Long-Range Reactivity Modulations in Geranyl Chloride Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01759

Derivatives of geraniol are versatile synthetic intermediates that are useful for synthesizing a variety of terpenoid natural products; however, the results presented herein show that subtle differences in the structures of functionalized geranyl chlorides can significantly impact their abilities to function as effective electrophiles in synthetic reactions. A series of focused kinetics experiments identify specific structure-activity relationships that illustrate the importance not only of steric bulk, but also of electronic effects from distant regions of the molecules that contribute to their overall levels of reactivity. Computational modeling suggests that destabilization of the reactant by filled-filled orbital mixing events in some, but not all, conformations may be a critical contributor to these important electronic effects.

Full text of DOI:10.1021/acs.joc.6b01759

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Article
Long-Range Reactivity Modulations in Geranyl Chloride Derivatives
Michael B. Reardon, Muyun Xu, Qingzhe Tan, Peter G. Baumgartel,
Danielle J. Augur, Shuanghong Huo, and Charles E. Jakobsche
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01759 • Publication Date (Web): 05 Oct 2016
Downloaded from http://pubs.acs.org on October 6, 2016
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LongꢀRange Reactivity Modulations in Geranyl Chloride Derivatives
Michael B. Reardon, Muyun Xu, Qingzhe Tan, Peter G. Baumgartel, Danielle J. Augur,
Shuanghong Huo, Charles E. Jakobsche*
*corresponding author
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Address and Contact Information
Carlson School of Chemistry & Biochemistry
Clark University
950 Main Street
Worcester, MA 01610 USA
email: cjakobsche@clarku.edu
phone: 508ꢀ793ꢀ8866
fax: 508ꢀ793ꢀ7117
TOC graphic
Abstract
Derivatives of geraniol are versatile synthetic intermediates that are useful for synthesizing a
variety of terpenoid natural products; however, the results presented herein show that subtle
differences in the structures of functionalized geranyl chlorides can significantly impact their
abilities to function as effective electrophiles in synthetic reactions. A series of focused kinetics
experiments identify specific structure–activity relationships that illustrate the importance not
only of steric bulk, but also of electronic effects from distant regions of the molecules that
contribute to their overall levels of reactivity. Computational modeling suggests that
destabilization of the reactant by filled–filled orbital mixing events in some, but not all,
conformations may be a critical contributor to these important electronic effects.
Introduction
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The large and remarkably diverse family of naturally occurring terpenoid molecules, many
of which possess a variety of biological activities, have served as targets and motivation to
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synthetic chemists for several decades.
Since terpene biosynthesis utilizes oligoprenyl
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pyrophosphates as synthetic precursors, a variety of cyclic terpene subfamilies retain these
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prenyl units in their final structures (Figure 1). The casbenes, the dolabellanes, and the
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germacrenes, for example, each contain a geranyl unit (the 10ꢀcarbon fragments highlighted in
red in Figure 1) that is connected to the rest of the structure by each of its two terminal carbon
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atoms. The prevalence of this motif in a variety of potential target structures suggests that
synthon 1, a geranyl unit with an extra functional group on its terminal carbon, should be a
broadly useful synthetic precursor. Indeed, these compounds have recently been utilized as
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synthetic intermediates in total syntheses of sarcophytonolide H, oridamycin B, and
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partheonolide, as well as a terpenoidꢀlike transꢀbicyclic structure made by us.
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Figure 1. Representative terpene families, their biosynthetic precursors, and an important
intermediate for their organic syntheses. Geranyl units are indicated in red, and prenyl units are
indicated in teal. LG = leaving group.
In this paper we analyze how synthon 1's electrophilic reactivity varies depending on subtle
changes to its structure, specifically on how that reactivity is affected by the presence of the
second alkene and the nature of the extra functional group on its far end. The results show that
the extra group does substantially impact the compound's overall reactivity even though it is
quite far from the electrophilic site. Previously, with the goal of synthesizing particular
diterpeneoid compounds from the dolabellane family, we developed a regioꢀ and stereoꢀselective
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alkylation reaction between ketone 2 and geranyl chloride (Figure 2, R = H). Although this
reaction produces a single isomer of product 6 in a reasonable yield of 56%, our current line of
inquiry has led us to discover that analogous reactions with functionalized derivatives of geraniol
provide substantially lower yields. Specifically, OTBSꢀ and OTHPꢀfunctionalized geranyl
chlorides 4–5 produce only 2/3 or less than 1/2 as much product, respectively, compared to the
reaction of the parent geranyl chloride (Figure 2). Since ketone 2 (but not products 6–8)
gradually decomposes under these strongly basic conditions, the rate of alkylation is critically
connected to the yield of product in this reaction. Although there are numerous wellꢀknown
examples of electrophiles whose reactivities are modulated by groups on distant regions of those
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molecule,
we found the differences in reaction efficiency in our system to be both
surprising and interesting because although the R groups are bulky and electronꢀwithdrawing,
they are located quite far – eight bonds away – from the reactive site on a nonꢀconjugated and
highly flexible molecule.
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Figure 2. Effect of distal substituents on the alkylation of ketone 2.
Results and Discussion
Initial Kinetics Analysis
We hypothesized that a more precise comparison of the reaction rates of these electrophiles
would enable a more detailed understanding of how these distal functional groups are able to so
dramatically affect the reactivities of these geranyl chloride derivatives. To directly compare the
electrophilic reaction rates of geranyl chlorides 3–5, we reacted each with pyridine and used H
NMR to monitor these reactions over time (Figure 3A, B). Compared to the alkylations of ketone
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, the alkylations with pyridine are simpler and can be monitored more directly because they do
not require additional reagents, complicating acid–base steps, or rigorously dry reaction
conditions. The geranyl pyridinium products (9–11) are easily identifiable by their NMR signals,
which can be monitored over time to assess the percent conversion of the geranyl chlorides
(Supplementary Sections 1.4–1.5). Our experimental setup uses an excess of pyridine, which
causes the pyridine's concentration to remain approximately constant and causes the reaction to
exhibit pseudoꢀfirstꢀorder kinetics. As expected, plots of [ꢀln(% unreacted geranyl chloride)]
show linear increases over time during the initial 15 hours of the reaction (Supplemental Figure
S8), during which time >90% of the geranyl chloride is consumed. According to firstꢀorder
kinetics theory, the reaction rate constant (k) can be calculated by dividing the slopes of these
plots by the initial (pseudo constant) concentration of the pyridine nucleophile, which we kept
equivalent in each of our experiments. Therefore, the relative rates of two electrophiles can be
easily calculated by directly comparing the slopes of two reactions (which we always performed
in sideꢀbyꢀside conditions). Most of our experiments use 6–9 hour durations, after which time the
differences in rates are readily observable (Figure 3C and Supplementary Figures S1–S6).
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Figure 3. Kinetics analysis of geranyl chloride and two derivatives. A. Overview of the reaction
to be studied. Conditions: (a) allylic chloride (1 equiv = 0.21 M in CDCl ), pyridine (3 equiv =
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.63 M), 24 +/ꢀ 0.5 ºC, monitored by H NMR. B. Structures of the three allylic chlorides to be
compared. C. Comparison of the amount of conversion of chloride starting material into
pyridinium product over time from a representative experiment. D. Comparison of the relative
rates of reaction. Averages of two separate sideꢀbyꢀside comparisons. Error bars represent
standard deviations from duplicate experiments.
Comparing the relative rate constants from geranyl chlorides 3–5 (averages of two separate
sideꢀbyꢀside comparisons, Figure 3D) shows that the presence of the OTBS group reduces the
reactivity by 40%, and the presence of the OTHP group reduces the reactivity by 47% in this
reaction. These trends are qualitatively consistent with the lower yields observed for these
electrophiles in the ketoneꢀalkylation reaction described above. Clearly, these groups do
substantially impact the electrophilic reactivities of these molecules despite being eight bonds
away from the reactive carbon atom and not being connected to it by conjugation.
Focused Kinetics Experiments
From these initial rate comparison results, it is unclear whether steric or electronic
contributions from the OTBS and OTHP groups are the major causes for the observed
differences in reactivity. Although each of these groups is relatively bulky, the flexibility and
length of the geranyl core should allow a variety of conformations, some of which position the
bulk in nonꢀinfluential locations. Also, although each of these groups is inductively electronꢀ
withdrawing, it is unlikely that polarization of sigma bonds would substantially impact the
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electron density at the reaction center from such a distance. To distinguish the impact of steric
and electronic components, we designed and synthesized additional geranyl chloride analogues
that would enable lessꢀambiguous comparisons to be made.
First, to study the isolated effects of steric bulk, we synthesized lengthened geranyl chloride
16 and monounsaturated geranyl chloride analogue 22 (Scheme 1). The key step for synthesizing
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lengthened analogue 16, which has an extra ethyl group added to the far end, is the alkylation of
bromide 13 with sulfone 14 to incorporate the two extra carbon atoms. Bromide 13 can be
accessed from alcohol 12, which can be formed by a known allylic oxidation of geranyl
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acetate. The key step for forming monounsaturated analogue 22, which lacks the double bond
at its far end, is a Horner–Wadsworth–Emmons olefination of ketone 19 (Scheme 1B). This
reaction favors the desired E isomer, and this product can be separated from the minor Z isomer
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by column chromatography. Ketone 19 is accessed from a nickelꢀmediated coupling between
methyl vinyl ketone (17) and isobutyl iodide (18). Although the yield of this step is low, since it
is the first step and can be done on a multiꢀgram scale with readily available materials, sufficient
material can be obtained to complete the synthesis.
Scheme 1. Synthesis of geranyl chloride analogues 16 and 22. Conditions: (a, b) See reference
16, 52% (2 steps); (c) DCM (0.4 M), 0 °C, 2,6ꢀlutidine (3 equiv), tetrabutylammonium bromide
(2.5 equiv), Ms O (1.5 equiv), 4 h, quant.; (d) sulfone 14 (4 equiv), THF (0.08 M), 0 °C,
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KHMDS (3 equiv), 30 min, then 13, 3 h, 49% (2 steps); (e) MeOH (0.1 M), 0 ºC, 20% Na/Hg
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20 equiv), to ambient temp., 4 h, 68%; (f) LiCl (1.2 equiv, dried), DMF (0.25 M), 2,6ꢀlutidine (4
equiv), methanesulfonyl chloride (2 equiv), 85%; (g) NiCl •6H O (0.4 equiv), heat under
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vacuum, zinc (2.2 equiv), 2:1 THF/pyridine, methyl vinyl ketone (2 equiv), reflux (1.5 h), to
ambient temp., 1ꢀiodoꢀ2ꢀmethylpropane (1 equiv), 30 min, reflux (16 h), 17%; (h) NaH (2
equiv), THF, 0 ºC, ester 20 (2.2 equiv), 30 min, then ketone 19, THF (final conc. 0.09 M), to
ambient temp., 17 h, 66% overall yield (4:1 E/Z), 28% yield of pure E after chromatography; (i)
DCM (0.3 M), ꢀ84 ºC, DiBAl–H (3 equiv), 1 h, 85%; (j) LiCl (1.2 equiv, dried), DMF (0.25 M),
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,6ꢀlutidine (2.5 equiv), methanesulfonyl chloride (2 equiv), 90%.
