Mechanistic and computational studies of exocyclic stereocontrol in the synthesis of bryostatin-like cis-2,6-disubstituted 4-alkylidenetetrahydropyrans by prins cyclization

Article abstract of DOI:10.1021/jo301953h

The Prins cyclization of syn-β-hydroxy allylsilanes and aldehydes gives cis-2,6-disubstituted 4-alkylidenetetrahydropyrans as sole products in excellent yields regardless of the aldehyde (R) or syn-β-hydroxy allylsilane substituent (R) used. By reversing the R and R groups, complementary exocyclic stereocontrol can be achieved. When the anti-β-hydroxy allylsilanes are used, the Prins cyclization gives predominantly cis-2,6-disubstituted 4-alkylidenetetrahydropyrans, now with the opposite olefin geometry in excellent yield. The proposed reaction mechanism and the observed stereoselectivity for these processes are supported by DFT calculations.

Full text of DOI:10.1021/jo301953h

Article
pubs.acs.org/joc
Mechanistic and Computational Studies of Exocyclic Stereocontrol in
the Synthesis of Bryostatin-like Cis-2,6-Disubstituted
4‑Alkylidenetetrahydropyrans by Prins Cyclization
Yasuyuki Ogawa,‡ Phillip P. Painter,† Dean J. Tantillo,*,† and Paul A. Wender*,‡
†Department of Chemistry, University of California, Davis, California 95616, United States
‡Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, California 94305-5080, United States
S
* Supporting Information
ABSTRACT: The Prins cyclization of syn-β-hydroxy allylsilanes and aldehydes gives cis-2,6-disubstituted 4-alkylidenetetrahy-
dropyrans as sole products in excellent yields regardless of the aldehyde (R″) or syn-β-hydroxy allylsilane substituent (R′) used.
By reversing the R″ and R′ groups, complementary exocyclic stereocontrol can be achieved. When the anti-β-hydroxy allylsilanes
are used, the Prins cyclization gives predominantly cis-2,6-disubstituted 4-alkylidenetetrahydropyrans, now with the opposite
olefin geometry in excellent yield. The proposed reaction mechanism and the observed stereoselectivity for these processes are
supported by DFT calculations.
in the low nanomolar to picomolar range, i.e., comparable to or
better than bryostatin 1.2b Our lead, designed analogues exhibit
potent functional activity in cellular studies related to
Alzheimer’s disease,3c HIV/AIDS eradication,11 and cancer
cell apoptosis12 and in animal models of cancer involving
suppression of MYC-oncogene induced lymphoma.13 Further
underscoring the potential value of these designed agents,
patient accrual in a recent bryostatin lymphoma clinical trial
was terminated early “given the more potent bryostatin analogs
in development”14 in our laboratory.
One of our earlier bryostatin pharmacophore hypotheses was
that the lactone carbonyl, C19 hydroxyl, and C26 hydroxyl
groups contact the protein target (PKC) and thus influence
binding affinity and that the A- and B-rings serve to control the
correct spatial array of these pharmacophoric contacts.5 This
analysis suggests that simplifications could be made in the A-
and B-rings of bryostatin without significantly changing affinity
and it thus opens this approach up to synthesis-informed design
of A- and B-ring simplified systems. Toward this end, in the
design of our first-generation analogues, we took the liberty of
removing all unnecessary A- and B-ring appendages and
replaced the C14 carbon of the B-ring pyran with an oxygen
atom to allow for macrocycle formation through a then-
INTRODUCTION
■
Bryostatin 1 is a marine-derived macrolactone that has
justifiably attracted considerable interest because of its novel
structure and its initially observed antitumor activity.1,2 It has
since been found to exhibit activity in animal models of
cognitive dysfunction pertinent to treatments for Alzheimer’s
disease3 and in first-in-class strategies aimed at the eradication
of HIV/AIDS.4 Over 25 years ago, we initiated the first studies
aimed at identifying the structural features of the bryostatin
family of natural products (Figure 1) that contribute to their
novel biological activities.5 Anticipating then the challenges that
would attend a practical synthesis of the natural product as well
as the potential need for better leads, the purpose of our
program was to use structure-based pharmacophoric hypoth-
eses to design simpler but potentially superior functional
analogues that could be synthetically accessed in a step-
economical fashion.6 In 1998, we reported the first of these
designed molecules which proved to be comparable to
bryostatin 1 in binding affinity to protein kinase C (PKC), a
putative target mediating its activity.7 Subsequently, second-
generation analogues were prepared that were more potent
than bryostatin 1 itself in binding to PKC.8 The syntheses of
these analogues were approximately 40−50 steps shorter than
the reported syntheses of the natural bryostatins at the time,9
illustrating an advantage of this function-oriented synthesis
strategy.10 Subsequently, over 100 designed analogues have
been prepared in our studies with 35 exhibiting PKC affinities
Special Issue: Robert Ireland Memorial Issue
Received: September 14, 2012
Published: November 2, 2012
© 2012 American Chemical Society
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Figure 1. Bryostatins and exiguolide, examples of (E)- and (Z)-alkylidene-cis-2,6-disubstituted pyrans.
Figure 2. Ring-forming macrocyclizations.
unexplored macrotransacetalization in which an oxo-carbenium
ion intermediate is trapped by a nucleophilic C14 hydroxyl
group to form a B-ring dioxane (Figure 2). This strategy
allowed step-economical access to analogues with bryostatin-
like potency.7,8,15 Recognizing that the nucleophilic oxygen in
this strategy could be replaced by a nucleophilic C14 carbon of
a C13−C14 alkene, we next explored whether a Prins-driven
macrocyclization could be used in place of our macro-
transacetalization to access macrocycles now with a pyranyl
B-ring.16 The Marko group reported impressive early examples
of an intermolecular allyl silane driven Prins reaction (a.k.a. silyl-
modified Sakurai reaction) for pyran synthesis,17 and this
intermolecular process was later used effectively in the Keck
group approach to bryostatin analogues.18 This intermolecular
process has also been creatively deployed in syntheses of other
natural systems.9e,g,19 Our own work provided the first
investigation of whether this process could be used intra-
molecularly to form macrocycles incorporating pyran rings. This
novel Prins-driven macrocyclization strategy proved highly
effective and was used in the preparation of bryostatin
analogues (bryologs)11,20 and bryostatin 9.9f Concurrent
studies from several laboratories provided additional and
impressive examples of the utility of this Prins-driven
macrocyclization in accessing a wide range of natural products
with pyranyl subunits.21
In the course of the above studies, it became apparent that
while much impressive effort has gone into studies on various
aspects of the Prins reaction,22 little is known about its use in
controlling exocyclic alkylidene stereochemistry. This synthetic
problem is encountered in exocyclic unsaturated esters
associated with the B- and C-rings of natural bryostatins,
some bryostatin analogues, and other natural products such as
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Figure 3. Silyl-terminated Prins cyclizations for endocyclic and endo- and exocyclic stereocontrol.
Scheme 1. Synthetic Route to β-Hydroxy Allylsilanes 9−12
exiguolide (Figure 1). The bryostatin B-ring problem is
especially challenging as the atoms flanking the C13 exocyclic
alkene are virtually identical, thus providing no steric or
electronic bias to control alkene geometry. Indeed direct
olefination of a C13 carbonyl of a pyranone proceeds with no
selectivity.20 Current approaches to this problem preset the
alkene geometry before formation of the pyran ring23 or use
reagent-controlled strategies to set the geometry after pyran
formation.24 A third general approach to this problem is to set
followed by treatment with allyl cuprate gave racemic hydroxyl
silane 3.29 Alcohol 3 was protected with TBSCl and then
treated with O3 followed by Me2S to give aldehyde 4 in 85%
yield in two steps. Introduction of an α-methylene group with
formaldehyde30 followed by reduction gave alcohol 6, which
was converted to the allylic bromide 8 by mesylation, bromide
displacement, and deprotection. Allylic zinc bromide was
generated in situ from allylic bromide 8 and zinc powder and
then reacted individually with four different aldehydes to
provide after protection syn- and anti-diastereomers 9−12.
These allylations proceeded with little stereoselectivity as
desired because both diastereomers were required in this study.
The aldehydes were selected on the basis of anticipated
synthetic situations involving this process and include
conjugated and nonconjugated aldehydes as well as straight
chain and branched chain aldehydes. The diastereomers 9−12
were separated using silica gel chromatography. The stereo-
chemistry of syn- and anti-12 was determined by 1H NMR and
by transformation to the cyclic derivatives as shown in Scheme
2. For the determination of the stereochemistry of 12, the
mixture of diastereomers of 1,5-diol 13 was separated using
silica gel chromatography to give 13a and 13b. Individual
tosylation of 13a and 13b proceeded with a 1,2-silicon shift to
give tetrahydrofurans 14a and 14b, respectively. The stereo-
chemistry of each compound was confirmed by NOE
experiments, indicating that 14a has a cis configuration and
alkene geometry during the course of pyran formation,25
a
result that could be realized, for example, if the stereogenic
center of an allylic silane26 were to control alkene geometry
during a silyl-terminated Prins cyclization (Figure 3). More
specifically, if the silyl-terminated Prins cyclization were to
proceed by capture of a trans-oxocarbenium ion exclusively
through either an anti-SE′ or syn-SE′ process,27 then control of
the exocyclic double bond would be achieved. If these pathways
compete or if both cis- and trans-oxocarbenium ions participate,
mixtures of E- and Z-alkenes would be obtained. We report
herein synthetic, mechanistic and computational studies on this
unexplored strategy.
RESULTS AND DISCUSSION
■
To evaluate this concept, we prepared the syn- and anti-β-
hydroxy allylsilanes 9−12 through a conventional but scalable
route as given in Scheme 1. Epoxidation of 1 with m-CPBA28
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Scheme 2. Assignment of Relative Stereochemistry of β-
Hydroxy Allylsilane 12
Figure 4. Relative stereochemistry of 15a.
Table 2. Substituents Effects in the Prins Cyclization of syn-
β-Hydroxy Allylsilanes 10−12 with
3‑Phenylpropionaldehyde
14b has a trans configuration. This indicates that 13a has the
syn-configuration and 13b has the anti-configuration. Finally, to
confirm the stereochemistry of 12, 13a and 13b were converted
to syn-12 and anti-12, respectively. The relative stereochemistry
of the other β-hydroxy allylsilanes 9−11 was determined by
a
entry allylsilane
R
time (h) product yield (%) 16:15
1
2
3
syn-10
syn-11
syn-12
Et
1
1
1
16a
16b
16d
96
95
93
>95:5
>95:5
>95:5
c-Hex
Ph
1
comparison of their H NMR spectra with that of 12.
