A study of exocyclic radical reductions of polysubstituted tetrahydropyrans

Article abstract of DOI:10.1021/jo400721e

Exocyclic radical reductions were thoroughly investigated in the context of the synthesis of polysubstituted tetrahydropyrans, which are found in numerous macrolides. The radical precursors studied herein were generated by tandem cycloetherification and iodoetherification reactions or, alternatively, by semicyclic acetals substitutions. DFT calculations (BHandHLYP/TZVP) performed at the transition-state level for the hydrogen radical delivery are in good accordance with the experimental data and enabled the identification of important conformational factors that govern the selectivities obtained. This study demonstrates that both the preferred reactive conformation of the radical and steric interactions with the incoming hydride have to be considered in order to fully rationalize the levels of diastereoselection generated in acyclic free-radical processes.

Full text of DOI:10.1021/jo400721e

Article
pubs.acs.org/joc
A Study of Exocyclic Radical Reductions of Polysubstituted
Tetrahydropyrans
Franco
̧
is Godin,†,‡ Michel Prevost,†,‡ Frederick Viens,†,‡ Philippe Mochirian,†,‡ Jean-Franco
̧
is Brazeau,†,‡
́
́
́
Serge I. Gorelsky,∥ and Yvan Guindon*,†,‡,§
†Institut de recherches cliniques de Montrea
Quebec, Canada H2W 1R7
‡Dep
artement de Chimie, Universite
§Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montrea
́ ́
l (IRCM), Bio-Organic Chemistry Laboratory, 110 avenue des Pins Ouest, Montreal,
́
́
́
de Montrea
́
́ ́
l, C.P. 6128, succursale Centre-ville, Montreal, Quebec, Canada H3C 3J7
́
l, Quebec, Canada H3A 2K6
́
∥Department of Chemistry and Center for Catalysis Research and Innovation, University of Ottawa, 10 Marie Curie, Ottawa, Ontario,
Canada K1N 6N5
S
* Supporting Information
ABSTRACT: Exocyclic radical reductions were thoroughly investigated in the context of the synthesis of polysubstituted
tetrahydropyrans, which are found in numerous macrolides. The radical precursors studied herein were generated by tandem
cycloetherification and iodoetherification reactions or, alternatively, by semicyclic acetals substitutions. DFT calculations
(BHandHLYP/TZVP) performed at the transition-state level for the hydrogen radical delivery are in good accordance with the
experimental data and enabled the identification of important conformational factors that govern the selectivities obtained. This
study demonstrates that both the preferred reactive conformation of the radical and steric interactions with the incoming hydride
have to be considered in order to fully rationalize the levels of diastereoselection generated in acyclic free-radical processes.
INTRODUCTION
■
Biologically relevant ionophores,1 such as zincophorin (1a),2
salinomycin (1b), and narasin (1c),3 have attracted the attention
of many groups interested in their synthesis and biological
evaluation.4 These molecules feature complex polypropionate
motifs and substituted tetrahydropyranyl (THP) fragments for
which different synthetic strategies were developed (Figure 1).5
One of the original aspects of the stereoselective strategies that
our group has developed is the use of hydrogen transfers to
acyclic carbon-centered free radical intermediates. These
reactions allowed us to generate most of the stereogenic centers
bearing a secondary methyl group present in ionophores.6 As a
requirement for the reaction to be stereoselective, the radical
must be flanked on one side by an ester and, on the other, by a
stereogenic center bearing an electron-withdrawing group (i.e.,
alkoxy groups in the context of polypropionate synthesis). We
were particularly interested in the high 2,3-anti selectivities
reached when performing the hydrogen-transfer reactions on
substrates embedding the vicinal C3−O bond within a ring
(THP or THF). The enhancement of selectivity obtained with
these systems was referred as the exocyclic effect (I, Scheme 1).7
The complementary 2,3-syn isomer was achieved by performing
the radical reduction in presence of a bidentate Lewis acid (II).6a
Figure 1. Structure of zincophorin (1a), salinomycin (1b), and narasin
(1c).
Their common radical precursors at C2 (X = Br, I) are obtained
efficiently by the addition of enoxysilanes 2 to acetals or from an
aldehyde by cycloetherification8 (III or IV, Scheme 1).6c,d
Alternatively, C4-methyl-substituted cyclic precursors were
Received: April 10, 2013
© XXXX American Chemical Society
A
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free radical in the axial conformation, an orientation that was
demonstrated experimentally in rigidified systems to provide low
selectivities.10 Alternatively, destabilizing interactions between
cyclic substituents and the incoming hydride in the anti- and syn-
predictive transition states (TS) could also influence the
difference in energy and, thus, the level of selectivity under
kinetic control. To further investigate these hypotheses, we
embarked on the synthesis of several THP precursors bearing
different substitution patterns to evaluate their impact on the
outcome of the exocyclic reduction. A transition state DFT
analysis (BHandHLYP/TZVP) was also initiated to better
rationalize the stereochemical outcome of free-radical reduction
on polysubstituted THP precursors.
Scheme 1. Strategies To Generate Polysubstituted THP
Bearing a Radical Precursor at C2 for Exocyclic Hydrogen-
Transfer Reactions
RESULTS AND DISCUSSION
■
Synthesis of the Radical Precursors. Radical precursors
that would lead to isomers of the C1−C9 fragment of
zincophorin (1a) were first synthesized.6c−e These tertiary
halides could be obtained from a corresponding propionate
sequence, which were generated using a sequential strategy
involving Mukaiyama aldol and hydrogen-transfer reactions from
a β-hydroxy-α-methyl aldehyde.11 The stereochemical outcome
of the acyclic radical reaction step was controlled by the nature of
the Lewis acids, as illustrated in Scheme 3. Various THP
analogues with different substitutions at C7 were also
synthesized by varying the nature of the starting aldehyde (R1).
accessed by diastereoselective iodoetherification of α,β-unsatu-
rated olefins (V).6e
Excellent diastereoselectivities were routinely observed, as
exemplified by the reduction of tertiary halides 3a,b (Scheme
2a).7a,b In the course of our synthetic efforts toward ionophores
Scheme 2. Exocyclic Radical Reductions of C1−C9 Fragments
of Zincophorin (5a), Salinomycin (6a), and Narasin (7a).9
Scheme 3. Lewis Acid-Controlled Synthesis of Acyclic
Propionates
A representative example for the synthesis of THP radical
precursors 14a,b, corresponding to the C6-isomer of zincophor-
in 1a, is presented in Scheme 4.9 β-Silyloxy aldehyde 8 was first
reacted with enoxysilane 2 in the presence of BF3·OEt2 at −78 °C
to afford the 7,8-syn relationship selectively.6d A mixture of
tertiary bromides 9a,b was then submitted to the hydrogen-
transfer reaction in the presence of AlMe3 to take advantage of
the endocyclic stereocontrol,6a which provided the 6,7-syn isomer
10. The radical reaction was initiated with Et3B at −78 °C.12 The
secondary alcohol 10 was then protected by a TES group before
reduction of the ester and oxidation of the resulting alcohol to
aldehyde 11. A Wittig olefination using the appropriate
triphenylphosphoranylidene was then realized to provide the
α,β-unsaturated ester. The olefin was hydrogenated and the ester
transformed to the corresponding aldehyde 12. The tetrahy-
dropyran was prepared using enoxysilane 2 and Evans’
procedure8 with BiBr3, yielding a mixture of C2 tertiary bromides
13a,b with a 3,7-trans stereochemistry selectively. Tertiary
bromides 14a,b were obtained after cleavage of TBDPS on the
(1a−c), however, we observed that certain THP substitution
patterns had a dramatic impact on the stereochemical outcome of
the radical reduction at C2. A somewhat lower 2,3-anti selectivity
was obtained for the hydrogen transfer leading to the C1−C9
zincophorin fragment 5a (Scheme 2b),6d while a significant loss
of 2,3-anti selectivity was noted with the corresponding fragment
leading to salinomycin 6a (Scheme 2c). The presence of an
additional methyl group at C4 on the latter scaffold led to the
recovery of the 2,3-anti selectivity, which enabled the stereo-
selective formation of the C1−C9 fragment of narasin 7a
(Scheme 2c).6c
The impact of these different THP substitutions on the
outcome of exocyclic radical reductions was challenging to
rationalize. We first postulated that the various substituents on
the THP (i.e., at C3, C4, C6, and C7)9 could, in certain cases,
favor positioning of the C2-chain bearing the carbon-centered
B
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Scheme 4. Synthesis of Radical Precursors 14a,b as the C6-
Epimer of Zincophorin C1−C9 Fragment
Table 1. Radical Reductions of THP Analogues 15−22a,b
a
a
Reactions and conditions: (a) BF3·OEt2, 2, CH2Cl2, −78 °C; (b)
AlMe3, CH2Cl2, −78 °C then Bu3SnH, Et3B, air, CH2Cl2, −78 °C; (c)
TESOTf, 2,6-lutidine, CH2Cl2, 0 °C; (d) DIBAL-H, CH2Cl2, −40 °C;
(e) (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C; (f) Ph3PC(H)
CO2Me, toluene, reflux; (g) H2, Pd/C, EtOAc, rt; (h) DMP,
NaHCO3, CH2Cl2, rt; (i) BiBr3, 2, CH2Cl2/MeCN, −78 °C; (j)
HF·py, THF, 0 °C; (k) BnOCNHCCl3, TfOH, c-Hex/CH2Cl2,
0 °C.
oxygen at C9 with HF·pyridine and protection by a benzyl group.