These monounsaturated and ethyl analogues enable direct structure–activity comparisons
with prenyl chloride and geranyl chloride, respectively, to measure the effects of increasing
steric bulk at the far end of the molecules without simultaneously withdrawing electron density
(Figure 4A). Pyridineꢀalkylation experiments analogous to those described above were used to
compare the relative reactivities of these electrophiles under pseudoꢀfirstꢀorder conditions
(Supplementary Figures S3–S6). Monounsaturated analogue 22 reacts 27% more slowly than
prenyl chloride (23, Figure 4B), which suggests that the hydrocarbon chain is able to fold into 3ꢀ
dimensional shapes that position the extra steric bulk close enough to the chlorideꢀbearing
carbon atom to have a meaningful impact on its reactivity as an electrophile. Furthermore,
elongated ethyl analogue 16 reacts 16% more slowly than geranyl chloride, which further shows
that the far regions of these molecules – which would be approximately one nanometer from the
reactive site in an unfolded, linear conformation – are in fact still able to impact reactivity,
presumably due to the importance of folded states that occur even in nonꢀpolar solvents such as
chloroform.
Figure 4. Impact of steric bulk on reaction rate. A. Structures to compare. B. Comparison of the
relative rates of reaction. Averages of two separate sideꢀbyꢀside comparisons at either 23 +/ꢀ 0.5
or 24 +/ꢀ 0.5 ºC. Error bars represent standard deviations from duplicate experiments.
Next, to study the importance of electronic effects, we compared the reaction rates of pairs of
isosteric molecules, which have similar sizes and shapes as each other yet possess different
electronic properties on their distal ends (Figure 5A). The relative rates of their pseudoꢀfirstꢀ
order S 2 reactions with excess pyridine (Figure 5B, Supplementary Figures S3–S6) show that
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monounsaturated analogue 22 reacts 17% more slowly than geranyl chloride itself. Since these
molecules have similar shapes and sizes, the difference in rate suggests that the presence of the
alkene on the far end of these molecules is able to enhance their rates of reaction despite not
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being directly conjugated to the allylic chloride. Comparing the rates of elongated ethyl analogue
16 and methoxyꢀfunctionalized geranyl chloride 24 (see Supplementary Scheme S1 for
synthesis), which are analogous in size and shape, shows that the methoxy geranyl chloride,
whose second alkene is less electron rich due to the inductively electronꢀwithdrawing nature of
the methoxy group, reacts 16% more slowly.
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Figure 5. Impact of electronics on reaction rate. A. Structures to compare. B. Comparison of the
relative rates of reaction. Averages of two separate sideꢀbyꢀside comparisons at either 23 +/ꢀ 0.5
or 24 +/ꢀ 0.5 ºC. Error bars represent standard deviations from duplicate experiments.
Taken together, these comparisons suggest that the presence of an electronꢀrich alkene on the
nonꢀreactive side of geranyl chloride helps to enhance its reactivity as an electrophile. We
initially hypothesized that this rate enhancement could result from the distal π bond being able to
donate electron density towards the electrophilic portion of the molecule, and thus being able to
help stabilize a partial positive charge in the S 2 transition state. We further hypothesized that
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this donation of electron density could occur by a throughꢀspace orbitalꢀmixing interaction that
could exist in one or more of the folded conformations that are relevant to these geranyl
structures. Alternatively, we thought it could also be possible that the π and π* orbitals of the
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two alkene groups could participate in hyperconjugation interactions with the sigma bonds that
connect them, thus allowing the two alkenes to interact with each other "through" the connecting
single bonds.
Computational analysis
To help clarify the electronic effects created by geranyl chloride's distal alkene, we used
computational modeling to evaluate and compare the reactant and transitionꢀstate structures of
prenyl and geranyl chloride. Prenyl chloride is a relatively small compound with minimal
conformational flexibility, and for its reactant and transition state we were able to find one
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energyꢀminimized geometry for each. Using Gaussian 09, ground state geometries were found
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using the B3LYP functional and the 6ꢀ311g(d) basis set with the PCM solvation model for
dichloromethane. Transitionꢀstate geometries were found using the Berny method at the same
level of theory, and energies for both these structures were calculated using the M06ꢀ2X
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method with the 6ꢀ31+g(d,p) basis set and the same solvation method. These same basis sets
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have been previously used by Clement and Houk to analyze the structures and energies of
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transition states for prolineꢀcatalyzed aldol reactions. Unlike prenyl chloride, which has
minimal conformational flexibility, geranyl chloride can adopt several conformations. Using the
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Molecular Operating Environment 2015.10 program with the LowModeMD method and the
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Amber10:EHT forcefield, we identified 14 unique energy minima (excluding enantiomeric
conformations). For further analysis, we selected four of these conformations that seem to
encompass most of the macroscopic diversity of the 14 total conformations (Figure 6). Using
analogous computational methods, we were also able to find an energyꢀminimized geometry for
each of these four reactants and transition states.
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Figure 6. Conformations of geranyl chloride. Fourteen conformations, which each correspond to
a freeꢀenergy minimum, are overlaid. The four conformations selected for further analysis are
highlighted in colors and given nicknames. Structure overlapping and visualization was
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performed using the UCSF Chimera Package 1.10.2.
We focused our analysis on the HOMO and HOMOꢀ1 orbitals, among which there is notable
variation between prenyl chloride and the four conformations of geranyl chloride. In contrast,
visual inspection of the LUMO and lowerꢀenergy filled orbitals (HOMOꢀ2 through HOMOꢀ8)
shows minimal variation between those orbitals from the five reactants or transition states
(Supplementary Figures S9, S12, and S15–S17). For two of the four geranyl chloride reactant
conformations (labeled "far down" and "far up"), the HOMOꢀ1 orbitals resemble prenyl
chloride's HOMO orbital in that the majority of the orbital's volume is located around the alkene
adjacent to the chloride atom (Figure 7A). In the other two conformations (labeled "up" and
"down"), however, the HOMOꢀ1 orbitals encompass both alkene groups with approximately
equal volumes. A similar trend can be seen in the HOMO of the four geranyl chloride reactant
conformations; in the farꢀdown and farꢀup conformations the volumes of the orbitals are
localized around the distal alkene group, whereas in the down and up conformations the volumes
encompass both alkenes (Figure 7B left side). In the HOMO and HOMOꢀ1 of the geranyl
chloride transition states, each of the four conformations has orbitals that extend over both
alkene groups, yet the relative volumes around each alkene vary among the four conformations
(Figure 7B right side, and Supplementary Figures S13–S14).
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Figure 7. Calculated orbitals and energies. A. Filled orbitals from prenyl chloride or geranyl
chloride reactants. B. Changes in HOMOs as different conformations of geranyl chloride react.
Free energies of activation (E ) are listed in kcal/mol. Free energies of the starting materials are
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listed in kcal/mol relative to the farꢀdown conformation. C. Comparison of HOMO energy levels
and free energies in geranyl chloride reactant conformations.
While the HOMO and HOMOꢀ1 orbitals that are localized around individual alkene groups
can be thought of as essentially being isolated π bonding orbitals, the other ones, which
encompass both alkenes, can instead be thought of as linear combinations of the two π bonding
orbitals mixing together and "delocalizing" across both alkene groups. Since this mixing
interaction occurs between two filled orbitals, it should increase the energy of the HOMO and
destabilize the molecule in conformations that enable more mixing. Another example of
destabilizing orbitalꢀmixing interactions between two filled orbitals is the n)(
π repulsive
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interaction that has been identified to destabilize some conformations of proline mimics.
Among the four geranyl chloride conformations, a couple distinct correlations, which are
described below, support this interpretation.
Among the four conformations of the geranyl chloride reactant, the amount of delocalization
in the HOMOs correlates with the relative energies of those orbitals as well as with the relative
free energies of the conformations such that more mixing corresponds to higherꢀenergy orbitals
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and structures (Figure 7B left side and Supplemental Table S2). The direct relationship between
the relative energies of the HOMOs and the relative free energies of the structures, such that
conformations with higher energy HOMOs also have higher free energies (Figure 7C), supports
the idea that these orbitalꢀmixing interactions are important contributors to the overall properties
and reactivities of these molecules. The two conformations with minimal delocalization (far up
and far down) have lower energies, and the two conformations with substantial delocalization
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(up and down) have higher energies (+2.7 and +2.8 kcal/mol versus the free energy of the farꢀ
down conformation). Interestingly, the two highly folded conformations (whose two π bonds are
near each other in space) have less delocalization than the two lessꢀfolded conformations, which
suggests that these orbitalꢀmixing effects are not "throughꢀspace" interactions.
Additional correlations between orbital delocalization and free energies can also be seen
from the transitionꢀstate structures. Free energies of activation for each geranyl chloride
conformation were calculated as the difference between the free energy of the transition state and
the sum of the free energies of the reactants (geranyl chloride and pyridine, calculated
individually). The four conformations differ substantially in their activation energies (25.0–29.5
kcal/mol), and again these energies correlate to the delocalization of the HOMO; specifically,
they correlate to how the amount of delocalization changes between the starting material and the
transition state (Figure 7B). The amount of HOMO delocalization in the farꢀdown conformation
increases substantially from almost none in the starting material to a large amount (the most of
all the conformations) in the transition state. Of the four, this conformation has the lowest energy
starting material (with no destabilizing orbital mixing), but the highest energy transition state
(with much destabilizing orbital mixing), which causes this conformation to have the highest
activation energy (29.5 kcal/mol). The amount of HOMO delocalization in the farꢀup
conformation increases from the starting material to the transition state, but not as much as it
does in the farꢀdown conformations, and this conformation has the second highest activation
energy (27.8 kcal/mol). The amount of HOMO delocalization in the down conformation remains
approximately constant, and it has the second smallest activation energy (26.8 kcal/mol). And
finally, the amount of HOMO delocalization in the up conformation actually decreases from the
starting material to the transition state (in which the 0.02 isovalue volumes around the two π
bonds can be seen to no longer connect in the transition state), and this conformation has the
smallest activation energy (25.0). Indeed, the activation energy for this conformation is similar to
that calculated for the fastꢀreacting prenyl chloride (24.0 kcal/mol).
Conclusion
In conclusion, we present herein a combination of kinetics and computational analyses to
help understand the difference in reactivity among various geranyl chloride derivatives that are
relevant to total syntheses of numerous terpenoid natural products. Comparative analyses of
relative reaction rates show that both steric and electronic factors influence the reactivities of
these terminally functionalized geranyl chlorides. The impact of increased steric bulk on distal
regions of the electrophile shows the importance of folded conformations to these molecules.
While from the electronic perspective, the presence of an electronꢀrich alkene on the distal
region of the molecule increases its electrophilic reactivity versus compounds that lack the
second alkene or only have an electronꢀpoor one. Computational analysis suggests that the
enhanced electrophilic reactivity results from the fact that some, but not all, of geranyl chloride's
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conformations enable repulsive π–π orbitalꢀmixing interactions that can selectively destabilize
the reactants more than the corresponding transition states. Thus, for the synthetic chemist, being
aware of how bulky and electronꢀwithdrawing groups can affect these types of electrophiles,
even when they are far from the electrophile's reactive site, can help enable the development and
optimization of synthetic reactions that involve geranyl electrophiles or related reagents.
