in CHCl ₃ (6 mL) was NH ₄ OH (2.5 mL, 2.26 g, 18.1 mmol) at rt. After stirring vigorously for 2 hours, the reaction mixture was extracted with CHCl ₃ (3 xlO mL). The organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give the product 17 (1.17 g, 3.60 mmol, 99%). ¹ H NMR (400 MHz, CDCl ₃ ) 7.86-7.88 (m, 2H), 7.29-7.35 (m, 2H), 5.03 (s, 2H), 0.78-1.68 (m, 25H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 139.2, 128.4, 127.8, 126.5, 47.9, 46.1, 40.0, 38.1, 36.7, 31.9, 29.7, 29.5, 29.2, 27.5, 22.7, 14.1.

Example 26 Cbz Proline Sulfonamide 19, Scheme 3: To a solution of Cbz-L-proline 18 (0.609 g, 2.45 mmol) in CH ₂ Cl ₂ (24 mL) was added sulfonamide 17 (0.795 g, 2.45 mmol), DMAP (0.048 g, 0.391 mmol) and EDCI (0.470 g, 2.45 mmol) respectively. The reaction mixture was stirred at room temperature for 72 hours before being partitioned between EtOAc (30 mL) and aq. HCl (20 mL, IN). The organic layer was washed with half-saturated brine. The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 10%

EtOAc/CH ₂ Cl ₂ , to give 19 (1.15 g, 2.06 mmol, 84%) as a colourless liquid. [α] _D ²³ = -89° (c= 2.5, CHCl ₃ ); IR (neat) 3148, 2955, 2925, 2856, 1720, 1677, 1449, 1411, 1355, 1174, 1131, 1088, 826, 692 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 10.4 (br s, IH), 7.93-7.95 (m, 2H), 7.26-7.40 (m, 7H), 5.23 (s, 2H), 4.31 (br s, IH), 3.42 (m, 2H), 2.45-2.57 (m, IH), 0.85-1.87 (m, 28H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 169.0, 157.2, 135.9, 128.6, 128.4, 128.3, 128.1, 127.5, 68.1, 60.8, 47.2, 46.2, 38.8, 38.1, 36.6,

31.8, 29.6, 29.3, 27.5, 27.2, 26.7, 24.3, 22.7, 14.1; HRMS (EI+) calcd. for C _3I H ₄₅ N ₂ O ₅ S (M+l), 557.3049 found 557.3067.

Example 27 Hua Cat 15, Scheme 3: To a solution of Cbz-L-sulfonamide 19 (1.02 g,

1.84 mmol) in MeOH (56 niL) was added 10% Pd/C (110 mg). The mixture was stirred at room temperature for 20 h under an atmosphere of hydrogen. After 24 hours, the reaction was filtered through Celite and silica gel pad, and the filtrate was concentrated in vacuo to give white solid. The crude product was purified by chromatography, eluting with 10% MeOH / CH ₂ Cl ₂ , to give the product 15 (0.699 g, 1.66 mmol, 90%) as a white solid. Mp: 184-186 ⁰ C; [α] _D ²³ = -95° (c= 1.0, CHCl ₃ ); IR (neat) 3135, 2955, 2920, 2852, 1626, 1458, 1372, 1308, 1144, 1084, 843 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) 8.73 (br s, IH), 8.06 (br s, IH), 7.85 (d, J= 8.0 Hz, 2H), 122-126 (m, 2H), 4.33 (t, J= 8.0 Hz, IH), 3.23-3.43 (m, 2H), 2.33-2.40 (m, IH), 0.82-2.05 (m, 28H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 173.8, 140.4, 127.8, 127.2, 126.4, 62.8, 47.8, 39.9, 38.2, 36.8, 31.9, 31.8, 30.1, 29.7, 29.6, 29.3, 29.2, 27.6, 27.2, 24.5, 22.7, 14.1; HRMS (EI+) calcd. for C ₂₂ H ₃₉ N ₂ O ₃ S (M+l), 423.2681 found 423.2701.

Example 28 13 14

Sulfonamide 14. To a solution ofp-dodecylbenzenesulfonyl chloride (13) (1.25 g, 3.62 mmol) in CHCl ₃ (6 mL) was NH ₄ OH (2.5 mL, 2.26 g, 18.1 mmol) at rt. After stirring vigorously for 2 h, the reaction mixture was extracted with CHCl ₃ (3 xlO mL). The organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give the product 14 (1.17 g, 3.60 mmol, 99%). Compound 13 is sold as a mixture of isomers on the C12H25 alkyl chain. No attempt was made to separate the isomers in this sequence and the isomeric mixture does not appear to adversely affect the reactivity. ¹ H NMR (400 MHz, CDCl ₃ ) 7.86-7.88 (m, 2H), 7.29-7.35 (m, 2H), 5.03 (s, 2H), 0.78-1.68 (m, 25H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 139.2, 128.4, 127.8, 126.5, 47.9, 46.1, 40.0, 38.1, 36.7, 31.9, 29.7, 29.5, 29.2, 27.5, 22.7, 14.1.

