Stereoselective VO(acac)₂ Catalyzed Epoxidation of Acyclic Homoallylic Diols. Complementary Preparation of C2-syn-3,4-Epoxy Alcohols

Abstract

A substrate-controlled stereoselective epoxidation of free and monoprotected homoallylic diols was developed. This second-generation approach is based on the incorporation of a primary hydroxy directing group at the C2 methyl carbon, which changes the nature of the vanadium ester intermediate providing a new diastereoselectivity manifold for the preparation of 3,4-epoxy alcohols. This modification favored the formation of the challenging C2-syn epoxy alcohol product not previously available using the standard homoallylic alcohol substrates. These new epoxy alcohol diastereomers expand the scope and generality for the utilization of 3,4-epoxy alcohols as precursors for stereoselective polypropionate synthesis.

1. Introduction

The 3,4-epoxy alcohol moiety is a useful synthetic precursor that has been extensively used for the preparation of 1,3 diols,¹ oxetanes,² furans,³ and polypropionate fragments⁴ (Figure 1). This functionality is usually prepared from the epoxidation of acyclic homoallylic alcohols using transition metal catalyzed oxidations,⁵ iodocarbonation methodologies⁶ or peroxy acid conditions.⁷ These substrate-controlled approaches have shown good to excellent syn/anti diastereoselectivities, depending on the cis/trans double bond geometry, the directing influence of the C1 hydroxy and the stereochemical disposition of the C2 methyl group.

Figure 1.

Preparation and common transformations of 3,4-epoxy alcohols

In contrast to the epoxidation of allylic alcohols, the enantioselective epoxidation of acyclic homoallylic alcohols to produce chiral 3,4-epoxy alcohols has been more difficult. Methods employing metal catalysts⁸ and organocatalysis⁹ have been explored. Despite the advances in this field, there are no truly general methods for the efficient enantioselective epoxidation of homoallylic alcohols. Moreover, homoallylic alcohols that contain chiral centers are susceptible to kinetic resolution, as found for the vanadium-catalyzed asymmetric epoxidation conditions.8a,b This feature, which has been used as an advantage, entails the inherent limitation of a 50% maximum product yield. Therefore, substrate-controlled methodologies for the stereoselective epoxidation of homoallylic alcohols continue to be a practical approach for the preparation of chiral 3,4-epoxy alcohols (Scheme 1).¹⁰

Scheme 1.

Substrate-controlled C2-syn/anti selectivity in the epoxidation of 2-methyl homoallylic alcohols

The vanadium-catalyzed epoxidation reaction (VO(acac)₂/t-butyl hydroperoxide) has become a very popular procedure for the stereoselective epoxidation of acyclic homoallylic alcohols.⁵ This reaction works well for cis and terminal homoallylic alcohols, favoring the C2-anti epoxide 3 (1,2-relative asymmetric induction), whereas poor stereoselectivities are observed with trans alkenols. The improved diastereoselectivity obtained for cis homoallylic alcohols is rationalized by the vanadium “chair-like” cyclic transition state model proposed by Mihelich that minimizes the syn-pentane repulsion between the C2 and allylic methyl groups. The poor selectivity observed for the trans systems is due to the formation of a competing boat-like transition state.^5,11

Different from the C2-anti pathway, the stereoselective C2-syn epoxidation of cis- or trans-2-methyl-1-homoallylic alcohols has been more challenging and fewer practical methods have been reported. Yamagushi and coworkers obtained 1,2-syn-selectivity for cis homoallylic alkenols after protecting the secondary alcohol with a bulky non-coordinating TIPS group using a tungsten-based epoxidizing complex.^5c Guanti and coworkers reported the C2-syn epoxidation of chemoenzymatically generated ⌠-symmetric chiral cis homoallylic diols using m-CPBA or VO(acac)₂/TBHP.^5b,11b Since both hydroxy groups were primary, the application of a 3–4 steps protecting group manipulation protocol was required prior to the epoxidation reaction. In both studies, trans alkenols showed to be poor substrates. To circumvent this limitation, Sato and collaborators introduced a removable TMS group at the C3 epoxide carbon to generate a trisubstituted Z-alkene substrate. This modification provided high 1,2-syn selectivity in the VO(acac)₂/TBHP epoxidation, that after the removal of the TMS group gave rise to the elusive trans epoxy alcohols.^4d

Recently, in studies related to the development of an epoxide-based methodology for polypropionate synthesis, we applied the VO(acac)₂ catalyzed epoxidation reaction to a series of hindered cis- and trans-2-methyl-3-alkenols using a microwave assisted procedure (MW).^5a In this study the reaction time for the epoxidation was dramatically reduced compared to the use of conventional heating (CH). Similar to the standard conditions, under MW irradiation, the cis homoallylic alkenols provided excellent C2-anti selectivities, while the trans systems showed a small C2-syn preference. This approach provided a series of diastereomeric 2-methyl-3,4-epoxy alcohols, where the C2-anti,cis-epoxides 3a-anti and 3c-anti were obtained as the only diastereomer, while both trans homoallylic alcohols produced the C2-syn epoxide 2d-syn and C2-anti epoxide 3b-anti with moderate diastereoselectivity (Figure 2). 2-Methyl-3,4-epoxy alcohols are useful precursors for polypropionate synthesis as their regioselective cleavage produces configurationally defined stereotetrads.^4c,6a,12 In fact, this methodology was successfully used in the synthesis of the all-anti C5–C10 fragment of streptovaricin U, starting from 3a-anti.^4a Unfortunately, this approach is not suitable for the stereoselective preparation of the complementary C2-syn epoxides 2a–c-syn and the anti epoxide 3d-anti.

