Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans by Pd-Catalyzed Tandem Oxidative Cyclization-Redox Relay Reactions Controlled by Intramolecular Hydrogen Bonding

Article abstract of DOI:10.1021/acs.joc.6b02053

Palladium-catalyzed oxidative cyclization of alkenols provides a convenient entry into cyclic ethers but typically proceeds with little or no diastereoselectivity for cyclization of trisubstituted olefins to form tetrahydrofurans due to the similar energi

Full text of DOI:10.1021/acs.joc.6b02053

Article
pubs.acs.org/joc
Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans
by Pd-Catalyzed Tandem Oxidative Cyclization−Redox Relay
Reactions Controlled by Intramolecular Hydrogen Bonding
Joshua L. Brooks,† Liping Xu,§,∥ Olaf Wiest,∥,⊥ and Derek S. Tan*,†,‡
†Chemical Biology Program and ‡Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue,
Box 422, New York, New York 10065, United States
§School of Chemical Engineering, Shandong University of Technology, Zibo 255049, China
∥Lab of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate
School, Shenzhen 518055, China
⊥Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: Palladium-catalyzed oxidative cyclization of
alkenols provides a convenient entry into cyclic ethers but
typically proceeds with little or no diastereoselectivity for
cyclization of trisubstituted olefins to form tetrahydrofurans
due to the similar energies of competing 5-membered
transition-state conformations. Herein, a new variant of this
reaction has been developed in which a PdCl2/1,4-benzoqui-
none catalyst system coupled with introduction of a hydrogen-
bond acceptor in the substrate enhances both diastereoselectiv-
ity and reactivity. Cyclization occurs with 5-exo Markovnikov
regioselectivity. Mechanistic and computational studies support an anti-oxypalladation pathway in which intramolecular hydrogen
bonding increases the nucleophilicity of the alcohol and enforces conformational constraints that enhance diastereoselectivity.
The cyclization is followed by a tandem redox-relay process that provides versatile side-chain functionalities for further derivatization.
INTRODUCTION
■
Highly substituted tetrahydrofurans are found in myriad natural
products with diverse biological activities (Figure 1).1 Among
these are the macrocyclic norcembrenoids,2 isolated from
Sinularia soft corals and exemplified by the first identified
family member, norcembrenolide (5-episinuleptolide),2a,b
which inhibits production of the proinflammatory cytokine
tumor necrosis factor-α.2i The plakortin family of polyketides,3
isolated from Plakortis marine sponges, includes plakortone
D,3a an activator of a Ca2+-pumping ATPase involved in proper
cardiac relaxation, and plakortether A,3e which exhibits selective
cytotoxicity against a macrophage-like cell line. Other examples
include squalene-derived polyethers such as venustratriol,4
an antiviral natural product isolated from Laurencia red algae,
and aplysqualenol A,5 a potent antitumor and antiviral agent
isolated from the Laurencia-consuming Caribbean sea slug
Aplysia dactylomela.
A variety of methods have been developed for the synthesis
of THFs.6 Intramolecular oxypalladation of alkenols,7,8
pioneered by Hosokawa and co-workers,9 is a particularly power-
ful method for the construction of such oxygen heterocycles.
Semmelhack later demonstrated that the resulting palladium−
alkyl intermediate can be trapped with carbon monoxide in
methanol to provide ester products (Figure 2).10 Indeed, plakor-
tone natural products have been synthesized using this approach
Figure 1. Natural products containing 1,1,4-trisubstituted tetrahy-
drofuran motifs.
via oxidative cyclization of tertiary alcohols onto 1,2-disubstituted
olefins to form the THF ring with subsequent carbonylative
Received: August 21, 2016
© XXXX American Chemical Society
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Table 1. Discovery and Optimization of Diastereoselective
a
Tandem Oxidative Cyclization−Redox Relay Reaction
Figure 2. Models of diastereocontrol in intramolecular oxypalladations
of alkenols to form 1,1,4-trisubstituted tetrahydrofurans.
lactonization to form the fused ring system.11 However, in the
converse approach, Semmelhack found that cyclization of
secondary alcohols onto 1,1-disubstituted olefins resulted, after
carbonylation, in a 1:1 mixture of diastereomers. This was attri-
buted to similar energies of the two competing 5-membered
ring reactive conformations.10
We became interested in this problem in the context of our
ongoing program on the synthesis of libraries based on under-
represented scaffolds from natural products.12 Herein, we
report a novel variant of this Pd-catalyzed oxidative cyclization
in which intramolecular hydrogen bonding provides increased
diastereoselectivity (up to 7:1 dr) in the conversion of trisub-
stituted alkenols to 1,1,4-trisubstituted THFs. The resulting
Pd−alkyl intermediate then undergoes a tandem redox-relay
reaction,13 leading to synthetically useful side chain function-
alities. A rationale for the observed diastereoselectivity is pro-
posed based on mechanistic studies and computational modeling.
The reaction accommodates a variety of substituent patterns and
chelating functionalities.
a
Reaction conditions: alkenediol 1 (1 equiv) dissolved in THF at 0.1
M was added to a mixture of catalyst (5 mol %) and oxidant (1 equiv)
and the mixture stirred at rt. Inseparable mixture of diastereomers; dr
b
determined by NMR integration of C5-H and/or C1-Me resonances;
relative stereochemistry assigned by 1D NOE and 2D NOESY
analyses.16 2 equiv of oxidant. 10 mol % of pyridine. 1 equiv of
c
d
e
f
PdCl2. Isolated as corresponding diethyl acetal of 2b. BQ = 1,4-
benzoquinone; DCE = 1,2-dichloroethane; nr = no reaction; pyr =
pyridine.
stereomers were inseparable, but the stereochemical config-
uration of the major diastereomer was assigned by extensive 1D
and 2D NMR analysis.16 Notably, none of the expected
β-hydride elimination product 2a was observed. Formation of
an aldehyde (2b) side chain, rather than an alkene (2a), in the
product suggested that the initial oxidative cyclization was
followed by a tandem redox-relay process (vide infra).
Addition of catalytic pyridine, which has been shown to
increase catalytic efficiency in Wacker oxidations,14 completely
inhibited the reaction (entry 6). Pd(PPh3)2Cl2 was also
ineffective as a catalyst, resulting in no reaction (entry 7). No
reaction was observed in the absence of 1,4-benzoquinone as a
co-oxidant, even with stoichiometric PdCl2 (entry 8). Evalu-
ation of other solvents (entries 9−13) identified THF and
toluene as the most effective with respect to both diastereo-
selectivity and yield.
With these conditions in hand, we next investigated the
scope of the tandem oxidative cyclization−redox relay reaction.
Reactions of other substituted alcohols revealed that diaster-
eoselectivity correlated positively with the steric bulk of the
cyclizing alcohol (t-Bu > Ph > isopropenyl > n-Bu > Me)
(Table 2, entries 1−4, and Table 1, entry 5), reaching 7:1 dr for
the tert-butyl-substituted substrate 4d. Ester-substituted diol 4e
also underwent efficient cyclization, albeit with diminished 2:1
diastereoselectivity (entry 5). A triol substrate 4f also cyclized
to the corresponding THF with complete regioselectivity over
RESULTS AND DISCUSSION
■
Reaction Discovery, Optimization, and Scope. In the
course of exploratory studies of metal-catalyzed cyclizations of
alkenols to access oxygen heterocycles, we discovered that
Pd(OAc)2/Cu(OAc)2-mediated oxidative cyclization9 of alkene-
diol 1 provided 1,1,4-trisubstituted THF 2a with modest
but non-zero 2:1 diastereoselectivity (Table 1, entry 1). Based
on this unexpected result, we investigated other copper
co-oxidants, but all led to either lower yields or decomposition
of starting material (data not shown). Interestingly, use of a
PdCl2/CuCl2 catalyst system led instead to 6-endo cyclization
product 3 (entry 2). Returning to Pd(OAc)2, we found that
1,4-benzoquinone (BQ) was also an effective co-oxidant (entry 3),
while use of Pd(TFA)2/BQ resulted in a much lower yield
(entry 4). Strikingly, the combination of PdCl2 and BQ resulted
in increased 6:1 diastereoselectivity, a dramatic shift in reactivity,
with aldehyde 2b isolated in excellent yield (entry 5). The dia-
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Table 2. Scope of the Diastereoselective Tandem Oxidative
Cyclization−Redox Relay Reaction
Table 3. Effects of Distal Functionalities on the
a
Diastereoselective Tandem Oxidative Cyclization−Redox
a,b
Relay Reaction
a
Reaction conditions: alkenediol 4 (1 equiv) dissolved in THF at
0.1 M was added to a mixture of PdCl2 (5 mol %) and 1,4-benzoquinone
b
(1 equiv) and the mixture stirred at rt for 8 h. Inseparable mixture of
diastereomers; dr determined by NMR integration of C5-H and/or
C1-Me resonances; relative stereochemistry assigned by 1D NOE and
c
2D NOESY analyses.16 Reaction carried out at 60 °C. na = not
applicable.
tetrahydropyran formation (entry 6), although again with lower
2:1 diastereoselectivity (cf. entry 4). Notably, tertiary alcohols
4g and 4h were unreactive at 25 °C but underwent efficient
oxidative cyclizations at 60 °C (entries 7 and 8). Variation in
chain length for the distal (noncyclizing) alcohol led to
somewhat decreased diastereoselectivies and yields (entries 9
and 10). Taken together, the observed decreases in diastereo-
selectivity in the presence of competing coordinating function-
alities and with alternative chain lengths are suggestive of a role
for the distal alcohol in transition-state organization.
a
Reaction conditions: substrate (1 equiv) dissolved in THF at 0.1 M
was added to mixture of PdCl2 (5 mol %) and 1,4-benzoquinone
(1 equiv) and the mixture stirred at 60 °C for 8 h, except as otherwise
b
noted. Inseparable mixture of diastereomers; dr determined by NMR
integration of C5-H and/or C1-Me resonances; relative stereochemistry
assigned by 1D NOE and 2D NOESY analyses.16 Heated to 80 °C in
c
d
1,4-dioxane. Reaction carried out with Pd(OAc)2 (5 mol %) and
Cu(OAc)2 (2 equiv) and stirred at rt for 8 h.
Role of the Distal Alcohol on Diastereoselectivity and
Reactivity. To gain further insights into the possible role of
the distal alcohol in the reaction, we investigated substrates
with related distal functionalities (Table 3). When the alcohol
was capped as a TBS ether in substrate 6, no reaction took
place under our standard reaction conditions or upon heating
to 60 °C (entry 1), consistent with a role for the distal alcohol
in promoting the reaction. Further heating to 80 °C in
1,4-dioxane led to substrate decomposition to form a complex
mixture. In contrast, when Hosokawa’s original Pd(OAc)2/
Cu(OAc)2 catalyst system was employed at 25 °C, the
cyclization product 7 was isolated in 2:1 dr (entry 2), identical
to the result obtained with the parent diol substrate 1 (Table 1,
entry 1). This suggests that the distal alcohol does not impact
reactivity or diastereoselectivity under Hosokawa’s classical oxi-
dative cyclization conditions.9 When the distal alcohol was
capped as a methyl ether in 8, the PdCl2/BQ reaction did
proceed at 60 °C to form aldehyde 3 in modest yield and
diastereoselectivity (Table 2, entry 3). We posit that the side-
chain aldehyde is formed as a result of the subsequent redox
relay process rather than via initial demethylation of the
substrate 8 to reform diol 1 (vide infra). Ester, carboxylic acid,
and Weinreb amide directing groups in 9−11, respectively,
were also effective under PdCl2/BQ catalysis at 60 °C, yielding
the corresponding α,β-unsaturated ester, acid, and amide products
12−14, respectively (entries 4 and 5), albeit with modest dia-
stereoselectivities.
Mechanistic Studies via Deuterium-Labeling Experi-
ments. We next evaluated structural isomers of the parent
alkene diol substrate 1 in the reaction (Figure 3). The isomeric
diol 15, in which the phenyl substituent is moved to the
noncyclizing side chain bearing the distal alcohol, also
underwent efficient cyclization with 5-exo Markovnikov regio-
selectivity to give phenyl ketone 16. To probe the mechanism
of the redox-relay process, we carried out the same reaction
with the corresponding deuterium-labeled substrate 17.
Complete deuterium transfer to the α-carbon of the ketone
in 18 was observed, consistent with a processive Pd−H migra-
tion mechanism leading directly to the carbonyl product rather
than initial formation of an enol product followed by spon-
taneous tautomerization (vide infra).13b,c
Other PdCl2-catalyzed oxypalladations have been shown to
proceed via both syn- and anti-oxypalladation pathways.15
To differentiate between these two possibilities, we synthesized
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Figure 3. Deuterium-labeling experiment to probe mechanism of side-
chain carbonyl formation.
Figure 5. Proposed models for organization of anti-oxypalladation
transition state by intramolecular hydrogen bonding (pathway A) or
Pd chelation (pathway B) by the distal (noncyclizing) alcohol followed
by tandem redox-relay reaction to generate an aldehyde side-chain
functionality.
Computational Studies. The experimental results strongly
suggest a role of the distal functionality in enhancing both
reactivity and diastereoselectivity in the reaction. Moreover,
inclusion of other potentially competing functionalities as
solvent (Table 1, entries 11−13) or in the substrate (Table 2,
entries 5 and 6, and Table 3, entries 4−6) leads to reduced
diastereoselectivity. Thus, we considered two possible mecha-
nistic hypotheses for a role of the distal hydroxyl functionality in
organizing the transition state, leading to the unusual diastereo-
selectivity of this intramolecular oxypalladation (Figure 5). In one
scenario, the distal functionality engages in an intramolecular
hydrogen-bonding interaction with the cyclizing alcohol to orga-
nize the anti-oxypalladation transition state 25 (pathway A).
Ess and co-workers have reported similar hydrogen-bonding
interactions in AuI- and PdII-catalyzed intramolecular cyclizations
of allylic alcohols.17 Alternatively, the distal functionality could
chelate the Pd to organize the transition state 26 (pathway B).
This chelation effect has been proposed to rationalize chirality
transfer in oxypalladation reactions,18 although experimental
studies on a redox-relay Heck reaction13f have excluded chelation
of the Pd. In both cases, 5-exo Markovnikov oxidative cyclization
would be followed by a redox-relay process that, based on the
deuterium-labeling experiment above (Figure 3), terminates with
β-hydride elimination across the terminal C−O bond to form the
observed aldehyde products (2b or 5) directly.13b,d
Figure 4. Deuterium-labeling experiments to differentiate between syn-
and anti-oxypalladation mechanisms.
deuterium-labeled substrates 19a and 19b and subjected them
to PdCl2/BQ-catalyzed cyclization at 60 °C to yield THFs 23a
and 23b, respectively, as single diastereomers (Figure 4 and
Figure S1).16 Relative stereochemical configurations were
assigned by hydrogenolytic cleavage of the THF ring and
conversion to cyclic acetals 24a and 24b, followed by 1H NMR
analysis of coupling constants and NOE interactions (Figure S2
and Figure S3).16 This confirmed that the α-deuterium
(adjacent to the THF ring) and C1-methyl group were syn
in 23a and anti in 23b, consistent with the intermediacy of
anti-oxypalladation intermediates 20a and 20b. In contrast, if a
syn-oxypalladation mechanism were operative, the α-deuterium
and C1-methyl group would be anti in 23a and syn in 23b,
consistent with a syn relationship between the methyl group
and the palladium in intermediate (cf. 20).
To evaluate these mechanistic hypotheses, we carried out
computational studies of the two putative reaction pathways by
calculating the stereodifferentiating (diastereomeric) transition
structures for the cyclization of alkene diol substrate 4a at
the M06/LanL2DZ+f/6-31g(d,p) level of theory.16,19 For the
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CONCLUSION
■
Several features of this unusually diastereoselective tandem
oxidative cyclization−redox relay reaction are notable. In parti-
cular, the choice of catalyst is critical to the outcome of the
reaction. First, under PdCl2/BQ catalysis herein, a hydrogen-
bond accepting distal functionality is required for the oxidative
cyclization reaction to proceed (Table 3, entry 1). In contrast,
reaction with Hosokawa’s classical Pd(OAc)2/Cu(OAc)2 catalyst
system does not require a distal hydrogen-bonding functionality
(Table 3, entry 2).
Second, under PdCl2/BQ catalysis, diastereoselectivity of the
oxidative cyclization is dependent upon tether length (Table 2,
entries 9 and 10) and the electronics of the distal functional
group (Table 3). This suggests that the distal functionality plays
a critical role in organizing the transition state, as supported by
our computational modeling studies (Figure 6). In contrast,
under Pd(OAc)2/Cu(OAc)2 catalysis, the distal functionality
does not appear to impact diastereoselectivity (Table 1, entry 1,
vs Table 3, entry 2). This suggests that the 2:1 dr observed for
oxidative cyclization of both 1 and 6 represents the inherent
diastereoselectivity of the isolated THF-forming portion of
the substrate. The 6:1 dr observed for oxidative cyclization of 1
under PdCl2/BQ catalysis then indicates the increased
diastereoselectivity attributable to the distal functionality.
Third, PdCl2/BQ catalysis herein leads to aldehyde (or
α,β-unsaturated carboxylate derivative) side chains via a puta-
tive tandem redox-relay process that follows the oxidative
cyclization reaction.13 In contrast, under Pd(OAc)2/Cu(OAc)2
catalysis, the tandem redox-relay process does not take place,
and vicinal olefin side chains are formed via immediate
β-hydride elimination of the initial alkyl-Pd intermediate
(Table 1, entry 1 vs entry 5). The lack of reinsertion of Pd−
H across the olefin in the latter case suggests rapid dissociation
of the Pd−olefin complex and short lifetime of the resulting
Pd−H species.15 This may be due to differences between the
Pd ligands in these two catalyst systems.
In conclusion, we have developed a novel variant of the
classical Pd-catalyzed oxidative cyclization of alkenols in which
use of a PdCl2/BQ catalyst system and introduction of a distal
hydrogen-bonding functionality into the substrate dramatically
change the course of the reaction. The oxidative cyclization
reaction proceeds via an anti-oxypalladation mechanism with
5-exo Markovnikov regioselectivity and a tandem redox-relay
process converts distal side chain alcohols to aldehydes or
ketones that are poised for further functionalization. In this
tandem reaction, the distal hydrogen-bonding functionality
enhances both reactivity and diastereoselectivity, and computa-
tional modeling studies suggest that this results from intro-
duction of specific conformational constraints in the transition
state. While the absolute diastereoselectivity of these reactions
ranges from moderate to high depending on substrate structure,
this transition-state organization increases diastereoselectivity
well above the intrinsic levels observed under classical Hoso-
kawa conditions that are not influenced by intramolecular
hydrogen bonding. Further investigations of the scope and
mechanism of this reaction, particularly the role of catalyst
structure, and applications to natural product and library syn-
thesis are ongoing.
Figure 6. Stereodifferentiating transition structures 25a and 25b for
the cyclization of 4a (Ln = Cl2(BQ)) with bond distances in Å.
Pd chelation model (26), attempts to locate transition struc-
tures for the direct attack of the cyclizing alcohol on the
π-coordinated palladium were not successful. This suggests that
the free hydroxyl group is not sufficiently nucleophilic to attack
the Pd−olefin complex under these conditions. In agreement
with previous work,13d,f this indicates that the distal (noncyc-
lizing) alcohol does not chelate Pd. In contrast, in the hydrogen-
bonding model (25), we were able to locate the transition
structures 25a and 25b (Figure 6). Here, the distal hydroxyl
group activates the cyclizing alcohol by an intramolecular
hydrogen bond that increases the nucleophilicity of the hydro-
xyl group by partial deprotonation. It is noteworthy that, in
contrast to the work of Ess and co-workers,17 no dehydrative
elimination is observed in our system. This is consistent with
the experimental finding that elimination of the Pd from the
carbon chain is disfavored compared to the chain-walking
redox-relay process (Figure 3). It has been shown previously in
redox-relay−Heck reactions13b,d that elimination is highly
endergonic due to the instability of Pd bound to an electron-
withdrawing ligand, suggesting a possible role for the BQ
in controlling reactivity in our system. With the elimination
pathways energetically unfavorable, the distal alcohol is
converted into an aldehyde after a series of β-hydride elimi-
nation and reinsertion chain-walking steps.13b
Consistent with the experimentally observed 2:1 dr for
oxidative cyclization of 4a (Table 2, entry 1), transition struc-
ture 25a, which leads to the anti-1,4-diastereomer 5a, was
calculated to be 0.5 kcal/mol lower in free energy than the
diastereomeric transition structure 25b.19 Importantly, these
calculated structures provide insights into the structural origin
of the observed diastereoselectivity. In the favored transition
structure 25a, the methyl group α to the cyclizing alcohol is in
a pseudoequatorial orientation relative to the forming five-
membered ring. In contrast, this α-methyl group is an unfavorable
pseudoaxial position in transition structure 25b, inducing a
1,3-diaxial steric repulsion between the α-methyl group and an
axial hydrogen atom. This is in agreement with the observation
that diastereoselectivity increases as the size of this substituent
increases (Table 2, entries 1−4). Nevertheless, the effect is
modest due to the relatively small steric differences between the
equatorial and axial positions in five-membered rings.20
EXPERIMENTAL SECTION
General Methods. All reactions were performed in flame-dried
glassware under positive Ar pressure with magnetic stirring unless
otherwise noted. Solvents were degassed with Ar and purified on a
■
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solvent drying system as described21 unless otherwise indicated. Liquid
reagents and solutions were transferred through rubber septa via
syringes flushed with Ar prior to use. Cold baths were generated as
follows: 0 °C, wet ice/water; −78 °C, dry ice/acetone.