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Experimental Section
General Procedure for Alkylating Ketone 2 with Allylic Chlorides. Into a flameꢀdried flask
were added ketone 2 (1 equiv), the required geranyl chloride (2.5 equiv), and toluene. Volatiles
were removed under reduced pressure to remove any traces of water. The flask was fit with a
condensing column, capped with a rubber septum, and maintained under a nitrogen atmosphere.
THF was added, and the mixture was warmed to 30 ºC in an oil bath. Sodium
hexamethyldisilazide (1.0 M in THF, 1.5 equiv) was added dropwise (over 1.5 h). The mixture
was stirred (additional 1 h), quenched with potassium phosphate monobasic (1 M aqueous,
producing pH = 5), and extracted with EtOAc. The combined organic phase was washed with
brine and dried with sodium sulfate. Volatiles were removed under reduced pressure and the
crude material was purified via column chromatography.
General Procedure for Syntheses of Allylic Chlorides (4, 5, 16, 22, 24). Lithium chloride was
dried in a vacuum oven overnight. Into a flameꢀdried flask were added the required alcohol (1
equiv), lithium chloride (1.2 equiv), and toluene. Volatiles were removed under reduced pressure
(to remove any residual water). The flask was capped with a rubber septum and maintained
under a nitrogen atmosphere. To the flask were added DMF (0.3 M), 2,6ꢀlutidine (4 equiv) and
methanesulfonyl chloride (2 equiv). The mixture was stirred (4 h), quenched with sodium
bicarbonate (50% saturated), extracted with hexane, washed with sodium bisulfate (1 M
aqueous), washed with a 1:1 mixture of brine and 1 M aqueous sodium bisulfate, and dried with
sodium sulfate. Volatiles were removed under reduced pressure to yield the crude product. In
some cases, minor amounts of the isomeric tertiary chlorides, resulting from allylic substitution
pathways, were also observed. The allylic chlorides are not fully stable to silica gel.
General Procedure for Measuring Kinetics of Reactions between Pyridine and Allylic
Chlorides. The allylic chloride (approximately 25–60 mg) was added to a tared 1 dram vial and
dissolved in the appropriate volume of CDCl (typically 200–360 µL) to create a 0.83 M
solution. Pyridine (approximately 55–110 mg) was added to a second tared 1 dram vial and
3
dissolved in the appropriate volume of CDCl (typically 0.9–1.7 mL) to give a 0.83 M solution.
3
Into an NMR tube were combined 100 µL of the allylic chloride solutions and 300 µL of the
pyridine solution (final concentrations 0.21 M = 1 equiv chloride and 0.63 M = 3 equiv
pyridine). The tube was capped and mixed thoroughly, and the time of the mixing was recorded
as time zero. All experiments were conducted at 23–24 °C, and each experiment was maintained
in a +/ꢀ 0.5 °C range and compared to other runs performed simultaneously at the same
temperature.
1
Formation of pyridinium products was monitored by H NMR, specifically by the
disappearance of the CH –Cl doublet and the formation of the CH –N doublet, except in the case
2
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of THPꢀprotected geranyl chloride 5, whose CH –Cl doublet overlaps other signals, so
conversion was monitored by the disappearance of the two vinyl triplets from the starting
2
chloride and the formation of the CH –N doublet. NMR spectra of these reactions are provided
2
in the supporting information. All rate comparisons were made using experiments that were
performed simultaneously in sideꢀbyꢀside experiments. Any minor amounts of tertiary allylic
chlorides present did not react under these conditions.
As a representative example, an aliquot of pyridinium chloride 9 (geranylpyridinium
chloride) was isolated for characterization as a hydroscopic oil by removing the volatiles under
reduced pressure (chloroform azeotrope).
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Chloride 4 ((2E,6E)ꢀ8ꢀChloroꢀ1ꢀtertbutyldimethylsiloxyꢀ2,6ꢀdimethylꢀ2,6ꢀoctadiene). The
general procedure was followed using alcohol 4B (147 mg, 0.50 mmol, 1 equiv), LiCl (25 mg,
0
4
.60 mmol, 1.2 equiv), toluene (5 mL), DMF (2.0 mL, 0.25 M), 2,6ꢀlutidine (231 µL, 2.0 mmol,
.0 equiv), MsCl (78 µL, 1.0 mmol, 2.0 equiv), hexane (3 x 5 mL), and aqueous washes (5 mL
each). Crude chloride 4 (140 mg, 0.462 mmol, 89% crude yield, pale yellow oil), which is not
completely stable to silica gel, was assessed to be >95% pure by NMR and was used directly in
the subsequent experiments.
1
H NMR (CDCl , 600 MHz)
δ 5.45 (t, J = 7.9 Hz, 1H, C=CH), 5.36 (t, J = 6.9 Hz, 1H,
3
C=CH), 4.10 (d, J = 7.9 Hz, 2H, CH –Cl), 4.00 (s, 2H, CH –OTBS), 2.16 (q, J = 7.1 Hz, 2H,
2
2
C=C–CH ), 2.09 (t, J = 7.6 Hz, 2H, C=C–CH ), 1.73 (s, 3H, CH ), 1.59 (s, 3H, CH ), 0.91 (s,
2
2
3
3
9
H, Si–tBu), 0.06 (s, 6H, 2 x Si–Me).
13
C NMR (CDCl , 150 MHz)
δ 142.6, 135.2, 123.6, 120.8, 68.6, 41.1, 39.3, 26.1, 25.8, 18.6,
3
16.2, 13.4, ꢀ5.1. ꢀ
1
IR (neat, cm ) 2930, 2859, 1665, 1250, 1113, 1065, 832, 775, 668.
+
MS calculated for [C H OSiClNa] , requires m/z = 325.17, found m/z = 325.1 (ESI).
1
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HRMS (decomposes under ESI and EI conditions, analyzed as cation after loss of chloride
+
and as pyridinium adduct) calculated for [C H OSi] , requires m/z = 267.2144, found m/z =
1
6
31
+
2
67.2137 (ESI); calculated for [C H NOSi] , requires m/z = 346.2566, found m/z = 346.2562
21 36
(ESI).
TLC (5:1) hexane/EtOAc, permanganate, R = 0.86.
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Ether 4A ((2E,6E)ꢀ8ꢀtertbutyldimethylsiloxyꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienyl acetate). Into a
flask were added alcohol 12 (2.94 g, 13.9 mmol, 1 equiv), DCM (28 mL, 0.5 M), imidazole (1.37
g, 20.1 mmol, 1.5 equiv), and tꢀbutyldimethylchlorosilane (2.60 g, 17.3 mmol, 1.25 equiv). The
mixture was stirred (16 h), quenched with ammonium chloride (50% saturated, 60 mL), and
diluted with DCM (60 mL). The organic phase was isolated, washed with sodium chloride (50%
saturated aqueous, 60 mL), and dried with sodium sulfate. Volatiles were removed under reduced
pressure, and the crude material was purified by column chromatography (75 mL silica gel, 7:1
hexane / EtOAc) to yield pure ether 4A (3.85 g, 11.8 mmol, 85% yield, colorless oil).
1
H NMR (CDCl , 600 MHz)
δ 5.36 (t, J = 7.0 Hz, 1H, C=CH), 5.35 (t, J = 7.0 Hz, 1H,
3
C=CH), 4.58 (d, J = 7.0 Hz, 2H, CH –OAc), 4.00 (s, 2H, CH –OTBS), 2.15 (q, J = 7.4 Hz, 2H,
2
2
C=C–CH ), 2.09–2.06 (m, 2H, C=C–CH ), 2.05 (s, 3H, Ac), 1.70 (s, 3H, CH ), 1.59 (s, 3H,
2
2
3
CH ), 0.90 (s, 9H, Si–tBu), 0.05 (s, 6H, 2 x Si–Me).
3
1
3
C NMR (CDCl , 150 MHz)
δ
171.1, 142.0, 134.9, 123.7, 118.5, 68.6, 61.4, 39.3, 26.0,
3
2
5.8, 21.1, 18.5, 16.5, 13.5, ꢀ5.2.
ꢀ1
IR (neat, cm ) 2937, 2861, 1740, 1227, 1064, 838, 777.
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HRMS calculated for [C H O SiNa] , requires m/z = 349.2175, found m/z = 349.2169
ESI).
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(
TLC (7:1) hexane/EtOAc, permanganate, R = 0.61.
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Alcohol 4B ((2E,6E)ꢀ8ꢀtertbutyldimethylsiloxyꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienꢀ1ꢀol). Into a flask
were added acetate 4A (3.85 g, 11.8 mmol, 1 equiv), MeOH (40 mL, 0.3 M), and potassium
carbonate (490 mg, 3.55 mmol, 0.3 equiv). The mixture was stirred (20 h), quenched with
potassium phosphate monobasic (1.0 M aqueous, 40 mL, producing pH 5.0), and approximately
half of the volume was removed under reduced pressure. The remaining mixture was extracted
with ethyl acetate (3 x 50 mL), and the combined organic phase was washed with sodium
chloride (50% saturated aqueous, 60 mL) and dried with sodium sulfate. Volatiles were removed
under reduced pressure, and the crude material was purified by column chromatography (100 mL
silica gel, [6:1 to 2:1] hexane / EtOAc) to yield pure alcohol 4B (2.97 g, 10.5 mmol, 89% yield,
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colorless oil).
1
H NMR (CDCl , 600 MHz)
δ 5.42 (t, J = 6.7 Hz, 1H, C=CH), 5.36 (t, J = 7.0 Hz, 1H,
C=CH), 4.15 (d, J = 6.7 Hz, 2H, CH –OH), 4.00 (s, 2H, CH –OTBS), 2.16 (q, J = 7.5 Hz, 2H,
C=C–CH ), 2.05 (t, J = 7.5 Hz, 2H, C=C–CH ), 1.68 (s, 3H, CH ), 1.59 (s, 3H, CH ), 0.90 (s,
3
2
2
2
2
3
3
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H, SiꢀtBu), 0.06 (s, 6H, 2 x Si–Me).
1
3
C NMR (CDCl , 150 MHz)
δ 139.5, 134.8, 124.0, 123.7, 68.7, 59.4, 39.3, 26.1, 25.9, 18.6,
3
16.3, 13.6, ꢀ5.1. ꢀ
1
IR (neat, cm ) 3341, 2937, 2855, 1254, 1066, 835, 774.
+
HRMS calculated for [C H O SiNa] , requires m/z = 307.2069, found m/z = 307.2065
16
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(
ESI).
TLC (6:1) hexane/EtOAc, permanganate, R = 0.29.
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Chloride 5 ((2E,6E)ꢀ8ꢀChloroꢀ1ꢀtetrahydropyranyloxyꢀ2,6ꢀdimethylꢀ2,6ꢀoctadiene). The
general procedure was followed using alcohol 5B (160 mg, 0.600 mmol, 1 equiv), LiCl (30 mg,
.72 mmol, 1.2 equiv), toluene (5 mL), DMF (2.4 mL, 0.25 M), 2,6ꢀlutidine (277 µL, 2.4 mmol,
.0 equiv), MsCl (93 µL, 1.2 mmol, 2.0 equiv), hexane (3 x 5 mL), and aqueous washes (5 mL
each). Crude chloride 5 (142 mg, 0.520 mmol, 87% crude yield, pale yellow oil), which is not
0
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completely stable to silica gel, was assessed to be >95% pure by NMR and was used directly for
the subsequent experiments.
