In the Laboratory
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Diastereoselectivity in the Reduction of α-Hydroxyketones An Experiment for the Chemistry Major Organic Laboratory David B. Ball Department of Chemistry, California State University, Chico, Chico, CA 95929-0210;
[email protected] An NSF CCLI grant funded in 1999 was based on incorporating high-field FT-NMR spectroscopy into the undergraduate curriculum at CSU, Chico.1 The main thrust of the proposal was to replace the traditional laboratories of analytical, inorganic, and physical chemistry with an integrated laboratory sequence spanning three semesters (1). The four-year plan for a chemistry student at Chico State has the student beginning the integrated laboratory sequence in the first semester of the student’s junior year while concurrently taking both physical and inorganic chemistry lectures. Our students are expected to have sufficient laboratory experience to successfully carry out the research-like, interdisciplinary experiments offered in the integrated laboratories (2). To provide our students with this required laboratory expertise, we have introduced into the second-semester organic laboratory for chemistry majors several experiments that are research-like and inquiry-based utilizing laboratory techniques not routinely taught in the first-year organic laboratories, such as flash chromatography and TLC; syringe and cannula use for reagent transfer; inert atmosphere and subambient temperature conditions; and hands-on use of the high field FT-NMR spectrometer using both 1D and 2D experiments for analysis. In the recent past, we had developed an experiment that requires the use of the NMR spectrometer via a NOESY1D experiment to determine the diastereoselectivity in the reduction of α-methylbenzoin with various reducing agents. An obvious extension of this experiment is to have our students synthesize racemic α-hydroxyketones, perform reductions under chelating and non-chelating conditions, and quantitatively determine the relative amounts of diastereomeric diols produced. The stereoselectivity in metal hydride reductions of ketones can be controlled by the nature of the metal hydride or by the choice of the ketone (3). Neighboring groups to the carbonyl that exhibit Lewis basicity can also affect the stereochemical course of carbonyl reductions and other addition reactions (4). The reduction of several α-hydroxyketones and their silyl ether derivatives with Zn(BH4)2 and LiAlH4 affords the opportunity to investigate possible steric factors and chelating effects. Several models have been postulated to account for the stereochemical outcome in reduction of acyclic and cyclic ketones. Cram’s model (Cram’s rule), Cram’s chelation model, and the Felkin–Ahn model have been extensively used in rationalizing the observed diastereoselecºtivity in the reduction of prochiral carbonyls in acyclic molecules with a preexisting stereocenter (5). Since these reductions are kinetically controlled processes (5d), the diastereomeric selectivity (the erythro兾threo ratio) depends on the relative differences in the free energies of ac-
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tivation (∆∆G ‡) of reduction that, in turn, are dependent on several controllable factors. Among these are the nature of the reducing agent, temperature, the size of R in 1 (Figure 1), and the possible coordination of the reducing agent with both oxygen atoms. To investigate some of these factors, several α-hydroxyketones are synthesized varying the size of R, the hydroxy groups are derivatized with a bulky silyl protecting group producing 2, and stereoselective reductions of 1 and 2 are carried out with Zn(BH4)2 and LiAlH4, respectively. Synthesis A retrosynthetic analysis (Scheme I) of a generic αhydroxyketone 1 gives a disconnection producing aldehyde synthon 4 and an acyl anion synthetic equivalent 3 whose synthon is the dithiane anion 6. A functional group interchange transforms benzaldehyde to dithiane 6 (6).
O
R = = = = = =
R
Ph OX
X = H (1) = SiMe2t-Bu (2)
methyl propyl isopropyl isobutyl benzyl phenyl
Figure 1. α-Hydroxyketones, 1, and silyl ether, 2, derivatives.
O R
O
R
+
Ph
OH
Ph
OH 1
R = O 5
4
3
O
O =
S
S
S
S
Ph
Ph Ph
3
Ph
6
H
H
7
Scheme I. Retrosynthetic analysis of α-hydroxyketones.
