Diastereoselective intramolecular aldol ring closures of threonine derivatives leading to densely functionalised pyroglutamates related to oxazolomycin

Abstract

Intramolecular aldol reactions on oxazolidine templates derived from threonine may be used to generate libraries of densely functionalised pyroglutamates with a high level of diastereoselectivity; the oxazolidine precursors themselves are suitable for further direct manipulation by side chain alkylation, permitting rapid access to cyclised products with several points of chemical diversity. Although these systems may be considered to be structural mimics of the functionalised pyroglutamate portion of oxazolomycin, little antibacterial activity against S. aureus and E. coli was found. These systems may additionally have application as three-dimensional fragments for drug discovery and development.

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We have been interested in the development of methodology for rapid access to highly functionalised pyrrolidinones of particular relevance to the oxazolomycins (Fig. 1)¹ and have established that Dieckmann² and aldol³ ring closures may be used to access such systems. While a number of other groups have developed methodology to provide the relevant lactam–lactone spirocyclic and inthomycin subsets of the natural product,^4–11 we have established that some smaller structural mimics exhibit antibacterial activity^12–14 and therefore sought routes providing rapid access to other skeletal subsets of oxazolomycin which might similarly provide antibacterially active libraries. We recently reported that a biomimetic intramolecular aldol reaction using malonamide 2 (R¹ = H, R² = H, X = OMe) derived from oxazolidine template 1 may be used to generate densely functionalised pyroglutamates of type 3, possessing two contiguous quaternary chiral centres.¹⁵ Of interest to us was the possibility of extending this approach further, and we report here its application to threonine derivatives using systems of type 2 (R¹ = Me) giving a general approach which might be used to access diversely substituted systems, which have potential as three-dimensional scaffolds for fragment based drug discovery programmes, possessing well-defined structure, the capacity for synthetic manipulation and a natural product heritage.

Fig. 1 Oxazolomycin and related compounds.

Our first task was to establish a sequence which provided access to oxazolidines of type 2 (Scheme 1) with a diversity of substitution patterns, and which would ultimately translate into multiple ring substitution patterns on pyroglutamate 3. Critical to the success of this strategy was the simultaneous development of a direct method for the preparation of γ-substituted β-ketoesters by elaboration of Meldrum's acid,¹⁶ substrates which are of particular interest due to their scope for further functionalisation; analogous ring openings on dioxinones have been recently reported.¹⁷ Starting from substituted acetyl chlorides 4a–d, conversion to the corresponding acylated Meldrum's acids 5a–d proceeded in excellent yield (Scheme 2) using methodology which has recently been reported.¹⁸ Further collapse of this system with t-butanol was very efficient, giving esters 6a–d. In order to demonstrate that such intermediates could be used to perform the desired ring closing aldol reaction, one of them (6a) was hydrolysed to acid 7 and converted to malonamide 8 by DCC coupling with oxazolidine 1. Furthermore, during the course of this work, we found that acyl Meldrum's acids 5b–d could be opened directly with oxazolidine 1 (R = H),^15,16,19,20 giving malonamides 9a–c very efficiently; these sequences provided access to variously substituted analogues replacing the methoxy group at the chain terminus of 8. We also expected that intermediates of type 6 would prove to be pivotal, since alkylation at either or both of the α- and γ-positions using standard conditions should be possible, providing access to diversely functionalised pyroglutamates after cyclisation. Thus, we found that successive treatment of 6a with one equivalent of each of NaH and BuLi followed by benzyl bromide gave derivative 10, which using the sequence outlined above, was readily converted to acid 11 and thence malonamide 12, which was used without further purification. Furthermore, reaction of 6a–d with t-BuOK followed by methyl iodide was found to give α-methyl adducts 13a–d in very good yield (Scheme 2). Conversion to the acids 14a–d and then to the epimeric malonamides 15a–d and 15a′–d′ proved to be less efficient than some of the earlier examples, but gave sufficient material for further investigation; these compounds were obtained as an epimeric mixture at the side chain methyl group, whose ring stereochemistry could be assigned by nOe analysis, for which enhancements between syn-related groups on each side of the ring were easily detected (Fig. 2). That this sequence could be used to access even more hindered systems was shown by converting α-methyl 13a to α-methyl γ-benzyl adduct 16, followed by further conversion as before to acid 17 and thence malonamide 18 as a mixture of diastereomers which were used without separation. We also found that ester 6d could be similarly manipulated (Scheme 3), and base treatment followed by reaction with allyl bromide or benzyl bromide efficiently gave α-alkyl adducts 19a,b in very good yield (Scheme 3), which could be converted as earlier to acids 20a,b and malonamides 21a,b as a diastereomeric mixture. These routes very efficiently provided the necessary malonamide substrates with a variety of substitution patterns, ready for investigation of the key aldol ring closure.

Scheme 1

Scheme 2

Fig. 2 nOe interactions for selected cyclisation precursors.

Scheme 3

For the aldol cyclisation, we quickly found that treatment of 8 with NaOMe gave the desired product 22a in 22% yield as a single diastereomer (Scheme 4), whose stereochemistry was assigned by nOe analysis (Fig. 3); however, this assignment proved to be more difficult than anticipated, and a detailed discussion of the approach is given below. Although the yield was not high, the outcome is remarkable since three contiguous chiral centres, one tertiary and two quaternary, were assembled in this single step. Malonamides 9a–c behaved similarly, giving pyroglutamates 22b–d in isolated yields of 30–46%, along with significant amounts of readily separated unreacted starting material. When this process was applied to the more elaborate malonamides 12, 15a and 18, which differ from 22a by successive increases in substitution at the γ- and α-positions, pyroglutamates 22e, f and j were readily obtained, again as single diastereomers at the bicyclic ring substituents (although 22j was obtained as an epimeric mixture at the benzylic side chain position), albeit in yields of 6, 21 and 14%; these low yields are most likely to be due to the additional steric requirements of the ring closure along with the diastereomeric mixture of starting oxazolidine, but this outcome, giving up to 4 contiguous chiral centres under such mild conditions, is nonetheless remarkable. This approach could be similarly applied to 15b–d and 21a,b, all with more bulky groups at one or other of the γ- and α-positions, to afford products 22g–i and 22k,l in variable yield and as single stereoisomers, the stereochemistry of which was again established by nOe analysis (Fig. 3); as before, this was not straightforward and a detailed discussion of the assignment is given below. The yield of products 22g–i was particularly good, and this may be the result of a favourable Thorpe–Ingold effect which enhances the ring closure. Investigation of the ring closure conditions for 22b indicated that a reaction temperature of 30 °C with a time of 24 h gave best yields (46%), while higher or lower temperature or longer times only gave worse outcomes. Of interest is that the chemical shifts of C(2)H, C(4)H, C(4)Me in the ¹H NMR spectra of 22a–l were remarkably consistent, with typical values of 5.03 ± 0.03, 4.77 ± 0.06, and 1.60 ± 0.07, suggesting a rigid structure with conservation of the indicated stereochemistry across the compound series. Moreover, C(7)H_endo and C(7)H_exo appeared at 3.0–3.3 and 2.4 respectively, consistent with the conserved C(7)Me_endo stereochemistry for compounds 22g–l. This preference for the C(7)Me_endo isomer presumably reflects the thermodynamic stability achieved by placing this methyl group opposite to the bulky C(6)alkyl substituent. This outcome suggests a preference for a transition state of type A rather than type B in the aldol ring closure (Fig. 4), in which steric interactions involving the terminal functional group of the malonamide side chain are minimized, although it is not clear whether the final stereochemistry at C(7) arises during the ring closure, or from post-cyclisation equilibration. In terms of natural product synthesis, the formation of up to 4 contiguous chiral centres, two of which were tertiary and two quaternary, with excellent diastereocontrol, as well as the capacity to readily vary the substituent pattern, is noteworthy; the relative stereochemistry of these compounds is correct for 16-methyloxazolomycin.

Scheme 4

Fig. 3 nOe interactions for selected cyclised compounds.

Fig. 4 Transition state model for cyclisation.

As noted above, the stereochemical assignment of these systems by nOe analysis proved not to be fully straightforward, despite the rigid bicyclic system which has normally been instrumental in providing the capacity to readily assign the product stereochemistry using this approach.² For example, for 22f, the stereochemistry of the oxazolidine ring was readily confirmed by the presence of enhancements between C(2)H and C(4)Me, both known to be syn-related on the N-acyl-oxazolidine (Fig. 3). The methyl ester was confirmed to be on the exo face through an enhancement to the C(2)tBu, and an enhancement between C(2)H and C(7)Me indicated that the C(7)Me group also occupied the endo face. The C(6)OH showed an enhancement to C(7)Me, indicating it had an endo position. However, the C(1′)H₂ unexpectedly showed enhancements to C(7)Me, C(7)H and C(4)Me (shown in red in Fig. 3). A similar pattern was also observed in the pyroglutamate 22a with enhancements between C(1′)H₂ and endo-C(7)H, exo-C(7)H, CO₂Me and C(4)Me. Since these signals did not appear to be consistent with either epimer, an examination of the energy minimised conformer of 22a was undertaken that this suggested that the distance between C(4)Me and the closest C(1′Me)H could be as low as 3.25 Å. Similar unexpected enhancements for pyroglutamates 22b and 22c were also observed (Fig. 3, indicated in red), suggesting functional group proximity in these sterically congested systems, leading to unexpected nOe effects.

Fortunately, compounds 22a, 22c, 22f, 22h, 22i, 22j and 22j′ were crystalline, and single crystal X-ray analyses allowed unambiguous confirmation of their structure and stereochemistry (Fig. 5).²¹ Importantly, the stereochemistry of C(6) with OH in the endo position and the CH₂OMe in the exo position was observed in all cases. Additionally, the C(4)Me–C(1′)H₂ internuclear distances were between 2.35 and 2.75 Å, and the dihedral angles between C(6)CH₂ and C(7)H and C(7)Me for 22i, for example, were 55° and 76° respectively, meaning that the C(6)R groups effectively bisect the C(7) substituents. All compounds showed the same short internuclear distance between the C(4)Me and the C(1′)H protons, and between all the C(7)H and C(6) substituents, explaining why the ring substituents are in sufficiently close proximity to produce nOe enhancements. This analysis also confirmed that the major and minor isomers 22j and 22j′ were epimeric at the C(1′) stereocentre, the major isomer having a 1′-S configuration, with the minor being 1′-R (Fig. 5).

Fig. 5 X-ray crystallographic structures for selected cyclised compounds.

The N-acyloxazolidines and pyroglutamates synthesised were assayed against S. aureus D267 and E. coli X580 using the hole-plate method,²² and the data is shown in Table 1. This phenotypic assay is not able to accurately measure MIC values for active compounds, but does allow a simple active/inactive result on antibacterial activity to be obtained quickly and easily. N-Acyloxazolidines 12 and 9b were the only compounds displaying activity against Gram-positive S. aureus, with relative potencies of almost 10% relative to the cephalosporin C control. There were a number of active hits against Gram-negative E. coli, including four N-acyloxazolidines (15b, 15b′, 9b, 9c) and four pyroglutamates (22b, 22g, 22c, 22d) which showed inhibition zones against E. coli, though for compounds 22b and 22c this activity was weak. The relative potencies here are much smaller (0.03–0.04%) due to the higher sensitivity of E. coli to the reference compound cephalosporin C. Broth bioassays also identified three compounds with activity against H. influenza Hi4, 12, 22c, and 22h with MICs of 32, 64, and 16 μg mL⁻¹. We have recently demonstrated that the intrinsic antibacterial activity of simple pyroglutamates^23,24 and tetramates is low,²⁵ but that homologation with longer chain side-units restores some activity.^12,13,26 Against this background, it is perhaps not surprising then that antibacterial bioassay of a range of compounds prepared above did not show significant levels of activity, even though we have also shown that small changes such as the introduction of a methyl substituent improves bioactivity in simple tetramates.²⁷

Table 1 Bioassay results for N-acyloxazolidines and pyroglutamates

Compound number	R1	R2	S. aureus D267		E. coli X580
			Zone size (mm)	Rel. potency (Ceph C, %)	Zone size (mm)	Rel. potency (Ceph C, %)
8	H	CH2OMe	0	—	0	—
9a	H	Butenyl	0	—	0	—
9b	H	CH2C6H4Br	12.5	10.0%	12	0.04
9c	H	CH2SPh	0	—	13	0.04
12	H	CH(Bn)OMe	13	9.7%	0	—
15a	Me	CH2OMe	0	—	0	—
15b′	Me	Butenyl	0	—	12.5	0.03
15b	Me*	Butenyl	0	—	12	0.03
15c′	Me	CH2C6H4Br	0	—	0	—
15c	Me*	CH2C6H4Br	0	—	0	—
15d′	Me	CH2SPh	0	—	0	—
15d	Me*	CH2SPh	0	—	0	—
18	Me	CH(Bn)OMe	0	—	0	—
22a	H	CH2OMe	0	—	0	—
22b	H	Butenyl	0	—	12 (halo)	0.03
22c	H	CH2C6H4Br	0	—	12 (halo)	0.04
22d	H	CH2SPh	0	—	15	0.05
22e	H	CH(Bn)OMe	0	—	0	—
22f	Me	CH2OMe	0	—	0	—
22g	Me	Butenyl	0	—	14	0.04
22h	Me	CH2C6H4Br	0	—	0	—
22i	Me	CH2SPh	0	—	0	—
22j	Me	CH(Bn)OMe	0	—	0	—
22j′	Me	CH(Bn*)OMe	0	—	0	—

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In this work, we have shown that ring closing aldol reactions on a threonine-derived oxazolidine template, although not highly efficient in terms of chemical yield, nonetheless permits the rapid construction of diversely substituted diastereomerically pure pyroglutamates of relevance to the oxazolomycin series of natural products. However, it does not appear that this subunit is of itself responsible for significant levels of antibacterial bioactivity. This work is a significant expansion of the approach reported earlier using the corresponding serine template 2 (R¹ = H),¹⁵ since additional and bulky side chain groups at R² and X of template 2 are tolerated, even in the presence of a methyl group at R¹. Such fragments are of interest for their relevance as novel three-dimensional fragments with potential application in drug discovery; by side chain manipulation, they may permit rapid “escape from flatland”, which has been proposed to be beneficial for improved solubility and hydrophobicity and lower toxicity of drug discovery candidates.^28,29

Experimental

For general experimental procedures, see our earlier report.² Acid chloride 4d is commercially available.