1
H NMR (CDCl , 600 MHz)
δ 5.45 (t, J = 7.8 Hz, 1H, C=CH), 5.40 (t, J = 6.9 Hz, 1H,
C=CH), 4.60 (t, J = 3.6 Hz, 1H, O–CH–O), 4.10 (d, J = 11.8 Hz, 1H, CH –OTHP), 4.09 (d, J =
7.8 Hz, 2H, CH –Cl), 3.88 (ddd, J = 11.2 Hz , J = 8.1 Hz , J = 2.9 Hz, 1H, CH –O), 3.85 (d, J
= 11.8 Hz, 1H, CH –OTHP), 3.51 (dt, J = 11.2 Hz , J = 5.3 Hz, 1H, CH –O), 2.18 (q, J = 7.3
3
2
2
1
2
3
2
2
d
t
2
Hz, 2H, C=C–CH ), 2.10 (t, J = 7.6 Hz, 2H, C=C–CH ), 1.88–1.82 (m, 1H, CH ), 1.74–1.69 (m,
2
2
2
1
H, CH ), 1.73 (s, 3H, CH ), 1.66 (s, 3H, CH ), 1.63–1.51 (m, 4H, 2 x CH ).
2 3 3 2
1
3
C NMR (CDCl , 150 MHz)
δ 142.4, 132.7, 126.8, 120.7, 97.6, 72.8, 62.2, 41.0, 39.1, 30.8,
3
26.0, 25.6, 19.6, 16.1, 14.1.
ꢀ1
IR (neat, cm ) 2950, 2857, 1665, 1116, 1080, 1019, 908, 873, 671.
MS calculated for [C H O ClNa] , requires m/z = 295.14, found m/z = 295.1 (ESI).
HRMS (decomposes, analyzed as elimination product and as pyridinium adduct) calculated
+
1
5
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2
+
for [C H O Na] , requires m/z = 259.1674, found m/z = 259.1673 (ESI); calculated for
C H NO ] , requires m/z = 316.2277, found m/z = 316.2274 (ESI).
1
5
24
2
+
[
20 30 2
TLC (3:1) hexane/EtOAc, permanganate, R = 0.61.
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Ether 5A ((2E,6E)ꢀ8ꢀtetrahydropyranyloxyꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienyl acetate). Into a
flameꢀdried flask were added alcohol 12 (1.10 g, 5.19 mmol, 1 equiv) and DCM (8.6 mL, 0.6
M). The flask was capped with a rubber septum and maintained under a nitrogen atmosphere. To
the flask were added pyridinium paraꢀtoluenesulfonate (390 mg, 1.56 mmol, 0.3 equiv) and
dihydropyran (1.25 mL, 13.0 mmol, 2.5 equiv). The flask was fit with a reflux condenser. The
mixture was warmed in an oil bath (40 ºC), stirred (17 h), diluted with sodium chloride (50%
saturated aqueous, 15 mL), and extracted with ethyl acetate (2 x 15 mL). The combined organic
phase was washed with sodium chloride (50% saturated aqueous, 30 mL) and dried with sodium
sulfate. Volatiles were removed under reduced pressure and crude ether 5A (1.57 g, quantitative
mass recovery) was used directly in the next step. For analysis, an aliquot was partially purified
by column chromatography (silica gel, 5:1 hexane / EtOAc) to yield material that was >90% pure
0
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by H NMR.
1
H NMR (CDCl , 600 MHz)
δ 5.41 (t, J = 6.9 Hz, 1H, vinyl), 5.35 (t, J = 7.2 Hz, 1H, vinyl),
3
4.60 (t, J = 3.5 Hz, 1H, O–CH–O), 4.59 (d, J = 7.3 Hz, 2H, CH –OAc), 4.10 (d, J = 11.5 Hz, 1H,
2
CH –OTHP), 3.90–3.86 (m, 1H, CH –O), 3.85 (d, J = 11.5 Hz, 1H, CH –OTHP), 3.53–3.49 (m,
2
2
2
1
H, CH –O), 2.18 (q, J = 7.2 Hz, 2H, CH –C=C), 2.09–2.05 (m, 2H, CH –C=C), 2.04 (s, 3H,
2 2 2
Ac), 1.88–1.82 (m, 1H, THP), 1.71 (s, 3H, CH ), 1.66 (s, 3H, CH ), 1.74–1.50 (m, 5H, THP).
3
3
1
3
C NMR (CDCl , 150 MHz)
δ
171.1, 141.9, 132.4, 127.1, 118.5, 97.4, 72.8, 62.1, 61.3,
3
39.1, 30.7, 25.9, 25.5, 21.1, 19.6, 16.5, 14.1.
ꢀ1
IR (neat, cm ) 2938, 2862, 1738, 1232, 1022.
HRMS calculated for [C H O Na] , requires m/z = 319.1885, found m/z = 319.1880 (ESI).
+
1
7
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TLC (3:1) hexane/EtOAc, permanganate, R = 0.57.
f
Alcohol 5B ((2E,6E)ꢀ8ꢀtetrahydropyranyloxyꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienꢀ1ꢀol). Into a flask
was added crude acetate 5A (5.19 mmol, 1 equiv), methanol (13 mL, 0.4 M), and potassium
carbonate (220 mg, 1.59 mmol, 0.3 equiv). The mixture was stirred (5 h), quenched with
potassium phosphate monobasic (1 M, 15 mL, producing pH = 5), and extracted with ethyl
acetate (3 x 30 mL). The combined organic phase was washed with sodium chloride (50%
saturated aqueous, 50 mL) and dried with sodium sulfate. Volatiles were removed, and the crude
material was purified by column chromatography (40 mL silica gel, 5:2 hexane / EtOAc) to yield
pure alcohol 5B (920 mg, 3.62 mmol, 70% yield from alcohol 12, colorless oil).
1
H NMR (CDCl , 600 MHz)
δ 5.43–5.38 (m, 2H, 2 x vinyl), 4.61 (t, J = 3.5 Hz, 1H, O–CH–
3
O), 4.14 (d, J = 6.8 Hz, 2H, CH –OH), 4.09 (d, J = 11.5 Hz, 1H, CH –OTHP), 3.89–3.85 (m,
2
2
1H, CH –O), 3.86 (d, J = 11.5 Hz, 1H, CH –OTHP), 3.53–3.49 (m, 1H, CH –O), 2.23–2.13 (m,
2
2
2
2H, CH –C=C), 2.08 (t, J = 7.4 Hz, 2H, CH –C=C), 1.87–1.81 (m, 1H, THP), 1.67 (s, 3H, CH ),
2
2
3
1
.66 (s, 3H, CH ), 1.74–1.50 (m, 5H, THP).
3
13
C NMR (CDCl , 150 MHz)
δ 138.6, 132.0, 127.8, 124.0, 96.9, 72.9, 62.0, 59.2, 39.1, 30.6,
3
2
5.8, 25.5, 19.4, 16.1, 14.1.
ꢀ1
IR (neat, cm ) 3406, 2927, 2868, 1118, 1016.
+
HRMS calculated for [C H O Na] , requires m/z = 277.1780, found m/z = 277.1777 (ESI).
1
5
26
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TLC (5:2) hexane/EtOAc, permanganate, R = 0.30.
f
Ketone 7 ((2R,3S,4S,5S)ꢀ2ꢀ[(2E,6E)ꢀ8ꢀtertbutyldimethylsiloxyꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienyl]ꢀ
4ꢀisopropenylꢀ5ꢀmethoxymethoxyꢀ3ꢀ{[(pꢀmethoxyphenyl)methoxy]methyl}ꢀ2ꢀ
methylcyclopentanone). The general alkylation procedure was followed using ketone 2 (143 mg,
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8
9
0
.41 mmol, 1 equiv), geranyl chloride 4 (311 mg, 1.03 mmol, 2.5 equiv), toluene (15 mL), THF
(0.21 mL, 2 M), sodium hexamethyldisilazide (1.0 M in THF, 0.62 mL, 0.62 mmol, 1.5 equiv),
potassium phosphate (5 mL), EtOAc (3 x 4 mL), and brine (5 mL). The crude material was
purified via column chromatography (16 mL silica gel, 6:1 hexane/EtOAc) to yield ketone 7 (91
mg, 0.15 mmol, 36% yield, colorless oil) as a mixture of epimers at the CH–OMOM stereocenter
1
1
1
(6:1 S / R). H NMR signals of the major diasteromer were assigned by H– H COSY and by
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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48
49
50
51
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59
60
1
comparison to the starting materials. The minor diastereomer was identified by comparing its H
NMR signals to those of analogous ketone 6. Stereochemistry of the major diasteromer was
1
1
assigned by H– H NOESY and by comparison to ketone 6. No other stereoisomers,
1
constitutional isomers, or doubleꢀalkylation products were observed by H NMR.
Major Isomer (S stereochemistry at OMOM):
1
H NMR (CDCl , 600 MHz)
δ 7.12 (d, J = 8.6 Hz, 2H, Ar), 6.83 (d, J = 8.6 Hz, 2H, Ar),
3
5
.34 (t, J = 6.5 Hz, 1H, C=CH), 5.13 (t, J = 7.2 Hz, 1H, C=CH), 5.05 (brs, 2H, C=CH ) 5.03 (d,
2
J = 6.6 Hz, 1H, O–CH –O), 4.69 (d, J = 6.6 Hz, 1H, O–CH –O), 4.61 (d, J = 10.8 Hz, 1H, CH–
2
2
OMOM), 4.30 (d, J = 11.6 Hz, 1H, CH –Ar), 4.19 (d, J = 11.6 Hz, 1H, CH –Ar), 3.98 (s, 2H,
2
2
CH –OTBS), 3.79 (s, 3H, Ar–O–CH ), 3.37 (s, 3H, O–CH ), 3.28–3.26 (m, 2H, CH –OPMB),
2
3
3
2
2
.94 (dd, J = 10.8 Hz, J = 7.5 Hz, 1H, CH–C=C), 2.34 (dd, J = 14.3 Hz, J = 8.9 Hz, 1H,
1 2 1 2
C=C–CH ), 2.16–2.11 (m, 3H, C=C–CH , CH–C–OPMB), 2.08–2.04 (m, 2H, C=C–CH ), 1.95
2
2
2
(
dd, J = 14.3 Hz, J = 6.4 Hz, 1H, C=C–CH ), 1.79 (s, 3H, C=C–CH ), 1.63 (s, 3H, C=C–CH ),
1 2 2 3 3
1.59 (s, 3H, C=C–CH ), 1.09 (s, 3H, CH ), 0.90 (s, 9H, t–Bu), 0.05 (s, 6H, 2 x Si–CH ).
3
3
3
1
3
C NMR (CDCl , 150 MHz)
δ
219.5, 159.2, 141.6, 139.2, 134.7, 130.1, 129.1, 124.2, 118.8,
3
1
1
13.8, 111.6, 96.2, 73.0, 68.8, 67.2, 55.9, 55.4, 51.0, 49.4, 42.5, 39.9, 35.7, 26.3, 26.1, 22.9, 18.6,
6.8, 16.6, 13.6, –5.1.
