Wednesday, March 28, 2007

Stereo- and Regiochemical Divergence in the Substitution of a Lithiated Alk-1-en-3-yn-2-yl Carbamate: Synthesis of Highly Enantioenriched Vinylallenes

Stereo- and Regiochemical Divergence in the Substitution of a Lithiated Alk-1-en-3-yn-2-yl Carbamate: Synthesis of Highly Enantioenriched Vinylallenes or Alk-3-en-5-yn-1-ols

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114190082/ABSTRACT

From Prof. Dieter Hoppe's group at Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany

I think this is some interesting and intriguing chemistry presented in ACIEE EarlyView regarding the reactivity of organolithium in the presence of (-)-sparteine. It has been reported previously by the same research group that gamma-deprotonation of alkene carbamate of type 1, possessing negative-charge stabilizing group W (such as aryl, triorganosilyl, and 1-alkenyl groups), using n-BuLi in the presence of (-)-sparteine (2), a stereo-defined alkyllithium (3) could be generated which could add stereoselectively to electrophile to afford 4.

In the new development, when the W group was changed to an alkynyl group, the reactivity of the alkyllithium changed. That is when enyne 7 was deprotonated using n-BuLi/2 system, H(R) was selectively deprotonated and (S)-8 was produced.

When treated with acetone, (S)-8 added in an anti-SE' fashion to give allene (-)-(aR,E)-9a selectively (Method A). However, if (S)-8 was allowed to equilibrate over a longer period (15h), (R)-8 was produced and it added to acetone in the same anti-SE' fashion to give (+)-(aS,E)-9a instead (Method B). Method A was confirmed again with 4,4'-dibromobenzophenone to give (-)-(aR,E)-9b.

When (S)-8 was treated with ClTi(OiPr)3, lithium-titanium occurred that also inverted the C-metal center. The resulted organotitanium (S)-10 then added to acetone in the syn fashion at the allylic position to give homoallylic alcohol (S,Z)-11a (Method C). The TS for this addition was proposed to be 6-membered chairlike Zimmerman-Traxler transition state. As (R)-8, lithium-titanium exchange led to (R)-10, which afforded (R,Z)-11a upon addition to acetone (Method D).

Finally, two other experiments were performed to confirm the mechanisms of both organolithium and organotitanium. In the first experiment, (R)-8 was trapped with Ph3SnCl to give allene 9c, structure of which was confirmed by x-ray. Because previous study of stannylation of propargyllithium/2 system showed the mechanism to be anti-SE', thus this result showed that the configuration of 8 was R.

The kinetic organolithium (S)-8 was transmetalated with titanium to form (S)-10 which reacted with chiral aldehyde 12 to give 11b, the structure of which was confirmed by x-ray. Because it is known that chiral alpha-(carbamoyloxy)allyltitanium compounds react with chiral aldehydes with strict chirality transfer from the Zimmerman–Traxler transition state. Therefore, configuration shown in 11 must be generated from (S)-10, which in turn was obtained by inversion of configuration of (S)-8.

Reaction of 8 with other electrophiles were also reported as summarized in the table below.

Conclusion for the current system:

1) Organolithium ---> anti-SE' addition to give allenyl alcohols
2) Lithium-titanium exchange ---> inversion of configuration
3) Organotitanium ---> syn addition via Zimmerman-Traxler transition state to give homoallylic alcohol
4) Organolithium was generated stereoselectively with n-BuLi/(-)-sparteine system. This kinetic organolithium can epimerize to give the opposite configuration upon prolonged reaction time.

Enesulfonamides as Nucleophiles in Catalytic Asymmetric Reactions

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114190087/ABSTRACT

From Prof. Shu Kobayashi's group at The University of Tokyo, Tokyo, Japan

The recent article in ACIEE EarlyView from the lab of Prof. Kobayashi detailed a novel reaction of enesulfonamide as a nucleophile in nucleophilic addition catalyzed by copper-based Lewis acid in the presence of chiral ligand. Comparison was made with enecarbamate that enesulfonamide is more convenient to make than the enecarbamate the reactions demonstrated here were efficient. The product generated from the addition is sulfonylimine, which could be reduced to either 1,3-amino alcohol or sulfonamide, both of which are medicinally important.