Our initial studies focused on the Prins cyclization of the syn-
β-hydroxy allylsilanes. Prins cyclization reaction using syn-9 and
propionaldehyde proceeded smoothly with TMSOTf in Et2O at
−78 °C to give within 1 h 15a as the sole product in excellent
yield (Table 1, entry 1). No other diastereomers were detected.
a
1
Product ratios were determined by H NMR.
reacted to give the cyclized products in high yields and with
high selectivities. The comparative results of Tables 1 and 2
show that one can form either 15a,b,d or 16a,b,d in a highly
selective fashion. This strategy thus allows for the highly
selective synthesis of cis-2,6-disubstituted pyrans with either an
E- or Z-exocyclic alkene by the judicious selection of starting
materials.
Table 1. Prins Cyclization of syn-β-Hydroxy Allylsilane 9
with Representative Aldehydes
Our focus turned next to the Prins cyclization using anti-β-
hydroxy allylsilanes. As before, the Prins cyclization reaction
using anti-9 and propionaldehyde with TMSOTf at −78 °C was
examined first (Table 3, entry 1). The reaction proceeded
smoothly and in high yield but now gave two diastereomers in a
16:84 ratio favoring 16a over 15a. The lower diastereoselec-
tivity obtained with the anti substrate relative to the syn
substrate in this process could arise from epimerization of the
product under the reaction conditions. However, the possibility
a
entry
R
time (h)
product
yield (%)
15:16
1
2
3
4
5
Et
1
1
4
1
1
15a
15b
15c
15d
15e
96
93
90
92
95
>95:5
>95:5
>95:5
>95:5
>95:5
c-Hex
t-Bu
Ph
Table 3. Prins Cyclization Using anti-β-Hydroxy Allylsilane 9
with Representative Aldehydes
(E)-PhCH=CH
a
1
Product ratios were determined by H NMR.
The cis-disposition of the C2 and C6 substituents and the E
geometry of the exocyclic alkene in 15a were established by
NOE experiments (Figure 4). The results for several additional
examples are provided in Table 1. Branched (entries 2 and 3),
sterically encumbered (entry 3), aryl-conjugated (entry 4), and
styryl-conjugated (entry 5) aldehydes behaved similarly upon
reaction with syn-9, providing exclusively cis-pyranyl products
15b−e with a single exocyclic geometry in high yields and with
high selectivities. Even pivalaldehyde reacted smoothly albeit
somewhat less rapidly to give the cyclized product (entry 3).
We next examined the effect of variations in the substituents
of the syn-β-hydroxy allylsilanes with a fixed aldehyde, 3-
phenylpropionaldehyde (Table 2). Normal alkyl (syn-10),
branched (syn-11), and aryl (syn-12) substituted systems each
a
b
entry
R
time (h)
product
yield (%)
15:16
1
2
3
4
5
Et
1
15a, 16a
15b, 16b
15c, 16c
16d
95
95
80
89
94
16:84
16:84
8:92
c-Hex
t-Bu
Ph
1.5
8
1
5:>95
6:94
(E)-PhCH=CH
1
15e, 16e
a
b
1
Combined isolated yield. Product ratios were determined by H
NMR.
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of epimerization was discounted by two experiments. When
primarily to rotation around the internal O−C σ-bond. This
rotation brings the CC and CO π-bonds into proximity,
and their coupling occurs without an additional barrier (note
that chairlike structures are encountered along these reaction
coordinates once the initial conformational change is
complete).31 Interconversion of III and IV is associated with
a comparatively large barrier (through a transition state
structure for which β-silyl stabilization is lost), suggesting that
stereochemical scrambling at this stage is unlikely. The loss of
the silyl group in the second step, modeled here using an
attacking solvent molecule (dimethyl ether for simplicity) is
also predicted to be facile, but the inherent preference for an
anti silyl group is maintained in the corresponding transition
state structures (anti- and syn-TS2) and the minima preceding
them (Figure 5, bottom).
Given these results, it appears that the stereoselectivity of the
Prins cyclization is determined by the energy difference
between the transition-state structures for cyclization (anti-
TS1 and syn-TS1), although the preference for an anti silyl
group is maintained throughout the reaction. For the syn-β-
hydroxy allylsilane model I, the predicted difference in energy
between anti-TS1 and syn-TS1 is 1.6 kcal mol−1, favoring the
transition-state structure leading to the experimentally observed
product. When the analogous anti-β-hydroxy allylsilane model
with MeCHO (Figure 6b, R = R′ = R″ = Me) is used, the
predicted energy difference between the anti and syn transition
state structures for cyclization is only 0.5 kcal mol−1, which is
consistent with the observation of decreased selectivity for anti-
β-hydroxy allylsilane reactants.
product 16a was treated with TMSOTf, no isomerization was
1
observed. Moreover, when the reaction was monitored by H
NMR at 10, 30, and 60 min, the product ratio remained
constant. The results obtained with other aldehydes are
provided in Table 3. In general, the reactions proceeded in
very good to high yields for all aldehydes. The reactions were
somewhat slower for anti-9 and branched aldehydes (entries 2
and 3) than for syn-9 with the same aldehydes. All reactions
provided 16 as main product with 15 as minor product, i.e., the
stereochemical complement of the selectivity observed when
syn-9 was used (Table 1). When pivalaldehyde was used, the
selectivity of olefin geometry was increased (entry 3). Higher
selectivity was also observed when aromatic aldehyde and
conjugated aldehyde were used (entries 4 and 5). When
benzaldehyde was used, only one diastereomer (16d) was
obtained.
We next examined the effect of variations in the substituents
of the anti-β-hydroxy allylsilanes with a common aldehyde
(Table 4). The ethyl- and cyclohexyl-substituted β-hydroxy
Table 4. Substituents Effects in the Prins Cyclization of anti-
β-Hydroxy Allylsilanes 10−12 with
3‑Phenylpropionaldehyde
The selectivity for these Prins cyclizations can be rationalized
through a combination of simple steric and electronic effects.
For syn-β-hydroxy allylsilanes (Figure 6a), cyclization occurs
through chairlike structures in which the alkyl substituent
occupies an equatorial position. Second, the SiR3 group aligns
itself perpendicular to the CC π-bond to maximize the
incipient β-silyl stabilization. The anti arrangement is preferred,
which places the alkyl group α to the silyl on the side of the
molecule where the new σ-bond forms. The situation is the
same for anti-β-hydroxy allylsilanes (Figure 6b), except that the
α-alkyl group now resides on the side of the molecule away
from the forming bond. This environment is more sterically
crowded, resulting in a diminution of the preferences for an anti
silyl group: with CαH2 rather than CαH(CH3) the preference
for anti is predicted to be 2.5 kcal mol−1 which is reduced upon
replacing one or the other hydrogen with a methyl group.
Truncation of the anti and syn cyclization transition state
structures for the system with CαH2 to Ph(CH3)2SiCH2vinyl
groups and recalculation of their energies (without optimiza-
tion of their geometries) indicated that the preference for the
anti arrangement is almost entirely localized to this structural
unit (i.e., the anti preference for the truncated system ≈ the anti
preference for the full system). It appears that in order to
reduce steric clashes in the syn transition state structure, the Si−
Cα−CβC dihedral angle deviates from 90° (this dihedral
angle is predicted to be 91° in the anti transition state structure,
but −67° in the syn transition state structure), leading to a
reduction in hyperconjugation between the C−Si σ-bond and
the CC π-bond. This diminished interaction is manifested in
a slight reduction of the Si−Cα bond length (by 0.1 Å), a slight
elongation of the Cα−Cβ bond length (by 0.05 Å) and an
opening of the Si−Cα−Cβ angle (by 3°).32
a
entry allylsilane
R
time (h)
product
yield (%) 16:15
1
2
3
anti-10
anti-11
anti-12
Et
1
3
8
15a, 16a
15b, 16b
15d, 16d
94
95
79
18:82
21:79
c-Hex
Ph
8:92
a
b
1
Combined isolated yield. Product ratios were determined by H
NMR.
allylsilanes reacted in good yields but with moderate
selectivities (Table 4, entries 1 and 2) while the phenyl
substituted system gave better selectivity but a lower yield
(entry 3). In all cases, only the cis-2,6-disubstituted products are
obtained. However, in contrast to the reactions using syn-β-
hydroxy allylsilanes, the yields and selectivities for the reaction
of anti-β-hydroxy allylsilanes are more sensitive to coreactant
aldehydes and substituents.
To probe the mechanism of this reaction and the origin of
observed stereoselectivity, density functional theory (DFT)
calculations were carried out for model syn-β-hydroxy allylsilane
I (Figure 5) and its anti-β-hydroxy allylsilane analogue (Figure
6b, R = R′ = Me). It was found that cyclization and loss of the
silyl group occur in separate steps, although the barriers for
these steps are predicted to be small. In the first step, there are
two possible cyclization modes (anti and syn; syn is defined here
as the silicon group being oriented toward the forming C−C
bond in the transition state structure) that take advantage of
hyperconjugation between the C−Si σ-bond and the CC π-
bond. The transition-state structures for cyclization, anti-TS1,
and syn-TS1 are quite early (not surprising, given the
exothermicity/exergonicity of the cyclizations), with the motion
associated with their imaginary frequencies corresponding
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Figure 5. Mechanism for the Prins cyclization with syn-β-hydroxy allylsilane proposed on the basis of computational results. Relative energies shown
were computed with B3LYP/6-31+G(d,p)//B3LYP/6-31G(d).
ans as the sole products in excellent yields. The olefin geometry
is set with high selectivity regardless of the aldehydes and the
substituents of the syn-β-hydroxy allylsilanes used. When the
anti-β-hydroxy allylsilanes were used, the Prins cyclization gave
predominantly cis-2,6-disubstituted 4-alkylidenetetrahydropyr-
ans, now with the opposite olefin geometry in excellent yield.
The proposed reaction mechanism and the observed stereo-
selectivity for this reaction are consistent with results from the
DFT calculations. This strategy can provide stereoselectively
both (E)- and (Z)-cis-2,6-disubstituted 4-alkylidenetetrahydro-
pyrans as required to access natural bryostatins and their
CONCLUSION
■
In conclusion, we have shown that the silyl-terminated Prins
cyclization can be used to control both endocyclic and exocyclic
stereochemistry, thus providing selective access to cis-2,6-
disubstituted tetrahydropyrans with either a (Z)- or (E)-4-
alkylidene group. The influence of the relative stereochemistry
of silicon and oxygen-bearing chiral centers of the β-hydroxy
allylsilanes on the product geometry in Prins cyclization has
been established experimentally and supported computation-
ally. When the syn-β-hydroxy allylsilanes were used, the Prins
cyclization gave cis-2,6-disubstituted 4-alkylidenetetrahydropyr-
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triplet, br = broad), coupling constant(s) in Hz, integration). 13C
chemical shifts are reported relative to the residual deuterated solvent
13C signals (CDCl3 = 77.1, C6D6 = 128.0 ppm). Infrared spectra were
recorded on a Fourier transform spectrometer (FTIR) and are
reported in wavenumbers (cm−1). High-resolution mass spectra were
recorded on a hybrid quadrupole time-of-flight (Q-Tof) LC/MS
instrument.
2.28 1H NMR (400 MHz, CDCl3): δ = 7.59−7.53 (m, 2H), 7.41−
7.33 (m, 3H), 2.93 (t, J = 5.6 Hz, 1H), 2.56 (dd, J = 5.6, 4.0 Hz, 1H),
2.39 (dd, J = 5.2, 4.0 Hz, 1H), 0.36 (s, 3H), 0.31 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ = 136.0, 134.0, 129.6, 128.0, 44.7, 43.6, −5.2,
−5.5. IR (thin film): 3047, 2959, 1428, 1315, 1250, 1232, 1117 cm−1.
3.29 1H NMR (400 MHz, CDCl3): δ = 7.56−7.50 (m, 2H), 7.39−
7.34 (m, 3H), 5.90−5.78 (m, 1H), 5.08−5.02 (m, 1H), 5.01−4.95 (m,
1H), 3.79 (ddd, J = 10.8, 6.0, 4.4 Hz, 1H), 3.69 (ddd, J = 10.8, 7.2, 5.2
Hz, 1H), 2.36−2.27 (m, 1H), 2.22−2.10 (m, 1H), 1.42 (dd, J = 6.0,
5.2 Hz, 1H), 1.29−1.21 (m, 1H), 0.35 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ = 139.5, 138.0, 133.9, 129.2, 127.9, 115.5, 63.8, 32.3, 30.2,
−3.6, −3.8. IR (thin film): 3369, 3070, 2956, 2903, 1638, 1427, 1250,
1156, 1111 cm−1.
4. To a solution of 3 (4.65 g, 21.1 mmol) in DMF (50 mL) were
added TBSCl (3.80 g, 25.1 mmol) and imidazole (3.44 g, 50.6 mmol).
The mixture was stirred at rt for 1 h and diluted with water and Et2O.
The separated aqueous phase was extracted with Et2O, and the
combined organic solutions were washed with brine, dried with
Na2SO4, and concentrated in vacuo to give crude TBS ether, which
was used in the next step without further purification. The crude TBS
ether was dissolved in CH2Cl2 (100 mL). The solution was cooled to
−78 °C and treated with ozone until the solution turned light blue.
The reaction was quenched at −78 °C with dimethyl sulfide (3.10 mL,
42.2 mmol), warmed to rt, stirred for 12 h, and concentrated in vacuo.
The residual oil was purified by column chromatography (silica gel,
0%→10% EtOAc/pentane) to give 4 (6.05 g, 85% yield in two steps)
1
as a colorless oil. Rf (pentane/EtOAc 10/1) = 0.63. H NMR (400
MHz, CDCl3): δ = 9.68 (dd, J = 3.2, 1.2 Hz, 1H), 7.53−7.46 (m, 2H),
7.40−7.32 (m, 3H), 3.76 (dd, J = 10.0, 4.0 Hz, 1H), 3.58 (dd, J = 10.0,
8.0 Hz, 1H), 2.43 (ddd, J = 16.8, 10.4, 3.2 Hz, 1H), 2.33 (ddd, J =
16.8, 4.0, 1.2 Hz, 1H), 1.82−1.74 (m, 1H), 0.86 (s, 9H), 0.34 (s, 3H),
0.33 (s, 3H), −0.01 (s, 3H), −0.01 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ = 203.5, 137.1, 133.9, 129.4, 128.0, 63.8, 42.4, 26.0, 25.4,
18.3, −3.9, −4.2, −5.50, −5.52. IR (thin film): 3070, 2955, 2857, 2712,
1725, 1471, 1428, 1253, 1094 cm−1. HRMS (ESI+, m/z): calcd for
C18H32NaO2Si2 [(M + Na)]+ 359.1833, found 359.1833.
5. To a mixture of aqueous formaldehyde solution (37%
formaldehyde in water, 1.45 mL, 17.9 mmol) and 4 (6.0 g, 17.9
mmol) in i-PrOH (4 mL) were added propionic acid (132 mg, 1.79
mmol) and pyrrolidine (127 mg, 1.79 mmol). The reaction mixture
was stirred at 45 °C for 3 h. The reaction was quenched with satd
NaHCO3 aq and then extracted with CH2Cl2. The combined extracts
were washed with brine, dried with Na2SO4, and concentrated in
vacuo. The residual oil was purified by column chromatography (silica
gel, 0%→5% EtOAc/pentane) to give 5 (4.40 g, 70% yield) as a
Figure 6. Model for rationalizing observed selectivity.
structural and functional analogues as well as other pyranyl
targets.
EXPERIMENTAL SECTION
■
1
colorless oil. Rf (pentane/EtOAc 10/1) = 0.68. H NMR (400 MHz,
General Procedures. All reactions were run under a N2
atmosphere in flame- or oven-dried glassware. Reactions were stirred
using Teflon-coated magnetic stirrer bars. Reactions were monitored
using thin-layer silica gel chromatography (TLC) using 0.25 mm silica
gel 60F plates with fluorescent indicator. Plates were visualized by
treatment with UV, acidic p-anisaldehyde stain, KMnO4 stain with
gentle heating. Products were purified by silica gel (230−400 mesh)
column chromatography using the solvent systems indicated. When
necessary, solvents and reagents were purified before use. THF was
distilled from sodium benzophenone ketyl under N2. CH2Cl2, Et2O,
and toluene were passed through an alumina drying column using N2
pressure. Et3N was distilled from CaH2 under N2. All other reagents
were purchased from commercial supplies and were used as received
without additional purification. NMR spectra were measured on
magnetic resonance spectrometers (1H at 500, 400 MHz, 13C at 125,
C6D6): δ = 9.21 (s, 1H), 7.50−7.44 (m, 2H), 7.24−7.12 (m, 3H), 5.85
(s, 1H), 5.38 (s, 1H), 3.77 (dd, J = 10.0, 7.6 Hz, 1H), 3.72 (dd, J =
10.0, 4.8 Hz, 1H), 2.93 (dd, J = 7.2, 4.8 Hz, 1H), 0.89 (s, 9H), 0.29 (s,
3H), 0.27 (s, 3H), −0.06 (s, 3H), −0.07 (s, 3H). 13C NMR (100
MHz, C6D6): δ = 193.6, 150.8, 137.2, 134.4, 132.1, 129.4, 128.0, 63.8,
31.0, 26.1, 18.4, −3.0, −4.1, −5.39, −5.43. IR (thin film): 3071, 2955,
2857, 1693, 1612, 1471, 1253, 1087 cm−1. HRMS (ESI+, m/z): calcd
for C19H32NaO2Si2 [(M + Na)]+ 371.1833, found 371.1834.
6. Compound 5 (4.40 g, 12.6 mmol) was dissolved in toluene (100
mL). The solution was cooled to −78 °C, and DIBAL in toluene (1.0
M, 25.2 mL) was added dropwise. The mixture was stirred at −78 °C
for 3 h. After the reaction was quenched with MeOH, satd Rochelle’s
salt solution was introduced, and the heterogeneous reaction mixture
was allowed to rt for 2 h. The separated aqueous phase was extracted
with EtOAc, and the combined organic solutions were washed with
brine, dried with Na2SO4, and concentrated. The residual oil was
purified by column chromatography (silica gel, 10%→20% EtOAc/
1
100 MHz), as noted. H chemical shifts are reported relative to the
residual solvent peak (chloroform = 7.26 ppm; benzene = 7.15 ppm)
as follows: chemical shift (δ), (multiplicity (s = singlet, d = doublet, t =
110
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pentane) to give 6 (4.06 g, 92% yield) as a colorless oil. Rf (pentane/
EtOAc 10/1) = 0.18. 1H NMR (400 MHz, C6D6): δ = 7.49−7.43 (m,
2H), 7.21−7.15 (m, 3H), 5.10 (td, J = 2.8, 0.8 Hz, 1H), 4.81 (d, J = 0.8
Hz, 1H), 3.89−3.78 (m, 4H), 2.06 (dd, J = 8.4, 5.2 Hz, 1H), 1.81 (t, J
= 6.0 Hz, 1H), 0.93 (s, 9H), 0.32 (s, 3H), 0.29 (s, 3H), 0.00 (s, 3H),
−0.01 (s, 3H). 13C NMR (100 MHz, C6D6): δ = 149.7, 138.0, 134.2,
129.4, 128.0, 109.3, 67.4, 65.3, 37.0, 26.1, 18.5, −3.4, −3.8, −5.39,
−5.42. IR (thin film): 3367, 3070, 2955, 2856, 1643, 1471, 1253, 1084
cm−1. HRMS (ESI+, m/z): calcd for C19H34NaO2Si2 [(M + Na)]+
373.1990, found 373.1992.
1.98−1.87 (m, 2H), 1.73−1.64 (m, 1H), 1.17 (s, 9H), 0.12 (s, 3H),
0.09 (s, 3H). 13C NMR (100 MHz, C6D6): δ = 146.2, 143.0, 137.1,
136.02, 135.93, 134.1, 133.63, 133.60, 130.03, 130.02, 129.4, 128.9,
128.6, 128.12, 128.09, 128.0, 125.9, 111.9, 67.3, 65.4, 48.0, 39.3, 39.2,
32.8, 27.0, 19.4, −4.2, −4.8. IR (thin film): 3474, 3071, 2931, 2858,
1632, 1427, 1250, 1112, 1070 cm−1. HRMS (ESI+, m/z): calcd for
C38H48NaO2Si2 [(M + Na)]+ 615.3085, found 615.3079.
anti-9. Colorless oil. Yield: 346 mg, 35% (in two steps). Rf
(pentane/EtOAc 10/1) = 0.51. 1H NMR (400 MHz, C6D6): δ =
7.80−7.70 (m, 4H), 7.31−7.26 (m, 2H), 7.24−7.04 (m, 14H), 4.93 (s,
1H), 4.76 (s, 1H), 4.02−3.94 (m, 2H), 3.92−3.83 (m, 1H), 3.34 (s,
1H), 2.91 (ddd, J = 13.6, 9.6, 5.2 Hz, 1H), 2.75 (ddd, J = 13.6, 9.6, 6.8
Hz, 1H), 2.59−2.51 (m, 1H), 2.12 (dd, J = 13.2, 2.8 Hz, 1H), 1.93
(dd, J = 13.2, 9.6 Hz, 1H), 1.90−1.79 (m, 1H), 1.75−1.63 (m, 1H),
1.17 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H). 13C NMR (100 MHz, C6D6):
δ = 147.9, 142.9, 137.1, 136.03, 135.96, 134.2, 133.5, 133.4, 130.1,
130.0, 129.4, 128.9, 128.6, 128.10, 128.06, 128.0, 125.9, 110.7, 72.6,
66.1, 48.2, 41.4, 39.7, 32.4, 26.9, 19.3, −4.0, −5.0. IR (thin film): 3459,
3070, 2931, 2858, 1632, 1427, 1250, 1112, 1071 cm−1. HRMS (ESI+,
m/z): calcd for C38H48NaO2Si2 [(M + Na)]+ 615.3085, found
615.3082.
syn-10. Colorless oil. Yield: 327 mg, 38% (in two steps). Rf
(pentane/EtOAc 10/1) = 0.56. 1H NMR (500 MHz, C6D6): δ =
7.79−7.74 (m, 4H), 7.31−7.27 (m, 2H), 7.25−7.08 (m, 9H), 5.03 (s,
1H), 4.84 (s, 1H), 4.04 (t, J = 10.5 Hz, 1H), 3.96 (dd, J = 10.5, 4.0 Hz,
1H), 3.91−3.84 (m, 1H), 2.88 (brs, 1H), 2.23 (dd, J = 10.5, 4.0 Hz,
1H), 2.04 (dd, J = 13.5, 10.0 Hz, 1H), 1.98−1.92 (m, 1H), 1.69−1.58
(m, 1H), 1.50−1.39 (m, 1H), 1.17 (s, 9H), 1.06 (t, J = 7.5 Hz, 3H),
0.14 (s, 3H), 0.11 (s, 3H). 13C NMR (125 MHz, C6D6): δ = 146.4,
137.2, 136.0, 135.9, 134.1, 133.7, 133.6, 130.01, 129.99, 129.4, 128.10,
128.07, 128.0, 111.8, 69.3, 65.4, 47.8, 39.4, 30.2, 26.9, 19.4, 10.7, −4.2,
−4.8. IR (thin film): 3483, 3071, 2959, 2858, 1631, 1427, 1249, 1112,
1069 cm−1. HRMS (ESI+, m/z): calcd for C32H44NaO2Si2 [(M +
Na)]+ 539.2772, found 539.2761.
anti-10. Colorless oil. Yield: 302 mg, 35% (in two steps). Rf
(pentane/EtOAc 10/1) = 0.50. 1H NMR (400 MHz, C6D6): δ =
7.82−7.71 (m, 4H), 7.33−7.28 (m, 2H), 7.26−7.09 (m, 9H), 4.99 (s,
1H), 4.79 (s, 1H), 4.01 (t, J = 10.4 Hz, 1H), 3.97 (dd, J = 10.0, 4.8 Hz,
1H), 3.85−3.77 (m, 1H), 3.16 (d, J = 2.4 Hz, 1H), 2.56 (dd, J = 10.0,
4.8 Hz, 1H), 2.17 (dd, J = 13.2, 3.2 Hz, 1H), 1.94 (dd, J = 13.2, 9.6 Hz,
1H), 1.63−1.42 (m, 2H), 1.17 (s, 9H), 1.01 (t, J = 7.6 Hz, 3H), 0.15
(s, 3H), 0.13 (s, 3H). 13C NMR (100 MHz, C6D6): δ = 148.1, 137.2,
136.02, 135.96, 134.2, 133.5, 133.4, 130.03, 129.97, 129.4, 128.1,
128.0, 127.9, 110.5, 74.7, 66.0, 47.7, 41.4, 30.7, 26.9, 19.3, 10.4, −3.9,
−4.9. IR (thin film): 3466, 3071, 2959, 2859, 1631, 1428, 1250, 1186,
1112, 1064 cm−1. HRMS (ESI+, m/z): calcd for C32H44NaO2Si2 [(M
+ Na)]+ 539.2772, found 539.2772.
syn-11. Colorless oil. Yield: 314 mg, 33% (in two steps). Rf
(pentane/EtOAc 10/1) = 0.58. 1H NMR (500 MHz, C6D6): δ =
7.80−7.75 (m, 4H), 7.33−7.29 (m, 2H), 7.25−7.19 (m, 6H), 7.18−
7.09 (m, 3H), 5.06 (s, 1H), 4.86 (s, 1H), 4.05 (t, J = 10.5 Hz, 1H),
3.97 (dd, J = 10.5, 4.0 Hz, 1H), 3.79−3.73 (m, 1H), 2.83 (d, J = 2.0
Hz, 1H), 2.24 (dd, J = 10.5, 4.0 Hz, 1H), 2.19−2.12 (m, 1H), 2.09
(dd, J = 13.0, 10.5 Hz, 1H), 1.99 (d, J = 12.5 Hz, 1H), 1.82−1.60 (m,
4H), 1.48−1.39 (m, 1H), 1.30−1.09 (m, 14H), 0.16 (s, 3H), 0.13 (s,
3H). 13C NMR (125 MHz, C6D6): δ = 146.7, 137.2, 136.05, 135.95,
134.1, 133.70, 133.67, 130.01, 129.99, 129.4, 128.12, 128.08, 128.0,
111.8, 71.6, 65.4, 45.2, 43.8, 39.1, 29.6, 29.1, 27.1, 27.0, 26.8, 26.7,
19.4, −4.2, −4.7. IR (thin film): 3488, 3071, 2929, 2856, 1632, 1428,
1250, 1112, 1064 cm−1. HRMS (ESI+, m/z): calcd for C36H50NaO2Si2
[(M + Na)]+ 593.3242, found 593.3234.
anti-11. Colorless oil. Yield: 286 mg, 30% (in two steps). Rf
(pentane/EtOAc 10/1) = 0.57. 1H NMR (500 MHz, C6D6): δ =
7.83−7.77 (m, 2H), 7.76−7.71 (m, 2H), 7.33−7.29 (m, 2H), 7.26−
7.08 (m, 9H), 5.04 (s, 1H), 4.82 (s, 1H), 4.03 (t, J = 10.5 Hz, 1H),
3.99 (dd, J = 10.5, 5.0 Hz, 1H), 3.74−3.69 (m, 1H), 3.28 (d, J = 2.5
Hz, 1H), 2.62 (dd, J = 10.5, 4.5 Hz, 1H), 2.25 (dd, J = 13.0, 2.0 Hz,
1H), 2.09−2.03 (m, 1H), 1.99 (dd, J = 13.0, 10.0 Hz, 1H), 1.81−1.67
(m, 3H), 1.66−1.60 (m, 1H), 1.47−1.38 (m, 1H), 1.26−1.10 (m,
14H), 0.16 (s, 3H), 0.14 (s, 3H). 13C NMR (125 MHz, C6D6): δ =
7. To a solution of 6 (4.06 g, 11.6 mmol) and Et3N (3.51 g, 34.8
mmol) in CH2Cl2 (100 mL) was added MsCl (1.98 g, 17.4 mmol) at 0
°C. The mixture was stirred at rt for 2 h, and then water was added.
The separated aqueous phase was extracted with CH2Cl2, and the
combined organic solutions were washed with brine, dried with
Na2SO4 ,and concentrated in vacuo to give crude mesylate, which was
used in the next step without further purification. To a solution of
crude mesylate in THF (100 mL) was added LiBr (3.03 g, 34.8 mmol)
at rt. The mixture was stirred at 60 °C for 2 h, cooled to rt, and diluted
with Et2O and H2O. The separated aqueous phase was extracted with
Et2O, and the combined organic solutions were washed with brine,
dried with Na2SO4, and concentrated. The residual oil was purified by
column chromatography (silica gel, 0%→5% EtOAc/pentane) to give
7 (4.55 g, 95% yield in 2 steps) as a colorless oil. Rf (pentane/EtOAc
1
10/1) = 0.88. H NMR (400 MHz, C6D6): δ = 7.48−7.42 (m, 2H),
7.21−7.15 (m, 3H), 4.96 (d, J = 0.8 Hz, 1H), 4.85 (d, J = 0.8 Hz, 1H),
3.86 (d, J = 6.0 Hz, 2H), 3.55 (dd, J = 10.0, 0.8 Hz, 1H), 3.39 (dd, J =
10.0, 0.8 Hz, 1H), 2.23 (t, J = 6.0 Hz, 1H), 0.95 (s, 9H), 0.33 (s, 3H),
0.32 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H). 13C NMR (100 MHz, C6D6):
δ = 146.5, 138.0, 134.2, 129.4, 128.0, 114.0, 65.7, 39.9, 37.1, 26.1, 18.5,
−3.3, −3.6, −5.38, −5.42. IR (thin film): 3070, 2955, 2857, 1627,
1471, 1254, 1208, 1084 cm−1. HRMS (ESI+, m/z): calcd for
C19H33BrNaOSi2 [(M + Na)]+ 435.1146, found 435.1146.
8. To a solution of 7 (2.20 g, 5.34 mmol) in MeOH (50 mL) was
added PPTS (134 mg, 0.534 mmol) at rt. The mixture was stirred at rt
for 12 h. The reaction was quenched with satd NaHCO3 aq and then
diluted with Et2O and H2O. The separated aqueous phase was
extracted with Et2O, and the combined organic solutions were washed
with brine, dried with Na2SO4, and concentrated. The residual oil was
purified by column chromatography (silica gel, 10%→15% EtOAc/
pentane) to give 8 (1.54 g, 97% yield) as a colorless oil. Rf (pentane/
EtOAc 10/1) = 0.19. 1H NMR (400 MHz, C6D6): δ = 7.38−7.31 (m,
2H), 7.21−7.12 (m, 3H), 4.92 (t, J = 0.8 Hz, 1H), 4.66 (s, 1H), 3.72−
3.62 (m, 2H), 3.49 (dd, J = 10.0, 0.8 Hz, 1H), 3.31 (dd, J = 10.0, 0.8
Hz, 1H), 2.18 (dd, J = 8.4, 6.0 Hz, 1H), 1.25 (brs, 1H), 0.17 (s, 3H),
0.16 (s, 3H). 13C NMR (100 MHz, C6D6): δ = 145.3, 137.2, 134.2,
129.5, 128.1, 113.9, 63.5, 39.6, 38.1, −4.1, −4.3. IR (thin film): 3401,
3069, 2957, 2878, 1626, 1427, 1250, 1209, 1112, 1048 cm−1. HRMS
(ESI+, m/z): calcd for C13H19BrNaOSi [(M + Na)]+ 321.0281, found
321.0276.
General Procedure for β-Hydroxy Allylsilanes. A mixture of 8
(500 mg, 1.67 mmol), zinc powder (120 mg, 1.84 mmol), and
aldehyde (1.84 mmol) in THF−satd NH4Cl aq (9.6 mL−1.6 mL) was
stirred for 2 h. After dilution with Et2O, the separated aqueous phase
was extracted with Et2O, and the combined organic solutions were
dried with Na2SO4 and concentrated to give crude 1,5-diol. To a
solution of crude 1,5-diol in DMF (8 mL) were added TBDPSCl (477
mg, 1.67 mmol) and imidazole (227 mg, 3.34 mmol). The mixture was
stirred at rt for 1 h and diluted with Et2O and H2O. The separated
aqueous phase was extracted with Et2O, and the combined organic
solutions were washed with brine, dried with Na2SO4, and
concentrated in vacuo. The residue was purified by chromatography
with EtOAc−pentane to give syn- and anti-β-hydroxy allylsilane,
respectively.
syn-9. Colorless oil. Yield: 405 mg, 41% (in two steps). Rf (pentane/
EtOAc 10/1) = 0.56. 1H NMR (500 MHz, C6D6): δ = 7.79−7.73 (m,
4H), 7.30−7.26 (m, 2H), 7.25−7.06 (m, 14H), 5.02 (s, 1H), 4.84 (s,
1H), 4.03 (t, J = 10.5 Hz, 1H), 4.01−3.95 (m, 1H), 3.94 (dd, J = 10.5,
4.0 Hz, 1H), 3.00−2.93 (m, 2H), 2.76 (ddd, J = 14.0, 10.0, 6.5 Hz,
1H), 2.19 (dd, J = 10.5, 4.0 Hz, 1H), 2.05 (dd, J = 13.5, 10.0 Hz, 1H),
111
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148.7, 137.2, 136.06, 135.98, 134.2, 133.5, 133.4, 130.05, 129.98,
129.4, 128.1, 128.1, 128.0, 110.6, 77.6, 66.0, 44.8, 44.2, 41.6, 29.6, 28.5,
27.1, 26.9, 26.8, 26.7, 19.3, −3.9, −4.9. IR (thin film): 3465, 3071,
2928, 2856, 1630, 1427, 1249, 1187, 1112, 1064 cm−1. HRMS (ESI+,
m/z): calcd for C36H50NaO2Si2 [(M + Na)]+ 593.3242, found
593.3228.
syn-12. Colorless oil. Yield: 377 mg, 40% (in two steps). Rf
(pentane/EtOAc 10/1) = 0.60. 1H NMR (500 MHz, C6D6): δ =
7.82−7.77 (m, 4H), 7.51−7.47 (m, 2H), 7.30−7.08 (m, 14H), 5.12−
5.07 (m, 1H), 5.06 (s, 1H), 4.88 (s, 1H), 4.09 (t, J = 10.5 Hz, 1H),
4.01 (dd, J = 10.5, 4.5 Hz, 1H), 3.30 (d, J = 2.0 Hz, 1H), 2.38−2.22
(m, 3H), 1.18 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). 13C NMR (125
MHz, C6D6): δ = 145.9, 145.0, 137.1, 136.06, 135.98, 134.1, 133.64,
133.61, 130.07, 130.05, 129.5, 128.4, 128.13, 128.11, 128.0, 127.1,
126.1, 112.6, 70.5, 65.2, 50.5, 39.3, 27.0, 19.4, −4.2, −4.6. IR (thin
film): 3467, 3071, 2956, 2859, 1632, 1250, 1195, 1112, 1061 cm−1.
HRMS (ESI+, m/z): calcd for C36H44NaO2Si2 [(M + Na)]+ 587.2772,
found 587.2758.
anti-12. Colorless oil. Yield: 348 mg, 37% (in two steps). Rf
(pentane/EtOAc 10/1) = 0.50. 1H NMR (500 MHz, C6D6): δ =
7.82−7.78 (m, 2H), 7.77−7.73 (m, 2H), 7.50−7.46 (m, 2H), 7.30−
7.07 (m, 14H), 5.08−5.02 (m, 2H), 4.83 (s, 1H), 4.04 (t, J = 10.5 Hz,
1H), 4.01 (dd, J = 10.5, 5.0 Hz, 1H), 3.66 (d, J = 2.5 Hz, 1H), 2.61
(dd, J = 10.5, 4.5 Hz, 1H), 2.51 (dd, J = 13.5, 3.0 Hz, 1H), 2.28 (dd, J
= 14.0, 10.0 Hz, 1H), 1.18 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H). 13C
NMR (125 MHz, C6D6): δ = 147.5, 145.3, 137.0, 136.04, 136.00,
134.2, 133.5, 133.4, 130.1, 130.0, 129.4, 128.4, 128.1, 128.1, 128.0,
127.2, 126.0, 111.2, 75.8, 66.1, 50.5, 41.5, 26.9, 19.3, −3.9, −5.0. IR
(thin film): 3443, 3070, 2956, 2858, 1630, 1427, 1250, 1194, 1112,
1065 cm−1. HRMS (ESI+, m/z): calcd for C36H44NaO2Si2 [(M +
Na)]+ 587.2772, found 587.2765.
Hz, 1H), 0.40 (s, 3H), 0.39 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
= 154.4, 142.3, 139.8, 133.8, 128.8, 128.3, 127.8, 127.3, 125.8, 103.9,
79.4, 79.2, 41.7, 22.9, −1.6, −2.0. IR (thin film): 3069, 2955, 2922,
2853, 1665, 1427, 1247, 1112, 1086 cm−1. HRMS (ESI+, m/z): calcd
for C20H24NaOSi [(M + Na)]+ 331.1489, found 331.1486.
14b. To a solution of 13b (8.6 mg, 0.0263 mmol) and Et3N (27.0
mg, 0.263 mmol) in CH2Cl2 (0.5 mL) was added TsCl (7.5 mg,
0.0395 mmol) at rt. The mixture was stirred at rt for 17 h, and water
was added. The separated aqueous phase was extracted with CH2Cl2,
and the combined organic solutions were washed with brine, dried
with Na2SO4, and concentrated in vacuo. The residue was purified by
chromatography (silica gel, 10% CH2Cl2/pentane) to give 14b (5.6
mg, 69% yield) as a colorless oil. Rf (pentane/CH2Cl2 10/1) = 0.45.
1H NMR (500 MHz, CDCl3): δ = 7.60−7.56 (m, 2H), 7.37−7.22 (m,
8H), 5.04 (t, J = 7.0 Hz, 1H), 4.92 (dd, J = 4.0, 2.0 Hz, 1H), 4.83 (dd,
J = 4.0, 2.0 Hz, 1H), 4.70−4.65 (m, 1H), 3.04−2.97 (m, 1H), 2.64−
2.58 (m, 1H), 1.27 (dd, J = 15.0, 9.5 Hz, 1H), 1.23 (dd, J = 15.0, 5.0
Hz, 1H), 0.41 (s, 3H), 0.38 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
= 154.1, 143.0, 139.7, 133.8, 128.9, 128.3, 127.8, 127.2, 125.8, 104.3,
78.4, 77.6, 40.6, 23.4, −1.6, −2.2. IR (thin film): 3068, 2954, 2922,
2853, 1667, 1427, 1246, 1112, 1056 cm−1. HRMS (ESI+, m/z): calcd
for C20H24NaOSi [(M + Na)]+ 331.1489, found 331.1491.
syn-12. To a solution of 14a (8.5 mg, 0.0261 mmol) in DMF (0.5
mL) were added TBDPSCl (8.9 mg, 0.0313 mmol) and imidazole (4.4
mg, 0.0653 mmol). The mixture was stirred at rt for 1 h and diluted
with water and Et2O. The separated aqueous phase was extracted with
Et2O, and the combined organic solutions were washed with brine,
dried with Na2SO4, and concentrated in vacuo. The residue was
purified by chromatography (silica gel, 0%→2% EtOAc/pentane) to
give syn-12 (12.0 mg, 82% yield) as a colorless oil.
anti-12. To a solution of 14b (7.0 mg, 0.0215 mmol) in DMF (0.5
mL) was added TBDPSCl (9.2 mg, 0.0258 mmol) and imidazole (3.7
mg, 0.0538 mmol). The mixture was stirred at rt for 1 h and diluted
with water and Et2O. The separated aqueous phase was extracted with
Et2O, and the combined organic solutions were washed with brine,
dried with Na2SO4, and concentrated in vacuo. The residue was
purified by chromatography (silica gel, 0%→2% EtOAc/pentane) to
give anti-12 (9.7 mg, 80% yield) as a colorless oil.
13a and 13b. A mixture of 8 (50.0 mg, 0.167 mmol), zinc powder
(12.0 mg, 0.184 mmol), and benzaldehyde (19.7 mg, 0.184 mmol) in
THF−satd NH4Cl aq (1 mL−0.1 mL) was stirred for 2 h. After
dilution with Et2O, the separated aqueous phase was extracted with
Et2O, and the combined organic solutions were dried with Na2SO4
and concentrated. The residual oil was purified by column
chromatography (silica gel, 0%→20% EtOAc/pentane) to give 13a
(21.8 mg, 40% yield) and 13b (19.1 mg, 35% yield), respectively.
General Procedure for TMSOTf-Promoted Cyclization of β-
Hydroxy Allylsilanes. To a solution of β-hydroxy allylsilane (0.030
mmol) in Et2O (1.0 mL) was added aldehyde (0.060 mmol), and the
mixture was cooled to −78 °C. TMSOTf (8.1 μL, 0.045 mmol) was
added, and the mixture was stirred until the starting material
completely disappeared (monitored by TLC). The reaction was
quenched with satd NaHCO3 aq, and then aqueous layer was extracted
with Et2O. The combined organic layer was dried with Na2SO4 and
concentrated in vacuo. The residue was purified by chromatography
with EtOAc−pentane to give cyclized product.
1
13a. Colorless oil. Rf (pentane/EtOAc 5/1) = 0.45. H NMR (500
MHz, C6D6): δ = 7.39−7.34 (m, 4H), 7.22−7.14 (m, 5H), 7.12−7.07
(m, 1H), 5.02 (s, 1H), 4.93 (dd, J = 10.5, 3.0 Hz, 1H), 4.77 (s, 1H),
3.70−3.58 (m, 3H), 2.50 (brs, 1H), 2.29 (dd, J = 14.0, 11.0 Hz, 1H),
2.18−2.09 (m, 2H), 0.16 (s, 6H). 13C NMR (125 MHz, C6D6): δ =
145.4, 145.1, 137.3, 134.2, 129.5, 128.5, 128.1, 127.2, 126.0, 112.9,
70.6, 63.2, 50.1, 38.8, −4.2, −4.8. IR (thin film): 3351, 3069, 2954,
1633, 1427, 1249, 1112, 1058 cm−1. HRMS (ESI+, m/z): calcd for
C20H26NaO2Si [(M + Na)]+ 349.1594, found 349.1601.
1
13b. Colorless oil. Rf (pentane/EtOAc 5/1) = 0.44. H NMR (500
15a. Colorless oil. Yield: 14.3 mg, 96% (from syn-9); 14.0 mg, 94%,
1
MHz, C6D6): δ = 7.40−7.34 (m, 4H), 7.21−7.13 (m, 5H), 7.12−7.06
(m, 1H), 4.97 (s, 1H), 4.84 (dd, J = 9.5, 3.5 Hz, 1H), 4.75 (s, 1H),
3.68 (br, s), 3.63 (d, J = 8.5 Hz, 2H), 2.39 (dd, J = 13.0, 3.5 Hz, 1H),
2.36 (d, J = 8.5 Hz, 1H), 2.16 (dd, J = 13.0, 9.5 Hz, 1H), 2.03 (brs,
1H), 0.16 (s, 3H), 0.15 (s, 3H). 13C NMR (125 MHz, C6D6): δ =
147.4, 145.3, 137.2, 134.3, 129.5, 128.5, 128.1, 127.3, 126.0, 110.9,
76.6, 64.0, 50.2, 41.7, −4.0, −5.1. IR (thin film): 3338, 3069, 2954,
1631, 1427, 1249, 1112, 1060 cm−1. HRMS (ESI+, m/z): calcd for
C20H26NaO2Si [(M + Na)]+ 349.1594, found 349.1604.
14a. To a solution of 13a (16.0 mg, 0.0491 mmol) and Et3N (50.0
mg, 0.491 mmol) in CH2Cl2 (0.5 mL) was added TsCl (14.0 mg,
0.0737 mmol) at rt. The mixture was stirred at rt for 17 h, and water
was added. The separated aqueous phase was extracted with CH2Cl2,
and the combined organic solutions were washed with brine, dried
with Na2SO4, and concentrated in vacuo. The residue was purified by
chromatography (silica gel, 10% CH2Cl2/pentane) to give 14a (7.1
mg, 47% yield) as a colorless oil. Rf (pentane/CH2Cl2 10/1) = 0.49.
1H NMR (500 MHz, CDCl3): δ = 7.61−7.56 (m, 2H), 7.37−7.23 (m,
8H), 4.94−4.91 (m, 1H), 4.86−4.83 (m, 1H), 4.81 (dd, J = 10.0, 5.5
Hz, 1H), 4.52−4.46 (m, 1H), 2.92 (dd, J = 15.5, 5.5 Hz, 1H), 2.50−
2.42 (m, 1H), 1.34 (dd, J = 15.0, 4.0 Hz, 1H), 1.24 (dd, J = 15.0, 9.5
82:18 dr (from anti-10). Rf (pentane/EtOAc 10/1) = 0.88. H NMR
(500 MHz, CDCl3): δ = 7.69−7.65 (m, 4H), 7.44−7.33 (m, 6H),
7.30−7.25 (m, 2H), 7.21−7.15 (m, 3H), 5.37 (t, J = 6.5 Hz, 1H), 4.23
(dd, J = 12.5, 6.5 Hz, 1H), 4.19 (dd, J = 12.5, 6.5 Hz, 1H), 3.21−3.14
(m, 1H), 2.96−2.89 (m, 1H), 2.80 (ddd, J = 13.5, 9.5, 5.5 Hz, 1H),
2.69 (dt, J = 13.5, 9.0 Hz, 1H), 2.21 (d, J = 13.5 Hz, 1H), 2.05 (d, J =
13.0 Hz, 1H), 1.94 (t, J = 12.0 Hz, 1H), 1.90−1.81 (m, 1H), 1.74−
1.65 (m, 1H), 1.56−1.46 (m, 2H), 1.44−1.33 (m, 1H), 1.03 (s, 9H),
0.94 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ = 142.4,
137.0, 135.71, 135.69, 134.00, 133.96, 129.6, 128.6, 128.4, 127.70,
127.68, 125.8, 122.6, 78.9, 77.0, 60.1, 42.2, 37.9, 34.9, 31.8, 29.4, 26.9,
19.2, 10.4. IR (thin film): 3070, 3027, 2931, 2857, 1671, 1603, 1589,
1428, 1111, 1069 cm−1. HRMS (ESI+, m/z): calcd for C33H42NaO2Si
[(M + Na)]+ 521.2846, found 521.2834.
15b. Colorless oil. Yield: 15.4 mg, 93% (from syn-9); 15.7 mg, 95%,
1
79:21 dr (from anti-11). Rf (pentane/EtOAc 10/1) = 0.89. H NMR
(500 MHz, CDCl3): δ = 7.70−7.65 (m, 4H), 7.44−7.33 (m, 6H),
7.31−7.24 (m, 2H), 7.21−7.16 (m, 3H), 5.37 (t, J = 6.5 Hz, 1H), 4.22
(dd, J = 12.5, 6.5 Hz, 1H), 4.19 (dd, J = 12.5, 6.5 Hz, 1H), 3.17−3.10
(m, 1H), 2.83−2.65 (m, 3H), 2.27 (d, J = 13.5 Hz, 1H), 2.03 (d, J =
13.0 Hz, 2H), 1.96−1.80 (m, 2H), 1.78−1.61 (m, 4H), 1.60−1.46 (m,
112
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The Journal of Organic Chemistry
Article
2H), 1.26−1.08 (m, 4H), 1.03 (s, 9H), 1.02−0.85 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ = 142.4, 137.3, 135.7, 134.0, 129.6, 128.7,
128.3, 127.7, 125.7, 122.7, 81.7, 76.8, 60.0, 43.3, 42.4, 38.0, 32.2, 31.8,
29.3, 29.0, 26.9, 26.7, 26.2, 26.1, 19.2. IR (thin film): 3070, 3026, 2929,
2855, 1671, 1603, 1589, 1428, 1111, 1059 cm−1. HRMS (ESI+, m/z):
calcd for C37H48NaO2Si [(M + Na)]+ 575.3316, found 575.3316.
15c. Colorless oil. Yield: 14.2 mg, 90% (from syn-9). Rf (pentane/
127.66, 125.7, 122.7, 82.5, 76.0, 60.1, 43.3, 39.4, 38.1, 35.4, 31.8, 29.5,
28.9, 26.9, 26.7, 26.3, 26.1, 19.2. IR (thin film): 3070, 3026, 2928,
2855, 1671, 1603, 1589, 1428, 1111, 1058 cm−1. HRMS (ESI+, m/z):
calcd for C37H48NaO2Si [(M + Na)]+ 575.3316, found 575.3303.
16c. Colorless oil. Yield: 12.6 mg, 80%, 92:8 dr (from anti-9). Rf
1
(pentane/EtOAc 10/1) = 0.90. H NMR (500 MHz, CDCl3): δ =
7.70−7.64 (m, 4H), 7.43−7.30 (m, 6H), 7.29−7.24 (m, 2H), 7.21−
7.14 (m, 3H), 5.39 (t, J = 6.5 Hz, 1H), 4.23−4.14 (m, 2H), 3.03−2.96
(m, 1H), 2.85 (dd, J = 11.5, 2.0 Hz, 1H), 2.76 (ddd, J = 14.0, 9.0, 5.0
Hz, 1H), 2.64 (dt, J = 14.0, 8.5 Hz, 1H), 2.11 (d, J = 13.5 Hz, 1H),
2.06 (d, J = 13.5 Hz, 1H), 1.94 (t, J = 12.0 Hz, 1H), 1.80−1.71 (m,
1H), 1.62−1.54 (m, 1H), 1.49 (t, J = 12.0 Hz, 1H), 1.02 (s, 9H), 0.94
(s, 9H). 13C NMR (125 MHz, CDCl3): δ = 142.6, 137.8, 135.7,
134.01, 134.00, 129.6, 128.6, 128.3, 127.69, 127.66, 125.7, 122.6, 85.6,
76.0, 60.2, 38.2, 36.3, 35.3, 34.3, 31.8, 26.9, 26.1, 19.2. IR (thin film):
3070, 2954, 2858, 1671, 1603, 1589, 1428, 1361, 1111, 1061 cm−1.
HRMS (ESI+, m/z): calcd for C35H46NaO2Si [(M + Na)]+ 549.3159,
found 549.3148.
16d. Colorless oil. Yield: 15.2 mg, 93% (from syn-12); 14.6 mg, 89%
(from anti-9). Rf (pentane/EtOAc 10/1) = 0.88. 1H NMR (500 MHz,
CDCl3): δ = 7.71−7.66 (m, 4H), 7.45−7.33 (m, 10H), 7.35−7.23 (m,
3H), 7.20−7.14 (m, 3H), 5.49 (t, J = 6.5 Hz, 1H), 4.30 (dd, J = 11.5,
2.5 Hz, 1H), 4.28−4.19 (m, 2H), 3.28−3.20 (m, 1H), 2.78 (ddd, J =
13.5, 9.0, 5.0 Hz, 1H), 2.68 (ddd, J = 13.5, 9.0, 7.0 Hz, 1H), 2.36 (d, J
= 13.5 Hz, 1H), 2.28−2.17 (m, 2H), 1.94−1.84 (m, 1H), 1.75−1.63
(m, 2H), 1.05 (s, 9H). 13C NMR (125 MHz, CDCl3): δ = 142.7,
142.3, 136.5, 135.71, 135.70, 134.0, 133.9, 129.7, 128.6, 128.4, 127.73,
127.71, 127.4, 125.82, 125.79, 123.3, 79.8, 76.7, 60.1, 43.9, 38.0, 34.8,
31.7, 26.9, 19.2. IR (thin film): 3069, 3027, 2930, 2856, 1673, 1603,
1589, 1427, 1111, 1056 cm−1. HRMS (ESI+, m/z): calcd for
C37H42NaO2Si [(M + Na)]+ 569.2846, found 569.2838.
1
EtOAc 10/1) = 0.90. H NMR (500 MHz, CDCl3): δ = 7.71−7.65
(m, 4H), 7.44−7.33 (m, 6H), 7.31−7.25 (m, 2H), 7.21−7.16 (m, 3H),
5.38 (t, J = 6.5 Hz, 1H), 4.22 (dd, J = 12.5, 6.5 Hz, 1H), 4.19 (dd, J =
12.5, 6.5 Hz, 1H), 3.19−3.12 (m, 1H), 2.80 (ddd, J = 14.0, 9.0, 5.0 Hz,
1H), 2.72−2.64 (m, 2H), 2.20 (d, J = 13.0 Hz, 1H), 2.05 (d, J = 13.0
Hz, 1H), 1.92−1.77 (m, 2H), 1.73−1.64 (m, 1H), 1.52 (t, J = 12.5 Hz,
1H), 1.03 (s, 9H), 0.86 (s, 9H). 13C NMR (125 MHz, CDCl3): δ =
142.6, 137.9, 135.7, 134.0, 129.6, 128.7, 128.3, 127.7, 125.7, 122.5,
84.7, 76.8, 60.0, 42.4, 38.1, 34.4, 31.8, 29.1, 26.9, 26.1, 19.2. IR (thin
film): 3070, 2953, 2858, 1671, 1608, 1589, 1428, 1361, 1111, 1062
cm−1. HRMS (ESI+, m/z): calcd for C35H46NaO2Si [(M + Na)]+
549.3159, found 549.3154.
15d. Colorless oil. Yield: 15.1 mg, 92% (from syn-9); 12.9 mg, 79%,
1
92:8 dr (from anti-12). Rf (pentane/EtOAc 10/1) = 0.88. H NMR
(500 MHz, CDCl3): δ = 7.70−7.65 (m, 4H), 7.42−7.14 (m, 16H),
5.48 (t, J = 6.5 Hz, 1H), 4.28 (dd, J = 12.5, 6.5 Hz, 1H), 4.22 (dd, J =
12.5, 6.5 Hz, 1H), 4.11 (dd, J = 11.5, 2.0 Hz, 1H), 3.44−3.38 (m, 1H),
2.82 (ddd, J = 13.5, 9.0, 5.5 Hz, 1H), 2.77−2.69 (m, 1H), 2.48 (d, J =
13.5 Hz, 1H), 2.16 (d, J = 13.0 Hz, 1H), 2.08 (t, J = 12.0 Hz, 1H),
2.00−1.91 (m, 1H), 1.89−1.76 (m, 2H), 1.04 (s, 9H). 13C NMR (125
MHz, CDCl3): δ = 142.6, 142.3, 136.5, 135.71, 135.67, 133.93, 133.85,
129.7, 128.6, 128.4, 128.3, 127.7, 127.5, 125.9, 125.8, 123.4, 79.0, 77.5,
60.1, 41.7, 37.9, 36.8, 31.7, 26.9, 19.2. IR (thin film): 3069, 3027, 2931,
2857, 1671, 1603, 1428, 1111, 1058 cm−1. HRMS (ESI+, m/z): calcd
for C37H42NaO2Si [(M + Na)]+ 569.2846, found 569.2839.
16e. Colorless oil. Yield: 16.1 mg, 94%, 94:6 dr (from anti-9). Rf
1
(pentane/EtOAc 10/1) = 0.90. H NMR (500 MHz, CDCl3): δ =
15e. Colorless oil. Yield: 16.3 mg, 95% (from syn-9). Rf (pentane/
1
7.71−7.66 (m, 4H), 7.45−7.14 (m, 16H), 6.63 (d, J = 16.0 Hz, 1H),
6.26 (dd, J = 16.0, 6.0 Hz, 1H), 5.46 (t, J = 6.5 Hz, 1H), 4.27−4.17 (m,
2H), 3.95−3.89 (m, 1H), 3.19−3.12 (m, 1H), 2.77 (ddd, J = 13.5, 9.0,
5.0 Hz, 1H), 2.67 (ddd, J = 14.0, 9.0, 7.5 Hz, 1H), 2.26−2.10 (m, 3H),
1.92−1.82 (m, 1H), 1.71−1.64 (m, 1H), 1.61 (t, J = 12.5 Hz, 1H),
1.04 (s, 9H). 13C NMR (125 MHz, CDCl3): δ = 142.2, 136.9, 136.1,
135.7, 133.93, 133.89, 130.3, 130.2, 129.7, 128.6, 128.4, 127.72,
127.66, 126.6, 125.8, 123.4, 78.6, 76.5, 60.1, 42.1, 37.9, 34.8, 31.8, 26.9,
19.2. IR (thin film): 3069, 3026, 2931, 2857, 1672, 1601, 1589, 1428,
1111, 1056 cm−1. HRMS (ESI+, m/z): calcd for C39H44NaO2Si [(M +
Na)]+ 595.3003, found 595.3001.
Computational Methods. All structures were optimized with the
B3LYP/6-31G(d) model chemistry33,34 using Gaussian 09.35 Fre-
quency calculations were used to characterize stationary points as
minima or transition-state structures along with intrinsic reaction
coordinate (IRC) calculations36 to connect transition-state structures
to their respective minima. Single-point energies were calculated for
the B3LYP/6-31G(d) geometries at multiple model chemistries
including CAM-B3LYP/6-31+G(d,p),37 M06-2X/6-31+G(d,p),38 and
B3LYP/6-31+G(d,p). Single-point solvent calculations were carried
out using the SMD solvent model39 with diethyl ether. Figures were
generated using Ball & Stick.40 Coordinates for all optimized
structures, as well as energies computed with the various methods
listed above, can be found in the Supporting Information.
EtOAc 10/1) = 0.90. H NMR (500 MHz, CDCl3): δ = 7.71−7.66
(m, 4H), 7.44−7.16 (m, 16H), 6.53 (d, J = 16.0 Hz, 1H), 6.18 (dd, J =
16.0, 5.5 Hz, 1H), 5.45 (t, J = 6.5 Hz, 1H), 4.28 (dd, J = 12.5, 6.5 Hz,
1H), 4.27 (dd, J = 12.5, 6.5 Hz, 1H), 4.22 (dd, J = 12.5, 6.0 Hz, 1H),
3.76−3.70 (m, 1H), 3.36−3.29 (m, 1H), 2.82 (ddd, J = 13.5, 9.0, 5.5
Hz, 1H), 2.77−2.68 (m, 1H), 2.35 (d, J = 13.5 Hz, 1H), 2.13 (d, J =
13.0 Hz, 1H), 2.05−1.89 (m, 2H), 1.82−1.71 (m, 2H), 1.04 (s, 9H).
13C NMR (125 MHz, CDCl3): δ = 142.2, 136.9, 136.1, 135.73, 135.70,
133.94, 133.86, 130.3, 130.1, 129.7, 128.6, 128.4, 127.74, 127.72,
127.65, 126.5, 125.8, 123.4, 77.7, 77.3, 60.1, 41.7, 37.8, 35.2, 31.8, 26.9,
19.2. IR (thin film): 3069, 3026, 2931, 2857, 1672, 1601, 1589, 1428,
1111, 1057 cm−1. HRMS (ESI+, m/z): calcd for C39H44NaO2Si [(M +
Na)]+ 595.3003, found 595.2994.
16a. Colorless oil. Yield: 14.3 mg, 96% (from syn-10); 14.2 mg,
1
95%, 84:16 dr (from anti-9). Rf (pentane/EtOAc 10/1) = 0.90. H
NMR (500 MHz, CDCl3): δ = 7.69−7.64 (m, 4H), 7.43−7.30 (m,
6H), 7.29−7.24 (m, 2H), 7.19−7.14 (m, 3H), 5.39 (t, J = 6.5 Hz, 1H),
4.21 (dd, J = 12.5, 6.5 Hz, 1H), 4.17 (dd, J = 12.5, 6.5 Hz), 3.15−3.08
(m, 1H), 3.06−2.99 (m, 1H), 2.76 (ddd, J = 13.5, 9.5, 5.5 Hz, 1H),
2.65 (dt, J = 14.0, 8.5 Hz, 1H), 2.15 (d, J = 13.5 Hz, 1H), 2.11 (d, J =
13.0 Hz, 1H), 1.90 (t, J = 12.5 Hz, 1H), 1.85−1.75 (m, 1H), 1.64−
1.43 (m, 4H), 1.03 (s, 9H), 1.00 (t, J = 7.5 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ = 142.3, 136.9, 135.7, 134.0, 129.7, 128.6, 128.4,
127.69, 127.67, 125.8, 122.6, 79.8, 76.2, 60.1, 41.8, 38.0, 35.2, 31.8,
29.4, 26.9, 19.2, 10.3. IR (thin film): 3070, 3026, 2931, 2857, 1670,
1603, 1589, 1428, 1111 cm−1. HRMS (ESI+, m/z): calcd for
C33H42NaO2Si [(M + Na)]+ 521.2846, found 521.2844.
ASSOCIATED CONTENT
■
S
* Supporting Information
16b. Colorless oil. Yield: 15.7 mg, 95% (from syn-11); 15.7 mg,
1H and 13C NMR spectra of all new compounds. Additional
details on computations, including coordinate and energies for
computed structures. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
95%, 84:16 dr (from anti-9). Rf (pentane/EtOAc 10/1) = 0.89. H
NMR (500 MHz, CDCl3): δ = 7.69−7.64 (m, 4H), 7.43−7.24 (m,
8H), 7.20−7.15 (m, 3H), 5.39 (t, J = 6.5 Hz, 1H), 4.20 (dd, J = 12.5,
7.0 Hz, 1H), 4.17 (dd, J = 12.5, 6.5 Hz, 1H), 3.02−2.95 (m, 1H), 2.92
(ddd, J = 11.0, 7.5, 2.0 Hz, 1H), 2.76 (ddd, J = 14.0, 8.5, 4.5 Hz, 1H),
2.66 (dt, J = 14.0, 8.0 Hz, 1H), 2.19−2.06 (m, 3H), 1.89 (t, J = 11.5
Hz, 1H), 1.84−1.63 (m, 5H), 1.62−1.49 (m, 2H), 1.45−1.34 (m, 1H),
1.32−1.12 (m, 3H), 1.08−0.96 (m, 11H). 13C NMR (125 MHz,
CDCl3): δ = 142.4, 137.2, 135.7, 134.0, 129.6, 128.7, 128.4, 127.68,
AUTHOR INFORMATION
■
Corresponding Author
*Email: djtantillo@ucdavis.edu; wenderp@stanford.edu.
113
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Article
(13) DeChristopher, B. A.; Fan, A. C.; Felsher, D. W.; Wender, P. A.
Oncotarget 2012, 3, 58−66.
(14) Barr, P. M.; Lazarus, H. M.; Cooper, B. W.; Schluchter, M. D.;
Panneerselvam, A.; Jacobberger, J. W.; Hsu, J. W.; Janakiraman, N.;
Simic, A.; Dowlati, A.; Remick, S. C. Am. J. Hematol. 2009, 84, 484−
487.
(15) Wender, P. A.; De Brabander, J.; Harran, P. G.; Jimenez, J.-M.;
Koehler, M. F. T.; Lippa, B.; Park, C.-M.; Siedenbiedel, C.; Pettit, G. R.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6624−6629.
(16) For a review of pyran synthesis, see: Clark, P. A.; Santos, S. Eur.
J. Org. Chem. 2006, 2045−2053.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Institutes of
Health (P.A.W., CA31845) and the National Science
Foundation (D.J.T., CHE-0957416 and supercomputer re-
sources through CHE030089).
DEDICATION
(17) (a) Marko, I. E.; Bayston, D. J. Tetrahedron Lett. 1993, 34,
6595−6598. (b) Mekhalfia, A.; Marko, I. E.; Adams, H. Tetrahedron
Lett. 1991, 32, 4783−4786. (c) Marko, I. E.; Mekhalfia, A. Tetrahedron
Lett. 1992, 33, 1799−1802. (d) Marko, I. E.; Mekhalfia, A.; Bayston,
D. J.; Adams, H. J. Org. Chem. 1992, 57, 2211−2213.
(18) (a) Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4,
1189−1192. (b) Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2149−
2152. (c) Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2153−2156.
(d) Keck, G. E.; Welch, D. S.; Poudel, Y. B. Tetrahedron Lett. 2006, 47,
8267−8270. (e) Keck, G. E.; Kraft, M. B.; Truong, A. P.; Li, W.;
Sanchez, C. C.; Kedei, N.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem.
Soc. 2008, 130, 6660−6661. (f) Keck, G. E.; Li, W.; Kraft, M. B.;
Kedei, N.; Lewin, N. E.; Blumberg, P. M. Org. Lett. 2009, 11, 2277−
2280.
(19) For recent examples of application of silyl-terminated Prins
cyclization to natural product synthesis, see: (a) Gesinski, M. R.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2011, 133, 9727−9729. (b) Zhu,
K.; Panek, J. S. Org. Lett. 2011, 13, 4652−4655. (c) Ghosh, A. K.;
Cheng, X. Org. Lett. 2011, 13, 4108−4111. (d) Wrona, I. E.; Gozman,
A.; Taldone, T.; Chiosis, G.; Panek, J. S. J. Org. Chem. 2010, 75, 2820−
2835. (e) Takahashi, K.; Akao, R.; Honda, T. J. Org. Chem. 2009, 74,
3424−3429. (f) Lowe, J. T.; Panek, J. S. Org. Lett. 2008, 10, 3813−
3816. (g) Qin, H.-L.; Panek, S. J. Org. Lett. 2008, 10, 2477−2479.
(20) Wender, P. A.; DeChristopher, B. A.; Schrier, A. J. J. Am. Chem.
Soc. 2008, 130, 6658−6659.
(21) For a recent review, see: (a) Crane, E. A.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2010, 49, 8316−8326. For previous work, see:
(b) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc.
2008, 130, 804−805. (c) Woo, S. K.; Kwon, M. S.; Lee, E. Angew.
Chem., Int. Ed. 2008, 47, 3242−3244. (d) Bahnck, K. B.; Rychnovsky,
S. D. J. Am. Chem. Soc. 2008, 130, 13177−13181. (e) Gesinski, M. R.;
Tadpetch, K.; Rychnovsky, S. D. Org. Lett. 2009, 11, 5342−5345.
(f) Custar, D. W.; Zabawa, T. P.; Hines, J.; Crews, C. M.; Scheidt, K.
A. J. Am. Chem. Soc. 2009, 131, 12406−12414. (g) Yadav, J. S.;
Krishana, G. G.; Kumar, S. N. Tetrahedron 2010, 66, 480−487.
(h) Woo, S. K.; Lee, E. J. Am. Chem. Soc. 2010, 132, 4564−4565.
(22) For recent reviews of the Prins reaction, see: (a) Pastor, I. M.;
Yus, M. Curr. Org. Chem. 2007, 11, 925−957. (b) Olier, C.; Kaafarani,
M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron 2010, 66, 413−445.
(23) Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc.
2006, 128, 6745−6754.
(24) Tanaka, K.; Ohta, Y.; Fuji, K.; Taga, T. Tetrahedron Lett. 1993,
34, 4071−4074. It is also used in bryostatin synthesis; see ref 9b,c,e,g.
(25) For a variant involving bis-allylic silanes, see: Lu, J.; Song, Z.;
Zhang, Y.; Gan, Z.; Li, H. Angew. Chem., Int. Ed. 2012, 51, 5367−5370.
(26) For an example of a constrained allyl silane (cyclohexenylsilane)
in a Prins process, see: Pham, M.; Allatabakhsh, A.; Minehan, T. G. J.
Org. Chem. 2008, 73, 741−744.
(27) For an excellent review, see: Masse, C. E.; Panek., J. S. Chem.
Rev. 1995, 95, 1293−1316.
(28) Fukuda, K.; Miyashita, M.; Tanino, K. Tetrahedron Lett. 2010,
51, 4523−4525.
(29) Harb, H. Y.; Collins, K. D.; Garcia Altur, J. V.; Bowker, S.;
Campbell, L.; Procter, D. J. Org. Lett. 2010, 12, 5446−5449.
(30) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538−2541.
(31) This type of scenario also has been observed in terpene-forming
carbocation rearrangements; see: Tantillo, D. J. J. Phys. Org. Chem.
2008, 21, 561−570.
■
This article is dedicated to the memory of Professor Robert E.
Ireland whose inspiration continues.
REFERENCES
■
(1) Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold,
E.; Clardy, J. J. Am. Chem. Soc. 1982, 104, 6846−6848.
(2) For reviews, see: (a) Wender, P. A.; Loy, B. A.; Schrier, A. J. Isr. J.
Chem. 2011, 51, 453−472. (b) Wender, P. A.; Baryza, J. L.; Hilinski,
M. K.; Horan, J. C.; Kan, C.; Verma, V. A. Beyond Natural Products:
Synthetic Analogues of Bryostatin 1. In Drug Discovery Research;
Huang, Z., Ed.; Wiley: Hoboken, 2007; pp 127−162. (c) Pettit, G. R.;
Herald, C. L.; Hogan, F. In Anticancer Drug Development; Baguley, B.
C., Kerr, D. J., Eds.; Academic Press: San Diego, 2002; pp 203−235.
(d) Kortmansky, J.; Schwartz, G. K. Cancer Invest. 2003, 21, 924−936.
(e) Hale, K. J.; Hummersone, M. G.; Manaviazar, S.; Frigerio, M. Nat.
Prod. Rep. 2002, 19, 413−453. (f) Hale, K. J.; Manaviazar, S. Chem.
Asian J. 2010, 5, 704−754.
(3) (a) Nelson, T. J.; Alkon, D. L. Trends Biochem. Sci. 2009, 34,
136−145. (b) Sun, M.-K.; Alkon, D. L. Arch. Pharm. 2009, 342, 689−
698. (c) Khan, T. K.; Nelson, T. J.; Verma, V. A.; Wender, P. A.;
Alkon, D. L. Neurobiol. Dis. 2009, 34, 332−339. (d) Sun, M.-K.; Alkon,
D. L. Pharmacol. Ther. 2010, 127, 66−77.
(4) Mehla, R.; Bivalkar-Mehla, S.; Zhang, R.; Handy, I.; Albrecht, H.;
Giri, S.; Nagarkatti, P.; Nagarkatti, M.; Chauhan, A. PLoS One 2010, 5,
e11160.
(5) Wender, P. A.; Cribbs, C. M.; Koehler, K. F.; Sharkey, N. A.;
Herald, C. L.; Kamano, Y.; Pettit, G. R.; Blumberg, P. M. Proc. Natl.
Acad. Sci. U.S.A. 1988, 85, 7197−7201.
(6) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197−201.
(7) Wender, P. A.; De Brabander, J.; Harran, P. G.; Jimenez, J.-M.;
Koehler, M. F. T.; Lippa, B.; Park, C.-M.; Shiozaki, M. J. Am. Chem.
Soc. 1998, 120, 4534−4535.
(8) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, C.; Brenner, S. E.;
Clarke, M. O.; Horan, J. C.; Kan, C.; Lacote, E.; Lippa, B.; Nell, P. G.;
Turner, T. M. J. Am. Chem. Soc. 2002, 124, 13648−13649.
(9) For total syntheses of natural bryostatins, see: (a) Kageyama, M.;
Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai, P.; Whritenour, D.
C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407−7408. (b) Evans,
D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.;
Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540−7552. (c) Ohmori, K.;
Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S.
Angew. Chem., Int. Ed. 2000, 39, 2290−2294. (d) Trost, B. M.; Dong,
G. Nature 2008, 456, 485−488. (e) Keck, G. E.; Poudel, Y. B.;
Cummins, T. J.; Rudra, A; Covel, J. A. J. Am. Chem. Soc. 2011, 133,
744−747. (f) Wender, P. A.; Schrier, A. J. J. Am. Chem. Soc. 2011, 133,
9228−9231. (g) Lu, Y.; Woo, S. K.; Krische, M. J. J. Am. Chem. Soc.
2011, 133, 13876−13879. For a formal synthesis, see: (h) Manaviazar,
S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.; Aliev, A. E.; Hale,
K. J. Org. Lett. 2006, 8, 4477−4480 and references therein.
(10) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40−49.
(11) DeChristopher, B. A.; Loy, B. A.; Marsden, M. D.; Schrier, A. J.;
Zack, J. A.; Wender, P. A. Nature Chem. 2012, 4, 705−710.
(12) Stang, S. L.; Lopez-Campistrous, A.; Song, X.; Dower, N. A.;
Blumberg, P. M.; Wender, P. A.; Stone, J. C. Exp. Hematol. 2009, 37,
122−134.
114
dx.doi.org/10.1021/jo301953h | J. Org. Chem. 2013, 78, 104−115

The Journal of Organic Chemistry
Article
(32) The calculations are consistent with our proposed mechanism
but, of course, do not rule out the possibility that other mechanisms
are also reasonable.
(33) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372−1377. (b) Becke,
A. D. J. Chem. Phys. 1993, 98, 5648−5652. (c) Lee, C.; Yang, W.; Parr,
R. G. Phys. Rev. B 1988, 37, 785−789. (d) Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623−
11627. (e) Wheeler, S. E.; Moran, A.; Pieniazek, S. N.; Houk, K. N. J.
Phys. Chem. A 2009, 113, 10376−10384. (f) Pieniazek, S. N.;
Clemente, F. R.; Houk, K. N. Angew. Chem., Int. Ed. 2008, 47, 7746−
7749.
(34) For examples of DFT applied to the Prins process, see:
(a) Jacolot, M.; Jean, M.; Levoin, N.; van de Weghe, P. Org. Lett. 2011,
14, 58−61. (b) Alder, R. W.; Carta, F.; Reed, C. A.; Stoyanova, I.;
Willis, C. L. Org. Biomol. Chem. 2010, 8, 1551−1559. (c) Jasti, R.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2006, 128, 13640−13648.
(e) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002,
124, 4960−4961.
(35) Gaussian 09, Revision B.01; Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.;
Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc.,
Wallingford, CT, 2009.
(36) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363−368. (b) Gonzalez,
C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154−2161. (c) Gonzalez,
C.; Schlegel, H. B. J. Chem. Phys. 1991, 95, 5853−5860.
(37) Yanai, T.; Tew, D. P.; Handy, N. C. Chem. Phys. Lett. 2004, 393,
51−57.
(38) (a) Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008, 120, 215−241.
(b) Valero, R.; Costa, R.; Moreira, I.; de, P. R.; Truhlar, D. G.; Illas, F.
J. Chem. Phys. 2008, 128, 114103−114108.
(39) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378−6396.
(40) Muller, N.; Falk, A. Ball & Stick 4.0a12, molecular graphics
software for MacOS, Johannes Kepler University, Linz, 2004.
115
dx.doi.org/10.1021/jo301953h | J. Org. Chem. 2013, 78, 104−115