ꢀ1
IR (neat, cm ) 3088, 2965, 2931, 2855, 1744, 1618, 1517, 1249, 1102, 1027, 835, 779.
+
HRMS calculated for [C H O SiNa] , requires m/z = 637.3900, found m/z = 637.3904
36
58
6
(ESI).
TLC (5:1) hexane / EtOAc, permanganate, R = 0.43.
f
Minor Isomer (R stereochemistry at OMOM):
1
H NMR (CDCl , 600 MHz, partially reported, nonoverlapping signals)
δ 7.25 (d, J = 8.0
3
Hz, 2H, Ar), 6.88 (d, J = 8.1 Hz, 2H, Ar), 4.72 (d, J = 6.9 Hz, 1H, O–CH –O), 4.45 (d, J = 11.6
2
Hz, 1H, CH –Ar), 4.39 (d, J = 11.9 Hz, 1H, CH –Ar), 4.24 (d, J = 7.2 Hz, 1H, CH–OMOM),
2
2
3
.99 (s, 2H, CH –OTBS), 3.51 (d, J = 6.9 Hz, 2H, CH –OPMB), 3.36 (s, 3H, O–CH ), 2.54 (q, J
2 2 3
=
7.0 Hz, 1H, CH–C–OPMB), 1.73 (s, 3H, C=C–CH ), 1.57 (s, 3H, C=C–CH ).
3
3
TLC (5:1) hexane / EtOAc, permanganate, R = 0.37.
f
Ketone 8 ((2R,3S,4S,5S)ꢀ2ꢀ[(2E,6E)ꢀ8ꢀtetrahydropyranyloxyꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienyl]ꢀ4ꢀ
isopropenylꢀ5ꢀmethoxymethoxyꢀ3ꢀ{[(pꢀmethoxyphenyl)methoxy]methyl}ꢀ2ꢀ
methylcyclopentanone).The general alkylation procedure was followed using ketone 2 (147 mg,
0.42 mmol, 1 equiv), geranyl chloride 5 (287 mg, 1.05 mmol, 2.5 equiv), toluene (15 mL), THF
(0.21 mL, 2 M) sodium hexamethyldisilazide (1.0 M in THF, 0.63 mL, 0.63 mmol, 1.5 equiv),
potassium phosphate (5 mL), EtOAc (3 x 4 mL), and brine (5 mL). The crude material was
purified via column chromatography (20 mL silica gel, 5:1 hexane / EtOAc) to yield ketone 8
(
60 mg, 0.10 mmol, 24% yield, colorless oil) as predominantly a single epimer at the CH–
13
OMOM stereocenter. Analysis by C NMR shows an approximate 1:1 mixture of diastereomers
at the THP group. H NMR signals were assigned by H– H COSY and comparison to the
1
1
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4
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5
5
5
5
5
5
5
6
1
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starting materials. Stereochemistry was assigned by H– H NOESY and by comparison to ketone
6
.
1
H NMR (CDCl , 600 MHz, two diastereomers at THP)
(d, J = 8.6 Hz, 2H, Ar), 5.39 (t, J = 6.6 Hz, 1H, C=CH), 5.12 (t, J = 7.4 Hz, 1H, C=CH), 5.04
brs, 2H, C=CH ), 5.02 (d, J = 6.9 Hz, 1H, O–CH –O), 4.69 (d, J = 6.9 Hz, 1H, O–CH –O), 4.61
2 2 2
d, J = 10.7 Hz, 1H, CH–OMOM), 4.58 (t, J = 3.4 Hz, 1H, O–CH–O), 4.30 (d, J = 11.6 Hz, 1H,
δ
7.12 (d, J = 8.6 Hz, 2H, Ar), 6.83
3
(
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH –Ar), 4.19 (d, J = 11.6 Hz, 1H, CH –Ar), 4.08 (d, J = 11.6 Hz, 1H, CH –OTHP), 3.88–3.85
2
2
2
(
m, 1H, CH –O), 3.82 (d, J = 11.6 Hz, 1H, CH –OTHP), 3.79 (s, 3H, Ar–O–CH ) 3.51–3.48 (m,
2 2 3
1H, CH –O), 3.37 (s, 3H, O–CH ), 3.27 (brs, 2H, CH –OPMB), 2.94 (dd, J = 10.7 Hz, J = 7.6
Hz, 1H, CH–C=C), 2.33 (dd, J = 14.5 Hz, J = 8.9 Hz, 1H, C=C–CH ), 2.17–2.12 (m, 3H,
C=C–CH , CH–C–OPMB), 2.09–2.06 (m, 2H, C=C–CH ), 1.96 (dd, J = 14.5 Hz, J = 6.1 Hz,
2
3
2
1
2
1
2
2
2
2
1
2
1
H, C=C–CH ), 1.86–1.75 (m, 1H, THP), 1.79 (s, 3H, C=C–CH ), 1.73–1.67 (m, 1H, THP), 1.65
2
3
(
s, 3H, C=C–CH ), 1.63 (s, 3H, C=C–CH ), 1.62–1.50 (m, 4H, THP), 1.08 (s, 3H, CH ).
3
3
3
1
3
C NMR (CDCl , 150 MHz, two diastereomers at THP)
30.1, 129.1, 127.5, 127.5, 119.0, 118.9, 113.8, 111.6, 97.6, 97.5, 96.1, 73.0, 67.2, 62.3, 55.8,
5.3, 51.0, 49.4, 42.5, 39.8, 35.7, 30.8, 26.4, 26.4, 25.6, 22.9, 19.6, 16.8, 16.6, 16.5, 14.2.
δ
219.4, 159.2, 141.5, 139.0, 132.3,
3
1
5
ꢀ1
IR (neat, cm ) 3088, 2941, 2860, 1749, 1613, 1517, 1441, 1254, 1102, 1027, 820.
HRMS calculated for [C H O Na] , requires m/z = 607.3611, found m/z = 607.3616 (ESI).
TLC (5:1) hexane / EtOAc, permanganate, R = 0.31.
+
3
5
52
7
f
1
Formation of pyridinium 9 from geranyl chloride was monitored by H NMR, specifically by
the disappearance of the CH –Cl doublet and the formation of the CH –N doublet. For
characterization, an aliquot of the crude reaction product was isolated as a hydroscopic oil by
2
2
1
removing the volatiles under reduced pressure (chloroform azeotrope). H NMR signals were
1
1
assigned by H– H COSY.
1
H NMR (CDCl with 0.6 M pyridine, 600 MHz)
H, py), 8.04 (t, J = 7.4 Hz, 2H, py), 5.52 (d, J = 7.5 Hz, 2H, CH –py), 5.40 (t, J = 7.5 Hz, 1H,
CH=C), 4.88 (brs, 1H, CH=C), 1.99 (brs, 4H, 2 x CH ), 1.77 (s, 3H, CH ), 1.51 (s, 3H, CH ),
δ 9.36 (brs, 2H, py), 8.42 (t, J = 7.4 Hz,
3
1
2
2
3
3
1
.44 (s, 3H, CH ).
3
1
H NMR (CDCl , 600 MHz, after isolation)
δ 9.46 (d, J = 5.3 Hz, 2H, py), 8.49 (t, J = 7.4
Hz, 1H, py), 8.10 (t, J = 6.9 Hz, 2H, py), 5.67 (d, J = 7.4 Hz, 2H, CH –py), 5.49 (t, J = 7.4 Hz,
H, CH=C), 5.03–4.98 (brs, 1H, CH=C), 2.15–2.08 (brs, 4H, 2 x CH ), 1.88 (s, 3H, CH ), 1.64
3
2
1
2 3
(
s, 3H, CH ), 1.56 (s, 3H, CH ).
3 3
1
3
C NMR (CDCl , 150 MHz, after isolation)
δ 148.7, 145.1, 144.9, 132.6, 128.4, 123.2,
3
115.9, 59.4, 39.6, 26.1, 25.8, 17.9, 17.3.
ꢀ1
IR (neat, cm ) 3387, 3063, 2978, 2924, 2861, 1635, 1490, 1154, 776, 682.
HRMS calculated for [C H N] , requires m/z = 216.1752, found m/z = 216.1751 (ESI).
+
1
5
22
1
Formation of pyridinium 10 from chloride 4 was monitored by H NMR, specifically by the
disappearance of the CH –Cl doublet and the formation of the CH –N doublet.
H NMR (CDCl with 0.6 M pyridine, 600 MHz)
H, py), 8.04 (t, J = 7.2 Hz, 2H, py), 5.54 (d, J = 7.2 Hz, 2H, CH –py), 5.42 (t, J = 7.2 Hz, 1H,
C=CH), 5.21 (brs, 1H, C=CH), 3.86 (s, 2H, CH –OTBS), 2.04 (brs, 4H, 2 x C=C–CH ), 1.79 (s,
H, CH ), 1.45 (s, 3H, CH ), 0.78 (s, 9H, Si–tBu), ꢀ0.07 (s, 6H, 2 x Si–Me).
2
2
1
δ
9.38 (brs, 2H, py), 8.40 (t, J = 7.2 Hz,
3
1
2
2
2
3
3 3
+
HRMS calculated for [C H NOSi] , requires m/z = 346.2566, found m/z = 346.2562 (ESI).
2
1
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Formation of pyridinium 11 from chloride 5 was monitored by H NMR. Since the CH –Cl
2
doublet overlaps other signals, conversion was monitored by the disappearance of the two vinyl
triplets from the starting chloride and the formation of the CH –N doublet.
9.36 (brs, 2H, py), 8.39 (t, J = 7.2 Hz,
H, py), 8.03 (t, J = 7.2 Hz, 2H, py), 5.52 (d, J = 7.2 Hz, 2H, CH –py), 5.40 (t, J = 7.2 Hz, 1H,
2
1
H NMR (CDCl with 0.6 M pyridine, 600 MHz)
δ
3
1
2
C=CH), 5.21 (brs, 1H, C=CH), 4.42 (brs, 1H, O–CH–O), 3.93 (d, J = 11.6 Hz, 1H, CH –OTHP),
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
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38
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42
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46
47
48
49
50
51
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53
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55
56
57
58
59
60
3
2
.76–3.70 (m, 1H, CH –O), 3.67 (d, J = 11.6 Hz, 1H, CH –OTHP), 3.38–3.30 (m, 1H, CH –O),
2 2 2
.04 (brs, 4H, 2 x C=C–CH ), 1.77 (s, 3H, CH ), 1.72–1.31 (m, 6H, 3 x CH ), 1.50 (s, 3H, CH ).
2
3
2
3
+
HRMS calculated for [C H NO ] , requires m/z = 316.2277, found m/z = 316.2274 (ESI).
2
0
30
2
Bromide 13 ((2E,6E)ꢀ8ꢀBromoꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienyl acetate). A flameꢀdried flask was
capped with a rubber septum and maintained under a nitrogen atmosphere. Into the flask were
added alcohol 12 (500 mg, 2.36 mmol, 1 equiv) and DCM (6.0 mL 0.4 M). The flask was cooled
in an ice bath (0 °C). Into the flask were added 2,6ꢀlutidine (820 µL, 7.08 mmol, 3.0 equiv),
tetrabutylammonium bromide (1.96 g, 5.90 mmol, 2.5 equiv), and methanesulfonic anhydride
(615 mg, 3.54 mmol, 1.5 equiv). The mixture was stirred (4 h), allowed to warm to ambient
temperature, quenched with water (10 mL), and extracted with pentane (3 x 15 mL). The
combined organic phase was washed with sodium bisulfate (1 M aqueous, 20 mL), washed with
a 1:1 mixture of brine and 1 M aqueous sodium bisulfate (25 mL), and dried with sodium sulfate.