NMR spectra were recorded on a 500 MHz NMR or 600 MHz
NMR with a DCH CryoProbe at 24 °C in CDCl3 unless otherwise
indicated. Chemical shifts are expressed in ppm relative to TMS (1H,
0 ppm) or solvent signals: CDCl3 (13C, 77.0 ppm); coupling constants
are expressed in hertz. High-resolution mass spectra were obtained
at the MSKCC Analytical Core Facility on an LC-TOF-MS by
electrospray ionization (ESI).
Ethyl (E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-enoate
(S4). In a 50 mL round-bottom flask, allylic alcohol S3 (3.00 g,
8.14 mmol), triethyl orthoacetate (15 mL), and propionic acid (60 μL,
0.81 mmol, 0.1 equiv) were added. The flask was equipped with a
distillation head and heated to 140 °C, during which time ethanol was
collected. Heating was continued at this temperature until complete
conversion had occurred as judged by TLC. The mixture was cooled
to rt and quenched with 1 M HCl (25 mL). The mixture was extracted
with Et2O (3 × 50 mL), washed with 1 M NaOH (10 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford
the crude product as a yellow oil. Purification by silica flash chroma-
tography (9:1 hexanes/EtOAc) yielded ester S4 (3.25 g, 91%) as a
colorless oil. IR (neat) (cm−1): 2956, 2858, 1735, 1445, 1428, 1156,
822, 737, 701, 649. 1H NMR (600 MHz): δ 7.67 (d, J = 6.5 Hz, 4H),
7.45−7.33 (m, 6H), 5.12 (t, J = 1.4 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H),
3.64 (t, J = 6.3 Hz, 2H), 2.37 (t, J = 6.1 Hz, 2H), 2.30−2.24 (m, 2H),
2.07 (q, J = 7.4 Hz, 2H), 1.64−1.55 (m, 5H), 1.24 (t, J = 7.1 Hz, 3H),
1.05 (s, 9H). 13C NMR (151 MHz): δ 173.5, 135.5, 134.0, 133.7,
129.5, 127.6, 124.8, 63.3, 60.2, 34.7, 33.2, 32.6, 26.8, 24.1, 19.2, 15.9,
14.3. HRMS (ESI): m/z calcd for (C27H39O3Si [M + H]+) 439.2668,
found 439.2663.
Compounds not cited explicitly in the main text are numbered from
S1 below. Detailed synthetic schemes are shown in Figures S8−S25.
1. Synthesis of Diol Substrates. 1a. Synthesis of Ester
Intermediate S4 and Aldehyde Intermediate S6. tert-Butyl(pent-4-
en-1-yloxy)diphenylsilane (S1). In a 250 mL round-bottom flask,
4-penten-1-ol (6.00 mL, 58.1 mmol) and imidazole (7.90 g, 116 mmol,
2 equiv) were dissolved in CH2Cl2 (100 mL), and the solution was
cooled to 0 °C. TBDPSCl (58.1 mL, 15.1 mmol, 1 equiv) was added
slowly with stirring. The solution was allowed to warm to rt and stirred
until complete conversion had occurred as judged by TLC. The
mixture was quenched with 1 M HCl (100 mL), extracted with
CH2Cl2 (3 × 50 mL), dried (MgSO4), filtered, and concentrated by
rotary evaporation to afford the crude product S1 as a colorless oil
(17.1 g, 91%) that was carried onto the next step without further
purification. IR (neat) (cm−1): 2929, 2857, 2337, 2271, 1671, 1015,
(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-en-1-ol (S5). In
a 250 mL round-bottom flask, ester S4 (2.00 g, 4.56 mmol) was
dissolved in THF (50 mL), and the solution was cooled to 0 °C.
LiAlH4 (173 mg, 4.56 mmol, 1 equiv) was added slowly and the
solution stirred at 0 °C until complete conversion had occurred as
judged by TLC. The mixture was carefully quenched with 1 M HCl
(25 mL). The mixture was extracted with Et2O (3 × 10 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford
the crude product as a colorless oil. Purification by silica flash chroma-
tography (4:1 hexanes/EtOAc) yielded alcohol S5 (1.80 g, 4.53 mmol,
99%) as a colorless oil. IR (neat) (cm−1): 3702−3114, 2933, 2858,
1
821, 737, 700, 614. H NMR (600 MHz): δ 7.70−7.64 (m, 4H),
7.44−7.35 (m, 6H), 5.83−5.77 (m, 1H), 5.03−4.91 (m, 2H), 3.67
(t, J = 6.4 Hz, 2H), 2.15 (q, J = 6.4, 2H), 1.66 (quint, J = 6.4, 2H), 1.05
(s, 1H). 13C NMR (151 MHz): δ 138.5, 135.6, 134.0, 129.5, 127.6,
114.5, 63.2, 31.78, 30.0, 26.8, 19.2. HRMS (ESI): m/z calcd for
(C21H29OSi [M + H]+) 325.1988, found 325.1985.
1
1589, 1470, 1428, 1107, 821, 737, 701, 612. H NMR (600 MHz): δ
4-((tert-Butyldiphenylsilyl)oxy)butanal (S2). In a 500 mL round-
bottom flask, alkene S1 (16.0 g, 49.3 mmol) was dissolved in CH2Cl2
(150 mL), and the solution was cooled to −78 °C. Ozone was bubbled
through the solution until the blue color was persistent. The stream of
ozone was replaced with oxygen until the blue color dissipated, and
then the reaction was quenched with zinc powder (16.0 g, 246 mmol,
5 equiv) in acetic acid (50 mL), allowed to slowly warm to rt, and
stirred overnight. The solution was concentrated by rotary evaporation
to afford the crude product as a yellow oil. Purification by silica flash
chromatography (9:1 hexanes/EtOAc) yielded aldehyde S2 (15.3 g,
46.7 mmol, 95%) as a colorless oil. IR (neat) (cm−1): 2936, 2862,
7.70−7.64 (m, 4H), 7.45−7.34 (m, 6H), 5.14 (t, J = 7.3 Hz, 1H), 3.65
(t, J = 6.4 Hz, 2H), 3.61 (t, J = 6.5 Hz, 2H), 2.08 (q, J = 7.4 Hz, 2H),
2.04 (t, J = 7.3, 2H), 1.69−1.58 (m, 5H), 1.27 (s, 3H), 1.05 (s, 9H).
13C NMR (151 MHz): δ 135.6, 135.0, 134.1, 129.5, 127.6, 124.6, 63.4,
62.8, 35.9, 32.7, 30.7, 26.8, 24.2, 19.2, 15.8. HRMS (ESI): m/z calcd
for (C25H37O2Si [M + H]+) 397.2563, found 397.2558.
(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-enal (S6). In a
250 mL round-bottom flask, alcohol S5 (1.85 g, 4.66 mmol) was
dissolved in CH2Cl2 (100 mL), and PCC (2.01 g, 9.33 mmol, 2 equiv)
was added. The solution was stirred at rt until complete conversion
had occurred as judged by TLC. The mixture was filtered through a
pad of silica with hexane/EtOAc 9:1 and concentrated by rotary
evaporation to afford aldehyde S6 (1.42 g, 3.60 mmol, 77%) as a
colorless oil. IR (neat) (cm−1): 2931, 2858, 1725, 1427, 1106, 822,
738, 701, 612. 1H NMR (600 MHz): δ 9.73 (t, J = 1.9 Hz, 1H), 7.69−
7.64 (m, 4H), 7.44−7.34 (m, 6H), 5.12 (t, J = 7.3 Hz, 1H), 3.64 (t, J =
6.3 Hz, 2H), 2.48 (td, J = 7.6, 1.9 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H),
2.08 (q, J = 7.3 Hz, 2H), 1.62−1.55 (m, 5H), 1.05 (s, 9H). 13C NMR
(151 MHz, CDCl3): δ 202.7, 135.6, 134.0, 133.3, 129.5, 127.6, 125.2,
63.3, 42.2, 32.5, 31.8, 26.8, 24.2, 19.2, 16.0. HRMS (ESI): m/z calcd
for (C25H34O2NaSi [M + Na]+) 417.2226, found 417.2212.
1b. Synthesis of Diol Substrates 1 and 4a-d from Aldehyde
Intermediate S6. (E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-
phenyloct-4-en-1-ol (S7). In a 25 mL round-bottom flask, aldehyde
S6 (200 mg, 0.51 mmol) was dissolved in THF (5 mL), and the
solution was cooled to 0 °C. PhMgBr (1.0 M in THF, 0.61 mL,
0.61 mmol, 1.2 equiv) was added dropwise with stirring. Once addi-
tion was complete, the solution was allowed to warm to rt, and stirring
was continued until complete conversion had occurred as judged by
TLC. The mixture was quenched with 1 M HCl (5 mL), extracted
with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by
rotary evaporation to afford the crude product as a yellow oil.
Purification by silica flash chromatography (4:1 hexanes/EtOAc)
yielded benzylic alcohol S7 (211 mg, 0.45 mmol, 88%) as a colorless
oil. IR (neat) (cm−1): 3683−3118, 3068, 2931, 2857, 1427, 1106, 821,
737, 699, 612. 1H NMR (600 MHz): δ 7.68−7.64 (m, 4H), 7.42−7.30
(m, 11H), 5.12 (t, J = 7.0 Hz, 1H), 4.62 (dd, J = 7.8, 5.3 Hz, 1H),
1
1729, 1431, 1112, 944, 826, 743, 706, 616. H NMR (600 MHz): δ
9.79 (s, 1H), 7.65 (d, J = 6.5 Hz, 4H), 7.46−7.33 (m, 6H), 3.69 (t, J =
6.0 Hz, 4H), 2.55 (t, J = 1.7 Hz, 2H), 1.89 (quint., J = 6.0 Hz, 2H),
1.04 (s, 15H). 13C NMR (151 MHz): δ 202.5, 135.5, 133.5, 129.7,
127.7, 62.9, 40.7, 26.8, 25.2, 19.2. HRMS (ESI): m/z calcd for
(C20H27O2Si [M + H]+) 327.1780, found 327.1769.
6-((tert-Butyldiphenylsilyl)oxy)-2-methylhex-1-en-3-ol (S3). In a
500 mL round-bottom flask, aldehyde S2 (15.3 g, 49.3 mmol) was
dissolved in THF (100 mL), and the solution was cooled to 0 °C.
Isopropenylmagnesium bromide (1.0 M in THF, 93.5 mL, 46.7 mmol,
1 equiv) was added slowly via an addition funnel. Once addition was
complete, the cooling bath was removed, and the solution was allowed
to stir at rt until complete conversion had occurred as judged by TLC.
The mixture was recooled to 0 °C and quenched with 1 M HCl
(100 mL). The mixture was extracted with Et2O (3 × 50 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford
the crude product as a yellow oil. Purification by silica flash
chromatography (4:1 hexanes/EtOAc) yielded allylic alcohol S3
(16.1 g, 43.7 mmol, 93%) as a yellow oil. IR (neat) (cm−1): 3690−
1
3147, 2936, 2862, 1431, 1111, 1001, 741, 704, 616. H NMR (600
MHz): δ 7.69−7.63 (m, 4H), 7.43−7.33 (m, 6H), 4.94 (s, 1H), 4.83
(s, 1H), 4.06 (t, J = 6.4 Hz, 1H), 3.73−3.59 (m, 2H), 2.20 (s, 1H),
1.72 (s, 3H), 1.67−1.55 (m, 4H), 1.06 (s, 9H). 13C NMR (151 MHz,
CDCl3): δ 147.4, 135.5, 133.7, 129.6, 127.6, 110.9, 75.5, 63.9,
31.7, 28.5, 26.8, 19.2, 17.7. HRMS (ESI): m/z calcd for (C23H33O2Si
[M + H]+) 369.2250, found 369.2242.
F
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Article
3.65 (t, J = 6.4 Hz, 2H), 2.11−2.04 (m, 3H), 2.02−1.95 (m, 1H),
1.91−1.81 (m, 1H), 1.81−1.74 (m, 1H), 1.62−1.55 (m, 5H), 1.05 (s,
9H). 13C NMR (151 MHz): δ 144.7, 135.5, 134.9, 134.0, 129.5, 128.4,
127.5, 127.4, 125.9, 124.6, 74.3, 63.4, 37.2, 35.9, 32.6, 26.8, 24.1, 19.2,
16.0. HRMS (ESI): m/z calcd for (C31H40O2NaSi [M + Na]+)
495.2695, found 495.2681.
(E)-4-Methyl-1-phenyloct-4-ene-1,8-diol (1). In a 10 mL round-
bottom flask, protected alcohol S7 (200 mg, 0.42 mmol) was dissolved
in THF (4 mL) at rt. TBAF (1.0 M in THF, 0.85 mL, 0.85 mmol,
2 equiv) was added, and the solution was stirred until complete
conversion had occurred as judged by TLC. The reaction mixture was
concentrated by rotary evaporation. Purification by silica flash
chromatography (1:1 hexanes/EtOAc) yielded diol 1 (96 mg,
0.41 mmol, 97%) as a colorless oil. IR (neat) (cm−1): 3715−3092,
2932, 2864, 1720, 1496, 1059, 1033, 765, 703. 1H NMR (600 MHz): δ
7.29−7.24 (m, 4H), 7.22−7.18 (m, 1H), 5.10 (t, J = 7.0, 1H), 4.56
(dd, J = 7.8, 5.3 Hz, 1H), 3.54 (t, J = 6.5 Hz, 2H), 2.08−1.90 (m, 1H),
1.85−1.78 (m, 1H), 1.77−1.70 (m, 1H), 1.57−1.49 (m, 5H). 13C
NMR (151 MHz): δ 144.8, 135.4, 128.4, 127.5, 125.9, 124.3, 74.3,
62.7, 37.2, 36.0, 32.7, 24.3, 16.0. HRMS (ESI): m/z calcd for
(C14H20O2Na [M + Na]+) 243.1361, found 243.1363.
1.65−1.52 (m, 7H), 1.52−1.37 (m, 3H), 1.37−1.24 (m, 3H), 1.05 (s,
9H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 135.9,
135.5, 135.4, 134.1, 129.5, 127.6, 71.9, 63.4, 37.1, 36.0, 35.4, 32.7, 27.8,
26.8, 24.2, 22.8, 19.2, 15.9, 14.1. HRMS (ESI): m/z calcd for
(C29H45O2Si [M + H]+) 453.3189, found 453.3180.
(E)-5-Methyldodec-4-ene-1,8-diol (4b). In a 10 mL round-bottom
flask, protected alcohol S9 (100 mg, 0.22 mmol) was dissolved in THF
(2 mL) at rt. TBAF (1.0 M in THF, 0.44 mL, 0.44 mmol, 2 equiv) was
added, and the solution was stirred until complete conversion had
occurred as judged by TLC. The reaction mixture was concentrated
by rotary evaporation. Purification by silica flash chromatography
(1:1 hexanes/EtOAc) yielded diol 4b (29 mg, 0.17 mmol, 92%) as a
colorless oil. IR (neat) (cm−1): 3686−3076, 2860, 1378, 1055.
1H NMR (600 MHz): δ 5.21 (t, J = 7.2 Hz, 1H), 3.65 (t, J = 6.5 Hz,
2H), 3.61−3.55 (m, 1H), 2.19−2.02 (m, 4H), 1.65−1.55 (m, 7H),
1.54−1.37 (m, 3H), 1.37−1.27 (m, 3H), 0.91 (t, J = 7.1 Hz, 3H).
13C NMR (151 MHz): δ 135.9, 124.1, 71.9, 62.7, 37.2, 36.0, 35.4, 32.7,
27.8, 24.3, 22.8, 16.0, 14.1. HRMS (ESI): m/z calcd for (C13H26O2Na
[M + Na]+) 237.1831, found 237.1828.
(E)-10-((tert-Butyldiphenylsilyl)oxy)-2,6-dimethyldeca-1,6-dien-3-
ol (S10). In a 25 mL round-bottom flask, aldehyde S6 (100 mg,
0.25 mmol) was dissolved in THF (5 mL), and the solution was
cooled to 0 °C. Isopropenylmagnesium bromide (0.5 M in THF,
0.61 mL, 0.30 mmol, 1.2 equiv) was added dropwise with stirring.
Once addition was complete, the solution was allowed to warm to rt,
and stirring was continued until complete conversion had occurred as
judged by TLC. The mixture was quenched with 1 M HCl (5 mL),
extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and
concentrated by rotary evaporation to afford the crude product as a
yellow oil. Purification by silica flash chromatography (4:1 hexanes/
EtOAc) yielded allylic alcohol S10 (98 mg, 0.22 mmol, 88%) as a
colorless oil. IR (neat) (cm−1): 3660−3157, 2932, 2858, 1380, 1106,
899, 822, 736, 701, 612. 1H NMR (600 MHz): δ 7.68−7.65 (m, 4H),
7.43−7.35 (m, 6H), 5.14 (t, J = 7.2, 1H), 4.93 (s, 1H), 4.84 (s, 1H),
4.03 (dd, J = 7.4, 5.5 Hz, 1H), 3.65 (t, J = 6.4 Hz, 2H), 2.08 (q, J = 7.5
Hz, 2H), 2.06−2.01 (m, 1H), 2.01−1.94 (m, 1H), 1.72 (t, J = 1.2 Hz,
3H), 1.65−1.56 (m, 7H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3):
δ 147.5, 135.6, 135.0, 134.1, 129.5, 127.6, 124.5, 111.0, 75.7, 63.4, 35.7,
33.2, 32.7, 26.8, 24.2, 19.2, 17.6, 16.0. HRMS (ESI): m/z calcd for
(C28H40O2SiNa [M + Na]+) 459.2695, found 459.2710.
(E)-5,9-Dimethyldeca-4,9-diene-1,8-diol (4c). In a 10 mL round-
bottom flask, protected alcohol S10 (100 mg, 0.23 mmol) was
dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.46 mL,
0.46 mmol, 2 equiv) was added, and the solution was stirred until
complete conversion had occurred as judged by TLC. The reaction
mixture was concentrated by rotary evaporation. Purification by silica
flash chromatography (1:1 hexanes/EtOAc) yielded diol 4c (40 mg,
0.20 mmol, 88%) as a colorless oil. IR (neat) (cm−1): 3667−3128,
2937, 2866, 1444, 1375, 1058, 899, 732. 1H NMR (600 MHz): δ 5.20
(t, J = 7.1 Hz, 1H), 4.94 (s, 1H), 4.84 (s, 1H), 4.04 (t, J = 6.2 Hz, 1H),
3.64 (t, J = 6.5 Hz, 2H), 2.11−2.04 (m, 3H), 2.03−1.96 (m, 1H), 1.73
(s, 3H), 1.71−1.57 (m, 7H). 13C NMR (151 MHz, CDCl3): δ 147.5,
135.5, 124.2, 111.0, 75.6, 62.7, 35.7, 33.1, 32.7, 24.3, 17.6, 16.0. HRMS
(ESI): m/z calcd for (C12H22O2Na [M + Na]+) 221.1517, found
221.1524.
(E)-9-((tert-Butyldiphenylsilyl)oxy)-5-methylnon-5-en-2-ol (S8). In
a 25 mL round-bottom flask, aldehyde S6 (100 mg, 0.25 mmol) was
dissolved in THF (5 mL), and the solution was cooled to 0 °C.
MeMgBr (1.0 M in THF, 0.30 mL, 0.30 mmol, 1.2 equiv) was added
dropwise with stirring. Once addition was complete, the solution
was allowed to warm to rt, and stirring was continued until com-
plete conversion had occurred as judged by TLC. The mixture was
quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL),
dried (MgSO4), filtered, and concentrated by rotary evaporation to
afford the crude product as a yellow oil. Purification by silica flash
chromatography (4:1 hexanes/EtOAc) yielded alcohol S8 (102 mg,
0.25 mmol, 98%) as a colorless oil. IR (neat) (cm−1): 3660−3131,
1
2930, 2858, 1469, 1427, 1106, 821, 735, 700, 612. H NMR (600
MHz): δ 7.67 (d, J = 6.8 Hz 4H), 7.44−7.34 (m, 6H), 5.15 (t, J = 7.3
Hz, 1H), 3.76 (q, J = 6.2 Hz, 1H), 3.65 (t, J = 6.3 Hz, 2H), 2.12−1.98
(m, 4H), 1.63−1.67 (m, 4H), 1.56−1.47 (m, 1H), 1.18 (d, J = 6.2 Hz,
3H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 135.6, 135.3,
134.1, 129.5, 127.6, 124.4, 68.0, 63.4, 37.3, 36.1, 32.7, 26.8, 24.2, 23.4,
19.2, 15.9. HRMS (ESI): m/z calcd for (C26H39O2Si [M + H]+)
411.2719, found 411.2719.
(E)-5-Methylnon-4-ene-1,8-diol (4a). In a 10 mL round-bottom
flask, protected alcohol S8 (75 mg, 0.18 mmol) was dissolved in THF
(2 mL) at rt. TBAF (1.0 M in THF, 0.37 mL, 0.37 mmol, 2 equiv) was
added, and the solution was stirred until complete conversion had
occurred as judged by TLC. The reaction mixture was concentrated
by rotary evaporation. Purification by silica flash chromatography
(1:1 hexanes/EtOAc) yielded diol 4a (29 mg, 0.17 mmol, 92%) as a
colorless oil. IR (neat) (cm−1): 3667−3095, 2967, 2933, 2886, 1452,
1
1378, 1132, 1061, 737. H NMR (600 MHz): δ 5.20−5.18 (m, 1H),
3.78 (sextet, J = 6.2 Hz, 1H), 3.63 (t, J = 6.5 Hz, 2H), 2.14−2.01 (m,
4H), 1.92 (s, 2H), 1.66−1.50 (m, 7H), 1.19 (d, J = 6.2 Hz, 3H). 13C
NMR (151 MHz): δ 135.7, 124.2, 68.0, 62.6, 37.2, 36.1, 32.6, 24.3,
23.4, 15.9. HRMS (ESI): m/z calcd for (C10H20O2Na [M + Na]+)
195.1361, found 195.1357.
