aluminum alkoxide complexes from highly substituted 3,4-epoxy alcohols: an nmr and computational...

Aluminum alkoxide complexes from highlysubstituted 3,4-epoxy alcohols: An NMR andcomputational studyGerardo Torres, Yasuyuki Ishikawa and José A. Prieto*

The organoaluminum mediated epoxide ring opening of epoxy alcohols is a key step in the oxirane-based approachfor polypropionate synthesis. However, this reaction has shown unanticipated regioselectivities when applied to2-methyl-3,4-epoxy alcohols. In order to gain mechanistic insight into the factors controlling the epoxide ringopening process, diastereomeric 2-methyl-3,4-epoxy alcohols were reacted with triethylaluminum in order toidentify the aluminum complexes formed by these systems. Different epoxide–aluminum complexes were calculatedusing ab initio HF/[13s7p/11s5p] and B3PW91/6-31G** gauge-including atomic orbital (GIAO) methods andcompared to the experimental NMR data. The calculated and experimental data correlates with the aluminum dimercomplex (TIPSOCH2CH(OAlEt2)CH(CH)3CHCH(O)(AlEt3))2 (VIII) for the systems favoring the nucleophilic attack at theexternal C4 epoxide carbon, while an unusual trialuminum species TIPSOCH2CH(OAlEt2)CH(CH)3CHCH(O)(AlEt3)2 (X)is consistent with the systems favoring the internal C3 attack. The 27Al NMR data established the tetracoordinatednature of the aluminum metal in all alkoxy aluminum intermediates, while the 13C NMR data provided insight intothe aluminum-oxygen coordination. The formation of the complexes was dictated by the stereochemical dispositionof the substituents. These complexes are different from the generally accepted bidentate intermediates proposedfor 2,3-epoxy alcohols and simpler 3,4-epoxy alcohols. Copyright © 2012 John Wiley & Sons, Ltd.Supporting information may be found in the online version of this paper.

Keywords: aluminum coordination; epoxide cleavage; organoaluminum; NMR calculations

INTRODUCTION

Epoxides and their ring opening products are versatile reagentsand intermediates that have found extensive use insynthesis.[1–3] This popularity results from their propensity toform carbon–carbon bonds when reacted as electrophiles witha suitable organometallic reagent.[4–6] We have been mostlyinterested in alkynyl aluminum reagents, in the context ofstereoselective synthesis of polypropionate chains employingepoxy alcohols as the epoxide substrate.[7,8] Being organoalanereagents electrophilic in nature, they can offer intrinsic epoxideactivation and chelation control via coordination of the epoxideoxygen with the aluminum, thus providing a reactivity manifoldusually not available to other common main group organometallicreagents. As with other nucleophilic reagents, the cleavage ofunactivated disubstituted epoxides with organoaluminum reagentscan bring regiochemical issues that need to be addressed whenused for synthetic purposes.Most studies on the cleavage of epoxy alcohols with organoalu-

minum reagents have focused on 2,3-epoxy alkanols, where thehydroxy can be free or protected as an ether derivative.[9–14] Thesestudies have provided the broadly accepted notion that the regios-electivity of the epoxide ring opening of 2,3-epoxy alcohols withalkyl or alkynyl alane reagents proceeds through a bidentate (I)or monodentate (II) aluminum complex (Scheme 1). The moreaccepted bidentate complex promotes the attack at the externalC3 (route a) or the internal C2 (route b) epoxide carbons throughan intermolecular or intramolecular alkyl or alkynyl transfer froma second oxygen-coordinated alane equivalent (shown for I). The

second alane equivalent, required for the reaction to proceed,may associate with the epoxide or the alkoxide oxygen, orboth.[15,16] The regiochemical outcome of the cleavage reaction iscontrolled by the syn/anti epoxide–alcohol relationship and thecis/trans geometry of the epoxide. Additionally, Lewinski et al.discovered a regiochemical switching in the epoxide ring openingof 2,3-epoxy-1-propanol by changing the aluminum alkylsubstituent from methyl to ethyl.[14]