Example 29

15 14 16

Cbz sulfonamide 16: To a solution of Z-L-proline 15 (3.16 g, 12.7 mmol) in CH ₂ Cl ₂ (127 niL) was added sulfonamide 14 (4.13 g, 12.7 mmol), DMAP (0.248 g, 2.03 mmol) and EDCI (2.44 g, 12.7 mmol) respectively. The reaction mixture was stirred at room temperature for 72 h before being partitioned between EtOAc (180 mL) and aq. HCl (120 mL, 1 N). The organic layer was washed with half-saturated brine (2 x 50 mL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 10% EtOAc/CH ₂ Cl ₂ , to give 16 (5.85 g, 10.5 mmol, 83%) as a colorless liquid. Compound 13 is sold as a mixture of isomers on the C12H25 alkyl chain. No attempt was made to separate the isomers in this sequence and the isomeric mixture does not appear to adversely affect the reactivity. [α] _D ²³ = +90° (c= 2.2, CHCl ₃ ); IR (neat) 3148, 2955, 2925, 2856, 1720, 1677, 1449, 1411, 1355, 1174, 1131, 1088, 826, 692 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) 10.4 (br s, IH), 7.93-7.95 (m, 2H), 7.26-7.40 (m, 7H), 5.23 (s, 2H), 4.31 (br s, IH), 3.42 (m, 2H), 2.45-2.57 (m, IH), 0.85-1.87 (m, 28H); ¹³ C NMR (IOO MHZ, CDCl ₃ ) δ 169.0, 157.2, 135.9, 128.6, 128.4, 128.3, 128.1, 127.5, 68.1, 60.8, 47.2, 46.2, 38.8, 38.1, 36.6, 31.8, 29.6, 29.3, 27.5, 27.2, 26.7, 24.3, 22.7, 14.1; HRMS (EI+) calcd. for C ₃ iH ₄₅ N ₂ O ₅ S (M+l), 557.3049 found 557.3067.

Example 30

Sulfonamide 11: To a solution of Z-L-sulfamide 16 (4.99 g, 8.97 mmol) in MeOH (178 mL) was added Pd/C (536 mg, 10 %). The mixture was stirred at rt for under an atmosphere of hydrogen. After 24 h, the reaction was filtered through Celite and silica gel pad, and the filtrate was concentrated in vacuo to give white solid. The crude product was purified by chromatography over silica gel, eluting with 10% MeOH / CH ₂ Cl ₂ , to give the product 11 (3.26 g, 7.73 mmol, 86%) as a white solid. Compound 13 is sold as a mixture of isomers on the C12H25 alkyl chain.

No attempt was made to separate the isomers in this sequence and the isomeric mixture does not appear to adversely affect the reactivity. Mp: 184-186 ⁰ C; [α]o = +94° (c= 0.95, CHCl ₃ ); IR (neat) 3135, 2955, 2920, 2852, 1626, 1458, 1372, 1308, 1144, 1084, 843 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) 8.73 (br s, IH), 8.06 (br s, IH), 7.85 (d, J= 8.0 Hz, 2H), 122-126 (m, 2H), 4.33 (t, J= 8.0 Hz, IH), 3.23-3.43 (m, 2H), 2.33-2.40 (m, IH), 0.82-2.05 (m, 28H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 173.8, 140.4, 127.8, 127.2, 126.4, 62.8, 47.8, 39.9, 38.2, 36.8, 31.9, 31.8, 30.1, 29.7, 29.6, 29.3, 29.2, 27.6, 27.2, 24.5, 22.7, 14.1; HRMS (EI+) calcd. for C ₂₂ H ₃₉ N ₂ O ₃ S (M+l), 423.2681 found 423.2701.

Procedure A - (DCE, 20 mol% catalyst): To a solution of aldehyde (0.5 mmol) and cyclohexanone (0.245 g, 0.26 rnL, 2.5 mmol, 5 equiv.) in DCE (0.24 rnL) was added sulfonamide 11 (42.2 mg, 0.1 mmol) and water (0.5 mmol, 9 mg, 1 equiv.) at 4 ⁰ C. After stirring at same temperature, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the corresponding aldol product.

Procedure B (neat, 2 mol % catalyst): To a solution of aldehyde (0.5 mmol) and cyclohexanone (0.098 g, 0.1 mL, 1.0 mmol, 2 equiv.) was added sulfonamide 11 (4.2 mg, 0.01 mmol) and water (0.5 mmol, 9 mg, 1 equiv.) at rt. After stirring at same temperature, reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the corresponding aldol product.