(E)-10-((tert-Butyldiphenylsilyl)oxy)-2,2,6-trimethyldec-6-en-3-ol
(S11). In a 25 mL round-bottom flask, aldehyde S6 (100 mg,
0.25 mmol) was dissolved in THF (5 mL) and the solution was cooled
to 0 °C. tBuMgBr (1.6 M in THF, 0.19 mL, 0.30 mmol, 1.2 equiv) was
added dropwise with stirring. Once addition was complete, the
solution was allowed to warm to rt, and stirring was continued until
complete conversion had occurred as judged by TLC. The mixture was
quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL),
dried (MgSO4), filtered, and concentrated by rotary evaporation to
afford the crude product as a yellow oil. Purification by silica flash
chromatography (4:1 hexanes/EtOAc) yielded alcohol S11 (109 mg,
0.24 mmol, 95%) as a colorless oil. IR (neat) (cm−1): 3677−3211,
(E)-12-((tert-Butyldiphenylsilyl)oxy)-8-methyldodec-8-en-5-ol
(S9). In a 25 mL round-bottom flask, aldehyde S6 (100 mg,
0.25 mmol) was dissolved in THF (5 mL), and the solution was
cooled to 0 °C. nBuLi (2.5 M in hexanes, 0.12 mL, 0.30 mmol,
1.2 equiv) was added dropwise with stirring. Once addition was
complete, the solution was allowed to warm to rt, and stirring was
continued until complete conversion had occurred as judged by TLC.
The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O
(3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary
evaporation to afford the crude product as a yellow oil. Purification by
silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S9
(108 mg, 0.24 mmol, 94%) as a colorless oil. IR (neat) (cm−1): 3683−
1
1
3120, 2930, 2858, 1428, 1106, 1004, 822, 701, 612. H NMR (600
1471, 1428, 1107, 822, 737, 701, 612. H NMR (600 MHz): δ 7.67
MHz): δ 7.69−7.65 (m, 4H), 7.44−7.33 (m, 6H), 5.15 (t, J = 7.1 Hz,
1H), 3.66 (t, J = 6.3 Hz, 2H), 3.60−3.54 (m, 1H), 2.16−1.98 (m, 4H),
(d, J = 6.5 Hz, 4H), 7.44−7.34 (m, 6H), 5.18 (t, J = 6.4 Hz, 1H),
3.66 (t, J = 6.3 Hz, 2H), 3.16 (d, J = 10.5 Hz, 1H), 2.24−2.19 (m, 1H),
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2.09 (q, J = 7.4 Hz, 2H), 2.05−1.97 (m, 1H), 1.66−1.53 (m, 7H),
1.38−1.29 (m, 1H), 1.05 (s, 9H), 0.89 (s, 9H). 13C NMR (151 MHz):
δ 135.6, 135.5, 134.1, 129.5, 127.5, 124.5, 79.6, 63.4, 37.2, 34.9, 32.7,
29.5, 26.8, 25.7, 24.2, 19.2, 15.9. HRMS (ESI): m/z calcd for
(C29H45O2Si [M + H]+) 453.3189, found 453.3184.
The combined organic layers were washed with H2O (2 × 20 mL) and
brine (20 mL), dried (MgSO4), filtered, and concentrated by rotary
evaporation to afford the crude product as a colorless oil. Purification
by silica flash chromatography (9:1 hexanes/EtOAc) yielded diester
S13 (1.86 g, 6.93 mmol, 75%) as a yellow oil. IR (neat) (cm−1): 2956,
2917, 1737, 1437, 1338, 1272, 1237, 1201, 1150, 1026, 687. 1H NMR
(600 MHz): δ 5.06 (q, J = 6.7 Hz, 2H), 3.73 (s, 6H), 3.38 (t, J =
7.7 Hz, 1H), 2.61 (t, J = 7.5 Hz, 2H), 2.04 (t, 2H), 1.98 (d, J = 6.2 Hz,
1H), 1.67 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H). 13C NMR (151 MHz): δ
169.6, 166.9, 138.7, 131.5, 124.0, 119.4, 52.6, 52.4, 51.9, 41.1, 39.7,
27.6, 26.5, 25.7, 17.7, 16.0. HRMS (ESI): m/z calcd for (C15H24O4Na
[M + Na]+) 291.1572, found 291.1521.
(E)-5,9,9-Trimethyldec-4-ene-1,8-diol (4d). In a 10 mL round-
bottom flask, protected alcohol S11 (100 mg, 0.22 mmol) was
dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.44 mL, 0.44
mmol, 2 equiv) was added, and the solution was stirred until complete
conversion had occurred as judged by TLC. The reaction mixture was
concentrated by rotary evaporation. Purification by silica flash
chromatography (1:1 hexanes/EtOAc) yielded diol 4d (37 mg,
0.17 mmol, 78%) as a colorless oil. IR (neat) (cm−1): 3673−3092,
2951, 2889, 1711, 1445, 1364, 1062, 1010, 911, 733. 1H NMR
(600 MHz): δ 5.27−5.19 (m, 1H), 3.65 (dt, J = 79.9, 6.5 Hz, 2H),
3.17 (d, J = 9.0 Hz, 1H), 2.28−2.21 (m, 1H), 2.13−2.01 (m, 3H),
1.68−1.60 (m, 6H), 1.51 (s, 1H), 1.42 (s, 1H), 1.38−1.30 (m, 1H),
0.90 (s 9H). 13C NMR (151 MHz): δ 135.9, 124.2, 79.6, 62.5, 37.2,
34.9, 32.7, 29.5, 25.8, 24.3, 15.9. HRMS (ESI): m/z calcd for
(C13H26O2Na [M + H]+) 237.1831, found 237.1832.
1c. Synthesis of Diol Substrate 4e from Aldehyde intermediate
S6. Ethyl (E)-10-((tert-Butyldiphenylsilyl)oxy)-3-hydroxy-6-methyl-
dec-6-enoate (S12). In a 25 mL round-bottom flask, LDA was freshly
prepared in THF (2 mL) at 0 °C from diisopropylamine (54 μL,
0.38 mmol, 1.5 equiv) and nBuLi (2.5 M in hexane, 0.15 mL,
0.38 mmol, 1.5 equiv). The flask was cooled to −78 °C, and EtOAc
(50 μL, 0.38 mmol, 2 equiv) as a solution in THF (0.5 mL) was added
dropwise with stirring. The solution was stirred at −78 °C for 30 min,
and aldehyde S6 (100 mg, 0.25 mmol) was added as a solution in THF
(1 mL). Stirring was continued until complete conversion had
occurred as judged by TLC. The mixture was quenched at −78 °C
with the addition of satd aq NH4Cl (5 mL). The mixture was extracted
with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by
rotary evaporation to afford the crude product as a yellow oil.
Purification by silica flash chromatography (4:1 hexanes/EtOAc)
yielded S12 (120 mg, 0.25 mmol, 98%) as a yellow oil. IR (neat)
(cm−1): 3712−3113, 2932, 2858, 1723, 1427, 1185, 1106, 821, 734,
701, 612. 1H NMR (600 MHz): δ 7.67 (d, J = 6.6 Hz, 4H), 7.45−7.33
(m, 6H), 5.14 (t, 7.2 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4,00−3.95 (m,
1H), 3.65 (t, J = 6.2 Hz, 2H), 2.99 (s, 1H), 2.49 (dd, J = 16.3, 3.3 Hz,
1H), 2.41 (dd, J = 16.3, 8.9 Hz, 1H), 2.18−2.00 (m, 4H), 1.63−1.55
(m, 6H), 1.55−1.48 (m, 1H), 1.27 (t, J = 7.2 Hz, 2H), 1.05 (s, 9H).
13C NMR (151 MHz, CDCl3): δ 173.0, 135.5, 134.8, 134.0, 129.5,
Methyl (E)-5,9-Dimethyldeca-4,8-dienoate (S14). In a 50 mL
round-bottom flask, LiCl (750 mg, 17.7 mmol, 5 equiv) was added,
followed by a solution of diester S13 (950 mg, 3.54 mmol) dissolved
in DMSO (15 mL). The solution was heated to 150 °C until complete
conversion had occurred as judged by TLC. The mixture was diluted
with H2O (20 mL) and extracted with Et2O (3 × 20 mL). The
combined organic layers were washed with H2O (20 mL) and brine
(20 mL), dried (MgSO4), filtered, and concentrated by rotary
evaporation to afford the crude product as a colorless oil. Purification
by silica flash chromatography (9:1 hexanes/EtOAc) yielded ester S14
(725 mg, 3.45 mmol, 97%) as a yellow oil. IR (neat) (cm−1): 2919,
1
1739, 1437, 1162. H NMR (500 MHz): δ 5.14−5.03 (m, 2H), 3.67
(s, 3H), 2.38−2.28 (m, 4H), 2.11−2.02 (m, 2H), 1.98 (t, J = 8.9 Hz,
2H), 1.68 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 173.8, 136.7, 131.4, 124.1, 122.2, 51.4, 39.6, 34.3, 26.6, 25.6,
23.5, 17.7, 15.9. HRMS (ESI): m/z calcd for (C13H22O2Na [M +
Na]+) 233.1517, found 233.1515.
(E)-5,9-Dimethyldeca-4,8-dien-1-ol (S15). In a 100 mL round-
bottom flask, ester S14 (700 mg, 3.33 mmol) was dissolved in THF
(50 mL), and the solution was cooled to 0 °C. LiAlH4 (126 mg,
3.33 mmol, 1 equiv) was added slowly and the solution stirred at 0 °C
until complete conversion had occurred as judged by TLC. The
mixture was carefully quenched with 1 M HCl (25 mL). The mixture
was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and
concentrated by rotary evaporation to afford the crude product as a
colorless oil. Purification by silica flash chromatography (4:1 hexanes/
EtOAc) yielded S15 (580 mg, 3.18 mmol, 96%) as a colorless oil.
IR (neat) (cm−1): 3699−3125, 2924, 1723, 1449, 1379, 1055, 909,
1
732. H NMR (600 MHz): δ 5.14 (t, J = 6.4 Hz, 1H), 5.09 (t, J =
5.8 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.12−2.04 (m, 4H), 1.99 (d, J =
6.3 Hz, 2H), 1.68 (s, 3H), 1.65−1.59 (m, 8H). 13C NMR (151 MHz):
δ 135.8, 131.4, 124.3, 123.8, 68.0, 62.7, 39.7, 32.7, 26.6, 25.7,
25.7, 25.6, 24.3, 17.7, 16.0. HRMS (ESI): m/z calcd for (C12H23O
[M + H]+) 183.1749, found 183.1751.
127.6, 124.6, 67.8, 63.4, 60.6, 41.3, 35.6, 34.7, 32.7, 26.8, 24.2, 19.2,
15.9, 14.2. HRMS (ESI): m/z calcd for (C29H42O4NaSi [M + H]+)
505.2750, found 505.2746.
Ethyl (E)-3,10-Dihydroxy-6-methyldec-6-enoate (4e). In a 10 mL
round-bottom flask, protected alcohol S12 (75 mg, 0.16 mmol) was
dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.31 mL,
0.31 mmol, 2 equiv) was added, and the solution was stirred until
complete conversion had occurred as judged by TLC. The reaction
mixture was concentrated by rotary evaporation. Purification by silica
flash chromatography (1:1 hexanes/EtOAc) yielded diol 4e (33 mg,
0.14 mmol, 86%) as a colorless oil. IR (neat) (cm−1): 3640−3131,
2931, 1721, 1375, 1299, 1185, 1156, 1031, 879, 731. 1H NMR
(600 MHz): δ 5.20 (t, J = 7.3 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.03−
3.94 (m, 1H), 3.64 (t, J = 6.5 Hz, 2H), 3.03 (s, 1H), 2.55−2.37
(m, 2H), 2.18−2.11 (m, 1H), 2.08 (q, J = 7.0 Hz, 3H), 1.67−1.59
(m, 7H), 1.58−1.49 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz): δ 173.0, 135.2, 124.4, 67.7, 62.6, 60.7, 41.3, 35.6, 34.6,
32.6, 24.3, 15.9, 14.2. HRMS (ESI): m/z calcd for (C13H24O4Na
[M + Na]+) 267.1572, found 267.1568.
1d. Synthesis of Triol Substrate 4f from Geranyl Bromide.
Dimethyl (E)-2-(3,7-Dimethylocta-2,6-dien-1-yl)malonate (S13). In
a 100 mL round-bottom flask, K2CO3 (2.55 g, 18.4 mmol, 2 equiv)
was added, followed by a solution of geranyl bromide (2.00 g,
9.21 mmol) dissolved in DMF (40 mL). Dimethyl malonate (1.27 mL,
11.1 mmol, 1.2 equiv) was added and the solution stirred at rt until
complete conversion had occurred as judged by TLC. The mixture
was diluted with H2O (50 mL) and extracted with Et2O (3 × 20 mL).
(S,E)-5,9-Dimethyldec-4-ene-1,8,9-triol (4f). In a 100 mL round-
bottom flask, diene S15 (500 mg, 2.74 mmol) was dissolved in
t-BuOH/H2O (1:1, 50 mL), and the solution was cooled to 0 °C. AD
mix-α (3.85 g, 1.4 g/mol) was added, and the solution was stirred at
0 °C until complete conversion had occurred as judged by TLC.
The reaction was diluted with H2O (50 mL) and extracted with Et2O
(3 × 25 mL), and the organic layers were pooled washed with 10%
HCl (10 mL), brine (10 mL), and dried (MgSO4), filtered, and con-
centrated by rotary evaporation to afford the crude product as a
colorless oil. Purification by silica flash chromatography (1:1 hexanes/
EtOAc) yielded 4f (220 mg, 1.02 mmol, 37%) as a colorless oil. IR
(neat) (cm−1): 3682−3112, 2932, 2858, 1739, 1384, 1108, 821, 737,
700, 612. 1H NMR (600 MHz): δ 5.24 (d, J = 6.8 Hz, 1H), 3.66 (t, J =
6.5 Hz, 2H), 3.38−3.32 (m, 1H), 2.30−2.21 (m, 2H), 2.14−2.03
(m, 4H), 1.70−1.55 (m, 8H), 1.47−1.36 (m, 1H), 1.21 (s, 3H), 1.16
(s, 3H). 13C NMR (151 MHz): δ 124.6, 78.2, 73.0, 62.7, 36.8, 32.6,
29.6, 26.4, 24.3, 23.2, 15.9. HRMS (ESI): m/z calcd for (C12H24O3Na
[M + Na]+) 239.1623, found 239.1615.
1e. Synthesis of Diol Substrates 4g,h from Ester Intermediate S4.
(E)-9-((tert-Butyldiphenylsilyl)oxy)-2,5-dimethylnon-5-en-2-ol (S16).
In a 25 mL round-bottom flask, ester S4 (200 mg, 0.46 mmol) was
dissolved in THF (5 mL), and the solution was cooled to 0 °C.
MeMgBr (1.0 M in THF, 1.00 mL, 1.00 mmol, 2.2 equiv) was added
dropwise with stirring. Once addition was complete, the solution was
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Article
allowed to warm to rt, and stirring was continued until complete
conversion had occurred as judged by TLC. The mixture was
quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL),
dried (MgSO4), filtered, and concentrated by rotary evaporation to
afford the crude product as a yellow oil. Purification by silica flash
chromatography (4:1 hexanes/EtOAc) yielded alcohol S16 (110 mg,
0.45 mmol, 98%) as a colorless oil. IR (neat) (cm−1): 3695−3115,
2965, 2936, 2862, 1473, 1431, 1110, 912, 826, 736, 705, 616. 1H NMR
(600 MHz): δ 7.67 (d, J = 6.8 Hz, 4H), 7.45−7.33 (m, 6H), 5.15
(d, J = 5.7 Hz, 1H), 3.65 (t, J = 6.3 Hz, 2H), 2.11−1.99 (m, 4H),
1.64−1.57 (m, 5H), 1.57−1.51 (m, 2H), 1.34 (s, 1H), 1.22 (s, 8H),
1.05 (d, J = 2.2 Hz, 9H). 13C NMR (151 MHz): δ 135.7, 135.6, 129.5,
127.6, 124.1, 71.1, 63.4, 42.0, 34.4, 32.6, 29.2, 26.8, 24.2, 19.2, 16.1.
HRMS (ESI): m/z calcd for (C27H41O2Si [M + H]+) 425.2876, found
425.2876.
(E)-5,8-Dimethylnon-4-ene-1,8-diol (4g). In a 10 mL round-
bottom flask, protected alcohol S22 (180 mg, 0.42 mmol) was
dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.85 mL,
0.85 mmol, 2 equiv) was added, and the solution was stirred until
complete conversion had occurred as judged by TLC. The reaction
mixture was concentrated by rotary evaporation. Purification by silica
flash chromatography (1:1 hexanes/EtOAc) yielded diol 4g (55 mg,
0.30 mmol, 69%) as a colorless oil. IR (neat) (cm−1): 3727−3067,
2884, 1657, 1321, 1189, 1123, 1060, 966, 925. 1H NMR (600 MHz): δ
5.20 (t, J = 7.2 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.13−2.04 (m, 4H),
1.64 (s, 3H), 1.63−1.60 (m, 2H), 1.60−1.55 (m, 2H), 1.23 (s, 6H).
13C NMR (151 MHz, CDCl3): δ 136.2, 123.8, 71.1, 62.6, 41.9, 34.5,
and stirred until complete conversion had occurred as judged by TLC.
The mixture was quenched with 1 M HCl (10 mL) and extracted with
CH2Cl2 (3 × 10 mL), dried (MgSO4), filtered, and concentrated by
rotary evaporation to afford the crude product as a colorless oil
(4.24 g, 98%) that was taken onto the next step without further
purification. IR (neat) (cm−1): 2928, 2361, 1558, 1427, 1105, 822,
737, 700, 613. 1H NMR (600 MHz): δ 7.76−7.62 (m, 4H), 7.48−7.31
(m, 6H), 5.91−5.76 (m, 1H), 5.10−4.97 (m, 2H), 3.71 (t, J = 6.7 Hz,
2H), 2.32 (q, J = 7.1, 6.3 Hz, 2H), 1.05 (s, 9H). 13C NMR
(151 MHz): δ 135.6, 135.4, 133.9, 129.5, 127.6, 116.3, 63.5, 37.2, 26.8,
19.2. HRMS (ESI): m/z calcd for (C20H27OSi [M + H]+) 311.1831,
found 311.1821.
3-((tert-Butyldiphenylsilyl)oxy)propanal (S19). In a 250 mL
round-bottom flask, alkene S18 (1.50 g, 4.83 mmol) was dissolved
in CH2Cl2 (50 mL), and the solution was cooled to −78 °C. Ozone
was bubbled through the solution until the blue color was persistent.
The stream of ozone was replaced with oxygen until the blue color
dissipated, and then the reaction was quenched with triphenylphos-
phine (1.58 g, 6.04 mmol, 1.25 equiv), allowed to slowly warm to rt,
and stirred for 0.5 h. The solution was concentrated by rotary
evaporation to afford the crude product as a yellow oil. Purification by
silica flash chromatography (9:1 hexanes/EtOAc) yielded aldehyde
S19 (1.40 g, 4.48 mmol, 92%) as a colorless oil. IR (neat) (cm−1):
1
2959, 2934, 2724, 1729, 1470, 1426, 1095, 824, 745, 702, 613. H
NMR (600 MHz): δ 9.81 (t, J = 2.2 Hz, 1H), 7.69−7.63 (m, 4H),
7.47−7.36 (m, 6H), 4.02 (t, J = 6.0 Hz, 2H), 2.60 (td, J = 6.0, 2.2 Hz,
2H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 201.9, 135.5, 133.2, 129.8,
127.7, 58.3, 46.4, 26.7, 19.1. HRMS (ESI): m/z calcd for
(C19H24O2NaSi [M + H]+) 335.1443, found 335.1447.
32.7, 29.2, 24.3, 16.1. HRMS (ESI): m/z calcd for (C11H22O2Na [M +
Na]+) 209.1517, found 209.1518.
(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1,1-diphenyloct-4-
en-1-ol (S17). In a 25 mL round-bottom flask, ester S4 (200 mg,
0.45 mmol) was dissolved in THF (5 mL), and the solution was
cooled to 0 °C. PhMgBr (1.0 M in THF, 1.00 mL, 1.00 mmol,
2.2 equiv) was added dropwise with stirring. Once addition was
complete, the solution was allowed to warm to rt, and stirring was
continued until complete conversion had occurred as judged by TLC.
The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O
(3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary
evaporation to afford the crude product as a yellow oil. Purification by
silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S17
(220 mg, 0.40 mmol, 88%) as a colorless oil. IR (neat) (cm−1): 3712−
3254, 3068, 2931, 2858, 1592, 1187, 1107, 1003, 909, 822, 733, 698,
5-((tert-Butyldiphenylsilyl)oxy)-2-methylpent-1-en-3-ol (S20). In a
25 mL round-bottom flask, aldehyde S19 (1.00 g, 3.20 mmol) was
dissolved in THF (5 mL), and the solution was cooled to 0 °C.
Isopropenylmagnesium bromide (1.0 M in THF, 6.40 mL, 3.20 mmol,
1 equiv) was added slowly. Once the addition was complete, the
cooling bath was removed, and the solution was stirred at rt until
complete conversion had occurred as judged by TLC. The mixture was
recooled to 0 °C and quenched with 1 M HCl (10 mL). The mixture
was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and
concentrated by rotary evaporation to afford the crude product as a yellow
oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc)
yielded allylic alcohol S20 (1.10 g, 3.10 mmol, 96%) as a yellow oil. IR
(neat) (cm−1): 3699−3144, 3053, 2937, 2779, 1720, 1431, 1111, 873,
743 706, 648. 1H NMR (600 MHz): δ 7.68 (d, J = 7.0 Hz, 4H), 7.49−
7.34 (m, 6H), 5.05 (s, 1H), 4.86 (s, 1H), 4.34 (dd, J = 7.1, 4.6 Hz,
1H), 3.91−3.85 (m, 1H), 3.81 (d, J = 3.2 Hz, 1H), 3.22 (s, 1H), 1.83−
1.77 (m, 2H), 1.72 (s, 3H), 1.06 (s, 9H). 13C NMR (151 MHz): δ
147.0, 135.5, 133.0, 129.8, 127.7, 110.5, 74.8, 62.8, 36.8, 26.8, 19.0,
18.3. HRMS (ESI): m/z calcd for (C22H31O2Si [M + H]+) 355.2093,
found 355.2083.
