Scheme 1.8. Intramolecular Enolate Alkylation
1.2.6. Control of Enantioselectivity in Alkylation Reactions
The alkylation of an enolate creates a new stereogenic center when the - substituents are nonidentical. In enantioselective synthesis, it is necessary to control the direction of approach and thus the configuration of the new stereocenter.
O– R RZ
RE
RCH2 X
O R
RZ RE
CH2R +
O
R RZ
RE CH2R or
Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereo- chemistry.) The most frequently used are theN-acyloxazolidinones.89The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respec- tively, and thecis-4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90
C NH O
O
CH(CH3)2
NH O
CH2Ph
NH O Ph CH3
NH O
Ph C
O
C O
C O
Several other oxazolidinones have been developed for use as chiral auxiliaries. The 4-isopropyl-5,5-dimethyl derivative gives excellent enantioselectivity.91 5,5-Diaryl derivatives are also quite promising.92
NH O
Ph Ph CH(CH3)2
NH O
CH(CH3)2 Naph
Naph CNH
O O
CH(CH3)2 CH3
CH3
C O
C O
The reactants are usuallyN-acyl derivatives. The lithium enolates form chelate structures withZ-stereochemistry at the double bond. The ring substituents then govern the preferred direction of approach.
N O
CH3
O R
R' H Ph
O O
CH(CH3)2 R CN
O– Li+
OC O
H N O
CH(CH3)2 R'R
C N O
O
CH3 O– Li+
R
12 Ph
R'X R'X
13 R'X
R'X
C O
89 D. A. Evans, M. D. Ennis, and D. J. Mathre,J. Am. Chem. Soc.,104, 1737 (1982); D. J. Ager, I. Prakash, and D. R. Schaad,Chem. Rev.,96, 835 (1996); D. J. Ager, I. Prakash, and D. R. Schaad,Aldrichimica Acta,30, 3 (1997).
90 E. Nicolas, K. C. Russell, and V. J. Hruby,J. Org. Chem.,58, 766 (1993).
91 S. D. Bull, S. G. Davies, S. Jones, and H. J. Sanganee,J. Chem. Soc., Perkin Trans. 1, 387 (1999);
S. G. Davies and H. J. Sangaee,Tetrahedron: Asymmetry,6, 671 (1995); S. D. Bull, S. G. Davies, R. L. Nicholson, H. J. Sanganee, and A. D. Smith,Org. Biomed. Chem.,1, 2886 (2003).
92 T. Hintermann and D. Seebach,Helv. Chim. Acta, 81, 2093 (1998); C. L. Gibson, K. Gillon, and S. Cook,Tetrahedron Lett.,39, 6733 (1998).
42
CHAPTER 1 Alkylation of Enolates and Other Carbon Nucleophiles
In12the upper face is shielded by the isopropyl group, whereas in13the lower face is shielded by the methyl and phenyl groups. As a result, alkylation of the two derivatives gives products of the opposite configuration. The initial alkylation product ratios are typically 95:5 in favor of the major isomer. Since these products are diastereomeric mixtures, they can be separated and purified. Subsequent hydrolysis or alcoholysis provides acids or esters in enantiomerically enriched form. Alternatively, the acyl imides can be reduced to alcohols or aldehydes. The final products can often be obtained in greater than 99% enantiomeric purity.
A number of other types of chiral auxiliaries have been employed in enolate alkylation. Excellent results are obtained using amides of pseudoephedrine. Alkylation occursantito the-oxybenzyl group.93The reactions involve theZ-enolate and there is likely bridging between the two lithium cations, perhaps by di-(isopropyl)amine.94
C
OLi N CH3
CH3 OLi
CH3
OH N CH3
CH3 O
CH3 CH3 1) LDA,
LiCl 2) n-BuI
R H LiO N CH3 CH3
H OLi H
X
Both enantiomers of the auxiliary are available, so either enantiomeric product can be obtained. This methodology has been applied to a number of enantioselective syntheses.95 For example, the glycine derivative 14can be used to prepare-amino acid analogs.96
OH OH
N CH3O
NH2.H2O
CH2I N
CH3O NH2 2)
1) LiHMDS, LiCl (3.2 eq.)
