Vinyl Grignard-Mediated Stereoselective Carbocyclization of Lactone Acetals

Article abstract of DOI:10.1021/acs.joc.7b03079

A novel Ferrier-type carbocyclization is reported. It involves a carbohydrate-derived lactone acetal synthesized from methyl α-d-glucopyranoside, which upon treatment with excess vinylmagnesium bromide provides a highly substituted carbocyclic product as a single stereoisomer. The yield is greatly increased when N,N,N′,N′-tetramethylethylenediamine is added to the reaction mixture. Optimized reaction conditions have been applied to lactone acetals derived from other carbohydrates. Based on the obtained results, a possible reaction mechanism has been proposed. Furthermore, scalability of the reaction up to 15 g scale and derivatization of the carbocyclic product has been demonstrated, including the formation of a rare trans-bicyclo[4.3.0]nonene scaffold via a ring-closing metathesis. The structure of this and all carbocyclic products were confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1021/acs.joc.7b03079

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Article
Vinyl Grignard-mediated Stereoselective Carbocyclization of Lactone Acetals
Christinne Hedberg, Morten Estrup, Espen Z. Eikeland, and Henrik Helligsø Jensen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03079 • Publication Date (Web): 16 Jan 2018
Downloaded from http://pubs.acs.org on January 17, 2018
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Vinyl Grignardꢀmediated Stereoselective Carbocyclization of Lactone Acetals
Christinne Hedberg†, Morten Estrup†, Espen Z. Eikeland‡§ and Henrik H. Jensen†*
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†
Department of Chemistry, Aarhus University, DKꢀ8000 Aarhus C, Denmark.
‡
Center for Materials Chemistry, Department of Chemistry and iNANO, Aarhus University, DKꢀ8000 Aarhus C, Denmark.
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§
Nano Production and Micro Analysis, Danish Technological Institute, DKꢀ2630 Taastrup, Denmark.
hhj@chem.au.dk
Abstract
A novel Ferrierꢀtype carbocyclization is reported. It involves a carbohydrateꢀderived lactone acetal
synthesized from methyl αꢀDꢀglucopyranoside, which upon treatment with excess vinylmagnesium
bromide provides a highly substituted carbocyclic product as a single stereoisomer. The yield is
greatly increased when N,N,N’,N’ꢀtetramethylethylenediamine is added to the reaction mixture.
Optimized reaction conditions have been applied to lactone acetals derived from other
carbohydrates. Based on the obtained results, a possible reaction mechanism has been proposed.
Furthermore, scalability of the reaction up to 15 g scale and derivatization of the carbocyclic
product has been demonstrated, including the formation of a rare transꢀbicyclo[4.3.0]nonene
scaffold via a ringꢀclosing metathesis. The structure of this and all carbocyclized products were
confirmed by Xꢀray crystallographic analysis.
Introduction
Carbasugars are stable analogues of carbohydrates where the endocyclic oxygen has been replaced
with a carbon atom. These highly oxygenated alicyclic molecules form the central scaffold of
various natural and synthetic products of biological importance.1 Many methods have been adopted
towards the synthesis of carbasugars from carbohydrates2ꢀ5 or nonꢀcarbohydrate precursors.6ꢀ8
Generally, utilization of carbohydrates from the natural chiral pool for synthesis of complex
enantiopure compounds have shown many advantages.9ꢀ12 The classical approach for assembling
carbacycles from carbohydrate precursors exploits the wellꢀknown Ferrier carbocyclization (or
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Ferrier II reaction) using an exoꢀglycal derived from a carbohydrate precursor (Scheme 1a).13ꢀ16
Originally, the reaction proceeds in aqueous acetone with stoichiometric HgCl2 but other conditions
have been implemented to provide the βꢀhydroxyꢀcyclohexanone 2.17ꢀ19 This reaction remains a
valuable tool for creating a highly functionalized cyclohexane framework.20ꢀ22
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Scheme 1. Ferrier carbocyclization and newly found carbocyclization
a) Ferrier carbocyclization (ref. 13-16)
O
BnO
BnO
BnO
BnO
HgCl2
O
H2O/(CH3)2CO
reflux, 90 min
84%
OMe
OH
OBn
OBn
2
1
b) Newly found carbocyclization (this study)
O
OH
BnO
BnO
BnO
BnO
MgBr, TMEDA
O
THF
-78 °C (2 h) to rt (1 h)
64-77%
OMe
OH
OBn
OBn
3
4
c) Derivatization of 4 for crystallization
OH
OH
3,5-DNB-Cl
Et3N, DMAP
BnO
BnO
BnO
BnO
CH2Cl2
rt, overnight
84%
OH
O
NO2
OBn
OBn
O
4
5
NO2
Figure 1. Molecular structure of 5
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Results and Discussion
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We recently discovered a novel reaction, which can be considered a variety of the Ferrier
carbocyclization, where a lactone acetal 3 (or pseudolactone23) upon treatment with
vinylmagnesium bromide resulted in the carbocyclic product 4 as the only stereoisomer (Scheme
1b). We have studied this reaction in detail and in this paper, we report on our findings. First, the
structure and stereochemistry of the carbocyclic product 4 was confirmed by single crystal Xꢀray
crystallographic analysis of the crystalline 3,5ꢀdinitrobenzoyl (3,5ꢀDNB) derivative 5 (Scheme 1c
and Figure 1). The lactone acetal starting material for the carbocyclization 3 was prepared from the
known iodide 6 by elimination followed by ozonolysis of the resulting exoꢀcyclic double bond
(Scheme 2).24,25 The elimination step from this iodide has been reported several times with different
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bases including t
ꢀBuOK, NaH and DBU,16,19,26 but in our hands satisfactory and reproducible results
were only achieved with AgF in pyridine.
Scheme 2. Synthesis of the substrate 3 from primary iodide 6
To explore this new type of carbocyclization, the influence on product yield by varying reaction
conditions was explored (Table 1). Excess Grignard reagent was added as a commercial 1 M
solution in THF and THF, Et2O and toluene were tested as coꢀsolvents (entry 1ꢀ3). As the most
coordinating solvent, THF provided the best initial result. N,N,N’,N’ꢀTetramethylethylenediamine
(TMEDA) was added to the reaction mixture and was found to result in a large increase in yield
independent of the coꢀsolvent (entries 4ꢀ6). Omitting the coꢀsolvent and simply conducting the
reaction in the commercial THF solution of vinylmagnesium bromide further increased the yield
slightly (entry 7). The reaction was furthermore carried out at different temperatures and with
varying amounts of both vinylmagnesium bromide and TMEDA establishing the conditions in entry
7 with 9 equivalents of Grignard reagent (of which 3 is consumed in the reaction) and 1.2
equivalents of TMEDA per Grignard reagent going from ꢀ78 °C to rt as the optimal conditions. The
results in Table 1 were all obtained on a 300 mg scale and upꢀscaling of the reaction was found to
have a beneficial effect on the reaction yield as 64% of the carbocyclic product 4 was achieved on
this scale while 70% was achieved on 1 g scale and 77% on 15 g scale.
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Table 1. Optimization of reaction conditions
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O
OH
Varying reaction
conditions
BnO
BnO
BnO
BnO
O
OMe
OH
OBn
3
OBn
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Entry Grignard/TMEDAa Temp. (°C)b Additive
Yieldc
34%
25%
26%
60%
57%
60%
64%
55%
62%
52%
28%
46%
40%
1
9/ꢀ
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
0 to rt
THF
2
9/ꢀ
Et2O
3
9/ꢀ
Toluene
4
9/1.2
9/1.2
9/1.2
9/1.2
9/0.6
9/2.4
6/1.2
9/1.2
9/1.2
9/1.2
9/ꢀ
THF
5
Et2O
6
Toluene
7
ꢀ
ꢀ
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ꢀ78 to ꢀ35d
ꢀ78 to rte
ꢀ78 to rt
CuCN· 2LiCl 14%
aEquiv. vinylMgBr compared to 3 and equiv. TMEDA compared to vinylMgBr. bUnless other is stated, the reaction was
c
d
stirred at ꢀ78 °C for 2 h followed by 1 h at rt. Isolated yield in comparison to the amount of 3. 6 h at ꢀ78 °C. e6 h at ꢀ
78 °C, then rt overnight.
To investigate the reaction efficiency and to potentially isolate reaction intermediates, lactone acetal
3 was treated with a lower amount of Grignard reagent. The amount of TMEDA was maintained at
1.2 equivalents per Grignard reagent. When 2 or 3 equivalents of Grignard reagent were used, the
carbocyclic product 4 was obtained in 5% and 18% yield, respectively. The only other product that
could be isolated was the aromatized product 8 (Scheme 3), that was obtained in yields of 4% and
5%, respectively.
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Scheme 3. Formation of aromatized compound 8 with lower amounts of Grignard reagent
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Next, it was chosen to investigate whether other carbohydrateꢀderived lactone acetals would
undergo the newly discovered reaction. Therefore, the anomeric epimer of 3 (12) and lactone
acetals derived from
Dꢀmannose (16) and Dꢀgalactose (20) were synthesized (Scheme 4). The
syntheses resembles the synthesis of 3, starting with conversion of the free alcohol into the iodide
followed by elimination and ozonolysis.4,27,28
Scheme 4. Synthesis of substrates 12, 16 and 20
It was first shown that 12 underwent the same reaction as 3 to give 4, albeit in a slightly diminished
yield of 49% (Scheme 5a). The
Dꢀmannoseꢀderived lactone acetal 16 afforded a combined yield of
67% of carbocyclic products with the same relative orientation of the substituents on the new
stereocenters with the major product 21 resembling the original product 4 derived from Dꢀglucose
(Scheme 5b).
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Scheme 5. Carbocyclization from other substrates
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When the reaction conditions were applied to the substrate derived from Dꢀgalactose 20 a prolonged
reaction time at room temperature was found to be required to obtain the carbocyclic product.
Reaction for just 1 h at ambient temperature resulted in openꢀchain compound 23 containing an
aldehyde functionality, while prolonging the reaction time increased the yield of carbocyclic
product 24 to 27%. The new stereocenters of 24 were all found to have the opposite stereochemistry
compared to the original product 4. The stereochemistry of the carbocyclic products 21, 22 and 24
was also determined by Xꢀray crystallographic analysis. Compound 21 was crystallized without any
need for derivatization in contrast to the compounds 22 and 24, which were crystallized as their
camphanic acid ester derivatives (Supporting Information).
Based on the aboveꢀmentioned results and inspired by the mechanism suggested by Valéry and coꢀ
workers for their addition of two equivalents of vinylmagnesium bromide to a gluconoꢀ1,5ꢀ
lactone,29 we envisage the reaction to occur through either of the following two mechanisms via a
SN2’ reaction or a 1,4ꢀaddition (Scheme 6).
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Scheme 6. Suggested mechanism and reasoning for stereochemical outcome
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Addition of the first equivalent of vinylmagnesium bromide to the carbonyl carbon gives the
tetrahedral intermediate I. This intermediate can then either react with another equivalent of
vinylmagnesium bromide in an SN2’ reaction to give the openꢀchain intermediate II (blue arrows),
or the Grignard reagent can attack the unsaturated carbonyl of the openꢀchain intermediate III in a
1,4ꢀaddition (red arrows) giving the same intermediate II. After revealing the aldehyde functionality
of IV, an intramolecular aldol reaction can occur with attack of the enolate onto the aldehyde.
Surprisingly, the aldehyde of IV is not attacked by the Grignard reagent in solution, but instead
participates in the ringꢀclosing aldol step. The isolation of 23 from the Dꢀgalactoseꢀderived substrate
20 confirms the existence of intermediate II and/or IV in the reaction pathway. After ringꢀclosing
another molecule of vinylmagnesium bromide can attack the ketone to give the observed product 4
after acidic workꢀup. Given the proposed involvement of either a Michael addition or SN2’ reaction
of vinylꢀMgBr, CuCN·2LiCl known to promote conjugate addition of Grignard reagents was
explored as an additive without success (Table 1, Entry 14).30
For the Ferrier carbocyclization it is believed that the stereochemistry of the βꢀcarbon of the
cyclohexanone is determined by a coordination between the mercuric ion and the two oxygen atoms
from the resulting hydroxy and carbonyl group, respectively (Scheme 6 (box)). This belief has been
substantiated by literature examples where substrates that would adopt one chair conformation gives
the opposite stereochemistry at this carbon compared to substrates that would adopt the other
possible chair conformation in the transition state.15,19,31 The stereochemical outcome of the newly
discovered reaction on the substrate 4 can also be explained from the coordination of the
magnesium ion to two of the oxygens in the transition state of the cyclization step (Scheme 6 (box))
where the chair conformation with the three benzyl ethers and the allyl group in equatorial positions
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is adopted. Attack of the last equivalent of vinylmagnesium bromide from the least hindered
equatorial trajectory sets the final stereocenter. It is interesting to notice that for all carbocyclic
products obtained from different lactone acetals the substituents on the new stereocenters were
found to have the same relative orientation providing some evidence for the proposed transition
state in Scheme 6 with coordination of the magnesium ion. Changing the stereochemistry of one
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stereocenter neighboring the acetal functionality, as with the
Dꢀmannoseꢀderived substrate 16,
probably causes the two possible chair conformations in the transition state to become closer in
energy due to one of the substituents changing from an equatorial to axial orientation. This enables
the formation of two diastereomeric carbocyclic products which is also seen by the formation of
both compound 21 and 22 (Scheme 5b). Surprisingly, changing the stereochemistry of the carbon
center next to the carbonyl, as in the substrate 20 derived from Dꢀgalactose, has a major influence
on the reaction outcome as both the opposite diastereomer compared to the original reaction is
isolated and the reaction yield is greatly diminished.