As mentioned previously, other analogues were prepared using a
similar reaction sequence starting either from (R)-Roche ester,
isobutyraldehyde, or β-hydroxyaldehyde. Detailed schemes for
the syntheses of the different radical precursors studied are
provided in the Experimental Section.
Reductions of Radical Precursors Analogues of the
C1−C9 Subunit of Zincophorin. Radical precursors 15−
22a,b were first examined (Table 1). Radical reductions were
performed at −78 °C in toluene in the presence of Ph3SnH using
Et3B as the radical chain initiator. Benzyloxy-protected precursor
15a,b provided a marginal increase in 2,3-anti selectivity, as
compared to the corresponding silyl-protected THP 5a (entry 1,
Table 1 and Scheme 2b). Inversion of the configuration at C8
(entry 2) and removal of the C9-benzyloxy group (entry 3) or of
the C8-methyl group (entry 4) did not significantly influence the
observed 2,3-anti selectivity. Substrates without the C6-methyl
group also provided comparable levels of selectivity (entries 5
and 6). The high induction obtained with 3,7-cis substrates 21a
and 22a,b is, however, noteworthy (entries 7 and 8) and indicates
that the 3,7-stereochemical relation has an impact on the levels of
inductions in exocyclic reductions (entry 1 vs 8).
THP precursors bearing a 6,7-cis relationship were found to
undergo radical reduction with markedly lower anti-inductions
(Table 2). Indeed, a considerable loss of diastereoselectivity was
first observed with 6,7-cis THPs fragments 31a,b (entry 1). The
epimer at C8 of the latter (14a,b, entry 2) and fragment 32a,b
lacking the C9-benzyloxy group (entry 3), furnished comparable
modest selectivities, while THP analogue 33a,b lacking a methyl
group at C8 (entry 4) led to a significant increase in 2,3-anti
product selectivity. It is notable from these experimental results
that structural modifications at C6 and C8 influence greatly the
levels of diastereoselectivity, while being distant to the reacting
carbon-centered free radical at C2.
a
See the Experimental Section for details on the synthesis of radical
b
1
precursors. Product ratios were determined by H NMR analysis of
c
d
the crude reaction mixture. Yields of isolated products. The yield
reported was obtained with Bu3SnH, which provided the same
selectivity as Ph3SnH.
DFT CALCULATIONS FOR THE REDUCTION OF THP
RADICAL PRECURSORS
■
Description of the Computational Method. Geometry
optimizations of modeled compounds were realized using
standard gradient techniques and tight SCF convergence as
implemented in Gaussian 0913 with the BHandHLYP func-
tional,14 which was demonstrated15 to be well suited for radical
C
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Table 2. Radical Reductions of 6,7-cis-THP Analogues 14a,b
and 31−33a,b
Figure 2. Proposed transition states for the reduction of radical
intermediates.21
predictive TS A was preferred among the other possible
transitions states (Figure 2).21 When the C3−O alkoxy group
is embedded in an exocycle, higher 2,3-anti selectivities are
observed, unless the radical-bearing chain is oriented in the axial
position.10
Previous in silico evaluation for unsubstituted THP radical
intermediates suggested that Curtin−Hammett conditions22
were met for the hydrogen radical delivery in these simple
systems.10 In order to ensure that the more substituted THP
systems presented herein were also reduced under kinetic
conditions, the radical intermediates were examined, as depicted
in Figure 3 for 17c (generated from 17a,b). A significant energy
a
See the Experimental Section for details on the synthesis of radical
b
1
precursors. Product ratios were determined by H NMR analysis of
the crude reaction mixture. Yields of isolated products. The
enantiomer is depicted for clarity.
c
d
systems.16 Transition-state calculations were performed with
Me3SnH, which was demonstrated to provide selectivities
comparable to other hydrides.10 The effective core potential
LANL2DZ (Hay and Wadt)17 supplemented with a single set of
d-type polarization functions was used for tin (d(ζ)Sn
=
0.20),16b,d,18 in combination with the valence triple-ζ TZVP
basis set19 for all other atoms. The difference in Gibbs free
energies of activation (ΔΔG⧧) was calculated for each reaction
between the lowest energy anti- and syn-predictive TS after
consideration of all conformers, and the ratio of products was
calculated from eq 1. Gibbs free energies in solution were
determined from geometry optimizations using the IEFPCM
implicit solvation model.20 More details concerning the
computational method used are provided in the Experimental
Section and in the Supporting Information.
[2,3‐anti]
[2,3‐syn]
ΔΔG⧧ = RT ln
(1)
Figure 3. Energy barriers of radical intermediates for E−Z isomerization
and chair ring-flip (depicted for 17c).
DFT Study of Radical Intermediates Conformers. A
previously reported DFT study (BHandHLYP/TZVP level) by
our group demonstrated that the experimental diastereoselec-
tivity observed for the reduction of carbon-centered radicals,
vicinal to an ester and a stereogenic center bearing an alkoxy
group, correlated with the difference in Gibbs free energy
between TS A and TS B (Figure 2).10 Minimization of pseudo
allylic-1,3 strain and optimal dipole minimization between the
alkoxy group and the ester were proposed to explain why anti-
barrier was noted for the isomerization between E and Z
configuration of the enol radical resulting from radical
delocalization in the vicinal ester (TS C) and another
corresponding to the THP ring-flip through half-chair con-
formers (TS D). These two energy barriers are markedly lower
than TS A and B located for the hydrogen radical delivery (Table
3). It is noteworthy that all the possible rotamers of the C7−C8
D
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Table 3. Relative Gibbs Free Energies (kcal mol−1) in Toluene of Radical Intermediates and TS Hydrogen Delivery Relative to
Their Respective Lowest Radical GS
a
b
Numbering of atoms was attributed according to that of ionophores 1a−c. The value reported corresponds to the electronic energy maximum
c
determined by the unrestricted dihedral scan in vacuum. No axial chair conformer was located for 38c.
Figure 4. Transition states of hydrogen delivery to 6,7-trans THP radical intermediate 17c. Gibbs free energies (kcal mol−1) are reported relative to the
energy of 17c.
The relative Gibbs free energies of modeled compounds for
the GS radical conformers and for hydrogen radical delivery at
the TS are represented in Table 3. The isomerization barrier
bond and chair conformations were considered in these
calculations.23
E
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Figure 5. Transition states of hydrogen delivery to 6,7-cis THP radical intermediate 32c. Gibbs free energies (kcal mol−1) are reported relative to the
energy of 32c.
between the two possible enols (TS C) was found to vary
between 6 and 10 kcal mol−1, well under the TS energy measured
for the different transition states located in this study (Table 3,
entries 1−7). The appropriate transition state corresponding to
the interconversion between the two chair conformations of 3,7-
trans THPs through half-chair conformers (TS D) was first
established by an unrestricted scan of all dihedral angles of the
two chair conformer (bearing the C3-chain either equatorial or
axial). Each energy maximum identified was then further
examined by TS analysis using the QST3 method implemented
in Gaussian. The Gibbs free energies are reported for the lowest
energy half-chair (E or Z) involved in the interconversion of the
chair conformers (eq or ax) to their corresponding twist-boats, as
confirmed by the evaluation of the imaginary frequency. The
energy barriers of chair ring-flip (TS D) and enol radical
isomerization (TS C) were determined to also be significantly
lower than the energies for hydrogen radical delivery (Figure 3
and Table 3, entries 1−4, 6, and 7), therefore allowing for the
consideration of all ground-state conformations in the transition-
state analysis. For substrate 38c (3,7-cis), it was not possible to
determine the energy of the half-chair barrier (entry 5, Table 3).