Volatiles were removed under reduced pressure to yield crude bromide 13 (654 mg, brown oil,
quantitative mass recovery, mostly pure by H NMR), which was used directly in the next step.
Bromide 13 is not fully stable to silica gel.
1
1
H NMR (CDCl , 600 MHz)
δ 5.57 (t, J = 6.9 Hz, 1H, HC=C), 5.34 (t, J = 6.9 Hz, 1H,
3
HC=C), 4.59 (d, J = 6.9 Hz, 2H, CH –OAc), 3.96 (s, 2H, CH –Br), 2.17 (q, J = 6.9 Hz, 2H,
C=C–CH ), 2.09 (t, J = 7.4 Hz, 2H, C=C–CH ), 2.06 (s, 3H, Ac), 1.76 (s, 3H, CH ), 1.70 (s, 3H,
CH ).
2
2
2
2
3
3
13
C NMR (CDCl , 150 MHz)
δ 170.9, 141.2, 132.5, 130.4, 119.0, 61.2, 41.5, 38.6, 26.4,
3
21.0, 16.4, 14.7.ꢀ
1
IR (neat, cm ) 3023, 2934, 2857, 1733, 1667, 1445, 1364, 1233, 1022, 949, 604.
+
MS calculated for [C H O BrNa] , requires m/z = 297.05 and 299.04, found m/z = 297.1
1
2
19
2
and 299.1 (ESI).
HRMS (decomposes under ESI and EI conditions, analyzed as symmetric ether dimer)
+
calculated for [C H O Na] , requires m/z = 429.2617, found m/z = 429.2610 (ESI).
2
4
38
5
TLC (4:1) hexane/EtOAc, permanganate, R = 0.59.
f
Sulfone 14 ((Ethylsulfonyl)benzene). A flameꢀdried flask was capped with a rubber septum
and maintained under a nitrogen atmosphere. Into the flask were added sodium benzenesulfinate
(5.79 g, 35.3 mmol, 1.4 equiv), DMF (5 mL, 5 M), and iodoethane (2.05 mL, 25.6 mmol, 1
equiv). The mixture was stirred (24 h), diluted with sodium chloride (50% saturated aqueous, 10
mL), and extracted with Et O (3 x 10 mL). The combined organic phase was washed with
sodium chloride (50% saturated aqueous, 20 mL) and dried with sodium sulfate. Volatiles were
removed under reduced pressure, and the crude material was purified by column chromatography
2
(60 mL silica gel, 3:1 hexane / EtOAc) to yield pure sulfone 14 (3.84 g, 22.6 mmol, 88% yield,
1
32
colorless solid). H NMR analysis is consistent with previously reported data.
1
H NMR (CDCl , 200 MHz) δ 7.91 (d, J = 7.6 Hz, 2H, Ar), 7.74–7.47 (m, 3H, Ar), 3.12 (q, J
3
= 7.6 Hz, 2H, CH ), 1.27 (t, J = 7.7 Hz, 3H, CH ).
2
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Sulfone 15 ((2E,6E)ꢀ3,7ꢀDimethylꢀ9ꢀ(phenylsulfonyl)ꢀ2,6ꢀdecadienꢀ1ꢀol). A flameꢀdried flask
was capped with a rubber septum and maintained under a nitrogen atmosphere. Into the flask
were added ethyl phenyl sulfone (14, 1.61 g, 9.44 mmol, 4 equiv) and THF (9.5 mL). The flask
was cooled in an ice bath (0 °C). To the mixture were added KHMDS (0.5 M in toluene, 14.2
mL, 7.08 mmol, 3.0 equiv). The mixture was stirred (30 min). Bromide 13 (654 mg, 2.36 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
equiv) was dissolved in THF (5.0 mL) and added dropwise to the flask (final concentration
.08 M). The reaction was stirred (3 h), quenched with potassium phosphate monobasic (1 M
aqueous, 30 mL, producing pH = 5), allowed to warm to ambient temperature, and extracted with
EtOAc (3 x 30 mL). The combined organic phase was washed with sodium chloride (50%
saturated aqueous, 50 mL) and dried with sodium sulfate. Volatiles were removed under reduced
pressure, and the crude material was purified by column chromatography (45 mL silica gel, [2:1
to 3:2] hexane / EtOAc) to yield pure sulfone 15 (129 mg) plus mixed fractions (containing
material in which the acetate appeared to not yet have been removed). The mixed fractions were
combined with methanol (1.5 mL) and potassium carbonate (26 mg), stirred at ambient
temperature (1 h), worked up as described above, and purified by silica gel chromatography to
yield pure sulfone 15 (375 mg total, 1.16 mmol, 49% yield, colorless oil).
1
H NMR (CDCl , 600 MHz) δ 7.89 (d, J = 7.4 Hz, 2H, Ar), 7.66 (t, J = 7.4 Hz, 1H, Ar), 7.57
3
(t, J = 7.4 Hz, 2H, Ar), 5.38 (t, J = 6.6 Hz, 1H, HC=C), 5.15 (t, J = 6.3 Hz, 1H, HC=C), 4.13 (d,
J = 6.6 Hz, 2H, CH –O), 3.18–3.12 (m, 1H, CH), 2.68 (d, J = 12.4 Hz, 1H, CH –C–S), 2.11 (q, J
2
2
=
7.0 Hz, 2H, CH –C=C). 2.05–1.99 (m, 3H, C=C–CH , CH –C–S), 1.65 (s, 3H, CH ), 1.52 (s,
2 2 2 3
3
H, CH ), 1.16 (d, J = 6.8 Hz, 3H, CH ).
3
3
1
3
C NMR (CDCl , 150 MHz)
δ 138.7, 137.2, 133.7, 129.9, 129.1, 129.0, 128.7, 123.9, 59.2,
3
58.2, 39.3, 39.1, 26.2, 16.2, 15.5, 12.7.
ꢀ1
IR (neat, cm ) 3446, 3070, 2980, 2920, 2857, 1444, 1299, 1146, 1090, 1004, 732, 691.
+
HRMS calculated for [C H O SNa] , requires m/z = 345.1500, found m/z = 345.1497
18
26
3
(ESI).
TLC (1:1) hexane/EtOAc, UV/permanganate, R = 0.38.
f
Alcohol 15A ((2E,6E)ꢀ3,7ꢀDimethylꢀ2,6ꢀdecadienꢀ1ꢀol). A flameꢀdried flask was capped with
a rubber septum and maintained under a nitrogen atmosphere. Into the flask were added sulfone
5 (246 mg, 0.764 mmol, 1 equiv) and MeOH (distilled from Na SO , 7.6 mL, 0.1 M). The flask
1
2
4
was cooled in an ice bath (0 °C). Sodium mercury amalgam (20% Na, 1.76 g, 15.2 mmol, 20.0
equiv) was added. The mixture was stirred (4 h, gradually warming to ambient temperature)
diluted with Et O (20 mL), and washed with water (20 mL). Insolubles were removed from the
2
organic phase by gravity filtration and chased with Et O (20 mL). The combined organic phase
2
was dried with sodium sulfate. Volatiles were gently removed under reduced pressure, and the
crude material was purified by column chromatography (20 mL silica, 2:1 pentane/Et O) to yield
2
pure alcohol 15A (94 mg, 0.52 mmol, 68% yield, volatile colorless oil).
1
H NMR (CDCl , 600 MHz)
δ 5.42 (t, J = 6.5 Hz, 1H, C=CH), 5.09 (t, J = 6.4 Hz, 1H,
3
C=CH), 4.15 (d, J = 6.5 Hz, 2H, CH –OH), 2.12 (q, J = 6.9 Hz, 2H, C=C–CH ), 2.05 (t, J = 7.8
2
2
Hz , 2H, C=C–CH ), 1.94 (t, J = 7.3 Hz, 2H, C=C–CH ), 1.68 (s, 3H, CH ), 1.58 (s, 3H, CH ),
2
2
3
3
1
.40 (sext, J = 7.3 Hz, 2H, CH ), 1.24 (brs, 1H, OH), 0.86 (t, J = 7.3 Hz, 3H, CH ).
2
3
1
3
C NMR (CDCl , 150 MHz)
δ 139.9, 135.6, 123.9, 123.5, 59.5, 41.9, 39.7, 26.4, 21.1, 16.4,
3
16.0, 13.8.
ꢀ1
IR (neat, cm ) 3314, 3052, 2962, 2927, 2869, 1670, 1447, 1380, 1002.
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+
HRMS calculated for [C H O] , requires m/z = 182.1671, found m/z = 182.1679 (EI)..
1
2
22
TLC (2:1) hexane/EtOAc, permanganate, R = 0.58.
f
Chloride 16 ((2E,6E)ꢀ1ꢀChloroꢀ3,7ꢀdimethylꢀ2,6ꢀdecadiene). The general procedure was
followed using alcohol 15A (94 mg, 0.52 mmol, 1 equiv), LiCl (26 mg, 0.62 mmol, 1.2 equiv),
no toluene azeotrope due to alcohol 15A's volatility, DMF (2.1 mL, 0.25 M), 2,6ꢀlutidine (240
µL, 2.08 mmol, 4.0 equiv), MsCl (96 µL, 1.2 mmol, 2.0 equiv), hexane (3 x 5 mL), and aqueous
washes (5 mL each). Crude chloride 16 (89 mg, 0.44 mmol, 85% crude yield, pale yellow oil),
which is not completely stable to silica gel, was assessed to be approximately 90% pure by NMR
and was used directly for the subsequent experiments.
δ 5.44 (t, J = 7.7 Hz, 1H, C=CH), 5.08 (t, J = 6.5 Hz, 1H,
C=CH), 4.09 (d, J = 7.7 Hz, 2H, CH –Cl), 2.12 (q, J = 7.2 Hz, 2H, C=C–CH ), 2.07 (t, J = 6.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
H NMR (CDCl , 600 MHz)
3
2
2
Hz, 2H, C=C–CH ), 1.94 (t, J = 7.3 Hz, 2H, C=C–CH ), 1.73 (s, 3H, CH ), 1.58 (s, 3H, CH ),
1.40 (sext, J = 7.3 Hz, 2H, CH ), 0.85 (t, J = 7.3 Hz, 3H, CH ).
2
2
3
3
2
3
1
3
C NMR (CDCl , 150 MHz)
δ 142.9, 135.8, 123.6, 120.5, 41.9, 41.3, 39.6, 26.2, 21.1, 16.2,
3
1
6.0, 13.8.
ꢀ1
IR (neat, cm ) 3057, 2962, 2931, 2874, 1668, 1455, 1383, 1254, 878, 674.
MS (decomposes under ESI conditions)
HRMS (decomposes under ESI conditions, analyzed as pyridinium adduct) calculated for
+
[C H N] , requires m/z = 244.2065, found m/z = 244.2063 (ESI).