Enesulfonamide can be simply made from condensation of a ketone and a sulfonamide. E- and Z-alkene isomers could be separated by column chromatography.

Most of the examples of enesulfonamide were made from aromatic ketones. But aliphatic ketones were also shown to be feasible to make and to be employed in the reaction. The early example from the study was the addition of p-methoxyphenyl-substituted enesulfonamide, generate from condensation of p-methoxysulfonamide and phenyl ethyl ketone, to ethyl glyoxylate. The product, sulfonylimine, could be hydrolyzed to give ketone. Several hydrolysis conditions were investigated as shown in Table 1.

From the table, the use of too little acid led to decrese in yield and diastereoselectivity of keto ester 7a (entry 1). However, increasing the amount of acid, as in entry 2, both yield and diastereoselectivity improved significantly. Increase in the amount of acid probably prevented formation of enesulfonamide 8a which led to epimerization.

The optimal reaction conditions were screened with different enesulfonamide using ethyl glyoxylate as the reaction partner. General trend: electron-rich aryl substituent on the sulfonyl group is more reactive than electron-poor aryl substituent. The reaction is also stereospecific: Z-enesulfonamide afforded syn-product, and E-enesulfonamide afforded anti-product.

As mentioned before, the sulfonylimine product could be reduced stereoselectively to give a sulfonamide alcohol, as represented in Scheme 2.

Enesulfonamide also added to azodicarboxylate as shown in Equation 2 between sulfonamide (E)-4b and diisopropyl azodicarboxylate. In this case, diamine 11 was used as the chiral ligand.

In summary, a novel method copper-catalyzed enesulfonamide addition to glyoxylate has been developed. The reactions proceeded in high yield and high diastereo- and enantioselectivities, even with catalyst loading as low as 0.2 mol%.

Tuesday, March 27, 2007

Rearrangement of Alkynyl Sulfoxides Catalyzed by Gold(I) Complexes

From Prof. F. Dean Toste's group at University of California, Berkeley, CA

This article appeared recently in JACS ASAP from Prof. Toste's group at UC, Berkeley, demonstrating the utility of gold(I) complex as a catalyst for formation of gold-carbenoid species from alkynes and their subsequent reactions. The reaction was proposed to start with an activation of an alkyne with gold(I) catalyst, followed by an attack from a nucleophile (attached to a leaving group). Electron from gold species then moved in to form a carbenoid species concurrently with the expulsion of the leaving group.

In this paper, the nucleophile employed was sulfoxide which would generate sulfonium ion as a leaving group upon attacking gold-activated alkyne. It was found that under the reaction conditions, Friedel-Craft type reaction occurred to give ketone 3 as shown in Equation 2 above. Initially, several ligands were screened. The best result was found in an NHC ligand carrying mesitylene groups (IMes).

The reaction was screened with a variety of substrates. All reactions proceeded well, for instance, electron-rich as well as electro-poor aryl systems tolerated well. In addition, substitutions at both propargylic and homopropargylic positions proceeded without problem. Notably, in entry 5 one diastereomer (as shown) was more reactive than the other.

A marked difference was seen between entries 6, and 7 and entry 8. When substituent of alkyne is non-aliphatic (entries 6, 7), 5-exo-dig mode of cyclization was observed. But when the substituent was aliphatic group, as an ethyl group in 18, 6-endo-dig cyclization prevailed. These modes of mechanism are summarized in the scheme below.

With this mode of reaction with aliphatic substituent, complex furan 22 could be prepared in one step from diyne 20 in 56% yield.

Additional experiment with sulfimine 27 to generate N-tosyl enamine 28 confirmed that the oxygen atom was delivered intramolecularly from sulfur.

Gold(I) complexes were also found to catalyze the conversion of propargyl sulfoxides to alpha-thioenones in high yields as shown in equations below.

