The synthetic route began with the condensation of (RS)-tert-butanesulfinamide 38 and ethyl pyruvate (36) in the presence of Ti(OEt)4 in THF at reflux for 6 hours as previously reported for this
reaction.197 However, under these conditions only 30% of the desired tert-butanesulfinyl imine 42
was obtained (Table 3.1). With the aid of 2D NMR and mass spectrometry the major side product was identified as lactone 43 which was formed in a 5:3 ratio to the desired imine 42. It was proposed that the formation of 43 occured via an in situ aldol reaction between initially formed imine 42 and remaining ethyl pyruvate (36) catalysed by Ti(OEt)4, followed by an intramolecular cyclisation and
tautomerisation (Table 3.1). Promisingly 43 was isolated as a single diastereomer (dr >98%), indicating that the tert-butanesulfinyl group had a directing effect on the aldol reaction. 43 is tentatively assigned as the (RS,R)-diastereomer based on the later X-ray crystal structure analysis of related compound 46 (Scheme 3.11).
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Table 3.1. A selection of the key results obtained from a screen of reaction conditions for the condensation of ethyl pyruvate (36) and (RS)-tert-butanesulfinamide 38.Reagents and conditions: (a) (RS)-tert-butanesulfinamide 38, THF. Ratio of 42:43 was determined by 1H NMR analysis of the crude reaction mixture. The proposed mechanism for synthesis of 43
from 42 is shown, involving an asymmetric aldol reaction of 42 and ethyl pyruvate (36) to provide 44, followed by an intramolecular cyclisation to form 43.
Entry Lewis acid Temperature
(C) Time (hours) 42 (isolated yield) 42:43 (% by NMR) 1 Ti(OEt)4 65 6 36 3:5 2 Ti(OEt)4 r.t. 6 23 8:1 3
MgSO
4 65 6 - - 4ZnBr
2 65 6 - - 5Ti(OiPr)
4 65 6 22 2:5 6TiCl
4 0 r.t. 3 - - 7 Ti(OEt)4 40 6 29 4:1 8 Ti(OEt)4 60 6 60 3:1Although 43 is not a synthetically useful intermediate for the synthesis of harzianic acid (19), the one-pot, highly diastereoselective synthesis of 43 could be used as a highly efficient first step in the synthesis of Sch210972 (20) (Figure 3.10). A screen of reaction conditions (a selection of which are shown in Table 3.1) was undertaken to improve the ratio of the desired tert-butanesulfinyl imine 42
to the undesired lactone 43. This led to the following observations. At room temperature the aldol reaction to give 42 was favoured, which resulted in a higher ratio of 42:43 but in a lower overall yield due to a competing homo-aldol condensation of ethyl pyruvate resulting in polymerisation (entry 2). Changing the Lewis acid to MgSO4 or ZnBr2 resulted in no reaction whereas Ti(OiPr)4 provided a
mixture of 42 and 43 but in a lower overall yield than Ti(OEt)4 (entries 3-5). It was found that using
TiCl4 (entry 6) or carrying out the reaction at temperatures below 60 C with Ti(OEt)4 (entries 2 and
7), favoured the homo-aldol reaction, promoting polymerisation of ethyl pyruvate (36) resulting in a significantly reduced yield of 42. Based on these observations it was proposed that in order to obtain both a good ratio of 42:43 and a good overall yield, ethyl pyruvate 36 would need to be added to the (RS)-38 and Ti(OEt)4 in THF at 60 C. This should limit the competing aldol condensation during the
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heating of the reaction to 60 C and allow the ethyl pyruvate (36) to react quickly with 38 on addition. These optimised conditions resulted in the isolation of 42 in a 3:1 ratio to 43 with an isolated yield of 42 of 60% (entry 8).
The next step involved a LDA-mediated aldol reaction between 42 and ethyl dimethylpyruvate (37) (Scheme 3.11). This provided the desired aldol product 45 which similarly to 44 cyclised in situ to form lactone 46 in a very good yield and diastereoselectivity (dr >98%). Although the source of diastereocontrol is unclear, Ellman and coworkers have previously proposed a Zimmerman-Traxler- type transition state198 guided by the formation of M-O and M-N interactions for the related condensation of N-sulfinyl imines to simple aldehydes.196 Invoking a similar stereochemical model, in which the bulky isopropyl substituent of 42 is placed in the pseudo-equatorial position to reduce 1,3- diaxial interactions would predict the formation of the (Rs,S) diastereomer of 46 (Scheme 3.11). Subsequently a small molecule X-ray crystal structure was obtained which confirmed that 46 was the expected (Rs,S) diastereomer (Scheme 3.11).
Scheme 3.11. Synthesis and small molecule X-ray crystal structure of 46. The observed stereoselectivity is consistent with a Zimmerman-Traxler-type transition state 47 in which the bulky isopropyl group is in a pseudo-equatorial position.
Reagents and conditions: (a) (i) i-Pr2NH, n-BuLi (2.2M in hexanes), THF, 0 C. (ii) Ethyl dimethylpyruvate (37), ZnBr2, -78 C,
88%. X-ray crystallographic data provided by Prof. Alexandra Slawin.
Although the one-pot domino aldol-cyclisation reaction removed an additional cyclisation step to form key intermediate 46, it introduced some significant concerns regarding the selective reduction of 46 to the corresponding amine 51 (Scheme 3.13). In Ellman’s proposed stereochemical model for the diastereoselective reduction of the β-hydroxy-N-sulfinyl imine 48 to the corresponding 1,3- amino alcohol, the hydroxyl group plays a key role in the transition state (Scheme 3.12).196 The
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reduction of 48 with LiBHEt3 and catecholborane has been shown to give the anti-49 and syn-50 1,3-
amino alcohols respectively, with high diastereoselectivity (Scheme 3.12).