The reaction of 3,4-epoxy alcohols with organoaluminumreagents has been less explored. Flippin et al. studied theregioselectivity of the epoxide ring opening of diastereomeric1-alkoxy-3,4-epoxides with mixed alkyl organoaluminun/organoaluminate reagents.[17] These studies suggested a prefer-ence for attack at the C4 epoxide carbon in systems amenable tochelation control. Interestingly, the nature of the remote 1-alkoxygroup was not a determinant factor in the regioselectivity of thereaction. Maruoka studied the reaction of 1-alkoxy-3,4-epoxideswith trialkylaluminum reagents employing NMR techniques.[18] Inthese studies, they suggested a pentacoordinate aluminumchelate as the active intermediate in the cleavage of these

* Correspondence to: José A. Prieto, Department of Chemistry, University ofPuerto Rico, Río Piedras Campus, San Juan, P.R. 00931–3346, USA.E-mail: [email protected]

Department of Chemistry, University of Puerto Rico, Río Piedras Campus, SanJuan, P.R. 00931–3346, USA

Research Article

Received: 22 March 2012, Revised: 12 July 2012, Accepted: 31 July 2012, Published online in Wiley Online Library:

(wileyonlinelibrary.com) DOI: 10.1002/poc.3024

J. Phys. Org. Chem. (2012) Copyright © 2012 John Wiley & Sons, Ltd.

epoxides, again, proposing the involvement of a bidentatealuminum–epoxide complex as well.

In this framework, and with the interest to use epoxides asprecursor to 2-methyl-1,3-diols, the distinctive feature ofpolypropionate systems, we undertook a study on the reactionof 2-methyl-3,4-epoxy alcohols with alkynyl aluminum reagents(Scheme 2). We prepared a series of diastereomeric 3,4-epoxyalcohols (Fig. 1) using halocyclization/methanolysis reactions,peroxyacid or metal-catalyzed epoxidations,[19,20] and studiedtheir ring opening reaction employing diethylpropynylaluminum.[8] Based on the above studies with epoxy alcoholsand the increased steric demands introduced by the 2-methylgroup, we expected the external C4 carbon attack to be thefavored regiochemical outcome, producing the corresponding2-methyl-1,3-diol product. Surprisingly, the reaction of all eightdiastereomeric 2-methyl-3,4-epoxy alcohols gave alkynyl substi-tution products with variable regioselectivities and yields. Whileepoxides 2, 3, 5 and 7 provided the 1,3-diol as the mayor regioi-somer in moderate to good yields, epoxides 1 and 6 favored theexclusive attack at the internal C3 carbon. Epoxide 4 showedpoor regioselectivity and epoxide 8 gave exclusively the desired1,3-diol but in a disappointing 17% yield. These outcomesrevealed that the diethylpropynyl aluminum-mediated epoxidering opening of unprotected trans- and cis-2-methyl-3,4-epoxyalcohols is not controlled by steric factors alone and that thestereochemical disposition of the substituents have to play acritical role in the formation of the aluminum complexes leadingto the epoxide cleavage products. This led us to further investigatethis reaction to gain mechanistic insight to better understand thefactors controlling the regioselectivity of the reaction.

Herein, we present a combined experimental NMR andab initio theoretical study to aid in the elucidation of the

epoxide–aluminum complexes involved in the reaction of2-methyl-3,4-epoxy alcohols with organoaluminum reagents. Thismechanistic insight will allow us to better understand the factorscontrolling the regioselectivity of the epoxide ring opening reaction.

RESULTS AND DISCUSSION27Al and 13C NMR studies

Based on earlier studies on protected 3,4-epoxy alcohol deriva-tives,[17,18] we initially envisaged a bidentate aluminum/epoxidecomplex similar to I during the cleavage of the free epoxyalcohols with the diethylpropynyl aluminum reagent. Thus, forour 3,4-epoxy alcohols 1–8, a bidentate complex III could beformed and produce the external cleavage 1,3-diols productsvia an intermolecular alkynyl transfer (Scheme 3). Because ofthe unexpected results on the 2-methyl-3,4-epoxy alcohols thatformed the undesired 1,4-diol products (i.e. 1 and 6), werationalized that due to the increased steric demands of the2-methyl-3,4-epoxy alcohol substrates, a monodentate intermedi-ate IV could also be formed and may even produce the internalcleavage products via an intramolecular propynyl grouptransfer.[8] Monodentate intermediates such as IV have beenproposed as alternative coordination models for organoaluminumreaction.[16,21] As with 2,3-epoxy alcohol systems, it is not clear ifthe second alane equivalent, required for the reaction to proceed,associates with the epoxide or alkoxide oxygen or both. [16]