Still enticed by the reaction, it was decided to explore the outcome of treatment of 3 with other
Grignard reagents like MeMgCl. The product of the reaction of 3 with MeMgCl was found to be the
hemiacetal 25 (Scheme 7), which is a stereoisomeric analogue of the natural compound (+)ꢀnoviose,
being a carbohydrate fragment of the naturally occurring antitumor agent novobiocin.32ꢀ34 For easier
purification and identification, hemiacetal 25 was acetylated to give 26 as a single isomer. Even
though a carbocyclic product is not seen with the methyl Grignard reagent, this reaction has some
similarity to the carbocyclization as the product hemiacetal is not attacked by excess
methylmagnesium chloride. It was surprising to us that the aldehyde functionality of intermediate
IV (Scheme 6) and hemiacetal of 25 (Scheme 7) was not attacked by Grignard reagent in solution.
A reason for this could be a stabilized hemiacetal (intermediate II, Scheme 6) through coordination
of magnesium to the neighboring ether oxygen. Also, due to the presence of a neighboring electron
withdrawing ether functional group, intermediate II could have a diminished tendency to expel
MeOMgBr and thereby reveal a strongly electron deficient and highly reactive aldehyde.35
Scheme 7. Reaction with MeMgCl
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For further investigation of this hypothesis, a substrate derived from 2ꢀdeoxyꢀDꢀglucose 29 was
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synthesized and subjected to the carbocylization conditions (Scheme 8aꢀb).36 From this lactone
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acetal a cyclized product 30 was obtained in 30% yield with a stereochemical outcome resembling
that obtained from the Dꢀglucoseꢀderived starting material 3. The stereochemistry of this compound
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was again determined by Xꢀray crystallographic analysis of the camphanic acid ester derivative
(Supporting Information). Additionally, an openꢀchain compound 31 was isolated in 27% yield. The
formation of 31 is proposed to occur through a mechanism that includes the same initial attack of
Grignard reagent to the carbonyl as proposed in Scheme 6. After ringꢀopening, the aldehyde is
revealed and attacked by another Grignard reagent and eventually 31 is obtained after a 1,2ꢀaddition
to the ketone. Products of this type was not found for derivatives 3, 12, 16 and 20 with a benzyl
ether flanking the aldehyde carbon atom.
Scheme 8. a) Synthesis of lactone acetal 29 b) Carbocyclization of 29 c) Reaction of 29 with
MeMgCl
Lactone acetal 29 was also reacted with the methyl Grignard reagent (Scheme 8c). Again, a
hemiacetal 32 resembling 25 was obtained but also the openꢀchain compound 33 was isolated,
analogously to the result obtained from the reaction between 29 and vinylmagnesium bromide.
These results with both methylꢀ and vinyl Grignard reagents support our hypothesis that the ether
group next to the acetal is important for the reactivity of the intermediate hemiacetal/aldehyde.
To demonstrate the synthetic utility of these carbocyclic products, a route for further derivatization
was pursued for the carbocyclic product 4. We investigated whether the diene would undergo ringꢀ
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closing metathesis (RCM) (Scheme 9). This transformation could be challenging as the product is a
fiveꢀmembered ring transꢀfused to a sixꢀmembered ring, which could imply some ring strain.
However, 34 was indeed obtained in 68% yield with the HoveydaꢀGrubbs (HG) 2nd generation
catalyst. The structure of 34 was confirmed by Xꢀray crystallographic analysis (Figure 2). The
double bond could subsequently be dihydroxylated with catalytic osmium tetroxide and
Nꢀmethylmorpholine Nꢀoxide (NMO) in a yield of 74%. The expected antiꢀaddition to the cyclic
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3
allylic alcohol was rationalized by the JHH coupling constants and 1DꢀROESY experiments
(Supporting Information).37ꢀ38 The bicyclic system with a sixꢀmembered ring transꢀfused to a fiveꢀ
membered ring is a motif wellꢀknown as the Cꢀ and Dꢀring of steroids including examples such as
cholesterol, testosterone and estradiol. Furthermore, 35 resembles a group of polyhydroxylated
bicyclic compound compounds which have shown activity as glucosidase inhibitors.39ꢀ40 Further
exploration of these highly substituted carbocyclic compound in the synthesis of potential
glycosidase inhibitors is currently ongoing in our group.
Scheme 9. Derivatization of carbocyclic product
OH
HO
HG 2nd
HO
HO
OH
BnO
BnO
BnO
BnO
BnO
BnO
(5 mol%)
OsO4, NMO
H
H
CH2Cl2
Reflux, 2 h
68%
H2O/MeCN/
Acetone 1:1:1
rt, 4 days
74%
OH
OH
OH
OBn
4
OBn
34
OBn
35
Figure 2. Molecular structure of 34
Conclusion
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In conclusion, a novel type of carbocyclization has been presented and a mechanism proposed. The
reaction was found to be operationally straightforward even on large scale and was applied to
substrates of varying stereochemistry and substituents. The structures of carbocyclic molecules
were verified by Xꢀray crystallographic analysis. The transformation of lactone acetals into highly
substituted carbocyclic structures makes it possible to obtain more complex molecules than e.g.
with the Ferrier carbocyclization and have the potential to be a key reaction for the synthesis of new
biological relevant compounds. Furthermore, it circumvents the use of the toxic mercury salts
which is used for the Ferrier carbocyclization.
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Experimental Section
General
All reagents were except otherwise stated used as purchased without further purification. All
reactions with airꢀ and moisture sensitive compounds were conducted in flameꢀdried glassware
under an atmosphere of nitrogen or argon. CH2Cl2, THF, MeCN and toluene were dried over
aluminium oxide via a solvent purification system. Pyridine was dried over molecular sieves. DMF
was purchased as anhydrous. Flash column chromatography was carried out either with a silica gel
60 Å pore size, 230ꢀ400 mesh particle size or a silica gel 60 (0.015ꢀ0.040 mm). TLCꢀanalysis was
carried out on silica gel on aluminum foil (Kieselgel 60, F254). The TLCꢀplates were observed
under UVꢀlight or visualized by using Cꢀmol stain (cerium(IV) sulfate and ammonium molybdate in
1
10% sulfuric acid) or KMnO4 stain (KMnO4 and NaOH in H2O) and heating to dryness. Hꢀ,
gCOSYꢀ and gHMQCꢀNMR were recorded at 400 MHz and 13CꢀNMR and DEPTꢀ135 at 100 MHz.
Signals from CDCl3 (δ 7.26 ppm for proton and δ 77.16 ppm for carbon) and C6D6 (δ 7.16 ppm for
proton and δ 128.06 ppm for carbon) were used as internal references. Assignment of NMRꢀspectra
is based on gCOSYꢀ, gHMQCꢀ and DEPTꢀ135 techniques. 1DꢀROESY experiments (SI) were
1
conducted with a 500 MHz NMR spectrometer equipped with a 5mm Hꢀ13Cꢀ15N TXI probe. Mass
spectra were recorded on a MicroTOFꢀQ High Performance LCꢀMS system. Melting points are
uncorrected. Optical rotations are given in deg*cm2*gꢀ1 and concentrations are given in g/100 mL.
(3S,4R,5R,6S)ꢀ3,4,5ꢀTris(benzyloxy)ꢀ6ꢀmethoxytetrahydroꢀ2Hꢀpyranꢀ2ꢀone (3)
7 (2.555 g, 5.72 mmol) was dissolved in dry CH2Cl2 (125 mL). The solution was cooled to ꢀ78 °C.
O2 was bubbled through the solution for 5 min followed by O3 for 15 min until the solution turned
light blue. O2 was then again bubbled through the solution for 5 min followed by nitrogen for
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5 min. Me2S (0.85 mL, 11.4 mmol, 2 eq) was added to the solution at ꢀ78 °C. The mixture was
stirred for 30 min while being allowed to reach rt. The reaction mixture was concentrated under
7
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9
reduced pressure and subsequently purified by flash column chromatography (CH2Cl2) to afford 3
299K
(2.121 g, 4.73 mmol, 83%) as a white solid. Rf (CH2Cl2) 0.36. [α]D
ꢀ46.5 (c 0.4, CHCl3). Mp
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92.1ꢀ94.3 °C. HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.47ꢀ7.22 (m, 15H, ArH), 5.09 (d, Jgem 11.2
Hz, 1H, CHHPh), 4.98 (d, J6,5 2.5 Hz, 1H, H6), 4.82 (d, Jgem 12.1 Hz, 1H, CHHPh), 4.75 (s, 2H,
CH2Ph), 4.73 (d, Jgem 11.2 Hz, 1H, CHHPh), 4.72 (d, Jgem 12.1 Hz, 1H, CHHPh), 4.15 (t,
J
4,3/5 7.9 Hz, 1H, H4), 4.03 (d, 1H, H3), 3.74 (dd, 1H, H5), 3.55 (s, 3H, CH3). 13CꢀNMR (100 MHz,
CDCl3): δC (ppm) 169.9 (C=O, C2), 138.0, 137.6, 137.3 (ArC), 128.7ꢀ128.0 (ArCH), 100.7 (C6),
79.3 (C3), 78.8 (C4), 76.8 (C5), 74.9, 74.4, 73.8 (CH2Ph), 57.5 (CH3). HRMS(ESI): Calcd. for
C27H28O6Na+ m/z 471.1778; found m/z 471.1783. NMRꢀdata were in accordance with previously
reported data.41
General procedure for carbocyclization
For the optimization of the reaction conditions, the following procedure was followed with varying
amounts of vinylmagnesium bromide and TMEDA and at varying temperatures. When a coꢀsolvent
was used, it was added to the starting material 3 before the addition of any other reagents. When
CuCN*2LiCl was used, it was premixed with the Grignard reagent in the place of TMEDA. The
vinylmagnesium bromide was purchased as a 1 M solution in THF. However, it was titrated to a
concentration of 0.9 M.42
(1R,2R,3S,4S,5R,6S)ꢀ2ꢀAllylꢀ4,5,6ꢀtris(benzyloxy)ꢀ1ꢀvinylcyclohexaneꢀ1,3ꢀdiol (4)
Vinylmagnesium bromide (0.9 M in THF, 6.7 mL, 6.0 mmol, 9 eq) and TMEDA (1.1 mL, 7.4
mmol, 11 eq) were mixed at rt and added to 3 (0.299 g, 0.67 mmol) at ꢀ78 °C. The mixture was
stirred at ꢀ78 °C for 2 h and was then allowed to reach rt. It was stirred at this temperature for 1 h
before being quenched with water and 1 M aq. HCl. The solution was extracted with CH2Cl2 (x3).
The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated
in vacuo. The crude mixture was purified by flash column chromatography (CH2Cl2/EtOAc 100:1
ꢀ
25:1) to give 4 (0.215 g, 0.43 mmol, 64%) as a colorless oil. Rf (CH2Cl2/EtOAc 20:1) 0.67.
293K
1
[α]D
ꢀ52.2 (c 0.5, CHCl3). HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.43ꢀ7.27 (m, 15H, ArH),
5.85ꢀ5.72 (dddd, Jtrans 17.1 Hz, Jcis 10.2 Hz, Jvic 8.3 Hz, Jvic 6.2 Hz, 1H, allyl CH=CH2), 5.64 (dd,
Jtrans 17.1 Hz, Jcis 10.5 Hz, 1H, vinyl CH=CH2), 5.45 (dd, Jgem 1.6 Hz, 1H, vinyl CH=CHH), 5.36
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(dd, 1H, vinyl CH=CHH), 5.14 (d, 1H, allyl CH=CHH), 5.09 (d, 1H, allyl CH=CHH), 5.00 (d,
Jgem 10.7 Hz, 1H, CHHPh), 4.86 (d, Jgem 10.7 Hz, 1H, CHHPh), 4.82 (d, Jgem 10.4 Hz, 1H, CHHPh),
4.81 (d, Jgem 11.7 Hz, 1H, CHHPh), 4.75 (d, Jgem 11.7 Hz, 1H, CHHPh), 4.56 (d, Jgem 10.4 Hz, 1H,
CHHPh), 4.18ꢀ4.13 (m, 1H, H3), 4.12 (t, J5,4/6 9.5 Hz, 1H, H5), 3.49ꢀ3.40 (m, 2H, 2xOH), 3.45 (dd,
J4.3 3.0 Hz, 1H, H4), 3.37 (d, 1H, H6), 2.51 (ddd, Jgem 14.4 Hz, JCHH,2 10.9 Hz, 1H, allyl CHH),
2.36ꢀ2.27 (m, 1H, allyl CHH), 1.37 (dt, J2,3/CHH 3.0 Hz, 1H, H2). 13CꢀNMR (100 MHz, CDCl3):
δc (ppm) 140.9 (vinyl CH=CH2), 139.0, 138.4, 138.1 (ArC), 136.6 (allyl CH=CH2), 128.6ꢀ127.7
(ArCH), 117.2 (allyl CH=CH2), 116.5 (vinyl CH=CH2), 85.0 (C6), 82.9 (C4), 80.4 (C5), 79.8 (C1),
76.2, 76.2, 72.4 (CH2Ph), 68.5 (C3), 42.3 (C2), 28.7 (allyl CH2). HRMS(ESI): Calcd. for
C32H36O5Na+ m/z 523.2455; found m/z 523.2463.