Indeed, the 1,3-diaxial interactions between the substituents at
C3 and C7 present in the chair conformer when oriented axial are
likely prohibitively high in energy. This could suggest that this
THP radical intermediate may only react in the chair conformer
with an equatorial radical chain at C3.
trans) both displayed an equatorial orientation of the C3-chain
bearing the radical (Figure 4). The calculated ΔΔG⧧ of 1.10 kcal
mol−1 predicted formation of 2,3-anti product 25a with high
selectivity in vacuum. The 6,7-cis THP 32c was likewise
calculated to undergo radical reduction with C3-chain bearing
the radical in the equatorial orientation for TS A (Figure 5), but
the lowest syn-predictive TS B was determined to bear the C3-
chain in an axial orientation. For the calculated ΔΔG⧧ in vacuum,
toluene and DCM are in good accordance with the observed
diastereoselectivity. The syn-pentane interaction (C6′−C6−
C7−C8−C9) probably destabilizes TS A-eq, thus reducing the
gap with syn-predictive TS B-ax in 6,7-cis THP systems.
It is of interest that DFT calculations considering solvent
effects correctly modeled the decrease in anti-selectivity that was
observed experimentally in DCM (3:1, Figure 4). This decrease
in selectivity in more polar media is likely the result of less
favorable stabilization in TS A from the antiperiplanar dipole
orientation of the ester group relative to the C3-alkoxy group.
The solvent correction in toluene provided a calculated ΔΔG⧧
value that is not as consistent with the observed ratio for this
particular substrate.
Reductions of 3,7-trans- versus 3,7-cis-Substituted
THP. In the different 3,7-trans systems analyzed (17c and
32c), the C7-substituent was oriented in the trajectory of the
incoming hydride for anti-predictive TS A (Figures 4 and 5).
This unfavorable interaction is not present in less substituted
THP systems, which are reduced with significantly higher
selectivities, such as 3c generated from 3a,b (Scheme 2a).
Similarly, this interaction could also be partially alleviated in 3,7-
cis radical intermediate 38c (corresponding to the C7−iPr
analogue generated from 22a,b) that was determined in silico to
preferably react through equatorial TS (A and B, Figure 6). The
Reductions of 6,7-trans- versus 6,7-cis-Substituted
THP. The origin of the decreased 2,3-anti selectivity (17:1 vs
5:1) for the reduction of 6,7-trans 17c and 6,7-cis substrates 32c
(respectively generated from radical precursors 17a,b and 32a,b)
was investigated by examining their lowest energy anti-predictive
and syn-predictive transition states. TS A and B of 17c (6,7-
F
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Figure 6. Transition states of hydrogen delivery to 3,7-cis THP radical intermediate 38c. Gibbs free energies (kcal mol−1) are reported relative to the
energy of 38c.
greater ΔΔG⧧ calculated between these TS correctly predicts the
observed experimental selectivities. As discussed previously, the
calculated interconversion barrier between the chair conformers
of the radical intermediates are significantly lower than the
activation energy required for hydrogen radical delivery, allowing
access to the axial conformations at the transition state level.
Reductions of β-Methyl-Substituted THP Systems.
Reductions of the 6,7-trans radical precursors 40a generated
from a stereoselective iodoetherification reaction were previously
demonstrated to provide product 41a selectively6e and were
further examined in silico using C7−iPr analogue 39c (Figure 7).
The substitution pattern of this THP substrate corresponds to
the C1−C9 fragment of zincophorin 1a, where the radical
reduction occurs at C8 in comparison with substrate 17c bearing
the reacting center at C2 (Figure 4). As determined for the other
6,7-trans substrates, the lowest anti-predictive TS A was
calculated to prefer an equatorial orientation of the C3 radical-
bearing chain. The most striking difference is observed, however,
in the syn-predictive TS B; the equatorial methyl group at C6 in
substrate 39c presenting a severe steric clash with the incoming
hydride. This interaction is potentially raising the activation
energy required to reach the syn-predictive TS, and as a
consequence, the resulting larger ΔΔG⧧ gap calculated allows for
high anti-selectivity. A decreased ΔΔG⧧ of 1.54 kcal mol−1 was
calculated in THF, although this energy gap is sufficient to
account for the observed exclusive formation of the 7,8-anti
product.
predictive TS B noted for 6,7-trans substrate 39c also furnishes
higher 7,8-anti selectivity (Figure 7).
CONCLUSION
■
In the context of the reductions of radical intermediates bearing a
vicinal polysubstituted THP, it was observed that certain
substitution patterns influence significantly the observed
selectivities. The analysis of transition states by DFT calculations
for 6,7-cis and 6,7-trans THP intermediates allowed to identify
unfavorable interactions between the axial chain at C7 with the
incoming hydride. Moreover, important steric interactions
between the C6 and C7 alkyl chains could destabilize
significantly TS conformers with an equatorial chain bearing
the radical, which in turn would reduce the energy gap between
anti- and syn-predictive TS. This work led to the elaboration of a
highly predictive model that takes into account the relative
energy of radical intermediates in combination with potential
interactions at the transition state. The analysis in silico of
experimental diastereoselectivities provided substantial insight to
further improve our collective knowledge of the reactivity of
radicals in stereocontrolled processes.
EXPERIMENTAL SECTION
■
General Comments. The experimental procedure and physical
characterization of silylated enol ether 2 and product 10 have already
been described by our group.6a All procedures requiring anhydrous
conditions were carried out under a positive argon atmosphere in oven-
dried glassware using standard syringe techniques (exception should be
noted that free-radical reactions were conducted under nitrogen). All
solvents were purified by standard methods. Flash chromatography was
performed on silica gel (0.040−0.063 mm) using compressed air
pressure. Analytical thin-layer chromatography (TLC) was carried out
It is noteworthy that the computational analysis presented
herein demonstrates the importance of considering both the
minor- and major-predicting TS to rationalize trends in
selectivity. In the case of 3,7-cis substrate 38c (Figure 6), the
reduced destabilizing interaction in the anti-predictive TS A
allows to explain the increase in ΔΔG⧧ and corresponding 2,3-
anti selectivity. Conversely, destabilizing interaction in syn-
1
on aluminum-precoated (0.25 mm) silica gel plates. H (400 or 500
MHz) and 13C spectra (100 or 125 MHz) were referenced to residual
solvents peak for CHCl3 (7.26 ppm for H NMR, 77.16 ppm for 13C
1
1
NMR), and ratios of products were measured from crude H spectra.
Multiplets were assigned with s (singlet), bs (broad singlet), app s
G
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Figure 7. Transition states of hydrogen delivery to 6,7-trans THP radical intermediate 39c. Gibbs free energies (kcal mol−1) are reported relative to the
energy of 39c.
(apparent singlet), d (doublet), app d (apparent doublet), t (triplet),
app t (apparent triplet), q (quartet), sept (septet) and m (multiplet).
Optical rotations were measured at room temperature from the sodium
D line (589 nm) using a cell of 1 mL measuring 1 dm in length. Infrared
spectra were recorded on a FTIR spectrophotometer on a NaCl support.
Mass spectra were recorded through electrospray ionization (ESI)
coupled to an ion trap (IT) on an instrument operating at 70 eV.
Computational Method for the Conformational Analysis of
Radical Intermediates. All geometry optimizations were performed
using standard gradient techniques and tight SCF convergence in
Gaussian 0913 with the BHandHLYP exchange-correlation (XC)
functional14 using restricted (RBHandHLYP) and unrestricted
(UBHandHLYP) methods for closed- and open-shell systems,
respectively.24 It was previously demonstrated15 that BHandHLYP
functional performed better for radical systems than other XC
functionals,16 disparity often associated with inadequate treatment of
the exchange terms.25 The effective core potential of Hay and Wadt17
LANL2DZ supplemented with a single set of d-type polarization
functions was used for tin (d(ζ)Sn = 0.20)16b,d,18 together with the
valence triple-ζ TZVP basis set19 for all other atoms. Ground state (GS)
radicals were evaluated by unconstrained optimization of all possible
rotating bonds including both E- and Z-enol radical conformations.
Staggered transition states (TS) for hydrogen radical delivery using
Me3SnH (anti- and syn-predictive TS) were considered for each
conformation of methyl ester radical intermediates. Unscaled harmonic
frequency calculations at the appropriate temperature were performed
for each optimized structure to characterize it as an energy minimum or
a TS structure and to calculate Gibbs free energies (ΔG). To calculate
Gibbs free energies in solution, geometry optimizations and harmonic
frequency calculations were performed with the IEFPCM model20 and
the UFF atomic radii for either toluene or dichloromethane. Wiberg
bond indices26 were calculated using the natural bonding orbitals27 as
implemented in Gaussian 09.13 The stereochemistry of the radical
precursor at C2 was demonstrated experimentally to be unrelated to the
stereochemical outcome of radical reduction reaction.6a−d It was thus
reasonable to consider the same radical intermediates for both halide
isomers at the C2 position at the transition state.