We first performed 27Al NMR studies on the initial aluminum/epoxide complex formed after the reaction of the diastereomeric3,4-epoxy alcohols with Et3Al to rationalize the results on the2-methyl-3,4-epoxy alcohols and to gain mechanistic insight intothe factors that govern the regiochemical outcome of the

Scheme 1. Bidentate complexes for 2,3-epoxy alcohols and derivatives producing the attack at the C2 or C3 carbons

Scheme 2. Epoxide ring opening of 3,4-epoxy alcohols using diethylpropynyl aluminum

Figure 1. 2-Methy-3,4-epoxy alcohol diastereomers as precursors to 2-methyl-1,3-diols

G. TORRES, Y. ISHIKAWA AND J. A. PRIETO

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epoxide ring opening reaction. The results are summarized inTable 1. The observed range of the 27Al NMR chemical shiftsbetween 135.8 and 140.8 ppm correspond to tetracoordinatealuminum.[22] Since aluminum peaks are very broad (due to Alquadrupolar relaxation), differentiation between the interveningtetracoordinate aluminum species could not be obtained, evenwhen the experiments were performed at lower temperatures(�33 to �60 �C). On the sharper 13C NMR spectra, the chemicalshifts for the epoxide carbons were displaced downfield (Δd) inall the systems, except for epoxide 3. This observation reveals,as expected, a strong interaction between the aluminum andthe epoxide oxygen, regardless of the complex formed. TheTIPSO-bearing C1 carbon also showed a downfield shift for allsystems. Epoxides 2, 4, 7 and 8, which favor the external epoxidering opening, showed a Δd of ~8.0 ppm at the C2 hydroxy carbon.[8]

The presence of a large Δd for these epoxides suggests the coordi-nation of a second aluminum atom to the aluminum alkoxide oxy-gen as in bidentate complex III. On the other hand, epoxides 1 and6, which favor internal cleavage, showed a small �2.0 ppm. Thesmall shifts observed for 1 and 6 when reacted with Et3Al is con-sistent with the formation of a simple aluminum alkoxide and thelack of a second aluminum coordination as would be expectedfor IV.[15] Although these 13C NMR results appear to be consis-tent with structures III and IV, they do not account for thedivergence of epoxide 3, or the variations observed in termof the regioselectivity ratios and yields. It is evident that

the NMR data alone does not provide unambiguous informationof the nature and structure of the organoalane intermediate ini-tially formed when a 2-methyl-3,4-epoxy alcohol is reacted withan organoalane reagent.

Calculations of bidentate and monodentate complexes

The use of ab initio calculations to support the analysis andassignment of NMR data has become prevalent over theyears.[23–27] Computational methods based on molecular orbitaltheory can provide structural insight, and the comparisonbetween calculated and observed NMR spectra can help in theidentification of new compounds or species. The combinationof experimental NMR and theoretical calculations for structuralelucidation and discrimination between isomeric possibilities,when the spectroscopic data may show ambiguities, hasbecome an increasingly popular tool.[27–29] Taking into consider-ation these recent advances, it was decided to explore ab initiomethods of sufficient accuracy to calculate the 27Al and 13CNMR spectra of the proposed bidentate complexes and comparethem with the experimental NMR data. The calculated chemicalshifts for the different proposed structures can aid in the corrob-oration of the structure of the actual intermediate, especially forour sterically hindered epoxides. In this study, a three-stepprocess was applied.[28] First, Spartan 04[30] was used to identifythe energy minimum for each structure using a Monte Carloconformational search with the MMFF force field.[31] Second,the minimum equilibrium structure of the aluminum complexwas optimized with Gaussian 03[32] using the HF/6-31G* method.This method leads to accurate geometries with moderatecomputational costs. Third, we calculated the NMR chemicalshifts by means of the gauge-including atomic orbital (GIAO)method using two methods.[33–35] The first method for thecalculation of the NMR parameters was HF/[13s7p/11s5p]. Thismethod includes relatively tight functions (particularly of ssymmetry) that describes the neighborhood of the nucleus,which is the region of the molecule relevant for the calculationof NMR parameters.[36] We also implemented the DFT B3PW91/6-31G** method, first described by Forsyth & Sebag.[37] Thismethod has been used in relatively complex organic moleculeswith great success.[38,39]