1
612. H NMR (600 MHz): δ 7.69−7.63 (m, 4H), 7.46−7.23 (m,
14H), 7.26−7.18 (m, 2H), 5.08 (d, J = 7.1 Hz, 1H), 3.64 (t, J = 6.4 Hz,
2H), 2.39−2.34 (m, 2H), 2.06 (d, J = 7.4 Hz, 2H), 2.00−1.94
(m, 2H), 1.60 (s, 3H), 1.59−1.54 (m, 2H), 1.04 (s, 9H). 13C NMR
(151 MHz): δ 147.0, 135.5, 134.0, 129.5, 128.1, 127.5, 126.7, 125.9,
124.5, 78.5, 63.3, 40.0, 33.9, 32.6, 26.8, 24.2, 19.2, 16.2. HRMS (ESI):
m/z calcd for (C37H44O2SiNa [M + Na]+) 571.3008, found 571.3000.
(E)-4-Methyl-1,1-diphenyloct-4-ene-1,8-diol (4h). In a 10 mL
round-bottom flask, protected alcohol S17 (200 mg, 0.36 mmol) was
dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.73 mL, 0.73
mmol, 2 equiv) was added, and the solution was stirred until complete
conversion had occurred as judged by TLC. The reaction mixture was
concentrated by rotary evaporation. Purification by silica flash chroma-
tography (1:1 hexanes/EtOAc) yielded diol 4h (85 mg, 0.27 mmol,
75%) as a colorless oil. IR (neat) (cm−1): 3709−3128, 2934, 2862,
1717, 1492, 1447, 1057, 1032, 944, 698. 1H NMR (600 MHz): δ 7.42
(d, J = 6.6 Hz, 4H), 7.31 (t, J = 7.0 Hz, 4H), 7.22 (t, J = 7.3 Hz, 2H),
5.14 (t, J = 7.2 1H), 3.63 (t, J = 6.5 Hz, 2H), 2.43−2.36 (m, 2H), 2.06
(q, J = 7.3 Hz, 2H), 1.99 (dd, J = 9.9, 6.2 Hz, 2H), 1.65−1.56 (m, 5H).
13C NMR (151 MHz): δ 146.9, 136.1, 128.1, 126.8, 126.0, 124.2, 78.5,
Ethyl (E)-7-((tert-Butyldiphenylsilyl)oxy)-4-methylhept-4-enoate
(S21). In a 25 mL round-bottom flask, allylic alcohol S20 (1.00 g,
2.82 mmol), triethyl orthoacetate (5 mL), and propionic acid (20 μL,
0.28 mmol, 0.1 equiv) were added. The flask was equipped with a
distillation head and heated to 140 °C during which time ethanol was
collected. Heating was continued at this temperature until complete
conversion had occurred as judged by TLC. The mixture was cooled
to rt and quenched with 1 M HCl (10 mL). The mixture was extracted
with Et2O (3 × 10 mL), washed with 1 M NaOH (10 mL),
dried (MgSO4), filtered, and concentrated by rotary evaporation to
afford the crude product as a yellow oil. Purification by silica flash
chromatography (9:1 hexanes/EtOAc) yielded ester S21 (820 mg,
68%) as a colorless oil. IR (neat) (cm−1): 2957, 2900, 1735, 1445,
62.6, 40.0, 34.0, 32.6, 24.2, 16.2. HRMS (ESI): m/z calcd for
1
(C21H26O2Na [M + Na]+) 333.1831, found 333.1840.
1107, 701, 612. H NMR (600 MHz): δ 7.71−7.63 (m, 4H), 7.45−
7.35 (m, 6H), 5.15 (t, J = 7.2 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.62
(t, J = 7.0 Hz, 2H), 2.37 (d, J = 7.2 Hz, 2H), 2.34−2.22 (m, 4H), 1.56
(s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.04 (h, 9H). 13C NMR (151 MHz):
δ 173.5, 135.6, 135.3, 134.0, 129.5, 127.6, 121.2, 63.6, 60.2, 34.7, 33.1,
31.5, 26.8, 19.2, 16.0, 14.2. HRMS (ESI): m/z calcd for
(C26H36O3NaSi [M + Na]+) 447.2331, found 447.2312.
1f. Synthesis of Diol Substrate 4i from 3-Buten-1-ol. (But-3-en-1-
yloxy)(tert-butyl)diphenylsilane (S18). In a 250 mL round-bottom
flask, 3-buten-1-ol (1.00 g, 13.9 mmol) and imidazole (944 mg,
13.9 mmol, 2 equiv) were dissolved in CH2Cl2 (15 mL), and the
solution was cooled to 0 °C. TBDPSCl (3.60 mL, 13.9 mmol, 1 equiv)
was added slowly with stirring. The solution was allowed to warm to rt
I
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The Journal of Organic Chemistry
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(E)-7-((tert-Butyldiphenylsilyl)oxy)-4-methylhept-4-en-1-ol (S22).
In a 25 mL round-bottom flask, ester S21 (500 mg, 1.18 mmol) was
dissolved in THF (10 mL), and the solution was cooled to 0 °C.
LiAlH4 (45 mg, 1.18 mmol, 1 equiv) was added slowly and the
solution stirred at 0 °C until complete conversion had occurred as
judged by TLC. The mixture was carefully quenched with 1 M HCl
(5 mL). The mixture was extracted with Et2O (3 × 10 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford
the crude product as a colorless oil. Purification by silica flash
chromatography (4:1 hexanes/EtOAc) yielded alcohol S22 (405 mg,
1.06 mmol, 89%) as a colorless oil. IR (neat) (cm−1): 3670−3134,
2893, 2858, 1470, 1170, 1087, 821, 804, 735, 700, 611. 1H NMR (600
MHz, Chloroform-d) δ 7.70−7.65 (m, 4H), 7.44−7.34 (m, 6H), 5.17
(t, J = 6.7 Hz, 1H), 3.64 (t, J = 7.0 Hz, 2H), 3.59 (t, J = 6.5 Hz, 2H),
2.27 (q, J = 7.2 Hz, 2H), 2.04 (t, J = 7.4 Hz, 2H), 1.64 (quint, J =
6.7 Hz, 2H), 1.56 (s, 3H), 1.05 (s, 9H). 13C NMR (151 MHz): δ
136.6, 135.6, 134.0, 129.5, 127.6, 120.8, 63.7, 62.7, 36.0, 31.5, 30.7,
26.8, 19.2, 16.0. HRMS (ESI): m/z calcd for (C24H35O2Si [M + H]+)
383.2406, found 383.2422.
37.1, 36.1, 31.4, 16.2. HRMS (ESI): m/z calcd for (C14H20O2Na
[M + Na]+) 243.1361, found 243.1363.
1g. Synthesis of Diol Substrate 4j from 5-Hexen-1-ol. tert-
Butyl(hex-5-en-1-yloxy)diphenylsilane (S25). In a 250 mL round-
bottom flask, 5-hexen-1-ol (1.00 g, 9.98 mmol) and imidazole (1.36 g,
20.0 mmol, 2 equiv) were dissolved in CH2Cl2 (10 mL), and the
solution was cooled to 0 °C. TBDPSCl (2.60 mL, 9.98 mmol, 1 equiv)
was added slowly with stirring. The solution was allowed to warm to rt
and stirred until complete conversion had occurred as judged by TLC.
The mixture was quenched with 1 M HCl (10 mL) and extracted with
CH2Cl2 (3 × 10 mL), dried (MgSO4), filtered, and concentrated by
rotary evaporation to afford the crude product S25 as a colorless oil
(3.21 g, 95%) that was carried onto the next step without need for
further purification. IR (neat) (cm−1): 2929, 2857, 2361, 2337, 1558,
1427, 1105, 822, 700, 614. 1H NMR (600 MHz): δ 7.70−7.64
(m, 4H), 7.44−7.34 (m, 6H), 5.79 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H),
5.01−4.89 (m, 2H), 3.66 (t, J = 6.4 Hz, 2H), 2.03 (t, J = 7.2 Hz, 2H),
1.58 (quint, J = 6.9 Hz, 2H), 1.46 (quint, J = 7.8 Hz, 2H), 1.05 (s, 9H).
13C NMR (151 MHz, CDCl3): δ 138.9, 135.6, 134.1, 129.5, 127.6,
114.3, 63.7, 33.5, 32.0, 26.8, 25.1, 19.2. HRMS (ESI): m/z calcd for
(E)-7-((tert-Butyldiphenylsilyl)oxy)-4-methylhept-4-enal (S23). In
a 25 mL round-bottom flask, alcohol S22 (250 mg, 0.65 mmol) was
dissolved in CH2Cl2 (10 mL). PCC (140 mg, 0.65 mmol, 2 equiv) was
added, and the solution was stirred at rt until complete conversion had
occurred as judged by TLC. The mixture was filtered through a pad of
silica with hexane/EtOAc 9:1 and concentrated by rotary evaporation
to afford aldehyde S23 (225 mg, 0.59 mmol, 90%) as a colorless oil.
IR (neat) (cm−1): 316, 3050, 2933, 2883, 1468, 1108, 1005, 858, 702,
(C22H31OSi [M + H]+) 339.2144, found 339.2132.
5-((tert-Butyldiphenylsilyl)oxy)pentanal (S26). In a 250 mL round-
bottom flask, alkene S25 (1.50 g, 4.43 mmol) was dissolved in CH2Cl2
(50 mL), and the solution was cooled to −78 °C. Ozone was bubbled
through the solution until the blue color was persistent. The stream of
ozone was replaced with oxygen until the blue color dissipated, then
the reaction was quenched with triphenylphosphine (1.45 g,
5.54 mmol, 1.25 equiv), allowed to slowly warm to rt, and stirred
for 0.5 h. The solution was concentrated by rotary evaporation to
afford the crude product as a yellow oil. Purification by silica flash
chromatography (9:1 hexanes/EtOAc) yielded aldehyde S26 (1.38 g,
4.05 mmol, 91%) as a colorless oil. IR (neat) (cm−1): 2934, 2858,
2723, 1729, 1426, 1097, 1008, 702, 612. 1H NMR (600 MHz): δ 9.74
(t, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.0, 1.5 Hz, 4H), 7.44−7.36 (m, 6H),
3.67 (t, J = 6.2 Hz, 2H), 2.41 (td, J = 7.4, 1.8 Hz, 2H), 1.73 (quint, J =
7.4 Hz, 2H), 1.62−1.56 (m, 2H), 1.05 (s, 9H). 13C NMR (151 MHz):
δ 202.7, 135.5, 133.8, 129.6, 127.6, 127.6, 63.3, 43.5, 31.8, 26.8, 19.2,
18.5. HRMS (ESI): m/z calcd for (C21H28O2SiNa [M + Na]+)
363.1757, found 363.1795.
7-((tert-Butyldiphenylsilyl)oxy)-2-methylhept-1-en-3-ol (S27). In a
25 mL round-bottom flask, aldehyde S26 (1.00 g, 2.94 mmol) was
dissolved in THF (5 mL), and the solution was cooled to 0 °C.
Isopropenylmagnesium bromide (1.0 M in THF, 5.87 mL, 2.94 mmol,
1 equiv) was added slowly. Once addition was complete, the cooling
bath was removed, and the solution was allowed to stir at rt until
complete conversion had occurred as judged by TLC. The mixture was
recooled to 0 °C and quenched with 1 M HCl (10 mL). The mixture
was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and
concentrated by rotary evaporation to afford the crude product as a
yellow oil. Purification by silica flash chromatography (4:1 hexanes/
EtOAc) yielded allylic alcohol S27 (1.12 g, 2.93 mmol, 99%) as a
yellow oil. IR (neat) (cm−1): 3709−3167, 2933, 2859, 1710, 1469,
1427, 1107, 1000, 937, 898, 822, 739, 701, 612. 1H NMR (600 MHz):
δ 7.66 (d, J = 6.8 Hz, 2H), 7.45−7.33 (m, 8H), 4.92 (s, 1H), 4.82
(s, 1H), 4.03 (t, J = 6.5 Hz, 1H), 3.66 (t, J = 6.5 Hz, 2H), 1.70 (s, 3H),
1.64−1.56 (m, 2H), 1.56−1.48 (m, 2H), 1.48−1.40 (m, 1H), 1.40−
1.30 (m, 1H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 147.5, 135.5,
134.02, 129.5, 127.6, 111.0, 75.9, 63.8, 34.6, 32.4, 26.8, 26.8, 21.8, 19.2,
17.4. HRMS (ESI): m/z calcd for (C24H34O2NaSi [M + Na]+)
405.2226, found 405.2217.
1
647, 611. H NMR (600 MHz): δ 9.73 (t, J = 1.9 Hz, 1H), 7.67
(dd, J = 8.0, 1.5 Hz, 4H), 7.44−7.34 (m, 6H), 5.16 (td, J = 7.2, 1.3 Hz,
1H), 3.63 (t, J = 6.9 Hz, 2H), 2.48 (td, J = 7.6, 1.9 Hz, 2H), 2.32−2.23
(m, 4H), 1.57 (s, 3H), 1.04 (s, 9H). 13C NMR (151 MHz, CDCl3): δ
202.5, 135.7, 134.9, 133.9, 129.5, 127.8, 121.6, 63.5, 42.2, 31.8, 31.5,
27.5, 26.8, 26.8, 19.2, 16.2. HRMS (ESI): m/z calcd for (C24H33O2Si
[M + H]+) 381.2250, found 381.2234.
(E)-7-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-phenylhept-4-en-
1-ol (S24). In a 25 mL round-bottom flask, aldehyde S23 (200 mg,
0.52 mmol) was dissolved in THF (5 mL), and the solution was
cooled to 0 °C. PhMgBr (1.0 M in THF, 0.66 mL, 0.66 mmol,
1.25 equiv) was added dropwise with stirring. Once addition was
complete, the solution was allowed to warm to rt, and stirring was
continued until complete conversion had occurred as judged by TLC.
The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O
(3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary
evaporation to afford the crude product as a yellow oil. Purification by
silica flash chromatography (4:1 hexanes/EtOAc) yielded S24 (220 mg,
0.47 mmol, 91%) as a colorless oil. IR (neat) (cm−1): 3735−3131,
1
3050, 2931, 2893, 1892, 1822, 1724, 1108, 1086, 701, 612. H NMR
(600 MHz): δ 7.69−7.64 (m, 4H), 7.43−7.31 (m, 10H), 7.29−7.24
(m, 1H), 5.15 (t, J = 7.7, 6.8 Hz, 1H), 4.63 (t, J = 6.8, 6.0 Hz, 1H),
3.63 (t, J = 7.0 Hz, 2H), 2.26 (q, J = 7.1 Hz, 2H), 2.13−2.06 (m, 1H),
2.03−1.96 (m, 1H), 1.92−1.83 (m, 2H), 1.83−1.75 (m, 1H), 1.55
(s, 3H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 144.7, 136.5, 135.6,
134.0, 129.5, 128.4, 127.6, 125.9, 120.9, 115.2, 74.3, 63.7, 37.1, 35.9,
31.5, 26.8, 19.2, 16.1. HRMS (ESI): m/z calcd for (C30H38O2NaSi
[M + Na]+) 489.2539, found 489.2529.
(E)-4-Methyl-7-phenylhept-3-ene-1,7-diol (4i). In a 10 mL round-
bottom flask, protected alcohol S24 (150 mg, 0.33 mmol) was
dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.66 mL,
0.66 mmol, 2 equiv) was added and the solution was stirred until
complete conversion had occurred as judged by TLC. The reaction
mixture was concentrated by rotary evaporation. Purification by silica
flash chromatography (1:1 hexanes/EtOAc) yielded diol 4i (50 mg,
0.23 mmol, 69%) as a colorless oil. IR (neat) (cm−1): 3722−3124,
2936, 2863, 1812, 1491, 1059, 1025, 760, 700, 613. 1H NMR
(600 MHz): δ 7.37−7.30 (m, 4H), 7.29−7.24 (m, 1H), 5.16 (t, J =
7.6 Hz, 1H), 4.63 (dd, J = 7.9, 5.1 Hz, 1H), 3.58 (t, J = 6.7, 5.6 Hz,
2H), 2.30−2.21 (m, 2H), 2.18−2.10 (m, 1H), 2.09−2.00 (m, 1H),
1.93−1.85 (m, 1H), 1.84−1.76 (m, 1H), 1.63 (s, 3H). 13C NMR
(151 MHz): δ 144.8, 138.1, 128.4, 127.5, 125.9, 120.5, 74.2, 62.3,
Ethyl (E)-9-((tert-Butyldiphenylsilyl)oxy)-4-methylnon-4-enoate
(S28). In a 25 mL round-bottom flask, allylic alcohol S27 (1.00 g,
2.61 mmol), triethyl orthoacetate (5 mL), and propionic acid (20 μL,
0.26 mmol, 0.1 equiv) were added. The flask was equipped with a
distillation head and heated to 140 °C during which time ethanol was
collected. Heating was continued at this temperature until complete
conversion had occurred as judged by TLC. The mixture was cooled
to rt and quenched with 1 M HCl (5 mL). The mixture was extracted
with Et2O (3 × 5 mL), washed with 1 M NaOH (5 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford the
J
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The Journal of Organic Chemistry
Article
crude product as a yellow oil. Purification by silica flash chroma-
tography (9:1 hexanes/EtOAc) yielded ester S28 (0.85 g, 1.88 mmol,
71%) as a colorless oil. IR (neat) (cm−1): 3051, 2929, 2857, 2775,
dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.41 mL,
0.41 mmol, 2 equiv) was added, and the solution was stirred until
complete conversion had occurred as judged by TLC. The reaction
mixture was concentrated by rotary evaporation. Purification by silica
flash chromatography (1:1 hexanes/EtOAc) yielded diol 4j (40 mg,
0.16 mmol, 78%) as a colorless oil. IR (neat) (cm−1): 3677−3144,
3029, 2858, 1451, 1059, 911, 733, 699. 1H NMR (600 MHz): δ 7.37−
7.33 (m, 4H), 7.30−7.27 (m, 1H), 5.17 (t, J = 7.1 Hz, 1H), 4.66
(dd, J = 7.9, 5.3 Hz, 1H), 3.63 (t, J = 6.6 Hz, 2H), 2.16−2.08 (m, 1H),
2.06−1.97 (m, 4H), 1.94−1.86 (m, 1H), 1.85−1.78 (m, 1H), 1.61 (s,
3H), 1.56 (quint, J = 8.5 Hz, 2H), 1.40 (quint, J = 10.1 Hz, 2H), 1.32
(s, 1H). 13C NMR (151 MHz): δ 144.7, 134.9, 128.4, 127.5, 125.9,
124.8, 74.4, 62.9, 37.2, 36.0, 32.3, 27.6, 25.9, 16.0. HRMS (ESI): m/z
calcd for (C16H24O2Na [M + H]+) 271.1674, found 271.1667.
1
2337, 2270, 1735, 1372, 822, 667, 615. H NMR (600 MHz): δ 7.67
(dd, J = 8.0, 1.5 Hz, 4H), 7.44−7.34 (m, 6H), 5.16−5.11 (m, 1H),
4.11 (q, J = 7.1 Hz, 2H), 3.65 (t, J = 6.4 Hz, 2H), 2.41−2.37 (m, 2H),
2.29 (dd, J = 9.2, 6.4 Hz, 2H), 1.96 (q, J = 7.3 Hz, 2H), 1.58 (s, 3H),
1.58−1.51 (m, 2H), 1.44−1.36 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.04
(s, 9H). 13C NMR (151 MHz): δ 173.5, 135.5, 134.1, 133.3, 129.5,
127.6, 125.4, 63.8, 60.2, 34.7, 33.3, 32.1, 27.6, 26.8, 25.9, 19.2,
15.9, 14.3. HRMS (ESI): m/z calcd for (C28H40O3NaSi [M + H]+)
475.2644, found 475.2662.
(E)-9-((tert-Butyldiphenylsilyl)oxy)-4-methylnon-4-en-1-ol (S29).
In a 25 mL round-bottom flask, ester S28 (500 mg, 1.10 mmol)
was dissolved in THF (10 mL), and the solution was cooled to 0 °C.
LiAlH4 (42 mg, 1.10 mmol, 1 equiv) was added slowly and the
solution stirred at 0 °C until complete conversion had occurred as
judged by TLC. The mixture was carefully quenched with 1 M HCl
(10 mL). The mixture was extracted with Et2O (3 × 10 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford
the crude product as a colorless oil. Purification by silica flash
chromatography (4:1 hexanes/EtOAc) yielded alcohol S29 (410 mg,
0.99 mmol, 90%) as a colorless oil. IR (neat) (cm−1): 3667−3141,
1h. Synthesis of TBS-Protected Substrate 6. (E)-8-((tert-
Butyldimethylsilyl)oxy)-4-methyl-1-phenyloct-4-en-1-ol (6). In a
10 mL round-bottom flask, diol 1 (20 mg, 0.085 mmol) and imidazole
(12 mg, 0.17 mmol, 2 equiv) were dissolved in CH2Cl2 (2 mL). The
solution was cooled to 0 °C, and TBSCl (13 mg, 0.085 mmol, 1 equiv)
was added. The solution was allowed to warm to rt and stirred until
complete conversion had occurred as judged by TLC. The mixture was
quenched with 1 M HCl (1 mL) and extracted with CH2Cl2 (3 ×
1 mL), dried (MgSO4), filtered, and concentrated by rotary evapo-
ration to afford the crude product as a colorless oil. Purification by
silica flash chromatography (4:1 hexanes/EtOAc) yielded TBS ether 6
(24 mg, 0.069 mmol, 80%) as a colorless oil. IR (neat): 3711−3103,
1
2862, 2775, 1474, 1110, 805, 742, 704, 615. H NMR (600 MHz): δ
7.71−7.62 (m, 4H), 7.45−7.34 (m, 6H), 5.20−5.11 (m, 1H), 3.65
(t, J = 6.5 Hz, 2H), 3.64−3.60 (m, 2H), 2.10−2.02 (m, 2H), 1.97
(q, J = 7.3 Hz, 2H), 1.72−1.62 (m, 2H), 1.62−1.49 (m, 5H), 1.47−
1.37 (m, 2H), 1.36 (s, 1H), 1.05 (s, 9H). 13C NMR (151 MHz): δ
135.6, 134.1, 129.5, 127.6, 127.6, 125.1, 63.8, 62.8, 36.0, 32.2,
30.7, 27.6, 26.9, 26.0, 19.2, 15.9. HRMS (ESI): m/z calcd for
(C26H38O2SiNa [M + H]+) 433.2539, found 433.2531.