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(1
benzoate (5)
4 (0.205 g, 0.41 mmol) was dissolved in dry CH2Cl2 (6 mL). The solution was cooled to 0
S,2R,3R,4S,5R,6S)ꢀ2ꢀAllylꢀ4,5,6ꢀtris(benzyloxy)ꢀ3ꢀhydroxyꢀ3ꢀvinylcyclohexyl 3,5ꢀdinitroꢀ
°C before
the addition of Et3N (0.11 mL, 0.82 mmol, 2 eq), DMAP (0.011 g, 0.041 mmol, 0.1 eq) and
3,5ꢀdinitrobenzoyl chloride (0.143 g, 0.61 mmol, 1.5 eq). The reaction mixture was stirred
overnight at rt. The reaction mixture was diluted with CH2Cl2 and subsequently washed with 1 M
aq. HCl, sat. aq. NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was purified by flash column
chromatography (Pentane/CH2Cl2 1:2
ꢀ 1:4) to afford 5 (0.239 g, 0.34 mmol, 84%) as white
crystals. The compound was recrystallized from diethyl ether to produce crystals suitable for Xꢀray
299K
crystallography. Rf (Pentane/CH2Cl2 1:2) 0.51. [α]D
ꢀ4.0 (c 1.0, CHCl3). Mp 152.6ꢀ154.8 °C
1
(Et2O). HꢀNMR (400 MHz, CDCl3): δH (ppm) 9.31 (d, Jmeta 2.3 Hz, 2H, ArH), 9.23 (t, 1H, ArH),
7.39ꢀ7.24 (m, 15H, ArH), 5.88 (t, J1,2/6 2.5 Hz, 1H, H1), 5.83ꢀ5.70 (m, 2H, allyl CH=CH2, vinyl
CH=CH2), 5.52 (d, Jtrans 17.0 Hz, 1H, vinyl CH=CHH), 5.44 (d, Jcis 10.6 Hz, 1H, vinyl CH=CHH),
5.09 (d, Jcis 10.0 Hz, 1H, allyl CH=CHH), 4.97ꢀ4.82 (m, 4H, allyl CH=CHH, 3xCHHPh), 4.76 (d,
Jgem 10.5 Hz, 1H, CHHPh), 4.66 (d, Jgem 10.1 Hz, 1H, CHHPh), 4.61 (d, Jgem 10.9 Hz, 1H, CHHPh),
4.08 (t, J5,4/6 9.6 Hz, 1H, H5), 3.67 (dd, 1H, H6), 3.47 (d, 1H, H4), 2.82 (s, 1H, OH), 2.44ꢀ2.35 (m,
1H, allyl CHH), 2.23ꢀ2.11 (m, 1H, allyl CHH), 1.71ꢀ1.65 (m, 1H, H2). 13CꢀNMR (100 MHz,
CDCl3): δC (ppm) 162.2 (C=O), 148.8 (ArCꢀNO2), 142.2 (allyl CH=CH2), 138.7, 137.8, 137.8
(ArC), 135.8 (vinyl CH=CH2), 134.5 (ArCꢀC=O), 130.1, 128.5ꢀ127.7, 122.4 (ArCH), 118.1 (allyl
CH=CH2), 116.9 (vinyl CH=CH2), 84.6 (C4), 81.1 (C6), 79.6 (C5), 78.1 (C3), 76.5, 76.1, 72.7
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+
(CH2Ph), 70.7 (C1), 42.8 (C2), 29.0 (allyl CH2). HRMS(ESI) Calcd. for C39H38N2O10NH4 m/z
5
6
712.2865; found m/z 712.2867.
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Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ5ꢀmethyleneꢀαꢀDꢀxylopyranoside (7)
6 (3.682 g, 6.44 mmol) was dissolved in dry pyridine (40 mL) and transferred to a flask containing
AgF (3.266 g, 25.7 mmol, 4 eq) under an atmosphere of nitrogen. The reaction mixture was stirred
in the dark for 48 h at rt. The reaction mixture was concentrated under reduced pressure and
subsequently purified by flash column chromatography (CH2Cl2) to afford 7 (2.555 g, 5.72 mmol,
293K
89%) as a white solid. Rf (CH2Cl2) 0.47. [α]D
ꢀ22.2 (c 0.4, CHCl3), lit. ꢀ18 (c 1.3, CHCl3)43.
Mp 55.3ꢀ57.1 °C, lit. 57ꢀ58 °C.16 1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.42ꢀ7.31 (m, 15H, ArH),
4.97ꢀ4.72 (m, 6H, 3xCHHPh, 2xCHHPh, H6a), 4.78ꢀ4.75 (bs, 1H, H6b), 4.72 (d, Jgem 12.2 Hz, 1H,
CHHPh), 4.68 (d, J1,2 3.4 Hz, 1H, H1), 4.03 (t, J3,2/4 9.2 Hz, 1H, H3), 3.96 (dt, J4,6a/6b 1.9 Hz, 1H,
H4), 3.65 (dd, 1H, H2), 3.47 (s, 3H, CH3). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 153.7 (C5),
138.7, 138.1, 138.1 (ArC), 128.5ꢀ127.7 (ArCH), 99.1 (C1), 96.9 (C6), 81.3 (C4), 79.6 (C3), 79.3
(C2), 75.8, 74.6, 73.7 (CH2Ph), 55.5 (CH3). HRMS(ESI): Calcd. for C28H30O5Na+ m/z 469.1985;
found m/z 469.1987. NMRꢀdata were in accordance with previously reported data.44
2ꢀAllylꢀ4,6ꢀbis(benzyloxy)phenol (8)
1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.46ꢀ7.30 (m, 10H, ArH Bn), 6.53 (d, Jmeta 2.7 Hz, 1H,
H3/H5), 6.42 (d, Jmeta 2.7 Hz, 1H, H3/H5), 6.00 (ddt, Jtrans 17.1 Hz, Jcis 10.2 Hz, Jvic 6.5 Hz, 1H,
CH=CH2), 5.36 (s, 1H, OH), 5.13ꢀ5.05 (m, 2H, CH=CH2), 5.05 (s, 2H, CH2Ph), 4.97 (s, 2H,
4
CH2Ph), 3.40 (dt, J 1.2 Hz, 2H, CH2CH=CH2). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 152.1
(C4/C6), 146.1 (C4/C6), 138.1, 137.4 (ArC), 136.6 (CH=CH2), 136.4 (ArC), 128.9ꢀ127.8 (ArCH
Bn), 126.2 (ArC), 115.8 (CH=CH2), 107.6 (C3/C5), 99.6 (C3/C5), 71.4, 70.9 (CH2Ph), 34.2
(CH2CH=CH2). HRMS(ESI) Calcd. for C23H22O3H+ m/z 347.1642; found m/z 347.1646.
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀdeoxyꢀ6ꢀiodoꢀβꢀDꢀglucopyranoside (10)
9 (2.006 g, 4.3 mmol) was dissolved in dry toluene (80 mL) under an atmosphere of nitrogen.
Imidazole (0.598 g, 8.6 mmol, 2 eq), PPh3 (2.837 g, 10.8 mmol, 2.5 eq) and I2 (1.319 g, 5.2 mmol,
1.2 eq) were added. The reaction mixture was stirred overnight at 70 °C. The reaction mixture was
allowed to reach rt before it was quenched with 10% aq. Na2S2O3 (30 mL) and subsequently stirred
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for 10 min. The aqueous phase was extracted with EtOAc (x3). The combined organic layers were
washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product
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9
was purified by flash column chromatography (Pentane/CH2Cl2 5:1
ꢀ
Pentane/EtOAc 10:1)
293K
affording 10 (2.456 g, 4.3 mmol, 99%) as a white solid. Rf (Pentane/EtOAc 30:1) 0.50. [α]D
+19.0 (c 2.0, CHCl3). Mp 87.5ꢀ88.7 °C. 1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.41ꢀ7.30 (m, 15H,
ArH), 5.00 (d, Jgem 11.0 Hz, 1H, CHHPh), 4.98 (d, Jgem 11.1 Hz, 1H, CHHPh), 4.96 (d, Jgem 11.0
Hz, 1H, CHHPh), 4.83 (d, Jgem 11.0 Hz, 1H, CHHPh), 4.76 (d, Jgem 11.1 Hz, 1H, CHHPh), 4.73 (d,
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J
gem 11.0 Hz, 1H, CHHPh), 4.42 (d, J1,2 7.8 Hz, 1H, H1), 3.73 (t, J3,2/4 9.0 Hz, 1H, H3), 3.65 (s, 3H,
CH3), 3.56 (dd, J6a,6b 10.3 Hz, J6a,5 2.3 Hz, 1H, H6a), 3.51 (dd, 1H, H2), 3.44 (t, J4,5 9.0 Hz, 1H,
13
H4), 3.30 (dd, J6b,5 7.2 Hz, 1H, H6b), 3.24 (ddd, 1H, H5). CꢀNMR (100 MHz, CDCl3): δC (ppm)
138.6, 138.5, 138.0 (ArC), 128.6ꢀ127.8 (ArCH), 104.5 (C1), 84.3 (C3), 82.5 (C2), 81.4 (C4), 75.7,
+
75.4, 74.8 (CH2Ph), 73.9 (C5), 55.3 (CH3), 6.5 (C6). HRMS(ESI): Calcd. for C28H31IO5NH4 m/z
592.1554; found m/z 592.1560
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ5ꢀmethyleneꢀβꢀDꢀxylopyranoside (11)
10 (2.231 g, 3.88 mmol) was dissolved in dry THF (30 mL) under an atmosphere of nitrogen. DBU
(2.32 mL, 15.5 mmol, 4 eq) was added and the reaction mixture was heated to reflux for 6 h. The
reaction mixture was allowed to reach rt and left stirring overnight. The reaction mixture was
quenched with sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc (x3). The combined
organic layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash column chromatography (Pentane/EtOAc
15:1) affording 11 (1.450 g, 3.25 mmol, 84%) as a white solid. Rf (Pentane/EtOAc 30:1) 0.52.
293K
1
[α]D
ꢀ41.9 (c 2.0, CHCl3). Mp 63.1ꢀ65.8 °C. HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.43ꢀ7.31
(m, 15H, ArH), 4.85ꢀ4.78 (m, 5H, H6a, 3xCHHPh, CHHPh), 4.76ꢀ4.71 (m, 3H, H6b, 2xCHHPh),
4.68 (d, J1,2 6.3 Hz, 1H, H1), 4.13 (dt, J4,3 7.8 Hz, J4,6a/6b 1.3 Hz, 1H, H4), 3.71 (dd, J3,2 6.9 Hz, 1H,
H3), 3.66ꢀ3.61 (m, 1H, H2), 3.62 (s, 3H, CH3). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 153.9 (C5),
138.4, 138.3, 138.0 (ArC), 128.5ꢀ127.7 (ArCH), 104.1 (C1), 94.7 (C6), 82.2 (C3), 81.5 (C2), 78.4
(C4), 74.4, 73.9, 73.1 (CH2Ph), 57.0 (CH3). HRMS(ESI): Calcd. for C28H30O5Na+ m/z 469.1985;
found m/z 469.1988.
(3
S,4
R
,5R,6
R
)ꢀ3,4,5ꢀTris(benzyloxy)ꢀ6ꢀmethoxytetrahydroꢀ2Hꢀpyranꢀ2ꢀone (12)
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11 (1.229 g, 2.75 mmol) was dissolved in dry CH2Cl2 (55 mL). The solution was degassed for 5
min with nitrogen before it was cooled to ꢀ78 °C. O2 was bubbled through the solution for 5 min
followed by O3 for 15 min until the solution turned blue. O2 was bubbled through the solution for 5
min followed by nitrogen for 5 min. Me2S (0.40 mL, 5.51 mmol, 2 eq) was added to the solution at
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°
ꢀ78 C and the reaction mixture was stirred for 30 min while allowed to reach rt. The reaction
mixture was concentrated under reduced pressure and subsequently purified by flash column
chromatography (Pentane/EtOAc 10:1) to afford 12 (0.804 g, 1.79 mmol, 65%) as a yellow oil. Rf
293K
1
(Pentane/EtOAc 5:1) 0.41. [α]D
ꢀ48.9 (c 2.0, CHCl3). HꢀNMR (400 MHz, CDCl3): δH (ppm)
7.36ꢀ7.32 (m, 2H, ArH), 7.29ꢀ7.14 (m, 13H, ArH), 5.05 (dd, J6,5 2.5 Hz, J6,4 0.7 Hz, 1H, H6), 4.97
(d, Jgem 11.2 Hz, 1H, CHHPh), 4.64 (d, Jgem 11.8 Hz, 1H, CHHPh), 4.56 (d, Jgem 11.2 Hz, 1H,
CHHPh), 4.54 (d, Jgem 11.8 Hz, 1H, CHHPh), 4.41 (d, Jgem 11.9 Hz, 1H, CHHPh), 4.37 (d, Jgem 11.9
Hz, 1H, CHHPh), 4.36 (d, J3,4 8.2 Hz, 1H, H3), 3.77 (ddd, J4,5 2.5 Hz, 1H, H4), 3.70 (t, 1H, H5),
13
3.43 (s, 3H, CH3). CꢀNMR (100 MHz, CDCl3): δC (ppm) 169.8 (C=O, C2), 137.6, 137.4, 137.0
(ArC), 128.6ꢀ127.9 (ArCH), 103.1 (C6), 80.1 (C4), 79.0 (C5), 77.7 (C3), 73.9, 73.5, 71.9 (CH2Ph),
57.3 (CH3). HRMS(ESI): Calcd. for C27H28O6H+ m/z 449.1959; found m/z 449.1959.