Example 31

2-[Hydroxy-(4-nitro-phenyl)-methyl]-cyclohexan-l-one (12): (Procedure A: time 30 h, 118 mg, 95%, 99% ee, >99:1 dr. Procedure B: time 36 h, 119 mg, 96% ee, >99: 1 dr) [α] _D ²³ = +8.0° (c=1.3, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J= 8.7 Hz, 2H), 7.53 (d, J= 8.7 Hz, 2H), 4.92 (dd, J= 8.4, 3.2 Hz, IH),

4.10 (d, J= 3.2 Hz, IH), 2.38-2.62 (m, 3H), 2.11-2.16 (m, IH), 1.38-1.87 (m, 5H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 214.8, 148.4, 147.6, 127.9, 123.6, 74.0, 57.2, 42.7, 30.8, 27.7, 24.7; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 1 niL min ^"1 , 254 nm: fo (major) = 41.1 min; fo (minor) = 32.7 min.

Large scale preparation of aldol product 12: To a solution ofp- nitrobenzaldehyde (181 g, 1.2 mol) and cyclohexanone (235 g, 248 mL, 2.4 mol, 2 equiv.) was added sulfonamide 11 (10.1 g, 0.024 mol) and water (21.6 g, 21.6 mL, 1.2 mol) at rt. After stirring at same temperature for 48 h, the reaction mixture was filtered, and the solid filtrate 12 (163.6 g, 0.66 mol) was kept. The mother liquor recrystallized by dilution with hexanes and filtration to give additional material 12 (98.4 g, 39.5 mol - 88% total yield, 97% ee, 98: 1 dr). The catalyst was isolated via purification of the mother liquor through a small pad of silica gel (EtOAc - 20% MeOH / CH ₂ Cl ₂ ). The MeOH / CH ₂ Cl ₂ solution was concentrated and recrystallized in MeOH to yield recovered catalyst 11 (6.42 g, 15.2 mmol, 63% recovery).

Example 32

17

2-[Hydroxy-(2-nitro-phenyl)-methyl]-cyclohexan-l-one (17): {Procedure A: time 72 h, 113 mg, 91%, 99% ee, >99:1 dr) [α] _D ²³ = +16.3° (c=2.0, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (dd, J= 8.4, 1.6 Hz, 2H), 7.78 (dd, J= 8.0, 2.4 Hz, IH), 7.65 (td, J= 8.0, 0.8 Hz, IH), 7.44 (td, J= 8.0, 1.6 Hz, IH), 5.46 (d, J= 6.8 Hz, IH), 4.13 (br s, IH), 2.74-2.79 (m, IH), 2.34-2.48 (m, 2H), 2.09-2.13 (m, IH), 1.58- 1.88 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 215.0, 148.7, 136.6, 133.1, 129.0, 128.4, 124.1, 70.0, 57.3, 42.8, 31.1, 27.8, 25.0; HPLC: Daicel Chiralpak OJ. Hexanes-z-PrOH, 95:5, 1 mL min ^"1 , 254 nm: t _R (major) = 23.8 min; t _R (minor) = 21.8 min.

Example 33

2- [Hydroxy-(2,4-dinitro-phenyl)-methyl] -cy clohexan- 1-one (18):

(Procedure A: time 72 h, 74.4 mg, 52%, 97% ee, >99:1 dr) [α] _D ²³ = +9.4° (c=2.3, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J= 2.4 Hz, IH), 8.48 (dd, J= 8.4, 2.0 Hz, IH), 8.09 (d, J= 8.8 Hz, IH), 5.53 (br s, IH), 4.32 (d, J= 4.0 Hz, IH), 2.31- 2.80 (m, 3H), 2.11-2.17 (m, IH), 1.63-1.94 (m, 5H); ¹³ C NMR (IOO MHz, CDCl ₃ ) δ 214.5, 148.2, 147.0, 143.9, 131.0, 127.1, 119.8, 70.1, 57.0, 42.9, 31.4, 27.7, 25.0; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 85:15, 1.0 niL min ^"1 , 254 nm: t _R (major) = 25.9 min; fo (minor) = 23.0 min.

Example 34

2- [Hydroxy-(2-chloro-phenyl)-methyl] -cy clohexan- 1-one (19): (Procedure A: time 72 h, 94.2 mg, 79%, 98% ee, >99: 1 dr. Procedure B: time 72 h, 79.7 mg, 67%, 99% ee, >99:1 dr) [α] _D ²³ = +21.2° (c=0.9, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (dd, J= 7.6, 1.6 Hz, IH), 7.21-7.37 (m, 3H), 5.37 (dd, J= 8.0, 3.6 Hz, IH), 4.05 (d, J= 4.0 Hz, IH), 2.32-2.72 (m, 3H), 2.09-2.14 (m, IH), 1.56-1.86 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 215.3, 139.1, 133.0, 129.2, 128.8, 128.3, 127.3, 70.5, 57.6, 42.8, 30.4, 27.8, 24.9; HPLC: Daicel Chiralpak OD. Hexanes-z- PrOH, 95:5, 0.8 mL min ^"1 , 220 nm: fo (major) = 13.8 min; t _R (minor) = 17.3 min.