Figure 2.

All possible diastereomeric C2-syn and C2-anti 2-methyl-3,4-epoxy alcohols

Herein, we present a second-generation approach for the diastereoselective preparation of syn-3,4-epoxy diols. This approach consists on the introduction of a primary hydroxy group at the 2-methyl carbon, providing a competing directing effect relative to the standard secondary C1 hydroxy group. Consequently, the diasteroselectivity of the vanadium-catalyzed epoxidation reaction is modified to achieve C2-syn diastereoselectivities, not previously attainable with the standard homoallylic alcohols.

2. Results and Discussion

The approach for the preparation of the second-generation C2-syn-3,4-epoxy diols 6a–d and their C2-anti counterparts 7a–d involved a sequence similar to that used for the preparation of epoxy alcohols 2 and 3,^5a except for the use of epoxides 4-cis and 4-trans as staring materials (Scheme 2). Having an additional directing hydroxy group at the C2 methyl group adds flexibility to the vanadium catalyzed epoxidation reaction. This primary hydroxy group is also homoallylic but chemically differentiable from the sterically hindered secondary alcohol at the C1 position. It was expected that the primary hydroxy group in alkene diols 5a–d should preferentially form the vanadate ester epoxidizing intermediate, instead of the secondary C1 hydroxy, thus altering the normal diastereoselectivity of the epoxidation reaction. This concept could be further expanded by the selective protection of the primary or secondary alcohols in 5a–d.

Scheme 2.

Second-generation epoxy diol-based approach for syn- and anti-3,4-epoxy alcohols

Protection of the C1 secondary alcohol would further enhance the diastereoselectivity provided by the primary alcohol. Conversely, selective protection of the primary alcohol should improve the natural diastereoselectivity of the secondary C1 alcohol by introducing additional steric factors. These modifications should provide access to complementary diastereoselectivities to yield C2-syn 6a–d or C2-anti 7a–d epoxides, some of which have not been stereoselectively available by earlier methodologies.

The starting epoxy alcohol 4-cis was prepared from the TIPS monoprotection of commercially available cis-buten-1,4-diol, followed by epoxidation of the resulting allylic alcohol with m-CPBA. Similarly, 4-trans was prepared from commercially available 2-butynyl-1,4-diol via its monoprotection, reduction with Red-Al and m-CPBA epoxidation. Epoxides 4-cis and 4-trans were also enantioselectively prepared using the Sharpless asymmetric epoxidation. Epoxide 4-cis and 4-trans were obtained in 81% (76% ee) and 73% (94% ee), respectively.

The anti,cis diol 5a was obtained in 66% yield from the regioselective cleavage of epoxy alcohol 4-cis using a copper-catalyzed cis-propenyl Grignard reaction, previously developed by our group.¹² The corresponding anti,trans homoallylic diol 5b was prepared in 77% yield by the regioselective epoxide ring opening of 4-cis using the diethylpropynylalanate conditions developed by Miyashita¹³ followed by the sodium/ammonia reduction of the resulting alkynol (Scheme 3). The synthesis of the free primary homoallylic alcohols 8a and 8b was achieved by the diprotection of 5a and 5b as the TBS ethers, followed by selective deprotection of the primary TBS group. The selective TBS protection of the primary hydroxyl group in 5a and 5b produced 9a and 9b, correspondingly.

Scheme 3.

Synthesis of alkenols 5a,b, 8a,b and 9a,b

The application of the copper-catalyzed Grignard conditions on 4-trans produced the syn,cis homoallylic alcohol 5c in 88% yield. Propynyl alane cleavage of 4-trans, followed by trans reduction produced the syn,trans homoallylic alcohol 5d in 70% yield (Scheme 4). The TBS diprotection-deprotection sequence on 5c and 5d produced the free primary homoallylic alcohols 8c and 8d in 73% and 90% yield, respectively. The selective TBS protection of the primary alcohol in 5c and 5d produced alkenols 9c and 9d in 74% and 66% yield, correspondingly.

Scheme 4.