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀdeoxyꢀ6ꢀiodoꢀαꢀDꢀmannopyranoside (14)
13 (18.225 g, 39.2 mmol) was dissolved in dry toluene (225 mL). PPh3 (25.734 g, 98.1 mmol, 2.5
eq), imidazole (5.354 g, 78.6 mmol, 2 eq) and I2 (11.957 g, 47.1 mmol, 1.2 eq) were added. The
reaction mixture was heated to 90 °C and stirred at this temperature for 2 h before being allowed to
reach rt. The reaction was quenched by the addition of 10% aq. Na2S2O3. The aqueous phase was
extracted with EtOAc (x3) and the resulting organic phase was washed with brine, dried over
MgSO4, filtered and concentrated in vacuo. The crude residue was purified was flash column
chromatography (Pentane/CH2Cl2 3:1
ꢀ
CH2Cl2) to give 14 (21.763 g, 37.9 mmol, 97%) as a
299K
slightly yellow oil. Rf (CH2Cl2) 0.57. [α]D
+30.4 (c 2, CHCl3), lit. +26 (c 1.39, CHCl3).27 1Hꢀ
NMR (400 MHz, CDCl3): δH (ppm) 7.41ꢀ7.27 (m, 15H, ArH), 4.98 (d, Jgem 11.0 Hz, 1H, CHHPh),
4.75 (d, Jgem 12.4 Hz, 1H, CHHPh), 4.75 (d, J1,2 1.5 Hz, 1H, H1), 4.71 (d, Jgem 12.4 Hz, 1H,
CHHPh), 4.67 (d, Jgem 11.0 Hz, 1H, CHHPh), 4.60 (s, 2H, CH2Ph), 3.88 (dd, J3,4 9.3 Hz, J3,2 3.2 Hz,
1H, H3), 3.80ꢀ3.73 (m, 2H, H2, H4), 3.56 (dd, J6a,6b 10.2 Hz, J6a,5 2.4 Hz, 1H, H6a), 3.54ꢀ3.48 (m,
1H, H5), 3.37 (s, 3H, CH3), 3.35ꢀ3.29 (m, 1H, H6b). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 138.1,
138.1, 138.1 (ArC), 128.3ꢀ127.5 (ArCH), 98.8 (C1), 79.7 (C3), 78.4 (C4), 75.2 (CH2Ph), 74.5 (C2),
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+
72.5, 71.9 (CH2Ph), 71.3 (C5), 54.9 (CH3), 7.1 (C6). HRMS(ESI): Calcd. for C28H31IO5NH4 m/z
5
6
592.1554; found m/z 592.1563. NMRꢀdata were in accordance with previously reported data.27
7
8
9
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ5ꢀmethyleneꢀαꢀDꢀlyxopyranoside (15)
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14
15
16
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18
19
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14 (8.794 g, 15.3 mmol) was dissolved in dry pyridine (90 mL) and added to a flask containing AgF
(7.702 g, 60.7 mmol, 4 eq), which was weighed under an atmosphere of nitrogen. The reaction
mixture was stirred at rt for 48 h in the dark and concentrated in vacuo. The crude residue was
purified by flash column chromatography (CH2Cl2) to give 15 (5.903 g, 13.2 mmol, 86%) as a
299K
colorless oil. Rf (Pentane/EtOAc 8:1) 0.46. [α]D
ꢀ27.2 (c 1, CH3OH), lit. ꢀ18.2 (c 1, CH3OH).45
1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.40ꢀ7.27 (m, 15H, ArH), 4.84ꢀ4.72 (m, 8H, H1, H6a+b,
3xCHHPh, 2xCHHPh), 4.67 (d, Jgem 12.0 Hz, 1H, CHHPh), 4.37 (dt, J4,5 8.6 Hz, J4,6a/6b 1.6 Hz, 1H,
H4), 3.90 (dd, J3,2 3.0 Hz, 1H, H3), 3.87 (t, J2,1 3.0 Hz, 1H, H2), 3.42 (s, 3H, CH3). 13CꢀNMR (100
MHz, CDCl3): δC (ppm) 154.9 (C5), 138.6, 138.3 (ArC), 128.4ꢀ127.6 (ArCH), 100.8 (C1), 96.7
(C6), 78.7 (C4), 76.6 (C2), 75.7 (C3), 73.7, 73.3, 73.0 (CH2Ph), 55.5 (CH3). HRMS(ESI): Calcd.
for C28H30O5Na+ m/z 469.1985; found m/z 469.1992. NMRꢀdata were in accordance with
previously reported data.46
(3S,4R,5S,6S)ꢀ3,4,5ꢀTris(benzyloxy)ꢀ6ꢀmethoxytetrahydroꢀ2Hꢀpyranꢀ2ꢀone (16)
15 (5.903 g, 13.2 mmol) was dissolved in dry CH2Cl2 (250 mL) and the solution was cooled
to ꢀ78 °C. O2 was bubbled through the solution for 5 min, followed by O3 for 20 min, O2 for 5 min
and N2 for 10 min. Me2S (2.0 mL, 26.8 mmol, 2 eq) was added and the reaction mixture was
allowed to reach rt and was stirred at this temperature for 30 min. The mixture was concentrated in
vacuo and the crude residue was purified by flash column chromatography (Pentane/EtOAc 7:1) to
give 16 (5.058 g, 11.3 mmol, 85%) as a colorless oil. Rf (CH2Cl2) 0.37. [α]D299K ꢀ31.0 (c 2, CHCl3).
1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.46ꢀ7.27 (m, 15H, ArH), 5.14 (d, Jgem 11.0 Hz, 1H,
CHHPh), 5.08 (d, J6,5 2.6 Hz, 1H, H6), 4.81 (d, Jgem 12.0 Hz, 1H, CHHPh), 4.76 (d, Jgem 11.0 Hz,
1H, CHHPh), 4.76 (d, Jgem 11.9 Hz, 1H, CHHPh), 4.72 (d, Jgem 12.0 Hz, 1H, CHHPh), 4.64 (d,
Jgem 11.9 Hz, 1H, CHHPh), 4.47 (d, J3,4 9.3 Hz, 1H, H3), 4.12 (dd, J4,5 2.6 Hz, 1H, H4), 3.94 (t, 1H,
H5), 3.48 (s, 3H, CH3). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 170.4 (C=O, C2), 138.0, 137.6,
137.5 (ArC), 128.6ꢀ127.6 (ArCH), 101.8 (C6), 77.4 (C3), 76.5 (C4), 75.1 (CH2Ph), 74.5 (C5), 73.4,
+
73.2 (CH2Ph), 56.9 (OCH3). HRMS(ESI): Calcd. for C27H28O6NH4 m/z 466.2224; found m/z
466.2227.
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Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀdeoxyꢀ6ꢀiodoꢀαꢀDꢀgalactopyranoside (18)
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8
9
17 (3.399 g, 7.3 mmol) was dissolved in dry toluene (140 mL). Imidazole (0.998 g, 15 mmol, 2 eq),
PPh3 (4.799 g, 18 mmol, 2.5 eq) and I2 (2.231 g, 8.8 mmol, 1.2 eq) were added to the solution. The
reaction mixture was stirred at 70 °C for 2 h, cooled to rt and quenched by the addition of 10%
Na2S2O3. The aqueous phase was extracted with EtOAc (x3). The combined organic layers were
washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude
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60
product was purified by flash column chromatography (Pentane/CH2Cl2 3:1
ꢀ
1:2) to afford 18
293K
D
(3.397 g, 5.9 mmol, 81%) as a colorless oil. Rf (Pentane/EtOAc 20:1) 0.43. [
α]
+20.9 (c 2.0,
CHCl3), lit. +23 (c 1.1, CHCl3).27 1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.48ꢀ7.27 (m, 15H, ArH),
5.08 (d, Jgem 11.2 Hz, 1H, CHHPh), 4.94 (d, Jgem 11.7 Hz, 1H, CHHPh), 4.87 (d, Jgem 12.1 Hz, 1H,
CHHPh), 4.80 (d, Jgem 11.7 Hz, 1H, CHHPh), 4.72 (d, Jgem 12.1 Hz, 1H, CHHPh), 4.68 (d, J1,2 3.5
Hz, 1H, H1), 4.67 (d, Jgem 11.2 Hz, 1H, CHHPh), 4.09ꢀ4.03 (m, 2H, H2, H4), 3.97 (dd, J3,2 10.3 Hz,
J3,4 2.3 Hz, 1H, H3), 3.88 (t, J5,6a/6b 6.8 Hz, 1H, H5), 3.45 (s, 3H, CH3), 3.28ꢀ3.24 (m, 1H, H6a),
3.10 (dd, J6a,6b 10.1 Hz, 1H, H6b). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 138.7, 138.4, 138.3
(ArC), 128.5ꢀ127.6 (ArCH), 98.9 (C1), 79.1 (C3), 76.0 (C2), 75.8 (C4), 75.1, 73.7, 73.7 (CH2Ph),
+
71.3 (C5), 55.8 (CH3), 3.7 (C6). HRMS(ESI): Calcd. for C28H31IO5NH4 m/z 592.1554; found m/z
592.1561. NMRꢀdata were in accordance with previously reported data.27,28
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ5ꢀmethyleneꢀβꢀLꢀarabinopyranoside (19)
18 (2.833 g, 4.9 mmol) was dissolved in dry pyridine (40 mL) and transferred to a flask containing
AgF (2.523 g, 20 mmol, 4 eq) under an atmosphere of nitrogen. The reaction mixture was stirred in
the dark for 96 h at rt. The reaction mixture was concentrated under reduced pressure and the crude
residue was purified by flash column chromatography (CH2Cl2) to afford 19 (2.039 g, 4.6 mmol,
293K
D
1
93%) as a colorless oil. Rf (CH2Cl2) 0.69. [
α]
+13.6 (c 2.0, CHCl3). HꢀNMR (400 MHz,
CDCl3): δH (ppm) 7.44ꢀ7.27 (m, 15H, ArH), 4.92 (d, Jgem 12.0 Hz, 1H, CHHPh), 4.79ꢀ4.69 (m, 5H,
H1, H6a, 2xCHHPh, CHHPh), 4.61 (d, Jgem 11.9 Hz, 1H, CHHPh), 4.47ꢀ4.41 (m, 2H, H6b,
CHHPh), 4.18 (dd, J2,3 9.8 Hz, J2,1 2.5 Hz, 1H, H2), 4.07 (d, J4,3 2.5 Hz, 1H, H4), 3.97 (dd, 1H,
H3), 3.43 (s, 3H, CH3). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 151.7 (C5), 138.7, 138.7, 138.0
(ArC), 128.5ꢀ127.6 (ArCH), 102.0 (C6), 100.0 (C1), 76.7 (C3), 75.8 (C2), 74.9 (C4), 74.1, 72.6,
69.4 (CH2Ph), 55.8 (CH3). HRMS(ESI): Calcd. for C28H30O5Na+ m/z 469.1985; found m/z
469.1990.
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(3R,4R,5R,6S)ꢀ3,4,5ꢀTris(benzyloxy)ꢀ6ꢀmethoxytetrahydroꢀ2Hꢀpyranꢀ2ꢀone (20)
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19 (1.853 g, 4.2 mmol) was dissolved in dry CH2Cl2 (80 mL). The solution was cooled to ꢀ78 °C.
O2 was bubbled through the solution for 5 min followed by O3 for 10 min until the solution turned
light blue. O2 was again bubbled through the solution for 5 min followed by nitrogen for 5 min.
Me2S (0.61 mL, 8.3 mmol, 2 eq) was added to the solution at ꢀ78 °C and the reaction mixture was
stirred for 30 min while being allowed to reach rt. The reaction mixture was concentrated under
reduced pressure and the crude residue was purified by flash column chromatography
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(Pentane/EtOAc 10:1
ꢀ
4:1) to afford 20 (1.513 g, 3.4 mmol, 81%) as a colorless oil. Rf
1
(Pentane/EtOAc 7:1) 0.38. [
α]
293K +104.5 (c 2.0, CHCl3). HꢀNMR (400 MHz, CDCl3): δH (ppm)
D
7.39ꢀ7.25 (m, 13H, ArH), 7.20ꢀ7.15 (m, 2H, ArH), 5.24 (d, J6,5 3.0 Hz, 1H, H6), 5.06 (d, Jgem 12.0
Hz, 1H, CHHPh), 4.83 (d, Jgem 11.9 Hz, 1H, CHHPh), 4.67 (d, Jgem 12.0 Hz, 1H, CHHPh), 4.64 (d,
J
gem 12.0 Hz, 1H, CHHPh), 4.59 (d, Jgem 11.9 Hz, 1H, CHHPh), 4.53 (d, Jgem 12.0 Hz, 1H, CHHPh),
4.53 (d, J3,4 3.8 Hz, 1H, H3), 3.98 (t, J4,5 3.8 Hz, 1H, H4), 3.85 (dd, 1H, H5), 3.58 (s, 3H, CH3).