The bidentate aluminum complexes III were calculated for all2-methyl-3,4-epoxy alcohol diastereomers 1–8. While six of theeight epoxy alcohol complexes converged to lower energy struc-ture, epoxides 6 and 8 did not lead to an energy minimum forcomplex III. The 13C NMR chemical shifts for compound 1, 2, 3and 7 were calculated and compared to the experimental values(Table 2). The correlation was poor for the four systems,

Scheme 3. Proposed bidentate and monodentate complexes for 2-methyl-3,4-epoxy alcohol systems

Table 1. 27Al NMR data and selected 13C NMR Δd for thealuminum complexes formed by the reaction of epoxyalcohols 1–8 with Et3Al

Epoxide d 27Ala Δd 13Cab

C1 C2 C3 C4 C5 C6 Me

1 140.8 3.1 2.0 1.9 4.4 7.7 1.4 0.72 136.8 4.9 8.4 �1.2 7.6 7.7 1.0 0.63 135.8 5.4 �0.3 0.2 �1.1 0.0 0.6 �0.24 139.6 2.5 8.1 0.4 0.5 9.9 0.3 0.36 136.5 4.6 �1.9 �1.6 10.7 10.0 1.2 �0.87 136.4 9.9 8.1 0.2 9.5 5.7 0.5 0.98 137.9 10.3 9.3 0.6 6.1 2.3 0.8 0.4ad (ppm)bChemical shift differences after addition of Et3Al

ALUMINUM ALKOXIDE COMPLEXES: AN NMR AND COMPUTATIONAL STUDY

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producing a mean absolute error (MAE) of 4.21 ppm.[24–27] Theseresults do not support the formation of the proposed bidentatecomplex III as the plausible structure.

Calculations of dimeric aluminum complexes

After discarding the bidentate complex III as a possible activeintermediate, we proceeded to explore other aluminum alkoxidestructural possibilities. It is known that, because of its electrondeficiency, aluminum compounds readily form dimeric struc-tures in non-donor solvents[40,41] This tendency has been wellestablished for aluminum alkoxide, through NMR and X-raystudies.[42,43] Although to date, an X-ray structure of an epoxidecoordinated alkoxide has remained elusive, Lewinski was ableto isolate and characterize the first group 13 metal-epoxidecomplex using GaMe3.

[16] They showed that an equilibriumexists in solution between a closed-shell, five coordinategallium/glycerol complex V and the open-shell four coordinatedimeric isomer VI, the latter being the predominant species.Because of the similarities between Ga and Al, we adapted thedimeric complexes V and VI to our more complex epoxy alcoholsystems (VII and VIII) and proceeded to calculate their NMRspectra (Fig. 2).

Although the initial HF structure optimization of the expecteddimeric complex VII with epoxide 2 did not converge, we weredelighted to find that six of the eight epoxide systemsconverged to the proposed dimeric monodentate complex VIII.The NMR chemical shifts for the aluminum complexes formedfrom 2, 3, 4, 7 and 8 were then calculated. Epoxide 5 wasomitted from the NMR calculations since no experimental NMRdata for its aluminum complex was available.[44] The 13C NMR datacompared favorably with the experimental data of the dimericcomplexes derived from epoxides 2, 3, 4, 7 and 8, all of which favorexternal cleavage at the C4 epoxide carbon when reacted with

diethylpropynyl aluminum (Table 3). The HF structure optimizationfor epoxy alcohols 1 and 6 did not converge to the dimeric alumi-num complexes VIII. Cleavage of the epoxide was observed inboth systems.The calculated NMR shifts were analyzed by subtracting the

isotropic shift for each carbon atom from the corresponding shiftfor TMS, calculated using the same method (196.38 ppm forB3PW91/6-31G** and 201.96 ppm for HF/[13s7p/11s5p]). Bothmethods show good correlation with the experimental values(Table 3). Epoxides 3 and 8 gave lower than expected correlationcoefficients. This can be attributed to the fact epoxide 3 showslower coordination affinity as revealed by the smaller chemicalshift changes.[45] On the other hand, epoxide 8 produces anoxetane when reacted with diethylpropynyl aluminum.[8] Wealso examined the MAE for the studied epoxy alcohols. Forsystems 2, 4, and 7, the MAE is 2.95 ppm, and for systems 3and 8, it is 3.45 ppm. This difference is in agreement with thecorrelation coefficients obtained.The difference between experimental and theoretical 27Al