Synthesis of alkenols 5c,d, 8c,d and 9c,d

Having the cis- and trans-homoallylic bis-diols 5a–d on hand, a study on their epoxidation was undertaken. Although it is known that trans alkenols do not provide good diastereoselectivity for this reaction, being the trans diols 5b and 5d atypical substrates, they were also included in the study. To assess the best conditions in terms of reaction time, yield and diastereoselectivity, diols 5a–d were submitted to the VO(acac)₂ catalyzed epoxidation reaction at rt, with conventional heating (CH) and the microwave (MW) assisted conditions. While it was expected that the reaction would proceed faster with heating, we were also interested in exploring differences in diastereoselectivity under the rt conditions. In general, the diastereoselectivities were not affected by the conditions, even though the reaction at rt required longer reaction times (36 h–7 d) and produced lower yields. Under the CH and MW conditions, the reaction time was significantly reduced to less than 30 min in most cases. The MW assisted conditions gave the shortest reaction completion times, thus these were the conditions of choice. The epoxidation of the anti,cis-alkenediol 5a gave moderate diastereoselectivity favoring the C2-syn epoxide 10a-syn (Table 1, entry 1). Epoxidation of the syn,cis-diol 5c provided the syn,syn,cis-epoxide 10c-syn with the best C2-syn selectivity (84:16), although in a disappointingly low yield (entry 3). Whereas, the anti,trans-alkenediol 5b showed no selectivity (entry 5), the syn,trans-diol 5d showed a moderate 65:35 C2-syn selectivity favoring epoxide 10d-syn in 10 minutes (entry 7). This result is comparable to the first generation-methodology, which provided the structurally related epoxy alcohols 2d-syn in 3 h with a similar stereoselectivity. Even though the VO(acac)₂ catalyzed epoxidation of the free diols 5a–d provided variable diastereoselectivities, it is remarkable that the C2-syn selectivity was favored in all cases, regardless of the alkene geometry or the relative configuration of the C1 and C2 carbons. In these exploratory studies, epoxides 10a-syn, 10c-syn and 10d-syn were obtained as the mayor products. These 3,4-epoxy alcohols cannot be prepared diastereoselectively by the standard first-generation homoallylic alcohol substrates.

Table 1.

Diastereoselectivity of the epoxidation of homoallylic 1,3-diols 5a–d

entry	alkenol	conditionsa	C2-synproduct R = TIPS	C2- syn/anti selectivityb	% yield
1	5a	VO(acac)2		59:41	65
2	5a	mCPBA		30:70	88c
3	5c	VO(acac)2		84:16	25
4	5c	mCPBA		34:66	100c
5	5b	VO(acac)2		52:48	60d
6	5b	mCPBA		63:37	88
7	5d	VO(acac)2		65:35	68

^aVO(acac)₂ (1.4 mol%) in a 0.08M alkenol soln in toluene under MW or mCPBA, NaHCO₃ in DCM at rt.

^bDetermined by ¹H NMR spectroscopy.

^cCrude yield.

^d14% of the furan product was also obtained.

Having prepared the free epoxy diols 5a–d, it gave us the opportunity to also explore the reaction of these second-generation homoallylic alkene diol with mCPBA. Although this epoxidation reagent usually gives poor to moderate anti diastereoselectivities on aliphatic epoxy alcohols, it has shown excellent C2-anti selectivity in some sterically hindered systems.^5b,7d,e,11 Thus, the epoxidation of 5a and 5c with mCPBA provided an approximately 2:1 C2-anti:C2-syn selectivity (entries 2 and 4). Interestingly, a 63:37 C2-syn selectivity was observed for epoxy alcohol 5b (entry 6).

To gain insight into the discrimination of the vanadium catalyst between the primary and secondary homoallylic alcohols in the relatively hindered diols 5a–d, we performed a semi-empirical calculation on the exchange reaction between the epoxy alcohols and the vanadium catalyst (Table 2).¹⁴ The formation of a vanadate ester is well precedented and represents the first step in the mechanism of the vanadium epoxidation proposed by Sharpless.¹⁵ For the four systems, the vanadium complex formed from the primary homoallylic alcohol is energetically favored over the secondary hydroxy, ranging from 4.5 kcal/mol for system 5c to 20.8 kcal/mol in 5b. These energy differences confirm that the initial vanadate ester complex is formed with the primary alcohol, discarding competition from the secondary alcohols. These results imply that the free primary alcohol solely controls the diastereoselectivity of the epoxidation reaction producing the inverted C2-syn selectivity.

Table 2.

Differences in calculated ΔH_f between the primary and secondary vanadium ester complexes

entry	alkene diol	ΔE (kcal/mol) a,b
1	5a	11.0
2	5b	20.8
3	5c	4.5
4	5d	12.6

^aSemi-empirical PM3 method (ref. ¹⁴).

^bThe primary vanadate ester was more stable in all cases.