General procedure A: acylation of Meldrum's acid

Pyridine (2.0 eq.) was added dropwise to a solution of Meldrum's acid (1.0 eq.) in DCM (10 mL mmol⁻¹ of Meldrum's acid) at −10 °C and the resulting mixture was stirred for 20 min. A solution of the required acid chloride (1.0 eq.) in DCM (0.5 mL mmol⁻¹ of acid chloride) was added dropwise and the resulting mixture was stirred for 1 h at −10 °C before being warmed to rt and stirred for a further 2 h. The mixture was quenched with 1 M HCl (1 mL mL⁻¹ DCM) and extracted with DCM (3×). The combined organic layers were washed with brine (50 mL), dried and concentrated in vacuo to give the crude product, which was used without further purification.

General procedure B: ring-opening/decarboxylation/esterification of Meldrum's acid derivatives

A solution of the Meldrum's acid derivative in 1 : 1 toluene–tBuOH (4 mL mmol⁻¹) was stirred at reflux for 2 h. The mixture was cooled to rt and concentrated in vacuo to give the crude product which was purified by column chromatography (petrol–EtOAc).

General procedure C: direct Meldrum opening with oxazolidine 1

The acylated Meldrum's acid (3.1 mmol) was dissolved in MeCN (15 mL) and oxazolidine 320/1 (2.8 mmol) in MeCN (8 mL) was added. The resulting mixture was stirred at 60 °C for 2 h and then concentrated in vacuo. Purification via column chromatography gave the product.

General procedure D: hydrolysis of β-keto-esters

A solution of the β-keto-ester in DCM (1 mL mmol⁻¹) was cooled to 0 °C and TFA (1 mL mmol⁻¹) was added dropwise. The solution was stirred for 3 h at rt before the solvent was removed in vacuo to give the β-keto-acid which was used without further purification.

General procedure E: synthesis of N-acyl-oxazolidines by amide coupling

A solution of oxazolidine 1 (1.0 eq.) in DCM (3 mL mmol⁻¹ of 1) was cooled to 0 °C before DCC (1.05 eq.) and DMAP (7 mol%) were added. A solution of the carboxylic acid (1.05 eq.) in DCM (1 mL mmol⁻¹ of acid) was added and the mixture was stirred at 0 °C for 15 min and then at rt for 3–5 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product mixture.

General procedure F: alkylation at the γ-position

A solution of β-keto-ester (1.0 eq.) in THF (2 mL mmol⁻¹) was added dropwise to a stirred suspension of NaH (1.0 eq.) in THF (10 mL mmol⁻¹). After stirring at 0 °C for 10 min, BuLi (1.6 M in hexanes, 1.05 eq.) was added dropwise. After a further 10 min at 0 °C, the stated alkylating agent (1.05 eq.) was added in one portion and the mixture allowed to warm to rt over 15 min. The mixture was quenched with 2 M HCl (5 mL) and extracted with Et₂O (2×). The combined organic layers were washed with H₂O until the aqueous layer remained neutral, dried and concentrated in vacuo to give the crude product which was purified by column chromatography (petrol–EtOAc).

General procedure G: alkylation of the α-position giving 13a–d

A solution of β-keto-ester in THF (10 mL mmol⁻¹) was cooled to 0 °C and tBuOK (1.05 eq.) was added. The mixture was then warmed to rt and stirred for 40 min before the addition of MeI (1.05 eq.). The mixture was stirred for a further 5 h at rt, after which time it was partitioned between Et₂O (1 mL mL⁻¹ THF) and brine (1 mL mL⁻¹ THF). The aqueous layer was extracted with Et₂O (2×) and the combined organic layers were dried and concentrated in vacuo to give the crude α-methyl-β-keto-ester which was purified by column chromatography (petrol–EtOAc).

General procedure H: aldol cyclisation of N-acyl-oxazolidines

NaOMe (1.1 eq.) was added portionwise to a stirred solution of N-acyl-oxazolidine (1.0 eq.) in MeOH (10 mL mmol⁻¹ of oxazolidine) and the resulting mixture was stirred at rt for 24 h. The mixture was partitioned between Et₂O (2 mL mL⁻¹ MeOH) and sat. aq. NH₄Cl (2 mL mL⁻¹ MeOH), and the aqueous layer was extracted with Et₂O (2×) before the combined organic layers were washed with brine (0.5 mL mL⁻¹ Et₂O), dried and concentrated in vacuo to give the crude product mixture.

Methoxyacetyl chloride 4a (ref. 30)

Methoxyacetic acid (8.5 mL, 110 mmol) was added dropwise to a flask of stirring thionyl chloride (24.2 mL, 332 mmol) and stirred at rt for 15 min. The mixture was then heated to reflux at 110 °C for 2 h, allowed to cool and then purified by distillation at atmospheric pressure to give the product 4a as a colourless oil (7.67 g, 64%); bp 98 °C (lit.²⁸ bp 98 °C); δ_H (400 MHz, CDCl₃) 3.49 (3H, s, CH₃), 4.36 (2H, s, CH₂); δ_C (100 MHz, CDCl₃) 59.7 (CH₃), 77.5 (CH₂), 171.8 (C=O).

4-Pentenoyl chloride 4b (ref. 31)

A solution of 4-pentenoic acid (500 mg, 5 mmol) in DCM (3 mL) was stirred at rt, and oxalyl chloride (0.44 mL, 5.0 mmol) was added dropwise over 5 min. The resulting solution was heated to 40 °C for 2 h. The mixture was then concentrated in vacuo before a portion of DCM (2 mL) was added and the solution was reconcentrated to give 4b as a pale pink oil (405 mg, 68%); δ_H (400 MHz, CDCl₃) 2.43–2.50 (2H, m, C(3)H₂), 3.00 (2H, t, J 7.2, C(2)H₂), 5.07–5.16 (2H, m, C(5)H₂), 5.74–5.86 (1H, m, C(4)H); δ_C (100 MHz, CDCl₃) 28.9 (C(3)), 46.2 (C(2)), 116.9 (C(5)), 134.6 (C(6)), 173.2 (C(1)).

4-Bromophenylacetyl chloride 4c (ref. 32)

A solution of 4-bromophenylacetic acid (1.0 g, 4.65 mmol) in DCM (6 mL) was stirred at rt, and oxalyl chloride (0.6 mL, 6.9 mmol) was added dropwise over 5 min. The resulting solution was heated to 40 °C for 4 h. The mixture was then concentrated in vacuo before a portion of DCM (3 mL) was added and the solution reconcentrated to give 4c as a colourless oil (1.13 g, quant); δ_H (400 MHz, CDCl₃) 4.11 (2H, s, CH₂), 7.16 (2H, d, J 8.2, C(2)H, C(6)H), 7.52 (2H, d, J 8.2, C(3)H, C(5)H); δ_C (100 MHz, CDCl₃) 52.3 (CH₂), 122.4 (C(1)), 130.2 (C(4)), 131.2, 132.1 (C(2), C(3), C(5), C(6)), 171.5 (C=O); m/z (TOF FI⁺) 233 (M⁺, 100%).

5-(2′-Methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 5a (ref. 15)

Following general procedure A, pyridine (3.46 mL, 43.0 mmol), Meldrum's acid (3.10 g, 21.5 mmol) and methoxyacetyl chloride 4a (2.56 g, 23.7 mmol) were reacted to give 5a as a dark brown oil (3.5 g, 75%) which was used without further purification; δ_H (400 MHz, CDCl₃) 1.75 (6H, s, C(CH₃)₂), 3.52 (3H, s, OCH₃), 4.86 (CH₂); δ_C (100 MHz, CDCl₃) 26.9 (C(2)(CH₃)₂), 59.9 (OCH₃), 72.1 (CH₂), 90.1 (C(5)), 105.9 (C(2)), 162.9 (C=O), 194.1 (COCH₂OMe); m/z (ESI⁺) 215 ([M − H]⁻, 40%).

5-(4′-pentenoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 5b

Following general procedure A, pyridine (0.49 mL, 6.13 mmol) was added to a solution of Meldrum's acid (447 mg, 3.1 mmol) in DCM (5 mL) at −10 °C and stirred for 20 min. A solution of acid chloride 4b (405 mg, 3.41 mmol) in DCM (2 mL) was added dropwise and the resulting mixture was stirred for 1 h at −10 °C before being warmed to rt and stirred for a further 2 h. The mixture was quenched with 1 M HCl (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried and concentrated in vacuo to give 5b as a yellow oil (644 mg, 84%) which was used without further purification; ν_max (film) 3080, 3002, 2922, 1739, 1667, 1574; δ_H (400 MHz, CDCl₃) 1.74 (3H, s, CH₃), 1.79 (3H, s, CH₃), 2.44–2.51 (2H, m, C(3′)H₂), 3.21 (2H, t, J 7.5, C(2′)H₂), 5.01–5.13 (2H, m, C(5′)H₂), 5.78–5.91 (1H, m, C(4′)H); δ_C (100 MHz, CDCl₃) 26.8, 27.6 (CH₃), 29.8 (C(3′)), 34.9 (C(2′)), 91.6 (C(5′)), 104.9 (C(2)), 116.2 (C(5′)), 136.0 (C(4′)), 170.5 (C(1), C(3)), 197.0 (C(1′)); m/z (ESI⁻) 255 ([M − H]⁻, 25%); HRMS (ESI⁺) C₁₁H₁₄NaO₅⁺ ([M + Na]⁺) requires 249.0733, found 249.0739.

5-(4′-Bromophenylacetoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 5c

Following general procedure A, pyridine (0.75 mL, 9.3 mmol) was added to a solution of Meldrum's acid (670 mg, 4.65 mmol) in DCM (20 mL) at −10 °C and stirred for 20 min. A solution of acid chloride 4c (1.08 g, 4.65 mmol) in DCM (5 mL) was added dropwise and the resulting mixture was stirred for 1 h at −10 °C before being warmed to rt and stirred for a further 2 h. The mixture was quenched with 1 M HCl (10 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried and concentrated in vacuo to give 5c as a red solid (1.49 g, 93%); mp 112–115 °C; ν_max (film) 3000, 1741, 1648; δ_H (400 MHz, CDCl₃) 1.73 (6H, s, CH₃), 4.37 (2H, s, CH₂), 7.27 (2H, d, J 8.3, C(2′)H, C(6′)H), 7.46 (2H, d, J 8.3, C(3′)H, C(5′)H); δ_C (100 MHz, CDCl₃) 26.8 (CH₃), 40.2 (CH₂), 91.5 (C(5)), 105.1 (C(2)), 121.7 (C(4′)), 131.3 (C(2′), C(6′)), 131.8 (C(3′), C(5′)), 133.0 (C(1′)), 170.5 (C(4), C(6)), 193.8 (C=O); m/z (ESI⁻) 388 ([M − H]⁻, 100%); HRMS (ESI⁺) C₁₄H₁₃BrO₅⁺ ([M + Na]⁺) requires 362.9839, 364.9829, found 362.9826, 364.9807.

5-(1′-Hydroxy-2′-(phenylthio)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 5d

Following general procedure A, pyridine (0.86 mL, 10.7 mmol) and Meldrum's acid (771 mg, 5.35 mmol) in DCM (25 mL) were combined with a solution of acid chloride 4d (1.00 g, 5.35 mmol) in DCM (5 mL) to give 5d as an orange oil (1.62 g, quant); ν_max (film) 3000, 1737, 1666; δ_H (400 MHz, CDCl₃) 1.67 (6H, s, CH₃), 4.38 (2H, s, C(2′)H₂), 7.28–7.32 (3H, m, Ph), 7.47–7.51 (2H, m, Ph), 14.57 (1H, br s, OH); δ_C (100 MHz, CDCl₃) 26.8 (CH₃), 36.4 (C(2′)), 91.1 (C(5)), 105.2 (C(2)), 127.0, 128.0, 132.1 (o,m,p-Ph), 133.5 (i-Ph), 170.4 (C(4), C(6)), 192.1 (C(1′)); m/z (ESI⁻) 293 ([M − H]⁻, 40%); HRMS (ESI⁻) C₁₄H₁₃O₅S⁻ ([M − H]⁻) requires 293.0489, found 293.0489.

tert-Butyl 4-methoxy-3-oxo-butanoate 6a (ref. 15)

Following general procedure B, a solution of 5a (3.5 g, 16.2 mmol) in 1 : 1 toluene–^tBuOH (36 mL) was stirred at reflux for 2 h. The mixture was cooled to rt and concentrated in vacuo to give 6a as a dark brown liquid (2.2 g, 73%); R_f 0.3 (eluent 9 : 1 petrol–EtOAc); δ_H (400 MHz, CDCl₃) 1.47 (9H, s, C(CH₃)₃), 3.41 (2H, s, C(2)H₂), 3.42 (3H, s, OCH₃), 4.08 (2H, s, C(4)H₂); δ_C (100 MHz, CDCl₃) 27.9 (C(CH₃)₃), 47.2 (C(2)), 59.3 (OCH₃), 77.3 (C(4)), 83.4 (CMe₃), 166.2 (C(1)), 202.0 (C(3)); m/z (ESI⁺) 211 ([M + Na]⁺, 50%), 399 ([2M + Na]⁺, 75%).

tert-Butyl 3-oxohept-6-enoate 6b

Following general procedure B, a solution of 5b (312 mg, 1.4 mmol) in 1 : 1 toluene–t-BuOH (4 mL) was stirred at reflux for 2 h. The mixture was cooled to rt and concentrated in vacuo to give 6b as a yellow liquid (290 g, quant); R_f 0.55 (eluent 50 : 1 petrol–EtOAc); ν_max (film) 3080, 2981, 1734, 1643; δ_H (400 MHz, CDCl₃) 1.47 (9H, s, C(CH₃)₃), 2.32–2.39 (2H, m, C(5)H₂), 2.64 (2H, t, J 7.3, C(4)H₂), 3.36 (2H, s, C(2)H), 4.97–5.11 (2H, m, C(7)H₂), 5.75–5.89 (1H, m, C(6)H); δ_C (100 MHz, CDCl₃) 27.4 (C(5)), 27.9 (C(CH₃)₃), 41.9 (C(4)), 50.7 (C(2)), 82.0 (CMe₃), 115.4 (C(7)), 136.7 (C(6)), 166.5 (C(1)), 202.3 (C(3)); m/z (ESI⁺) 221 ([M + Na]⁺, 75%), 419 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₁₁H₁₈NaO₃⁺ ([M + Na]⁺) requires 221.1148, found 221.1144.

tert-Butyl 4-(4′-bromophenyl)3-oxobutanoate 6c

Following general procedure B, a solution of 5c (750 mg, 2.19 mmol) in 1 : 1 toluene–t-BuOH (10 mL) was stirred at reflux for 2 h. The mixture was cooled to rt and concentrated in vacuo to give 6c as a pale yellow oil (680 mg, quant); R_f 0.6 (eluent, 5 : 1 petrol–EtOAc) ν_max (film) 2979, 1731, 1648; δ_H (400 MHz, CDCl₃) 1.49 (9H, s, C(CH₃)₃), 3.41 and 3.79 (2 × 2H, s, C(2)H₂, C(4)H₂), 7.10 (2H, d, J 7.3, C(2′)H, C(6′)H), 7.49 (2H, d, J 7.3, C(3′)H, C(5′)H); δ_C (100 MHz, CDCl₃) 28.0 (C(CH₃)₃), 49.1, 49.8 (C(2), C(4)), 82.3 (CMe₃), 121.4 (C(4′)), 131.3 (C(2′), C(6′)), 131.9 (C(3′), C(5′)), 132.3 (C(1′)), 166.2 (C(1)), 200.2 (C(3)); m/z (ESI⁺) 335, 337 ([M + Na]⁺, 95%); HRMS (ESI⁺) C₁₄H₁₇BrNaO₃⁺ ([M + Na]⁺) requires 335.0253, 337.0233, found 335.0243, 337.0225.

tert-Butyl (4-phenylthio)-3-oxo-butanoate 6d

Following general procedure B, a solution of 5d (714 mg, 2.42 mmol) in 1 : 1 toluene–t-BuOH (10 mL) was stirred at reflux for 2 h. The mixture was cooled to rt and concentrated in vacuo to give 6d as a brown liquid (643 mg, quant); R_f 0.75 (eluent 5 : 1 40–60 petrol–EtOAc); ν_max (film) 3060, 2979, 1715, 1649; δ_H (400 MHz, CDCl₃) 1.47 (9H, s, C(CH₃)₃), 3.56 (2H, s, C(2)H₂), 3.82 (2H, s, C(4)H₂), 7.22–7.37 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 27.9 (C(CH₃)₃), 43.9 (C(4)), 47.8 (C(2)), 82.3 (CMe₃), 127.1, 129.2, 129.7 (o,m,p-Ph), 134.3 (i-Ph), 166.2 (C(1)), 198.4 (C(3)); m/z (ESI⁺) 289 ([M + Na]⁺, 80%); HRMS (ESI⁺) C₁₄H₁₈NaO₃S⁺ ([M + Na]⁺) requires 289.0867, found 289.0869.