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The general synthetic sequence used to prepare generic target molecule 1 and its silyl-protected derivative 2 is shown in Scheme II. As was indicated in Scheme I, the synthesis uses a polarity reversal, that is, umpolung (7), of the carbonyl functional group from the carbon being electrophilic (in benzaldehyde) to being nucleophilic (in 6) allowing for the aldol-like nucleophilic addition of 6 to an aldehyde. The umpolung reagent 7 is produced by the Lewis acid catalyzed reaction between benzaldehyde and 1,3-propanedithiol. Then the dithiane addition products are subsequently unmasked to form the desired racemic α-hydroxyketones 1. The α-hydroxy group in 1 is then converted to the bulky silyl ether group in 2.
O
SH
Ph
H
S
S
S
Ph 6
R
NH4Cl(aq)
H
−78 oC
R
Ph HO 8
CH3CN/H2O
O
O t-BuMe2SiCl
R Ph
R Ph
imidazole/DMF
OTBS
OH 2
1
Scheme II. Synthesis of α-hydroxyketones and silyl-protected αhydroxyketones.
O
H
M
Si face
O
O
O
and
H R
Ph
H
H
M
Si face
H
Re face
R H
Ph Re face
Figure 2. Reduction diastereoselectivity.
TBS-Cl imidazole DMF
O Zn(BH4)2
R Ph OH 1
O
OH
OH
R LiAlH4
R
TBAF
Ph
Hazards
OTBS
•
H
−78 oC
Ph
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S
−78 oC
O
CaCO3
Most of the organic solvents and some of the reagents used in these experiments are flammable, moisture-sensitive, irritants, or corrosive. Specifically HgCl2, imidazole, and ZnCl2 are toxic or highly toxic. Acetaldehyde is a suspect cancer agent. Dimethylformamide is a teratogen. Both 1,3propanedithiol and isovaleraldehyde have disagreeable odors (stench). Column chromatography involves the use of fine mesh SiO2 and large volumes of volatile, flammable solvents. Adequate ventilation must be provided in making and using these silica columns. Appropriate disposal of waste products especially the mercury(II) salts is required.
n-BuLi
S
Ph
HgCl2,
The diastereomeric selectivity (affecting erythro兾threo ratios) in the reduction of chiral hydroxyketone 1 results from prior coordination of the reducing agent with the α-hydroxy group and the carbonyl of the substrate producing diastereotopic faces (Figure 2). Reduction of racemic 1 with Zn(BH4)2, a known coordinating reducing agent (8), provides data of the diastereoselectivity dependence on the varying size of R versus H in 1 assuming the coordinated structures shown in Figure 1 are precursors to the reduction process. Conversion of the α-hydroxy group in 1 to a bulky silyl ether in 2 precludes a coordinated ground state as in Figure 2 for the reduction process. It is expected that there would be different ground-state conformations of 2 that undergo reduction by LiAlH4 than postulated for a chelated species of 1, resulting in different erythro兾threo ratios. Removing the silyl protecting groups (if required; see discussion) of the mono alcohol reduction products 9 produces diols 10 (Scheme III). The analyses of high field 1H NMR spectra of mixtures of diastereotopic diol 10 determine the ratio of the erythro and threo diols but cannot determine which is the major product. Conversion of these diastereomeric diols to their corresponding acetonides 11 (Scheme III) provides a fairly rigid structure amenable to stereochemical analysis by 1H NMR spectroscopy. Experimentally each isomer is identified by proton NOESY1D (a 1D NOE experiment using pulsed field gradients) experiments (9). Irradiation of the benzylic hydrogen of each of the diastereomers (as they have different chemical shifts except when R = phenyl) in an NOESY1D experiment allows for the differentiation of the erythro isomer from the threo isomer. From this the erythro兾threo ratio and the degree of diastereomeric selectivity in the reduction is determined.
S
7
Reductions
102
SH
BF3 ·OEt2
OH 10
OTBS
2
R
Ph
9
OMe acetone OMe PPTS
O
O
R 11 erythro/threo Scheme III. α-Hydroxyketones conversion to acetonides.
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Ph
•
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In the Laboratory
Synthetic Results
Table 1. Yields of Reactions in Schemes II and III Yield of Compounds (%)
R Group
008
01
002
10
a
10
b
11
Methyl
100
35
100
089
043
72
Propyl
085
44
091
068
064
78
Isopropyl
098
46
068
056
100
78
Isobutyl
091
39
096
074
061
79
Benzyl
097
41
100
068
075
80
Phenyl
090
40
100
085
067
88
a
b
Reduction of 1 with Zn(BH4)2. accompanied by desilylation.