After exploring the reactivity and diastereoselectivity of the VO(acac)₂ catalyzed epoxidation of the unprotected homoallylic alkene diols and establishing a bias towards the elusive C2-syn selectivity, we turned to the TBS monoprotected homoallylic alcohol derivatives employing the MW conditions (Table 3). The monoprotected alkenols 8a–d, which have a free primary alcohol, were subjected to the VO(acac)₂ catalyzed epoxidation conditions. These systems showed somewhat shorter reaction times and overall better yields than the free diols 5. This time, the cis homoallylic alkenols showed excellent diastereoselectivities. Thus, cis alkenols 8a and 8c exclusively produced epoxides 11a-syn and 11c-syn (entries 1 and 3). Interestingly, the epoxidation of trans alkenol 8b favored epoxide 11b-syn in a much better 70:30 syn/anti ratio and 90% yield (entry 5), when compared to the free alkene diol 5b (Table 1, entry 5). Epoxides 11a-syn, 11b-syn and 11c-syn correspond to the C2-syn diastereoisomers not accessible by the first-generation VO(acac)₂ catalyzed epoxidations. As an exception, and different from the free diol precursor 5d, the trans alkenol 8d showed a lack of diastereoselectivity (entry 7). This is the only free primary alcohol system that does not favor the C2-syn selectivity. Because the trans alkenediol 5b showed a 63:37 preference for the C2-syn epoxide product under the mCPBA conditions (Table 1, entry 6), we subjected its monoprotected derivative 8b to the same procedure. Gratifyingly, a 90:10 diastereoselectivity was obtained favoring 11b-syn, in a 68% yield (entry 6). This is a significant outcome as we have efficiently generated a C2-syn epoxide product starting from a trans alkenol using the mCPBA conditions that typically favor the anti products. Compound 11b-syn has the required C1–C4 and C12–C15 configuration of the lankanolide polypropionate chain.¹⁶

Table 3.

Stereoselectivity of epoxidation of monoprotected homoallylic 1,3-diols 8 and 9

entry	alkenola	major product R = TIPS	C2-syn/anti selectivityb	% yieldc
1	8a		>95:5d	55e
2	9a		<5:95d	80
3	8c		>95:5d	72f
4	9c		17:83	57
5	8b		70:30	90
6	8bg		90:10	68h
7	8d		58:42	89

^aVO(acac)₂ (1.4 mol%) in a 0.08M alkenol soln in toluene under MW (except for entry 6).

^bDetermined by ¹H NMR spectroscopy.

^c% isolated product.

^dOnly one isomer was observed by NMR analysis.

^e13% of an oxetane product was obtained.

^fCH heating, 27% of an oxetane product was obtained.

^gmCPBA, NaHCO₃ in DCM at rt.

^h6% of an oxetane product was obtained.

Homoallylic alkenols 9a–d, which have a free secondary alcohol at C1, analogous to our first-generation alkenol substrates 1,^5a were also studied. As expected, these secondary alcohols exhibited diastereoselectivities very similar to those previously obtained for the first-generation alkenols 1. The epoxidation of the cis homoallylic alcohols 9a and 9c produced the expected C2-anti epoxides 12a-anti and 12c-anti (entries 2 and 4) with excellent and good diastereoselectivities (>95:5 and 81:17), respectively. The trans alkenols 9b and 9d provided the C2-anti epoxides 12b-anti and 12d-anti in an approximately 2:1 ratio, similar to the epoxides 3b-anti a 3d-anti (see supporting information). These monoprotected homoallylic alkene diols do not present an advantage for the vanadium catalyzed epoxidation reaction when compared to the first generation alkenols 1.

The syn/anti stereoselectivity of the epoxy alcohols products was established by ¹³C NMR following the tendencies found on the previously reported characterization data for the first-generation epoxides 2 and 3, using the diagnostic C3 and C4 epoxide carbons.^5a For the trans-2-alkoxymethyl-3,4-epoxy alcohols, when an anti 2-alkoxymethyl-3,4-epoxy relationship is present (C2-anti), the epoxide C3 and C4 carbons show signals near 59 and 53 ppm (Δ ~ 5.0 ppm), while a C2-syn relationship displays slightly higher chemical shifts near 59 and 55 ppm (Δ ~ 3.4 ppm). For the cis epoxides, a C2-syn, relationship showed signals around 56 ppm and 53 ppm (Δ ~ 3.0 ppm), while the epoxides with an anti relationship show signals near 56 ppm and 52 ppm (Δ ~ 3.5 ppm). While these differences seem to be small, they show consistency for the studied diastereomeric series.

In addition to providing access to new 3,4-epoxyalcohol diastereomers, the new primary hydroxy offers a new dimension in terms of potential usefulness and flexibility, as it can be used for further synthetic manipulations or even become part of the target molecule. For example, the hydroxy group can control the regioselectivity of the epoxide cleavage by assisting the entering organometallic nucleophile.¹² The hydroxy group can also become part of the target molecule. For example, the streptovaricin D ansa chain has a functionalized methyl group at C10¹⁷ and scytophycin E has a hydroxymethyl group at C26.¹⁸ Finally, if the hydroxy group is not further required after exploiting its function, as in the lankanolide polypropionate chain,¹⁶ it can be removed at any step by tosylation-hydride reduction.^4c These targets are part of our current synthetic interests.

3. Conclusion

The VO(acac)₂ catalyzed epoxidation of free and monoprotected homoallylic 1,3-diols was conducted in order to determine the C2-syn/C2-anti diastereoselectivity. This second-generation approach provided preparative access the 3,4-epoxy alcohol 10a-syn, 10b-syn, 10c-syn 11a-syn, 11b-syn, 11c-syn in moderate to excellent diastereoselectivities from cis and trans alkene diols. The trans epoxide 11b-syn was also obtained with high diastereoselectivity using mCPBA. These epoxy alcohol configurations were previously unattainable by standard homoallylic alcohol epoxidation procedures, opening the door for the elaboration of new target molecules, not accessible by the first-generation approach. This expansion converts our epoxide-based approach into a general preparative method for polypropionate synthesis regardless of the stereochemical requirements.