4-Methoxy-3-oxobutanoic acid 7 (ref. 15)

Following general procedure D, a solution of 6a (200 mg, 1.06 mmol) in DCM (1 mL) was cooled to 0 °C and TFA (1 mL) was added dropwise. The resulting solution was stirred for 24 h at rt before the solvent was removed in vacuo to give 7 as a yellow oil (140 mg, quant) in a 5 : 1 keto–enol ratio; δ_H (400 MHz, CDCl₃) keto-tautomer – 3.44 (3H, s, OCH₃), 3.57 (2H, s, C(2)H₂), 4.10 (2H, s, C(4)H₂), 9.73 (1H, br s, OH), enol-tautomer – 3.44 (3H, s, OCH₃), 4.02 (2H, s, C(4)H₂), 5.32 (1H, s, C(2)H), 9.73 (1H, br s, OH); δ_C (100 MHz, CDCl₃) 45.1 (keto-C(2)) 59.2, 59.3 (2 × OCH₃), 71.1 (enol-C(4)), 77.2 (keto-C(4)), 87.8 (enol-C(2)), 171.9 (keto-C(1)), 201.8 (keto-C(8)).

(2R,4S,5R)-2 tert-butyl-3-(4′-methoxy-3′-oxobutanoyl)-4-methoxycarbonyl-5-methyloxazolidine 8

Following general procedure E, oxazolidine 1 (211 mg, 1.05 mmol) was reacted with DCC (227 mg, 1.01 mmol), DMAP (9 mg, 7 mol%) and the acid 7 (144 mg, 1.10 mmol). The crude mixture of 8 (350 mg) was used without purification; m/z (ESI⁺) 338 ([M + Na]⁺, 50%).

(2R,4S,5R)-2-tert-Butyl-3-(3′-oxohept-6′-enoyl)-4-methoxycarbonyl-5-methyloxazolidine 9a

Following general procedure C, acylated Meldrum's acid 5b (2.5 g, 11.0 mmol) was dissolved in MeCN (25 mL) and oxazolidine 1 (2.11 mg, 10.5 mmol) in MeCN (25 mL) was added. The resulting mixture was stirred at 60 °C for 2 h and then concentrated in vacuo and purified by column chromatography (SiO₂, eluent 20 : 2 to 5 : 1 petrol–EtOAc) to give 9a as a yellow oil (1.86 g, 52%); R_f 0.2 (eluent 20 : 1 petrol–EtOAc); ν_max (film) 2958, 1753, 1667, 1632; δ_H (400 MHz, CDCl₃) 0.91 (9H, s, C(CH₃)₃), 1.35 (3H, d, J 6.3, C(5)CH₃), 2.28–2.38 (2H, m, C(5′)H₂), 2.59–2.81 (2H, m, C(4′)H₂), 3.60 (2H, AB q, J 14.8, C(2′)H₂), 3.79 (3H, s, CO₂CH₃), 4.27 (1H, d, J 3.8, C(4)H), 4.72–4.79 (1H, m, C(5)H), 4.96–5.09 (2H, m, C(7′)H₂), 5.41 (1H, s, C(2)H), 5.74–5.86 (1H, m, C(6′)H); δ_C (100 MHz, CDCl₃) 20.1 (C(5)CH₃), 25.8 (C(CH₃)₃), 26.7 (C(5′)), 37.8 (CMe₃), 42.3 (C(4′)), 50.7 (C(2′)), 52.5 (CO₂CH₃), 65.3 (C(4)), 76.1 (C(5)), 96.1 (C(2)), 115.5 (C(7′)), 136.6 (C(6′)), 168.0 (C(1′)), 170.3 (CO₂Me), 203.8 (C(3′)); m/z (ESI⁺) 326 ([M + H]⁺, 55%), 348 ([M + Na]⁺, 70%), 673 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₁₇H₂₇NNaO₅⁺ ([M + Na]⁺) requires 348.1777, found 348.1781.

(2R,4S,5R)-2-tert-Butyl-3-(3′-oxo-4′-(4′′-p-bromophenyl)butanoyl)-4-methoxycarbonyl-5-methyloxazolidine 9b

Following general procedure C, acylated Meldrum's acid 5c (700 mg, 2.05 mmol) was dissolved in MeCN (10 mL) and oxazolidine 1 (392 mg, 1.95 mmol) in MeCN (5 mL) was added. The resulting mixture was stirred at 60 °C for 2 h and then concentrated in vacuo. Purification via column chromatography (SiO₂, eluent 10 : 1 petrol–EtOAc) gave 9b as a colourless oil (524 mg, 58%); R_f 0.45 (eluent 3 : 1 petrol–EtOAc); ν_max (film) 2957, 1747, 1685; δ_H (500 MHz, MeOD) 0.90 (9H, s, C(CH₃)₃), 1.32 (3H, d, J 6.0, C(5)CH₃), 3.77 (3H, s, CO₂CH₃), 3.87 (2H, AB q, J 16.4, C(4′)H₂), 4.31 (1H, d, J 3.4, C(4)H), 4.73–4.79 (1H, m, C(5)H), 5.36 (1H, s, C(2)H), 7.18 (2H, d, J 8.2, o-Ph), 7.50 (2H, d, J 8.2, m-Ph); δ_C (125 MHz, MeOD) 20.4 (C(5)CH₃), 26.4 (C(CH₃)₃), 38.8 (CMe₃), 53.3 (C(4′)), 66.5 (C(4)), 77.5 (C(5)), 97.2 (C(2)), 122.2 (CBr), 132.7, 132.9 (o,m-Ph), 134.5 (i-Ph), 171.0, 171.5 (CO₂CH₃, C(1′)), 203.4 (C(3′)); m/z (ESI⁺) 462/464 ([M + Na]⁺, 75%), 903 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₂₀H₂₆BrNNaO₆⁺ ([M + Na]⁺) requires 462.0887, 464.0867, found 462.0869, 464.0850.

(2R,4S,5R)-2-tert-Butyl-3-(3′-oxo-4′-phenylthiobutanoyl)-4-methoxycarbonyl-5-methyloxazolidine 9c

Following general procedure C, acylated Meldrum's acid 5d (907 mg, 3.1 mmol) was dissolved in MeCN (15 mL) and oxazolidine 1 (563 mg, 2.8 mmol) in MeCN (8 mL) was added. The resulting mixture was stirred at 60 °C for 2 h and then concentrated in vacuo. Purification via column chromatography (SiO₂, eluent 20 : 1–5 : 1 petrol–EtOAc) gave 9c as a yellow oil (558 mg, 45%) as a mixture of keto and enol forms; R_f 0.37(eluent 5 : 1 pterol–EtOAc); ν_max (film) 2975, 2957, 1745, 1716, 1662; δ_H (400 MHz, MeOD) 0.87 (s, C(CH₃)₃), 1.21 (3H, d, J 6.3, C(5)CH₃), 3.77 (3H, s, CO₂CH₃), 3.93 (2H, AB q, J 15.4, C(4′)H₂), 4.16 (1H, d, J 3.8, C(4)H), 4.68–4.74 (1H, m, C(5)H), 5.33 (1H, s, C(2)H), 7.21–7.45 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 19.2 (C(5)CH₃), 25.3 (C(CH₃)₃), 37.8 (CMe₃), 43.1 (C(4′)) 52.3 (CO₂CH₃), 65.4 (C(4)), 76.3 (C(5)), 96.1 (C(2)), 126.9 (p-Ph), 129.2, 129.3 (o,m-Ph), 170.4, 170.5 (CO₂Me, C(1′)), 200.0 (C(3′)); m/z (ESI⁺) 809 ([2M + Na]⁺, 100%), 394 ([M + H]⁺, 80%); HRMS (ESI⁺) C₂₀H₂₈NO₅S⁺ ([M + H]⁺) requires 394.1680, found 394.1683.

tert-Butyl 4-methoxy-5-phenyl-3-oxo-pentanoate 10

Following general procedure G, a stirred suspension of NaH (47 mg, 1.17 mmol) in THF (20 mL) was cooled to 0 °C and a solution of 6a (200 mg, 1.06 mmol) in THF (2 mL) was added dropwise. Stirring was continued for 10 min at 0 °C before the dropwise addition of BuLi (0.7 mL, 1.6 M in hexanes, 1.12 mmol). After stirring for a further 10 min, BnBr (0.14 mL, 1.17 mmol) was added in one portion and the mixture was allowed to warm to rt over 15 min. The mixture was quenched with 2 M HCl (7 mL) and extracted with Et₂O (2 × 15 mL). The combined organic layers were washed with H₂O until the aqueous layer remained neutral, dried and concentrated in vacuo. Purification by column chromatography (SiO₂, eluent 10 : 1 40–60 petrol–EtOAc) gave 10 as a colourless oil (90 mg, 30%) as a 3 : 1 keto–enol mixture; R_f 0.5 (eluent 10 : 1 40–60 petrol–EtOAc); ν_max (film) 3064, 3030, 2980, 2829, 1717, 1650; δ_H (400 MHz, CDCl₃) keto: 1.47 (9H, s, C(CH₃)₃), 2.93 (1H, d, J 7.8, C(5)H_AH_B), 3.02 (1H, d, J 4.6, C(5)H_AH_B), 3.28 (1H, d, J 5.1, C(2)H_AH_B), 3.32 (3H, s, OCH₃), 3.46 (1H, d, J 15.9, C(2)H_AH_B), 3.92 (1H, dd, J 7.8, 4.6, C(4)H), 7.20–7.33 (5H, m, Ph), enol: 1.51 (9H, s, C(CH₃)₃), 2.90 (1H, d, J 7.8C(5)H_AH_B), 3.06 (1H, d, J 4.3, C(5)H_AH_B), 3.32 (3H, s, OCH₃), 3.76 (1H, dd, J 8.6, 4.3, C(4)H), 5.11 (1H, s, C(2)H), 7.20–7.33 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 28.0, 28.3 (C(CH₃)₃), 37.8 (C(5)), 46.7 (C(2) keto), 57.9, 58.7 (OCH₃), 81.8 (CMe₃), 87.6 (C(4) keto), 90.7 (C(2) enol), 126.7, 128.2, 128.4, 129.3, 129.4 (o,m,p-Ph), 136.8 (i-Ph), 166.4 (C(1)), 205.5 (C(3)); m/z (ESI⁺) 301 ([M + Na]⁺, 80%), 579 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₁₆H₂₂NaO₄⁺ ([M + Na]⁺) requires 301.1410, found 301.1410.

4-Methoxy-3-oxo-5-phenylpentanoic acid 11

Following general procedure D, a solution of 11 (90 mg, 0.32 mmol) in DCM (0.5 mL) was cooled to 0 °C and TFA (0.5 mL) was added dropwise. The resulting solution was stirred for 1.5 h at rt before the solvent was removed in vacuo to give 11 as an yellow oil (78 mg, quant); R_f 0.56 (eluent 3 : 1 40–60 petrol–EtOAc); ν_max (film) 2936, 1714, 1496, 1455; δ_H (400 MHz, CDCl₃) 2.91–2.91 (1H, m, C(5)H_AH_B), 3.03–3.09 (1H, m, C(5)H_AH_B), 3.35 (3H, s, OCH₃), 3.40 (1H, d, J 16.9, C(2)H_AH_B), 3.59 (1H, d, J 16.9, C(2)H_AH_B), 3.95 (1H, dd, J 7.3, 4.6, C(4)H), 7.16–7.34 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 37.7 (C(5)), 44.5 (C(2)), 58.8 (OCH₃), 87.5 (C(4)), 126.9, 128.5, 129.4 (o,m,p-Ph), 136.3 (i-Ph), 171.5 (C(1)), 205.8 (C(3)); m/z (ESI⁺) 245 ([M + Na]⁺, 80%), 221 ([M − H]⁻, 100%); HRMS (ESI⁺) C₁₂H₁₄NaO₄⁺ ([M + H]⁺) requires 245.0784, found 245.788.