NMR shift was also examined. Al(H2O)6+3 was used as

reference,[46] giving 633.5 and 601.1 ppm for the B3PW91/6-31G** and HF/[13s7p/11s5p] methods, respectively. The HF/[13s7p/11s5p] method gave an average chemical shift differenceof 6.2 ppm for the epoxy alcohol derived complexes examined,while the DFT B3PW91/6-31G** method gave a difference of9.4 ppm (Table 4). This better agreement with the HF methodis based on the fact that the functions used better describe the

Table 2. Correlation coefficients for experimental andcalculated 13C NMR data of themonomeric bidentate aluminumcomplex III

Epoxyalcohol

Correlationcoeff.

Epoxyalcohol

Correlationcoeff.

1 0.978 3 0.9302 0.970 7 0.991

Figure 2. Gallium glycidol complexes V and VI and aluminum dimeric complexes VII and VIII

Table 3. Correlation coefficients for experimental andcalculated 13C NMR data of the dimeric monodentate aluminumcomplex VIII

Epoxide

Relative energya Correlation coeff.

HF/6-31G* HF/(13S, 7P)[11S, 5P]

DFT B3PW91/6-31G**

2 0.87 0.997 0.9943 0.77 0.968 0.9744 0.19 0.996 0.9957 2.24 0.992 0.9908 0.00 0.972 0.979

aHF/6-31G* (kcal/mol)



area closer to the nucleus.[33–35] The theoretical values obtainedare in good agreement with the experimental values. Thesechemical shift differences are comparable to what Gauss et al.found for aluminum (I) complexes using the GIAO-MP2method.[47] Again, these results are consistent with tetracoordi-nated aluminum species.

Calculations of other aluminum complexes

Although the dimeric complex VIII is adequate to describe thealuminum alkoxides formed from epoxides 2, 3, 4 and 7, itcannot be used to describe the complexes formed by epoxides1 and 6 and the reaction occurring with 8. Given that the ringopening reaction of epoxy alcohols can be a multichannelprocess, different types of intermediate species have to beconsidered to rationalize the data obtained for the 3,4-epoxyalcohols.[21] We explored alternative aluminum complexes thatcould correlate with the experimental data. We also discardedthe bidentate complex III, which was not sustained by epoxide6. Moreover, the geometry optimization for complex IVconverged for epoxides 1 and 6, but the correlation factor was0.972 and 0.982, respectively. This outcome, together with theexperimental observation that three equivalents of the alanereagent are needed for the cleavage of systems 1 and 6 asopposed to only two equivalents for the other systems,[8]

prompted us to explore two other possibilities, the counterintu-itive tricoordinate aluminum complexes IX and X (Fig. 3).Complex IX has another aluminum coordinating the alkoxideoxygen and one at the epoxide, while complex X has two alumi-nums at the epoxide and one in the alkoxide oxygen. It could beargued that aluminum alkoxides predominantly form dimericcomplexes in non-coordinating solvents and that monomericaluminum alkoxides have only been found in highly stericallycrowded systems.[48,49] However, the intrinsic steric factorsamplified by the spatial disposition of the substituents in our2-methyl-3,4-epoxy alcohols may curtail de formation of theAl-O-Al dimer. Notwithstanding, this proposal does not precludethe formation of related dimeric structures based on Al(u-Et)Albridges having complex X as the monomeric unit.[50]

The geometry optimization and NMR calculations forcomplexes IX and X were done following the same procedureused for the previous complexes. We first calculated the alumi-num complexes IX and X on systems 1 and 6. The correlationfor the experimental and theoretical data for complex IX was0.988 for 1 and 0.983 for 6. Correlation for the aluminumcomplex X was calculated as 0.991 and 0.995 for 1 and 6, respec-tively, employing the DFT B3PW91/6-31G** basis set (Table 5).The calculated MAE is 1.94 ppm for 1 and 2.37 ppm for 6. A verysimilar result (0.992 and 0997, respectively) was obtained withthe HF/[13s7p/11s5p] basis set. This superior correlation foundwith complex X supports this complex as a possible intermediateinitially formed with systems 1 and 6. This is apparent in the3D structures generated by the computation (vide infra). Inaddition, complex X is in line with the small chemical shiftdifferences (� 2 ppm) observed for the C1 alkoxide carbon ofepoxides 1 and 6 (Table 1).