4. Experimental

4.1. General Experimental Details

All reactions were carried out under nitrogen. All solvents were dried and purified in an automated solvent purification system before use. All commercially available compounds were used as received. All reactions under MW irradiation were performed in a laboratory microwave system (115 °C, 150W max) equipped with an IR sensor. Compound 5c was prepared by a published procedure.¹ Unless otherwise noted, all products were purified by silica gel column chromatography and fully characterized by 1D and 2D (standard COSY and HMQC) NMR. ¹H NMR (300 or 500 MHz) and ¹³C NMR (75 or 125 MHz) spectra were obtained as solutions in deuterochloroform. NMR chemical shifts (δ) are given in ppm relative to TMS and coupling constants (J) in Hz. Elemental analyses were done by a commercial analytical laboratory.

4.2. General Procedure for the VO(acac)₂ catalyzed epoxidation reaction

VO(acac)₂ (0.014 equiv) was added to a reaction flask followed by toluene (≈ 0.08 M solution), the alkenol (0.24 mmol), and TBHP (1.1 equiv, 3.80 M in toluene). The reaction was carried out at rt, CH (reflux) or MW irradiation (113 °C, 150 W max). The reaction was followed by TLC. Saturated aqueous Na₂S₂O₃ was added and the mixture was extracted with hexane (3×). The combined organic phase was dried over anhyd MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (2:1 or 50:3 hexane/ethyl acetate).

4.3. (±)-(2S*,3R*)-2-((2R*,3S*)-3-methyloxiran-2-yl)-4-(triisopropylsilyloxy)butane-1,3-diol (10a-syn and 10a-anti)

¹H NMR δ 3.95 (m, J = 12.0, 9.2 Hz, 1H), 3.94 (m, J = 10.0, 7.6, 3.7 Hz, 1H), 3.90 (dd, J = 12.0, 6.0 Hz, 1H), 3.78 (dd, J = 9.5, 3.0 Hz, 1H), 3.71 (dd, J = 9.5, 7.6 Hz, 1H), 3.21 (dd, J = 9.6, 3.6 Hz, 1H), 3.16 (dq, J = 4.6, 3.6 Hz, 1H), 2.77 (s, 1H), 2.41 (s, 1H), 1.66 (dddd, J = 10.0, 9.6, 9.2, 6.0 Hz, 1H), 1.31 (d, J = 5.4 Hz, 3H), 1.07 (m, 21H). ¹³C NMR δ 72.2, 65.3, 63.4, 56.1, 53.2, 40.5, 17.9, 13.9, 11.8. Anal. Calcd for C₁₆H₃₄O₄Si: C, 60.33; H, 10.76. Found: C 59.98; H, 10.80. Spectral data for the minor isomer (±)-(2S*,3R*)-2-((2S*,3R*)-3-methyloxiran-2-yl)-4-(triisopropylsilyloxy)butane-1,3-diol (10a-anti): ¹H NMR δ 4.12 (ddd, J = 9.0, 4.5, 3.7 Hz, 1H), 3.93 (dd, J = 10.3, 9.0 Hz, 1H), 3.87 (dd, J = 11.4, 1.0 Hz, 1H), 3.81 (dd, J = 11.4, 1.7 Hz, 1H), 3.78 (dd, J = 10.3, 3.7 Hz, 1H), 3.21 (dd, J = 9.1, 3.9 Hz, 1H), 3.11 (dq, J = 5.4, 3.9 Hz, 1H), 3.02 (s, 1H), 2.86 (s, 1H), 1.55 (dddd, J = 9.1, 4.5, 1.7, 1.0 Hz, 1H), 1.31 (d, J = 5.4 Hz, 3H), 1.07 (m, 21H). ¹³C NMR δ 74.2, 65.7, 62.7, 54.6, 51.9, 41.7, 17.9, 13.5, 11.9.

4.4. (±)-(2S*,3R*)-2-((2R*,3R*)-3-methyloxiran-2-yl)-4-(triisopropylsilyloxy)butane-1,3-diol (10b-syn and 10b-anti)

¹H NMR δ 3.97 (ddd, J = 7.3, 5.0, 5.0 Hz, 1H), 3.85 (d, J = 10.0 Hz, 2H), 3.78 (dd, J = 10.0, 5.0 Hz, 1H), 3.73 (dd, J =10.0, 7.3 Hz, 1H), 2.98 (dd, J = 7.4, 2.2 Hz, 1H), 2.93 (dq, J = 5.2, 2.2 Hz, 1H), 1.58 (dddd, J = 7.4, 6.5, 5.0, 2.5 Hz, 1H), 1.33 (d, J = 5.2 Hz, 3H), 1.07 (m, 21H). ¹³C NMR δ 72.4, 65.4, 62.6, 58.3, 54.7, 44.7, 17.9, 17.5, 11.8. Anal. Calcd for C₁₆H₃₄O₄Si: C, 60.33; H, 10.76. Found: C 60.30; H, 10.74. Spectral data for the minor isomer (±)-(2S*,3R*)-2-((2S*,3S*)-3-methyloxiran-2-yl)-4-(triisopropylsilyloxy)butane-1,3-diol (10a-anti): ¹H NMR δ 3.97 (m 1H), 3.85 (m, 2H), 3.85 (m, 2H), 2.99 (dd, J = 7.3, 2.2 Hz, 1H), 2.92 (m, 1H), 1.48 (m, 1H), 1.33 (d, J = 5.2 Hz, 3H), 1.08 (m, 21H). ¹³C NMR δ 73.4, 65.7, 62.9, 57.9, 53.4, 45.6, 17.9, 17.5, 11.8. Anal. Calcd for C₁₆H₃₄O₄Si: C, 60.33; H, 10.76. Found: C 60.13; H, 10.66.