(E)-9-((tert-Butyldiphenylsilyl)oxy)-4-methylnon-4-enal (S30). In a
25 mL round-bottom flask, alcohol S29 (250 mg, 0.61 mmol) was
dissolved in CH2Cl2 (10 mL). PCC (262 mg, 1.22 mmol, 2 equiv) was
added, and the solution was stirred at rt until complete conversion had
occurred as judged by TLC. The mixture was filtered through a pad of
silica with hexane/EtOAc 9:1 and concentrated by rotary evaporation
to afford aldehyde S30 (220 mg, 0.54 mmol, 88%) as a colorless oil.
IR (neat) (cm−1): 3070, 2931, 2858, 1725, 1388, 1107, 822, 738, 701.
1H NMR (600 MHz): δ 9.74 (s, 1H), 7.71−7.64 (m, 4H), 7.46−7.33
(m, 6H), 5.18−5.09 (m, 1H), 3.65 (t, J = 6.3 Hz, 2H), 2.50 (td, J = 7.5,
1.9 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.97 (q, J = 7.4 Hz, 2H), 1.58
(s, 3H), 1.55 (dd, J = 8.7, 6.3 Hz, 2H), 1.40 (quint, J = 7.6 Hz, 2H),
1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 202.7, 135.7, 134.1,
132.9, 129.5, 127.8, 125.7, 63.8, 42.2, 32.2, 31.8, 27.6, 26.9, 25.8,
19.2, 16.1. HRMS (ESI): m/z calcd for (C26H36O2NaSi [M + H]+)
431.2382, found 431.2390.
(E)-9-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-phenylnon-4-en-1-
ol (S31). In a 25 mL round-bottom flask, aldehyde S30 (200 mg,
0.49 mmol) was dissolved in THF (5 mL), and the solution was
cooled to 0 °C. PhMgBr (1.0 M in THF, 0.61 mL, 0.61 mmol,
1.2 equiv) was added dropwise with stirring. Once addition was
complete, the solution was allowed to warm to rt, and stirring was
continued until complete conversion had occurred as judged by TLC.
The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O
(3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary
evaporation to afford the crude product as a yellow oil. Purification by
silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S31
(130 mg, 0.27 mmol, 54%) as a colorless oil. IR (neat) (cm−1): 3683−
3183, 2930, 2857, 1454, 1428, 1107, 821, 737, 699. 1H NMR
(600 MHz): δ 7.66 (d, J = 6.5 Hz, 4H), 7.44−7.31 (m, 10H), 7.29−
7.24 (m, 1H), 5.15 (t, J = 7.3 Hz, 1H), 4.64 (dd, J = 7.8, 5.3 Hz, 1H),
3.65 (t, J = 6.4 Hz, 2H), 2.13−2.06 (m, 1H), 2.04−1.93 (m, 3H),
1.93−1.85 (m, 1H), 1.84−1.76 (m, 1H), 1.63−1.51 (m, 5H), 1.40 (dq,
J = 9.9, 7.6 Hz, 2H), 1.04 (s, 9H). 13C NMR (151 MHz, CDCl3): δ
144.7, 135.5, 134.6, 134.1, 129.5, 128.4, 127.6, 127.5, 125.9, 125.1,
74.3, 63.8, 37.2, 36.0, 32.2, 27.6, 26.9, 26.0, 19.2, 16.0. HRMS (ESI):
m/z calcd for (C32H42O2NaSi [M + H]+) 509.2852, found 509.2862.
(E)-4-Methyl-1-phenylnon-4-ene-1,9-diol (4j). In a 10 mL round-
bottom flask, protected alcohol S31 (100 mg, 0.21 mmol) was
1
2933, 2858, 1602, 1450, 1254, 1059, 871, 835, 769, 699. H NMR
(600 MHz): δ 7.32−7.27 (m, 4H), 7.25−7.19 (m, 1H), 5.12 (t, J =
7.2 Hz, 1H), 4.58 (dd, J = 7.8, 5.3 Hz, 1H), 3.55 (t, J = 6.5 Hz, 2H),
2.10−2.02 (m, 2H), 2.02−1.92 (m, 3H), 1.89−1.80 (m, 1H), 1.80−
1.71 (m, 1H), 1.56 (s, 3H), 1.50 (q, J = 6.6 Hz, 2H), 0.85 (s, 9H),
0.00 (s, 6H). 13C NMR (151 MHz): δ 144.8, 134.9, 128.4, 127.4,
125.9, 124.6, 74.3, 62.7, 37.2, 35.9, 32.9, 26.0, 24.2, 18.3, 15.9, −5.3.
HRMS (ESI): m/z calcd for (C12H22O3Na [M + Na]+) 237.1467,
found 237.1476.
1i. Synthesis of Methyl Ether Substrate 8. (E)-8-Hydroxy-4-
methyl-1-phenyloct-4-en-1-one (S32). In a 10 mL round-bottom
flask, diol 1 (75 mg, 0.320 mmol) was dissolved in CH2Cl2 (3 mL) at
rt. MnO2 (690 mg, 8.0 mmol, 25 equiv) was added, and the solution
was stirred until complete conversion had occurred as judged by TLC.
The slurry was filtered through a pad of Celite, washed with CH2Cl2
(10 mL), and concentrated by rotary evaporation to afford the crude
product as a colorless oil. Purification by silica flash chromatography
(4:1 hexanes/EtOAc) yielded ketone S32 (63 mg, 0.074 mmol, 85%)
as a colorless oil. IR (neat): 3695−3140, 2931, 1818, 1491, 1379, 909,
1
729. H NMR (600 MHz): δ 7.96 (dd, J = 7.1, 7.6 Hz, 2H), 7.56 (t,
1H), 7.47 (t, J = 7.7 Hz, 2H), 5.20 (tq, J = 7.2, 1.4 Hz, 1H), 3.64 (t, J =
6.5 Hz, 2H), 3.07 (t, J = 7.4 Hz, 2H), 2.42 (t, J = 7.9 Hz, 2H), 2.09 (q,
J = 6.8 Hz, 2H), 1.68 (s, 3H), 1.60 (quint, J = 7.0 Hz, 2H). 13C NMR
(151 MHz): δ 200.1, 136.9, 134.6, 133.0, 128.6, 128.1, 124.5, 62.6,
37.3, 34.0, 32.6, 24.3, 16.2. HRMS (ESI): m/z calcd for (C15H21O2
[M + H]+) 233.1542, found 233.1549.
(E)-8-Methoxy-4-methyl-1-phenyloct-4-en-1-one (S33). In a
10 mL round-bottom flask, NaH (12 mg, 0.32 mmol, 1.5 equiv, as a
60% dispersion in oil) was suspended in THF (1 mL), and the
solution was cooled to 0 °C. The alcohol S32 (50 mg, 0.22 mmol) was
added as a solution in THF (1 mL); once addition was complete,
stirring was continued for 15 min, iodomethane (26 μL, 0.43 mmol,
2 equiv) was added, and the solution was stirred until complete
conversion had occurred as judged by TLC. The reaction was
quenched by the addition of 10% HCl (1 mL) and extracted with Et2O
(3 × 1 mL). The organic layers were combined, washed with brine,
dried (MgSO4), filtered, and concentrated by rotary evaporation to
afford the crude product as a colorless oil. Purification by silica flash
chromatography (9:1 hexanes/EtOAc) yielded methyl ether S33
(42 mg, 0.17 mmol, 79%) as a colorless oil. IR (neat): 2923, 2857,
1
1685, 1597, 1448, 1357, 1289, 1203, 1117, 1037, 971, 742, 692. H
NMR (400 MHz): δ 8.00−7.94 (m, 2H), 7.56 (ddt, J = 7.9, 6.9,
1.3 Hz, 1H), 7.50−7.43 (m, 2H), 5.18 (tq, J = 7.2, 1.4 Hz, 1H), 3.35
(t, J = 6.6 Hz, 2H), 3.32 (s, 3H), 3.10−3.02 (m, 2H), 2.48−2.38
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(m, 2H), 2.11−2.01 (m, 2H), 1.67 (s, 3H), 1.63−1.57 (m, 2H).
13C NMR (125 MHz): δ 200.2, 137.0, 134.4, 132.9, 128.6, 128.1,
124.5, 72.2, 58.6, 37.4, 34.1, 29.6, 24.4, 16.1. HRMS (ESI): m/z calcd
for (C16H23O2 [M + H]+) 247.1698, found 247.1703.
concentrated by rotary evaporation to afford the crude product as a
colorless oil. Purification by silica flash chromatography (hexanes/
EtOAc 2:1) yielded ester 9 (42 mg, 0.17 mmol, 83%) as a colorless oil.
IR (neat) (cm−1): 3735−3131, 2980, 2915, 1731, 1450, 1374, 1181,
1
8-Methoxy-4-methyl-1-phenyloct-4-en-1-ol (8). In a 10 mL
round-bottom flask, ketone S33 (40 mg, 0.16 mmol) was dissolved
in EtOH (2 mL) at rt. NaBH4 (6 mg, 0.16 mmol, 1 equiv) was added
and the mixture stirred until complete conversion had occurred as
judged by TLC. The reaction was quenched by the addition of 10%
HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers
were combined, washed with brine, dried (MgSO4), filtered, and
concentrated by rotary evaporation to afford the crude product as a
colorless oil. Purification by silica flash chromatography (4:1 hexanes/
EtOAc) yielded alcohol 8 (36 mg, 0.14 mmol, 89%) as a colorless oil.
IR (neat): 3720−3114, 2936, 2899, 1456, 1117, 1060, 1027, 775, 738,
699. 1H NMR (400 MHz): δ 7.38−7.31 (m, 4H), 7.30−7.26 (m, 1H),
5.16 (tq, J = 7.2, 1.3 Hz, 1H), 4.66 (dd, J = 7.8, 5.4 Hz, 1H), 3.35
(t, J = 6.5 Hz, 2H), 3.32 (s, 3H), 2.16−2.08 (m, 1H), 2.08−1.99 (m,
3H), 1.97 (s, 1H), 1.94−1.85 (m, 1H), 1.85−1.78 (m, 1H), 1.65−1.54
(m, 5H). 13C NMR (125 MHz): δ 144.7, 135.1, 128.4, 127.5, 125.9,
124.4, 74.3, 72.3, 58.6, 37.2, 36.0, 29.6, 24.4, 15.9. HRMS (ESI): m/z
calcd for (C16H24O2Na [M + Na]+) 271.1674, found 271.1666.
1j. Synthesis of Ethyl Ester Substrate 9. (E)-5-Methyl-8-oxo-8-
phenyloct-4-enoic Acid (S34). In a 50 mL round-bottom flask, diol 1
(400 mg, 1.71 mmol) was dissolved in acetone (17 mL), and the
solution was cooled to 0 °C. Jones reagent (1.19 mL, 3.58 mmol,
3.0 M) was added over a period of 10 min, until the orange color
persisted. Excess reagent was destroyed by addition of i-PrOH (5 mL),
as indicated by the reappearance of a deep green color. The reaction
was quenched by the addition of 10% HCl (10 mL) and extracted with
Et2O (3 × 20 mL). The organic layers were combined, washed with
brine, dried (MgSO4), filtered, and concentrated by rotary evaporation
to afford the crude product as a colorless oil. Purification by silica flash
chromatography (1:1 hexanes/EtOAc) yielded acid S34 (360 mg, 1.46
mmol, 85%) as a colorless oil. IR (neat) (cm−1): 3705−3107, 2861,
1035, 762, 701. H NMR (600 MHz): δ 7.37−7.31 (m, 4H), 7.31−
7.24 (m, 1H), 5.16−5.10 (m, 1H), 4.63 (t, J = 6.8 Hz, 1H), 4.11 (q, J =
7.1 Hz, 2H), 2.36−2.27 (m, 4H), 2.13−2.06 (m, 2H), 2.05−1.97 (m,
1H), 1.88 (dddd, J = 13.6, 9.2, 7.8, 5.7 Hz, 1H), 1.79 (dddd, J = 13.6,
9.6, 6.2, 5.3 Hz, 1H), 1.62 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz): δ 173.4, 144.7, 136.2, 128.4, 127.5, 125.9, 122.8, 122.8,
74.2, 60.3, 37.1, 35.9, 34.4, 23.5, 16.0, 14.2. HRMS (ESI): m/z calcd
for (C17H24O3Na [M + Na]+) 299.1623, found 299.1624.
1k. Synthesis of Carboxylic Acid Substrate 10. 8-Hydroxy-5-
methyl-8-phenyloct-4-enoic Acid (10). In a 10 mL round-bottom
flask, ketone S34 (50 mg, 0.20 mmol) was dissolved in EtOH (2 mL)
at rt. NaBH4 (7.7 mg, 0.20 mmol, 1 equiv) was added and the mixture
stirred until complete conversion had occurred as judged by TLC.
The reaction was quenched by the addition of 10% HCl (1 mL) and
extracted with Et2O (3 × 1 mL). The organic layers were combined,
washed with brine, dried (MgSO4), filtered, and concentrated by
rotary evaporation to afford the crude product as a colorless oil.
Purification by silica flash chromatography (CH2Cl2/MeOH 9:1)
yielded acid 10 (42 mg, 0.17 mmol, 83%) as a colorless oil. IR
(neat) (cm−1): 3677−3118, 3030, 2934, 1707, 1450, 1409, 1267, 1200,
1059, 1014, 915, 763, 699. 1H NMR (600 MHz): δ 7.37−7.32
(m, 4H), 7.29−7.27 (m, 1H), 5.14 (t, J = 7.0 Hz, 1H), 4.64 (dd, J =
7.8, 5.3 Hz, 1H), 2.40−2.27 (m, 4H), 2.17−1.98 (m, 2H), 1.94−1.76
(m, 2H), 1.63 (s, 3H). 13C NMR (151 MHz): δ 178.4, 144.6, 136.5,
128.5, 127.6, 125.8, 122.5, 74.2, 37.0, 35.8, 34.0, 23.2, 16.0. HRMS
(ESI): m/z calcd for (C15H19O3 [M + H]+) 247.1334, found 247.1329.
1l. Synthesis of Weinreb Amide Substrate 11. 8-((tert-
Butyldimethylsilyl)oxy)-N-methoxy-N,5-dimethyl-8-phenyloct-4-en-
amide (S36). In a 10 mL round-bottom flask, acid S34 (100 mg,
0.41 mmol) was dissolved in benzene (4 mL) at rt. To this was added
DMF (2 μL, 0.020 mmol, 5 mol %) followed by the dropwise addition
of oxalyl chloride (35 μL, 0.41 mmol, 1 equiv) and the mixture stirred
for 2 h. To this solution was added N,O-dimethylhydroxylamine
hydrochloride (79 mg, 0.81 mmol, 2 equiv) followed by pyridine
(1 mL) and the solution stirred for 4 h. The reaction was quenched by
the addition of 10% HCl (5 mL) and extracted with Et2O (3 × 2 mL).
The organic layers were combined, washed with brine, dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford
the crude product as a colorless oil. Purification by silica flash chroma-
tography (hexanes/EtOAc 4:1) yielded amide S36 (105 mg, 0.36 mmol,
89%) as a colorless oil. IR (neat) (cm−1): 2971, 2941, 1665, 1451,
1387, 1290, 1206, 1182, 1118, 1075, 998, 746, 696. 1H NMR
(600 MHz): δ 7.98−7.94 (m, 2H), 7.58−7.54 (m, 1H), 7.47 (t, J =
7.6 Hz, 2H), 5.19 (t, J = 6.0 Hz, 1H), 4.62 (s, 3H), 3.51 (t, J = 6.6 Hz,
2H), 3.36 (s, 3H), 3.10−3.03 (m, 2H), 2.42 (t, J = 7.6 Hz, 2H), 2.08
(quintp, J = 6.9 Hz, 2H), 1.67 (s, 3H). 13C NMR (151 MHz): δ 200.1,
137.0, 134.4, 132.9, 128.6, 128.0, 124.4, 96.4, 67.3, 55.1, 37.4, 34.0,
29.7, 24.5, 16.2. HRMS (ESI): m/z calcd for (C17H24NO3 [M + H]+)
290.1756, found 290.1747.
8-Hydroxy-N-methoxy-N,5-dimethyl-8-phenyloct-4-enamide
(11). In a 10 mL round-bottom flask, ketone S36 (50 mg, 0.17 mmol)
was dissolved in EtOH (2 mL) at rt. NaBH4 (6.5 mg, 0.17 mmol,
1 equiv) was added and the mixture stirred until complete conversion
had occurred as judged by TLC. The reaction was quenched by the
addition of 10% HCl (1 mL) and extracted with Et2O (3 × 1 mL).
The organic layers were combined, washed with brine, dried (MgSO4),
filtered, and concentrated by rotary evaporation to afford the crude
product as a colorless oil. Purification by silica flash chromatography
(hexanes/EtOAc 2:1) yielded amide 11 (38 mg, 0.13 mmol, 75%) as a
colorless oil. IR (neat): 3712−3113, 2932, 2857, 1641, 1450, 1386,
1317, 1178, 1060, 993, 916, 761, 700. 1H NMR (400 MHz): δ 7.35 (d,
J = 4.4 Hz, 4H), 7.31−7.24 (m, 1H), 5.19 (tq, J = 7.2, 1.3 Hz, 1H),
4.65 (dd, J = 7.9, 5.3 Hz, 1H), 3.67 (s, 3H), 3.17 (s, 3H), 2.45 (t, J =
7.6 Hz, 2H), 2.33 (q, J = 7.4 Hz, 2H), 2.15−2.08 (m, 1H), 2.07−1.99
(m, 1H), 1.94−1.85 (m, 1H), 1.86−1.77 (m, 1H), 1.64 (s, 3H).
13C NMR (125 MHz): δ 144.8, 135.8, 128.4, 127.5, 125.9, 123.5,
1
1705, 1683, 1410, 1204, 911, 842, 690, 655. H NMR (600 MHz): δ
7.95 (d, J = 6.8 Hz, 6H), 7.56 (t, J = 6.8 Hz, 3H), 7.46 (t, J = 7.7 Hz,
2H), 5.18 (t, J = 6.7 Hz, 3H), 3.06 (dd, J = 8.4, 7.0 Hz, 2H), 2.40
(dd, J = 8.5, 6.6 Hz, 6H), 1.69 (s, 3H). 13C NMR (151 MHz): δ 200.0,
179.0, 136.9, 135.8, 133.0, 128.6, 128.0, 122.7, 37.2, 34.0, 33.9, 23.2,
16.2. HRMS (ESI): m/z calcd for (C15H19O3 [M + H]+) 247.1334,
found 247.1325.
Ethyl (E)-5-Methyl-8-oxo-8-phenyloct-4-enoate (S35). In a 10 mL
round-bottom flask, acid S34 (100 mg, 0.41 mmol) was dissolved in
benzene (4 mL) at rt. To this was added DMF (2 μL, 0.020 mmol,
5 mol %) followed by the dropwise addition of oxalyl chloride (35 μL,
0.41 mmol, 1 equiv) and the mixture stirred for 2 h. To this solution
was added EtOH (47 μL, 0.81 mmol, 2 equiv) as a solution in pyridine
(1 mL) and the solution stirred for 4 h. The reaction was quenched by
the addition of 10% HCl (5 mL) and extracted with Et2O (3 × 2 mL).
The organic layers were combined, washed with brine, dried (MgSO4),
filtered, and concentrated by rotary evaporation to afford the crude
product as a colorless oil. Purification by silica flash chromatography
(hexanes/EtOAc 4:1) yielded ester S35 (102 mg, 0.37 mmol, 91%) as
a colorless oil. IR (neat): 3065, 2984, 2917, 1735, 1688, 1601, 1451,
1374, 1295, 1268, 1205, 1100, 974, 746, 695. 1H NMR (600 MHz): δ
7.96 (d, J = 7.0 Hz, 2H), 7.56 (t, J = 7.0 Hz, 1H), 7.46 (t, J = 7.8 Hz,
2H), 5.20−5.14 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.10−3.02 (m,
2H), 2.41 (t, J = 7.8 Hz, 2H), 2.35−2.30 (m, 4H), 1.69 (s, 3H), 1.25
(t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 200.0, 173.3, 136.9,
135.4, 133.0, 128.6, 128.0, 123.0, 60.3, 37.3, 34.4, 33.9, 23.5, 16.2, 14.2.
HRMS (ESI): m/z calcd for (C17H23O3 [M + H]+) 275.1647, found
275.1645.
Ethyl 8-Hydroxy-5-methyl-8-phenyloct-4-enoate (9). In a 10 mL
round-bottom flask, ketone S35 (40 mg, 0.15 mmol) was dissolved in
EtOH (2 mL) at rt. NaBH4 (5.5 mg, 0.15 mmol, 1 equiv) was added
and the mixture stirred until complete conversion had occurred as
judged by TLC. The reaction was quenched by the addition of 10%
HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers
were combined, washed with brine, dried (MgSO4), filtered, and
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Article
74.2, 61.2, 37.1, 35.9, 23.2, 16.0. HRMS (ESI): m/z calcd for
(C17H25NO3Na [M + Na]+) 314.1732, found 314.1732.