(2R,4S,5R)-2-tert-Butyl-3-(4′-methoxy-5′-phenyl--3′-oxopentanoyl)-4-methoxycarbonyl-5-methyloxazolidine 12

Following general procedure C for the synthesis of N-acyloxazolidines, oxazolidine 1 (67 mg, 0.33 mmol) was reacted with DCC (72 mg, 0.35 mmol), DMAP (3 mg, 7 mol%) and the acid 11 (78 mg, 0.35 mmol). The crude mixture of 12 (115 mg) was used without purification; ν_max (film) 3322, 2932, 2118, 1745, 1633; m/z (ESI⁺) 428 ([M + Na]⁺, 70%), 833 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₂₂H₃₁NNaO₆⁺ ([M + Na]⁺) requires 428.2044, found 428.2041.

tert-Butyl 4-methoxy-2-methyl-3-oxobutanoate 13a (ref. 15)

Following general procedure G, a solution of 6a (2.0 g, 10.6 mmol) in THF (30 mL) was stirred at 0 °C and tBuOK (1.30 g, 11.7 mmol) was added. The mixture was then warmed to rt and stirred for 40 min before the addition of MeI (0.73 mL, 11.7 mmol). The mixture was left to stir for a further 5 h at rt. After this time the mixture was partitioned between Et₂O (30 mL) and brine (30 mL). The aqueous layer was extracted with Et₂O (2 × 20 mL) and the combined organic layers were dried and concentrated in vacuo to give 13a as a yellow oil (1.60 g, 74%); R_f 0.4 (eluent 9 : 1 petrol–EtOAc); δ_H (400 MHz, CDCl₃) 1.30 (3H, d, J 7.1, C(2)CH₃), 1.45 (9H, s, C(CH₃)₃), 3.41 (3H, s, OCH₃), 3.55 (1H, q, J 7.1, C(2)H), 4.07–4.15 (2H, m, C(4)H₂); δ_C (100 MHz, CDCl₃) 12.2 (C(2)CH₃), 27.9 (C(CH₃)₃), 50.1 (C(2)), 59.2 (OCH₃), 76.8 (C(4)), 81.8 (CMe₃), 169.4 (C(1)), 204.5 (C(3)); m/z (ESI⁺) 225 ([M + Na]⁺, 80%), 427 ([2M + Na]⁺, 100%).

tert-Butyl 2-methyl-3-oxohept-6-enoate 13b (ref. 31)

Following general procedure G, a solution of 6b (277 mg, 1.4 mmol) in THF (7 mL) was stirred at 0 °C and tBuOK (180 mg, 1.46 mmol) was added. The mixture was then warmed to rt and stirred for 40 min before the addition of MeI (0.09 mL, 1.46 mmol). The mixture was left to stir for a further 5 h at rt. After this time the mixture was partitioned between Et₂O (15 mL) and brine (15 mL). The aqueous layer was extracted with Et₂O (2 × 10 mL) and the combined organic layers were dried and concentrated in vacuo. Purification by column chromatography (SiO₂, eluent 100 : 1 to 50 : 1 petrol–EtOAc) gave 13b as a yellow oil (128 mg, 43%); R_f 0.45 (eluent 50 : 1 petrol–EtOAc); ν_max (film) 2980, 1715, 1642; δ_H (400 MHz, CDCl₃) 1.28 (3H, d, J 7.1, C(2)CH₃), 1.45 (9H, s, C(CH₃)₃), 2.30-2.37 (2H, m, C(5)H₂), 2.50–2.73 (2H, m, C(4)H₂), 3.42 (1H, q, J 7.1, C(2)H), 4.96–5.06 (2H, m, C(7)H₂), 5.74–5.85 (1H, m, C(6)H); δ_C (100 MHz, CDCl₃) 12.6 (C(2)CH₃), 27.6 (C(5)), 27.9 (C(CH₃)₃), 40.4 (C(4)), 53.9 (C(2)), 81.7 (CMe₃), 115.3 (C(7)), 136.9 (C(6)), 169.7 (C(1)), 205.4 (C(3)); m/z (ESI⁺) 235 ([M + Na]⁺, 100%).

tert-Butyl 4-(4′-bromophenyl)-2-methyl-3-oxobutanaoate 13c

Following general procedure G, a solution of 6c (638 mg, 2.19 mmol) in THF (15 mL) was stirred at 0 °C and t-BuOK (280 mg, 2.29 mmol) was added. The mixture was then warmed to rt and stirred for 40 min before the addition of MeI (0.14 mL, 2.29 mmol). The mixture was left to stir for a further 5 h at rt. After this time the mixture was partitioned between Et₂O (25 mL) and brine (20 mL). The aqueous layer was extracted with Et₂O (2 × 10 mL) and the combined organic layers were dried and concentrated in vacuo to give 13c as a yellow oil (631 mg, 88%); R_f 0.75 (eluent 5 : 1 40–60 petrol–EtOAc); ν_max (film) 2983, 2937, 2360, 1745, 1715; δ_H (400 MHz, CDCl₃) 1.29 (3H, d, J 7.1, C(2)CH₃), 1.46 (9H, s, C(CH₃)₃), 3.53 (1H, q, J 7.1, C(2)H), 3.76 (1H, d, J 16.4, C(4)H_AH_B), 3.84 (1H, d, J 16.4, C(4)H_AH_B), 7.08 (2H, d, J 8.5, C(2′)H, C(6′)H), 7.45 (2H, d, J 8.5, C(3′)H, C(5′)H); δ_C (100 MHz, CDCl₃) 12.7 (C(2)CH₃), 27.9 (C(CH₃)₃), 47.7 (C(4)), 53.1 (C(2)), 82.1 (CMe₃), 121.2 (C(4′)), 131.1 (C(2′), C(6′)), 131.5 (C(3′), C(5′)), 132.6 (C(1′)), 169.4 (C(1)), 203.0 (C(3)); m/z (ESI⁺) 349, 351 ([M + Na]⁺, 80%), m/z (ESI⁺) 675, 677, 679 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₁₅H₁₉BrO₃⁺ ([M + Na]⁺) requires 349.0410, 351.0390, found 349.0396, 351.0378.

tert-Butyl (4-phenylthio)-3-oxo-2-methylbutanoate 13d

Following general procedure G, a solution of 6d (717 mg, 2.56 mmol) in THF (20 mL) was stirred at 0 °C and tBuOK (328 mg, 2.68 mmol) was added. The mixture was then warmed to rt and stirred for 40 min before the addition of MeI (0.17 mL, 2.68 mmol). The mixture was left to stir for a further 5 h at rt. After this time the mixture was partitioned between Et₂O (20 mL) and brine (20 mL). The aqueous layer was extracted with Et₂O (2 × 10 mL) and the combined organic layers were dried and concentrated in vacuo to give 13d as a brown oil (620 mg, 86%); R_f 0.85 (eluent 5 : 1 petrol–EtOAc); ν_max (film) 3059, 1737, 1713; δ_H (400 MHz, CDCl₃) 1.27 (3H, d, J 7.1, C(2)CH₃), 3.84 (1H, q, J 7.1, C(2)H), 3.81–3.92 (2H, m, C(4)H₂), 7.26–7.36 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 12.8 (C(2)CH₃), 27.9 (C(CH₃)₃), 43.9 (C(4)), 50.9 (C(2)), 82.1 (CMe₃), 127.0 (p-Ph), 129.0, 129.1, 129.2, 129.7 (o,m,p-Ph), 134.6 (i-Ph), 169.2 (C(1)), 201.1 (C(3)); m/z (ESI⁺) 303 ([M + Na]⁺, 75%); HRMS (ESI⁺) C₁₅H₂₀NaO₃S⁺ ([M + Na]⁺) requires 303.1025, found 303.1023.

4-Methoxy-2-methyl-3-oxobutanioic acid 14a (ref. 15)

Following general procedure D, a solution of 13a (282 mg, 1.39 mmol) in DCM (1.5 mL) was cooled to 0 °C and TFA (1.5 mL) was added dropwise. The resulting solution was stirred for 3 h at rt before the solvent was removed in vacuo to give 14a as an orange oil (190 mg, 93%); δ_H (400 MHz, CDCl₃) 1.39 (3H, d, J 7.3, C(2)CH₃), 3.44 (3H, s, OCH₃), 3.76 (1H, q, J 7.3, C(2)H), 4.13–4.17 (2H, m, C(4)H₂), 6.50 (1H, br s, OH); δ_C (100 MHz, CDCl₃) 12.2 (C(2)CH₃), 48.5 (C(2)), 59.4 (OCH₃), 76.7 (C(4)), 175.2 (C(1)), 204.1 (C(3)).

2-Methyl-3-oxohept-6-enoic acid 14b

Following general procedure D, a solution of 13b (128 mg, 0.60 mmol) in DCM (0.7 mL) was cooled to 0 °C and TFA (0.7 mL) was added dropwise. The resulting solution was stirred for 1.5 h at rt before the solvent was removed in vacuo to give 14b as a colourless oil (103 mg, quant); ν_max (film) 2984, 1712, 1642; δ_H (400 MHz, CDCl₃) 1.39 (3H × 0.5, d, J 7.3, C(2)CH₃-keto), 1.42 (3H × 0.5, s, C(2)CH₃-enol), 2.30–2.40 (2H, m, C(5)H₂), 2.50–2.81 (2H, m, C(4)H₂), 3.59 (1H × 0.5, q, J 7.3, C(2)H-keto), 4.96–5.09 (2H, m, C(7)H₂), 5.74–5.87 (1H, m, C(6)H₂); δ_C (125 MHz, CDCl₃) 12.9 (C(2)CH₃-keto), 22.0 (C(2)CH₃-enol), 27.4, 27.8 (C(5)), 37.2, 41.1 (C(4)), 52.2 (C(2)), 115.2, 115.6 (C(7)), 136.5, 137.3 (C(6)), 178.9 (C(1)), 205.1 (C(3)); m/z (FI⁺) 156 ([M]⁺, 100%); HRMS (FI⁺) C₈H₁₂O₃⁺ ([M]⁺) requires 156.0786, found 156.0784.

4-(4′-Bromophenyl)-2-methyl-3-oxobutaoic acid 14c

Following general procedure D, a solution of 13c (631 mg, 1.92 mmol) in DCM (4 mL) was cooled to 0 °C and TFA (4 mL) was added dropwise. The resulting solution was stirred for 1.5 h at rt before the solvent was removed in vacuo to give 14c as a yellow oil (499 mg, 95%) in a 3 : 1 mixture of keto and enol forms; ν_max (film) 2980, 1712; δ_H (400 MHz, CDCl₃) keto – 1.37 (3H, d, J 7.1, C(2)CH₃), 3.69 (1H, q, J 7.1, C(2)H), 3.84 (1H, d, J 16.0, C(4)H_AH_B), 3.90 (1H, d, J 16.0, C(4)H_AH_B), 7.06–7.12 (2H, m, Ph), 7.42–7.50 (2H, m, Ph), 12.40 (1H, br s, OH), enol – 1.47 (3H, s, C(2)CH₃), 3.66 (2H, s, C(4)H₂), 7.06–7.12 (2H, m, Ph), 7.42–7.50 (2H, m, Ph), 12.40 (1H, br s, OH); δ_C (100 MHz, CDCl₃) 12.8 (C(2)CH3 keto), 22.0 (C(2)CH₃ enol), 48.0 (C(4) keto), 48.9 (C(4) enol), 51.5 (C(2) keto), 121.0, 121.4 (C(4′)), 131.1, 131.3, 131.6, 131.8, 131.9, 132.0, 133.3 (Ph, C(2) enol), 154.1, 154.2 (C(1′)), 175.4 (C(1)), 202.4 (C(3) keto), 202.4 (C(3) enol); m/z (ESI⁺) 292, 294 ([M + Na]⁺, 100%); HRMS (ESI⁺) C₁₁H₁₁BrNaO₃⁺ ([M + Na]⁺) requires 292.9784, 294.9764, found 292.9780, 294.9763.

2-Methyl-3-oxo-4-(phenylthio)butanoic acid 14d

Following general procedure D, a solution of 13d (620 mg, 2.21 mmol) in DCM (4 mL) was cooled to 0 °C and TFA (4 mL) was added dropwise. The resulting solution was stirred for 2 h at rt before the solvent was removed in vacuo by co-evaporation with toluene to give 14d as a brown oil (490 mg, quant) which was used without further purification; ν_max (film) 3059, 2985, 2940, 1707, 1583; δ_H (400 MHz, CDCl₃) 1.35 (3H, d, J 7.1, C(2)CH₃), 3.86, 3.91 (2H, AB q, J 15.3, C(4)H₂), 4.03 (1H, q, J 7.1, C(2)H), 7.15–7.38 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 12.9 (CH₃), 43.5 (C(4)), 49.1 (C(2)), 125.3, 127.3, 128.2, 129.2, 130.0 (o,m,p-Ph), 133.9 (i-Ph), 175.1 (CO₂H), 199.5 (C(3)); m/z (ESI⁺) 223 ([M − H]⁻, 40%).

(2R,4S,5R)-2-tert-Butyl-3-(4′-methoxy-2′-methyl-3′-oxobutanoyl)-4-methoxycarbonyl-5-methyloxazolidine 15a and 15a′

Following general procedure E, oxazolidine 1 (248 mg, 1.23 mmol) was reacted with DCC (268 mg, 1.30 mmol), DMAP (10 mg, 7 mol%) and the acid 14a (190 mg, 1.30 mmol). The crude mixture of 15a (340 mg) was used without purification; m/z (ESI⁺) 352 ([M + Na]⁺, 20%), 681 ([2M + Na]⁺, 100%).