4.5. (±)-(2R*,3R*)-2-((2S*,3R*)-3-methyloxiran-2-yl)-4-(triisopropylsilyloxy)butane-1,3-diol (10c-syn and 10c-anti)

¹H NMR δ 4.04 (dd, J = 11.8, 3.5 Hz, 1H), 3.95 (dd, J = 11.8, 5.0 Hz, 1H), 3.87 (ddd, J = 8.7, 6.0, 4.1 Hz, 1H), 3.79 (dd, J = 9.9, 4.1 Hz, 1H), 3.66 (dd, J = 9.9, 8.7 Hz, 1H), 3.14 (dq, J = 5.5, 4.0 Hz, 1H), 3.04 (dd, J = 9.7, 4.0 Hz, 1H), 3.01 (d, J = 3.22 Hz, 1H), 1.59 (dddd, J = 9.7, 6.0, 5.0, 3.5 Hz, 1H), 1.30 (d, J = 5.5 Hz, 3H), 1.07 (m, 21H). ¹³C NMR δ 72.9, 65.8, 62.6, 53.1, 53.0, 40.6, 17.9, 13.7, 11.9. Spectral data for the minor isomer (±)-(2R*,3R*)-2-((2R*,3S*)-3-methyloxiran-2-yl)-4-(triisopropylsilyloxy)butane-1,3-diol (10c-anti): ¹H NMR δ 4.04 (ddd, J = 8.8, 5.0, 4.0 Hz, 1H), 3.97 (dd, J = 10.2, 4.0 Hz, 1H), 3.83 (dd, J = 10.0, 4.0 Hz, 1H), 3.82 (dd, J = 10.2, 3.0 Hz, 1H), 3.69 (dd, J = 10.0, 8.8 Hz, 1H), 3.10 (d, J = 3.6 Hz, 1H), 3.04 (dq, J = 5.5, 4.0 Hz, 1H), 3.93 (dd, J = 9.5, 4.0 Hz, 1H), 1.55 (dddd, J = 9.5, 5.0, 4.0, 3.0 Hz, 1H), 1.32 (d, J = 5.5 Hz, 3H), 1.07 (m, 21H). ¹³C NMR δ 74.6, 66.0, 62.4, 55.7, 52.3, 41.8, 17.9, 13.5, 11.9.

4.6. (±)-(2R*,3R*)-2-((2S*,3S*)-3-methyloxiran-2-yl)-4-(triisopropylsilyloxy)butane-1,3-diol (10d-syn and 10d-anti)

¹H NMR δ 3.96 (dd, J = 11.0, 3.7 Hz, 2H), 3.88 (ddd, J = 7.8, 5.0, 4.0 Hz, 1H), 3.84 (dd, J = 11.0, 6.0 Hz, 1H), 3.82 (dd, J =10.0, 4.0 Hz, 1H), 3.69 (dd, J =10.0, 7.8 Hz, 1H), 2.92 (dq, J = 5.1, 2.0 Hz, 1H), 2.76 (dd, J = 5.2, 2.0 Hz, 1H), 1.56 (dddd, J = 6.0, 5.2, 5.0, 3.7 Hz, 1H), 1.32 (dd, J = 5.1, 1.3 Hz, 3H), 1.08 (m, 21H). ¹³C NMR δ 72.2, 65.8, 62.0, 58.5, 54.3, 44.8, 17.9, 17.5, 11.8. Anal. Calcd for C₁₆H₃₄O₄Si: C, 60.33; H, 10.76. Spectral data for the minor isomer (±)-(2R*,3R*)-2-((2R*,3R*)-3- methyloxiran-2-yl)-4-(triisopropylsilyloxy)butane-1,3-diol (10d-anti): ¹H NMR δ 3.95 (m, 2H), 3.88- 3.80 (m, 3H), 2.92 (m, 1H), 2.75 (m, 1H), 1.45 (m, 1H), 1.29 (d, J = 5.0 Hz, 3H), 1.08 (m, 21H). ¹³C NMR δ 73.6, 66.0, 62.1, 58.9, 53.8, 45.8, 17.9, 17.5, 11.8.