We also calculated the NMR parameters for the epoxy alcohols3 and 4 because these two systems give mixture of internal andexternal cleavage products. These two epoxy alcohols gavelower correlation coefficients for the aluminum complex X(Table 5). This lower correlation with the calculated aluminumcomplexes (e.g. VIII and X) can be attributed to the competingaluminum species that are possible for these systems, as a resultof the mobility of the aluminum atoms between the epoxide andalkoxide oxygen atoms, averaging out in the NMR experimenttime frame.

The 27Al NMR chemical shift data was also compared for thesystems calculated for complex X. The difference obtainedbetween experimental and theoretical values for 1 with theDFT/B3PW91/6-31G** method was 39 ppm; however, a 7 ppmdifference was obtained with the HF/[13s7p/11s5p] basis set(Table 6). This follows the same tendency observed for the calcu-lations of aluminum complex VIII where better agreement withthe 27Al NMR data was obtained with the HF basis set. Thecomparison of the experimental and calculated 27Al NMR shiftfor the aluminum complex X formed from epoxy alcohols 1, 3,

Table 4. Comparison of the experimental and calculated27Al NMR shift for dimeric monodentate aluminumcomplexes VIII

Epoxide

Experimental Δd 27Al (ppm)

d 27Al (ppm) HF/(13S, 7P)[11S, 5P]

DFT B3PW91/6-31G**

2 136.8 6.9 10.83 135.8 6.6 10.44 139.6 6.6 8.57 136.4 6.5 10.58 137.9 4.2 7.3

Figure 3. Trialuminum complexes IX and X

Table 5. Correlation coefficients for the experimental andcalculated 13C NMR data of the aluminum complex X

Epoxide

Correlation coeff.

HF/(13S, 7P)[11S, 5P] DFT B3PW91/6-31G**

1 0.992 0.9913 0.965 0.9824 0.986 0.9876 0.997 0.995

Table 6. Comparison of the experimental and calculated27Al NMR shift for the trialuminum complexes X

Epoxide

Experimental Δd 27Al (ppm)

d 27Al (ppm) HF/(13S, 7P)[11S, 5P]

DFT B3PW91/6-31G**

1 140.8 6.9 39.93 136.8 2.7 40.14 136.4 5.2 41.16 139.6 1.8 43.3



4 and 6 is shown in Table 6. Next, we explored if the formation ofcomplex X is amenable to the other epoxy alcohols. For this, wechose epoxides 2 and 7 since these systems showed excellentcorrelation for the dimeric aluminum complex VIII. The geome-try optimization on these systems did not converge to a stableconformation of complex X, thus discarding its formation as apossible aluminum intermediates for these systems.

Steric effects

Having the calculated geometries for complexes VIII and X onhand, we explored their structural features to assess if a predic-tive model for the epoxide cleavage reaction could be obtained.For this, an examination of the Space filling CPK models of thecalculated aluminum complexes formed by the epoxy alcoholswas done. First, we examined systems 2 and 7. The CPK modelfor the monodentate dimeric aluminum complex VIII formedfrom epoxide 2 shows a geometry where only the C4 carbon isexposed to intermolecular attack by the organoaluminumreagent (Fig. 4a). This correlates with the high regioselectivityobserved for this epoxide favoring the C4 cleavage. A similareffect was found for the anti,anti,cis epoxide 7, correlating withthe very high regioselectivity also obtained for this system.

In the case of the anti,syn,cis epoxide 8, which produces anoxetane as the major product of the cleavage reaction, the calcu-lated structure places the epoxide carbons facing inward in thealuminum dimer VIII making them less accessible for an attack(Fig. 4b). This gives a plausible steric-based explanation for theobserved low yield and the formation of the oxetane productresulting from an intramolecular aluminum alkoxide attack.Similarly, the aluminum complexes formed from epoxides 3and 4 were examined. As stated above, these two systemsproduced a mixture of internal and external epoxide cleavageproducts and converged to both aluminum complexes VIII andX, albeit with the lower correlation factors among the series(Tables 3 and 5). After examining the calculated CPK structuregeometry for 3, we discovered that in complex VIII, the C4carbon is exposed to attack, while for complex X, the C3 carbonis more accessible. A similar trend was observed for epoxide 4.This explains the lower regioselectivity obtained for 3 and 4.