(2R,4S,5R,2′R)- and (2R,4S,5R,2′S)-2-tert-butyl-3-(3′-oxo-2′-methylhept-6′-enoyl)-4-methoxycarbonyl-5-methyloxazolidine 15b and 15b′

Following general procedure E, oxazolidine 1 (522 mg, 2.6 mmol) was reacted with DCC (562 mg, 2.78 mmol), DMAP (23 mg, 7 mol%), and acid 14b (434 mg, 2.78 mmol) in DCM (13 mL). Purification via column chromatography (SiO₂, eluent 10 : 1 petrol–EtOAc) gave 15b as a colourless oil (130 mg, 14%); R_f 0.74 (eluent 3 : 1 petrol–EtOAc); [α]²³_D + 2.42 (c 0.44 in CHCl₃); ν_max (film) 2977, 2958, 1747, 1729, 1664; δ_H (400 MHz, CDCl₃) 0.90 (9H, s, C(CH₃)₃), 1.32 (3H, d, J 6.1, C(5)CH₃), 1.50 (3H, d, J 6.8, C(2′)CH₃), 2.30 (2H, app. q, J 6.8, C(5′)H₂), 2.57–2.74 (2H, m, C(4′)H₂), 3.66 (1H, q, J 6.8, C(2′)H), 3.81 (3H, s, CO₂CH₃), 4.44 (1H, d, J 3.0, C(4)H), 4.73–4.82 (1H, m, C(5)H), 4.95–5.06 (2H, m, C(7′)H₂), 5.44 (1H, s, C(2)H), 5.72–5.84 (1H, m, C(6′)H); δ_C (125 MHz, CDCl₃) 15.0 (C(2′)CH₃), 20.2 (C(5)CH₃), 25.8 (C(CH₃)₃), 27.2 (C(5′)), 37.8, 38.3 (C(4′), CMe₃), 52.8 (CO₂CH₃), 54.1 (C(2′)), 65.0 (C(4)), 76.0 (C(5)), 96.0 (C(2)), 115.3 (C(7′)), 136.7 (C(6′)), 170.2 (CO₂Me), 171.5 (C(1′)), 207.6 (C(3′)); m/z (ESI⁺) 362 ([M + Na]⁺, 40%), 701 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₁₈H₂₉NNaO₅⁺ ([M + Na]⁺) requires 362.1938, found 362.1931; and 15b′ as a yellow oil (180 mg, 20%); R_f 0.1 (eluent 10 : 1 petrol–EtOAc); [α]²³_D − 4.2 (c 1.0 in CHCl₃); ν_max (film) 2977, 2958, 2936, 1747, 1728, 1663; δ_H (400 MHz, CDCl₃) 0.93 (9H, s, C(CH₃)₃), 1.29 (3H, d, J 7.1, C(2′)CH₃), 1.35 (3H, d, J 6.3, C(5)CH₃), 2.29–2.38 (2H, m, C(5′)H₂), 2.58–2.77 (2H, m, C(4′)H₂), 3.49 (1H, q, J 7.1, C(2′)H), 3.81 (3H, s, CO₂CH₃), 4.11 (1H, d, J 4.3, C(4)H), 4.74–4.81 (1H, m, C(5)H), 4.93–5.05 (2H, m, C(7′)H₂), 5.42 (1H, s, C(2)H), 5.71–5.86 (1H, m, C(6′)H); δ_C (100 MHz, CDCl₃) 12.9 (C(2′)CH₃), 20.3 (C(5)CH₃), 25.9 (C(CH₃)₃), 27.5 (C(5′)), 38.0 (CMe₃), 39.1 (C(4′)), 52.4, 52.9 (C(2′), CO₂CH₃), 65.8 (C(4)), 75.9 (C(5)), 96.2 (C(2)), 115.1 (C(7′)), 137.1 (C(6′)), 169.9 (CO₂Me), 172.4 (C(1′)), 204.2 (C(3′)); m/z (ESI⁺) 362 ([M + Na]⁺, 30%), 701, ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₁₈H₂₉NNaO₅⁺ ([M + Na]⁺) requires 362.1938, found 362.1925.

(2R,4S,5R,2′R)- and (2R,4S,5R,2′S)-2-tert-butyl-3-(3′-oxo-4′-(4′′-bromophenyl)-2′-methylbutanoyl)-4-methoxycarbonyl-5-methyloxazolidine 15c and 15c′

Following general procedure E, oxazolidine 1 (336 mg, 1.67 mmol) was reacted with DCC (344 mg, 1.67 mmol), DMAP (14 mg, 7 mol%), and acid 14c (477 mg, 1.76 mmol). Purification via column chromatography (SiO₂, eluent 10 : 1 40–60 petrol–EtOAc) gave 15c and 15c′ as a pale yellow oil (86 mg, 11%); R_f 0.4 (eluent 5 : 1 40–60 petrol–EtOAc);[α]²³_D + 19.2 (c 1.0 in CHCl₃); ν_max (film) 2957, 1748, 1713, 1662; δ_H (400 MHz, CDCl₃) 0.90 (9H, s, C(CH₃)₃), 1.19 (3H, d, J 6.1, C(5)CH₃), 1.53 (3H, d, J 6.9, C(2′)CH₃), 3.66 (1h, q, J 6.9, C(2′)H), 3.67 (3H, s, CO₂CH₃), 3.77–3.84 (2H, m, C(4′)H₂), 3.92 (1H, d, J 4.3, C(4)H), 4.65 (1H, qd, J 6.1, 4.3, C(5)H), 5.42 (1H, s, C(2)H), 7.05 (2H, d, J 8.3, C(2′′)H, C(6′′)H), 7.45 (2H, d, J 8.3, C(3′′)H, C(5′′)H); δ_C (100 MHz, CDCl₃) 15.0 (C(2′)CH₃), 20.0 (C(5)CH₃), 25.9 (C(CH₃)₃), 38.0 (CMe₃), 45.7 (C(4′)), 52.8, 53.0 (CO₂CH₃, C(2′)), 65.0 (C(4)), 76.2 (C(5)), 96.1 (C(2)), 121.4 (C(4′′)), 131.3, 131.5, 131.7, 131.9 (C(2′′), C(6′′), C(3′′), C(5′′)), 132.3 (C(1′′), 170.0, 171.4 (CO₂Me, C(1′)), 205.0 (C(3′)); m/z (FI⁺) 453 (M⁺, 100%), 455 (M⁺, 100%); HRMS (FI⁺) C₂₁H₂₈BrNO₅⁺ (M⁺) requires 453.1151, 455.1133, found 453.1380, 455.1338; and 15c′ as a yellow solid (185 mg, 24%); R_f 0.2 (eluent 5 : 1 40–60 petrol–EtOAc); mp 148–150 °C; [α]²³_D + 1.7 (c 1.0 in CHCl₃); ν_max (film) 2958, 2359, 1747, 1733, 1662; δ_H (400 MHz, CDCl₃) 0.97 (9H, s, C(CH₃)₃), 1.32 (3H, d, J 6.9, C(2′)CH₃), 1.38 (3H, d, J 6.1, C(5)CH₃), 3.60 (1H, q, J 6.9, C(2′)H), 3.82 (3H, s, CO₂CH₃), 3.82–3.93 (2H, m, C(4′)H₂), 4.14 (1H, d, J 4.3, C(4)H), 4.75–4.83 (1H, m, C(5)H), 5.46 (1H, s, C(2)H), 7.10 (2H, d, J 8.3, C(2′′)H, C(6′′)H), 7.42 (2H, d, J 8.3, (C(3′′)H, C(5′′)H); δ_C (100 MHz, CDCl₃) 13.0 (C(2′)CH₃), 20.5 (C(5)CH₃), 26.0 (C(CH₃)₃), 38.2 (CMe₃), 45.9 (C(4′)), 52.6, 53.0 (CO₂CH₃, C(2′)), 65.8 (C(4)), 76.1 (C(5)), 96.4 (C(2)), 120.9 (C(4′′)), 131.2, 131.4, 131.5, 131.9 (C(2′′), C(6′′), C(3′′), C(5′′)), 132.9 (C(1′′)), 170.0, 172.1 (CO₂Me, C(1′′)), 201.7 (C(3′′)); m/z (FI⁺) 453 (M⁺, 100%), 455 (M⁺, 100%); HRMS (FI⁺) C₂₁H₂₈BrNO₅⁺ (M⁺) requires 453.1151, 455.1133, found 453.1393, 455.1442.

(2R,4S,5R,2′R)- and (2R,4S,5R,2′S)-2-tert-butyl-3-(3′-oxo-2′-methyl-4′-phenylthiobutanoyl)4-methoxycarbonyl-5-methyloxazolidine 15d and 15d′

Following general procedure E, oxazolidine 1 (422 mg, 2.1 mmol) was reacted with DCC (457 mg, 2.2 mmol), DMAP (18 mg, 7 mol%), and acid 14d (495 mg, 2.2 mmol). Purification via column chromatography (SiO₂, eluent 10 : 1 petrol–EtOAc) gave 15d as a yellow oil (117 mg, 14%); R_f 0.4 (eluent 20 : 1 petrol : EtOAc); [α]²³_D − 12.2 (c 0.72 in CHCl₃); ν_max (film) 2975, 2957, 1746, 1717, 1661; δ_H (400 MHz, CDCl₃) 0.90 (9H, s, C(CH₃)₃), 1.27 (3H, d, J 6.3, C(5)CH₃), 1.48 (3H, d, J 7.1, C(2′)CH₃), 3.78 (3H, s, CO₂CH₃), 3.80–3.93 (3H, m, C(2′)H, C(4′)H₂), 4.27 (1H, d, J 4.3, C(4)H), 4.65–4.72 (1H, m, C(5)H), 5.47 (1H, s, C(2)H), 7.19–7.24 (1H, m, Ph), 7.27–7.30 (4H, m, Ph); δ_C (100 MHz, CDCl₃) 15.0 (C(2′)CH₃), 20.1 (C(5)CH₃), 25.8 (C(CH₃)₃), 38.0 (CMe₃), 40.6 (C(4′)), 50.5 (C(2′)), 52.7 (CO₂CH₃), 65.3 (C(4)), 76.4 (C(5)), 96.1 (C(2)), 126.9 (p-Ph), 128.5, 129.3 (o,m-Ph), 134.0 (i-Ph), 170.1 (CO₂Me), 172.4 (C(1′)), 202.2 (C(3′)); m/z (ESI⁺) 408 ([M + H]⁺, 5%), 430 ([M + Na]⁺, 45%), 837 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₂₁H₂₉NNaO₅S⁺ ([M + Na]⁺) requires 430.1659, found 430.1647; and 15d′ as a yellow solid (140 mg, 16%); R_f 0.2 (eluent 20 : 1 petrol–EtOAc); mp 102–106 °C; [α]²³_D − 22.5 (c 0.39 in CHCl₃); ν_max (film) 2976, 2957, 1742, 1660; δ_H (400 MHz, CDCl₃) 0.95 (9H, s, C(CH₃)₃), 1.34 (3H, d, J 6.8, C(2′)CH₃), 1.37 (3H, d, J 6.1, C(5)CH₃), 3.81–3.88 (4H, m, CO₂CH₃, C(2′)H), 3.91, 3.98 (2H, AB q, J 15.8, C(4′)H₂), 4.14 (1H, d, J 4.0, C(4)H), 4.78–4.85 (1H, m, C(5)H), 5.43 (1H, s, C(2)H), 7.20 (1H, t, J 7.3, p-Ph), 7.28 (2H, app. t, J 7.6, m-Ph), 7.35 (2H, d, J 7.8, o-Ph); δ_C (100 MHz, CDCl₃) 13.2 (C(2′)CH₃), 20.4 (C(5)CH₃), 26.0 (C(CH₃)₃), 38.1 (CMe₃), 42.0 (C(4′)), 50.8 (C(2′)), 53.1 (CO₂CH₃), 65.7 (C(4)), 76.0 (C(5)), 97.2 (C(2)), 126.7 (p-Ph), 129.0, 129.5 (o,m-Ph), 134.8 (i-Ph); m/z (ESI⁺) 408 ([M + H]⁺, 5%), 430 ([M + Na]⁺, 55%), 837 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₂₁H₂₉NNaO₅S⁺ ([M + Na]⁺) requires 430.1659, found 430.1646.

tert-Butyl 4-methoxy-2-methyl-3-oxo-5-phenylpentanoate 16

A stirred suspension of NaH (43 mg, 1.00 mmol) in THF (20 mL) was cooled to 0 °C and a solution of 13b (200 mg, 1.0 mmol) in THF (2 mL) was added dropwise. Stirring was continued for 10 min at 0 °C before the dropwise addition of BuLi (0.73 mL, 1.6 M in hexanes, 1.09 mmol). After stirring for a further 10 min, BnBr (0.13 mL, 1.09 mmol) was added in one portion and the mixture was allowed to warm to rt over 15 min. The mixture was quenched with 2 M HCl (7 mL) and extracted with Et₂O (2 × 15 mL). The combined organic layers were washed with H₂O until the aqueous layer remained neutral, dried and concentrated in vacuo. Purification by column chromatography (SiO₂, eluent 40 : 1 to 20 : 1 40–60 petrol–EtOAc) gave 16 as a colourless oil (117 mg, 40%) in a 47 : 43 dr; R_f 0.5 (eluent 50 : 1 40–60 petrol–EtOAc); ν_max (film) 3437, 3030, 2980, 2830, 1716, 1604; δ_H (100 MHz, CDCl₃) major diastereomer: 1.18 (3H, d, J 7.3, C(2)CH₃), 1.44 (9H, s, C(CH₃)₃), 2.88–2.93 (1H, m, C(5)H_AH_B), 3.11 (1H, dd, J 14.0, 4.2, C(5)H_AH_B), 3.32 (3H, s, OCH₃), 3.56–3.63 (1H, m, C(4)H), 7.19–7.33 (5H, m, Ph), minor diastereoisomer: 1.25 (3H, d, J 7.1, C(2)CH₃), 1.46 (9H, s, C(CH₃)₃), 2.88–2.93 (1H, m, C(5)H_AH_B), 3.04 (1H, dd, J 14.2, 4.0, C(5)H_AH_B), 3.27 (3H, s, OCH₃), 3.56–3.63 (1H, m, C(2)H), 2.97–4.03 (1H, m, C(4)H), 7.19–7.33 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 12.5 (C(2)CH₃), 27.9 (C(CH₃)₃), 37.2 (C(5) major), 38.5 (C(5) minor), 49.4, 50.1 (C(2)), 58.6, 58.9 (OCH₃), 81.4, 81.8 (CMe₃), 86.9, 87.7 (C(4)), 126.6, 128.3, 128.4, 129.3, 129.6 (o,m,p-Ph), 137.2 (i-Ph), 169.3, 169.8 (C(1)), 207.2, 207.8 (C(3)); m/z (ESI⁺) 315 ([M + Na]⁺, 80%), 291 ([M − H]⁻, 100%); HRMS (ESI⁺) C₁₇H₂₄NaO₄⁺ ([M + Na]⁺) requires 315.1567, found 315.1565.

4-Methoxy-2-methyl-3-oxo-5-phenylpentanoic acid 17

Following general procedure D, a solution of 16 (357 mg, 1.22 mmol) in DCM (1.7 mL) was cooled to 0 °C and TFA (1.7 mL) was added dropwise. The resulting solution was stirred for 1.5 h at rt before the solvent was removed in vacuo to give 17 in a 53 : 47 dr as an orange oil (283 mg, 98%); ν_max (film) 2939, 1713, 1496, 1455; δ_H (400 MHz, CDCl₃) 1.24 (3H × 0.53, d, J 7.3, C(2)CH₃ major), 1.28 (3H × 0.47, d, J 7.1, C(2)CH₃ minor), 2.89–3.00 (1H, m, C(5)H_AH_B), 3.06–3.15 (1H, m, C(5)H_AH_B), 3.28 (3H × 0.47, s, OCH₃ min), 3.30 (3H × 0.53, s, OCH₃ maj), 3.60–3.72 (1H, m, C(2)H), 3.99–4.05 (1H, m, C(4)H), 7.18–7.32 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 12.4 (C(2)CH₃), 37.4, 38.2 (C(5)), 48.2, 48.9 (C(2)), 58.6, 58.9 (OCH₃), 87.0, 87.7 (C(4)), 126.6, 126.7, 128.4, 128.5, 129.3, 129.4, 129.6 (o,m,p-Ph), 136.8, 137.1 (i-Ph), 175.5, 176.2 (C(1)), 206.8, 207.1 (C(3)); m/z (ESI⁺) 259 ([M + Na]⁺, 80%), 235 ([M − H]⁻, 80%); HRMS (ESI⁺) C₁₃H₁₆NaO₄⁺ ([M + Na]⁺) requires 259.0941, found 259.0947.