13CꢀNMR (100 MHz, CDCl3): δC (ppm) 169.1 (C=O, C2), 137.8, 137.5, 137.4 (ArC), 128.6ꢀ127.9
(ArCH), 102.2 (C6), 76.6 (C4), 75.9 (C5), 74.6 (C3), 73.8, 73.6, 73.5 (CH2Ph), 57.9 (CH3).
+
HRMS(ESI) Calcd. for C27H28O6NH4 m/z 466.2224; found m/z 466.2232.
(1
R,2R,3S,4R,5R,6S)/(1S,2S,3R,4R,5R,6S)ꢀ2ꢀAllylꢀ4,5,6ꢀtris(benzyloxy)ꢀ1ꢀvinylcyclohexaneꢀ
1,3ꢀdiol (21 and 22)
Vinylmagnesium bromide (0.9 M in THF, 11.7 mL, 10.5 mmol, 9 eq) and TMEDA (1.9 mL,
13 mmol, 11 eq) were mixed at rt and added to 16 at ꢀ78 °C. The reaction mixture was stirred
at ꢀ78 °C for 2 h and allowed to reach rt and stirred at this temperature for 1 h. The reaction was
quenched by the addition of water and 1 M aq. HCl. The aqueous phase was extracted with CH2Cl2
(x3). The combined organic phases were washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The crude residue was purified by flash column chromatography
(CH2Cl2/EtOAc 200:1
ꢀ 100:1 ꢀ 25:1) to give 21 (0.355 g, 0.71 mmol, 60%) and 22 (0.043 g,
0.086 mmol, 7%) as colorless oils. 21 crystallized on standing. 21: Rf (Pentane/EtOAc 4:1) 0.45.
299K
D
1
[
α]
ꢀ49.9 (c 2.0, CHCl3). Mp 90.4ꢀ91.7 °C. HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.32ꢀ7.13
(m, 15H, ArH), 5.69 (dd, Jtrans 17.0 Hz, Jcis 10.9 Hz, 1H, vinyl CH=CH2), 5.59ꢀ5.56 (m, 1H, allyl
CH=CH2), 5.27 (dd, Jgem 1.3 Hz, 1H, vinyl CH=CHH), 5.25 (dd, 1H, vinyl CH=CHH), 5.05ꢀ4.98
(m, 1H, allyl CH=CHH), 4.95 (d, Jcis 10.0 Hz, 1H, allyl CH=CHH), 4.76 (d, Jgem 10.2 Hz, 1H,
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CHHPh), 4.70 (d, Jgem 12.2 Hz, 1H, CHHPh), 4.59 (s, 2H, CH2Ph), 4.55 (d, Jgem 12.2 Hz, 1H,
CHHPh), 4.52 (d, Jgem, 10.2 Hz, 1H, CHHPh), 3.97ꢀ3.91 (m, 2H, H4, H5), 3.83 (t, J3,2/4 3.3 Hz, 1H,
H3), 3.75ꢀ3.70 (m, 1H, H6), 2.87 (bs, 1H, OH), 2.28 (ddd, Jgem 14.4 Hz, JCHH,2 11.3 Hz, Jvic 8.3 Hz,
1H, allyl CHH), 2.16 (dtd, JCHH,2/vic 3.3 Hz, 4J 1.6 Hz, 1H, allyl CHH), 1.84 (dt, 1H, H2). 13CꢀNMR
(100 MHz, CDCl3): δC (ppm) 141.5 (vinyl CH=CH2), 138.8, 138.8, 138.3 (ArC), 136.8 (allyl
CH=CH2), 128.5ꢀ127.6 (ArCH), 116.7 (allyl CH=CH2), 115.8 (vinyl CH=CH2), 81.6 (C6), 80.7
(C1), 78.1, 77.5 (C4, C5), 76.1, 73.2, 72.7 (CH2Ph), 69.1 (C3), 39.1 (C2), 28.3 (allyl CH2).
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+
HRMS(ESI): Calcd. for C32H36O5NH4 m/z 518.2901; found m/z 518.2908. 22: Rf (Pentane/EtOAc
299K
D
1
6:1) 0.58. [
α]
ꢀ7.9 (c 2.0, CHCl3). HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.31ꢀ7.15 (m, 13H,
ArH), 7.11ꢀ7.05 (m, 2H, ArH), 5.88 (ddd, Jtrans 17.2 Hz, Jcis 10.8 Hz, JH,OH 1.6 Hz, 1H, vinyl
CH=CH2), 5.72 (dddd, Jtrans 16.9 Hz, Jcis 10.1 Hz, Jvic 8.6 Hz, Jvic 6.0 Hz, 1H, allyl CH=CH2), 5.42
(dd, Jgem 2.2 Hz, 1H, vinyl CH=CHH), 5.18 (dd, 1H, vinyl CH=CHH), 5.03 (d, 1H, allyl
CH=CHH), 4.95 (d, 1H, allyl CH=CHH), 4.61 (d, Jgem 11.8 Hz, 1H, CHHPh), 4.51 (d, Jgem 11.9 Hz,
1H, CHHPh), 4.43ꢀ4.38 (m, 3H, CHHPh, 2xCHHPh), 4.25 (d, Jgem 11.5 Hz, 1H, CHHPh), 4.20ꢀ
4.16 (m, 2H, H3, OH(1)), 3.83ꢀ3.80 (m, 1H, H5), 3.64 (t, J4,5/3 3.4 Hz, 1H, H4), 3.55 (d, J6,5 3.2 Hz,
1H, H6), 2.82 (d, JOH,3 1.8 Hz, 1H, OH(3)), 2.47 (ddd, Jgem 14.3 Hz, JCHH,2 11.4 Hz, 1H, allyl CHH),
2.17ꢀ2.09 (m, 1H, allyl CHH), 1.64 (dt, J2,3/CHH 2.8 Hz, H2). 13CꢀNMR (100 MHz, CDCl3): δC
(ppm) 140.9 (vinyl CH=CH2), 138.1, 137.8, 137.8 (ArC), 137.2 (allyl CH=CH2), 128.6ꢀ127.8
(ArCH), 116.8 (allyl CH=CH2), 115.4 (vinyl CH=CH2), 81.4 (C6), 76.6 (C5), 75.9 (C1), 75.7 (C4),
74.0, 73.0, 70.3 (CH2Ph), 68.5 (C3), 41.6 (C2), 29.1 (allyl CH2). HRMS(ESI): Calcd. for
C32H36O5H+ m/z 501.2636; found m/z 501.2946.
(2R,3R,4R)ꢀ2,3,4ꢀTris(benzyloxy)ꢀ5ꢀoxononꢀ8ꢀenal (23)
Vinylmagnesium bromide (0.9 M in THF, 4.6 mL, 4.2 mmol, 9 eq) was mixed with TMEDA (0.76
mL, 5.1 mmol, 11 eq) at rt. The mixture was slowly added to 20 (0.207 g, 0.46 mmol) at ꢀ78 °C.
The reaction was stirred at this temperature for 2 h followed by rt for 1 h before it was quenched
with H2O. The reaction mixture was extracted with CH2Cl2 (x3). The combined organic layers were
washed with 1 M aq. HCl and brine, dried over MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash column chromatography (CHCl3/EtOAc 100:1) to
afford 23 (0.100 g, 0.21 mmol, 46%) as a colorless oil. Rf (CHCl3/EtOAc 100:1) 0.55. [α]D298K +2.3
1
(c 2.0, CHCl3). HꢀNMR (400 MHz, CDCl3): δH (ppm) 9.79 (d, J1,2 0.7 Hz, 1H, CHO), 7.36ꢀ7.24
(m, 15H, ArH), 5.69 (ddt, Jtrans 16.9 Hz, Jcis 10.2 Hz, J8,7 6.6 Hz, 1H, H8), 4.95ꢀ4.86 (m, 2H, H9a,
H9b), 4.62ꢀ4.51 (m, 5H, 3xCHHPh, 2xCHHPh), 4.46 (d, Jgem 11.7 Hz, 1H, CHHPh), 4.32 (dd, J3,2
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5.2 Hz, J3,4 4.0 Hz, 1H, H3), 4.11 (d, 1H, H4), 3.96 (dd, 1H, H2), 2.74 (ddd, J6a,6b 18.7 Hz, Jvic 9.0
Hz, Jvic 5.9 Hz, 1H, H6a), 2.55 (ddd, Jvic 8.9 Hz, Jvic 5.9 Hz, 1H, H6b), 2.22ꢀ2.12 (m, 1H, H7a),
2.08ꢀ1.99 (m, 1H, H7b). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 210.1 (C=O, C5), 200.9 (C=O,
C1), 137.5 (C8), 137.2, 137.0, 136.8 (ArC), 128.6ꢀ128.0 (ArCH), 115.06 (C9), 83.2 (C4), 81.9
(C2), 81.8 (C3), 73.8, 73.3, 73.2 (CH2Ph), 39.1 (C6), 27.0 (C7). HRMS(ESI) Calcd. for C30H32O5H+
m/z 473.2323; found m/z 473.2327.
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(1
Vinylmagnesium bromide (0.9 M solution in THF, 4.5 mL, 4.1 mmol, 9 eq) was mixed with
TMEDA (0.74 mL, 5.0 mmol, 11 eq) at rt and added to 20 (0.202 g, 0.45 mmol) at ꢀ78 C. The
resultant mixture was stirred for 2 h at ꢀ78 C. The reaction mixture was allowed reach to rt and
S,2S,3R,4S,5R,6R)ꢀ2ꢀAllylꢀ4,5,6ꢀtris(benzyloxy)ꢀ1ꢀvinylcyclohexaneꢀ1,3ꢀdiol (24)
°
°
stirred for an additional 18 h before it was quenched with H2O. The reaction mixture was extracted
with CH2Cl2 (x3). The combined organic layers were washed with 1 M aq. HCl and brine, dried
over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by
flash column chromatography (CHCl3/EtOAc 100:1) to afford 24 (0.061 g, 0.12 mmol, 27%) as a
293K
1
colorless oil. Rf (CHCl3/EtOAc 100:1) 0.48. [α]D
+4.5 (c 2.0, CHCl3). HꢀNMR (400 MHz,
CDCl3): δH (ppm) 7.31ꢀ7.16 (m, 13H, ArH), 7.14ꢀ7.10 (m, 2H, ArH), 5.68 (dddd, Jtrans 16.7 Hz,
Jcis 9.9 Hz, Jvic 8.5 Hz, Jvic 6.0 Hz, 1H, allyl CH=CH2), 5.56 (dd, Jtrans 17.0 Hz, Jcis 10.5 Hz, 1H,
vinyl CH=CH2), 5.34 (dd, Jgem 1.6 Hz, 1H, vinyl CH=CHH), 5.24 (dd, 1H, vinyl CH=CHH), 5.03
(d, 1H, allyl CH=CHH), 4.94 (d, 1H, allyl CH=CHH), 4.56 (d, Jgem 11.7 Hz, 1H, CHHPh), 4.42 (d,
Jgem 12.1 Hz, 1H, CHHPh), 4.42ꢀ4.35 (m, 3H, CHHPh, 2xCHHPh), 4.32 (d, Jgem 12.1 Hz, 1H,
CHHPh), 3.96 (t, J4,3/5 3.1 Hz, 1H, H4), 3.85ꢀ3.78 (m, 2H, H3, H5), 3.64 (d, JOH,3 11.4 Hz, 1H,
OH(3)), 3.51 (d, J6,5 3.7 Hz, 1H, H6), 2.97 (s, 1H, OH), 2.45 (ddd, Jgem 14.0 Hz, JCHH,2 11.3 Hz, 1H,
allyl CHH), 2.24ꢀ2.14 (m, 1H, allyl CHH), 1.66 (dt, J2,3/CHH 3.1 Hz, 1H, H2). 13CꢀNMR (100 MHz,
CDCl3): δC (ppm) 142.0 (vinyl CH=CH2), 138.1, 138.0, 137.8 (ArC), 137.3 (allyl CH=CH2), 128.6ꢀ
127.8 (ArCH), 116.5 (allyl CH=CH2), 115.8 (vinyl CH=CH2), 79.0 (C1), 77.6 (C6), 75.9 (C5), 75.8
(C4), 73.1, 72.4, 72.4 (CH2Ph), 68.2 (C3), 41.5 (C2), 28.6 (allyl CH2). HRMS(ESI) Calcd. for
C32H36O5H+ m/z 501.2636; found m/z 501.2636.