4.7. (±)-(2R*,3R*)-2-((2R,3S)-3-methyloxiran-2-yl)-3-(t-butyldimethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol (11a-syn)

¹H NMR δ 4.02 (ddd, J = 10.6, 6.3, 3.4 Hz, 1H), 3.87 (ddd, J = 8.5, 4.2, 4.0 Hz, 1H), 3.80 (ddd, J = 10.0, 5.5, 4.2 Hz, 1H), 3.69 (dd, J = 10.0, 4.2 Hz, 1H), 3.62 (dd, J = 10.0, 8.6 Hz, 1H), 3.17 (dd, J = 9.5, 4.3 Hz, 1H), 3.11 (dq, J = 5.7, 4.3 Hz, 1H), 2.62 (dd, J = 3.4, 4.2 Hz, 1H), 1.91 (dddd, J = 9.5, 6.5, 5.5, 4.0 Hz, 1H), 1.34 (dd, J = 5.4, 1.1 Hz, 3H), 1.07 (m, 21H) 0.9 (s, 9H), 0.09 (s, 6H). ¹³C NMR δ 72.9, 65.6, 63.8, 56.7, 53.0, 41.6, 25.8, 18.0, 14.0, 11.9, −4.9. Anal. Calcd for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 61.08; H, 11.34.

4.8. (+)-(2R,3R)-2-((2R,3R)-3-methyloxiran-2-yl)-3-(t-butyldimethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol (11b-syn)

¹H NMR δ 3.96 (dd, J = 7.0, 6.2 Hz, 1H), 3.93 (ddd, J = 8.7, 5.5, 5.0 Hz, 1H), 3.77 (dd, J = 7.0, 3.6 Hz, 1H), 3.72 (dd, J = 9.8, 5.0 Hz, 1H), 3.60 (dd, J = 9.8, 8.7 Hz, 1H), 2.91 (dq, J = 5.2, 2.1 Hz, 1H), 2.83 (dd, J = 8.5, 2.1 Hz, 1H), 2.34 (q, J = 3.8 Hz, 1H), 1.73 (dddd, J = 8.5, 6.2, 5.5, 3.6 Hz, 1H), 1.32 (d, J = 5.3 Hz, 3H), 1.05 (m, 21H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H). ¹³C NMR δ 72.4, 65.2, 63.3, 58.6, 54.3, 46.2, 25.9, 17.9, 17.5, 11.9, −4.3, −5.0. Anal. Calcd for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 61.27; H, 11.27. [α]²⁰_D = +17.0, c = 1.00, CHCl₃.

4.9. (+)-(2R,3R)-2-((2R,3R)-3-methyloxiran-2-yl)-3-(t-butyldimethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol (11b-anti)

¹H NMR δ 3.97 (m, 1H), 3.78 (m, 1H), 3.76 (m, 1H), 3.73 (dd, J = 13.0, 6.2 Hz, 1H), 3.66 (dd, J = 13.0, 7.2 Hz, 1H), 2.98 (dq, J = 5.2, 2.3 Hz, 1H), 2.89 (dd, J = 6.9, 2.4 Hz, 1H), 2.70 (q, J = 4.21 Hz, 1H), 1.96 (m, 1H), 1.31 (d, J = 5.2 Hz, 3H), 1.06 (m, 21H) 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). ¹³C NMR δ 73.2, 65.5, 61.4, 58.2, 53.0, 46.1, 25.8, 17.9, 17.6, 11.9, −4.3, −5.1. Anal. Calcd for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 60.77; H, 11.00.

4.10. (±)-(2S*,3R*)-2-((2S*,3R*)-3-methyloxiran-2-yl)-3-(t-butyldimethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol (11c-syn)

¹H NMR δ 4.09 (dd, J = 10.3, 3.6 Hz, 1H), 3.92 (ddd, J = 8.6, 5.4, 2.5 Hz, 1H), 3.89 (dd, J = 10.3, 2.5 Hz, 1H), 3.73 (dd, J = 9.9, 8.6 Hz, 1H), 3.69 (dd, J = 9.9, 5.4 Hz, 1H), 3.29 (dd, J = 9.7, 4.2 Hz, 1H), 3.14 (dq, J = 5.5, 4.2 Hz, 1H), 2.90 (d, J = 8.9 Hz, 1H), 1.78 (dddd, J = 9.7, 3.6, 2.5, 2.5 Hz, 1H), 1.31 (d, J = 5.4 Hz, 3H), 1.07 (m, 21H) 0.9 (s, 9H), 0.09 (s, 6H). ¹³C NMR δ 74.4, 64.6, 61.2, 56.9, 52.6, 40.0, 25.7, 18.0, 13.5, 11.8, −4.4 and −5.1. Anal. Calcd for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 60.97; H, 11.37.