42.1, 38.5, 31.7, 22.8, 16.1. HRMS (ESI): m/z calcd for (C15H18O2Na
[M + Na]+) 253.1204, found 253.1204.
1m. Synthesis of Diol Substrate 15. Methyl (E)-2-Benzoyl-5,9-
dimethyldeca-4,8-dienoate (S37). In a 250 mL round-bottom flask
containing K2CO3 (12.7 g, 92.1 mmol, 2 equiv) was added geranyl
bromide (10.00 g, 46.0 mmol) dissolved in DMF (100 mL). Ethyl
benzoylacetate (11.1 mL, 57.6 mmol, 1.22 equiv) was added and the
solution stirred at rt until complete conversion had occurred as judged
by TLC. The mixture was diluted with H2O (100 mL) and extracted
with Et2O (3 × 50 mL). The combined organic layers were washed
with H2O (2 × 50 mL) and brine (50 mL), dried (MgSO4), filtered,
and concentrated by rotary evaporation to afford the crude product
as a colorless oil. Purification by silica flash chromatography (9:1
hexanes/EtOAc) yielded ester S37 (14.8 g, 45.0 mmol, 97%) as a
colorless oil. IR (neat) (cm−1): 2966, 1740, 1438, 1162, 834. 1H NMR
(600 MHz): δ 7.99 (d, J = 7.7 Hz, 2H), 7.62−7.55 (m, 1H), 7.47
(t, J = 7.8 Hz, 2H), 5.12 (d, J = 6.5 Hz, 1H), 5.03 (d, J = 6.5 Hz, 1H),
4.31 (t, J = 7.3 Hz, 1H), 4.14 (qd, J = 7.1, 2.2 Hz, 2H), 2.80−2.64 (m,
2H), 2.05−1.91 (m, 4H), 1.64 (s, 4H), 1.62 (s, 3H), 1.56 (s, 3H), 1.17
(t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 195.1, 169.7, 138.3,
136.4, 133.4, 131.5, 128.7, 128.6, 124.0, 120.0, 61.3, 54.5, 39.7, 27.7,
26.5, 25.6, 17.7, 16.1, 14.0. HRMS (ESI): m/z calcd for (C21H29O3
[M + H]+) 329.2117, found 329.2126.
(E)-5-Methyl-1-phenyloct-4-ene-1,8-diol (15). In a 50 mL round-
bottom flask, keto aldehyde S39 (1.50 g, 6.51 mmol) was dissolved in
EtOH (20 mL) at rt. NaBH4 (250 mg, 6.51 mmol, 1 equiv) was added
and the mixture stirred until complete conversion had occurred as
judged by TLC. The reaction was quenched by the addition of 10%
HCl (10 mL) and extracted with Et2O (3 × 10 mL). The organic
layers were combined, washed with brine, dried (MgSO4), filtered, and
concentrated by rotary evaporation to afford the crude product as a
colorless oil. Purification by silica flash chromatography (hexanes/
EtOAc 2:1) yielded diol 15 (1.27 g, 5.42 mmol, 83%) as a colorless oil.
1
IR (neat) (cm−1): 3722−3118, 2934, 1450, 1058, 915, 759, 699. H
NMR (600 MHz): δ 7.31−7.24 (m, 4H), 7.23−7.17 (m, 1H), 5.11 (t,
J = 6.0 Hz, 1H), 4.57 (dd, J = 7.9, 5.3 Hz, 1H), 3.55 (t, J = 6.5 Hz,
2H), 2.08−1.90 (m, 4H), 1.87−1.78 (m, 1H), 1.77−1.69 (m, 1H),
1.58−1.48 (m, 5H). 13C NMR (151 MHz): δ 144.8, 135.4, 128.4,
127.5, 125.9, 124.9, 74.3, 62.7, 37.2, 36.0, 32.7, 24.3, 16.0. HRMS
(ESI): m/z calcd for (C15H22O2Na [M + H]+) 257.1517, found
257.1526.
1n. Synthesis of Carbinol Deuterium-Labeled Diol Substrate 17.
(E)-8-Hydroxy-5-methyl-1-phenyloct-4-en-1-one (S40). In a 25 mL
round-bottom flask, diol 15 (200 mg, 0.85 mmol) was dissolved in
CH2Cl2 (10 mL) at rt. MnO2 (3.71 g, 42.7 mmol, 50 equiv) was
added, and the solution was stirred until complete conversion had
occurred as judged by TLC. The slurry was filtered through a pad of
Celite, washed with CH2Cl2 (50 mL), and concentrated by rotary
evaporation to afford the crude product as a colorless oil. Purification
by silica flash chromatography (4:1 hexanes/EtOAc) yielded ketone
S40 (182 mg, 0.78 mmol, 91%) as a colorless oil. IR (neat) (cm−1):
(E)-5,9-Dimethyl-1-phenyldeca-4,8-dien-1-one (S38).22 In a
250 mL round-bottom flask containing LiCl (7.74 g, 183.0 mmol,
5 equiv) was added ester S37 (12.0 g, 36.6 mmol) dissolved in DMSO
(100 mL). The solution was heated to 150 °C until complete con-
version had occurred as judged by TLC. The mixture was diluted with
H2O (100 mL) and extracted with Et2O (3 × 50 mL). The combined
organic layers were washed with H2O (100 mL) and brine (50 mL),
dried (MgSO4), filtered, and concentrated by rotary evaporation to
afford the crude product as a colorless oil. Purification by silica flash
chromatography (9:1 hexanes/EtOAc) yielded ketone S38 (8.58 g,
33.5 mmol, 92%) as a colorless oil. IR (neat) (cm−1): 2968, 2915,
1
3664−3141, 2936, 1681, 1448, 1273, 1203, 1052, 750, 690. H NMR
(500 MHz): δ 7.97 (d, J = 7.1 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.48
(q, J = 7.6 Hz, 2H), 5.24 (t, J = 7.2 Hz, 1H), 3.63 (t, J = 6.3 Hz, 2H),
3.02 (t, J = 7.4 Hz, 2H), 2.45 (q, J = 7.4 Hz, 2H), 2.08 (t, J = 9.8 Hz,
2H), 1.79 (s, 1H), 1.76−1.65 (m, 5H). 13C NMR (126 MHz): δ 200.1,
137.0, 136.0, 133.0, 128.6, 128.0, 123.2, 62.6, 38.6, 35.9, 30.7,
22.9, 15.9. HRMS (ESI): m/z calcd for (C15H20O2Na [M + Na]+)
255.1361, found 255.1366.
1
1685, 1597, 1448, 1270, 1180, 975, 911, 733, 690. H NMR (600
MHz): δ 7.96 (d, J = 7.0 Hz, 2H), 7.55 (d, J = 7.3 Hz, 1H), 7.46 (t, J =
7.7 Hz, 2H), 5.19 (d, J = 7.1 Hz, 1H), 5.08 (d, J = 7.0 Hz, 1H), 3.00
(d, J = 8.3 Hz, 2H), 2.44 (q, J = 7.4 Hz, 2H), 2.06 (q, J = 7.3 Hz, 2H),
1.98 (d, J = 9.2 Hz, 2H), 1.67 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H).
HRMS (ESI): m/z calcd for (C18H25O [M + H]+) 257.1900, found
257.1898.
(E)-5-Methyl-1-phenyloct-4-ene-1-d-1,8-diol (17). In a 10 mL
round-bottom flask, ketone S40 (50 mg, 0.22 mmol) was dissolved in
EtOH (2 mL) at rt. NaBD4 (18 mg, 0.43 mmol, 2 equiv) was added
and the mixture stirred until complete conversion had occurred as
judged by TLC. The reaction was quenched by the addition of 10%
HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers
were combined, washed with brine, dried (MgSO4), filtered, and
concentrated by rotary evaporation to afford the crude product as a
colorless oil. Purification by silica flash chromatography (hexanes/
EtOAc 2:1) yielded diol 17 (48 mg, 0.20 mmol, 95%) as a colorless
oil. IR (neat) (cm−1): 3732−3102, 2932, 1447, 1059, 946, 759, 698.
1H NMR (600 MHz): δ 7.39−7.32 (m, 4H), 7.31−7.24 (m, 1H), 5.20
(t, J = 5.9 Hz, 1H), 3.62 (t, J = 6.5 Hz, 2H), 2.14−2.00 (m, 4H), 1.84
(quint, J = 7.5 Hz, 1H), 1.78−1.71 (m, 1H), 1.67 (hept, J = 6.1 Hz,
2H), 1.59 (s, 3H). 13C NMR (151 MHz): δ 144.6, 135.5, 128.4, 127.5,
125.9, 124.2, 73.8(t), 62.8, 38.8, 36.0, 30.7, 24.3, 15.9. HRMS (ESI):
m/z calcd for (C15H21DO2Na [M + Na]+) 258.1580, found 258.1578.
2. Oxidative Cyclization−Redox Relay Reactions. 2a. Repre-
sentative Procedure for PdCl2/BQ Oxidative Cyclization−redox
Relay. 4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)butanal (2b). In a
5 mL round-bottom flask charged with PdCl2 (1.9 mg, 0.011 mmol,
0.05 equiv) and 1,4-benzoquinone (46.1 mg, 427 mmol, 2.0 equiv)
dissolved in THF (1 mL) was added diol 1 (50 mg, 0.22 mmol) as a
solution in THF (1 mL). The solution was then stirred at rt until
complete conversion had occurred as judged by TLC. The reaction
mixture was quenched by the addition of 5% NaOH (2 mL) and
extracted with Et2O (3 × 1 mL). The organic layers were combined,
washed with brine (1 mL), dried (MgSO4), filtered, and concentrated
by rotary evaporation to afford the crude product as a colorless oil.
Purification by silica flash chromatography (hexanes/EtOAc 9:1)
yielded tetrahydrofuran 2b (46 mg, 0.20 mmol, 93%) as a colorless oil.
(E)-4-Methyl-8-oxo-8-phenyloct-4-enal (S39).23 In a 100 mL
round-bottom flask, diene S38 (8.50 g, 33.2 mmol) was dissolved in
CH2Cl2 (30 mL), and the solution was cooled to 0 °C. m-CPBA (77%,
8.17 g, 36.5 mmol, 1.2 equiv) was added, and the solution was stirred
at 0 °C until complete conversion had occurred as judged by TLC.
The mixture was quenched with satd aq Na2S2O3 (50 mL) and
extracted with CH2Cl2 (3 × 20 mL). The organic fractions were
pooled, washed with 1 M NaOH (20 mL) and brine (20 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford
the crude epoxide product as a colorless oil which was taken on to the
next step without purification.
In a 250 mL round-bottom flask, the crude epoxide above was
dissolved in THF/H2O (9:1, 100 mL) and cooled to 0 °C. NaIO4
(3.30 g, 19.9 mmol, 0.6 equiv) and HIO4 (7.00 g, 36.5 mmol,
1.1 equiv) was added, and the solution was warmed to rt and stirred
until complete conversion had occurred as judged by TLC. The
mixture was quenched with satd aq Na2S2O3 (50 mL) and extracted
with Et2O (3 × 50 mL). The organic fractions were pooled, washed
with 1 M NaOH (50 mL) and brine (50 mL), dried (MgSO4), filtered,
and concentrated by rotary evaporation to afford the crude product as
a gray oil. Purification by silica flash chromatography (19:1 hexanes/
EtOAc) yielded aldehyde S39 (5.05 g, 21.9 mmol, 66%) as a colorless
oil. IR (neat) (cm−1): 2927, 2898, 2360, 2342, 1723, 1685, 1449, 1253,
1105, 837, 743, 691. 1H NMR (500 MHz): δ 9.75 (s, 1H), 7.96 (d, J =
8.2 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 7.9 Hz, 2H), 5.23 (t,
J = 7.2 Hz, 1H), 3.01 (t, J = 7.3 Hz, 2H), 2.52 (t, J = 7.9 Hz, 2H), 2.45
(q, J = 7.3 Hz, 2H), 2.33 (t, J = 7.5 Hz, 2H), 1.66 (s, 3H). 13C NMR
(126 MHz): δ 202.4, 199.8, 137.0, 134.4, 133.0, 128.6, 128.0, 123.9,
M
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Article
The stereochemical configuration of the major diastereomer was
assigned based on 1D NOE (Figure S4) and 2D NOESY analyses.16
2b. Analytical Data for Alternative Products 2a and 3. (E)-4-(2-
Methyl-5-phenyltetrahydrofuran-2-yl)but-3-en-1-ol (2a). Prepared
from diol 1 under the representative procedure above but with the
alternative catalyst systems shown in Table 1. IR (neat) (cm−1):
3732−3130, 2966, 2929, 2869, 1684, 1493, 1371, 1290, 1203, 1041,
972, 748, 698. 1H NMR (600 MHz): δ 7.40−7.35 (m, 2H), 7.35−7.30
(m, 2H), 7.27−7.23 (m, 1H), 5.83−5.77 (m, 1H), 5.67 (dt, J = 15.5,
7.1 Hz, 1H), 5.05−4.97 (m, 1H), 3.68−3.55 (m, 2H), 2.36−2.27 (m,
2H), 2.10−2.01 (m, 2H), 1.95−1.87 (m, 2H), 1.44 (d, J = 7.5 Hz,
3H). 13C NMR (151 MHz, CDCl3): δ 143.5, 139.8, 139.2, 128.3,
127.3, 126.0, 125.8, 123.6, 123.3, 83.0, 82.8, 80.7, 62.0, 38.6, 37.8, 35.7,
35.0, 34.8, 31.6, 27.5, 26.9, 22.7, 14.2. HRMS (ESI): m/z calcd for
(C15H 20O2 [M + Na]+) 255.1361, found 255.1371.
4-(5-(tert-Butyl)-2-methyltetrahydrofuran-2-yl)butanal (5d). Pre-
pared from diol 4d according to the representative procedure above.
IR (neat) (cm−1): 2967, 1723, 1458, 1371, 1313, 1261, 1135, 977, 883,
771, 703. 1H NMR (600 MHz): δ 9.78 (t, J = 1.8 Hz, 1H), 3.63 (dd, J =
7.9, 6.7 Hz, 0.12H minor, C5-H), 3.55 (dd, J = 8.9, 5.4 Hz, 0.88H
major, C5-H), 2.47 (td, J = 7.3, 1.7 Hz, 2H), 1.81−1.58 (m, 6H),
1.59−1.44 (m, 2H), 1.15 (s, 3H), 0.86 (s, 9H). 13C NMR (151 MHz):
δ 203.0, 87.3, 81.8, 44.3, 40.5, 37.2, 33.2, 26.7, 26.6, 25.9, 17.3. HRMS
(ESI): m/z calcd for (C13H25O2 [M + H]+) 213.1855, found 213.1846.
Ethyl 2-(5-Methyl-5-(4-oxobutyl)tetrahydrofuran-2-yl)acetate
(5e). Prepared from diol 4e according to the representative procedure
above. IR (neat) (cm−1): 2941, 1711, 1450, 1380, 1280, 1111, 1067,
1
1025, 703. H NMR (600 MHz): δ 9.77 (s, 1H), 4.35 (quint, J =
6.7 Hz, 0.37H minor, C5-H), 4.28 (dq, J = 8.1, 6.3 Hz, 0.63H major,
C5-H), 4.14 (q, J = 7.1 Hz, 2H), 2.62 (ddd, J = 18.9, 15.1, 6.4 Hz, 1H),
2.51−2.38 (m, 3H), 2.22−2.04 (m, 1H), 1.90−1.77 (m, 1H), 1.77−
1.65 (m, 5H), 1.59−1.42 (m, 1H), 1.32−1.23 (m, 3H), 1.21 (s, 2H),
1.20 (s, 1H). 13C NMR (151 MHz): δ 202.7, 171.3, 82.9, 75.1, 60.4,
44.2, 41.4, 40.5, 36.9, 31.7, 27.0, 17.2, 14.2. HRMS (ESI): m/z calcd
3-(2-Methyltetrahydro-2H-pyran-2-yl)-1-phenylpropan-1-one
(3). Prepared from diol 1 under the representative procedure above,
1
but with the alternative catalyst systems shown in Table 1. H NMR
(600 MHz): δ 7.93 (d, J = 6.7 Hz, 1H), 7.51−7.46 (m, 1H), 7.39
(t, J = 7.7 Hz, 2H), 7.26 (quint, J = 7.5 Hz, 1H), 3.57 (dddd, J = 15.1,
11.4, 6.4, 4.4 Hz, 2H), 3.06−2.93 (m, 2H), 2.13 (ddd, J = 15.1, 9.9, 5.7
Hz, 1H), 1.69 (ddd, J = 14.4, 9.9, 6.0 Hz, 1H), 1.64−1.57 (m, 1H),
1.48−1.39 (m, 4H), 1.14 (s, 3H). 13C NMR (151 MHz): δ 200.7,
137.1, 132.9, 128.6, 128.1, 72.3, 61.7, 35.6, 32.7, 32.6, 30.3, 29.7, 25.8,
23.8, 19.3.
+
for (C13H 22O4 Na [M + Na] ) 265.1416, found 265.1404.
4-((2S,5R)-5-(2-Hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-
yl)butanal (5f). Prepared from diol 4f according to the representative
procedure above. IR (neat) (cm−1): 3648−3154, 2972, 2871, 1727,
1
1463, 1378, 1064, 706. H NMR (600 MHz): δ 9.78 (t, J = 1.6 Hz,
1H), 3.79 (dd, J = 8.1, 6.6 Hz, 0.33H minor, C5-H), 3.74−3.69 (m,
0.67H major, C5-H), 2.48 (t, J = 7.4 Hz, 2H), 2.14 (s, 1H), 1.90−1.76
(m, 2H), 1.76−1.64 (m, 4H), 1.56−1.45 (m, 2H), 1.20 (s, 6H), 1.12
(s, 3H). 13C NMR (151 MHz): δ 202.7, 85.8, 82.8, 70.6, 44.2, 40.6,
37.4, 27.6, 26.5, 24.0, 17.2. HRMS (ESI): m/z calcd for (C12H22O3Na
2c. Analytical Data for Tetrahydrofuran Products 2b, 5a−j, 12−
14, 16, and 18. 4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)butanal
(2b). Prepared from diol 1 according to the procedure above. IR
1
(neat) (cm−1): 2933, 2862, 1450, 1058, 1030, 699, 535. H NMR
+
(600 MHz): δ 9.79 (t, J = 1.6 Hz, 1H), 7.38−7.30 (m, 4H), 7.26−7.20
(m, 1H), 4.96 (dd, J = 8.0, 6.4 Hz, 0.14H minor, C5-H), 4.91 (dd, J =
8.7, 5.8 Hz, 0.86H major, C5-H), 2.50 (t, J = 7.2 Hz, 2H), 2.33−2.26
(m, 1H), 2.00−1.87 (m, 2H), 1.87−1.82 (m, 1H), 1.82−1.72 (m, 2H),
1.71−1.59 (m, 2H), 1.35 (s, 3H). 13C NMR (151 MHz): δ 202.7,
143.3, 128.3, 127.2, 125.8, 83.2, 81.1, 44.3, 40.8, 37.6, 35.6, 26.9, 17.3.
[M + Na] ) 237.1467, found 237.1476.
4-(2,5,5-Trimethyltetrahydrofuran-2-yl)butanal (5g). Prepared
from diol 4g according to the representative procedure above, but at
a reaction temperature of 60 °C. IR (neat): 2973, 2360, 2337, 1714,
1652, 1451, 1269, 1188, 1039, 984, 749, 699. 1H NMR (600 MHz): δ
9.77 (t, J = 1.7 Hz, 1H), 2.45 (td, J = 7.3, 1.8 Hz, 2H), 1.94−1.83 (m,
2H), 1.83−1.74 (m, 2H), 1.75−1.65 (m, 2H), 1.59−1.43 (m, 2H),
1.26 (s, 3H), 1.21 (s, 6H). 13C NMR (151 MHz): δ 202.8, 82.9, 80.9,
44.3, 41.9, 38.5, 36.9, 29.9, 29.5, 27.5, 17.5. HRMS (ESI): m/z calcd
HRMS (ESI): m/z calcd for (C15H21O [M + H]+) 233.1542, found
2
233.1545.
4-(2,5-Dimethyltetrahydrofuran-2-yl)butanal (5a). Prepared from
diol 4a according to the representative procedure above. IR (neat)
+
for (C11H20O2Na [M + Na] ) 207.1361, found 207.1354.
1
(cm−1): 2970, 2879, 1712, 1451, 1377, 1282, 1114, 713. H NMR (600
4-(2-Methyl-5,5-diphenyltetrahydrofuran-2-yl)butanal (5h). Pre-
pared from diol 4h according to the representative procedure above,
but at a reaction temperature of 60 °C. IR (neat) (cm−1): 3058, 2966,
2872, 1723, 1684, 1598, 1448, 1047, 1010, 699. 1H NMR (600 MHz):
δ 9.71 (t, J = 1.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 4H), 7.30−7.23
(m, 4H), 7.17 (q, J = 7.3 Hz, 2H), 2.73−2.66 (m, 1H), 2.66−2.59 (m,
1H), 2.41 (q, J = 7.2 Hz, 2H), 1.89−1.76 (m, 3H), 1.73−1.63 (m,
1H), 1.59−1.47 (m, 2H), 1.28 (s, 3H). 13C NMR (151 MHz): δ 202.8,
148.0, 147.6, 128.0, 127.9, 126.5, 126.4, 125.8, 125.7, 88.0, 84.0, 44.2,
MHz): δ 9.77 (t, J = 1.7 Hz, 1H), 4.11−4.05 (m, 0.29H minor, C5-H),
4.05−3.98 (m, 0.71H major, C5-H), 2.46 (t, J = 7.2 Hz, 2H), 2.02−1.95
(m, 1H), 1.83−1.75 (m, 1H), 1.75−1.64 (m, 2H), 1.57−1.44 (m, 4H),
1.23 (d, J = 6.0 Hz, 3H), 1.21 (s, 2H), 1.20 (s, 1H). 13C NMR
(151 MHz, CDCl3) δ 202.7, 82.4, 75.0, 44.3, 40.8, 37.4, 33.8, 27.3, 21.8,
17.3. HRMS (ESI): m/z calcd for (C10H18O2 Na [M + Na] +) 193.1204,
found 193.1195.