2,3,4ꢀTriꢀ
O
ꢀbenzylꢀ5,5ꢀdimethylꢀ
α
/β
ꢀD
ꢀxylopyranose (25)
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Methylmagnesium chloride (3 M solution in THF, 2.0 mL, 6.1 mmol, 9 eq) was mixed with
TMEDA (1.1 mL, 7.4 mmol, 11 eq) at rt. The mixture was slowly added to 3 (0.303 g, 0.67 mmol)
at ꢀ78 °C and stirred at this temperature for 2 h followed by 1 h at rt. The reaction was quenched
with H2O and subsequently extracted with CH2Cl2 (x3). The combined organic layers were washed
with 1 M aq. HCl and brine before drying over MgSO4. The organic phase was filtered,
concentrated under reduced pressure and purified by flash column chromatography (CH2Cl2/EtOAc
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40:1
ꢀ 30:1) to afford 25 (0.228 g, 0.51 mmol, 75%) as a colorless oil consisting of a mixture of
isomers. Major isomer: Rf (CH2Cl2/EtOAc 30:1) 0.31. 1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.43ꢀ
7.30 (m, 15H, ArH), 5.01 (d, Jgem 11.2 Hz, 1H, CHHPh), 5.00ꢀ4.94 (m, 3H, H1, 2xCHHPh), 4.84
(d, Jgem 10.8 Hz, 1H, CHHPh), 4.83 (d, Jgem 11.0 Hz, 1H, CHHPh), 4.70 (d, Jgem 11.2 Hz, 1H,
CHHPh), 3.93 (d, JOH,1 5.7 Hz, OH), 3.79 (t, J3,4/2 9.4 Hz, 1H H3), 3.44 (dd, J2,1 7.8 Hz, 1H, H2),
13
3.38 (d, 1H, H4), 1.35 (s, 3H, CH3), 1.32 (s, 3H, CH3). CꢀNMR (100 MHz, CDCl3): δC (ppm)
138.7, 138.6, 138.5 (ArC), 128.6ꢀ127.7 (ArCH), 93.4 (C1), 84.9 (C4), 84.7 (C2), 82.3 (C3), 75.9,
75.8 (CH2Ph), 75.4 (C5), 75.0 (CH2Ph), 28.4 (CH3), 19.2 (CH3). HRMS(ESI): Calcd. for
C28H32O5Na+ m/z 471.2142; found m/z 471.2144.
Acetyl 2,3,4ꢀtriꢀOꢀbenzylꢀ5,5ꢀdimethylꢀβꢀDꢀxylopyranose (26)
25 (0.050 g, 0.11 mmol) was dissolved in dry pyridine (1 mL). Acetic anhydride (1 mL) was added
and the reaction mixture was stirred overnight before it was concentrated under reduced pressure.
The residue was coꢀevaporated with toluene (x3). The crude product was purified by flash column
chromatography (CH2Cl2) to afford 26 (0.037 g, 0.08 mmol, 67%) as a white solid. Rf (CH2Cl2)
0.37. [α]D293K ꢀ7.8 (c 1.0, CHCl3). Mp 114.8ꢀ116.2 °C. 1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.36ꢀ
7.29 (m, 15H, ArH), 5.87 (d, J1,2 8.3 Hz, 1H, H1), 4.94 (d, Jgem 11.2 Hz, 1H, CHHPh), 4.90 (d,
Jgem 10.8 Hz, 1H, CHHPh), 4.82 (d, Jgem 10.8 Hz, 1H, CHHPh), 4.81 (d, Jgem 11.4 Hz, 1H, CHHPh),
4.75 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.68 (d, Jgem 11.2 Hz, 1H, CHHPh), 3.84 (t, J3,2/4 9.4 Hz, 1H,
H3), 3.56 (dd, 1H, H2), 3.36 (d, J4,3 9.4 Hz, 1H, H4), 2.06 (s, 3H, acetyl CH3), 1.36 (s, 3H, CH3),
1.29 (s, 3H, CH3). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 169.5 (C=O), 138.5, 138.5, 138.3 (ArC),
128.6ꢀ127.7 (ArCH), 90.9 (C1), 84.8 (C4), 82.7 (C3), 82.4 (C2), 76.3 (C5), 75.9, 75.9, 75.2
(CH2Ph), 28.2 (CH3), 21.3 (acetyl CH3), 19.0 (CH3). HRMS(ESI): Calcd. for C30H34O6Na+ m/z
513.2248; found m/z 513.2253.
Methyl 3,4ꢀdiꢀOꢀbenzylꢀ2ꢀdeoxyꢀ5ꢀmethyleneꢀαꢀDꢀxylopyranoside (28)
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AgF (0.320 g, 0.64 mmol, 3.9 eq) was added to a vial under an atmosphere of nitrogen. 27 was
dissolved in dry pyridine (3 mL) and transferred to the vial containing AgF. The reaction mixture
was stirred at rt overnight in the dark. The crude mixture was concentrated in vacuo and purified by
flash column chromatography (Pentane/CH2Cl2 1:1
ꢀ 1:2 ꢀ CH2Cl2) to give 28 as a colorless oil
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298 K
(0.176 g, 0.52 mmol, 81%). Rf (Pentane/Et2O 4:1) 0.55. [α]D
+30.0 (c 2, CHCl3), lit. +27.9 (c
1.3, CHCl3)47. HꢀNMR (400 MHz, C6D6): δH (ppm) 7.39 (d, Jortho 7.3 Hz, 2H, ArH), 7.30 (d, Jortho
7.3 Hz, 2H, ArH), 7.25ꢀ7.12 (m, 6H, ArH), 5.02 (d, J6a,4 1.3 Hz, 1H, H6a), 4.93 (d, J6b,4 1.3 Hz, 1H,
H6b), 4.75 (d, Jgem 11.8 Hz, 1H, CHHPh), 4.71 (d, Jgem 11.8 Hz, 1H, CHHPh) 4.70 (t, J1,2eq/2ax 3.2
Hz, 1H, H1), 4.58 (d, Jgem 11.9 Hz, 1H, CHHPh), 4.46 (d, Jgem 11.9 Hz, 1H, CHHPh), 4.10 (ddd,
J3,2ax 9.6 Hz, J3,4 8.0 Hz, J3,2eq 4.5 Hz, 1H, H3), 3.98 (dt, 1H, H4), 3.26 (s, 3H, CH3), 2.27 (ddd,
J2eq,2ax 13.3 Hz, 1H, H2eq), 1.80 (ddd, 1H, H2ax). 13CꢀNMR (100 MHz, C6D6): δC (ppm) 155.7
(C5), 139.3, 139.0 (ArC), 128.5ꢀ127.6 (ArCH), 100.0 (C1), 96.7 (C6), 79.9 (C4), 76.3 (C3), 73.3,
72.1 (CH2Ph), 55.0 (CH3), 35.6 (C2). HRMS(ESI): Calcd. for C21H24O4H+ m/z 341.1749; found
m/z 341.1747. 13CꢀNMRꢀdata were in accordance with previously reported data obtained in
CDCl3.47
1
(3S,4R,6S)ꢀ3,4ꢀBis(benzyloxy)ꢀ6ꢀmethoxytetrahydroꢀ2Hꢀpyranꢀ2ꢀone (29)
28 (2.842 g, 8.35 mmol) was dissolved in dry CH2Cl2 (130 mL). The solution was cooled to ꢀ78 °C
and bubbled through with O2 for 5 min, O3 for 20 min and again O2 followed by N2 for 5 min and
10 min, respectively. Me2S (1.3 mL, 17.4 mmol, 2 eq) was added and the reaction mixture was
allowed to reach rt. The mixture was concentrated in vacuo and purified by flash column
chromatography (Pentane/EtOAc 19:1
ꢀ 9:1) to give 29 (1.763 g, 5.15 mmol, 62%) as a colorless
oil. Rf (CH2Cl2) 0.38. [α]D300K +12.1 (c 2, CHCl3). 1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.50ꢀ7.26
(m, 10H, ArH), 5.25 (t, J1,2eq/2ax 3.3 Hz, 1H, H1), 5.10 (d, Jgem 11.3 Hz, 1H, CHHPh), 4.75 (d, Jgem
11.3 Hz, 1H, CHHPh), 4.71 (d, Jgem 11.6 Hz, 1H, CHHPh), 4.63 (d, Jgem 11.6 Hz, 1H, CHHPh),
4.12 (td, J3,4/2ax 8.1 Hz, J3,2eq 4.6 Hz, 1H, H3), 4.04 (d, 1H, H4), 3.52 (s, 3H, CH3), 2.33 (dt, J2eq,2ax
13
14.0 Hz, 1H, H2eq), 2.08 (ddd, 1H, H2ax). CꢀNMR (100 MHz, CDCl3): δC (ppm) 170.1 (C=O),
137.8, 137.3 (ArC), 128.4ꢀ127.6 (ArCH), 101.1 (C1), 79.2 (C4), 74.1 (CH2Ph), 73.4 (C3), 72.5
+
(CH2Ph), 56.8 (CH3), 34.0 (C2). HRMS(ESI): Calcd. for C20H22O5NH4 m/z 360.1805; found m/z
360.1808.
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(1
R
,2
R,3R,5
R,6
S)ꢀ2ꢀAllylꢀ5,6ꢀbis(benzyloxy)ꢀ1ꢀvinylcyclohexaneꢀ1,3ꢀdiol (30) and (4S,5R)ꢀ4,5ꢀ
5
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bis(benzyloxy)ꢀ3ꢀvinylnonaꢀ1,8ꢀdieneꢀ3,7ꢀdiol (31)
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Vinylmagnesium bromide (0.9 M in THF, 18 mL, 16.5 mmol, 9 eq) and TMEDA (3.0 mL, 20
mmol, 11 eq) were mixed at rt. The mixture was added to the lactone acetal 29 (0.626 g,
1.83 mmol) at ꢀ78 °C. The reaction mixture was stirred at ꢀ78 °C for 2 h before it was allowed to
reach rt and stirred at this temperature for 1 h. The reaction was quenched by the addition of 1 M
aq. HCl. The mixture was extracted with CH2Cl2 (x3) and the combined organic phases were
washed with brine and subsequently dried over MgSO4, filtered and concentrated in vacuo. The
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crude residue was purified by flash column chromatography (Pentane/EtOAc 20:1
ꢀ 15:1 ꢀ 9:1)
to give 30 (0.216 g, 0.55 mmol, 30%) and 31 (0.195 g, 0.49 mmol, 27%) as a mixture of isomers.
298K
1
Both compounds were colorless oils. 30: Rf (CH2Cl2) 0.30. [α]D
ꢀ64.3 (c 2, CHCl3). HꢀNMR
(400 MHz, CDCl3): δ (ppm) 7.36ꢀ7.12 (m, 10H, ArH), 5.68 (m, 2H, allyl CH=CH2, vinyl
CH=CH2), 5.28 (d, Jcis 10.1 Hz, 1H, vinyl CH=CHH), 5.27 (d, Jtrans 17.4 Hz, 1H, vinyl CH=CHH),
5.03 (d, Jtrans 17.0 Hz, 1H, allyl CH=CHH), 4.96 (d, Jcis 9.9 Hz, 1H, allyl CH=CHH), 4.77 (d, Jgem
10.3 Hz, 1H, CHHPh), 4.64 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.58 (d, Jgem 11.4 Hz, 1H, CHHPh),
4.55 (d, Jgem 10.3 Hz, 1H, CHHPh), 4.05ꢀ3.85 (m, 2H, H3, H5), 3.55 (d, JOH,3 9.6 Hz, 1H, OH(3)),
3.28 (d, J6,5 9.0 Hz, 1H, H6), 2.89 (s, 1H, OH(1)), 2.54ꢀ2.40 (dt, J4eq,4ax 13.2 Hz, J4eq,5/3 4.2 Hz, 1H,
H4eq), 2.37ꢀ2.26 (m, 1H, allyl CHH), 2.20ꢀ2.10 (m, 1H, allyl CHH), 1.45ꢀ1.32 (m, 2H, H4ax, H2).
13CꢀNMR (100 MHz, CDCl3): δC (ppm) 141.5 (vinyl CH=CH2), 138.8, 138.2 (ArC), 137.0 (allyl
CH=CH2), 128.5ꢀ127.7 (ArCH), 116.8 (allyl CH=CH2), 115.9 (vinyl CH=CH2), 85.6 (C6), 81.0
(C1), 76.2 (C5), 76.0, 72.5 (CH2Ph), 67.4 (C3), 45.0 (C2), 37.8 (C4), 29.1 (allyl CH2). HRMS(ESI):
+
Calcd. for C25H30O4NH4 m/z 412.2482; found m/z 412.2484. 31a: Rf (Pentane/EtOAc 5:1) 0.54.