General Experimental Method for Radical Reduction:
Exocyclic Effect Control (A1). To a cold (−78 °C) solution of a
mixture of bromides (1 equiv) in dry toluene (0.1 M) were added
successively Ph3SnH (2 equiv), a 1 M solution of Et3B in CH2Cl2 (0.2
equiv), and air (syringe). The reaction mixture was maintained at
−78 °C as supplementary addition of Et3B solution (0.2 equiv) and air
was realized each 30 min, until reaction was judged complete by TLC
(3−4 h). The reaction mixture was treated with the addition of 1,4-
dinitrobenzene (0.2 equiv), followed by stirring of the mixture for 15
min at −78 °C. Once at room temperature, reaction was concentrated in
vacuo. The two diastereoisomers were separated by flash chromatog-
raphy on silica gel.
General Experimental Method for Hydrogenolysis with
Palladium (A2). To a solution of α,β-unsaturated ester or benzyl-
protected alcohol (1 equiv) in EtOAc (0.1 M) at room temperature was
added 10 wt % Pd on activated carbon (0.1 equiv). Inert gas atmosphere
was purged by three cycles of vacuum/H2 gas, and the reaction mixture
H
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was stirred until the reaction was judged complete by TLC. The mixture
was then filtered onto a pad of Celite and washed with hexanes. The
filtrate was concentrated in vacuo and purified by flash chromatography
on silica gel.
treatment with a saturated aqueous solution of NH4Cl and
concentration in vacuo. The aqueous layer was extracted with Et2O
(3×), and the combined organic fractions were washed with a saturated
brine solution, dried (MgSO4), filtered, and concentrated in vacuo. The
crude mixture was purified by flash chromatography on silica gel.
General Experimental Method for Preparation of Tertiary
Bromides from Protected Lactol (A10). To a cold (−78 °C)
solution of protected lactol (1 equiv) in dry CH2Cl2 (0.1 M) was added
silylated enol ether 2 (2.8 equiv). The mixture was stirred for 2 min at
−78 °C, followed by dropwise addition of a 1.0 M solution of SnCl4 in
CH2Cl2 (1.5 equiv) and stirring for 1.5 h at −78 °C. The reaction
mixture was then treated with a saturated aqueous solution of NH4Cl,
followed by separation of the organic phase at room temperature. The
aqueous layer was extracted with CH2Cl2 (3×), and the combined
organic fractions were dried (MgSO4), filtered, and concentrated in
vacuo. The crude mixture was purified by flash chromatography on silica
gel.
General Experimental Method for Swern Oxidation (A11). To
a cold (−78 °C) solution of oxalyl chloride (1.2 equiv) in dry CH2Cl2
(0.1 M) was added dropwise anhydrous DMSO (2.4 equiv), and the
mixture was stirred for 10 min at −78 °C. A solution of the alcohol (1
equiv) in dry CH2Cl2 (0.5 M) was cannulated into the reaction flask, and
the mixture was allowed to stir for an additional 30 min at −78 °C before
addition of dry Et3N (5 equiv). The mixture was stirred 1 h at −78 °C
and then treated with a saturated aqueous solution of NH4Cl followed
by separation of organic phase at room temperature. The aqueous layer
was extracted with Et2O (3×), and the combined organic fractions were
washed with a saturated brine solution, dried (MgSO4), filtered, and
concentrated in vacuo to afford aldehyde as a colorless oil.
General Experimental Method for Mukaiyama Aldol Reac-
tion: Felkin−Anh Control (A12). To a cold (−78 °C) solution of
aldehyde (1 equiv) in dry CH2Cl2 (0.1 M) were added successively
silylated enol ether 2 (2 equiv) and BF3·OEt2 (1.5 equiv). The reaction
mixture was stirred for 1 h at −78 °C before treatment with a saturated
aqueous solution of NH4Cl and separation of the organic phase at room
temperature. The aqueous layer was extracted with EtOAc (3×), and the
combined organic fractions were dried (MgSO4), filtered, and
concentrated in vacuo. The crude mixture was purified by flash
chromatography on silica gel.
General Experimental Method for Radical Reduction: Acyclic
Stereoselection Control (A13). To a cold (−78 °C) solution of a
mixture of bromides (1 equiv) in dry CH2Cl2 (0.1 M) were added
successively DIEA (1.5 equiv) and a 1 M solution of Bu2BOTf in
CH2Cl2 (1.3 equiv), followed by stirring for 1.5 h at −78 °C. The
mixture was then successively treated with Bu3SnH (2 equiv), a 1 M
solution of Et3B in CH2Cl2 (0.2 equiv), and air (syringe).
Supplementary addition of Et3B solution (0.2 equiv) and air was
realized each 30 min until reaction was judged completed by TLC (3−4
h). The reaction was treated with the addition of 1,4-dinitrobenzene (0.2
equiv) and stirring of the mixture for 15 min at −78 °C before being
treated by a saturated aqueous solution of NH4Cl. The organic phase
was separated at room temperature, and the aqueous layer was extracted
with Et2O (3×). The combined organic fractions were washed (2×)
with a saturated aqueous solution of KF and brine before being dried
(MgSO4). The filtrate was concentrated to a residue which was
solubilized in MeOH (0.1 M) and cooled to 0 °C before being treated by
a 35% w/w of H2O2 in water (3 equiv). The solution was stirred for 2 h at
0 °C and then treated with addition of water before extraction with Et2O
(3×). The combined organic fractions were washed with a saturated
brine solution and then dried (MgSO4), filtered, and concentrated in
vacuo. The crude mixture was purified by flash chromatography on silica
gel.
General Experimental Method for Protection of Alcohol with
Trialkylsilyl Trifluoromethanesulfonate Reagents (A3). To a cold
(0 °C) solution of alcohol (1 equiv) in dry CH2Cl2 (0.1 M) were added
successively 2,6-lutidine (1.2 equiv) and TESOTf (1.1 equiv). The
reaction mixture was stirred for 1.5 h at 0 °C or until alcohol was
completely consumed, as verified by TLC. The reaction mixture was
then treated with a saturated aqueous solution of NH4Cl, followed by
separation of the organic phase at room temperature. The aqueous layer
was extracted with CH2Cl2 (3×), and the combined organic fractions
were dried (MgSO4), filtered, and concentrated in vacuo. The crude
mixture was purified by flash chromatography on silica gel.
General Experimental Method for Reduction of Ester to
Primary Alcohol with DIBAL-H (A4). To a cold (−40 °C) solution of
ester (1 equiv) in dry CH2Cl2 (0.1 M) was added a 1.0 M solution of
DIBAL-H in hexanes (3 equiv). The mixture was stirred for 1 h at
−40 °C or until the ester was completely consumed, as verified by TLC.
The reaction mixture was treated first with the dropwise addition of
MeOH at −40 °C until gas evolution ceased, followed by a saturated
potassium sodium tartrate solution (Rochelle’s salt). The mixture was
stirred 1 h at room temperature (or until clarification of phases)
followed by separation of the organic phase. The aqueous layer was
extracted with Et2O (3×), and the combined organic fractions were
dried (MgSO4), filtered, and concentrated in vacuo. The crude mixture
was purified by flash chromatography on silica gel.
General Experimental Method for Oxidation of Primary
Alcohol with Dess−Martin Periodinane (A5). To a solution of
alcohol (1 equiv) in dry CH2Cl2 (0.1 M) were added successively
NaHCO3 (10 equiv) and Dess−Martin periodinane (1.5 equiv). The
reaction mixture was stirred for 1 h at room temperature and then
concentrated. The resulting white solid residue was digested in hexanes
and filtered onto a pad of Celite. The filtrate was then concentrated in
vacuo and purified by flash chromatography on silica gel.
General Experimental Method for Wittig Olefination of
Aldehyde (A6). To a solution of aldehyde (1 equiv) in dry toluene
(0.1 M) was added methyl (triphenylphosphoranylidene)acetate (1.5
equiv), and the resulting solution was heated to reflux overnight. The
mixture was cooled to room temperature and then concentrated in
vacuo. The solid yellow residue was digested in hexanes and filtered onto
a pad of Celite, leading to a filtrate that was concentrated in vacuo. The
crude mixture was purified by flash chromatography on silica gel.
General Experimental Method for Cycloetherification Re-
action with BiBr3 (A7). To a cold (−78 °C) solution of aldehyde (1
equiv) in dry CH2Cl2 (0.1 M) was added dropwise a solution of BiBr3 (1
equiv) in dry MeCN (0.5 M), followed by silylated enol ether 2 (1.5
equiv). The mixture was stirred for 1.5 h at −78 °C or until aldehyde was
completely consumed, as verified by TLC. The reaction mixture was
treated with a saturated aqueous solution of NH4Cl at −40 °C, followed
by separation of the organic phase at room temperature. The aqueous
layer was extracted with CH2Cl2 (3×) and combined organic fractions
were dried (MgSO4), filtered, and concentrated in vacuo. The crude
mixture was purified by flash chromatography on silica gel.