1
7
26
TLC (5:1) hexane/EtOAc, permanganate, R = 0.81.
f
1
Formation of pyridinium 16A from chloride 16 was monitored by H NMR, specifically by
the disappearance of the CH –Cl doublet and the formation of the CH –N doublet.
H NMR (CDCl with 0.6 M pyridine, 600 MHz)
H, py), 8.04 (t, J = 7.1 Hz, 2H, py), 5.56 (d, J = 7.2 Hz, 2H, CH –py), 5.42 (t, J = 7.2 Hz, 1H,
2
2
1
δ
9.43 (brs, 2H, py), 8.43 (t, J = 7.1 Hz,
3
1
2
C=CH), 4.91 (brs, 1H, C=CH), 2.02 (brs, 4H, 2 x C=C–CH ), 1.83–1.76 (m, 5H, CH , C=C–
2
3
CH ), 1.43 (s, 3H, CH ), 1.24 (sext, J = 7.1 Hz, 2H, CH ), 0.71 (t, J = 7.1 Hz, 3H, CH ).
2
3
2
3
+
HRMS calculated for [C H N] , requires m/z = 244.2065, found m/z = 244.2063 (ESI).
17 26
Ketone 19 (6ꢀMethylꢀ2ꢀheptanone). Nickel (II) chloride hexahydrate (9.80 g, 41.2 mmol, 0.4
equiv) was heated under vacuum with a Bunsen burner (changing from green to yellow).
Granular zinc (14.0 g, 213 mmol, 2.2 equiv) was added, and the flask was capped with a rubber
septum and maintained under an argon atmosphere. To the flask were added THF (100 mL),
pyridine (50 mL, producing a tealꢀcolor), and methyl vinyl ketone (17, 16.0 mL, 192 mmol, 2
equiv). The mixture was heated to reflux (1.5 h, producing a bloodꢀred colored solution) and
allowed to cool to ambient temperature. To the mixture was added 1ꢀiodoꢀ2ꢀmethylpropane (18,
1
1.3 mL, 98.2 mmol, 1 equiv). The mixture was stirred at ambient temperature (30 min), heated
to reflux (16 h), cooled to ambient temperature, diluted with DCM (100 mL), filtered through a
plug of Celite, washed with hydrochloric acid (1 M aqueous, 2 x 125 mL), washed with sodium
bicarbonate (saturated aqueous, 2 x 125 mL), washed with sodium chloride (saturated aqueous,
25 mL), and dried with sodium sulfate. Volatiles were gently removed under reduced pressure
35 °C, 350–450 mbar). The crude material (33.0 g) was washed with hydrochloric acid (1 M
aqueous, 2 x 100 mL) and sodium chloride (50% saturated aqueous, 100 mL). Volatiles were
1
(
again removed under reduced pressure (35 °C, 350–450 mbar). The crude material (12.7 g) was
purified via column chromatography (300 mL silica gel, 20:1 DCM / Et O). After volatiles were
2
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2
2
2
2
2
2
2
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3
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3
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4
4
4
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5
5
5
5
5
5
5
6
gently removed, ketone 19 was isolated along with residual DCM (3.27 g, 66% ketone by mass,
1
16.9 mmol, 17% yield, colorless liquid). H NMR analysis is consistent with commercially
available material.
1
H NMR (CDCl , 200 MHz) δ 2.41 (t, J = 7.5 Hz, 2H, CH –C=O), 2.14 (s, 3H, CH –C=O),
3
2
3
1
.67–1.44 (m, 3H, CH, CH ), 1.22–1.10 (m, 2H, CH ), 0.88 (d, J = 6.6 Hz, 6H, 2 x CH ).
2 2 3
TLC (20:1) DCM/diethyl ether, dinitrophenylhydrazine, R = 0.86.
f
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Phosphonate Ester 20 (ethyl (diethoxyphosphinyl)acetate). Into a flask were added ethyl
bromoacetate (6.62 mL, 60.0 mmol, 1 equiv) and triethyl phosphite (25.6 mL, 150 mmol, 2.5
equiv). The mixture was heated to reflux (22 h), allowed to cool to ambient temperature, and
distilled under reduced pressure (0.3 torr) to yield phosphonate ester 20 (11.6 g, 51.8 mmol, 86%
1
yield, colorless liquid). H NMR analysis is consistent with commercially available material.
1
H NMR (CDCl , 200 MHz) δ 4.22–4.03 (m, 6H, 3 x O–CH ), 2.91 (d, J = 21.6 Hz, 2H,
3
2
CH ), 1.30 (t, J = 7.1, 6H, 2 x CH ), 1.24 (t, J = 7.1, 3H, CH ).
2
3
3
B.P. 160–165 °C (0.3 torr)
Ester 21 (Ethyl (E)ꢀ3,7ꢀdimethylꢀ2ꢀoctenoate). Into a flameꢀdried flask were added sodium
hydride (60% dispersion in mineral oil, 1.07 g, 26.8 mmol, 2.0 equiv) and THF (100 mL). The
flask was capped with a rubber septum, maintained under a nitrogen atmosphere, and cooled in
an ice bath (0 °C). Phosphonate ester 20 (6.60 g, 29.5 mmol, 2.2 equiv) was added dropwise
(
1
(
producing gas evolution). The mixture was stirred (30 min, until gas evolution ceased). Ketone
9 (1.71 g, 13.4 mmol, 1 equiv) was dissolved in THF (50 mL) and added to the reaction mixture
final concentration 0.09 M). The mixture was stirred (75 min), allowed to warm to ambient
temperature, stirred (additional 17 h), diluted with DCM (100 mL), and quenched with sodium
chloride (50% saturated aqueous, 150 mL). The organic phase was isolated, washed with sodium
chloride (50% saturated aqueous, 2 x 100 mL), and dried with sodium sulfate. Volatiles were
1
removed under reduced pressure. Analysis of the crude material by H NMR showed a 4:1 ratio
of E and Z isomers. The crude mixture was purified via column chromatography (80 mL silica
gel, 10:1 DCM / Et O) yield ester 21-E (737 mg, 3.72 mmol, 28% yield, colorless oil), ester 21-
2
Z (92 mg, 0.46 mmol, 3% yield, colorless oil), and a mixture of the two (918 mg, 4.63 mmol,
1
33,34
35% yield, colorless oil). H NMR analysis is consistent with previously reported data.
E and
3
3
Z isomers were assigned by comparison to previously reported data for 21-E and for analogous
35
Zꢀcompounds.
Major isomer (E).
1
H NMR (CDCl , 600 MHz) δ 5.65 (brs, 1H, C=CH), 4.14 (q, J = 7.2 Hz, 2H, CH –O), 2.15
3
2
(s, 3H, C=C–CH ), 2.11 (t, J = 7.7 Hz, 2H, C=C–CH ), 1.54 (non, J = 6.7 Hz, 1H, CH), 1.47
3
2
(
pent, J = 7.7 Hz, 2H, CH ), 1.28 (t, J = 7.2 Hz, 3H, CH ), 1.18–1.13 (m, 2H, CH ), 0.87 (d, J =
2
3
2
6
.9 Hz, 6H, 2 x CH ).
3
1
3
C NMR (CDCl , 50 MHz)
δ 167.0, 160.4, 115.6, 59.5, 41.3, 38.6, 28.0, 25.3, 22.7, 18.8,
3
14.5.
ꢀ1
IR (neat, cm ) 2956, 1715, 1648, 1221, 1148, 1118, 1042.
+
MS calculated for [C H O Na] , requires m/z = 221.15, found m/z = 221.2 (ESI).
1
2
22
2
TLC (15:1) hexane/Et O, permanganate, R = 0.42.
2
f
Minor Isomer (Z)
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H NMR (CDCl , 200 MHz) δ 5.65 (brs, 1H, C=CH), 4.14 (q, J = 7.1 Hz, 2H, CH –O), 2.60
3
2
(
t, J = 7.7 Hz, 2H, C=C–CH ), 1.88 (d, J = 1.3 Hz, 3H, C=C–CH ), 1.69–1.33 (m, 3H, CH,
2
3
CH ), 1.29–1.16 (m, 2H, CH ), 1.27 (t, J = 7.1 Hz, 3H, CH ), 0.88 (d, J = 6.5 Hz, 6H, CH ).
2
2
3
3
TLC (15:1) hexane/Et O, permanganate, R = 0.50.
2
f
Alcohol 21A ((E)ꢀ3,7ꢀDimethylꢀ2ꢀoctenꢀ1ꢀol). Into a flameꢀdried flask were added ester 21
145 mg, 0.732 mmol, 1 equiv, pure Eꢀisomer) and DCM (2.4 mL, 0.3 M). The flask was capped
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
with a rubber septum, maintained under a nitrogen atmosphere, and cooled in an EtOAc/N (l)
2
bath (ꢀ84 °C). DiBAl–H (1 M in hexane, 2.2 mL, 2.2 mmol, 3.0 equiv) was added, and the
reaction was stirred (1 h), quenched with MeOH (2 mL) and then sodium hydroxide (1 M
aqueous, 3 mL), allowed to warm to ambient temperature, diluted with water (3 mL) extracted
with Et O (3 x 5 mL), washed with brine (5 mL), and dried with sodium sulfate. Volatiles were
2
gently removed under reduced pressure, and the crude material was purified by column
chromatography (16 mL silica gel, 3:1 hexane / Et O) to yield pure alcohol 21A (97 mg, 0.62
2
1
mmol, 85% yield, slightly volatile colorless oil). H NMR analysis is consistent with previously
3
4
reported data.
1
H NMR (CDCl , 600 MHz) δ 5.41 (t, J = 6.6 Hz, 1H, C=CH), 4.14 (d, J = 6.3 Hz, 2H,
3
CH –O), 1.99 (t, J = 7.7 Hz, 2H, C=C–CH ), 1.67 (s, 3H, CH ), 1.53 (non, J = 6.7 Hz, 1H, CH),
2
2
3
1
.40 (pent, J = 7.7 Hz, 2H, CH ), 1.20 (d, J = 10.6 Hz, 1H, OH), 1.17–1.12 (m, 2H, CH ), 0.87
2
2
(d, J = 6.7 Hz, 6H, CH ).
3
1
3
C NMR (CDCl , 150 MHz)
IR (neat, cm ) 3322, 2953, 2927, 2873, 1675, 1470, 1383, 1368, 999.
MS calculated for [C H ONa] , requires m/z = 179.14, found m/z = 179.2 (ESI).
δ
140.2, 123.2, 59.5, 39.9, 38.7, 28.0, 25.6, 22.7, 16.3.
3
ꢀ1
+
1
0
20
TLC (3:1) hexane/Et O, permanganate, R = 0.30.
2
f
Chloride 22 ((E)ꢀ1ꢀChloroꢀ3,7ꢀdimethylꢀ2ꢀoctene). The general procedure was followed
using alcohol 21A (170 mg, 1.09 mmol, 1 equiv), LiCl (55 mg, 1.3 mmol, 1.2 equiv), no toluene
azeotrope due to alcohol 21A's volatility, DMF (4.3 mL, 0.25 M), 2,6ꢀlutidine (315 µL, 2.72
mmol, 2.5 equiv), MsCl (169 µL, 2,18 mmol, 2.0 equiv), hexane (8 + 2 x 4 mL), and aqueous
washes (5 mL each). Crude chloride 22 (172 mg, 0.98 mmol, 90% crude yield, pale yellow oil),
which is not completely stable to silica gel, was assessed to be approximately 95% pure by NMR
1
1
1
and was used directly for the subsequent experiments. H NMR signals were assigned by H– H
COSY and by comparison to signals from the starting materials.