1HꢀNMR (400 MHz, CDCl3): δ (ppm) 7.39ꢀ7.27 (m, 10H, ArH), 6.14 (dd, Jtrans 17.4 Hz,
Jcis 10.6 Hz, 1H, H2), 6.06 (dd, Jtrans 17.3 Hz, Jcis 10.6 Hz, 1H, vinyl CH=CH2), 5.83 (ddd,
Jtrans 17.2 Hz, Jcis 10.4 Hz, J8,7 5.4 Hz, 1H, H8), 5.43 (dd, Jtrans 17.3 Hz, Jgem 1.4 Hz, 1H, H1a), 5.40
(dd, Jtrans 17.3 Hz, Jgem 1.3 Hz, 1H, vinyl CH=CHH), 5.26ꢀ5.14 (m, 3H, H1b, vinyl CH=CHH,
H9a), 5.08 (dt, Jgem/9b,7 1.4 Hz, 1H, H9b), 4.75 (d, Jgem 11.3 Hz, 1H, CHHPh), 4.66 (2xd, 2H,
CHHPh, CHHPh), 4.52 (d, Jgem 11.0 Hz, 1H, CHHPh), 4.27ꢀ4.20 (m, 1H, H7), 4.00 (ddd,
J5,6a 8.6 Hz, J5,4 4.9 Hz, J5,6b 3.9 Hz, 1H, H5), 3.52 (d, 1H, H4), 3.33 (s, 1H, OH), 2.07 (bs, 1H,
OH), 1.95 (ddd, J6a,6b 14.7 Hz, J6a,7 3.4 Hz, 1H, H6a), 1.82 (ddd, J6b,7 8.7 Hz, 1H, H6b). 13CꢀNMR
(100 MHz, CDCl3): δC (ppm) 141.1, 140.7, 140.7 (CH=CH2), 138.2, 137.9 (ArC), 128.6ꢀ128.0
(ArCH), 114.3 (C9), 114.1 (C1, vinyl CH=CH2), 83.9 (C4), 78.5 (C3), 77.2 (C5), 75.2, 73.3
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(CH2Ph), 70.3 (C7), 39.4 (C6). HRMS(ESI): Calcd. for C25H30O4NH4 m/z 412.2482; found m/z
5
6
1
412.2484. 31b: Rf (Pentane/EtOAc 5:1) 0.43. HꢀNMR (400 MHz, CDCl3): δ (ppm) 7.39ꢀ7.25 (m,
7
8
9
10H, ArH), 6.14 (dd, Jtrans 17.3 Hz, Jcis 10.7 Hz, 1H, H2), 6.07 (dd, Jtrans 17.3 Hz, Jcis 10.7 Hz, 1H,
vinyl CH=CH2), 5.78 (ddd, Jtrans 16.3 Hz, Jcis 10.4 Hz, J8,7 5.9 Hz, 1H, H8), 5.44 (dd, Jtrans 17.1 Hz,
Jgem 1.3 Hz, 1H, H1a), 5.40 (dd, Jtrans 16.8 Hz, Jgem 1.2 Hz, 1H, vinyl CH=CHH), 5.24ꢀ5.13 (m, 3H,
H1b, vinyl CH=CHH, H9a), 5.08 (d, 1H, H9b), 4.76 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.69 (d,
Jgem 11.4 Hz, 1H, CHHPh), 4.64 (d, Jgem 11.0 Hz, 1H, CHHPh), 4.49 (d, Jgem 11.0 Hz, 1H, CHHPh),
4.22ꢀ4.15 (m, 1H, H7), 3.92 (dt, J5,6a 7.1 Hz, J5,4/6b 5.2 Hz, 1H, H5), 3.55 (d, 1H, H4), 3.44 (bs, 1H,
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OH), 2.64 (bs, 1H, OH), 2.00ꢀ1.82 (m, 2H, H6a+b). CꢀNMR (100 MHz, CDCl3): δC (ppm) 140.8,
140.7, 140.5 (CH=CH2), 138.2, 137.7 (ArC), 128.6ꢀ128.0 (ArCH), 114.7, 114.1, 114.0 (CH=CH2),
83.6 (C4), 78.6 (C5), 78.4 (C3), 75.3, 72.9 (CH2Ph), 71.4 (C7), 39.4 (C6). HRMS(ESI): Calcd. for
+
C25H30O4NH4 m/z 412.2482; found m/z 412.2488.
2ꢀDeoxyꢀ5,5ꢀdimethylꢀ
heptaneꢀ2,6ꢀdiol (33)
α/βꢀDꢀxylopyranose (32) and (3S,4R)ꢀ3,4ꢀbis(benzyloxy)ꢀ2ꢀmethylꢀ
Methylmagnesium chloride (3 M in THF, 1.9 mL, 5.7 mmol, 9 eq) and TMEDA (1.0 mL, 6.7
mmol, 11 eq) were mixed at rt and added to 29 (0.214 g, 0.63 mmol) at ꢀ78 °C. The reaction
mixture was stirred at this temperature for 2 h and was then allowed to reach rt and stirred at this
temperature for 1 h. The reaction was quenched with water and 1 M aq. HCl. The aqueous phase
was extracted with CH2Cl2 (x3). The organic phase was washed with brine, dried over MgSO4,
filtered and concentrated. Flash column chromatography (CH2Cl2/EtOAc 19:1
(0.119 g, 0.35 mmol, 56%) as a 0.4:1 mixture of ꢀanomers and 33 (0.044 g, 0.12 mmol, 19%) as
a 1:0.6 mixture of isomers. 32: Rf (CH2Cl2/EtOAc 5:1) 0.57. 32
: 1HꢀNMR (400 MHz, CDCl3): δH
ꢀ 5:1) afforded 32
α/β
α
(ppm) 7.38ꢀ7.26 (m, 10H, ArH), 5.35 (t, J1,2ax/2eq 3.6 Hz, 1H, H1), 4.89 (d, Jgem 11.4 Hz, 1H,
CHHPh), 4.69ꢀ4.59 (m, 3H, CHHPh, CH2Ph), 4.04 (ddd, J3,2ax 8.8 Hz, J3,4 7.7 Hz, J3,2eq 4.4 Hz, 1H,
H3), 3.23 (d, 1H, H4), 2.80 (bs, 1H, OH), 2.22 (dt, J2eq,2ax 13.2 Hz, 1H, H2eq), 1.83 (ddd, 1H,
H2ax), 1.40 (s, 3H, CH3), 1.31 (s, 3H, CH3). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 138.8, 138.7
(ArC), 128.6ꢀ127.8 (ArCH), 91.9 (C1), 83.8 (C4), 77.4 (C5), 75.2 (CH2Ph), 74.6 (C3), 72.0
1
(CH2Ph), 36.1 (C2), 28.0, 25.3 (CH3). 32
β
: HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.38ꢀ7.26 (m,
10H, ArH), 5.02ꢀ4.97 (m, 2H, H1, CHHPh), 4.69ꢀ4.59 (m, 3H, CHHPh, CH2Ph), 3.75 (ddd,
J3,2ax 11.5 Hz, J3,4 9.2 Hz, J3,2eq 4.9 Hz, 1H, H3), 3.27 (d, 1H, H4), 3.11 (bs, 1H, OH), 2.43 (ddd,
J2eq,2ax 12.4 Hz, J2eq,1 2.3 Hz, 1H, H2eq), 1.53 (td, J2ax,1 10.0 Hz, 1H, H2ax), 1.31 (s, 3H, CH3), 1.22
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(s, 3H, CH3). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 138.9, 138.5 (ArC), 128.6ꢀ127.8 (ArCH),
89.9 (C1), 85.4 (C4), 77.4 (C5), 75.8 (C3), 75.7, 71.9 (CH2Ph), 39.5 (C2), 28.8, 19.6 (CH3).
HRMS(ESI): Calcd. for C21H26O4Na+ m/z 365.1723; found m/z 365.1724. 33: Rf (Pentane/EtOAc
1
1:1) 0.59. 33a: HꢀNMR (400 MHz, CDCl3): δ (ppm) 7.39ꢀ7.25 (m, 10H, ArH), 4.88 (d, Jgem 11.3
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Hz, 1H, CHHPh), 4.77 (d, Jgem 11.0 Hz, 1H, CHHPh), 4.63 (d, Jgem 11.3 Hz, 1H, CHHPh), 4.52 (d,
Jgem 11.0 Hz, 1H, CHHPh), 3.94ꢀ3.87 (m, 2H, H4, H6), 3.34 (d, J3,4 5.3 Hz, 1H, H3), 1.94ꢀ1.70 (m,
2H, H5a, H5b), 1.28 (s, 6H, C(CH3)2), 1.15 (d, J7,6 6.2 Hz, 3H, CH3(H7)).13CꢀNMR (100 MHz,
CDCl3): δ (ppm) 138.3, 137.7 (ArC), 128.7ꢀ127.9 (ArCH), 85.4 (C3), 79.4 (C4), 75.1, 73.2
(CH2Ph), 73.1 (C2), 67.6 (C6), 42.3 (C5), 27.4 (C(CH3)(CH3)), 26.6 (C(CH3)(CH3)), 23.9 (CH3).
33b: 1HꢀNMR (400 MHz, CDCl3): δ (ppm) 7.39ꢀ7.25 (m, 10H, ArH), 4.85 (d, Jgem 11.2 Hz, 1H,
CHHPh), 4.74 (d, Jgem 11.2 Hz, 1H, CHHPh), 4.61 (d, Jgem 11.2 Hz, 1H, CHHPh), 4.57 (d, Jgem 11.2
Hz, 1H, CHHPh), 4.04ꢀ3.95 (m, 2H, H4, H6), 3.32 (d, J3,4 5.1 Hz, 1H, H3), 1.94ꢀ1.70 (m, 2H, H5a,
H5b), 1.28 (s, 6H, C(CH3)2), 1.19 (d, J7,6 6.1 Hz, 3H, CH3). 13CꢀNMR (100 MHz, CDCl3): δ (ppm)
138.4, 138.3 (ArC), 128.7ꢀ127.9 (ArCH), 85.8 (C3), 76.6 (C4), 75.1 (CH2Ph), 73.4 (CH2Ph), 73.2
(C2), 65.3 (C6), 42.4 (C5), 27.3 (C(CH3)(CH3)), 26.8 (C(CH3)(CH3)), 24.2 (CH3). HRMS(ESI):
Calcd. for C22H30O4Na+ m/z 381.2036; found m/z 381.2042.
(1R,2S,3S,4R,5S,6R)ꢀ3,4,5ꢀTris(benzyloxy)ꢀbicyclo[4.3.0]nonꢀ7ꢀeneꢀ2,6ꢀdiol (34)
4 (0.657 g, 1.3 mmol) was dissolved in dry CH2Cl2 (13 mL). The solution was heated to reflux and
HoveydaꢀGrubbs 2nd generation catalyst (0.043 g, 0.069 mmol, 0.05 eq) was added. The reaction
mixture was stirred at reflux temperature for 2 h. The crude mixture was concentrated and purified
by flash column chromatography (Pentane/EtOAc 4:1
ꢀ 2:1) to give 34 as white crystals (0.419 g,
0.89 mmol, 68%). Rf (CH2Cl2/EtOAc 10:1) 0.31. [α]D299K +23.9 (c 2, CHCl3). Mp 95.3ꢀ97.3 °C. 1Hꢀ
NMR (400 MHz, CDCl3): δH (ppm) 7.35ꢀ7.15 (m, 15H, ArH), 6.07 (d, J7,8 5.4 Hz, 1H, H7), 5.78 (d,
1H, H8), 4.96 (d, Jgem 10.5 Hz, 1H, CHHPh), 4.84 (d, Jgem 11.3 Hz, 1H, CHHPh), 4.77 (d, Jgem 10.5
Hz, 1H, CHHPh), 4.75 (d, Jgem 11.8 Hz, 1H, CHHPh), 4.65 (d, Jgem 11.3 Hz, 1H, CHHPh), 4.63 (d,
J
gem 11.8 Hz, 1H, CHHPh), 4.23 (d, JOH,2 9.3 Hz, 1H, OH(2)), 4.18ꢀ4.11 (m, 2H, H2, H4), 3.49 (dd,
J3,4 9.4 Hz, J3,2 3.4 Hz, 1H, H3), 3.43 (d, J5,4 8.7 Hz, 1H, H5), 3.05 (s, 1H, OH(6)), 2.77 (dd,
13
J9a,9b 15.7 Hz, J9a,1 10.0 Hz, 1H, H9a), 2.23 (dd, J9b,1 6.8 Hz, 1H, H9b), 1.58 (t, 1H, H1). CꢀNMR
(100 MHz, CDCl3): δC (ppm) 138.9 (ArC), 138.3 (C7), 138.3, 138.2 (ArC), 133.2 (C8), 128.6ꢀ127.7
(ArCH), 86.0 (C6), 84.6 (C3), 84.1 (C5), 82.8 (C4), 76.5, 75.2, 72.0 (CH2Ph), 67.8 (C2), 45.5 (C1),
30.5 (C9). HRMS (ESI): Calcd. for C30H32O5Na+ m/z 495.2142; found m/z 495.2146.
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S,4
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,5
S,6S,
7
S,
8
S)ꢀ3,4,5ꢀTris(benzyloxy)ꢀbicyclo[4.3.0]nonaneꢀ2,6,7,8ꢀtetraol (35)
7
8
9
34 (0.270 g, 0.57 mmol) was dissolved in a 1:1:1 mixture of H2O/MeCN/Me2CO (10 mL).
NꢀMethylmorpholine Nꢀoxide (0.110 g, 0.94 mmol, 1.6 eq) was added. The mixture was cooled to
0 °C before the addition of OsO4 (2.5 wt.% in tBuOH, 0.7 mL, 0.056 mmol, 0.1 eq). The reaction
mixture was stirred at rt for 4 days before the addition of sat. aq. Na2SO3. After extraction with
EtOAc (x3), the combined organic phases were washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The crude residue was purified by flash column chromatography
10
11
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13
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15
16
17
18
19
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21
22
23
24
25
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58
59
60
(CH2Cl2/EtOAc 4:1
ꢀ 2:1) to give 35 (0.214 g, 0.42 mmol, 74%) as a white solid. Rf (EtOAc) 0.56.