In this case, (dimethylsulfide)gold(I) chloride proved to be a better catalyst and the reaction afforded enones 31 from propargyl sulfoxides 29 with excellent tolerance for substitution on the alkyne and the sulfoxide. Additionally, secondary and tertiary propargyl sulfoxides react under these conditions to provide trisubstituted (eq 6) and tetrasubstituted alkenes. For example, sulfide 33 was obtained from sulfoxide 32 in preference to cycloisomerization of 1,5-enyne.

In analogy to the mechanism described in Scheme 1, this rearrangement is postulated to proceed through gold(I)-promoted sequential 5-endo-dig cyclization/cleavage of the S-O bond leading to gold(I)-carbenoid intermediate 30 which undergoes a 1,2-sulfide shift. In a separate cross-over experiment, the intramolecular 1,2-sulfide shift process was confirmed as there was no cross-over product observed as shown in the equation below. Note that the SMs should be 29b and 29c and the products should be 31b and 31c, respectively.

This paper has presented an important aspect of reactivity of gold catalyst with alkynes and provided a method for an efficient generation of gold-carbenoid species.

Monday, March 26, 2007

Aminomethylations via Cross-Coupling of Potassium Organotrifluoroborates with Aryl Bromides

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070543e.html

From Prof. Gary A. Molander's group at University of Pennsylvania, Philadelphia, PA

The paper recently appeared in Org Lett ASAP presented a novel Suzuki-Miyaura cross-coupling reaction using potassium organotrifluoroborate salt as an aminomethyl transfering reagent in cross-coupling with aryl halide.
Prior to this work, only one example of aminomethyl transfer is known using organotin reagent as shown below. The use of tin reagent is naturally objectionable as tin is toxic and purification is usually not simple. Plus, the tin reagent sometimes requires a tedious synthesis of its own.

The use of potassium organotrifluoroborate salt as a coupling partner in Suzuki-Miyaura reaction is attractive because this reagent is nontoxic, and air- and moisture-stable. The studies were first conducted using potassium N-(trifluoroboratomethyl)piperidine, which could be conveniently prepared based on a known procedure. The reaction was screen with different aryl bromides. The results are summarized in the table below. Note: XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

As seen in the table, the reaction tolerated well with various aryl bromide derivatives, whether it was electron-rich, or electron-deficient. Steric hindrance in proximity of the coupling site was also well-tolerated. Some of the reactions were found to give higher yields when they were conducted in cyclopentyl methyl ether (CPME)/water mixture (10:1), possibly because reactions could be heated at higher temperature than THF/water.

The reaction of the same borate salt was expanded to react with a variety of heteroaromatic systems. (Table 2).Again, the reactions proceeded well with all heteroaromatic coupling partners examined. In these cases, the reactions were found to work better (higher yields) with the original THF/water system.

Next, different aminomethyl reagents were examined. Various aminomethyltrifluoroborate salts were prepared from potassium trifluoroboratomethyl bromide with stoichiometric amines and the results are summarized below.

As can be seen, in all cases tertiary amine borate salts could be prepared in good yields with great structural diversities. These salts were subjected to the standard coupling conditions in THF/water with 4-bromoanisole to afford coupling products in good to excellent yields (Table 4), with only exceptions of 5e and 5f where there was no reaction both in CPME/water and THF/water systems.

Enantioselective Organocatalytic Double Michael Addition Reactions

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070581y.html

From Prof. Wei Wang's group at the University of New Mexico, Albuquerque, NM

The method presented in this paper recently published in Org Lett ASAP detailed the using of chiral organo catalyst in performing domino double Michael additions to form chiral tetrahydrothiophene derivatives.
The reaction seemed to be quite simple to conduct. First, several catalysts (I-IV) were screened for reactivity in the representative reaction using enal 1a. However, the reaction only proceeded and stopped after the first Michael addition to give aldehyde 3. The authors reasoned that the steric hindrance of the benzene ring in the thiophenol framework perhaps prevented the second addition of the enamine intermediate to the ester.

Therefore, the thiol reacting partner was switched to thiol ester 4 and the reaction was screened again with all four organocatalysts and the results are summarized below.

This time, the reaction worked very well with catalysts I-III, while catalyst IV did not give any desired product. The reactions between 1a and 4 were found to be extremely efficient both in terms of yields and selectivities. After optimal conditions were found, the several substrates were screened for scope of the reaction and the results are summarized in Table 2.