HO Ph
O R
OH
H
H
Reduction of 2 with LiAlH4
H
O
O
H
H
O
O
H Ph
H
O
O
H Ph
R
O
O
H
R
R Ph
A
R
Diastereomeric Selectivity Results
Ph H OH (S)-1
HO
OH
H Ph
H
R
B
HO H Ph
O R
H
OH
R ent-A
R
H H
Ph HO H (R)-1
HO Ph
OH
H R ent-B
H Ph
Scheme IV. Reduction stereoisomers and acetonides.
threo
erythro
O
O
O
Ph H
Me H
irradiate
O
Ph H
H Me
irradiate
Figure 3. NOESY1D enhanced absorptions.
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Benzaldehyde is converted in a 83% yield to dithiane 7 by treatment with 1,3-propanedithiol and BF3⭈OEt2 in dichloromethane. Subsequent deprotonation of 7 with nBuLi (᎑78 ⬚C to 0 ⬚C to ᎑78 ⬚C), condensation with various aldehydes, and adding aqueous NH4Cl to the solution at ᎑78 ⬚C leads to dithiane alcohol 8 (Scheme II).2 Demasking 8 with mercuric chloride and calcium carbonate in refluxing aqueous acetonitrile produces α-hydroxyketones 1 in low but consistent yields.3 The reaction sequence then branches with the reduction of 1 with Zn(BH4)2 in THF at 0 °C giving diols 10 and with the conversion of 1 to t-butyldimethylsilyl ethers 2 (Scheme III). The TBS ethers 2 are then reduced with LiAlH4 in THF and, when worked up with water at 0 ⬚C result in the removal of the TBS protecting group, producing diols 10.4 Both sets of diastereomeric diols are readily converted to their diastereomer acetonides 11 with acetone, 2,2-dimethoxypropane and catalytic pyridium ptoluenesulfonate. The yields of these reactions from Schemes II and III are tabulated in Table 1. All compounds were characterized by 1H and 13C NMR spectroscopy.5
H
As we are starting with a racemic mixture of αhydroxyketones, (S )-1 and (R )-1, the reduction of the carbonyls will give a mixture of diastereomers (Scheme IV) where the pairs A and ent-A, B and ent-B are enantiomers (ent). And the pairs A and B, ent-A and ent-B are diastereomers. The former pair denoted as erythro and the latter pair as threo. The corresponding acetonides have these same stereochemical relationships. The 1H NMR spectra of the acetonide of the diol mixture from the Zn(BH 4 ) 2 reduction product of αhydroxyketone (1, where R = Me) has a doublet at δ 5.21 ( J = 7.0 Hz, 1H) due to the benzylic hydrogen on the major diastereomer (94%) and another doublet at δ 4.48 ( J = 8.5 Hz, 1H) arising from the benzylic hydrogen on the minor diastereomer (6%). A NOESY1D experiment irradiating (Figure 3) at δ 5.21 gives enhanced signals for the phenyl hydrogens (δ 7.33, m, 5H), for the vicinal hydrogen at δ 4.58, and for one of the methyl groups at δ 1.48 of the acetonide. Thus, these data are consistent with the major reduction product being the erythro diastereomer. All the other reductions with chelating Zn(BH4)2 show this same high erythro selectivity (Table 2). As expected, a lesser erythro selectivity is observed when a poorer chelating reducing agent is used (LiAlH4 in THF at 0 ⬚C) (Table 2, isopropyl and phenyl entries). By contrast, the LiAlH4 reduction of the TBS-protected α-hydroxyketones produce the opposite diol stereoisomer as the major product (Table 2). The 1H NMR spectrum of the acetonide from the reduction of 2 (where R is methyl) shows that the major diastereomer (87%) has a benzylic absorption at δ 4.48 and the minor product (13%) has its benzylic absorption at δ 5.21. The NOESY1D experiment irradiating the signal at δ 4.48 gives enhanced signals at δ 7.38 (phenyl hydrogens), at δ 1.53 (one of the acetonide methyl groups) and at δ 1.30 (methyl doublet), all indicative of the major product being the threo isomer. These NOESY1D experiments are illustrated in Figure 3.