Finally, we examined the aluminum complex X formed byepoxides 1 and 6, which showed regioselectivities favoring theC3 internal epoxide-opening product. The formation of themonomeric aluminum complex can be rationalized in terms ofthe highly hindered 2-methyl-3,4-epoxy alcohol molecules thatdo not allow formation of the intuitively more favorablealuminum dimer. On one hand, epoxy alcohol 1 shares a syn,syn relationship between all the substituents (C1 hydroxy, C2

methyl and epoxide), leading to a sterically crowded regionpreventing the dimer formation (Fig. 4c). Conversely, system 6has a syn,anti relationship; however, the cis configuration of theepoxide creates a 1,3 steric interaction between the C2 methyland themethyl next to the epoxide. Again, this limits the formationof the Al-O-Al based dimer VIII, allowing the trialuminum complexX reaction manifold. This study provides a better understandingand a predictive model for the regioselectivity of the epoxidering opening of 2-methyl-3,4-epoxy alcohols with organoalanereagents. These twomodels effectively fit the observed experimen-tal data, although other models can not been discarded.

CONCLUSION

We have characterized two aluminum complexes (VIII and X) forthe reaction of 2-methyl-3,4-epoxy alcohols with organoalanereagents. The formation of dimeric monodentate aluminumalkoxide complex VIII is supported by the good correlationbetween experimental and theoretical NMR data for epoxides2, 4 and 7. Intermediate VIII is different from the monomericbidentate complex II, which has been the accepted model forthe reaction of 2,3- and 3,4-epoxy alcohols and ethers withorganoaluminum reagents. The aluminum complex X, wheretwo aluminums are connected to the epoxide oxygen, repre-sents a possible reaction intermediate for epoxides 1 and 6. Thisreactivity manifold can be attributed to the increased sterichindrance provided by these highly substituted epoxides. Thiswork can be used as a predictive tool for the regioselectivity ofsimilar epoxide opening reactions, thus facilitating the furtherapplication of this methodology in synthesis.

EXPERIMENTAL SECTION

General experimental details

All experiments and reactions were carried out in oven-dried glassware(overnight at 120 �C). Standard handling techniques for air sensitivecompounds were employed throughout this study. A dry nitrogenatmosphere was maintained through oil bubblers in all reactions. Lowtemperature reactions were carried out using CO2/acetone baths toachieve �78 �C. Epoxy alcohols 1–8 were prepared using previouslypublished procedures (see references [8], [19] and [20]. Toluene-d8 andtriethylalane (25% in toluene) were used as received. The 13C NMRspectra were obtained at 125.7 MHz. The carbon chemical shifts (d) aregiven in ppm relative to TMS. The 27Al NMR spectra were obtained at130.3 MHz. The aluminum chemical shifts (d) are given in ppmrelative to aluminum hexachloride hexahydrate. General experimentalprocedures, analytical and spectroscopic data can be found in thesupporting information.

Figure 4. CPK representation of complexes VIII and X without hydrogen atoms



Preparation of the aluminum complexes: Reaction of2-methyl-3,4-epoxy alcohols 1–8 with triethylalane

The 2-methyl-3,4-epoxy alcohol 1–8 (50 mg) was added to a roundbottom flask under a positive N2 stream. The temperature was loweredto �78 �C. Then, toluene-d8 (1 mL) was added followed by Et3Al (1–3equiv) via syringe. The mixture was rapidly transferred to the NMR tubevia syringe and immediately placed on the NMR instrument previouslycooled at the appropriate temperature. The broad 27Al NMR peak near55 ppm corresponds to the NMR probe signature.

Calculations

The ab initio calculations were performed starting from a Monte CarloMMFF conformational search using Spartan 04.[30] The energy minimawere optimized with Gaussian 03 using the HF/6-31G* method. TheGaussian 03 package was also used to calculate the NMR spectra. TheNMR chemical shifts were calculated by subtracting the GIAO isotropicshielding using the HF/[13s7p/11s5p] and the DFT B3PW91/6-31G**methods.[32]

SUPPORTING INFORMATION

Supporting Information

Acknowledgements

This work was supported by NIH RISE (1R25-GM-61151-01A1)and SCORE (SC1 GM084826-03) Programs. We also thankElizabeth Valentín for helpful discussions.

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