The reactions were found to telerate well in a variety of substrates 1, whether it be electron-rich (entries 8 and 9) or electron-deficient aromatic rings (entries 2-7), or both (entry 10). In 2-substituted aromatic rings (entries 3, 7, and 9), the reaction also tolerated well with steric hindrance. Entry 11 demonstrated the tolerance of the reaction with heteroaromatic. Entry 12 showed that extended conjugation in aromatic ring also worked well, as well as with alkyl-substituted enal (entry 13).

A nice method, which can be used to build complex tetrahydrothiophene derivatives quickly with good to excellent yields and excellent enantio- and diastereoselectivities.

Sunday, March 25, 2007

Kinetic Resolution of Hydroperoxides with Enantiopure Phosphines: Preparation of Enantioenriched Tertiary Hydroperoxides

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja070482f.html

From Prof. Keith A. Woerpel's group at the University of California, Irvine

A new method for reductive kinetic resolution of tertiary hydroperoxide employing cyclophane diphosphine as a selective reducing agent was recently published in JACS ASAP.

Several phosphines were investigated as shown.
The test substrate was chosen as tertiary benzyl hydroperoxide 11. The results of the initial screening for the appropriate phosphine are shown in Table 1. As seen in the table, cyclophane-derived phosphine 10 showed the most promising result (entry 9). This commercially available phosphine was used to investigate the scope of the reaction with several benxyl tertiary hydroperoxides as shown in Table 2.
This phosphine worked well with all substrates, including secondary hydroperoxides (entries 7-10). Functionalized hydroperoxide (entry 6) could be resolved well, although selectivity was lower. In all cases, (R)-10 reduced the (-)-(S)-hydroperoxide preferentially, and the enantiomer, (S)-10, had the opposite selectivity.

Selectivities diminished with increasing length of the alkyl linker in the resolutions of non-benzylic hydroperoxides 23 and 24 with (R)-10 (Scheme 1). Presumably, as the tether length increases, the steric differentiation decreases at the reactive center.

Preparative-scale resolution was also possible. For instance, one gram of hydroperoxide (+/-)-11 was subjected to resolution conditions with commercially available phosphine (R)-10 (71% conversion, Scheme 2). The resulting enantiopure hydroperoxide (+)-(R)-11 and enriched alcohol (-)-(S)-12 could not be separated by physical means, but a strategy was developed to facilitate purification. When the mixture of hydroperoxide (+)-(R)-11 and alcohol (-)-(S)-12 was treated with Et3SiCl, the hydroperoxide was protected selectively, and the resulting silylperoxy ether could be separated from the alcohol by column chromatography. Subsequent desilylation provided enantiopure (>99% ee) hydroperoxide (+)-(R)-11 in 24% overall yield. This route also allows access to enantiopure tertiary alcohol (+)-(R)-12 by reduction with triphenyl phosphine (Scheme 2).

Preliminary mechanistic studies reveal that the two phosphines of xylyl-PHANEPHOS (10) operate independently. The supposed intermediate, mono(phosphine oxide) (R)-25, was isolated from the reaction of phosphine (R)-10 and 1 equiv of hydroperoxide 17. Utilizing this compound in the resolution of hydroperoxide 11 afforded starting material with 84% ee at 51% conversion (krel = 25, Scheme 3). This experiment demonstrates that the monophosphine intermediate (R)-25 reduces hydroperoxides with a similar selectivity to that of xylyl-PHANEPHOS. It also suggests that less complex monophosphines may also be useful for this type of resolution.

In conclusion, the authors have described a method for the stoichiometric kinetic resolution of hydroperoxides employing commercially available phosphines. The reaction provides access to enantiopure hydroperoxides and, therefore, the corresponding alcohols as well. In addition, the resulting bis(phosphine oxide) can be converted back to the phosphine in high yield (the bis(phosphine oxide) isolated from the resolution reaction can be reduced with HSiCl3 in >90% yield.)