Scheme 3.12. Proposed stereochemical model for the diastereoselective reduction of β-hydroxy-N-sulfinyl imine 48 to the corresponding syn or anti 1,3-amino alcohols.
It is proposed that the observed reversal in diastereofacial selectivity can be rationalised by considering the geometry of the N-sulfinyl imine 48 during the reduction step. Numerous X-ray crystal structures and NMR studies have demonstrated that the N-sulfinyl imines preferentially exist in the E-geometry.199,196,200 The addition of LiBHEt3 is unlikely to alter the imine geometry, resulting in
the attack of the hydride from the opposite face to the tert-butyl substituent of (RS)-38, which would furnish anti-49 (Scheme 3.12). In contrast, it is believed that catecholborane can form a stable six- membered intermediate which would promote isomerisation of 48 from the E- to Z-imine, resulting in the formation of syn-50 (Scheme 3.12). Due to the lactonisation step, the hydroxyl group of 46 is not free to chelate the metal and thus aid the formation of the transition state required for the selective hydride attack. In addition, 46 exists predominantly as the enamine tautomer in solution (the imine tautomer is not observed by 1H NMR analysis) due to the greater stability provided to the enamine tautomer as a result of conjugation with the lactone carbonyl. As a result of the enamine stability, 46 is considerably more resistant to reduction than the corresponding imine tautomer. An added complication arises due the presence of the reactive lactone and ester moieties in 46. Therefore, only mild reducing conditions could be utilised to prevent any unwanted reduction of these groups. A screen of hydride reducing agents (NaBH4, L-Selectride, NaBH3CN), transfer
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PtO2) confirmed that as predicted the enamine was stable to reduction, with either no reaction
occurring or unselective reduction in the case of L-Selectride. Due to the added stability conferred by the enamine tautomer, it was decided to attempt the reduction under acidic conditions with the aim of forming the corresponding iminium ion, which given its increased electrophilicity would be easier to reduce. Initial attempts using NaBH3CN/TFA,201 NaBH4/AcOH202 and NaBH3CN/HCl (1.25N in
MeOH)203 proved unsuccessful. A common method to cleave the N-tert-butanesulfinyl group is under acidic conditions (HCl, 4N in dioxane) which is proposed to protonate the sulfinamide nitrogen, activating it towards attack of Cl- at the sulfinyl group.204 With the knowledge that these conditions will protonate the amine, it was therefore decided to try to reduce 46 using NaBH3CN/HCl
(4N in dioxane). Gratifyingly these conditions furnished the desired amine 51 in good yield and very good diastereoselectivity (dr > 95%) with concomitant deprotection of the tert-butanesulfinyl group (Scheme 3.13).
Scheme 3.13. Diastereoselective reduction. Reagents and conditions:(a) (i) HCl (4N in dioxane), THF, 0 C, 10 minutes. (ii) NaBH3CN, MeOH, 1.5 hours, 0 C, 76%, dr >95%.
This reaction development was undertaken using 46 which contains a free NH. However, as harzianic acid (19) contains a methylated amino-group, it was decided that 46 was the optimal intermediate to methylate. This was achieved in very high yield using iodomethane to provide 52. The tandem deprotection-reduction was then carried out using 52 which provided 53 with improved yield and diastereoselectivity (dr >98%) when compared to 51 (Scheme 3.14).
Scheme 3.14. Synthesis of 53. Reagents and conditions:(a) LiHMDS, iodomethane (2 eq.), DMF, -15 C r.t., 95%. (b) (i) HCl (4N in dioxane), THF, 0 C, 10 minutes. (ii) NaBH3CN, MeOH, 1.5 hours, 0 C, 85%, dr > 98%.
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Initial NOE studies on crude 53 indicated that the amine and isopropyl substituents were cofacial, suggesting the formation of the desired (S,S)-diastereomer, which was subsequently confirmed by NOE analysis of the more advanced harzianic acid intermediate 55 (Section 3.4.3, Figure 3.11). Some further mechanistic studies were carried out to elucidate the reaction sequence in the tandem deprotection-reduction. The experimental procedure involved the addition of HCl (4N in dioxane) to
52 in THF at 0 C followed by addition of NaBH3CN in methanol after 10 minutes. Work-up of the
reaction prior to the addition of the reducing agent revealed the deprotected enamine was formed (Scheme 3.15). Subsequent NaBH3CN-mediated reduction of the iminium ion 54 in the presence of
HCl (4N in dioxane) provided the desired product 53 with similar diastereoselectivity but diminished yield when compared to the one-pot process. As the chiral auxiliary had been cleaved prior to the addition of the reducing agent, the observed diastereoselectivity appears to be purely substrate controlled with the hydride attacking from the same side as the ester substituent (Scheme 3.15). The high level of diastereocontrol would suggest that it may not be purely sterically induced and could be a result of chelation of the reducing agent by the ester, directing the facial attack of the hydride.
Scheme 3.15. Mechanistic studies of the deprotection-reduction reaction sequence revealed that it occurs via acid- mediated removal of the tert-butanesulfinyl group followed by a substrate controlled diastereoselective reduction of the resulting iminium to provide 53.
Due to the relatively high purity of the crude amine 53 isolated from the one-pot process and the difficulties generally associated with the purification of amines, it was decided to trap directly the crude amine 53 with the desired harzianic acid polyene side chain.