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Discussion The reductions of the α-hydroxyketones 1 with Zn(BH4)2 are highly stereoselective with erythro兾threo ratios ranging from 16:1 to > 99:1 (Table 2). Cram’s chelation model can account for the observed erythro selectivity (10). Two chelated equilibrating conformations that are capable of producing diols are shown in Figure 4. Erythro selectivity is predicted on two accounts: (i) the conformational equilibrium distribution should favor the less sterically hindered conformation (the complexed borohydride favors a near gauche relationship with H rather than R) and (ii) hydride delivery from the Re-face of the carbonyl is expected to have a lower ∆G‡ than delivery from the Si-face (the Bürgi–Dunitz trajectory of 109⬚ has delivery eclipsing H versus eclipsing R) (11). The threo selectivity of the LiAlH4 reductions of the TBS-protected hydroxy ketones is shown in Table 2. The bulky silyl protecting group should preclude the reduction process proceeding through a chelated conformation as above. The Felkin–Ahn model having the largest group (the bulky TBS group) perpendicular to the carbonyl group gives two possible conformations to account for the observed threo preference (Figure 5). The conformation without the phenyl–(R ) gauche interaction should be preferred and also should provide the reduction pathway of lower steric hindrance for hydride delivery (eclipsing H versus R) leading to the threo diol. One anomaly in Table 2 is the entry where R = Ph in 2; the threo isomer is less favored even though phenyl has greater steric requirements than the other R groups, which should result in a greater threo selectivity. However, if phenyl competes with the TBS group for being the largest group then there would be a significant conformational contribution in the Felkin–Ahn model for phenyl being perpendicular to the carbonyl. Using the same argument as above would lead to the observed increased amounts of the erythro isomer. To test this hypothesis, a bulkier protecting group (t-butyldiphenylsilyl) was used to protect the hydroxy group of benzoin. The TBDPS ether should lessen the equilibrium contribution of the Felkin–Ahn conformation that has the phenyl perpendicular to the carbonyl. As predicted, the LiAlH4 reduction of the TBDP-silyl protected benzoin gave an increased amount of threo isomer (83% versus 77% for the TBS protected benzoin).
Table 2. Stereoselectivity in the Reduction of α-Hydroxyketones 1 and TBS-Protected α-Hydroxyketones 2 to Yield Acetonide 11 Yield from Cpd 2 (%)
Yield from Cpd 1 (%) Zn(BH4)2
R Group
LiAlH4
LiAlH4
Erythro Threo Erythro Threo
Erythro Threo
Methyl
>94
>6
---
---
13
87
Propyl
>98
>2
---
---
12
88
Isopropyl
>99
97
>3
---
---
13
87
Benzyl
>97
>3
---
---
10
90
Phenyl
>99
>1
89
11
23
77
OH O
Zn
H
H
B
HO O
Zn H H B
H H
R
H
Ph
HO
HO OH H R
HH H Re face
R
Ph
Si face
OH
Ph
H
H H
R
Ph
erythro
threo
Figure 4. Cram’s chelation model.
O
O
R
H OSiMe2t-Bu
H
t-BuMe2 SiO
H
R
H Ph
Ph
Conclusion Students completing this laboratory experiment gain the necessary laboratory and analytical skills in organic chemistry to be successful in our integrated laboratory sequence and in carrying out undergraduate research. The experiment described here is the final experiment of the semester. It was designed to be the capstone of the course with the preceding work preparing the student for this inquiry-based experiment. The experimental design also allows for lesser expectations from the student in that the umpolung reagent 7 may be provided as the starting material, each student need not do both chelated and non-chelated reductions, and Zn(BH4)2 may be given as an available reagent. Our students become proficient in following reactions by TLC, purifying products using flash chromatography, sy-
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H
OH
R
Ph
OSiMe2t-Bu
H
t-BuMe2SiO
H
threo
O
O
t-BuMe2SiO
H Ph
H
Ph
Ph
•
H OSiMe2t-Bu Ph
Figure 5. Felkin–Ahn open chain model.