Example 35

2-[Hydroxy-(4-chloro-phenyl)-methyl]-cyclohexan-l-one (20): (Procedure A: time 48 h, 81.0 mg, 68%, 99% ee, >99:1 dr). Procedure B: time 48 h, 57.1 mg, 49%, 92% ee, >99: 1 dr) [α] _D ²³ = +24.4° (c=0.96, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ

7.34 (d, J= 8.4 Hz, 2H), 7.28 (d, J= 8.4 Hz, 2H), 4.78 (dd, J= 8.8, 2.4 Hz, IH), 4.01 (d, J= 2.8 Hz, IH), 2.37-2.61 (m, 3H), 2.07-2.14 (m, IH), 1.28-1.84 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 215.3, 139.5, 133.6, 128.6, 128.4, 74.1, 57.4, 42.7, 30.8, 27.7, 24.7; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 0.5 niL min ^{" 1} _J 220 nm: t _R (major) = 35.7 min; t _R (minor) = 30.7 min.

Example 36

2-[Hydroxy-(2,4-dichloro-phenyl)-methyl]-cyclohexan-l-one (21): (Procedure A: time 48 h, 128 mg, 94%, 99% ee, >99:1 dr) [α]D23 = -41.5° (c=2.1, CHC13); IH NMR (400 MHz, CDC13) δ 7.33 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.0 Hz, 2H), 5.86 (d, J = 9.6 Hz, IH), 3.69 (br s, IH), 3.49-3.55 (m, IH), 2.38-2.55 (m, 2H), 2.07-2.14 (m, IH), 1.34-1.86 (m, 5H); 13C NMR (100 MHz, CDC13) δ 214.5, 135.7, 134.7, 129.4, 70.6, 53.7, 42.7, 29.9, 27.6, 24.7; HPLC: Daicel Chiralpak OJ. Hexanes-i-PrOH, 95:5, 1.0 mL min-1, 254 nm: tR (major) = 12.6 min; tR (minor) = 10.9 min.

Example 37

2-[Hydroxy-(pentaflurophenyl)-methyl]-cyclohexan-l-one (22): {Procedure A: time 36 h, 134 mg, 91%, >99% ee, >99: 1 dr) [α] _D ²³ = -17° (c=l .4, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.34 (dd, J = 9.6, 3.2 Hz, IH), 3.94 (d, J = 3.2 Hz, IH), 2.99-3.06 (m, IH), 1.37-2.56 (m, 8H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 214.2, 145.3 (appt d, J _C - _F = 254 Hz), 140.9 (appt d, J _C - _F = 254 Hz), 137.6 (appt d, Jc- _F = 254 Hz), 113.7 (m), 66.0, 54.2, 42.4, 30.2, 27.5, 24.5; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90: 10, 0.5 mL min ^"1 , 254 nm: t _R (major) = 17.8 min; t _R (minor) = 22.1 min.

Example 38

2-[Hydroxy-(pyridin-4-yl)-methyl]-cyclohexan-l-one (23): {Procedure A: time 24 h, 100 mg, 98%, 99% ee, 29:1 dr. Procedure B: time 36 h, 93.0 mg, 91%, 91% ee, 7:1 dr) [α] _D ²³ = +30.2° (c=0.96, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (d, J= 6.0 Hz, 2H), 7.25 (d, J= 6.0 Hz, 2H), 4.80 (d, J= 8.4 Hz, IH), 4.29 (br s, IH), 2.31-2.63 (m, 3H), 2.07-2.12 (m, IH), 1.33-1.84 (m, 5H); ¹³ C NMR (100

MHz, CDCl ₃ ) δ 214.5, 150.1, 149.7, 122.1, 73.3, 56.9, 42.6, 30.7, 27.7, 24.7; HPLC: DDaaiicceell CChhiirraallppaakk AADD.. HHeexxaanneess--z-PrOH, 90:10, 1.0 mL min ^"1 , 254 nm: t _R (major) = 24.5 min; t _R (minor) = 22.6 min.