General Strategy for the Construction of Enantiopure Pyrrolidine-Based Alkaloids. Total Synthesis of (-)-Monomorine

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/joceah/asap/abs/jo062532p.htm

From Prof. Mark L. Trudell's group at the University of New Orleans, LA

This is a JOC Note ASAP article detailing the use of natural cocaine as a starting material in synthesizing a chiral building block which could be useful for further manipulation. The utility was proven in their total synthesis of (-)-monomorine alkaloid natural product.

I guess the major problem in working with cocaines is how to access to the substance since it is illegal to possess. This is what the authors had to say:

"Although not commercially available,confiscated grade cocaine can be obtained from the National Institute on Drug Abuse with appropriate DEA licensing in sufficient quantities to provide useful amounts of chiral building blocks."

So it is possible to get some. This is good information. What embedded in cocaine is the cis-dialkyl substituent on the pyrrolidine ring as in 2 through a series of chemical degradation. This cis-relationship was also found in some indolizidine-type natural products, as in 1.

As was reported earlier by the authors, cocaine could be easily converted to (+)-2-tropinone and so this is where they started.

Starting with (+)-2-tropinone 4, demethylation followed by Cbz installation afforded 6. The process was conducted to decrease the basicity of nitrogen and to protect nitrogen from being oxizided in the subsequent step. Usual chemical operations ensued to provide protected pyrrolidine 8 in good overall yield (Scheme 2). It was found that compound 8 existed as a mixture of rotomers which made it difficult to be properly characterized.

Onto the synthesis of (-)-monomorine, the synthetic sequence is illustrated in the scheme below.

The usual synthetic operations led from compound 8 to 11. The double bonds were then hedrogenated and at the same time with the deprotection of N-Cbz group. The free nitrogen then cyclized with the ketone carbonyl to form the intermediate imine which was hydrogenated under the reaction conditions to give the desired product 12 in 87% as a single enantiomer. This was in agreement with previous report (Conchon, E.; Gelas-Mialhe, Y.; Remuson, R. Tetrahedron: Asymmetry 2006, 17, 1253.) that in hydrogenation of imine double bond, hydrogen is delivered from the face syn to the hyfrogen at the 8a position on the ring.

Thus the paper demonstrated the successful and convenient way of generating cis-2,5-dialkylpyrrolidine from cocaine. The article also illustrated the utility of this useful chiral building block in a successful total synthesis of (-)-monomorine.

N-Heterocyclic Carbene Ligands in Cobalt-Catalyzed Sequential Cyclization/Cross-Coupling Reactions of 6-Halo-1-hexene Derivatives with Grignard Reagen

From Prof. Koichiro Oshima's group at Kyoto University, Japan

Another paper utilizing NHCs as ligands appeared in this month's Org Lett ASAP. This is the paper describing intramolecular cyclization of alkyl iodide and tethered alkene, followed by cross-coupling with Grignard reagents. The reaction is catalyzed by Co-catalyst.
Several NHC ligands were excamined. These are shown below.

In the initial studies, NHC ligand 1 and allyldimethylsilylmethylmagnesium chloride were subjected to react with alkene 5 to give coupling product 6 in good yield. The allyldimethylsilyl group in the product could be oxidized smoothly via Tamao-Flemming oxidation to alcohol 7. This initial result showed that the method could be used in a sequential operation to obtain a cyclic alcohol of type 7.

A number of imidazolium salts other than 1 were screened. Salts 2 and 3 showed moderate reactivity giving product 6 36% and 54% yields, respectively. The use of phosphine and diamine ligands resulted in much lower yield. The scope of the reaction is as shown below.

In a related example, secondary iodide 18 could be subjected to the reaction conditions to give 19, followed by Tamao-Flemming oxidation to give diol 20 in good overall yield.

In addition, the authors also found that the reaction conditions could be used in a normal cross-coupling reaction (without cyclization) of primary alkyl iodide and Grignard reagent. For example, treatment of isobutyl iodide (0.5 mmol) with allyldimethylsilylmethylmagnesium chloride (1.5 mmol, 1 M ether solution) in dioxane (2 mL) in the presence of 1 (0.025 mmol) and CoCl2 (0.025 mmol) for 30 min at 25 °C afforded the corresponding coupling product in 79% yield.