4-(5-Butyl-2-methyltetrahydrofuran-2-yl)butanal (5b). Prepared
from diol 4b according to the representative procedure above.
IR (neat) (cm−1): 2958, 2869, 1710, 1459, 1376, 1110, 1038,
41.7, 38.6, 37.6, 26.4, 17.6. HRMS (ESI): m/z calcd for (C21H24O
Na [M + Na] ) 331.1674, found 331.1670.
2
+
1
884, 742. H NMR (600 MHz): δ 9.77 (t, J = 1.7 Hz, 1H), 3.96
3-(2-Methyl-5-phenyltetrahydrofuran-2-yl)propanal (5i). Pre-
pared from diol 4i according to the representative procedure above.
IR (neat) (cm−1): 2934, 1713, 1685, 1450, 1281, 1114, 713. 1H NMR
(600 MHz): δ 9.80 (dd, J = 2.2, 1.5 Hz, 1H), 7.34−7.30 (m, 4H),
7.26−7.22 (m, 1H), 4.96 (dd, J = 8.4, 6.2 Hz, 0.37H minor, C5-H),
4.85 (dd, J = 8.6, 6.1 Hz, 0.73H major, C5-H), 2.68−2.52 (m, 3H),
2.36−2.29 (m, 1H), 2.04−1.83 (m, 4H), 1.36 (s, 2H), 1.32 (s, 1H).
13C NMR (151 MHz): δ 202.4, 143.0, 128.3, 127.3, 125.8, 82.5, 81.0,
39.4, 37.5, 35.3, 33.3, 27.1. HRMS (ESI): m/z calcd for (C14H18O2 Na
(dd, J = 8.0, 6.4 Hz, 0.22H minor, C5-H), 3.85 (dq, J = 8.8, 6.1 Hz,
0.78H major, C5-H), 2.46 (t, J = 7.4 Hz, 2H), 1.99−1.92 (m, 1H),
1.82−1.73 (m, 1H), 1.72−1.66 (m, 2H), 1.66−1.56 (m, 3H), 1.56−
1.44 (m, 2H), 1.44−1.37 (m, 1H), 1.37−1.23 (m, 4H), 1.19 (d, J =
2.7 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ
202.8, 82.0, 79.3, 44.3, 40.7, 37.1, 36.2, 31.8, 28.2, 27.1, 22.9, 17.3,
14.1. HRMS (ESI): m/z calcd for (C13H 25O2 [M + H]+) 213.1855,
found 213.1848.
4-(2-Methyl-5-(prop-1-en-2-yl)tetrahydrofuran-2-yl)butanal (5c).
Prepared from diol 4c according to the representative procedure
above. IR (neat) (cm−1): 2935, 2863, 1721, 1459, 1379, 1063, 902. 1H
NMR (600 MHz): δ 9.78 (t, J = 1.7 Hz, 1H), 5.00 (s, 1H), 4.79 (s,
1H), 4.37 (t, J = 7.1 Hz, 0.79H major, C5-H), 4.32 (t, J = 7.3 Hz,
0.21H minor, C5-H), 2.47 (td, J = 7.3, 1.7 Hz, 2H), 2.11−1.99 (m,
1H), 1.87−1.78 (m, 1H), 1.78−1.66 (m, 4H), 1.64−1.50 (m, 5H),
1.28−1.17 (m, 3H). 13C NMR (151 MHz): δ 202.7, 145.7, 134.8,
110.2, 81.4, 44.3, 41.2, 37.0, 31.3, 25.8, 18.1, 17.4. HRMS (ESI): m/z
calcd for (C12H 21O2 [M + H]+) 197.1542, found 197.1549.
+
[M + Na] ) 241.1204, found 241.1204.
5-(2-Methyl-5-phenyltetrahydrofuran-2-yl)pentanal (5j). Pre-
pared from diol 4j according to the representative procedure above.
IR (neat) (cm−1): 2945, 1707, 1279, 1175, 1113, 711. 1H NMR
(600 MHz): δ 9.78 (t, J = 1.8 Hz, 1H), 7.38−7.29 (m, 4H), 7.25−7.20
(m, 1H), 4.95 (dd, J = 8.4, 6.1 Hz, 0.22H minor, C5-H), 4.90 (dd, J =
8.6, 5.8 Hz, 0.78H major, C5-H), 2.47 (td, J = 7.3, 1.7 Hz, 2H), 2.34−
2.25 (m, 1H), 1.96−1.86 (m, 2H), 1.86−1.76 (m, 1H), 1.74−1.63
(m, 4H), 1.54−1.38 (m, 2H), 1.33 (s, 2.4H), 1.29 (s, 0.6H). 13C NMR
(151 MHz): δ 202.8, 143.4, 128.3, 127.2, 125.8, 83.3, 81.1, 43.9, 41.4,
N
DOI: 10.1021/acs.joc.6b02053
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37.6, 35.6, 27.0, 24.2, 22.6. HRMS (ESI): m/z calcd for (C16H22O2 Na
[M + Na] ) 269.1517, found 269.1520.
1.70−1.52 (m, 3H), 1.21 (s, 3H). 13C NMR (151 MHz): δ 200.3,
137.0, 132.9, 128.6, 128.0, 82.5, 67.2, 40.7, 38.9, 36.6, 26.1, 25.7, 19.6.
HRMS (ESI): m/z calcd for (C 15H21O2 [M + H]+) 233.1542, found
233.1546.
+
(E)-tert-Butyldimethyl((4-(2-methyl-5-phenyltetrahydrofuran-2-
yl)but-3-en-1-yl)oxy)silane (7). Prepared from TBS ether 6 under the
representative procedure above, but with the alternative catalyst
4-(2-Methyltetrahydrofuran-2-yl)-1-phenylbutan-1-one-2-d (18).
Prepared from diol 17 according to the representative procedure
above. IR (neat): 2965, 2870, 1682, 1597, 1449, 1373, 1268, 1178,
1045, 744, 692. 1H NMR (600 MHz): δ 7.89 (d, J = 7.5 Hz, 2H), 7.48
(t, J = 7.1 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 3.77 (q, J = 7.8 Hz, 1H),
3.72 (q, J = 7.3 Hz, 1H), 2.90 (qq, J = 6.1, 3.5, 2.9 Hz, 1H), 1.94−1.79
(m, 2H), 1.77−1.64 (m, 3H), 1.67−1.54 (m, 2H), 1.57−1.49 (m, 1H),
1.13 (s, 3H). 13C NMR (151 MHz): δ 200.4, 137.0, 132.9, 128.6,
128.0, 82.5, 67.2, 40.7, 38.7, 38.6, 38.4, 36.6, 26.1, 25.8, 19.5. HRMS
(ESI): m/z calcd for (C15O2H20 D [M + H] +) 234.1604, found
234.1608.
3. Deuterium Labeling Experiments. 3a. Singly Vinylic
Deuterium-Labeled Diol Substrate 19a (→ 23a, 24a). 6-((tert-
Butyldiphenylsilyl)oxy)-2-methylhex-1-en-3-one (S41). In a 100 mL
round-bottom flask, alcohol S3 (1.00 g, 2.71 mmol) was dissolved in
CH2Cl2 (30 mL). PCC (1.17 g, 5.43 mmol, 2 equiv) was added and
the solution was stirred at rt until complete conversion had occurred as
judged by TLC. The mixture was filtered through a pad of silica with
hexane/EtOAc 9:1 and concentrated by rotary evaporation to afford
ketone S41 (0.95 g, 2.59 mmol, 95%) as a colorless oil. IR (neat)
(cm−1): 3070, 3049, 3016, 2931, 2858, 1678, 1470, 1427, 1107, 964,
794, 738, 701. 1H NMR (600 MHz): δ 7.68−7.61 (m, 2H), 7.46−7.32
(m, 8H), 5.96 (s, 1H), 5.75 (s, 1H), 3.70 (t, J = 6.0 Hz, 2H), 2.80
(t, J = 7.4 Hz, 2H), 1.87 (s, 3H), 1.05 (s, 9H). 13C NMR (151 MHz,
CDCl3): δ 201.9, 144.4, 135.5, 133.8, 129.6, 127.7, 124.5, 63.1, 33.8,
27.3, 26.8, 19.2, 17.7. HRMS (ESI): m/z calcd for (C23H30O2SiNa
[M + Na]+) 389.1913, found 389.1908.
6-((tert-Butyldiphenylsilyl)oxy)-2-methylhex-1-en-3-d-3-ol (S42).
In a 25 mL round-bottom flask, ketone S41 (1.00 g, 2.73 mmol)
was dissolved in MeOH (10 mL) at rt. CeCl3·7(H2O) (1.01 g,
2.73 mmol) was added with stirring, followed by NaBD4 (114 mg,
2.73 mmol, 1 equiv). The solution was stirred until complete con-
version had occurred as judged by TLC. The reaction was quenched
by the addition of 10% HCl (10 mL) and extracted with Et2O (3 ×
10 mL). The organic layers were combined, washed with brine, dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford
the crude product as a colorless oil. Purification by silica flash chroma-
tography (hexanes/EtOAc 4:1) yielded allylic alcohol S42 (780 mg,
2.11 mmol, 77%) as a colorless oil. 1H NMR (600 MHz): δ 7.69−7.64
(m, 2H), 7.45−7.40 (m, 4H), 7.40−7.35 (m, 4H), 4.95 (s, 1H),
4.84 (s, 1H), 3.71−3.65 (m, 2H), 1.72 (s, 5H), 1.67−1.54 (m, 4H),
1.05 (s, 9H). 13C NMR (151 MHz): δ 147.4, 135.6, 133.7, 129.6,
127.6, 111.0, 75.1(t), 63.9, 31.6, 28.5, 26.8, 19.2, 17.7. HRMS (ESI):
m/z calcd for (C23H32DO2Si [M + H]+) 370.2311, found 370.2313.
Ethyl (E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-enoate-5-
d (S43). In a 25 mL round-bottom flask, allylic alcohol S42 (780 mg,
2.11 mmol), triethyl orthoacetate (10 mL), and propionic acid (16 μL,
0.21 mmol, 0.1 equiv) were added. The flask was equipped with a
distillation head and heated to 140 °C during which time ethanol was
collected. Heating was continued at this temperature until complete
conversion had occurred as judged by TLC. The mixture was cooled
to rt and quenched with 1 M HCl (10 mL). The mixture was extracted
with Et2O (3 × 10 mL), washed with 1 M NaOH (10 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation to afford the
crude product as a yellow oil. Purification by silica flash chroma-
tography (9:1 hexanes/EtOAc) yielded ester S43 (750 mg, 80%) as a
colorless oil. 1H NMR (600 MHz): δ 7.66 (d, J = 6.5 Hz, 2H), 7.44−
7.34 (m, 8H), 4.11 (q, J = 7.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 2.39−
2.34 (m, 2H), 2.28 (dd, J = 8.9, 6.2 Hz, 2H), 2.06 (t, J = 7.4 Hz, 2H),
1.67−1.50 (m, 5H), 1.24 (t, J = 7.2 Hz, 3H), 1.05 (s, 9H). 13C NMR
(151 MHz): δ 173.5, 135.6, 134.8, 134.1, 129.5, 127.6, 124.5 (t), 63.3,
60.2, 34.6, 33.2, 32.3, 26.8, 24.0, 19.2, 15.9, 14.3. HRMS (ESI): m/z
calcd for (C27H38DO3Si [M + H]+) 440.2731, found 440.2740.
(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1,1-diphenyloct-4-
en-5-d-1-ol (S44). In a 25 mL round-bottom flask, ester S43 (750 mg,
1.71 mmol) was dissolved in THF (10 mL), and the solution was
1
systems shown in Table 3. H NMR (600 MHz): δ 7.91 (d, J =
7.01 Hz, 0.6H), 7.50 (t, J = 6.64 Hz, 0.3H), 7.40 (t, J = 7.66, 0.6H),
7.34−7.29 (m, 1.5H), 7.26 (t, J = 7.25 Hz, 1.5H), 7.20−7.17
(m, 0.8H), 5.71−5.57 (m, 2H), 5.13 (t, J = 6.64 Hz, 0.28H minor,
C5-H), 4.97−4.92 (m, 0.72H major, C5-H), 3.62−3.58 (m, 1.32H
major, CH2OSi), 3.54 (t, J = 7.66 Hz, 0.68H minor, CH2OSi) 3.02−
3.00 (m, 0.5H), 3.36 (t, J = 6.13 Hz, 0.5H), 2.28−2.21 (m, 2H), 2.01−
1.96 (m, 1H), 1.94−1.91 (m, 0.4H), 1.87−1.79 (m, 1.5H), 1.49 (quint.
J = 6.13 Hz, 0.6H), 1.39 (s, 0.80H minor, C1-Me), 1.35 (s, 2.20H
major, C1-Me), 0.84 (s, 9H), 0.02 − −0.01 (m, 6H). 13C NMR
(151 MHz): δ 1.43.8, 1.43.1, 1.38.25, 1.37.6, 137.0, 134.1, 132.9, 128.6,
128.2, 18.1, 127.2, 126.1, 125.8, 124.8, 124.2, 124.1, 83.1, 82.8, 80.7,
80.4, 63.1, 62.6, 38.6, 37.5, 36.0, 35.0, 34.1, 32.9, 27.4, 26.9, 26.0, 24.2,
18.4, 16.2, −5.2. HRMS (ESI): m/z calcd for (C21H35O2 [M + H]+)
346.2328, found 346.2331.
Ethyl (E)-4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)but-2-enoate
(12). Prepared from hydroxy ester 9 according to the representative
procedure above, but at a reaction temperature of 60 °C. Diastereo-
meric ratio of crude reaction product was 4:1, which increased to 10:1
following purification by silica gel chromatography. IR (neat): 3030,
2971, 2933, 2872, 1716, 1653, 1493, 1451, 1309, 1270, 1188, 1040,
1
985, 940, 749, 699. H NMR (600 MHz): δ 7.38−7.26 (m, 4H),
7.28−7.22 (m, 1H), 7.03 (dt, J = 15.5, 7.7 Hz, 1H), 5.91 (dt, J = 15.6,
1.4 Hz, 1H), 5.03−4.97 (m, 0.09H minor, C5-H), 4.95 (dd, J = 8.7,
5.9 Hz, 0.91H major, C5-H), 4.20 (q, J = 7.1 Hz, 2H), 2.58−2.48
(m, 2H), 2.37−2.26 (m, 1H), 2.02−1.80 (m, 3H), 1.38 (s, 3H), 1.29
(t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 166.4, 145.1, 143.0,
128.3, 127.3, 125.8, 124.1, 82.8, 81.3, 60.3, 44.3, 37.2, 35.4, 27.5, 14.3.
+
HRMS (ESI): m/z calcd for (C17H22O3 Na [M + Na] ) 297.1467,
found 297.1461.
(E)-4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)but-2-enoic Acid
(13). Prepared from hydroxy acid 10 according to the representative
procedure above, but at a reaction temperature of 60 °C. IR (neat):
3772−3131, 3031, 2971, 2874, 2821, 2360, 1695, 1651, 1451, 1279,
1
1216, 1040, 986, 941, 909, 748, 698. H NMR (600 MHz): δ 7.38−
7.29 (m, 4H), 7.29−7.24 (m, 1H), 7.14 (dt, J = 15.5, 7.7 Hz, 3H), 5.93
(dt, J = 15.6, 1.4 Hz, 1H), 5.02−4.95 (m, 1H), 2.56 (dt, J = 7.6, 1.6 Hz,
2H), 2.37−2.26 (m, 1H), 2.02−1.84 (m, 3H), 1.38 (s, 2.03H major,
C1-Me), 1.35 (s, 0.97H minor, C1-Me). 13C NMR (151 MHz): δ
170.9, 148.1, 142.9, 128.4, 127.4, 125.8, 123.3, 82.7, 81.4, 44.9, 37.3,
+
35.2, 27.5. HRMS (ESI): m/z calcd for (C15H 18O3 Na [M + H] )
269.1154, found 269.1159.
(E)-N-Methoxy-N-methyl-4-(2-methyl-5-phenyltetrahydrofuran-
2-yl)but-2-enamide (14). Prepared from hydroxy Weinreb amide 11
according to the representative procedure above, but at a reaction
temperature of 60 °C. The 2:1 dr was determined based on relative
peak integrations of the NMe, OMe, and C1-Me groups. Resonances
for the minor diastereomer were also observable, but not resolved, for
C5-H and the amide side chain β-H. IR (neat) (cm−1): 2971, 2938,
1667, 1638, 1421, 1384, 1313, 1097, 1046, 1002, 705. 1H NMR
(600 MHz): δ 7.39−7.30 (m, 4H), 7.26−7.21 (m, 1H), 7.09−7.00
(m, 1H), 6.51 (d, J = 15.3 Hz, 1H), 5.01−4.93 (m, 1H), 3.71 (s, 2.07H
major, NMe), 3.70 (s, 0.93H minor, NMe), 3.26 (s, 2.03H major,
OMe), 3.25 (s, 0.97H minor, OMe), 2.63−2.53 (m, 2H), 2.38−2.27
(m, 1H), 2.06−1.97 (m, 1H), 1.96−1.79 (m, 2H), 1.39 (s, 2.03H
major, C1-Me), 1.36 (s, 0.97H minor, C1-Me). 13C NMR (151 MHz,
CDCl3): δ 143.4, 143.0, 128.3, 127.2, 125.9, 125.8, 121.6, 83.0, 82.8,
81.3, 80.3, 61.7, 44.7, 36.9, 35.5, 27.7. HRMS (ESI): m/z calcd for
(C17H24NO3 [M + H]+) 290.1756, found 290.1761.
4-(2-Methyltetrahydrofuran-2-yl)-1-phenylbutan-1-one (16). Pre-
pared from diol 15 according to the representative procedure above.
1
IR (neat): 2925, 2856, 1686, 1452, 1376, 1105, 754, 700. H NMR
(600 MHz): δ 7.96 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.46
(t, J = 7.8 Hz, 2H), 3.84 (q, J = 7.8 Hz, 1H), 3.80 (q, J = 6.9 Hz, 1H),
3.00 (td, J = 7.1, 1.6 Hz, 2H), 1.98−1.86 (m, 2H), 1.84−1.74 (m, 3H),
O
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cooled to 0 °C. PhMgBr (1.0 M in THF, 3.75 mL, 3.75 mmol,
2.2 equiv) was added dropwise with stirring. Once addition was
complete, the solution was allowed to warm to rt, and stirring was
continued until complete conversion had occurred as judged by TLC.
The mixture was quenched with 1 M HCl (10 mL), extracted with
Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by
rotary evaporation to afford the crude product as a yellow oil. Purifi-
cation by silica flash chromatography (4:1 hexanes/EtOAc) yielded
3.06 mmol) was suspended in D2O (3 mL), and DMAP (37 mg,
0.306 mmol, 10 mol %) was added. The suspension was heated to
70 °C for 12 h. The reaction mixture was diluted with 1 M HCl
(10 mL), extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered,
and concentrated by rotary evaporation to afford the crude product as
a colorless oil. The product was purified by silica flash chromatography
(9:1 hexanes/EtOAc) to yield diol S45 (0.99 g, 0.303 mmol, 99%) as a
colorless oil. 1H NMR (600 MHz): δ 9.79 (s, 1H), 7.65 (d, J = 6.5 Hz,
2H), 7.45−7.34 (m, 8H), 3.69 (t, J = 6.0 Hz, 2H), 1.87 (t, J = 6.0 Hz,
2H), 1.04 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 202.8, 135.5,
134.8, 133.5, 129.7, 127.7, 127.7, 62.9, 40.0 (p), 26.8, 26.5, 25.1, 19.2.
HRMS (ESI): m/z calcd for (C20H25D2O2Si [M + H]+) 329.1906,
found 329.1912.
6-((tert-Butyldiphenylsilyl)oxy)-2-methylhex-1-en-4,4-d2-3-ol
(S46). In a 25 mL round-bottom flask, aldehyde S45 (950 mg,
2.89 mmol) was dissolved in THF (5 mL), and the solution was
cooled to 0 °C. Isopropenylmagnesium bromide (0.5 M in THF,
5.8 mL, 2.9 mmol, 1 equiv) was added slowly via syringe. Once
addition of the Grignard was complete, the cooling bath was removed
and the solution was allowed to stir at rt until complete conversion had
occurred as judged by TLC. The mixture was recooled to 0 °C and
quenched with 1 M HCl (10 mL). The mixture was extracted with
Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by
rotary evaporation to afford the crude product as a yellow oil. Purifi-
cation by silica flash chromatography (4:1 hexanes/EtOAc) yielded
allylic alcohol S46 (850 mg, 2.29 mmol, 79%) as a yellow oil. 1H NMR
(600 MHz): δ 7.69−7.65 (m, 2H), 7.46−7.34 (m, 8H), 4.95 (s, 1H),
4.84 (s, 1H), 4.07 (s, 1H), 3.72−3.64 (m, 2H), 1.72 (s, 3H), 1.65−
1.54 (m, 2H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 147.5,
135.6, 135.5 134.8, 133.7, 129.6, 127.7, 110.9, 75.5, 63.9, 31.0(p), 28.3,
26.8, 26.5, 19.2, 17.7. HRMS (ESI): m/z calcd for (C23H31D2O2Si
[M + H]+) 371.2375, found 371.2358.