79%
91:9 dr
14 CH3 CH3
Enolates of phenylglycinol amides also exhibit good diastereoselectivity.97A chelating interaction with the deprotonated hydroxy group is probably involved here as well.
HO N
CH3 Ph O
CH3 HO
N CH3
O CH3 CH2Ph 1)s-BuLi,
LiCl, – 78°C 2) PhCH2Br
Ph
The trans-2-naphthyl cyclohexyl sulfone 15 can be prepared readily in either enantiomeric form. The corresponding ester enolates can be alkylated in good yield and diastereoselectivity.98In this case, the steric shielding is provided by the naphthyl
93 A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky, and J. L. Gleason,J. Am. Chem.
Soc.,119, 6496 (1997); A. G. Myers, M. Siu, and F. Ren,J. Am. Chem. Soc.,124, 4230 (2002).
94 J. L. Vicario, D. Badia, E. Dominguez, and L. Carrillo,J. Org. Chem.,64, 4610 (1999).
95 S. Karlsson and E. Hedenstrom,Acta Chem. Scand.,53, 620 (1999).
96 A. G. Myers, P. S. Schnider, S. Kwon, and D. W. Kung,J. Org. Chem.,64, 3322 (1999).
97 V. Jullian, J.-C. Quirion, and H.-P. Husson,Synthesis, 1091 (1997).
98 G. Sarakinos and E. J. Corey,Org. Lett.,1, 1741 (1999).
43
SECTION 1.2 Alkylation of Enolates
group and there is probably also a−interaction between the naphthalene ring and the enolate.
O S O
O
–O Ph H
n-PrI
O
O Ph
H
CH2CH2CH3 alkylation from
re face
O S O
As with the acyl oxazolidinone auxiliaries, each of these systems permits hydrolytic removal and recovery of the chiral auxiliary.
Scheme 1.9 gives some examples of diastereoselective enolate alkylations.
Entries 1 to 6 show the use of various N-acyloxazolidinones and demonstrate the Scheme 1.9. Diastereoselective Enolate Alkylation Using Chiral Auxiliaries
78%, dr 98:2 1a
2) PhCH2Br 1) LDA N
O O
Ph CH3 O
N O
O
Ph CH3CH2Ph O
2b O N
O O OCH3
1) NaHMDS 2) CH3I
CH3 CH3
O N
O O
CH3
OCH3
74%, dr = 94:6
3c
O
1) NaHMDS 2) BrCH2CO2C(CH3)3
77%, ds>95%
O O
N O CH2Ph
O O
N O CH2Ph (CH3)3CO2C
O O O
4d O
79%, >98:2dr O
N O
CH2Ph CH3 PhCH2O2C
(CH3)2CH CO2CCH2Ph
OSO2CF3 1) LDA, –78°C
2)CH3 O
N O O
CH2Ph (CH3)2CH
5e
1) LDA O
2) BrCH2CO2C(CH3)3 (CH3)2CH N
O O O
CH2Ph
(CH3)2CH N O O
CH2Ph (CH3)3CO2C
74% yield, >95%dr (Continued)
44
CHAPTER 1 Alkylation of Enolates and Other Carbon Nucleophiles
Scheme 1.9. (Continued)
N 8h
1) LDA, LiCl 2) PhCH2OCH2CH2I CH3
O CH3 O CH3
Ph
CH3 OH CH3
N Ph
CH3OH PhCH2O
9h
Li+
CH3I
N O
O Ph CH3O CH3 PhCH2O
CH3
64%, 3.6:1dr N O
O
Ph O– CH3 CH3 PhCH2O
7g N
1) LiHMDS THF, – 78°C
2) PhCH2Br O N O
CH3 O
CH2Ph CH3CH3
CH2Ph 94%
94:6dr O
O
CH3 O
CH2Ph CH3
CH3
6f N
O
CH(CH3)2 O
Ph
PhCH2SCH2
83%
98:2dr N
O
CH(CH3)2
–O Ph
Li+
PhCH2SCH2Br O O
a. D. A. Evans, M. D. Ennis, and D. J. Mathre,J. Am. Chem. Soc.,104, 1737 (1982).