1
H NMR (CDCl , 600 MHz)
δ 5.44 (t, J = 7.5 Hz, 1H, C=CH), 4.10 (d, J = 7.5 Hz, 2H,
3
CH –Cl), 2.01 (t, J = 7.6 Hz, 2H, C=C–CH ), 1.71 (s, 3H, C=C–CH ), 1.53 (non, J = 6.7 Hz, 1H,
2
2
3
CH), 1.43–1.38 (m, 2H, CH ), 1.14 (dt, J = 7.6 Hz, J = 6.7 Hz, 2H, CH ), 0.87 (d, J = 6.7 Hz,
2
d
t
2
6
H, 2 x CH ).
3
13
C NMR (CDCl , 150 MHz) δ 143.5, 120.1, 41.4, 39.8, 38.6, 28.0, 25.4, 22.8, 16.1.
3
ꢀ1
IR (neat, cm ) 2961, 2937, 2867, 1666, 1464, 1385, 1254, 674.
MS (decomposes under ESI conditions)
HRMS (decomposes under ESI conditions, analyzed as pyridinium adduct) calculated for
+
[
C H N] , requires m/z = 218.1909, found m/z = 218.1907 (ESI).
1
5
24
TLC (5:1) hexane/EtOAc, permanganate, R = 0.90.
f
1
Formation of pyridinium 22A from chloride 22 was monitored by H NMR, specifically by
the disappearance of the CH –Cl doublet and the formation of the CH –N doublet.
2
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5
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H NMR (CDCl with 0.6 M pyridine, 600 MHz)
δ
9.44 (d, J = 7.5 Hz, 2H, py), 8.43 (t, J =
3
7
.5 Hz, 1H, py), 8.06 (t, J = 7.5 Hz, 2H, py), 5.59 (d, J = 7.6 Hz, 2H, CH –py), 5.45 (t, J = 7.6
Hz, 1H, C=CH), 1.98 (t, J = 7.6 Hz, 2H, C=C–CH ), 1.82 (s, 3H, C=C–CH ), 1.38–1.46 (m, 1H,
CH), 1.37–1.27 (m, 2H, CH ), 1.09–1.00 (m, 2H, CH ), 0.83–0.73 (brm, 6H, CH ).
2
2
3
2
2
3
+
HRMS calculated for [C H N] , requires m/z = 218.1909, found m/z = 218.1907 (ESI).
1
5
24
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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8
9
0
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Formation of pyridinium 23A from prenyl chloride was monitored by H NMR, specifically
by the disappearance of the CH –Cl doublet and the formation of the CH –N doublet.
2
2
1
H NMR (CDCl with 0.6 M pyridine, 600 MHz)
δ
9.58 (d, J = 3.9 Hz, 2H, py), 8.54 (t, J =
3
6
.8 Hz, 1H, py), 8.18 (brt, J = 3.9 Hz, 2H, py), 5.66 (d, J = 6.5 Hz, 2H, CH –py), 5.56 (t, J = 6.8
Hz, 1H, C=CH), 1.93 (s, 3H, CH ), 1.83 (s, 3H, CH ).
2
3
3
+
HRMS calculated for [C H N] , requires m/z = 148.1126, found m/z = 148.1125 (ESI).
1
0
14
Chloride 24 ((2E,6E)ꢀ8ꢀChloroꢀ1ꢀmethoxyꢀ2,6ꢀdimethylꢀ2,6ꢀoctadiene). The general
procedure was followed using alcohol 24B (109 mg, 0.592 mmol, 1 equiv), LiCl (30 mg, 0.71
mmol, 1.2 equiv), toluene (5 mL), DMF (2.4 mL, 0.25 M), 2,6ꢀlutidine (270 µL, 2.36 mmol, 4.0
equiv), MsCl (92 µL, 1.2 mmol, 2.0 equiv), hexane (3 x 5 mL) and aqueous washes (5 mL each).
Crude chloride 24 (102 mg, 0.502 mmol, 85% crude yield, pale yellow oil), which is not
completely stable to silica gel, was assessed to be approximately 95% pure by NMR and was
1
1
1
used directly for the subsequent experiments. H NMR signals were assigned by H– H COSY
and by comparison to signals from the starting materials..
1
H NMR (CDCl , 600 MHz)
δ 5.45 (t, J = 7.9 Hz, 1H, C=CH), 5.37 (t, J = 7.0 Hz, 1H,
3
C=CH), 4.10 (d, J = 7.9 Hz, 2H, CH –Cl), 3.79 (s, 2H, CH –OMe), 3.27 (s, 3H, O–CH ), 2.18
(q, J = 7.2 Hz, 2H, C=C–CH ), 2.11 (t, J = 7.7 Hz, 2H, C=C–CH ), 1.73 (s, 3H, CH ), 1.64 (s,
2
2
3
2
2
3
3H, CH ).
3
1
3
C NMR (CDCl , 150 MHz)
δ 142.4, 132.8, 127.1, 120.8, 78.6, 57.5, 41.0, 39.2, 25.9, 16.1,
3
1
3.9.
ꢀ1
IR (neat, cm ) 2927, 1659, 1455, 1253, 1113, 1098, 844, 665.
MS (decomposes under ESI conditions)
HRMS (decomposes under ESI conditions, analyzed as pyridinium adduct) calculated for
+
[
C H ON] , requires m/z = 246.1858, found m/z = 246.1861 (ESI).
1
6
24
TLC (5:1) hexane/EtOAc, permanganate, R = 0.59.
f
Ether 24A ((2E,6E)ꢀ8ꢀMethoxyꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienyl acetate). Into a flameꢀdried flask
were added alcohol 12 (136 mg, 0.64 mmol, 1 equiv) and MeCN (1.0 mL, 0.6 M). The flask was
fitted with a rubber septum and maintained under a nitrogen atmosphere. Into the flask were
added silver oxide (296 mg, 1.28 mmol, 2.0 equiv) and then iodomethane (83 µL, 1.28 mmol,
2
.0 equiv). The flask was fit with a reflux condenser, stirred in a 45 ºC oil bath (17 h), diluted
with ethyl acetate (10 mL), filtered through a pad of Celite on silica gel, and dried with sodium
sulfate. Volatiles were removed under reduced pressure, and the crude material (157 mg, full
conversion by NMR, quantitative mass recovery) was used directly in the next step. For analysis,
an aliquot was purified by column chromatography (silica gel, 5:1 hexane / EtOAc).
1
H NMR (CDCl , 600 MHz)
δ 5.37 (t, J = 6.8 Hz, 1H, C=CH), 5.35 (t, J = 6.8 Hz, 1H,
3
C=CH), 4.59 (d, J = 6.8 Hz, 2H, CH –OAc), 3.79 (s, 2H, CH –OMe), 3.27 (s, 3H, O–CH ), 2.18
(q, J = 7.5 Hz, 2H, C=C–CH ), 2.09 (t, J = 7.5 Hz, 2H, C=C–CH ), 2.06 (s, 3H, Ac), 1.71 (s, 3H,
2
2
3
2
2
CH ), 1.64 (s, 3H, CH ).
3
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C NMR (CDCl , 150 MHz)
δ 171.2, 142.0, 132.6, 127.4, 118.6, 78.6, 61.4, 57.4, 39.2,
3
2
5.9, 21.2, 16.5, 13.9.
ꢀ1
IR (neat, cm ) 2927, 1738, 1230, 1092, 1028.
HRMS calculated for [C H O Na] , requires m/z = 249.1467, found m/z = 249.1461 (ESI).
TLC (4:1) hexane/EtOAc, permanganate, R = 0.63.
+
1
3
22
3
f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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39
40
41
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44
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59
60
Alcohol 24B ((2E,6E)ꢀ8ꢀMethoxyꢀ3,7ꢀdimethylꢀ2,6ꢀoctadienꢀ1ꢀol). Into a flask were added
crude acetate 24A (0.64 mmol, 1 equiv), MeOH (2.4 mL, 0.3 M), and potassium carbonate (28
mg, 0.21 mmol, 0.3 equiv). The mixture was stirred (24 h), quenched with potassium phosphate
monobasic (1 M aqueous, 5 mL, producing pH 5.0), and extracted with ethyl acetate (3 x 5 mL).
The combined organic phase was washed with sodium chloride (50% saturated aqueous, 5 mL),
and dried with sodium sulfate. Volatiles were removed under reduced pressure, and the crude
material was purified by column chromatography (15 mL silica gel, 1:1 hexane / EtOAc) to yield
pure alcohol 24B (92 mg, 0.50 mmol, 78%, yield from alcohol 12, colorless oil).
1
H NMR (CDCl , 600 MHz)
δ 5.42–5.34 (m, 2H, 2 x C=CH), 4.14 (d, J = 7.0 Hz, 2H, CH2–
3
OH), 3.77 (s, 2H, CH –OMe), 3.27 (s, 3H, O–CH ), 2.17 (q, J = 7.5 Hz, 2H, C=C–CH ), 2.07 (t,
2
3
2
J = 7.5 Hz, 2H, C=C–CH ), 1.67 (s, 3H, CH ), 1.63 (s, 3H, CH ), 1.52–1.48 (brs, 1H, OH).
2
3
3
1
3
C NMR (CDCl , 150 MHz)
δ 139.1, 132.4, 127.8, 123.9, 78.8, 59.4, 57.5, 39.2, 26.0, 16.3,
3
13.9.
ꢀ1
IR (neat, cm ) 3389, 2927, 1449, 1092, 999.
HRMS calculated for [C H O Na] , requires m/z = 207.1361, found m/z = 207.1357 (ESI).
+
1
1
20
2
TLC (3:1) hexane/EtOAc, permanganate, R = 0.23.
f
1
Formation of pyridinium 24C from chloride 24 was monitored by H NMR, specifically by
the disappearance of the CH –Cl doublet and the formation of the CH –N doublet.
2
2
1
H NMR (CDCl with 0.6 M pyridine, 600 MHz)
H, py), 8.01 (t, J = 7.3 Hz, 2H, py), 5.53 (d, J = 7.3 Hz, 2H, CH –py), 5.41 (t, J = 7.3 Hz, 1H,
δ
9.37 (brs, 2H, py), 8.41 (t, J = 7.3 Hz,
3
1
2
C=CH), 5.19 (brs, 1H, C=CH), 3.60 (s, 2H, CH –OMe), 3.12 (s, 3H, O–CH ), 2.05 (brs, 4H, 2 x
2
3
C=C–CH ), 1.78 (s, 3H, CH ), 1.46 (s, 3H, CH ).
2
3
3
+
HRMS calculated for [C H ON] , requires m/z = 246.1858, found m/z = 246.1861 (ESI).
1
6
24
Acknowledgements
Financial support was provided by Clark University. We would like to thank Prof. Ksenia
Bravaya and Prof. Ming Lei for helpful discussions on the computational aspects of this work.
Supporting Information
NMR spectra and results from kinetics experiments, computational methods, calculated
orbital structures and energies, NMR spectra from synthesis, atomic coordinates of computed
structures.
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