General Experimental Method for Lactonization (A8). To a
stirred solution of crude ester (1 equiv) in benzene (0.1 M) was added p-
TSOH (1 equiv), and the reaction was heated to reflux for 1 h. The
mixture was cooled to room temperature, followed by filtration onto a
pad of silica and washing with Et2O. The filtrate was concentrated in
vacuo, and the crude mixture was purified by flash chromatography on
silica gel.
General Experimental Method for Reduction of Lactone to
Protected Lactol (A9). To a cold (−40 °C) solution of lactone (1
equiv) in dry CH2Cl2 (0.1 M) was added dropwise a 1.0 M solution of
DIBAL-H in toluene (1.2 equiv). The mixture was stirred for 1.5 h at
−40 °C or until starting material was completely consumed, as verified
by TLC. To the reaction mixture were then added successively pyridine
(4.0 equiv), DMAP (1.2 equiv) and acetic anhydride (5 equiv). The
reaction mixture was then stirred overnight at room temperature before
General Experimental Method for Parikh−Doering Oxidation
of Primary Alcohols (A14). To a cold (0 °C) solution of alcohol (1
equiv) in dry CH2Cl2 (0.1 M) were added successively DMSO (7
equiv), DIEA (5 equiv), and SO3·py complex (3 equiv). The reaction
mixture was stirred for 15 min at 0 °C or until alcohol was completely
consumed, as verified by TLC before treatment with a saturated aqueous
solution of NaHCO3. The aqueous layer was extracted with Et2O (3×),
and the combined organic fractions were washed with a saturated
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Article
aqueous solution of NH4Cl, dried (MgSO4), filtered, and concentrated
in vacuo. The crude mixture was purified by flash chromatography on
silica gel.
100), 468.0 (44); HRMS calcd for C20H30O4Br [M + H+] 413.1322,
found 413.1326 (0.9 ppm).
(
)-(S)-Methyl 2-((2S,5S,6S)-6-((S)-1-(Benzyloxy)propan-2-
yl)-5-methyltetrahydro-2H-pyran-2-yl)propanoate (23a) and
( )-(R)-Methyl 2-((2S,5S,6S)-6-((S)-1-(Benzyloxy)propan-2-yl)-
5-methyltetrahydro-2H-pyran-2-yl)propanoate (23b).
Products 23a and 23b (33 mg, yield = 81%) were obtained as pale yellow
oils from a mixture of bromides 15a; 15b (50 mg) following general
procedure A1 and purification by flash chromatography on silica gel
(hexanes/EtOAc 85:15). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 15:1 ratio of
products 2,3-anti (23a):2,3-syn (23b).
( )-Methyl 2-((2S,5S,6S)-6-((S)-1-(Benzyloxy)propan-2-yl)-5-
methyltetrahydro-2H-pyran-2-yl)-2-bromopropanoate (15a,
15b).
23a: Rf = 0.22 (hexanes/EtOAc, 90:10); formula C20H30O4; MW
334.45 g/mol; IR (neat) νmax 2949, 2929, 2858, 1739, 1456, 1436, 1377,
1362, 1269, 1256, 1197, 1074, 1099, 1074 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.36−7.24 (m, 5H), 4.53 (d, J = 12.1 Hz, 1H), 4.47 (d, J = 12.1
Hz, 1H), 3.86 (dt, J = 8.8 Hz, 4.1 Hz, 1H), 3.57 (s, 3H), 3.40 (dd, J = 4.6
Hz, 9.1 Hz, 1H), 3.33 (dd, J = 4.0 Hz, 7.9 Hz, 1H), 3.23 (app t, J = 8.9 Hz,
1H), 2.95 (dq, J = 10.4 Hz, 6.9 Hz, 1H), 2.13−2.04 (m, 1H), 1.72−1.55
(m, 4H), 1.34−1.22 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.8
Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ
175.7, 138.8, 128.3, 127.44, 127.35, 77.7, 74.5, 74.1, 73.0, 51.4, 40.9,
34.2, 30.7, 26.7, 24.6, 17.8, 14.3, 10.7 ppm; MS (ESI-IT) m/z 171 (70),
227.2 (100), 303.2 (33), 352.9 (25), 517.1 (10), 687.1 (24); HRMS
calcd for C20H31O4 [M + H+] 335.2217, found 335.2216 (−0.2 ppm).
23b: Rf = 0.28 (hexanes/EtOAc, 90:10); formula C20H30O4; MW
334.45 g/mol; IR (neat) νmax 2930, 2859, 1737, 1456, 1377, 1255, 1195,
1168, 1111, 1049, 1021, 737, 697 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.36−7.26 (m, 5H), 4.51 (d, J = 11.9 Hz, 1H), 4.44 (d, J = 11.9 Hz, 1H),
3.84 (ddd, J = 2.9 Hz, 5.1 Hz, 10.1 Hz, 1H), 3.67 (s, 3H), 3.52 (dd, J = 7.7
Hz, 8.7 Hz, 1H), 3.32 (dd, J = 6.2 Hz, 8.9 Hz, 1H), 3.27 (dd, J = 3.4 Hz,
8.6 Hz, 1H), 3.01 (dq, J = 10.3 Hz, 6.8 Hz, 1H), 2.16−2.07 (m, 1H),
1.76−1.67 (m, 1H), 1.67−1.58 (m, 2H), 1.50−1.43 (m, 1H), 1.42−1.32
(m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.86 (d, J =
6.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 175.9, 138.6, 128.3,
127.6, 127.45, 75.3, 73.6, 73.4, 73.0, 51.6, 40.0, 34.0, 31.0, 27.4, 27.0,
17.7, 14.0, 10.3 ppm; MS (ESI-IT) m/z 227.2 (12), 335.2 (M + H+,
100); HRMS calcd for C20H31O4 [M + H+] 335.2217, found 335.2206
(−3.4 ppm).
To a cold (0 °C) solution of a mixture of product S6a,b6d (537 mg) in
dry THF (0.1 M, 9.6 mL) was added dropwise a solution of HF·pyridine
(ca. 70% HF, 1 mL per mmol of substrate, 0.95 mL). The reaction
mixture was stirred overnight at 0 °C and then treated slowly with a
saturated aqueous solution of NaHCO3, followed by separation of the
organic phase at room temperature. The aqueous layer was extracted
with CH2Cl2 (3×), and the combined organic fractions were dried
(MgSO4), filtered, and concentrated in vacuo. The crude mixture was
purified by flash chromatography on silica gel (hexanes/EtOAc, 80:20)
to afford an inseparable mixture of bromide adducts as a colorless oil. To
a cold (0 °C) solution of crude product in solvent mixture of
cyclohexane and CH2Cl2 (2:1, 0.1 M, 9.6 mL) were added successively
2,2,2-benzyltrichloroacetimidate (1.3 equiv, 230 μL) and TfOH (0.1
equiv, 8 μL). The reaction mixture was stirred overnight at 0 °C before
treatment with Et3N (0.15 equiv, 20 μL) and then concentration in
vacuo. The crude mixture was dissolved in hexanes and filtered onto a
1
pad of Celite, followed by concentration in vacuo of the filtrate. H
NMR spectroscopic analysis of the unpurified product indicated a pair of
2,3-diastereomers in a ∼1:1 ratio of products 15a:15b. The two
diastereoisomers were separated by flash chromatography on silica gel
(hexanes/EtOAc, 90:10) to afford product 15a and 15b as colorless oils
(261 mg, yield = 66% over two steps).
( )-(2R,3S,6S)-6-((R)-1-(Benzyloxy)propan-2-yl)-2-isopropyl-
3-methyltetrahydro-2H-pyran (S8).
15a: Rf = 0.46 (toluene/EtOAc, 98:2); formula C20H29BrO4; MW
413.35 g/mol; IR (neat) νmax 2955, 2932, 2868, 1742, 1452, 1377, 1263,
1202, 1143, 1097, 1047, 984, 858, 737, 697 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.37−7.25 (m, 5H), 4.50 (d, J = 12.1 Hz, 1H), 4.43 (d, J = 12.1
Hz, 1H), 4.13 (dd, J = 3.8 Hz, 10.8 Hz, 1H), 3.76 (s, 3H), 3.38 (dd, J =
2.7 Hz, 8.5 Hz, 1H), 3.35 (dd, J = 5.4 Hz, 9.2 Hz, 1H), 3.28 (dd, J = 5.5
Hz, 9.2 Hz, 1H), 2.27−2.18 (m, 1H), 1.90 (s, 3H), 1.90−1.67 (m, 4H),
1.51−1.43 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 171.4, 138.6, 128.3, 127.44,
127.41, 81.2, 73.9, 73.3, 73.0, 62.1, 53.0, 33.3, 27.3, 25.2, 22.5, 19.8, 18.3,
13.4 ppm; MS (ESI-IT) m/z 305.1 (8), 413.1 (M + H+, 100), 503.2 (7);
HRMS calcd for C20H30O4Br [M + H+] 413.1322, found 413.1319
(−0.7 ppm).