(2R,4S,5R)-2-tert-Butyl-3-(4′-methoxy-5′-phenyl-2′-methyl-3′-oxopentanoyl)-4-methoxycarbonyl-5-methyloxazolidine 18

Following general procedure E, oxazolidine 1 (229 mg, 1.14 mmol) was reacted with DCC (247 mg, 1.20 mmol), DMAP (10 mg, 7 mol%) and the acid 17 (236 mg, 1.20 mmol). The crude mixture of 18 (438 mg) was used without purification; R_f 0.25 (eluent 8 : 1 40–60 petrol–EtOAc); ν_max (film) 3339, 3030, 2934, 2118, 1822, 1741, 1651; m/z (ESI⁺) 442 ([M + Na]⁺, 60%), 861 ([2M + Na]⁺, 90%), 418 ([M − H]⁻, 30%); δ_H (400 MHz, CDCl₃) 0.90 (9H, s, C(CH₃)₃), 1.19 (3H, d, J 6.8, C(2′)CH₃), 1.50 (3H, d, J 6.1, C(5)CH₃), 2.63 (1H, q, J 6.8, C(2′)H), 2.88 (1H, dd, J 14.0, 5.2, C(5′)H_AH_B), 3.12 (1H, dd, J 14.0, 5.2, C(5′)H_AH_B), 3.30 (3H, s, OCH₃), 3.72 (3H, s, CO₂CH₃), 3.93 (1H, dd, J 5.2, 4.4, C(4′)H), 4.27 (1H, d, J 7.1, C(4)H), 4.51–4.58 (1H, m, C(5)H), 5.50 (1H, s, C(2)H), 7.12–7.32 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 8.2 (C(2′)CH₃), 21.0 (C(5)CH₃), 25.8/26.0 (C(CH₃)₃), 37.2/38.6 (CMe₃), 37.9 (C(5′)), 50.1 (C(2′)), 58.0/58.2 (OCH₃), 66.2 (C(4)), 77.6 (C(5)), 86.3 (C(4′)), 96.6 (C(2)), 126.3, 126.6, 128.3, 128.6, 129.1, 129.3, 129.4, 129.8 (o,m,p-Ph), 136.5 (i-Ph), 170.4 (CO₂Me), 172.8 (C(1′)), 206.8 (C(3′)); HRMS (ESI⁺) C₂₃H₃₃NNaO₆⁺ ([M + Na]⁺) requires 422.2200, found 422.2198.

tert-Butyl 3-oxo-2-allyl-4-(phenylthio)-butanoate 19a

A stirred suspension of NaH (33 mg, 0.83 mmol) in THF (6 mL) was cooled to 0 °C and a solution of 6d (200 mg, 0.75 mmol) in THF (2 mL) was added dropwise. Stirring was continued for 10 min at 0 °C before the dropwise addition of BuLi (0.53 mL, 1.48 M in hexanes, 0.79 mmol). After stirring for a further 10 min, allyl bromide (0.07 mL, 0.83 mmol) was added in one portion and the mixture was allowed to warm to rt over 15 min. The mixture was quenched with 2 M HCl (7 mL) and extracted with Et₂O (2 × 15 mL). The combined organic layers were washed with H₂O until the aqueous layer remained neutral, dried and concentrated in vacuo to give t-butyl 3-oxo-2-allyl-4-(phenylthio)-butanoate 19a as a yellow oil (232 mg, quant): R_f 0.2 (eluent 50 : 1 petrol–EtOAc); ν_max (film) 2978, 2927, 1738, 1710; δ_H (400 MHz, CDCl₃) 1.46 (9H, s, (C(CH₃)₃), 2.37–2.47 (1H, m, C(1′)H_AH_B), 2.51–2.62 (1H, m, C(1′)H_AH_B), 3.55 (1H, d, J 15.4, C(4)H_AH_B), 3.69 (1H, d, J 15.4, C(4)H_AH_B), 3.79 (1H, app. t, J 7.5, C(2)H), 5.07–5.17 (2H, m, C(3′)H₂), 5.76–5.89 (1H, m, C(2′)H), 7.26–7.42 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 28.0 (C(CH₃)₃), 33.8 (C(1′)), 47.6 (C(4)), 56.0 (C(2)), 82.0 (CMe₃), 118.0 (C(3′)), 128.7, 128.9, 129.1 (o,m,p-Ph), 133.9 (C(2′)), 134.6 (i-Ph), 166.3 (C(1)), 198.2 (C(3)); m/z (ESI⁺) 329 ([M + Na]⁺, 15%), 635 ([2M + Na]⁺, 20%); HRMS (ESI⁺) C₁₇H₂₂NaO₃S⁺ ([M + Na]⁺) requires 329.1182, found 329.1182.

tert-Butyl 3-oxo-2-benzyl-4-(phenylthio)-butanoate 19b

A stirred suspension of NaH (17 mg, 0.41 mmol) in THF (4 mL) was cooled to 0 °C and a solution of 6d (100 mg, 0.38 mmol) in THF (1 mL) was added dropwise. Stirring was continued for 10 min at 0 °C before the dropwise addition of BuLi (0.27 mL, 1.48 M in hexanes, 0.39 mmol). After stirring for a further 10 min, BnBr (0.05 mL, 0.41 mmol) was added in one portion and the mixture was allowed to warm to rt over 15 min. The mixture was quenched with 2 M HCl (7 mL) and extracted with Et₂O (2 × 15 mL). The combined organic layers were washed with H₂O until the aqueous layer remained neutral, dried and concentrated in vacuo. Purification by column chromatography (SiO₂, eluent 50 : 1 40–60 petrol–EtOAc) gave t-butyl 3-oxo-2-benzyl-4-(phenylthio)-butanoate 19b as a yellow oil (91 mg, 54%) in a 4 : 1 mixture with unreacted starting material; R_f 0.2 (eluent 50 : 1 petrol–EtOAc); ν_max (film) 2978, 2931, 1737, 1709; δ_H (400 MHz, CDCl₃) 1.41 (9H, s, C(CH₃)₃), 2.96 (1H, dd, J 14.4, 7.2, C(1′)H_AH_B), 3.22 (1H, dd, J 14.4, 7.6, C(1′)H_AH_B), 3.52 (1H, d, J 15.3, C(4)H_AH_B), 3.63 (1H, d, J 15.3, C(4)H_AH_B), 4.04 (1H, app. t, J 7.4, C(2)H), 7.14–7.37 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 27.9 (C(CH₃)₃), 35.9 (C(5)), 48.2 (C(2)), 57.9 (C(4)), 82.0 (CMe₃), 126.7–129.6 (o,m,p-Ph, -SPh), 133.8 (i-SPh), 138.0 (i-Ph), 166.1 (C(1)), 198.1 (C(3)); m/z (ESI⁻) 355 ([M − H]⁻, 100%); HRMS (ESI⁺) C₂₁H₂₄NaO₃S⁺ ([M + Na]⁺) requires 379.1228, found 379.1338.

2-Allyl-3-oxo-4-(phenylthio)-butanoic acid 20a

Following Procedure D, a solution of 19a (232 mg, 0.75 mmol) in DCM (1.0 mL) was cooled to 0 °C and TFA (1.0 mL) was added dropwise. The resulting solution was stirred for 1.5 h at rt before the solvent was removed in vacuo to give 21a as a pale yellow oil (190 mg, quant); ν_max (film) 3077, 2923, 1704; δ_H (400 MHz, CDCl₃) 2.43–2.64 (2H, m, C(1′)H₂), 3.75–3.79 (3H, m, C(4)H₂, C(2)H), 5.09–5.20 (2H, m, C(3′)H₂), 5.76–5.89 (1H, m, C(2′)H), 7.28–7.42 (5H, m, Ph), 8.57 (1H, br s, OH); δ_C (100 MHz, CDCl₃) 33.7 (C(1′)), 45.0 (C(4)), 56.5 (C(2)), 118.5 (C(3′)), 129.0, 129.2, 129.3, 130.0, 130.7 (o,m,p-Ph), 133.3, 134.0 (C(2′), i-Ph), 198.8 (C(3)); m/z (ESI⁺) 273 ([M + Na]⁺, 100%), (ESI⁻) 249 ([M − H]⁻, 60%); HRMS (ESI⁺) C₁₃H₂₄NaO₃S⁺ ([M + Na]⁺) requires 273.0556, found 273.0561.

2-Benzyl-3-oxo-4-(phenylthio)-butanoic acid 20b

According to procedure D, a solution of 19b (90 mg, 0.26 mmol) in DCM (0.5 mL) was cooled to 0 °C and TFA (0.5 mL) was added dropwise. The resulting solution was stirred for 1.5 h at rt before the solvent was removed in vacuo to give 20b as a yellow oil (71 mg, 92%) in a 3 : 1 mixture of keto–enol tautomers; ν_max (film) 3061, 3028, 2928, 1705; δ_H (400 MHz, CDCl₃) keto form – 2.89–3.28 (2H, m, CH₂Ph), 3.66–3.72 (2H, m, C(4)H₂), 4.03 (1H, app. t, J 7.6, C(2)H), 7.15–7.45 (10H, m, Ph, SPh); enol form – 2.89–3.28 (2H, m, CH₂Ph), 4.30 (1H, app. t, J 7.5, C(2)H), 4.83 (1H, s, C(4)H), 7.15–7.45 (10H, m, Ph, SPh); δ_C (100 MHz, CDCl₃) 34.0, 35.9 (CH₂Ph), 45.9 (C(4) keto), 57.1 (C(2) enol), 58.3 (C(2) keto), 90.1 (C(4) enol), 126.8, 126.9, 127.2, 127.5, 128.3, 128.4, 128.5, 128.6, 129.0, 129.1, 129.7, 130.0 (o,m,p-Ph, -SPh), 133.4, 134.0 (i-Ph), 137.7, 140.0 (i-SPh), 171.8, 173.8 (C(1)), 198. 3, 198.8 (C(3)); m/z (ESI⁺) 323 ([M + Na]⁺, 100%), (ESI⁻) 299 ([M − H]⁻, 100%); HRMS (ESI⁺) C₁₇H₁₆NaO₃S⁺ ([M + Na]⁺) requires 323.0712, found 323.0716%.

(2R,4S,5R)-2-tert-Butyl-3-(2′-allyl-3′-oxo-4′-phenylthio-butanoyl)-4-methoxycarbonyl-5-methyloxazolidine 21a

Following general procedure E, oxazolidine 1 (169 mg, 0.84 mmol) was reacted with DCC (183 mg, 0.88 mmol), DMAP (7 mg, 7 mol%) and acid 20a (211 mg, 0.84 mmol). Purification via column chromatography gave 21a as a mixture of indeterminate dr as a pale yellow oil (100 mg, 27%); R_f 0.2 (eluent 20 : 1 petrol–EtOAc); ν_max (film) 2956, 2926, 2871, 2855, 1746, 1714, 1667, 1625; δ_H (400 MHz, CDCl₃) 0.89 (9H, s, C(CH₃)₃), 1.32–1.40 (3H, m, C(5)CH₃) 2.41–2.73 (2H, m, C(1′′)H₂), 3.72–3.82 (4H, m, CO₂CH₃), C(4′)H_AH_B), 3.90–3.95 (1H, m, C(2′)H), 4.00 (1H, d, J 15.2, C(4′)H_AH_B), 3.81 and 4.26 (1H, d, J 2.8 and 3.5, C(4)H), 4.66–4.72 and 4.73–4.79 (1H, m, C(5)H), 5.07–5.20 (2H, m, C(3′′)H₂), 5.38–5.43 (1H, m, C(2)H), 5.75–5.91 (1H, m, C(2′′)H), 7.25–7.34 (3H, m, o,p-Ph), 7.34–7.46 (2H, m, m-Ph); δ_C (100 MHz, CDCl₃) 19.9, 20.0 (C(5)CH₃), 25.8 (C(CH₃)₃), 33.9 (C(1′′)), 37.7 (CMe₃), 46.9, 48.4 (C(4′)), 52.6, 52.7 (CO₂CH₃), 55.9, 46.0 (C(2′)), 65.1 (C(4)), 75.9 (C(5)), 95.9 (C(2)), 117.9, 118.0 (C(3′′)), 127.8, 127.9 (p-Ph), 128.7, 128.9, 129.0, 129.2 (o,m-Ph), 132.4, 133.7 (i-Ph), 134.0, 134.2 (C(2′′)), 167.9 (C(1′)), 170.1 (CO₂Me), 185.8 (C(3′)); m/z (ESI⁺) 456([M + Na]⁺, 100%), (ESI⁻) 432 ([M − H]⁻, 100%); HRMS (ESI⁺) C₂₃H₃₁NNaO₅S⁺ ([M + Na]⁺) requires 456.1815, found 456.1809.

(2R,4S,5R)-2-tert-Butyl-3-(2′-benzyl-3′-oxo-4′-phenylthio-butanoyl)-4-methoxycarbonyl-5-methyloxazolidine 21b

Following general procedure E, oxazolidine 1 (47 mg, 0.24 mmol) was reacted with DCC (51 mg, 0.25 mmol), DMAP (2 mg, 7 mol%) and acid 20b (71 mg, 0.24 mmol). Purification via flash column chromatography (SiO₂, eluent 20 : 1 petrol–EtOAc) gave 21b in a 1 : 1 dr as a colourless oil (20 mg, 17%); R_f 0.2 (eluent 20 : 1 petrol–EtOAc); ν_max (film) 3029, 2975, 2956, 2933, 2873, 1745, 1715, 1667, 1625; δ_H (500 MHz, CDCl₃) 0.87 (9H, s, C(CH₃)₃), 1.16 and 1.22 (3H, d, J 6.3, C(5)CH₃), 2.98–3.11 (1H, m, CH_AH_BPh), 3.16–3.30 (1H, m, CH_AH_BPh), 3.61–3.82 (5H, m, CO₂CH₃, C(4′)H₂-epimer A, C(4′)H_AH_B-epimer B, C(4)H-A), 3.95 (0.5 × 1H, d, J 15.1, C(4′)H_AH_B-B), 4.07–4.12 (0.5 × 2H, m, C(4)H–B, C(2′)H-A), 4.17 (0.5 × 1H, app. t, J 7.6, C(2′)H–B), 4.63–4.68 and 4.69–4.73 (1H, m, C(5)H), 5.20 and 5.39 (1H, s, C(2)H), 7.14–7.32 (10H, m, Ph, SPh); δ_C (125 MHz, CDCl₃) 19.8, 19.9 (C(5)CH₃), 25.7, 25.7 (C(CH₃)₃), 36.0, 36.3, 37.6, 37.7 (CH₂Ph, CMe₃), 48.2, 48.6 (C(4′)), 52.5, 52.7 (CO₂CH₃), 57.5, 57.8 (C(2′)), 64.9, 64.9 (C(4)), 75.7, 75.8 (C(5)), 95.8, 95.9 (C(2)), 126.8–129.2 (o,m,p-Ph, -SPh), 133.0, 133.5 (i-SPh), 137.5, 137.6 (i-Ph), 167.5, 168.1 (C(1′)), 170.0, 170.1 (CO₂Me), 199.6, 200.1 (C(3′)); m/z (ESI⁻) 482 ([M − H]⁻, 100%), (ESI⁺) 506 ([M + Na]⁺, 60%); HRMS (ESI⁺) C₂₇H₃₃NNaO₅S⁺ ([M + Na]⁺) requires 506.1972, found 506.1980.

