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
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.
3
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.
4
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
5
6
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
7
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.
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.
8
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 acetals5,6
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
(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 obtained5. Hopefully this is also the case for the diastereoselective
addition to β-aldehyde acetals.
Figure 11. Proposed complexation of Mg.5
9
Results and Discussion
Synthesis of the aldehyde
To obtain aldehyde 3 first compound 11 needs to be synthesized (figure 12). The αiodoenone (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 312, 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
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-NMRspectrum 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.
10
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.
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.
11
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.
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
12
exception, a plausible explanation is that the allylmagnesiumbromide reacts via an
intramolecular mechanism (figure 20)5 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).
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
13
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 parabromobenzoylchloride. 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 190193°C was obtained (16).
Figure 23. Derivatization of 2a with para-nitrobenzoylchloride.
14
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.
15
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
13
C 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 KMnO 4 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 Et2O (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%
yield. 1H-NMR (400 MHz, CDCl3): δ 2.43-2.47 (m, 4H), 2.13 (s, 3H), 1.86 (q, 3J(HH)=6
Hz, 2H).
(11) Synthesis of 6-iodo-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec6-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 DeanStark 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
2:1 and 4 mL EtN3).The product was obtained as a white solid in 62% yield. 1H-NMR
(400 MHz, C6D6): δ 7.71 (d, 3J(HH)=7.2 Hz, 2H), 7.37-7.19 (m, 8H), 5.62 (d, 3J(HH)=8.8
16
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), 1.611.56 (m, 1H), 1.00-0.90 (m, 3H).
(3) Synthesis of 7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6ene-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 NaH2PO4.
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
white crystals in 71% yield. 1H-NMR (400 MHz, C6D6): δ 10.35 (s, 1H), 7.49 (dd,
3
J(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,
3
J(HH)=8.8 Hz, 1H), 2.16-2.12 (m, 1H), 2.02-1.72 (m, 6H), 1.89 (s, 3H).
13
C-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 βaldehyde 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-6yl)(phenyl)methanol. PhMgBr was used as Grignard reagent. The
product was obtained as a colourless oil in 74% yield with a
diastereoselective ratio of 89:11. 1H-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).
17
C-NMR (100 Mhz, C6D6): δ 145.8, 143.8, 139.1, 136.8, 136.2, 110.3, 87.5, 85.7, 69.5,
13
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-6yl)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
obtained in 90% yield with a diastereoselective ratio of 81:19. 1H-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,
3
J(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
(s, 1H), 2.37-2.30 (m, 2H, 2.20-1.54 (m, 10H), 1.10 (s, 3H). 13C-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-6en-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
diastereoselective ratio of 93:7. 1H-NMR (400 MHz, C6D6): δ 7.45 (d,
3
J(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),
1.19 (d, 3J(HH)=6.8 Hz, 3H). 13C-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.
18
H-NMR (400 MHz, C6D6): δ 7.50 (d, 3J(HH)=8.4 Hz, 2H), 7.40 (d, 3J(HH)=8.0 Hz, 2H),
1
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),
2.95-2.87 (m, 1H), 2.17-1.69 (m, 6H), 1.95 (s, 3H).
C-NMR (100 Hz, C6D6) δ 140.5,
13
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-6yl)ethanol. MeMgCl was used as Grignard reagent. The product was
obtained as a colourless oil in 69% yield with a diastereoselective ratio of
66:34. 1H-NMR (400 MHz, C6D6): δ 7.50 (d, 3J(HH)=6.8 Hz, 1H), 7.37 (d,
3
J(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,
J(HH)=6.8 Hz, 3H). 13C-NMR (100 Hz, C6D6) δ 139.5, 137.2, 135.6, 110.6, 87.0, 85.5,
3
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 4nitrobenzoate. A solution of 2a (0.15 M) in CH2Cl2 was cooled to 0°C. Pyridine and pNO2BzCl 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. 1HNMR (400 MHz, C6D6): δ
19
Acknowledgements
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
20
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