15b: Rf = 0.40 (toluene/EtOAc, 98:2); formula C20H29BrO4; MW
413.35 g/mol; IR (neat) νmax 2954, 2932, 2868, 1739, 1452, 1378, 1264,
1204, 1110, 1055, 988, 736, 698 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.37−7.25 (m, 5H), 4.51 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H),
3.93 (dd, J = 3.0 Hz, 11.3 Hz, 1H), 3.77 (s, 3H), 3.45 (dd, J = 1.4 Hz, 9.2
Hz, 1H), 3.40 (dd, J = 5.1 Hz, 9.3 Hz, 1H), 3.32 (dd, J = 5.4 Hz, 9.3 Hz,
1H), 2.34−2.24 (m, 1H), 1.92−1.81 (m, 2H), 1.86 (s, 3H), 1.78−1.66
(m, 1H), 1.49−1.35 (m, 2H), 1.08 (d, J = 6.9 Hz, 3H), 1.07 (d, J = 6.7
Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 171.0, 138.6, 128.3,
127.44, 127.37, 81.4, 74.3, 73.6, 73.1, 65.6, 53.2, 33.2, 27.3, 24.6, 24.0,
20.9, 18.3, 14.1 ppm; MS (ESI-IT) m/z 305.1 (15), 413.1 (M + H+,
To a cold (0 °C) solution of alcohol S76d (9.2 mg) in dry CH2Cl2 (0.1
M, 300 μL) were added successively Et3N (3.0 equiv, 14 μL) and MsCl
(1.2 equiv, 3 μL). The reaction mixture was stirred for 3 h at 0 °C or until
alcohol was completely consumed, as verified by TLC. The reaction
mixture was then treated with a saturated aqueous solution of NH4Cl,
followed by separation of the organic phase at room temperature. The
aqueous layer was extracted with Et2O (3×), and the combined organic
fractions were dried (MgSO4), filtered, and concentrated in vacuo to
yield the mesylated product as a colorless oil which was used as crude
without further purification. To a cold (0 °C) solution of crude mesylate
in dry Et2O (0.1 M, 300 μL) was added a 1.0 M solution of LiAlH4 in
THF (1.1 equiv, 33 μL). The mixture was stirred for 3 days at 0 °C or
until mesylate was completely consumed, as verified by TLC. The
reaction mixture was then treated with a saturated aqueous solution of
NH4Cl, followed by separation of the organic phase at room
temperature. The aqueous layer was extracted with Et2O (3×), and
combined organic fractions were dried (MgSO4), filtered, and
concentrated in vacuo. Product S8 (4.9 mg, 56% over two steps) was
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Article
obtained as a colorless oil after purification by flash chromatography on
silica gel (hexanes/EtOAc 95:5): Rf = 0.35 (hexanes/EtOAc, 80:20);
formula C19H30O2; MW 290.44 g/mol; IR (neat) νmax 3062, 3030, 2957,
2928, 2872, 1456, 1363, 1096, 735 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.36−7.26 (m, 5H), 4.52 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H),
3.64 (dd, J = 3.8 Hz, 9.0 Hz, 1H), 3.48 (ddd, J = 4.4 Hz, 6.4 Hz, 9.4 Hz,
1H), 3.34 (dd, J = 7.6 Hz, 8.9 Hz, 1H), 2.97 (app t, J = 5.8 Hz, 1H),
2.13−2.04 (m, 1H), 2.05−1.94 (m, 1H), 1.70−1.62 (m, 2H), 1.62−1.55
(m, 1H), 1.54−1.47 (m, 1H), 1.37−1.28 (m, 1H), 0.95 (d, J = 6.2 Hz,
3H), 0.94 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.8
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 138.9, 128.3, 127.6,
127.3, 82.0, 73.1, 72.6, 72.5, 35.5, 29.7, 27.6, 26.3, 24.4, 20.29, 18.4, 16.9,
14.1 ppm; MS (ESI-IT) m/z 291.2 (M + H+, 35), 313.2 (M + Na+, 100),
360.3 (16), 371.2 (8); HRMS calcd for C19H31O2 [M + H+] 291.2319,
found 291.2313 (−1.9 ppm); calcd for C19H30O2Na [M + Na+]
313.2138, found 313.2134 (−1.1 ppm).
16.2, 14.4, 7.2, 5.5 ppm; MS (ESI-IT) m/z 353.2 (100), 375.2 (65);
HRMS calcd for C20H37O3Si [M + H]+ 353.2506, found 353.2499 (−2.0
ppm); calcd for C20H36O3SiNa [M + H]+ 375.2326, found 375.2317
(−2.5 ppm).
( )-(4R,5R,6S,E)-Methyl 7-(Benzyloxy)-4,6-dimethyl-5-
(triethylsilyloxy)hept-2-enoate (S14).
Aldehyde S13 was obtained as a pale yellow oil from alcohol S12 (1.11
g) following general procedure A5 and was used as crude without further
purification. Product S14 (1.01 g, yield = 79% over two steps) was
obtained as a colorless oil from crude aldehyde S13 following general
procedure A6 and purification by flash chromatography on silica gel
(hexanes/EtOAc 90:10): Rf = 0.32 (hexanes/EtOAc, 90:10); formula
C23H38O4Si; MW 406.63 g/mol; IR (neat) νmax 3030, 2957, 2910, 2877,
1726, 1271, 735 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.39−7.29 (m,
5H), 7.06 (dd, J = 8.5 Hz, 15.8 Hz, 1H), 5.80 (dd, J = 1.0 Hz, 15.8 Hz,
1H), 4.53 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 3.74 (s, 3H),
3.64 (dd, J = 3.8 Hz, 6.3 Hz, 1H), 3.51 (dd, J = 4.9 Hz, 9.1 Hz, 1H), 3.36
(dd, J = 6.7 Hz, 9.1 Hz, 1H), 2.60−2.52 (m, 1H), 1.97−1.88 (m, 1H),
1.09 (d, J = 6.9 Hz, 3H), 0.97 (t, J = 6.8 Hz, 9H), 0.95 (d, J = 6.6 Hz, 3H),
0.62 (q, J = 7.9 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.3,
152.2, 138.8, 128.4, 127.7, 127.6, 120.6, 77.9, 73.2, 72.5, 51.5, 40.5, 38.4,
17.7, 14.8, 7.2, 5.5 ppm; MS (ESI-IT) m/z 279.1 (13), 407.3 (M + H+,
100), 429.2 (78), 707.3 (5); HRMS calcd for C23H39O4Si [M + H+]
407.2612, found 407.2605 (−1.8 ppm).
(
)-(2S,2′R)-2,2′-((2S,3S,6S)-3-Methyltetrahydro-2H-pyran-
2,6-diyl)dipropan-1-ol (S9).
Product S9 (56 mg, yield =81%) was obtained as a white solid from
primary alcohol S76d (98 mg) following general procedure A2 and
purification by flash chromatography on silica gel (EtOAc). Structural
assignment of compound S9 was confirmed by X-ray analysis (cf.
Supporting Information, part III, X-ray): Rf = 0.38 (EtOAc); formula
C12H24O3; MW 216.32 g/mol; IR (neat) νmax 3366, 2928, 2876, 1459,
1379, 1233, 1079, 1017 cm−1; 1H NMR (500 MHz, CDCl3) δ 3.69−3.64
(m, 3H), 3.63−3.59 (m, 2H), 3.53 (dd, J = 3.7 Hz, 8.4 Hz, 1H), 2.53 (s,
2H), 2.30−2.19 (m, 1H), 2.03−1.93 (m, 1H), 1.74−1.61 (m, 4H),
1.39−1.29 (m, 1H), 0.96 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H),
0.86 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 77.6, 76.7,
67.1, 66.3, 35.8, 34.4, 31.5, 27.2, 26.3, 18.1, 14.5, 10.1 ppm; MS (ESI-IT)
m/z 217.2 (9, M + H+), 239.2 (100), 455.3 (17); HRMS calcd for
C12H25O3 [M + H+] 217.1798, found 217.1803 (2.1 ppm); calcd for
C12H24O3Na [M + Na+] 239.1618, found 239.1622 (1.7 ppm).
(
) - ( 4 R , 5 R , 6 S ) - 7 - ( B e n z y l o x y ) - 4 , 6 - d i m e t h y l - 5 -
(triethylsilyloxy)heptan-1-ol (S16).