(2R,4R,5R,6R)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-methoxymethyl-8-oxo-3-oxabicylco[3.3.0]octane 22a

Following general procedure H, 8 (440 mg, 1.40 mmol) and NaOMe (83 mg, 1.53 mmol) were reacted to give the crude reaction mixture. Purification via column chromatography (SiO₂, eluent 3 : 1 40–60 petrol–EtOAc) gave 22a as a white solid (99 mg, 22%); R_f 0.1 (eluent 3 : 1 40–60 petrol–EtOAc); mp 144–147 °C; [α]²³_D + 26.7 (c 1.0 in CHCl₃); ν_max (film) 3404 (br), 2956, 1704; δ_H (400 MHz, CDCl₃) 0.91 (9H, s, C(CH₃)₃), 1.63 (3H, d, J 6.6, C(4)CH₃), 2.34 (1H, d, J 16.2, C(7)H_AH_B), 3.06 (1H, d, J 16.2, C(7)H_AH_B), 3.09 (1H, s, OH), 3.35 (1H, d, J 9.7, CH_AH_BOMe), 3.36 (3H, s, OCH₃), 3.50 (1H, d, J 9.7, CH_AH_BOMe), 3.77 (3H, s, CO₂CH₃), 4.76 (1H, q, J 6.6, C(4)H), 5.04 (1H, s, C(2)H); δ_C (100 MHz, CDCl₃) 15.5 (C(4)CH₃), 25.6 (C(CH₃)₃), 37.0 (CMe₃), 45.8 (C(7)), 52.6 (CO₂CH₃), 59.3 (OCH₃), 74.3 (CH₂OMe), 78.6 (C(4)), 79.0, 82.2 (C(5), C(6)), 171.5 (CO₂Me), 178.2 (C(8)); m/z (ESI⁻) 314 ([M − H]⁻, 100%); HRMS (ESI⁺) C₁₅H₂₆NO₆⁺ ([M + H]⁺) requires 316.1755, found 316.1754.

(2R,5R,4R,6R)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-(but-3′-enyl)-8-oxo-oxabicyclo[3.3.0]octane 22b

Following general procedure H, N-acyloxazolidine 15b (143 mg, 0.44 mmol) and NaOMe (26 mg, 0.48 mmol) were reacted to give a crude mixture which was purified via column chromatography (SiO₂, eluent 20 : 1–6 : 1) to give unreacted 9a (74 mg, 51%) and 22b as a colourless oil (67 g, 46%); R_f 0.6 (eluent 2 : 1 petrol–EtOAc); [α]²³_D + 18.0 (c 0.95 in CHCl₃); ν_max (film) 3418 (OH), 3078, 2955, 1702 (ester C=O), 1642 (amide C=O); δ_H (400 MHz, CDCl₃) 0.91 (9H, s, C(CH₃)₃), 1.33–1.43 (1H, m, C(1′)H_AH_B), 1.70 (3H, d, J 6.6, C(4)CH₃), 1.90–1.98 (1H, m, C(1′)H_AH_B), 1.99–2.10 (1H, m, C(2′)H_AH_B), 2.30–2.37 (1H, m, C(2′)H_AH_B), 2.37 (1H, d, J 15.8, C(7)H_AH_B), 3.04 (1H, d, J 15.8, C(7)H_AH_B), 3.14 (1H, br s, OH), 3.80 (3H, s, CO₂CH₃), 4.79 (1H, q, J 6.6, C(4)H), 4.98–5.10 (2H, m, C(4′)H₂), 5.06 (1H, s, C(2)H), 5.76–5.87 (1H, m, C(3′)H); δ_C (100 MHz, CDCl₃) 15.3 (C(4)CH₃), 25.7 (C(CH₃)₃), 28.6 (C(2′)), 35.0 (C(1′)), 37.4 (CMe₃), 47.4 (C(7)), 52.7 (CO₂CH₃), 78.5 (C(4)), 80.9, 84.8 (C(6), C(5)), 96.2 (C(2)), 115.5 (C(4′)), 137.8 (C(3′)), 172.0, 178.5 (CO₂Me, C(8)); m/z (ESI⁺) 348 ([M + Na]⁺, 90%), 673 ([2M + Na]⁺, 100%), 324 ([M − H]⁻, 100%); HRMS (ESI⁺) C₁₇H₂₇NNaO₅⁺ ([M + H]⁺) requires 348.1781, found 348.1771.

(2R,4R,5R,6R)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-(p-bromophenyl)-8-oxo-3-oxabicyclo[3.3.0]octane 22c

Following general procedure H, N-acyl-oxazolidine 9b (460 mg, 1.05 mmol) and NaOMe (62 mg, 1.15 mmol) were reacted to give a product which was purified via column chromatography (SiO₂, eluent DCM) to give unreacted 9b (115 mg) and 22c as a yellow solid (198 mg, 42%); R_f 0.1 (eluent DCM); mp 122–125 °C; [α]²³_D − 4.6 (c 0.63 in CHCl₃); ν_max (film) 3414, 2956, 2874, 1703, 1488; δ_H (400 MHz, CDCl₃) 0.89 (9H, s, C(CH₃)₃), 1.76 (3H, d, J 6.6, C(4)CH₃), 1.85 (1H, d, J 15.9, C(1′)H_AH_B), 2.45 (1H, d, J 13.4, C(7)H_AH_B), 3.04–3.09 (2H, m, C(1′)H_AH_B, C(7)H_AH_B), 3.19 (1H, br s, OH), 3.83 (3H, s, CO₂CH₃), 4.79 (1H, q, J 6.6, C(4)H), 4.99 (1H, s, C(2)H), 7.04 (2H, d, J 8.3, o-Ph), 7.39 (2H, d, J 8.3, m-Ph); δ_C (100 MHz, CDCl₃) 15.3 (C(4)CH₃), 25.7 (C(CH₃)₃), 37.4 (CMe₃), 41.3 (C(7)), 47.2 (C(1′)), 52.9 (CO₂CH₃), 78.6 (C(4)), 80.6 (C(5)), 83.9 (C(6)), 96.2 (C(2)), 121.2 (i-Ph), 131.7, 131.9 (o,m-Ph), 143.4 (CBr), 172.0 (CO₂Me), 178.0 (C(8)); m/z (ESI⁻) 438/440 ([M − H]⁻, 100%); HRMS (ESI⁺) C₂₀H₂₆NNaO₅⁺ ([M + Na]⁺) requires 462.0887, 464.0867, found 462.0879, 464.0855.

(2R,4R,5R,6R)-1-Aza-2-tert-butyl-4methyl-5-methoxycarbonyl-6-hydroxy-6-(phenylthio-methyl)-8-oxo-3-oxabicyclo[3.3.0]octane 22d

Following general procedure H, N-acyl-oxazolidine 9c (550 mg, 1.39 mmol) and NaOMe (84 mg, 1.55 mmol) were reacted to give a crude mixture which was purified via column chromatography (SiO₂, eluent 5 : 1 petrol–EtOAc) to give 22d as a pale yellow oil (167 mg, 30%); R_f 0.25 (eluent 5 : 1 petrol–EtOAc); [α]²³_D + 8.9 (c 1.0 in CHCl₃); ν_max (film) 3400, 2956, 2874, 1743, 1703, 1584, 1481; δ_H (400 MHz, CDCl₃) 0.90 (9H, s, C(CH₃)₃), 1.69 (3H, d, J 6.6, C(4)CH₃), 2.33 (1H, d, J 15.8, C(7)H_AH_B), 2.89 (1H, d, J 15.8, C(7)H_AH_B), 3.03 (1H, d, J 13.9, C(1′)H_AH_B), 3.34 (1H, s, OH), 3.37 (1H, d, J 13.9, C(1′)H_AH_B), 3.82 (3H, s, CO₂CH₃), 4.75 (1H, q, J 6.6, C(4)H), 5.05 (1H, s, C(2)H), 7.22–7.33 (3H, m, Ph), 7.38–7.41 (2H, m, Ph); δ_C (100 MHz, CDCl₃) 15.4 (C(4)CH₃), 25.7 (C(CH₃)₃), 37.4 (CMe₃), 41.8 (C(1′)), 47.8 (C(7)), 53.0 (CO₂CH₃), 78.5 (C(4)), 80.1 (C(5)), 83.6 (C(6)), 96.6 (C(2)), 127.4 (p-Ph), 129.4, 130.5 (o,m-Ph), 135.0 (i-Ph), 171.6 (CO₂Me), 177.7 (C(8)); m/z (ESI⁺) 392 ([M − H]⁻, 100%); HRMS (ESI⁺) C₂₀H₂₆NO₅S⁺ ([M − H]⁻) requires 392.01537, found 392.1533.

(2R,4R,5R,6R)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-(1′-methoxy-2′-phenylethyl)-8-oxo-3-oxabicyclo[3.3.0]octane 22e

Following general procedure H, N-acyl-oxazolidine 12 (107 mg, 0.26 mmol) and NaOMe (16 mg, 0.29 mmol) were reacted to give the crude reaction mixture. Purification via column chromatography (SiO₂, eluent 20 : 1 40–60 petrol–EtOAc) gave 22e as a colourless oil (6.5 mg, 6%); R_f 0.05 (eluent 8 : 1 40–60 petrol–EtOAc); [α]²³_D + 11.6 (c 0.32 in CHCl₃); ν_max (film) 2956, 1698; δ_H (500 MHz, CDCl₃) 0.92 (9H, s, C(CH₃)₃), 1.68 (3H, d, J 6.6, C(4)CH₃), 1.78 (1H, d, J 16.1, C(7)H_AH_B), 2.77 (1H, dd, J 14.7, 6.0, C(2′)H_AH_B), 3.13 (3H, s, OCH₃), 3.15 (1H, dd, J 14.7, 4.1, C(2′)H_AH_B), 3.27–3.32 (1H, m, C(7)H_AH_B), 3.71 (1H, dd, J 6.0, 4.1, C(1′)H), 3.76 (3H, s, CO₂CH₃), 4.75 (1H, q, J 6.6, C(4)H), 5.00 (1H, s, C(2)H), 7.22–7.31 (5H, m, Ph); δ_C (125 MHz, CDCl₃) 15.4 (C(4)CH₃), 25.8 (C(CH₃)₃), 35.5 (C(2′)), 37.2 (CMe₃), 44.1 (C(7)), 52.4 (CO₂CH₃), 57.8 (OCH₃), 78.1 (C(5)), 78.9 (C(4)), 81.9 (C(1′)), 87.4 (C(6)), 96.4 (C(2)), 126.6 (p-Ph), 128.2, 128.6, 129.3, 129.6 (o,m-Ph), 138.3 (i-Ph), 171.5 (CO₂Me), 178.5 (C(8)); m/z (ESI⁺) 406 ([M + H]⁺, 30%), 428 ([M + Na]⁺, 80%), 404 ([M − H]⁻, 100%); HRMS (ESI⁺) C₂₂H₃₁NNaO₆⁺ ([M + H]⁺) requires 428.2044, found 428.2026.

(2R,4R,5R,6R,7S)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-methoxymethyl-7-methyl-8-oxo-3-oxabicyclo[3.3.0]octane 22f

Following general procedure H, 15a (280 mg, 0.85 mmol) and NaOMe (50 mg, 0.94 mmol) were reacted to give the crude reaction mixture. Purification via column chromatography (SiO₂, eluent 3 : 1 40–60 petrol–EtOAc) gave 22f as a colourless solid (30 mg, 21%); R_f 0.1 (eluent 3 : 1 40–60 petrol–EtOAc); mp 120–130 °C; [α]²³_D − 31.7 (c 1.0 in CHCl₃); ν_max (film) 3457 (br), 2956, 1725; δ_H (400 MHz, CDCl₃) 0.92 (9H, s, C(CH₃)₃), 1.05 (3H, d, J 7.1, C(7)CH₃), 1.68 (3H, d, J 6.6, C(4)CH₃), 2.53 (1H, s, OH), 3.19 (1H, q, J 7.1, C(7)H), 3.33 (3H, s, OCH₃), 3.40 (1H, d, J 9.9, CH_AH_BOMe), 3.47 (1H, d, J 9.9, CH_AH_BOMe), 3.76 (3H, s, CO₂CH₃), 4.72 (1H, q, J 6.6, C(4)H), 5.03 (1H, s, C(2)H); δ_C (100 MHz, CDCl₃) 6.6 (C(7)CH₃), 15.5 (C(4)CH₃), 25.7 (C(CH₃)₃), 37.3 (CMe₃), 45.4 (C(7)), 52.6 (CO₂CH₃), 59.2 (OCH₃), 72.4 (CH₂OMe), 77.2 (C(5)), 78.9 (C(4)), 85.2 (C(6)), 96.6 (C(2)), 171.5 (CO₂Me), 180.5 (C(8)); m/z (ESI⁺) 352 ([M + Na]⁺, 90%), (ESI⁻) 328 ([M − H]⁻, 100%); HRMS (ESI⁺) C₁₆H₂₇NNaO₆⁺ ([M + Na]⁺) requires 352.1731, found 352.1725.