Next, the cyclization-coupling process was examined for the cross-coupling reaction with alkynyl Grignard. Recently, the authors obtained promising result with trimethylsilyl-substituted alkynyl Grignard, but not with alkyl-substituted ones. However, for the cyclization-cross coupling process it was discovered that NHC ligand 2 proved to be effective. As shown in Scheme 3, cyclization-cross coupling sequence of various alkyl-substituted alkynyl Grignard reagents (21a-c) proceeded smoothly with CoCl2 in the presence of ligand 2 to give the coupling products 22a-c in good yields.

21a also underwent cyclization-cross coupling process with 9, and after Jones oxidation, provided lactone 23 in good yield over two steps.

The mechanism of this process is proposed to be:

1) generation of primary radical of the iodide via single electron transfer (SET) process
2) radical cyclization to give Co-carbocycle
3) transmetallation of Grignard reagent with Co species
4) reductive cyclization

Saturday, March 24, 2007

Synthesis of the Tricyclic Core of Vinigrol via an Intramolecular Diels-Alder Reaction

From Prof. Louis Barriault's group at the University of Ottawa, Ottawa, Canada

A recent article in Org Lett ASAP detailing a partial total synthesis of vinigrol (1), particularly the tricyclic core structure of the natural product. The natural product shows antihypertensive and platelet aggregation-inhibiting properties.
The authros planned to use intramolecualr Diels-Alder reaction to construct this core. The planned cycloaddition looked quite funky as the orientation of the dienophile seemed quite strained in order to have a good interaction with the diene, not to mention that the orientation of diene had to cooperate. Nonetheless, the strategy seemed ambitious. In their retrosyn, they were led back to aldehyde 10 as the simpler building block.

Another aspect of the cycloaddition that required attention was the different approach of the dienophile to give a regioisomeric product 13 as shown in Scheme 3. Although the transition state leading to cycloadduct 13 seemed unlikely, this partial synthesis would also serve as a confirmation of this hypothesis.

In the forward direction, the synthesis started with aldehyde 10 as shown below.

Takai elefination of aldehyde 10 gave vinyl iodide 15. Buchwald's coupling protocol of 15 with 16 gave the ether 17. The care with temperature had to be taken as slightly higher temperature than 90 C would increase the amount of aldehyde 18 with epimerization at the alpha carbon. After ether 17 was obtained, it was subjected to i-Bu3Al as the Lewis acid to promote stereocontrol [3,3] sigmatropic rearrangement followed by immediate reduction to alcohol 19. Silylation then afforded 20.

Alkene 20 was subjected to conditions in scheme below. A more direct synthesis of the nitrile 22 would be to use of Grubbs' catalyst to perform cross metathesis with acrylonitrile followed by hydrogenation. But this did not work; only SM was returned. So it was resorted to KCN displacement of OTs group obtained from hydroboration-oxidation and then tosylation of alkene 20.

Then alkyne 24 was synthesis from the corresponding aldehyde of 23 using modified Ohira's protocol ((a) Roth, G. J.; Muller, S.; Bestmann, H. J. Synthesis 2004, 59. (b) Ohira, S. Synth. Commun. 1989, 19, 561.) as the aldehyde is sensitive to epimerization. The Wittig olefination of aldehyde 25 to alkene 26 was performed using Conia conditions (Conia, J.-M.; Limasset, J.-C. Bull. Soc. Chim. Fr. 1967, 114, 1936.)

An always-cool enyne ring-closing metathesis using Grubbs' second generation catalyst then afforded diene 27. Attempts to directly convert nitrile to corresponding enone 11 using Grignard reagents and various additives failed. Therefore, it was resorted to step-wise operations as shown.

BF3-OEt2-catalyzed Diels-Alder reaction then afforded the desired cycloadduct 12 in almost quantitative yield (as the only regioisomer). This result was not surprising as DFT calculations using Khon-Sham DFT at the B3LYP19 level of theory with a 6-31G** basis set also confirmed that the transition state leading to regioisomer 13 was 10.7 kcal/mol higher than the one leading to 12 (Scheme 7).

An ok partial synthesis overall with the exception of some noteworthy steps. The synthesis was also a little too linear.