1
alcohol S44 (505 mg, 0.92 mmol, 54%) as a colorless oil. H NMR
(600 MHz): δ 7.69−7.63 (m, 4H), 7.45−7.33 (m, 10H), 7.31 (dd, J =
8.4, 7.1 Hz, 4H), 7.22 (t, J = 8.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H),
2.39−2.34 (m, 2H), 2.09−2.01 (m, 2H), 1.99−1.93 (m, 2H), 1.58 (tq,
5H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 147.0, 135.5, 134.8, 134.0,
129.5, 128.1, 127.6, 126.7, 126.0, 124.2 (t), 78.5, 63.4, 40.0, 34.0, 32.6,
26.8, 24.1, 19.2, 16.2. HRMS (ESI): m/z calcd for (C37H43DO2SiNa
[M + Na]+) 572.3068, found 572.3071.
(E)-4-Methyl-1,1-diphenyloct-4-ene-5-d-1,8-diol (19a). In a 10 mL
round-bottom flask, protected alcohol S44 (425 mg, 0.77 mmol) was
dissolved in THF (8 mL) at rt. TBAF (1.0 M in THF, 1.55 mL,
1.55 mmol, 2 equiv) was added, and the solution was stirred until
complete conversion had occurred as judged by TLC. The reaction
mixture was concentrated by rotary evaporation. Purification by silica
flash chromatography (1:1 hexanes/EtOAc) yielded diol 19a (220 mg,
1
0.71 mmol, 91%) as a colorless oil. H NMR (600 MHz): δ 7.41
(d, J = 8.1 Hz, 4H), 7.31 (t, J = 8.4 Hz, 4H), 7.22 (t, J = 7.3 Hz, 2H),
3.61 (t, J = 6.5 Hz, 2H), 2.45 (s, 1H), 2.42−2.35 (m, 2H), 2.05 (t, J =
7.4 Hz, 2H), 2.01−1.94 (m, 2H), 1.62 (s, 3H), 1.59 (quint, J = 7.3 Hz,
2H), 1.42 (s, 1H). 13C NMR (151 MHz): δ 146.9, 136.0, 128.1, 126.8,
125.9, 123.8 (t), 78.5, 62.6, 40.0, 33.9, 32.6, 24.1, 16.2. HRMS (ESI):
m/z calcd for (C21H25DO2Na [M + Na]+) 334.1893, found 334.1890.
4-(2-Methyl-5,5-diphenyltetrahydrofuran-2-yl)butanal-4-d (23a).
Prepared from diol 19a according to the representative procedure in
1
Ethyl (E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-enoate-
6,6-d2 (S47). In a 50 mL round-bottom flask, S46 (650 mg,
1.75 mmol), triethyl orthoacetate (5 mL), and propionic acid
(13 μL, 0.18 mmol, 0.1 equiv) were added. The flask was equipped
with a distillation head and heated to 140 °C during which time
ethanol was collected. Heating was continued at this temperature until
complete conversion had occurred as judged by TLC. The mixture was
cooled to rt and quenched with 1 M HCl (10 mL). The mixture was
extracted with Et2O (3 × 10 mL), washed with 1 M NaOH (10 mL),
dried (MgSO4), filtered, and concentrated by rotary evaporation to
afford the crude product as a yellow oil. Purification by silica flash
chromatography (9:1 hexanes/EtOAc) yielded ester S47 (470 mg,
section 2a, but at a reaction temperature of 60 °C. H NMR (600
MHz): δ 9.70 (s, 1H), 7.43 (d, J = 8.3 Hz, 4H), 7.26 (ddd, J = 8.1, 7.1,
4.9 Hz, 4H), 7.20−7.09 (m, 2H), 2.73−2.57 (m, 2H), 2.39 (qd, J =
7.6, 6.8, 1.8 Hz, 2H), 1.88−1.74 (m, 3H), 1.70−1.62 (m, 1H), 1.48
(dd, J = 12.2, 4.6 Hz, 1H), 1.27 (s, 3H). 13C NMR (151 MHz): δ
202.7, 148.0, 147.6, 127.9, 127.9, 126.4, 126.4, 125.8, 125.7, 88.0, 83.9,
44.2, 41.2 (t), 38.6, 37.6, 26.3, 17.5. HRMS (ESI): m/z calcd for
(C21H23DO2Na [M + Na]+) 332.1737, found 332.1741.
2-(3,3-Diphenylpropyl)-6-methoxy-2-methyltetrahydro-2H-
pyran-3-d (24a). In a 5 mL round-bottom flask, diphenyl THF 23a
(10 mg, 0.032 mmol) was dissolved in MeOH (2 mL), and 10% Pd/C
(100 mg) was added. The flask was placed in a Parr reactor, pre-
ssurized to 150 psi with H2, and stirred at rt for 12h. The mixture was
filtered through a pad of Celite and washed with Et2O and the solvent
removed under reduced pressure to afford the product as a mixture of
α- and β-isomers. The isomers were separated by preparative TLC
(benzene/EtOAc 99:1) to yield methoxytetrahydropyran α-24a
(4.7 mg, 0.014 mmol) and β-24a (4.3 mg, 0.012 mmol, 85%) as a
colorless oils.
1
61%) as a colorless oil. H NMR (600 MHz): δ 7.66 (d, J = 6.2 Hz,
2H), 7.43−7.32 (m, 8H), 5.12 (s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.64
(t, J = 6.3 Hz, 2H), 2.36 (q, J = 8.1 Hz, 2H), 2.28 (q, J = 7.6 Hz, 2H),
1.59 (s, 3H), 1.56 (t, J = 6.4 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.05 (s,
9H). 13C NMR (151 MHz): δ 173.5, 135.6, 134.1, 133.8, 129.5, 127.6,
127.6, 124.8, 63.3, 60.2, 34.7, 33.3, 32.5, 26.9, 23.5 (p), 19.2, 15.9, 14.3.
HRMS (ESI): m/z calcd for (C27H37D2O3Si [M + H]+) 441.2794,
found 441.2794.
1
α-24a. H NMR (600 MHz): δ 7.31−7.23 (m, 8H), 7.20−7.15
(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1,1-diphenyloct-4-
en-6,6-d2-1-ol (S48). In a 25 mL round-bottom flask, ester S47
(200 mg, 0.45 mmol) was dissolved in THF (5 mL), and the solution
was cooled to 0 °C. PhMgBr (1.0 M in THF, 1.00 mL, 1.00 mmol,
2.2 equiv) was added dropwise with stirring. Once addition was
complete, the solution was allowed to warm to rt, and stirring was
continued until complete conversion had occurred as judged by TLC.
The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O
(3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary
evaporation to afford the crude product as a yellow oil. Purification by
silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S48
(m, 2H), 4.42 (dd, J = 6.2, 3.0 Hz, 1H), 3.84 (t, J = 7.8 Hz, 1H), 3.41
(s, 3H), 2.12 (q, J = 7.9 Hz, 2H), 1.75−1.69 (m, 1H), 1.69−1.60 (m,
2H), 1.52−1.46 (m, 1H), 1.46−1.36 (m, 2H), 1.25 (s, 3H). 13C NMR
(151 MHz): δ 145.2, 144.9, 128.5, 127.8, 127.8, 126.1, 98.2, 74.5, 55.5,
51.9, 37.0, 35.0, 30.5 (t), 29.3, 26.6, 16.9. HRMS (ESI): m/z calcd for
(C22H27DO2Na [M + Na]+) 348.2050, found 348.2061.
β-24a. 1H NMR (600 MHz): δ 7.31−7.22 (m, 8H), 7.16 (dddd, J =
8.3, 7.0, 4.0, 1.7 Hz, 2H), 4.53 (dd, J = 8.6, 2.5 Hz, 1H), 3.85 (t, J =
7.0 Hz, 1H), 3.40 (s, 3H), 2.23−2.07 (m, 2H), 1.71 (tq, J = 4.1,
3.4 Hz, 2H), 1.61 (ddt, J = 11.7, 8.6, 4.5 Hz 1H), 1.58−1.53 (m, 2H),
1.49 (ddd, J = 13.6, 12.0, 4.9 Hz, 1H), 1.32 (tt, J = 6.1, 4.0 Hz, 1H),
1.17 (s, 3H). 13C NMR (151 MHz): δ 145.4, 144.8, 128.4, 128.4,
127.9, 127.8, 126.1, 126.0, 98.3, 75.1, 55.6, 51.9, 42.2, 34.2 (t),
31.1, 29.4, 21.4, 18.1. HRMS (ESI): m/z calcd for (C22H27DO2Na
[M + Na]+) 348.2050, found 348.2050.
1
(75 mg, 0.14 mmol, 30%) as a colorless oil. H NMR (600 MHz): δ
7.70−7.62 (m, 2H), 7.43−7.38 (m, 8H), 7.37−7.33 (m, 4H), 7.31
(dd, J = 8.4, 7.1 Hz, 4H), 7.24−7.20 (m, 2H), 5.08 (s, 1H), 3.64 (t, J =
6.3 Hz, 2H), 2.40−2.34 (m, 2H), 2.32 (s, 1H), 2.00−1.93 (m, 2H),
1.60 (s, 3H), 1.56 (t, J = 6.4 Hz, 2H), 1.04 (s, 9H). 13C NMR
(151 MHz): δ 147.0, 135.6, 135.5, 134.0, 129.5, 128.1, 127.6, 126.7,
126.0, 124.4, 78.5, 63.3, 40.0, 34.0, 32.4, 26.8, 23.5 (quint.), 19.2, 16.2.
3b. Doubly Allylic Deuterium-Labeled Diol Substrate 19b
(→ 23b, 24b). 4-((tert-Butyldiphenylsilyl)oxy)butanal-2,2-d2
(S45).24 In a 10 mL round-bottom flask, aldehyde S2 (1.00 g,
P
DOI: 10.1021/acs.joc.6b02053
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The Journal of Organic Chemistry
Article
HRMS (ESI): m/z calcd for (C37H42D2O2SiNa [M + Na]+) 573.3134,
found 573.3121.
3.41 (s, 3H), 2.12 (ddd, J = 10.1, 8.3, 7.1 Hz, 2H), 1.73 (dddd, J =
10.6, 8.9, 5.4, 3.5 Hz, 1H), 1.69−1.59 (m, 2H), 1.49 (tdt, J = 12.6, 8.0,
4.1 Hz, 1H), 1.45−1.38 (m, 2H), 1.32−1.21 (m, 5H). 13C NMR
(151 MHz, CDCl3): δ 145.2, 144.9, 128.5, 127.8, 127.8, 126.1, 98.2,
74.6, 55.5, 51.9, 37.0, 35.0, 30.5, 29.3, 26.6, 17.0. HRMS (ESI): m/z
calcd for (C22H28O2Na [M + Na]+) 347.1987, found 347.1972.
β-24-H3. IR (neat) (cm−1): 3060, 3026, 2942, 2872, 1736, 1674,
1599, 1493, 1451, 1377, 1263, 1229, 1160, 1119, 1079, 1033, 1004,
979, 909, 744, 701. 1H NMR (600 MHz): δ 7.30−7.21 (m, 8H), 7.16
(qd, J = 6.7, 3.2 Hz, 2H), 4.53 (dd, J = 8.5, 2.4 Hz, 1H), 3.85 (dd, J =
8.7, 7.0 Hz, 1H), 3.40 (s, 3H), 2.22−2.07 (m, 2H), 1.71 (tq, J = 13.1,
4.2 Hz, 2H), 1.67−1.60 (m, 1H), 1.57−1.53 (m, 2H), 1.49 (ddd, J =
13.6, 12.0, 4.9 Hz, 1H), 1.55 (ddd, J = 13.7, 11.9, 4.8 Hz, 2H), 1.17
(s, 3H). 13C NMR (151 MHz, CDCl3): δ 145.4, 144.8, 128.4, 128.4,
127.9, 127.8, 126.1, 126.0, 98.3, 75.2, 55.6, 51.9, 42.2, 34.2, 31.1, 29.4,
21.5, 18.2. HRMS (ESI): m/z calcd for (C22H28O2Na [M + Na]+)
347.1987, found 347.1982.
4. Computational Studies. 4a. Computational Methods. All
calculations were performed using the M0625 functional implemented
in Gaussian09.26 The Lanl2DZ27 (augmented with one f-function28)
and 6-31G(d,p) basis sets were used for Pd and all other atoms,
respectively. Frequency calculations at the same level of theory at the
optimized geometries were carried out to confirm the stationary points
as minima (zero imaginary frequencies) or transition states (one
imaginary frequency) and provided the thermal corrections to the
single-point energies. Single-point calculations using the SDD basis set
for Pd and the 6-311++G(d,p) basis set for all other atoms and the
SMD solvent model with the parameters for THF were used to
account for solvent effects.
(E)-4-Methyl-1,1-diphenyloct-4-ene-6,6-d2-1,8-diol (19b). In a
10 mL round-bottom flask, protected alcohol S48 (75 mg,
0.14 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in
THF, 0.27 mL, 0.27 mmol, 2 equiv) was added, and the solution was
stirred until complete conversion had occurred as judged by TLC. The
reaction mixture was concentrated by rotary evaporation. Purification
by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 19b
(29 mg, 0.092 mmol, 68%) as a colorless oil. 1H NMR (600 MHz): δ
7.41 (d, J = 7.3 Hz, 3H), 7.30 (t, J = 7.3 Hz, 4H), 7.22 (t, J = 7.3 Hz,
2H), 5.12 (s, 1H), 3.60 (t, J = 6.5 Hz, 2H), 2.42−2.35 (m, 2H), 2.03−
1.94 (m, 2H), 1.62 (d, J = 1.4 Hz, 3H), 1.57 (t, J = 6.6 Hz, 2H).
13C NMR (151 MHz): δ 147.0, 136.1, 128.2, 126.8, 126.0, 124.1, 78.5,
62.6, 40.1, 34.0, 32.4, 23.6 (p), 16.3. HRMS (ESI): m/z calcd for
(C21H24D2O2Na [M + Na]+) 335.1956, found 335.1955.
4-(2-Methyl-5,5-diphenyltetrahydrofuran-2-yl)butanal-3,4-d2
(23b). Prepared from diol 19b according to the representative
procedure in section 2a, but at a reaction temperature of 60 °C.
1H NMR (600 MHz): δ 9.71 (s, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.26
(td, J = 7.6, 3.6 Hz, 4H), 7.17 (q, J = 7.3 Hz, 2H), 2.69 (dt, J = 13.3,
6.8 Hz, 1H), 2.63 (dt, J = 12.8, 7.3 Hz, 1H), 2.39 (t, J = 6.2 Hz, 2H),
1.90−1.76 (m, 2H), 1.66 (quint, J = 7.3 Hz, 1H), 1.54 (d, J = 12.2 Hz,
1H), 1.28 (s, 3H). 13C NMR (151 MHz): δ 202.7, 148.0, 147.6, 127.9,
126.5, 126.4, 125.8, 125.7, 88.0, 84.0, 44.1, 41.2 (t), 38.6, 37.6, 26.4,
17.2 (t). HRMS (ESI): m/z calcd for (C21H22D2O2Na [M + Na]+)
333.1797, found 333.1800.
2-(3,3-Diphenylpropyl)-6-methoxy-2-methyltetrahydro-2H-
pyran-3,4-d2 (24b). In a 5 mL round-bottom flask, diphenyl THF 23b
(10 mg, 0.032 mmol) was dissolved in MeOH (2 mL) and 10% Pd/C
(100 mg) was added. The flask was placed in a Parr reactor, pres-
surized to 150 psi with H2, and stirred at rt for 12 h. The mixture was
filtered through a pad of Celite and washed with Et2O and the solvent
removed under reduced pressure to afford the product as a mixture of
α- and β-isomers. The isomers were separated by preparative TLC
(benzene/EtOAc 99:1) to yield methoxytetrahydropyran α-24b
(4.5 mg, 0.014 mmol) and β-24b (4.1 mg, 0.012 mmol, 85%) as a
colorless oils.
4b. Detailed Reaction Pathway for anti-oxypalladation of Diol
Substrate 4a. We have calculated PdCl2 with two 1,4-benzoquinone
molecules coordinating to Pd and found that the trans conformation is
energetically favored (25a-Cat1: 6.0 kcal/mol; 25a-Cat2: 12.4 kcal/mol)
(Figure 6 and Figure S5). The ligand-exchange step then forms
25a-INT1. This is a exothermic step, and 25a-INT1 is −14.7 kcal/mol
lower in free energy than 25a-Cat1. The anti-oxypalladation step then
takes place through 25a to form 25a-INT2 (−0.4 kcal/mol). The
activation barrier is 8.7 kcal/mol, and diastereoselectivity is determined
by the anti-oxypalladation transition structures.
1
α-24b. H NMR (600 MHz): δ 7.32−7.23 (m, 8H), 7.20−7.15
4c. Transition Structures for anti-Oxypalladation of Diol
Substrate 1. We have also calculated transition structures for
the anti-oxypalladation step in the oxidative cyclization of phenyl-
substituted diol 1 en route to tetrahydrofuran product 2b, as well as
the tert-butyl substituted diol 4d en route to tetrahydrofuran product
5d. In the first system, the energy difference between 25a-Ph and
25b-Ph is 0.5 kcal/mol, favoring 25a-Ph that leads to the major dia-
stereomer (Figure S6). Similary, in the second system, the energy
difference between 25a-tBu and 25b-tBu is 0.6 kcal/mol, favoring
25a-tBu that leads to the major diastereomer (Figure S7).
(m, 2H), 4.42 (dd, J = 6.3, 3.0 Hz, 1H), 3.84 (t, J = 7.8 Hz, 1H), 3.41
(s, 3H), 2.15−2.09 (m, 2H), 1.69−1.59 (m, 2H), 1.45 (s, 1H), 1.43−
1.38 (m, 2H), 1.25 (s, 3H). 13C NMR (151 MHz): δ 145.2, 144.9,
128.5, 127.8, 126.1, 98.2, 74.5, 55.5, 51.9, 37.0, 34.5 (t), 30.4,
29.3, 26.6, 16.6 (t). HRMS (ESI): m/z calcd for (C22H26D2O2Na
[M + Na]+) 349.2113, found 349.2114.
1
β-24b. H NMR (600 MHz): δ 7.31−7.22 (m, 8H), 7.20−7.12
(m, 2H), 4.53 (dd, J = 8.6, 2.6 Hz, 1H), 3.85 (t, J = 7.1 Hz, 1H), 3.40
(s, 3H), 2.23−2.07 (m, 2H), 1.72 (ddd, J = 12.7, 4.5, 2.6 Hz, 1H), 1.67
(q, J = 4.5 Hz, 1H), 1.57 (td, J = 13.5, 12.0 Hz, 2H), 1.49 (td, J = 13.6,
12.0 Hz, 1H), 1.36 (d, J = 4.4 Hz, 1H), 1.17 (s, 3H). 13C NMR
(151 MHz): δ 145.4, 144.8, 128.4, 128.3, 127.9, 127.8, 126.1, 126.0,
98.3, 75.1, 55.6, 51.9, 42.2, 33.7 (t), 31.0, 29.4, 21.5, 17.7 (t). HRMS
(ESI): m/z calcd for (C22H26D2O2Na [M + Na]+) 349.2113, found
349.2122.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02053.
3c. Synthesis of Unlabeled Cyclic Acetals 24-H3 for NMR
Comparison. 2-(3,3-Diphenylpropyl)-6-methoxy-2-methyltetrahy-
dro-2H-pyran (24-H3). In a 5 mL round-bottom flask, diphenyl
THF, 5h (10 mg, 0.032 mmol) was dissolved in MeOH (2 mL), and
10% Pd/C (100 mg) was added. The flask was placed in a Parr reactor,
pressurized to 150 psi with H2, and stirred at rt for 12h. The mixture
was filtered through a pad of Celite and washed with Et2O and the
solvent removed under reduced pressure to afford the product as a
mixture of α- and β-isomers. The isomers were separated by prepar-
ative TLC (benzene/EtOAc 99:1) to yield methoxytetrahydropyran
α-24-H3 (4.5 mg, 0.014 mmol) and β-24-H3 (4.0 mg, 0.012 mmol,
81%) as a colorless oils.
Complete experimental protocols and analytical data for
all new compounds; details of computational method-
ology, including coordinates and energies for all described
transition structures (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tand@mskcc.org.
ORCID
α-24-H3. IR (neat) (cm−1): 3060, 3026, 2935, 1736, 1599, 1493,
1451, 1373, 1261, 1225, 1202, 1156, 1123, 1066, 1034, 974, 914, 875,
802, 745, 700. 1H NMR (600 MHz): δ 7.31−7.23 (m, 8H), 7.21−7.15
(m, 2H), 4.42 (dd, J = 6.3, 3.0 Hz, 1H), 3.84 (t, J = 7.8 Hz, 1H),
Joshua L. Brooks: 0000-0002-9404-8173
Notes
The authors declare no competing financial interest.
Q
DOI: 10.1021/acs.joc.6b02053
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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ACKNOWLEDGMENTS
■
We thank Dr. George Sukenick, Rong Wang, Dr. Sylvi Rusli,
and Dr. Hiu Liu (MSKCC) for expert NMR and mass spectral
support, Michaelyn Lux (MSKCC) for assistance with NMR
spectra, and Gustavo Moura-Letts and Maria Chiriac
(MSKCC) for helpful discussions. D.S.T. and J.L.B. gratefully
acknowledge financial support from the NIH (P41 GM076267
to D.S.T., T32 CA062948-Gudas to J.L.B., P30 CA008748 to
C. B. Thompson), William and Alice Goodwin and the
Commonwealth Foundation for Cancer Research, and the
MSKCC Experimental Therapeutics Center. O.W. and L.X.
gratefully acknowledge financial support from the U.S. NSF
(CHE1058075, CHE1565669), National Science Foundation
of China (NSFC 21133002), Shenzhen Peacock Program
(JCYJ20140509093817689), and Nanshan District
(KC2014ZDZJ0026A).
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