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H
Ph
erythro
H
R
HO
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ringe techniques for reagent transfer, and working under an inert atmosphere at subambient temperatures. These experiments also require the student to have hands-on access to the high field FT-NMR for structure elucidation, as most of the products in this experiment are chiral exhibiting NMR spectra with diastereotopic hydrogens and carbons. W
Supplemental Material
General procedures (equipment and instrumentation); student laboratory handout containing detailed experimental procedures for the preparation of 1 (R = isopropyl), 2 (R = isopropyl), 7, 10 (R = Isopropyl and methyl), 11 (R = isopropyl), and Zn(BH4)2; spectral data for compounds; CAS registry numbers of chemicals; selected 1H spectra; and selected NOESY1D spectra are available in this issue of JCE Online. Notes 1. The integrated laboratory sequence was the basis of a funded National Science Foundation Course, Curriculum and Laboratory Improvement Program (grant # 99-50413) that provided for the purchase of the Varian Mercury VX300 BB NMR spectrometer used in this study. 2. Quenching with aqueous NH4Cl at 0 ⬚C substantially lowers the isolated yields of the condensation products. 3. The following hydrolysis conditions were not effective in converting the dithianes to α-hydroxy ketones: NBS兾DMSO (major product was a diketone); NBS兾collidine兾MeOH兾CH3CN (major product was the diketone, monomethyl acetal); NBS兾H2O兾acetone (several products); HgCl2兾CaCO3兾acetone兾H2O (gave the methyl acetal of the hydroxyketone); MeI兾acetone兾water (gave the diketone). 4. Very little silylated product was isolated when TBS was used as the silyl protecting group. However, when TBDP was the silyl protecting group, the desilylated product was a minor product. 5. As compounds 1, 2, and 8 through 11 contain at least one stereocenter, their 1H and 13C NMR spectra exhibited diastereotopic hydrogens and carbons (see the Supplemental MaterialW).
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Literature Cited 1. Ball, D. B.; Miller, R. J. Chem. Educ. 2002, 79, 665–666. 2. (a) Ball, D. B.; Miller, R. M. J. Chem. Educ. 2004, 81, 121–125. (b) Ball, D. B.; Wilson, R. J. Chem. Educ. 2002, 79, 112–115. 3. (a) House, H. O. Modern Synthetic Reactions, 2nd ed.; W. A. Benjamin, Inc.: Menlo Park, CA, 1972; pp 45–70. (b) SeydenPenne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis; ACH: New York, 1991; Chapter 2. 4. (a) Richardson, D. P.; Wilson, W.; Mattson, R. J.; Powers, D. M; Dolan, B. T. J. Chem. Educ. 1991, 68, 951–955. (b) Depres, J.-P.; Morat, C. J. Chem. Educ. 1992, 69, A232–A239. (c) Ciaccio, J. A.; Bravo, R. P.; Drahus, A. L.; Biggans, J. B.; Concepcion, R. V.; Cagrera, D. J. Chem. Educ. 2001, 78, 531–533. 5. (a) Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; American chemical Society: Washington DC, 1976; pp 84–132. (b) Cram, D. J.; AbdElhafez, F. A. J. Am. Chem. Soc. 1952, 74, 5824. (c) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748. (d) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New York, 1994; pp 875–880. (e) Stocker, J. H.; Sidisunthorn, P.; Benjamin, B. M.; Collins, C. J. J. Am. Chem. Soc. 1960, 82, 3913. (f ) Cram, D. J.; Wilson, D. R. J. Am. Chem. Soc. 1963, 85, 1245. (g) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199. (h) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205. 6. Corey, E. J.; Cheng, X. The Logic of Chemical Synthesis; John Wiley & Sons: New York, 1989; pp 1–16. 7. Smith, M. B. Organic Synthesis, 2nd ed.; McGraw Hill: New York, 2002; pp 633–642. 8. Narasimhan, S.; Balakumar, R. Aldrichimica Acta 1998, 31, 19–26. 9. Shaka, A. J. J. Magn. Res. 1997, 125, 302–324. 10. (a) Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1983, 24, 2653–2656. (b) Katzenellenbogen, J. A.; Bowlus, S. B. J. Org. Chem. 1973, 38, 627–632. (c) Katzenellenbogen, J. A.; Bowlus, S. B. J. Org. Chem. 1974, 39, 3309–3314. 11. Bürgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95, 5065. Bürgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563.
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