Example 39

2-[Hydroxy-phenyl-methyl]-cyclohexan-l-one (24): (Procedure A: time 60 h, 61.4 mg, 60%, >99% ee, >99:1 dr). Procedure B: time 48 h, 76.8 mg, 75%,

99% ee, 55:1 dr) [α] _D ²³ = +35.8° (c=l.l, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ

7.29-7.39 (m, 5H), 4.92 (dd, J= 8.8, 2.8 Hz, IH), 3.98 (d, J= 2.8 Hz, IH), 2.34-2.68

(m, 3H), 2.08-2.14 (m, IH), 1.25-1.83 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ

215.5, 141.0, 128.4, 127.9, 127.0, 74.8, 57.5, 42.7, 30.9, 27.8, 24.7; HPLC: Daicel CChhiirraallppaakk OOJJ.. HHeexxaanneesf -z-PrOH, 90:10, 1 mL min ^"1 , 254 nm: t _R (major) = 9.61 min; t _R (minor) = 11.5 min.

Example 40

2-[Hydroxy-(naphthalen-2-yl)-methyl]-cyclohexan-l-one (25):

(Procedure A: time 48 h, 65.0 mg, 63%, 99% ee, >99:1 dr) [α] _D ²³ = +17.3° (c=0.8, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.88 (m, 2H), 7.78 (s, IH), 7.48-7.52

(m, 3H), 4.99 (dd, J= 8.8, 2.0 Hz, IH), 4.09 (d, J= 2.4 Hz, IH), 2.51-2.78 (m, 2H), 2.40 (td, J= 13.4, 6.0 Hz, IH), 2.07-2.14 (m, IH), 1.28-1.80 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 215.6, 138.3, 133.20, 133.16, 128.3, 128.0, 127.7, 126.3, 126.2, 126.0, 124.7, 74.9, 57.4, 42.7, 30.9, 27.8, 24.7; HPLC: Daicel Chiralpak OD. Hexanes-z-PrOH, 80:20, 1.0 niL min ^"1 , 254 nm: t _R (major) = 12.2 min; t _R (minor) = 10.1 min.

Example 41

2-[Hydroxy-(4-methoxy-phenyl)-methyl]-cyclohexan-l-one (26):

{Procedure A: time 72 h, 18.6 mg, 16%, 98% ee, 80:1 dr) [α] _D ²³ = +17.8° (c=0.5, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 (d, J= 8.4 Hz, 2H), 6.90 (d, J= 8.8 Hz, 2H), 4.92 (d, J = 7.6 Hz, IH), 3.94 (d, J = 2.4 Hz, IH), 3.83 (s, 3H), 2.34-2.65 (m, 3H), 2.08-2.14 (m, IH), 1.25-1.83 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 215.7, 159.3, 133.2, 128.2, 113.8, 74.3, 57.5, 55.3, 42.7, 30.9, 27.8, 24.8; HPLC: Daicel Chiralpak OJ. Hexanes-z-PrOH, 90:10, 1 mL min ^"1 , 230 nm: t _R (major) = 14.7 min; ^ _R (minor) = 19.3 min.

Example 42

O O OH

^OHC -~-"~-γ-"^ ₁ .. _{ ^^^υ^S 9 27

2-[Hydroxy-(phenyl)-propyl]-cyclohexan-l-one (27): {Procedure A (no H2O was added, reaction performed at rt): time 72 h, 18.4 mg, 32%, 59% ee, 29:1 dr) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20-7.32 (m, 5H), 3.73-3.81 (m, IH), 3.55 (d, J = 6.4 Hz, IH), 2.66-2.95 (m, 2H), 1.63-2.43 (m, 1 IH); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 215.8, 142.3, 128.5, 128.4, 125.8, 70.9, 56.0, 42.9, 35.5, 31.6, 30.7, 27.8, 25.0; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 1 mL min ^"1 , 254 nm: t _R (major) = 9.68 min; t _R (minor) = 10.6 min.

Example 43

2- [Hydroxy-(4-nitro-phenyl)-methyl] -4-methylcyclohexan- 1-one (29) :

(Procedure A: time 72 h, 122 mg, 93%, 97% ee, 49:1 dr) [α]D23 = -48° (c=0.55, EtOAc); IH NMR (400 MHz, CDC13) δ 8.21 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 4.94 (dd, J = 8.4, 2.4 Hz, IH), 3.96 (d, J = 2.8 Hz, IH), 2.38-2.79 (m, 3H), 1.26-2.11 (m, 5H), 1.06 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDC13) δ 214.9, 148.5, 147.6, 127.8, 123.7, 74.1, 52.9, 38.2, 36.1, 33.0, 26.6, 18.2; HPLC: Daicel Chiralpak AD. Hexanes-i-PrOH, 90:10, 1.0 niL min-1, 254 nm: tR (major) = 33.4 min; tR (minor) = 37.7 min.