(2R,5R,4R,6R,7S)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-(but-3′-enyl)-7-methyl-8-oxo-oxabicyclo[3.3.0]octane 22g

Following general procedure H, N-acyl-oxazolidine 15b (258 mg, 0.76 mmol) and NaOMe (45 mg, 0.84 mmol) were reacted to give a crude mixture which was purified via column chromatography (SiO₂, eluent 10 : 1 petrol–EtOAc) to give 22g as a colourless oil (132 mg, 51%); R_f 0.56 (eluent 3 : 1 40–60 petrol–EtOAc); [α]²³_D + 1.88 (c 0.65 in CHCl₃); ν_max (film) 3454 (OH), 3071, 2957, 2251, 1725; δ_H (400 MHz, CDCl₃) 0.91 (9H, s, C(CH₃)₃), 1.11 (3H, d, J 7.2, C(7)CH₃), 1.68 (3H, d, J 6.6, C(4)CH₃), 1.70–1.80 (2H, m, C(1′)H₂), 2.08–2.20 (1H, m, C(2′)H_AH_B), 2.21–2.31 (1H, m, C(2′)H_AH_B), 3.11 (1H, q, J 7.2, C(7)H), 3.79 (3H, s, CO₂CH₃), 4.81 (1H, q, J 6.6, C(4)H), 4.94–5.07 (2H, m, C(4′)H₂), 5.01 (1H, s, C(2)H), 5.73–5.85 (1H, m, C(3′)H); δ_C (125 MHz, CDCl₃) 7.4 (C(7)CH₃), 15.9 (C(4)CH₃), 28.3 (C(2′)), 35.0 (C(1′)), 37.3 (C(CH₃)₃), 48.3 (C(7)), 52.7 (CO₂CH₃), 78.8 (C(4)), 79.1 (C(5)), 86.3 (C(6)), 96.1, (C(2)), 115.3 (C(4′)), 137.8 (C(3′)), 172.0 (CO₂Me), 180.0 (C(8)); m/z (ESI⁺) 362 ([M + Na]⁺, 100%); HRMS (ESI⁺) C₁₈H₂₉NNaO₅⁺ ([M + Na]⁺) requires 362.1938, found 362.1923; and unreacted 15b (50 mg, 38%).

(2R,4R,5R,6R,7S)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-(p-bromophenyl)-7-methyl-8-oxo-3-oxabicyclo[3.3.0]octane 22h

Following general procedure H, N-acyl-oxazolidine 15c (242 mg, 0.53 mmol) and NaOMe (32 mg, 0.58 mmol) were reacted the crude material, which was purified by column chromatography (SiO₂, eluent 5 : 1 petrol–EtOAc) to give 22h as a colourless solid (124 mg, 72%); R_f 0.35 (eluent 5 : 1 petrol–EtOAc); mp 150–153 °C; [α]²³_D + 1.82 (c 0.37 in CHCl₃); ν_max (film) 3458, 2955, 2873, 1708, 1659; δ_H (400 MHz, CDCl₃) 0.65 (3H, d, J 7.1, C(7)CH₃), 0.92 (9H, s, C(CH₃)₃), 1.66 (3H, d, J 6.6, C(4)CH₃), 2.09 (1H, br s, OH), 2.63 (1H, d, J 14.2, C(1′)H_AH_B), 3.17 (1H, d, J 14.2, C(1′)H_AH_B), 3.21 (1H, q, J 7.1, C(7)H), 3.85 (3H, s, CO₂CH₃), 4.83 (1H, q, J 6.6, C(4)H), 5.00 (1H, s, C(2)H), 7.14 (2H, d, J 8.3, o-Ph), 7.43 (2H, d, J 8.3, m-Ph); δ_C (100 MHz, CDCl₃) 7.5 (C(7)CH₃), 15.5 (C(4)CH₃), 25.8 (C(CH₃)₃), 37.4 (CMe₃), 41.1 (C(1′)), 48.2 (C(7)), 52.9 (CO₂CH₃), 78.8 (C(4)), 79.1 (C(5)), 85.4 (C(6)), 96.6 (C(2)), 121.4 (i-Ph), 131.5 (o-Ph), 132.5 (m-Ph), 134.0 (CBr), 172.1 (CO₂Me), 180.3 (C(8)); m/z (ESI⁺) 476/478 ([M + Na]⁺, 35%), 929, 931, 933 ([2M + Na]⁺, 100%); HRMS (ESI⁺) C₂₁H₂₈BrNNaO₅⁺ ([M + Na]⁺) requires 476.1043, 478.1024, found 476.1047, 478.1032.

(2R,4R,5R,6R,7S)-1-aza-2-tert-butyl-4methyl-5-methoxycarbonyl-6-hydroxy-6-(phenylthio-methyl)-7-methyl-8-oxo-3-oxabicyclo[3.3.0]octane 22i

Following general procedure H, N-acyl-oxazolidine 15d (122 mg, 0.3 mmol) and NaOMe (18 mg, 0.33 mmol) were reacted to give 22i as a yellow solid (92 mg, 75%); R_f 0.25 (eluent 5 : 1 petrol–EtOAc); mp 150–152 °C; [α]²³_D + 6.7 (c 1.0 in CHCl₃); ν_max (film) 3367 (br), 2956, 2938, 2873, 1722, 1695; δ_H (400 MHz, CDCl₃) 0.93 (9H, s, C(CH₃)₃), 1.02 (3H, d, J 7.1, C(7)CH₃), 1.68 (3H, d, J 6.6, C(4)CH₃), 2.82 (1H, br s, OH), 3.17 (1H, q, J 7.1, C(7)H), 3.31 (2H, s, CH₂SPh), 3.83 (3H, s, CO₂CH₃), 4.77 (1H, q, J 6.6, C(4)H), 5.02 (1H, s, C(2)H), 7.25–7.34 (3H, m, m,p-Ph), 7.41 (2H, d, J 8.3, o-Ph); δ_C (125 MHz, CDCl₃) 7.2 (C(7)CH₃), 15.7 (C(4)CH₃), 25.7 (C(CH₃)₃), 37.3 (CMe₃), 41.4 (CH₂Ph), 47.9 (C(7)), 52.9 (CO₂CH₃), 78.3 (C(4)), 78.8 (C(5)), 85.1 (C(6)), 96.4 (C(2)), 127.4, 129.3 (m,p-Ph), 130.6 (o-Ph), 135.6 (i-Ph), 171.6 (CO₂Me), 179.6 (C(8)); m/z (ESI⁻) 406 ([M − H]⁻, 40%); HRMS (ESI⁻) C₂₁H₂₈NO₅S⁻ ([M − H]⁻) requires 406.1694, found 406.1707.

(2R,4R,5R,6R,7R)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-(1′-methoxy-2′-phenylethyl)-7-methyl-8-oxo-3-oxabicyclo[3.3.0]octane 22j

Following general procedure H, N-acyl-oxazolidine 18 (400 mg, 0.95 mmol) and NaOMe (57 mg, 1.05 mmol) were reacted to give the crude reaction mixture. Purification via column chromatography (SiO₂, eluent 20 : 1 40–60 petrol–EtOAc) gave 22j as a white solid (54 mg, 14%); R_f 0.1 (eluent 8 : 1, 40–60 petrol–EtOAc); mp 198–201 °C; [α]²³_D + 4.9 (c 0.63 in CHCl₃); ν_max (film) 3315, 2937, 1736, 1682; δ_H (400 MHz, CDCl₃) 0.94 (9H, s, C(CH₃)₃), 1.15 (3H, d, J 7.0, C(7)CH₃), 1.72 (3H, d, J 6.6, C(4)CH₃), 2.63–2.77 (2H, m, C(2′)H₂), 2.96 (3H, s, OCH₃), 3.20 (1H, q, J 7.0, C(7)H), 3.23 (1H, s, OH), 3.66 (1H, dd, J 10.0, 2.4, C(1′)H), 3.83 (3H, s, CO₂CH₃), 4.80 (1H, q, J 6.6, C(4)H), 5.06 (1H, s, C(2)H), 7.21–7.35 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 7.6 (C(7)CH₃), 16.2 (C(4)CH₃), 25.7 (C(CH₃)₃), 37.3 (CMe₃), 38.4 (C(2′)), 45.2 (C(7)), 52.8 (CO₂CH₃), 61.7 (OCH₃), 76.7 (C(5)), 79.3 (C(4)), 83.3 (C(1′)), 87.3 (C(6)), 96.1 (C(2)), 126.7 (p-Ph), 128.6, 129.3 (o,m-Ph), 138.4 (i-Ph), 172.4 (CO₂Me), 179.6 (C(8)); m/z (ESI⁺) 418 ([M − H]⁻, 95%); HRMS (ESI⁺) C₂₃H₃₄NO₆⁺ ([M + H]⁺) requires 420.2381, found 420.2375; and a 58 : 42 mixture of the starting material 18 and 22j′ as a colourless gum; R_f 0.25 (eluent 8 : 1 40–60 petrol–EtOAc); ν_max (film) 3447, 2936, 1728; δ_H (400 MHz, CDCl₃) 0.92 (9H, s, C(CH₃)₃), 1.21 (3H, d, J 7.3, C(7)CH₃), 1.58 (3H, d, J 6.8, C(4)CH₃), 2.75 (1H, dd, J 14.4, 6.6, C(2′)H_AH_B), 3.06 (3H, s, OCH₃), 3.24 (1H, dd, J 14.4, 4.6, C(2′)H_AH_B), 3.57 (1H, q, J 7.1, C(7)H), 3.76 (3H, s, CO₂CH₃), 3.77–3.81 (1H, m, C(1′)H), 4.73 (1H, q, J 6.8C(4)H), 4.99 (1H, s, C(2)H), 7.12–7.32 (5H, m, Ph); δ_C (100 MHz, CDCl₃) 12.9 (C(7)CH₃), 15.4 (C(4)CH₃), 25.8/26.0 (C(CH₃)₃), 36.9 (C(2′)), 38.6 (CMe₃), 44.9 (C(7)), 52.4 (CO₂CH₃), 58.0 (OCH₃), 76.54 (C(5)), 79.0 (C(4)), 82.7 (C(1′)), 88.7 (C(6)), 96.4 (C(2)), 140.1 (i-Ph), 171.6 (CO₂Me), 180.7 (C(8)); m/z (ESI⁺) 420 ([M + H]⁺, 60%), 442 ([M + Na]⁺, 90%), 418 ([M − H]⁻, 100%); HRMS (ESI⁺) C₂₃H₃₄NO₆⁺ ([M + H]⁺) requires 420.2381, found 420.2374.

(2R,4R,5R,6R,7S)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-(phenylthio-methyl)-7-allyl-8-oxo-3-oxabicyclo[3.3.0]octane 22k

Following general procedure H, N-acyloxazolidine 21a (100 mg, 0.23 mmol) and NaOMe (14 mg, 0.25 mmol) were reacted to give a crude mixture which was purified via column chromatography (SiO₂, eluent 10 : 1 petrol–EtOAc) to give 22k as an off-white solid (8 mg, 8%); R_f 0.1 (eluent 10 : 1 petrol–EtOAc); mp 95–97 °C; [α]²³_D − 5.92 (c 0.4 in CHCl₃); ν_max (film) 3430, 2955, 2923, 2854, 1725; δ_H (500 MHz, CDCl₃) 0.93 (9H, s, C(CH₃)₃), 1.65 (3H, d, J 6.6, C(4)CH₃), 2.29–2.38 (1H, m, C(1′′)H_AH_B), 2.46–2.57 (1H, m, C(1′′)H_AH_B), 2.89 (1H, s, OH), 3.18 (1H, app. t, J 6.2, C(7)H), 3.30 (1H, d, J 14.2, C(1′)H_AH_B), 3.40 (1H, d, J 14.2, C(1′)H_AH_B), 3.83 (3H, s, CO₂CH₃), 4.81 (1H, q, J 6.6, C(4)H), 5.00–5.13 (2H, m, C(3′′)H₂), 5.05 (1H, s, C(2)H), 5.93–6.03 (1H, m, C(2′′)H), 7.24–7.41 (5H, m, Ph); δ_C (125 MHz, CDCl₃) 14.1 (C(4)CH₃), 25.6 (C(CH₃)₃), 28.1 (C(1′′)), 37.1 (CMe₃), 41.3 (C(1′)), 52.3 (C(7)), 53.0 (CO₂CH₃), 78.6, 78.7 (C(4), C(5)), 85.7 (C(6)), 96.0 (C(2)), 117.1 (C(3′′)), 127.3, 129.3, 130.3 (o,m,p-Ph), 135.6, 136.5 (i-Ph, C(2′′)), 171.7 (CO₂Me), 178.1 (C(8)); m/z (ESI⁺) 456 ([M + Na]⁺, 75%), (ESI⁻) 432 ([M − H]⁻, 100%); HRMS (ESI⁺) C₂₃H₃₁NNaO₅S⁺ ([M + Na]⁺) requires 456.1815, found 456.1811.

(2R,4R,5R,6R,7S)-1-Aza-2-tert-butyl-4-methyl-5-methoxycarbonyl-6-hydroxy-6-(phenylthio-methyl)-7-benzyl-8-oxo-3-oxabicyclo[3.3.0]octane 22l

Following general procedure H, N-acyloxazolidine 21b (20 mg, 4.0 μmol) and NaOMe (3 mg, 5.0 μmol) were reacted to give a crude mixture which was purified via column chromatography (SiO₂, eluent 10 : 1 petrol–EtOAc) to give 22l as a colourless oil (3 mg, 15%); R_f 0.3 (eluent 6 : 1 petrol–EtOAc); [α]²³_D + 7.56 (c 0.15 in CHCl₃); ν_max (film) 3437, 2956, 2924, 2854, 1722; δ_H (500 MHz, CDCl₃) 0.94 (9H, s, C(CH₃)₃), 1.65 (3H, d, J 6.6, C(4)CH₃), 2.89 (1H, dd, J 14.8, 7.4, CH_AH_BPh), 2.98 (1H, d, J 14.3, C(1′)H_AH_B), 3.08 (1H, d, J 14.3, C(1′)H_AH_B), 3.16 (1H, dd, J 14.8, 6.0, CH_AH_BPh), 3.42 (1H, app. t, J 6.6, C(7)H), 3.79 (3H, s, CO₂CH₃), 4.91 (1H, q, J 6.6, C(4)H), 5.05 (1H, s, C(2)H), 7.16–7.30 (10H, m, Ph, SPh); δ_C (125 MHz, CDCl₃) 16.9 (C(4)CH₃), 25.6 (C(CH₃)₃), 29.6 (CH₂Ph), 37.1 (CMe₃), 41.6 (C(1′)), 52.9 (CO₂CH₃), 54.8 (C(7)), 78.4, 79.2 (C(4), C(5)), 85.0 (C(6)), 95.1 (C(2)), 126.3, 127.2, 128.5, 129.2, 129.3, 130.0 (o,m,p-Ph, -SPh), 135.4 (i-SPh), 139.7 (i-Ph), 171.9 (CO₂Me), 177.2 (C(8)); m/z (ESI⁺) 506 ([M + Na]⁺, 95%), (ESI⁻) 506 ([M − Na]⁻, 100%); HRMS (ESI⁺) C₂₇H₃₃NNaO₅S⁺ ([M + Na]⁺) requires 506.1972, found 506.1976.

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Footnote

† Electronic supplementary information (ESI) available: [DETAILS]. CCDC reference numbers 952079–952083 and 980818–980819. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra01967a

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