Product S15 was obtained as a colorless oil from α,β-unsaturated ester
S14 (376 mg) following general procedure A2 and was used as crude
without further purification. Primary alcohol S16 (318 mg, yield = 91%
over two steps) was obtained as a colorless oil from crude ester S15
following general procedure A4 and purification by flash chromatog-
raphy on silica gel (hexanes/EtOAc 75:25): Rf = 0.21 (hexanes/EtOAc,
80:20); formula C22H40O3Si; MW 380.64 g/mol; IR (neat) νmax 3365,
1
3030, 2956, 2912, 2876, 1456, 1098, 1058, 1008, 735 cm−1; H NMR
(500 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 4.52 (d, J = 12.0 Hz, 1H), 4.49
(d, J = 12.0 Hz, 1H), 3.66−3.62 (m, 2H), 3.60 (dd, J = 4.1 Hz, 9.0 Hz,
1H), 3.45 (dd, J = 4.5 Hz, 5.7 Hz, 1H), 3.32 (dd, J = 7.8 Hz, 9.0 Hz, 1H),
2.01−1.91 (m, 1H), 1.73−1.40 (m, 4H), 1.15−1.05 (m, 1H), 1.00 (d, J =
6.9 Hz, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.93 (d, J = 6.8 Hz, 3H), 0.60 (q, J =
7.9 Hz, 6H) ppm. OH signal missing possibly due to exchange in CDCl3;
13C NMR (100 MHz, CDCl3) δ 139.0, 128.5, 127.8, 127.6, 79.7, 73.3,
73.1, 63.6, 37.3, 36.9, 31.2, 27.7, 17.1, 16.0, 7.4, 5.7 ppm; MS (ESI-IT)
m/z 381.3 (M + H+, 90), 382.3 (26), 383.3 (5), 403.3 (M + Na+, 100),
404.3 (30), 405.3 (5); HRMS calcd for C22H41O3Si [M + H+] 381.2825,
found 381.2810 (−2.6 ppm); calcd for C22H40O3SiNa [M + Na+]
403.2639, found 403.2629 (−2.5 ppm).
(
) - ( 2 R , 3 R , 4 S ) - 5 - ( B e n z y l o x y ) - 2 , 4 - d i m e t h y l - 3 -
(triethylsilyloxy)pentan-1-ol (S12).
( )-Methyl 2-((2R,5R,6R)-6-((S)-1-(Benzyloxy)propan-2-yl)-5-
methyltetrahydro-2H-pyran-2-yl)-2-bromopropanoate (16a,
16b).
Product S11 was obtained as a pale yellow oil from S106d (505 mg)
following general procedure A3 and was used as crude without further
purification. Product S12 (595 mg, yield = 89% over two steps) was
obtained as a colorless oil from crude ester S11 following general
procedure A4 and purification by flash chromatography on silica gel
(hexanes/EtOAc 85:15): Rf = 0.17 (hexanes/EtOAc, 90:10); formula
C20H36O3Si; MW 352.58 g/mol; IR (neat) νmax 3428, 3030, 2956, 2877,
1456, 1094, 1009, 735 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.27
(m, 5H), 4.53 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 3.74−3.68
(m, 2H), 3.59 (dt, J = 11.0 Hz, 5.6 Hz, 1H), 3.52 (dd, J = 5.4 Hz, 9.1 Hz,
1H), 3.36 (dd, J = 6.8 Hz, 9.1 Hz, 1H), 2.75 (t, J = 5.6 Hz, 1H), 2.13−
2.04 (m, 1H), 1.91−1.82 (m, 1H), 1.00 (d, J = 7.0 Hz, 6H), 0.96 (t, J =
7.9 Hz, 9H), 0.64 (q, J = 7.8 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3) δ 138.8, 128.5, 127.8, 127.7, 79.7, 73.3, 72.8, 66.0, 39.0, 36.9,
Aldehyde S17 was obtained as a colorless oil from alcohol S16 (197 mg)
following general procedure A5 and was used as crude without further
purification. Products 16a and 16b (152 mg, yield = 71% over two steps)
were obtained as colorless oils from crude aldehyde S17 following
general procedure A7 and purification by flash chromatography on silica
1
gel (hexanes/EtOAc 90:10). H NMR spectroscopic analysis of the
unpurified product indicated a pair of 2,3-diastereomers in a ∼1:1 ratio
of products 16a:16b.
K
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16a: Rf = 0.50 (hexanes/EtOAc, 85:15); formula C20H29BrO4; MW
413.35 g/mol; IR (neat) νmax 2961, 2868, 1742, 1452, 1262, 1095, 1047,
737 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.25 (m, 5H), 4.54 (d, J
= 12.0 Hz, 1H), 4.50 (d, J = 12.1 Hz, 1H), 4.14 (dd, J = 4.3 Hz, 10.4 Hz,
1H), 3.74 (s, 3H), 3.61 (dd, J = 3.3 Hz, 9.0 Hz, 1H), 3.33 (d, J = 10.3 Hz,
1H), 3.28 (dd, J = 7.5 Hz, 9.0 Hz, 1H), 2.40−2.30 (m, 1H), 1.90 (s, 3H),
1.89−1.80 (m, 2H), 1.80−1.70 (m, 2H), 1.56−1.48 (m, 1H), 1.12 (d, J =
7.0 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 171.6, 139.1, 128.5, 127.7, 127.6, 81.4, 73.5, 73.4, 72.6, 62.4,
53.2, 32.7, 26.6, 24.3, 22.7, 19.7, 18.6, 15.0 ppm; MS (ESI-IT) m/z 413.1
(M + H+, 100), 416.1 (31), 430.2 (57), 435.1 (M + Na+, 85), 437.1 (82),
438.1 (25); HRMS calcd for C20H30BrO4 [M + H+] 413.1327, found
413.1311 (−2.7 ppm); calcd for C20H29BrO4Na [M + Na+] 435.1141,
found 435.1132 (−2.2 ppm).
(−1.3 ppm); calcd for C20H30O4Na [M + Na+] 357.2036, found
357.2028 (−2.3 ppm).
16b: Rf = 0.40 (hexanes/EtOAc, 85:15); formula C20H29BrO4; MW
413.35 g/mol; IR (neat) νmax 2865, 1739, 1452, 1264, 1112, 1055, 736
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.23 (m, 5H), 4.57 (d, J =
12.1 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.01 (dd, J = 2.8 Hz, 11.6 Hz,
1H), 3.83 (dd, J = 3.2 Hz, 9.1 Hz, 1H), 3.78 (s, 3H), 3.41−3.35 (m, 2H),
2.43−2.33 (m, 1H), 1.89−1.78 (m, 2H), 1.86 (s, 3H), 1.74−1.63 (m,
1H), 1.51−1.44 (m, 1H), 1.38−1.32 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H),
0.98 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.2,
139.1, 128.5, 127.9, 127.6, 81.3, 74.0, 73.5, 72.8, 65.2, 53.4, 32.7, 26.5,
24.1, 23.7, 20.7, 18.6, 15.1 ppm; MS (ESI-IT) m/z 413.1 (M + H+, 100),
416.1 (30), 417.1 (3), 432.2 (46), 435.1 (M + Na+, 92), 438.1 (29),
439.1 (2); HRMS calcd for C20H30BrO4 [M + H+] 413.1327, found
413.1315 (−1.8 ppm); calcd for C20H29BrO4Na [M + Na+] 435.1141,
found 435.1134 (−1.7 ppm).
(
)-(2R,3R)-Methyl 2,4-Dimethyl-3-(triethylsilyloxy)-
pentanoate (S19).
Product S19 (326 mg, yield = 95%) was obtained as a pale yellow oil
from alcohol S18a28 (0.25 g) following general procedure A3 and
purification by flash chromatography on silica gel (hexanes/EtOAc
90:10): Rf = 0.56 (hexanes/EtOAc, 80:20); formula C14H30O3Si; MW
274.47 g/mol; IR (neat) νmax 2957, 2912, 2879, 1742, 1461, 1058, 786
cm−1; 1H NMR (500 MHz, CDCl3) δ 3.81 (dd, J = 3.9 Hz, 7.5 Hz, 1H),
3.69 (s, 3H), 2.64 (dq, J = 7.2 Hz, 7.2 Hz, 1H), 1.79 (dsept, J = 4.0 Hz,
6.8 Hz, 1H), 1.10 (d, J = 7.1 Hz, 3H), 0.97 (t, J = 8.0 Hz, 9H), 0.92 (d, J =
6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.61 (q, J = 7.9 Hz, 6H) ppm; 13C
NMR (125 MHz, CDCl3) δ 176.2, 78.7, 51.6, 45.3, 30.5, 20.1, 16.3, 13.5,
7.1, 5.5 ppm; MS (ESI-IT) m/z 143.1 (65), 243.2 (13), 275.2 (M + H+,
100); HRMS calcd for C14H31O3Si [M + H+] 275.2037, found 275.2034
(−1.3 ppm).