b. A. Fadel,Synlett, 48 (1992).
c. J. L. Charlton and G-L. Chee,Can. J. Chem.,75,1076 (1997).
d. C. P. Decicco, D. J. Nelson, B. L. Corbett, and J. C. Dreabit,J. Org. Chem.,60, 4782 (1995).
e. R. P. Beckett, M. J. Crimmin, M. H. Davis, and Z. Spavold,Synlett, 137 (1993).
f. D. A. Evans, D. J. Mathre, and W. L. Scott,J. Org. Chem.,50, 1830 (1985).
g. S. D. Bull, S. G. Davies, R. L. Nicholson, H. J. Sanganee, and A. D. Smith,Organic and Biomolec. Chem.,1, 2886 (2003).
h. J. D. White, C.-S. Lee and Q. Xu,Chem. Commun.2012 (2003).
stereochemical control by the auxiliary ring substituent. Entry 2 demonstrated the feasi- bility of enantioselective synthesis of-aryl acetic acids such as the structure found in naproxen. Entries 3 to 6 include ester groups in the alkylating agent. In the case of Entry 4, it was shown that inversion occurs in the alkylating reagent. Entry 7 is an example of the use of one of the more highly substituted oxazolidinone deriva- tives. Entries 8 and 9 are from the synthesis of a neurotoxin isolated from a saltwater bacterium. The pseudoephedrine auxiliary shown in Entry 8 was used early in the synthesis and the 4-phenyloxazolidinone auxiliary was used later, as shown in Entry 9.
The facial selectivity of a number of more specialized enolates has also been explored, sometimes with surprising results. Schultz and co-workers compared the cyclic enolateHwithI.99EnolateHpresents a fairly straightforward picture. Groups such as methyl, allyl, and benzyl all give selective-alkylation, and this is attributed to steric factors. Enolate I can give either - or -alkylation, depending on the conditions. The presence of NH3 or use of LDA favors-alkylation, whereas the use
99 A. G. Schultz, M. Macielag, P. Sudararaman, A. G. Taveras, and M. Welch,J. Am. Chem. Soc.,110, 7828 (1988).
45
SECTION 1.2 Alkylation of Enolates
of n-butyllithium as the base favors -alkylation. Other changes in conditions also affect the stereoselectivity. This is believed to be due to alternative aggregated forms of the enolate.
O N
–O
H OCH3
O–
N OCH3
H I
preferred alkylation
The compact bicyclic lactams15and16are examples of chiral systems that show high facial selectivity. Interestingly,15is alkylated from the convex face. When two successive alkylations are done, both groups are added from the endo face, so the configuration of the newly formed quaternary center can be controlled. The closely related16showsexostereoselectivity.100
O R N
O CH3
O R N
O CH3
R1 H
O R N
O
O R N
O R'
O R N
O CH3
R2 R1 15
16 R = Ph, i-Pr, t-Bu
1)s-BuLi 1)s-BuLi
1) s-BuLi 2)R1X
2) R'X
2) R2X
Crystal structure determination and computational studies indicate substantial pyra- midalization of both enolates with the higher HOMO density being on theendoface for both15and16. However, the TS energy [MP3/6-31G+d] correlates with experiment, favoring the endo TS for 15 (by 1.3 kcal/mol) and exo for 16 (by 0.9 kcal/mol).
A B3LYP/6-31G(d) computational study has also addressed the stereoselectivity of 16.101 As with the ab intitio calculation, the Li+ is found in the endoposition with an association with the heterocyclic oxygen. The exo TS is favored but the energy difference is very sensitive to the solvent model. The differences between the two systems seems to be due to theendoC(4) hydrogen that is present in16but not in15.
O N
O– Li H
100 A. I. Meyers, M. A. Seefeld, B. A. Lefker, J. F. Blake, and P. G. Williard,J. Am. Chem. Soc.,120, 7429 (1998).
101 Y. Ikuta and S. Tomoda,Org. Lett.,6, 189 (2004).
46
CHAPTER 1 Alkylation of Enolates and Other Carbon Nucleophiles
1.3. The Nitrogen Analogs of Enols and Enolates: Enamines