Example 44

30 31

6-[Hydroxy-(4-nitro-phenyl)-methyl]-2,2-dimethyl-l,3-dioxan- 5-one (31): (Procedure A: time 48 h, 140.2 mg, 99%, 78% ee, 11 : 1 dr) [α] _D ²³ = -139°

(c=0.8, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 5.02 (d, J= 6.4 Hz, IH), 4.24-4.32 (m, 2H), 4.10 (d, J= 17.6 Hz, IH), 3.85 (s, IH), 1.40 (s, 3H), 1.23 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 210.6, 147.7, 146.5, 127.9, 127.4, 123.5, 123.2, 101.4, 75.8, 71.7, 66.6, 23.5, 23.3; HPLC: Daicel Chiralpak OJ. Hexanes-z-PrOH, 90: 10, 0.5 mL min ^"1 , 254 nm: t _R (major) = 18.5 min; t _R (minor) = 21.4 min.

Example 45

3-[(l'-Hydroxy-l'-phenyl)-methyl]-tetrahydropyran-4-one(3 3):

(Procedure A (1.25 mmol 32): time 72 h, 24.0 mg, 47%, 94% ee, 41 :1 dr) [α] _D ²³ = +6° (c=0.8, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29-7.41 (m, 5H), 4.90 (dd, J = 8.8, 2.8 Hz, IH), 4.14-4.20 (m, IH), 3.64-3.83 (m, 3H), 3.40 (dd, J= 11.6, 9.6 Hz, IH), 2.54-2.94 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 210.0, 140.1, 128.7, 128.4, 126.7, 72.1, 70.0, 68.4, 58.1, 42.7; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 85:15, 1.0 niL min ^"1 , 220 nm: fa (major) = 16.4 min; fa (minor) = 18.5 min.

Example 46

3-[(l'-Hydroxy-l'-(4"-nitrophenyl))methyl]-tetrahydropyran-4 -one (34): (Procedure A (1.25 mmol 32): time 52 h, 57.9 mg, 92%, 96% ee, 5:1 dr) [α] _D ²³ = +1.3° (c=2.3, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J= 8.8 Hz, 2H), 7.53 (d, J= 8.8 Hz, 2H), 5.01 (dd, J= 8.0, 3.2 Hz, IH), 3.71-4.29 (m, 4H), 3.48 (t, J= 11.2 Hz, IH), 2.51-2.97 (m, 3H); ¹³ C NMR (IOO MHz, CDCl ₃ ) δ 209.2, 147.8, 147.6, 127.5, 123.8, 71.3, 69.8, 68.4, 57.7, 42.8; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 80:20, 1.0 mL min ^"1 , 254 nm: fa (major) = 27.4 min; fa (minor) = 24.1 min.

Example 47

3-[(l'-Hydroxy-l'-(4"-chlorophenyl))methyl]-tetrahydropyr an-4-one

(35): (Procedure A (1.25 mmol 32): time 72 h, 36.0 mg, 60%, 97% ee, >99:1 dr) [α] _D ²³ = +3.4° (c=0.7, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (d, J= 8.4 Hz, 2H), 7.25 (d, J= 8.4 Hz, 2H), 4.87 (dd, J= 8.4, 2.8 Hz, IH), 3.66-4.21 (m, 4H), 3.38 (t, J= 9.6 Hz, IH), 2.53-2.88 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 209.8, 138.7, 134.1, 128.9, 128.0, 71.5, 69.8, 68.4, 57.9, 42.8; HPLC: Daicel Chiralpak AD.

Hexanes-z-PrOH, 90:10, 1.0 niL min ^"1 , 220 nm: t _R (major) = 28.5 min; t _R (minor) = 22.6 min.

Example 48

4-hydroxy-4-phenyl-butan-2-one (37): (Procedure A: time 72 h, 34.4 mg, 42%, 87% ee) [α] _D ²³ = +52° (c=0.7, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29- 7.39 (m, 5H), 5.18 (d, J= 9.2 Hz, IH), 3.30 (s, IH), 2.83-2.95 (m, 2H), 2.22 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 209.1, 142.7, 128.6, 127.7, 125.6, 69.9, 52.0, 30.8; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90: 10, 1 mL min ^"1 , 257 nm: t _R (major) = 10.6 min; t _R (minor) = 11.4 min.

Example 49

4-hydroxy-4-(4-nitrophenyl)-butan-2-one (38): (Procedure A: time 72 h,

67.4 mg, 64%, 83% ee) [α] _D ²³ = +54° (c=0.55, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J= 8.8 Hz, 2H), 7.56 (d, J= 8.8 Hz, 2H), 5.27-5.31 (m, IH), 3.60 (d, J = 3.6 Hz, IH), 2.82-2.92 (m, 2H), 2.25 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 208.5, 149.9, 147.4, 126.4, 123.8, 68.9, 51.5, 30.7; HPLC: Daicel Chiralpak OJ. Hexanes-z- PrOH, 90: 10, 1 mL min ^"1 , 254 nm: t _R (major) = 35.5 min; t _R (minor) = 40.8 min.