[α]D299K + 45.0 (c 2, CHCl3). Mp 141.2ꢀ142.6 °C. 1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.42ꢀ7.21
(m, 15H, ArH), 4.96 (d, Jgem 10.8 Hz, 1H, CHHPh), 4.89 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.88 (d,
Jgem 10.8 Hz, 1H, CHHPh), 4.78 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.72 (s, 2H, CH2Ph), 4.54 (ddd,
J8,9a 8.3 Hz, J8,7 5.2 Hz, J8,9b 2.5 Hz, 1H, H8), 4.12ꢀ4.07 (m, 2H, H2, H4), 3.72 (d, J5,4 9.4 Hz, 1H,
H5), 3.64 (d, 1H, H7), 3.47 (dd, J3,4 9.5 Hz, J3,2 3.3 Hz, 1H, H3), 3.39 (bs, 1H, OH), 2.74 (bs, 1H,
OH), 2.52 (ddd, J9a,9b 13.5 Hz, J9a,1 11.7 Hz, 1H, H9a), 2.32 (bs, 1H, OH), 1.98 (ddd, J1,9b 9.2 Hz,
J1,2 2.2 Hz, 1H, H1), 1.80 (bs, 1H, OH), 1.49 (ddd, 1H, H9b). 13CꢀNMR (100 MHz, CDCl3): δC
(ppm) 138.8, 138.7, 138.0 (ArC), 128.5ꢀ127.6 (ArCH), 85.6 (C6), 83.6 (C3), 81.2 (C4), 80.0 (C5),
76.2 (CH2Ph), 74.6 (C7), 74.5, 72.6 (CH2Ph), 71.5 (C8), 68.5 (C2), 39.2 (C1), 31.3 (C9). HRMS
+
(ESI): Calcd. for C30H34O7NH4 m/z 524.2643; found m/z 524.2647.
Derivatization of 22, 24 and 30
Oꢀ((1R,2S,3S,4S,5R,6R)ꢀ2ꢀAllylꢀ4,5,6ꢀtris(benzyloxy)ꢀ3ꢀhydroxyꢀ3ꢀvinylcyclohexyl) (1S,4R)ꢀ
camphanoate (36)
22 (0.050 g, 0.10 mmol) was dissolved in dry CH2Cl2 (2 mL). Et3N (0.08 mL, 0.57 mmol, 5.7 eq),
DMAP (0.012 g, 0.11 mmol, 1.1 eq) and (1S)ꢀ(ꢀ)ꢀcamphanic chloride (0.056 g, 0.26 mmol, 2.6 eq)
were added. The reaction mixture was stirred at 40 °C overnight. 1M aq. HCl was added. The
mixture was extracted with CH2Cl2 (x3). The combined organic phases were washed with sat. aq.
NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by
flash column chromatography (Pentane/Et2O 2:1) to give 36 (0.055 g, 0.081 mmol, 81%), which
was crystallized from CH2Cl2 and heptane to give colorless crystals. Rf (Pentane/Et2O 2:1) 0.50.
[α]
299K ꢀ29.6 (c 2.0, CHCl3). Mp 125.1ꢀ126.9 °C (CH2Cl2/Heptane). 1HꢀNMR (400 MHz, CDCl3):
D
δH (ppm) 7.40ꢀ7.25 (m, 13H, ArH), 7.16ꢀ7.09 (m, 2H, ArH), 5.96 (ddd, Jtrans 17.2 Hz, Jcis 10.7 Hz,
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JH,OH 1.4 Hz, 1H, vinyl CH=CH2), 5.84 (t, J1,2/6 3.4 Hz, 1H, H1), 5.78 (dddd, Jtrans 17.0 Hz, Jcis 10.1
Hz, Jvic 8.0 Hz, Jvic 6.6 Hz, 1H, allyl CH=CH2), 5.57 (dd, Jgem 2.0 Hz, 1H, vinyl CH=CHH), 5.30
(dd, 1H, vinyl CH=CHH), 5.06 (d, Jcis 10.1 Hz, 1H, allyl CH=CHH), 5.00 (dd, Jtrans 17.0 Hz, 4J 1.4
Hz, 1H, allyl CH=CHH), 4.70 (d, Jgem 11.8 Hz, 1H, CHHPh), 4.61 (d, Jgem 11.4 Hz, 1H, CHHPh),
4.49 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.47 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.41 (d, Jgem 11.8 Hz, 1H,
CHHPh), 4.33 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.08 (d, 1H, OH), 3.84ꢀ3.77 (m, 2H, H5, H6), 3.60
(d, 1H, H4), 2.31ꢀ2.13 (m, 3H, allyl CH2, CHHꢀCH2), 2.03 (dt, J2,CHH 10.5 Hz, J2,CHH 3.4 Hz, 1H,
H2), 1.77 (ddd, Jgem 13.8 Hz, Jvic 9.0 Hz, Jvic 4.8 Hz, 1H, CHH-CH2), 1.56ꢀ1.40 (m, 2H, CH2ꢀCH2),
1.00 (s, 3H, CH3), 0.88 (s, 6H, C(CH3)2). 13CꢀNMR (100 MHz, CDCl3): δC (ppm) 178.2 (C=O),
167.1 (C=O), 140.7 (vinyl CH=CH2), 138.2, 137.5, 137.2 (ArC), 136.1 (allyl CH=CH2), 128.6ꢀ
127.8 (ArCH), 117.6 (allyl CH=CH2), 116.0 (vinyl CH=CH2), 91.7 (O2CꢀCꢀOCO), 80.9 (C4), 77.0
(C5), 75.1 (C3), 74.4 (C6), 74.0, 73.6, 71.3 (CH2Ph), 69.1 (C1), 55.0, 54.1 (CQ), 41.7 (C2), 30.9
(CH2ꢀCH2), 29.5 (allyl CH2), 29.1 (CH2ꢀCH2), 16.9 (C(CH3)CH3), 16.9 (C(CH3)CH3), 9.72 (CH3).
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+
HRMS(ESI): Calcd. for C42H48O8NH4 m/z 698.3687; found m/z 698.3699.
Oꢀ((1R,2S,3S,4R,5R,6S)ꢀ2ꢀAllylꢀ4,5,6ꢀtris(benzyloxy)ꢀ3ꢀhydroxyꢀ3ꢀvinylcyclohexyl) (1S,4R)ꢀ
camphanoate (37)
24 (0.101 g, 0.20 mmol) was dissolved in dry CH2Cl2 (4 mL). Et3N (0.17 mL, 1.2 mmol, 6 eq),
DMAP (0.011 g, 0.10 mmol, 0.5 eq) and (1S)ꢀ(ꢀ)ꢀcamphanic chloride (0.109 g, 0.50 mmol, 2.5 eq)
were added. The reaction mixture was stirred at 40 °C overnight. The reaction mixture was allowed
to reach rt before it was quenched with 1 M aq. HCl. The aqueous phase was extracted with CH2Cl2
(x3). The combined organic layers were washed with 1 M aq. HCl, sat. aq. Na2CO3 and brine, dried
over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by
flash column chromatography (Pentane/Et2O 4:1) to afford 37 (0.089 g, 0.13 mmol, 64%) as
293K
colorless crystals. Rf (Pentane/Et2O 2:1) 0.36. [α]D
+26.5 (c 2.0, CHCl3). Mp 130.1ꢀ132.5 °C.
1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.31ꢀ7.18 (m, 12H, ArH), 7.16ꢀ7.11 (m, 3H, ArH), 5.61ꢀ
5.44 (m, 3H, allyl CH=CH2, vinyl CH=CH2, vinyl CH=CHH), 5.27 (dd, Jcis 7.8 Hz, Jgem 4.5 Hz, 1H,
vinyl CH=CHH), 5.13 (t, J1,2/6 2.9 Hz, 1H, H1), 5.96ꢀ4.87 (m, 2H, allyl CH=CH2), 4.67 (d, Jgem
11.2 Hz, 1H, CHHPh), 4.54 (d, Jgem 11.9 Hz, 1H, CHHPh), 4.47 (d, Jgem 11.8 Hz, 1H, CHHPh)
4.44ꢀ4.35 (m, 3H, 3xCHHPh), 3.86 (t, J6,5 2.9 Hz, 1H, H6), 3.78 (bs, 1H, OH), 3.76 (t, J5,4 2.9 Hz,
1H, H5), 3.49 (d, 1H, H4), 2.35ꢀ2.24 (m, 1H, allyl CHH), 2.24ꢀ2.13 (m, 1H, allyl CHH), 1.98ꢀ1.84
(m, 2H, H2, CHH), 1.55ꢀ1.46 (m, 1H, CHH), 1.45ꢀ1.36 (m, 1H, CHH), 1.32 (ddd, Jgem 12.4 Hz, Jvic
13
9.0 Hz, Jvic 3.6 Hz, 1H, CHH), 0.96 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.85 (s, 3H, CH3). CꢀNMR
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(100 MHz, CDCl3): δC (ppm) 177.9 (C=O), 167.0 (C=O), 140.5 (vinyl CH=CH2), 138.0, 137.6,
137.1 (ArC), 136.1 (allyl CH=CH2), 128.9ꢀ127.9 (ArCH), 117.3 (allyl CH=CH2), 116.6 (vinyl
CH=CH2), 91.4 (O2CꢀCꢀOCO), 77.7 (C3), 77.6 (C4), 76.3 (C5), 74.7 (CH2Ph), 74.4 (C6), 73.2, 72.8
(CH2Ph), 70.5 (C1), 54.9 (CQ), 54.1 (CQ), 42.3 (C2), 30.1 (CH2), 29.0 (CH2), 28.8 (allyl CH2), 17.0
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+
(CH3), 16.9 (CH3), 9.8 (CH3). HRMS(ESI): Calcd. for C42H48O8NH4 m/z 698.3687; found m/z
698.3681.
Oꢀ((1
R,2R,3R,4S,5R)ꢀ2ꢀAllylꢀ4,5ꢀbis(benzyloxy)ꢀ3ꢀhydroxyꢀ3ꢀvinylcyclohexyl) (1S,4R)ꢀ
camphanoate (38)
30 (0.052 g, 0.13 mmol) was dissolved in dry CH2Cl2 (2 mL). Et3N (0.11 mL, 0.79 mmol, 6 eq),
DMAP (0.015 g, 0.13 mmol, 1 eq) and (1S)ꢀ(ꢀ)ꢀcamphanic chloride (0.072 g, 0.33 mmol, 2.5 eq)
were added. The reaction mixture was stirred at 40 °C overnight before the addition of 1 M aq. HCl.
The mixture was extracted with CH2Cl2 (x3) and the combined organic phases were washed with
sat. aq. NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated in
vacuo. The crude residue was purified by flash column chromatography (Pentane/EtOAc 10:1
ꢀ
5:1) to give 38 (0.065 g, 0.11 mmol, 86%), which was obtained as colorless crystals after
299K
recrystallization from CH2Cl2. Rf (Pentane/Et2O 2:1) 0.56. [α]D
ꢀ39.2 (c 1, CHCl3). Mp 104.0ꢀ
108.5 °C (CH2Cl2). 1HꢀNMR (400 MHz, CDCl3): δH (ppm) 7.38ꢀ7.21 (m, 10H, ArH), 5.75 (dd, Jtrans
17.0 Hz, Jcis 10.5 Hz, 1H, vinyl CH=CH2), 5.65 (m, 1H, allyl CH=CH2), 5.43 (d, 1H, vinyl
CH=CHH), 5.37 (d, 1H, vinyl CH=CHH), 5.31ꢀ5.26 (m, 1H, H1), 5.01 (d, Jcis 10.0 Hz, 1H, allyl
CH=CHH), 4.95 (d, Jtrans 17.0 Hz, 1H, allyl CH=CHH), 4.85 (d, Jgem 10.2 Hz, 1H, CHHPh),
4.68ꢀ4.61 (m, 3H, CHHPh, CH2Ph), 3.88 (ddd, J5,6ax 11.5 Hz, J5,4 9.2 Hz, J5,6eq 4.4 Hz, 1H, H5),
3.36 (d, 1H, H4), 2.61ꢀ2.36 (m, 3H, OH, H6a, CHHꢀCH2), 2.33ꢀ2.21 (m, 1H, allyl CHH), 2.17ꢀ2.04
(m, 1H, allyl CHH), 2.04ꢀ1.94 (m, 1H, CHHꢀCH2), 1.93ꢀ1.82 (m, 1H, CH2ꢀCHH), 1.73ꢀ1.54 (m,
13
3H, H2, H6b, CH2ꢀCHH), 1.08 (s, 3H, CH3), 0.99 (s, 3H, CH3), 0.85 (s, 3H, CH3). CꢀNMR (100
MHz, CDCl3): δC (ppm) 177.9 (C=O), 166.7 (C=O), 142.3 (vinyl CH=CH2), 138.5, 138.1 (ArC),
136.0 (allyl CH=CH2), 128.6ꢀ127.7 (ArCH), 117.5 (allyl CH=CH2), 116.3 (vinyl CH=CH2), 91.3
(O2CꢀCꢀOCO), 85.8 (C4), 78.4 (C3), 76.2 (CH2Ph), 74.9 (C5), 72.5 (CH2Ph), 70.5 (C1), 54.9, 53.8
(CQ), 45.0 (C2), 34.6 (C6), 30.9 (CH2ꢀCH2), 29.2 (CH2ꢀCH2), 29.0 (allyl CH2), 17.1 (CH3), 16.9
+
(CH3), 9.8 (CH3). HRMS(ESI): Calcd. for C35H42O7NH4 m/z 592.3269; found m/z 592.3272.
Determination of stereochemistry of 35
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