4.11. (±)-(2S*,3R*)-2-((2R*,3R*)-3-methyloxiran-2-yl)-3-(t-butyldimethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol (11d-anti and 11d-syn)

¹H NMR δ 3.98 (dd, J = 11.4, 3.9 Hz, 1H), 3.95 (ddd, J = 7.7, 6.8, 5.5 Hz, 1H), 3.83 (dd, J = 11.4, 4.0 Hz, 1H), 3.72 (dd, J = 11.7, 3.8 Hz, 1H), 3.70 (dd, J = 11.7, 5.5 Hz, 1H), 3.0 (dd, J = 5.0, 1.5 Hz, 1H), 2.86 (dq, J = 5.0, 1.5 Hz, 1H), 1.59 (dddd, J = 7.7, 5.0, 4.0, 3.9 Hz, 1H), 1.34 (d, J = 5.0 Hz, 3H), 1.05 (m, 21H) 0.89 (s, 9H), 0.09 (s, 6H). ¹³C NMR δ 72.4, 64.8, 61.0, 59.4, 54.3, 45.5, 25.7, 17.9, 17.7, 11.9, 4.4, −5.1. Anal. Calcd for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 60.93; H, 11.03. Spectral data for the minor isomer (±)-(2S*,3R*)-2-((2S*,3S*)-3-methyloxiran-2-yl)-3-(t-butyldimethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol (11d-anti): ¹H NMR δ 4.12 (ddd, J = 6.0, 5.5, 2.0 Hz, 1H), 3.97 (dd, J = 11.5, 2.0 Hz, 1H), 3.75 (m, J = 11.7, 6.0 Hz, 1H), 3.73 (m, J = 11.5, 3.5 Hz, 1H), 3.72 (m, J = 11.7, 5.5 Hz, 1H), 3.17 (d, J = 7.9 Hz, 1H), 2.97 (m, J = 5.8, 2.0 Hz, 1H), 2.96 (m, J = 6.0, 2.0 Hz, 1H), 1.68 (m, J = 6.0, 3.5, 2.0, 2.0 Hz, 1H), 1.35 (dd, J = 5.8, 1.0 Hz, 3H), 1.05 (m, 21H) 0.89 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H). ¹³C NMR δ 73.9, 64.9, 60.6, 59.2, 55.0, 43.9, 25.8, 17.9, 17.8, 11.9, −4.4, −5.1. Anal. Calcd for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 61.01; H, 11.24.

4.12. (±)-(2R*,3S*,4S*,5R*)-4,5-Epoxy-3-(t-butyldimethylsilyloxymethyl)-1-(triisopropylsilyloxy)-2-hexanol (12a-anti)

¹H NMR δ 4.07 (ddd, J = 8.2, 3.9, 2.2 Hz, 1H), 3.91 (dd, J = 10.5, 8.3 Hz, 1H), 3.83 (dd, J = 10.0, 6.2 Hz, 1H), 3.80 (dd, J = 10.5, 3.9 Hz), 3.76 (dd, J = 10.0, 6.2 Hz, 1H), 3.11 (dd, J = 9.5, 4.2 Hz, 1H), 3.07 (dq, J = 5.7, 4.3 Hz, 1H, 1H), 2.91 (s, 1H), 1.65 (dddd, J = 9.4, 6.2, 6.1, 2.1 Hz, 1H), 1.32 (dd, J = 5.7, 1.7 Hz, 3H), 1.08 (m, 21H) 0.92 (s, 9H), 0.09 (s, 6H). ¹³C NMR δ 72.4, 65.8, 62.1, 55.2, 51.6, 41.7, 25.9, 17.9, 13.9, 11.9, −5.5. Anal. Calcd for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 61.33; H, 11.20.

4.13. (±)-(2R*,3R*,4R*,5S*)-4,5-Epoxy-3-(t-butyldimethylsilyloxymethyl)-1-(triisopropylsilyloxy)-2-hexanol (12c-anti and 12c-syn)

¹H NMR δ 3.94 (ddd, J = 8.8, 6.2, 4.0 Hz, 1H), 3.93 (dd, J = 11.2, 4.0 Hz, 1H), 3.89 (dd, J = 10.1, 5.6 Hz, 1H), 3.84 (dd, J = 10.1, 4.0 Hz, 1H), 3.71 (dd, J = 11.2, 8.8 Hz, 1H), 3.09 (dq, J = 5.3, 4.5 Hz, 1H), 2.98 (dd, J = 8.9, 4.4 Hz, 1H), 1.55 (dddd, J = 8.9, 6.2, 5.6, 4.0 Hz, 1H), 1.29 (d, J = 5.5 Hz, 3H), 1.07 (m, 21H) 0.89 (s, 9H), 0.07 (s, 6H). ¹³C NMR δ 71.9, 66.3, 61.5, 56.8, 52.6, 41.9, 25.9, 17.9, 13.9, 11.9, −5.5. Spectral data for the minor isomer (±)-(2R*,3R*,4S*,5R*)-4,5-Epoxy-3-(t-butyldimethylsilyloxymethyl)-1-(triisopropylsilyloxy)-2-hexanol (12c-syn): ¹H NMR δ 3.96-3.70 (m, 5H), 3.21 (dd, J = 9.8, 4.1 Hz, 1H), 3.17 (dq, J = 5.3, 4.9 Hz, 1H), 1.67 (m, 1H), 1.29 (d, J = 5.5 Hz, 3H), 1.07 (m, 21H), 0.89 (s, 9H), 0.07 (s, 6H). ¹³C NMR δ 72.7, 65.8, 62.2, 55.7, 53.5, 39.9, 25.9, 17.9, 13.5, 11.9, −5.5.

Supplementary Material

01. Supplementary data.

Experimental details with spectroscopic data and copies of ¹H and ¹³C NMR spectra for all new compounds. Supplementary data associated with this article can be found in the online version at doi: