Faculteit Der Natuurwetenschappen, Wiskunde En Informatica

Faculteit der Natuurwetenschappen, Wiskunde en Informatica Bachelor Scheikunde

Diastereoselective Addition of Grignard Reagents to Chiral β-Aldehyde Acetals

Lianne Jongens 5631386

Bachelorproject Scheikunde Van ’t Hoff Institute for Molecular Science Synthetic Organic Chemistry Drs. G. Lutteke Prof. Dr. H. Hiemstra Dr. S. Ingemann (2nd reviewer) Amsterdam, juli 2009

2 3 Abstract A new approach towards the right-hand side of Solanoeclepin A (figure 3) is under investigation. The key step in the synthesis of the tricyclic core of the natural product is a [2+2] photocycloaddition. A challenging part of this approach is to obtain enantiomerically pure β-hydroxy-ketones (17, figure 1), which are required for the synthesis of the photo substrate (1). Chiral acetals are used to obtain β-hydroxy-ketones via diastereoselective addition of Grignard reagents to β-aldehyde acetals and cleavage of the acetal (figure 1). Five different Grignard reagents were investigated: a methyl, an allyl, a n-butyl, an i-propyl and a phenyl. The addition products obtained gave diastereoisomeric ratios of 55:45 to 93-7. It was discovered that bulkier Grignard reagents gave higher diastereomeric ratios. Separation of the diastereoisomers proved to be difficult. The addition product with R=allyl (2d) is the precursor for the photo substrate (figure 23 (14)). To obtain photo substrate 14, cleavage of the acetal is required, isolation of this product requires more investigation.

Figure 1. Synthesis of β-hydroxy-ketones via diastereoselective addition of Grignard reagents to β-aldehyde acetals.

4 Populaire samenvatting Aardappelmoeheid is een groot probleem in de wereld en het wordt veroorzaakt door aardappelcystenaaltjes. Deze aaltjes worden gelokt door een stofje, Solanoeclepin A genaamd, dat in heel kleine hoeveelheden wordt uitgescheiden door de wortels van de aardappelplanten. Het is belangrijk om Solanoeclepin A te synthetiseren en te ontdekken wat het actieve deel van het molecuul is, zodat er hopelijk een simpeler analoog gemaakt kan worden om aardappelmoeheid te bestrijden. In dit project is gebruik gemaakt van een nieuwe benadering om het rechtergedeelte van Solanoeclepin A te synthetiseren. Deze benadering houdt in dat er enantiomeer zuivere alcoholen moeten worden gesynthetiseerd. Om deze alcoholen te synthetiseren is er gebruik gemaakt van een chirale beschermgroep.

5 Table of Contents

Introduction 7 Potato sickness and Solanoeclepin A 7 New approach towards the right-hand side of Solanoeclepin A 8 Literature 8

Results & Discussion 10 Synthesis of the aldehyde 10 Optimization of the diastereoselective addition 11 Influence of the different R-groups 12 Attempted photochemistry 13 X-Ray Cystallographic Analysis 14

Conclusions & Outlook 15

Experimental 16

Acknowledgements 20

Abbreviations 20

References 21

6 7 Introduction

Potato sickness and Solanoeclepin A Potato sickness is a major problem worldwide, which is caused by potato cyst nematodes (figure 2). These are 1 millimeter roundworms and can survive in soil up to 20 years in the absence of a host. The mature fertilized bodies of the female nematodes will swell and form cysts, one cyst can contain up to 400 eggs. The eggs are hatched by a substance called Solanoeclepin A (figure 3) which is secreted in minute quantities by the potato roots. The larvae then invade the potato roots and establish a feeding site, which causes growth retardation.1

Figure 2. Potato cyst nematodes Figure 3. Solanoeclepin A

Synthesis of Solanoeclepin A is important to find the active part of the molecule and hopefully create a simpler analogue, as an environmentally friendly solution to potato sickness. Solanoeclepin A is a challenging molecule to synthesize; it has as many as 9 chiral carbon centers and it contains ring sizes from 3 up to 7. Retrosynthetically Solanoeclepin A can be divided in to two parts; a left-hand side (figure 4) and a right-hand side (figure 5). The left-hand side has been synthesized2 but the synthesis of the right-hand side is still challenging.

Figure 4. Left-hand side Figure 5. Right-hand side

8 New approach towards the right-hand side of Solanoeclepin A A new promising approach towards the right-hand side is under investigation (figure 6).

Figure 6. A new approach towards the right-hand side of Solanoeclepin A.

To test the approach, depicted in figure 6, it is necessary to synthesize ketone 1 enantiomerically pure. The aim of this project is to obtain enantiomerically pure alcohols via diastereoselective addition of Grignard reagents to β-aldehyde acetals. The retrosynthesis of 1 is shown in figure 7.

Figure 6. Retrosynthesis of the photo substrate.

Literature The sysnthesis of racemic alcohols similar to compound 2 (figure 8) is known and is reported by Carpino et al3. In the reaction depicted in figure 8 the aldehyde reacts exclusively at the α-position of compound 4 and forms alcohol 5. It is not known how to perform this reaction in an enantioselective fashion.

9 Figure 8. Addition of the aldehyde at the α-position.

With the help of a chiral acetal it is hopefully possible to perform this reaction with good diastereoselectivity. Addition of Grignard reagents to β-aldehyde acetals was performed in a previous project4 (figure 9). In this project photo substrate 8 was successfully synthesized. To synthesize 8, first aldehyde 6 reacted with propargylmagnesiumbromide to form alcohol 7 and after this reaction, photo substrate 8 was synthesized in several steps.

Figure 9. Synthesis of photo substrate 8 with addition of a Grignard reagent to a β-aldehyde acetal.

To the best of our knowledge only diastereoselective additions of Grignard reagents to α-keto acetals are known5,6 (figure 10). Another difference is that in literature an open chain is used (figure 10) instead of a cyclohexene ring (figure 7), which will be used in this project.

Figure 10. Examples of diastereoseleoselective addition to α-aldehyde acetalsError: Reference source not found,Error: Reference source not found

For reaction A in figure 10 it is proposed that the magnesium of a Grignard reagents forms a complex between the carbonyl oxygent and one of the oxygens of the acetal

10 (figure 11). This complex shows that it is only possible to attack the carbonyl from the exo side because the endo side is too sterically hindered and this accounts for the high diastereoselectivities obtainedError: Reference source not found. Hopefully this is also the case for the diastereoselective addition to β-aldehyde acetals.

Figure 11. Proposed complexation of Mg.Error: Reference source not found

Results and Discussion Synthesis of the aldehyde To obtain aldehyde 3 first compound 11 needs to be synthesized (figure 12). The α- iodoenone (9)7 was reacted with optically active (R,R)-hydrobenzoin (10)8 and compound 11 was obtained in 62% yield.

Figure 12. Synthesis of compound 11.

To synthesize aldehyde 3Error: Reference source not found, compound 11 needs to be lithiated followed by formylation of the α-position with DMF (figure 13).

Figure 13. Synthesis of aldehyde 3.

As lithiating agent first 1.1 equivalents of n-BuLi were used9, but this reaction gave a very low yield. In a second attempt t-BuLi was tried as lithiation agent, but no reaction was observed at all. A plausible explanation for the low reactivity of n-BuLi and t-BuLi is

11 that they are too bulky. In order to test this theory the less sterically encumbered MeLi was used. Suprisingly another product formed. The proposed reaction using MeLi as lithiating agent is most likely the reaction that is shown in figure 14. In the 1H-NMR- spectrum a new peak of a methyl was shown at 2.16 ppm. n-Buli was tried again, but instead of 1.1 equivalents now 2.2 equivalents were used and the aldehyde was obtained in a 71% yield.

Figure 14. Reaction that occurred when MeLi was used. Optimization of the diastereoselective addition Optimization of the diastereoselective addition was investigated by using four different reactions (figure 15-18).

Figure 15. Reaction 1: Compound 11 with benzaldehyde.

Figure 16. Reaction 2: Aldehyde 3 with phenyllithium.

Figure 17. Reaction 3: Aldehyde 3 with phenylmagnesiumbromide in THF.

12 Figure 18. Reaction 4: Aldehyde 3 with phenylmagnesiumbromide in toluene.

In reaction 1 compound 11 is first lithiated with n-BuLi and then reacted with benzaldehyde. This gave a d.r. of 86:14. In reaction 2 aldehyde 3 reacts with phenyllithium and gave a d.r. of 93:7. In reaction 3 phenylmagnesium was used instead of phenyllithium and reacted with aldehyde 3 in THF. A significant drop in d.r. was observed (d.r. 69:31). The difference in d.r. between reaction 2 and 3 can be explained. It is known that lithium compounds form clusters and this increases steric hindrance, and therefore increased the d.r.. Phenylmagnesiumbromide can form complexes with THF and thus exists mainly as monomers in solution and is therefore less bulky, which causes the drop in d.r.. Using toluene in reaction 4 instead of THF in reaction 3, the d.r. improved (90:10). This can be explained because toluene is a non-complexing solvent thus phenylmagnesiumbromide forms clusters and this increases steric hindrance, and therefore the d.r. improved. The diastereomeric ratios of reaction 2 and reaction 4 are comparable, however Grignard reagents are commercially available and easier to make than lithiumcompounds. For this reason there was a preference for reaction 4.

Influence of the different R-groups Five Grignard reagents are used in the diastereoselective addition (figure 19). The results are summarized in table 1.

Figure 19. Diastereoselective addition of Grignard reagents to β-aldehydes.

Entry Substituents (R) X % yield d.r.

13 1 Methyl (4e) Cl 69 66:34 2 Allyl (4d) Br 67 55:45 3 n-Butyl (4b) Cl 61 74:26 4 n-Butyl (4b) Br 90 81:19 5 Phenyl (4a) Br 77 89:11 6 i-Propyl (4c) Cl 73 93:7 Table 1. Results for the different substituents used.

Table 1 indicates that the diastereomeric ratio increases significantly if more bulky Grignard reagents are used. An increase in steric bulk results in a more effective shielding of one side of the aldehyde by the phenylgroup. Alcohol 2d is the only exception, a plausible explanation is that the allylmagnesiumbromide reacts via an intramolecular mechanism (figure 20)Error: Reference source not found and that the other Grignard reagents react via an intermolecular reaction mechanism.

Figure 20. Intramolecular mechanism of aldehyde 3 with allylmagnesiumbromide.

Influence of the halide (chloride or bromide) was investigated using an n-butyl-Grignard. A higher yield was observed using the bromide. Here it has to be noted when using freshly prepared n-butylmagnesiumbromide column chromatography was not required. A better d.r. was obtained using a bromide as well; this is probably caused by steric hindrance. Separation of the two diastereoisomers proved to be difficult. After removal of the acetal the ee of alcohol 2a will be 78% and for alcohol 2b 62%. Alcohols 2a and 2b can be compared with respectively alcohols 5b and 5a. This means that for alcohol 2a the ee improved with 78% and for alcohol 2b the ee improved with 62%.

Attempted synthesis of the photo substrate Earlier results for photocycloaddition using ketone 12 yields 14% of the desired compound 13 (figure 20).

14 Figure 21. Photochemistry with the photo substrate without the OH-group at the β-position.

For the photochemistry a similar product was meant to be tested (14, figure 22). This photo substrate contains an alcoholgroup at the β-position compared to ketone 12. Photo substrate 14 can be obtained by cleavage of the acetal of 2d. Cleavage of the acetal was tried wit PPTS first, however no reaction occurred. In a second attempt cleavage using the more acidic PTSA was performed. This reaction did work, since the acetal was isolated, however isolation of the product did not succeed. A plausible explanation is that the alcohol of the product was protonated and polymerization on the column occurred.

Figure 22. Synthesis of the photo substrate and the photochemistry

X-Ray Crystallographic Analysis To determine the relative stereochemistry of the synthesized addition products (2a-2e) it is necessary to grow X-Ray quality crystals. It is tried to grow crystals of alcohol 2a, since this compound exists as an oil it is tried to derivatize 2a with para- bromobenzoylchloride. This reaction resulted in a very complex mixture. In a second attempt it was tried to derivatize alcohol 2a with para-nitrobenzoylchloride (figure 23). This reaction did work and after purification a white solid with a melting point of 190- 193°C was obtained (16).

Figure 23. Derivatization of 2a with para-nitrobenzoylchloride.

15 Conclusions and Outlook Enantiomerically pure alcohols are obtained via diasteromeric addition in reasonable to good diasteromeric ratios. However separation proved to be difficult. Five addition products (2a-2e) with a chiral acetal are synthesized via diastereoselective addition of Grignard reagents to β-aldehyde acetals. Different diastereomeric ratios are obtained; from 55:45 to 93:7. It should be noted that using bulkier Grignard reagents in the addition leads to higher diastereomeric ratios. This is most likely because bulkier substituents are more sterically hindered and causes the Grignard reagent to only attack the side of the aldehyde, which is not shielded by one of the phenylgroups. The only exception is allylmagnesiumbromide; a plausible explanation is that allylmagnesiumbromide reacts via an intramolecular mechanism. It is also noteworthy that for 2b the bromide Grignard reagent gave a higher yield and a higher diastereomeric ratio than the chloride Grignard reagent. The diastereomeric ratio is most likely higher because the bromide is larger than the chloride and so it causes more steric hindrance. X-Ray quality crystals of 2a are grown, however they are still under investigation. Future research towards separation of the diastereomers is required and the relative stereochemistry needs to be determined. Last but certainly not least, cleavage of the acetal and isolation of the photo substrate should be optimized to investigate its photochemical properties.

16 Experimental Section General Experimental. All reactions involving moisture sensitive reagents were performed in oven-dried or flame-dried glassware under a positive pressure of nitrogen.

Toluene, DMF, DCM are distilled from CaH2. All reagents were obtained from commercial sources and used as received. Nuclear magnetic resonance spectra were recorded in benzene with a Bruker Avance 400 MHz. For 1H NMR, spectra are recorded at 400 MHz and for 13C NMR (APT) at 100 MHz. Chemical shifts are reported in ppm from tetramethylsilane. The mass spectra were carried out using a JEOL JMS-SX/SX 102 A Tandem Mass Spectrometer. Melting points are uncorrected. Thin layer chromatograms were visualized using 254 nm ultraviolet light, by KMnO4 or by anise. Chromatography was performed using Biosolve silica gel 60 Å (0.032-0.063 mm) and varying ratios of PE/Et2O as eluent.

(9) Synthesis of 2-iodo-3-mehtyl-cyclo-hex-2-enone.10 Iodine (68,6 g, 272

mmol) dissolved in 180 mL of CCl4/pyridine (1:1) was added drop wise to a

stirred solution of 3-methylcyclo-2-hexenone (10 g, 90,7 mmol) in CCl4 (90 mL) at 0°C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. After this the mixture was diluted with Et 2O (700 mL) and washed with Na2S2O5 (60 g/L, 1000 mL). The aqueous layers were extracted with

Et2O. The combined organic layers were washed with H2O (100 mL) and brine (100 mL), dried with MgSO4, filtered and concentrated in vacuo. The brown oil was dissolved in

200 mL CH2Cl2 and washed with 2 M HCl. The combined organic layers were dried with

MgSO4, filtered and concentrated in vacuo. The product was obtained as an oil in 50%

1 3 yield. H-NMR (400 MHz, CDCl3): δ 2.43-2.47 (m, 4H), 2.13 (s, 3H), 1.86 (q, J(HH)=6 Hz, 2H).

(11) Synthesis of 6-iodo-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec- 6-ene. A solution of 9 (5 g, 21,2 mmol), 1011 (9,1 g 42,4 mmol) and PPTS (0.53 g, 2.12 mmol) in benzene 200 mL was heated till reflux in a Dean-

Stark trap for 48 hours. After this Et2O was added and the organic layer was washed with 2x 100 mL water and 100 mL brine, dried with MgSO4, filtered and concentrated in vacuo. The mixture was purified with column chromatography (PE: Et2O

1 2:1 and 4 mL EtN3).The product was obtained as a white solid in 62% yield. H-NMR

3 3 (400 MHz, C6D6): δ 7.71 (d, J(HH)=7.2 Hz, 2H), 7.37-7.19 (m, 8H), 5.62 (d, J(HH)=8.8

17 Hz, 1H), 4.91(d, 8.8 Hz, 1H), 2.24-2.20 (m, 1H), 2.12-2.06 (m, 1H), 1.87 (s, 3H), 1.61- 1.56 (m, 1H), 1.00-0.90 (m, 3H).

(3) Synthesis of 7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6- ene-6-carbaldehyde.12 n-BuLi (11,9 mL, 1.6 M in hexanes, 19.04 mmol) was added to a solution of 11 (3.74 g, 8.65 mmol) in THF (7.5 mL) at -78°C and stirred for 30 minutes. Then DMF (1.66 mL, 21,63 mmol) was added and stirred for 30 minutes. The mixture was quenched with 20% m/m NaH 2PO4.

The water layer was extracted with Et2O (3x). The organic layer was washed with brine, then dried over MgSO4, filtered and concentrated in vacuo. The mixture was purified by column chromatography (PE:Et2O 3:1 and 2 mL Et3N). The product was obtained as

1 white crystals in 71% yield. H-NMR (400 MHz, C6D6): δ 10.35 (s, 1H), 7.49 (dd, 3J(HH)=7.2, 1.8 Hz, 2H), 7.31-7.19 (m, 8H), 5.40 (d, 3J(HH)=8.4 Hz, 1H), 4.88 (d, 3J(HH)=8.8 Hz, 1H), 2.16-2.12 (m, 1H), 2.02-1.72 (m, 6H), 1.89 (s, 3H). 13C-NMR (100

MHz, C6D6): δ 191.1, 158.1, 139.2, 137.1, 133.6, 129.1-127.3, 108.0, 87.5, 86.5, 35.7, 34.5, 20.3, 20.1. IR: 3063, 3032, 2944, 2870,2760. HRMS(FAB+): m/z calculated for

+ C22H23O3 is 335.1647, observed 335.1650. Melting point: 71-73ºC

General Procedure for the Addition of Grignard Reagents to β- aldehyde acetals. A 0.1 M solution of 3 (0.167 g, 0.5 mmol) in toluene was cooled to -78°C. RMgX (2.5 mmol) was added drop wise to the solution. The resulting solution was stirred for one hour and quenched by the addition of NH4Cl and the mixture was allowed to warm up to room temperature.

The mixture was extracted with Et2O (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:Et2O 3:1 ±2 mL Et3N). The NMR-data are only given for the major diastereomer.

(2a) 7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-en-6- yl)(phenyl)methanol. PhMgBr was used as Grignard reagent. The product was obtained as a colourless oil in 74% yield with a

1 diastereoselective ratio of 89:11. H-NMR (400 Mhz, C6D6): δ 8.14 (d, 3J(HH)=8.0 Hz, 2H), 7.42-7.34 (m, 2H), 7.29-7.17 (m, 3H), 7.13-7.06 (m, 3H), 4.90 (s, 2H), 3.44 (s, 1H), 2.28-2.24 (m, 1H), 2.17-2.09 (m, 1H), 1.94-1.56 (m, 6H), 1.64 (s, 3H).

18 13 C-NMR (100 Mhz, C6D6): δ 145.8, 143.8, 139.1, 136.8, 136.2, 110.3, 87.5, 85.7, 69.5, 35.6, 33.3, 21.2, 21.0. IR: 3449, 3062, 3031, 2935, 2887, 2828. HRMS(FAB+): m/z

+ calculated for C28H29O3 is 413.2117, observed 413.2115.

(2b) 7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-en-6- yl)pentan-1-ol. n-BuMgCl and n-BuMgBr were used as Grignard reagents. The product was obtained as a colourless oil. For the reaction with n-BuMgCl the product was obtained in 61% yield with a diastereoselective ratio of 74:26. For the reaction with n-BuMgBr the product was

1 obtained in 90% yield with a diastereoselective ratio of 81:19. H-NMR (400 MHz, C6D6): δ 7.52 (d, 3J(HH)=7.2 Hz, 1H), 7.40 (d, 3J(HH)=6.8 Hz, 3H), 7.34-7.16 (m, 6H), 5.14 (d, 3J(HH)=8.8 Hz, 1H), 4.98 (dd, 3J(HH)=10, 3.6 Hz, 1H), 4.91 (d, 3J(HH)= 8.4 Hz, 1H), 3.08

13 (s, 1H), 2.37-2.30 (m, 2H, 2.20-1.54 (m, 10H), 1.10 (s, 3H). C-NMR (100 MHz, C6D6): δ 140.3, 139.5, 137.3, 135.1, 110.7, 87.0, 85.5, 37.4, 35.9, 33.6, 30.6, 23.7, 21.1, 20.8, 14.9. IR: 3460, 3065, 3032, 2930, 2868, 2829. HRMS(FAB+): m/z calculated for

+ C26H33O3 is 393.2430, observed 393.2435.

(2c) 2-methyl-1-(7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6- en-6-yl)propan-1-ol. i-PrMgCl wais used as Grignard reagent. The product was obtained as a colourless oil in 73% yield with a

1 diastereoselective ratio of 93:7. H-NMR (400 MHz, C6D6): δ 7.45 (d, 3J(HH)=8.0 Hz, 2H), 7.31-7.16 (m, 8H), 5.24 (d, 3J(HH)=8.8 Hz, 1H), 4.91 (d, 3J(HH)=8.8 Hz, 1H), 4.62 (d, 9.6, 1H), 3.17 (s, 1H), 2.71-2.65 (m, 1H), 2.14-2.04 (m, 2H), 1.94-1.88 (m, 2H), 1.89 (s, 3H), 1.84-178 (m, 2H), 1.56 (d, 3J(HH)=6.8 Hz, 3H),

3 13 1.19 (d, J(HH)=6.8 Hz, 3H). C-NMR (100 MHz, C6D6): δ 141.1, 139.6, 136.9, 133.2, 110.9, 86.3, 85.7, 76.9, 35.9, 34.5, 33.6, 21.8, 21.2, 20.6, 20.6. IR: 3470, 3065, 3033,

+ 2937, 2867, 2828. HRMS(FAB+): m/z calculated for C25H31O3 is 379.2273, observed 379.2272.

(2d) 1-(7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-en-6- yl)but-3-en-1-ol. AllylMgBr was used as Grignard reagent. The product was obtained as a colourless oil in 67% yield with a diastereoselective ratio of 55:45.

19 1 3 3 H-NMR (400 MHz, C6D6): δ 7.50 (d, J(HH)=8.4 Hz, 2H), 7.40 (d, J(HH)=8.0 Hz, 2H), 7.29-7.18 (m, 6H), 6.32-6.21 (m, 1H), 5.39 (dd, 3J(HH)=17.2 Hz, 2J(HH)=2.0 Hz, 1H), 5.29 (dd, 3J(HH)=5.4, 2.2 Hz, 1H), 5.15 (dd, 3J(HH)=10.0 Hz, 2J(HH)=2.0 Hz, 1H), 5.09 (d, 3J(HH)=8.4 Hz, 1H), 4.89 (d, 3J(HH)=8.8 Hz, 1H), 3.33 (s, 1H), 3.12-2.98 (m, 1H),

13 2.95-2.87 (m, 1H), 2.17-1.69 (m, 6H), 1.95 (s, 3H). C-NMR (100 Hz, C6D6) δ 140.5, 139.3, 137.8, 137.1, 134.1, 116.7, 110.7, 87.0, 85.6, 71.2, 42.6, 35.7, 33.5, 21.1, 20.7.

+ HRMS(FAB+): m/z calculated for C25H29O3 is 377.2117, observed 377.2113.

(2e) 1-(7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-en-6- yl)ethanol. MeMgCl was used as Grignard reagent. The product was obtained as a colourless oil in 69% yield with a diastereoselective ratio of

1 3 66:34. H-NMR (400 MHz, C6D6): δ 7.50 (d, J(HH)=6.8 Hz, 1H), 7.37 (d, 3J(HH)=8.0 Hz, 1H), 7.33-7.16 (m, 8H), 5.26-5.18 (m, 1H), 5.10 (d, 3J(HH)=8.4 Hz, 1H), 4.89 (d, 3J(HH)=8.8 Hz, 1H), 3.07 (s, 1H), 2.16-1.65 (m, 6H), 2.04 (s, 3H), 1.91 (d,

3 13 J(HH)=6.8 Hz, 3H). C-NMR (100 Hz, C6D6) δ 139.5, 137.2, 135.6, 110.6, 87.0, 85.5, 66.2 46.9, 35.8, 33.6, 23.7, 20.9, 20.8. IR: 3449, 3064, 3032, 2931, 2828. HRMS(FAB+)

+ m/z calculated for C21H27O3 is 351.1960, observed 351.1966.

(16) 7-mehtyl-2,3-diphenyl-1,4-dioxaspiro[4,5]dec-6-en-6-yl)(phenyl)methyl 4- nitrobenzoate. A solution of 2a (0.15 M) in CH2Cl2 was cooled to 0°C. Pyridine and p-

NO2BzCl were added and the mixture was allowed to warm up to room temperature and stirred for 90 minutes. The reaction is quenched with H2O. The mixture was extracted with CH2Cl2 (2x). The combined organic layers were washed with NaHCO3, dried over

MgSO4, filtered and concentrated in vacuo. The mixture was purified by column chromatography (……..). The product was obtained as a white solid in …….% yield. 1H-

NMR (400 MHz, C6D6): δ

Acknowledgements

20 Drs. G. Lutteke Prof. Dr. H. Hiemstra Dr. S. Ingemann J. Geenevasen (NMR) H. Peeters (Exact mass)

Abbreviations TMS trimethylsilyl TBAF tetra-n-butylammoniumfluoride Bn benzyl PPTS pyridinium p-toluenesulfonate THF tetrahydrofuran DMF N,N-dimethylformamide d.r. diastereisomeric ratio equiv. equivalents ee entantiomeric excess PTSA p-toluenesulfonic acid RT room temperature DCM dichloromethane MHz megahertz NMR Nuclear Magnetic Resonance APT Attached Proton Test ppm parts per million PE petroleum ether M molar concentration IR Infrared HRMS High Resolution Mass Spectrometry FAB Fast Atom Bombardment Bz benzoyl

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