2-[Hydroxy-(4-nitro-phenyl)-methyl]-cyclopentan-l-one (40): αnti-40: (Procedure A: time 36 h, 34.1 mg, 29%, 92% ee) [α] _D ²³ =-77°

(c=0.5, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 8.8 Hz, 2H), 7.55 (d, J =

8.4 Hz, 2H), 4.86 (d, J= 9.2 Hz, IH), 4.77 (s, IH), 2.23-2.52 (m, 3H), 2.00-2.07 (m, IH), 1.54-1.83 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 222.2, 148.7, 147.7, 127.4, 123.7, 74.4, 55.1, 38.6, 26.8, 20.4; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 0.75 niL min ^"1 , 254 nm: fa (major) = 40.7 min; fa (minor) = 38.2 min. syn-40: (Procedure A: time 36 h, 68.1 mg, 58%, 85% ee) [α] _D ²³ =+183°

(c=0.6, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (d, J= 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 5.44 (t, J= 3.3 Hz, IH), 2.37-2.65 (m, 3H), 1.70-2.23 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 219.8, 150.3, 147.1, 126.4, 123.6, 70.4, 56.1, 39.0, 22.4, 20.3; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 90:10, 1 mL min ^"1 , 254 nm: fa (major) = 21.5min; fa (minor) = 16.1 min.

Example 51

2-[Hydroxy-(2-chloro-phenyl)-methyl]-cyclopentan- 1 -one (43) αnti-43: (Procedure A: time 48 h, 23.0 mg, 20%, 93% ee) ¹ H NMR (400

MHz, CDCl ₃ ) δ 7.61 (d, J= 7.6 Hz, IH), 7.22-7.37 (m, 3H), 5.33 (d, J= 9.2 Hz, IH), 4.55 (s, IH), 2.28-2.52 (m, 3H), 2.03-2.07 (m, IH), 1.71-1.80 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 222.9, 139.2, 132.4, 129.3, 128.9, 128.4, 127.4, 70.4, 55.6, 38.7, 26.4, 20.6 HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 99.5:0.5, 1.0 mL min ^"1 , 220 nm: fa (major) = 32.8 min; fa (minor) = 36.3 min. syn-43: (Procedure A: time 48 h, 34.4 mg, 31%, 81% ee) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J= 7.6 Hz, IH), 7.21-7.36 (m, 3H), 5.71 (t, J= 4.0 Hz, IH), 2.68-2.73 (m, IH), 1.72-2.48 (m, 7H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 220.0, 140.1,

131.1, 129.3, 128.4, 127.4, 126.9, 68.0, 53.5, 39.0, 22.6, 20.3; HPLC: Daicel CChhiirraallppaakk AADD.. HHeexxaanneess--zz--PPirOH, 99.5:0.5, 1 mL min ^"1 , 220 nm: fa (major) = 41.9 min; fa (minor) = 49.8 min.

Example 52

To a solution of carboxylic acid IV-I (0.2 g, 1.0 mmol) in DMF (6 niL) was added 1-Dodecanol (0.392 g, 0.47 niL, 2.0 mmol), DMAP (66 mg, 0.54 mmol) and EDCI (0.192 g, 1.0 mmol) respectively. The reaction mixture was stirred at room temperature for 16 h before being partitioned between EtOAc (20 mL) and aq. HCl (10 mL, 1 N). The organic layer was washed with half-saturated brine (2 x 15 mL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 5-30% EtOAc/CH ₂ Cl ₂ , to give ester IV- 2 (0.195 g, 0.528 mmol, 53%) as a white solid. Mp: 105-106 ⁰ C; IR (neat) 3330,

2916, 2845, 1713, 1467, 1282, 1157, 1124, 1092, 906, 765, 738, 694 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) 8.20 (d, J= 8.4 Hz, 2H), 8.02 (d, J= 8.4 Hz, 2H), 4.99 (s, 2H), 4.38 (t, J= 6.4 Hz, 2H), 1.79-1.83 (m, 2H), 1.29-1.46 (m, 19H), 0.90 (t, J= 6.4 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.2, 145.6, 134.4, 130.4, 126.5, 66.0, 31.9, 29.64, 29.58, 29.53, 29.4, 29.3, 28.6, 26.0, 22.7, 14.1.

Example 53

To a solution of Z-L-proline IV-5 (132 mg, 0.528 mmol) in CH ₂ Cl ₂ (5.3 mL) was added sulfonamide IV-2 (195 mg, 0.528 mmol), DMAP (10.3 mg, 0.0844 mmol) and EDCI (101 mg, 0.528 mmol) respectively. The reaction mixture was stirred at room temperature for 7 d before being partitioned between DCM (15 mL) and aq. HCl (I N, 10 mL). The organic layer was washed with half-saturated brine (2 x 10 mL). The dried (Na ₂ SO ₄ ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 10% EtOAc/CH ₂ Cl ₂ , to give sulfonamide IV-3 (243 mg, 0.405 mmol, 78%) as a colorless liquid. [α] _D ²³ = -94.8° (c= 3.1, CHCl ₃ ); IR (neat) 3477, 2922, 2851, 1718, 1691, 1680, 1615, 1457, 1435, 1266, 1212, 1141, 1119, 1092, 988, 863, 825, 770, 738, 700, 618 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) 8.02 (d, J= 8.0 Hz, 2H), 7.94 (d, J= 7.6 Hz, 2H), 7.12-7.29 (m,

5H), 5.06 (d, J= 12.4 Hz, IH), 4.91 (d, J= 12.4 Hz, IH), 4.23-4.31 (m, 3H), 3.35- 3.39 (m, 2H), 1.69-2.01 (m, 6H), 1.29-1.43 (m, 19H), 0.90 (t, J= 6.4 Hz, 3H); ¹³ C NMR (IOO MHz, CDCl ₃ ) δ 165.4, 156.2, 146.1, 136.3, 133.2, 129.6, 128.4, 127.9, 127.7, 127.0, 67.3, 65.5, 62.8, 46.9, 31.9, 29.65, 29.59, 29.4, 28.69, 26.0, 24.3, 22.7, 14.1.

Example 54

[HY8-11]. To a solution of Z-L-sulfamide IV-3 (200 mg, 0.333 mmol) in MeOH (10 niL) was added Pd/C (20 mg, 10 %). The mixture was stirred at rt for under an atmosphere of hydrogen. After 16 h, the reaction was filtered through Celite and silica gel pad, and the filtrate was concentrated in vacuo to give white solid. The crude product was purified by chromatography over silica gel, eluting with 10% MeOH / CH ₂ Cl ₂ , to give the product IV-4 (133 mg, 0.285 mmol, 86%) as a white solid. Mp: 166-168 ⁰ C; [α] _D ²³ = -88.1° (c= 0.7, CHCl ₃ ); IR (neat) 3129, 3074, 2954, 2922, 2851, 1729, 1620, 1560, 1391, 1266, 1141, 1113, 1092, 858, 732, 694, 618 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) 8.67 (br s, IH), 8.12 (d, J= 8.4 Hz, 2H), 8.00 (d, J= 8.4 Hz, 2H), 4.35(t, J= 6.8 Hz, IH), 3.37-3.51 (m, 2H), 1.75-2.38 (m, 6H), 1.29-1.45 (m, 18H), 0.90 (t, J= 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 174.2, 165.6, 146.9, 133.3, 129.8, 126.5, 65.7, 63.0, 46.8, 31.9, 29.9, 29.63, 29.55, 29.35, 29.30, 28.7, 26.0, 24.6, 22.7, 14.1.

Example 55

General procedure for Mannich reaction in DCE: To a solution of aldimine (0.125 mmol) and cyclohexanone (61.1 mg, 64.5 μL, 0.625 mmol, 5 equiv.) in DCE (60 μL) was added HC (10.5 mg, 0.025 mmol) and water (2.3 mg 0.125 mmol,) at rt. After stirring at same temperature for 17 h to 72 h, the reaction was loaded directly onto silica gel and was purified by chromatography, eluting with 10-30% EtOAc / hexanes, to give the corresponding Mannich product.

[α] _D ²³ = -41° (c=l.4, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.74-6.80 (m, 4H), 4.25 (d, J = 4.8 Hz, IH), 4.13-4.21 (m, 2H), 3.93 (br s, IH), 3.75 (s, 3H), 2.83 (dt, J = 12.4, 5.2 Hz, IH), 1.67-2.50 (m, 8H), 1.24 (t, J= 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 210.1, 173.5, 153.1, 141.1, 116.1, 114.8, 61.1, 58.1, 55.7, 53.6, 41.9, 29.6, 26.9, 24.8, 14.2; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 92:8, 1 niL min ^"1 , 254 nm: fa (major) = 23.1 min; fa (minor) = 26.6 min.

^OCH ₃ ^\^OCH ₃

O N' ^ O HN^^

OEt O

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.78-6.80 (m, 2H), 6.66-6.92 (m, 2H), 4.36 (t, J= 5.6 Hz, IH), 4.20 (q, J = 6.8 Hz, 2H), 3.77 (s, 3H), 2.99 (d, J = 5.6 Hz, IH), 2.21 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 205.9, 173.0, 153.1, 140.5, 115.8, 114.9, 61.5, 55.7, 54.3, 45.8, 30.4, 14.1; HPLC: Daicel Chiralpak AD. Hexanes-z-PrOH, 92:8, 1 mL min ^"1 , 254 nm: fa (major) = 33.8 min; fa (minor) = 29.3 min. In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.