( )-(R)-Methyl 2-((2R,5R,6R)-6-((S)-1-(Benzyloxy)propan-2-
yl)-5-methyltetrahydro-2H-pyran-2-yl)propanoate (24a) and
( )-(S)-Methyl 2-((2R,5R,6R)-6-((S)-1-(Benzyloxy)propan-2-yl)-
5-methyltetrahydro-2H-pyran-2-yl)propanoate (24b).
(
)-(2S,3R)-2,4-Dimethyl-3-(triethylsilyloxy)pentan-1-ol
(S20).
Product 24a and 24b (23 mg, yield = 79%) were obtained as colorless
oils from a mixture of bromides 16a,b (36 mg) following general
procedure A1 and purification by flash chromatography on silica gel
(hexanes/EtOAc 85:15). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 16:1 ratio of
products 2,3-anti (24a):2,3-syn (24b).
Product S20 (233 mg, yield =96%) was obtained as a colorless oil from
ester S19 (268 mg) following general procedure A4 and purification by
flash chromatography on silica gel (hexanes/EtOAc 80:20): Rf = 0.38
(hexanes/EtOAc, 80:20); formula C13H30O2Si; MW 246.46 g/mol; IR
1
(neat) νmax 3369, 2958, 2912, 2878, 1462, 1054, 736 cm−1; H NMR
24a: Rf = 0.32 (hexanes/EtOAc, 85:15); formula C20H30O4; MW
334.45 g/mol; IR (neat) νmax 2930, 2859, 1739, 1456, 1376, 1168, 1098,
737 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.25 (m, 5H), 4.53 (d, J
= 12.0 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H), 3.83 (dt, J = 10.0 Hz, 5.4 Hz,
1H), 3.68 (s, 3H), 3.66 (dd, J = 4.2 Hz, 9.3 Hz, 1H), 3.30−3.24 (m, 2H),
2.79 (dq, J = 9.5 Hz, 7.0 Hz, 1H), 2.30−2.21 (m, 1H), 1.80−1.65 (m,
2H), 1.60−1.54 (m, 2H), 1.37−1.30 (m, 1H), 1.08 (d, J = 7.0 Hz, 3H),
1.01 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 176.1, 139.2, 128.5, 127.7, 127.5, 80.1, 73.5, 73.3, 72.1,
51.8, 42.9, 33.6, 29.6, 26.1, 24.2, 18.5, 15.7, 14.2 ppm; MS (ESI-IT) m/z
335.2 (100), 336.2 (14), 352.2 (4), 357.2 (45), 358.2 (11); HRMS calcd
for C20H31O4 [M + H+] 335.2222, found 335.2212 (−1.3 ppm); calcd
for C20H30O4Na [M + Na+] 357.2036, found 357.2029 (−2.2 ppm).
24b: Rf = 0.38 (hexanes/EtOAc, 85:15); formula C20H30O4; MW
(500 MHz, CDCl3) δ 3.73 (dd, J = 3.8 Hz, 10.9 Hz, 1H), 3.59 (dd, J = 5.6
Hz, 10.9 Hz, 1H), 3.45 (t, J = 5.1 Hz, 1H), 2.75 (bs, 1H), 1.90−1.78 (m,
2H), 1.01 (d, J = 8.0 Hz, 3H), 1.00 (t, J = 8.1 Hz, 9H), 0.94 (d, J = 6.8 Hz,
6H), 0.68 (q, J = 7.9 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 83.4,
66.2, 37.1, 33.0, 19.3, 18.6, 16.5, 7.2, 5.5 ppm; MS (ESI-IT) m/z 229.2
(34), 247.2 (M + H+, 10), 361.3 (100), 363.3 (15); HRMS calcd for
C13H31O2Si [M + H+] 247.2088, found 247.2088 (0.04 ppm).
( )-(4S,5R,E)-Methyl 4,6-Dimethyl-5-(triethylsilyloxy)hept-2-
enoate (S22).
Aldehyde S21 was obtained as a pale yellow oil from alcohol S20 (219
mg) following general procedure A11 and was used as crude without
further purification. Product S22 (155 mg, yield = 60% over two steps)
was obtained as a colorless oil from crude aldehyde S21 following
general procedure A6 and purification by flash chromatography on silica
gel (hexanes/EtOAc 85:15): Rf = 0.51 (hexanes/EtOAc, 80:20);
formula C16H32O3Si; MW 300.51 g/mol; IR (neat) νmax 2958, 2913,
2878, 1724, 1657, 1272, 736 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.05
(dd, J = 8.4 Hz, 15.8 Hz, 1H), 5.80 (d, J = 15.8 Hz, 1H), 3.73 (s, 3H),
3.36 (app t, J = 4.9 Hz, 1H), 2.56−2.47 (m, 1H), 1.75−1.65 (m, 1H),
1.05 (d, J = 6.9 Hz, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.88 (d, J = 6.8 Hz, 3H),
0.86 (d, J = 6.9 Hz, 3H), 0.62 (q, J = 8.0 Hz, 6H) ppm; 13C NMR (125
1
334.45 g/mol; IR (neat) νmax 2931, 1737, 1455, 1108, 1049 cm−1; H
NMR (500 MHz, CDCl3) δ 7.38−7.25 (m, 5H), 4.53 (d, J = 12.3 Hz,
1H), 4.51 (d, J = 12.2 Hz, 1H), 3.78 (dt, J = 9.1 Hz, 5.4 Hz, 1H), 3.70−
3.65 (m, 1H), 3.67 (s, 3H), 3.30 (dd, J = 8.1 Hz, 9.1 Hz, 1H), 3.14 (t, J =
6.0 Hz, 1H), 2.80−2.73 (m, 1H), 2.32−2.24 (m, 1H), 1.80−1.65 (m,
2H), 1.55−1.49 (m, 2H), 1.42−1.33 (m, 1H), 1.19 (d, J = 6.9 Hz, 3H),
1.03 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 175.8, 139.0, 128.5, 127.7, 127.6, 80.0, 73.3, 72.6, 72.1,
51.8, 42.5, 33.6, 29.5, 26.3, 25.6, 18.5, 16.0, 13.8 ppm; MS (ESI-IT) m/z
335.2 (M + H+, 100), 336.2 (14), 352.2 (5), 357.2 (M + Na+, 35), 358.2
(9); HRMS calcd for C20H31O4 [M + H+] 335.2222, found 335.2212
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MHz, CDCl3) δ 167.4, 152.8, 120.5, 81.4, 51.5, 40.9, 32.4, 19.9, 18.2,
17.6, 7.3, 5.7 ppm; MS (ESI-IT) m/z 169.1 (29), 209.1 (100), 301.2
(10), 323.2 (M + Na+, 47); HRMS calcd for C16H32O3NaSi [M + Na+]
323.2013, found 323.2015 (0.8 ppm).
( )-Methyl 2-Bromo-2-((2S,5S,6R)-6-isopropyl-5-methylte-
trahydro-2H-pyran-2-yl)propanoate (17a, 17b).
(
)-(4S,5R)-Methyl 4,6-Dimethyl-5-(triethylsilyloxy)-
heptanoate (S23).
Products 17a and 17b (481 mg, yield = 67%) were obtained as pale
yellow oils from aldehyde S25 (643 mg) following general procedure A7
and purification by flash chromatography on silica gel (hexanes/EtOAc
90:10). 1H NMR spectroscopic analysis of the unpurified product
indicated a pair of 2,3-diastereomers in a ∼1:1 ratio of products 17a:17b.
17a: Rf = 0.43 (hexanes/EtOAc, 90:10); formula C13H23BrO3; MW
307.22 g/mol; IR (neat) νmax 2959, 2872, 1745, 1449, 1262, 1048 cm−1;
1H NMR (500 MHz, CDCl3) δ 4.11 (dd, J = 4.0 Hz, 10.6 Hz, 1H), 3.79
(s, 3H), 3.04 (d, J = 9.9 Hz, 1H), 2.19−2.09 (m, 1H), 1.93 (s, 3H),
1.89−1.82 (m, 2H), 1.80−1.68 (m, 2H), 1.52−1.48 (m, 1H), 1.10 (d, J =
7.0 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 171.7, 86.0, 73.5, 62.5, 53.2, 27.0, 26.9, 24.5,
22.7, 20.1, 19.8, 19.3, 18.7 ppm; MS (ESI-IT) m/z 209.2 (5), 307.1 (M +
H+, 19), 329.1 (M + Na+, 100), 637.2 (25); HRMS calcd for
C13H24BrO3 [M + H+] 307.0903, found 307.0914 (3.4 ppm); calcd for
C13H23BrNaO3 [M + Na+] 329.0728, found 329.0734 (3.4 ppm).
17b: Rf = 0.56 (hexanes/EtOAc, 90:10); formula C13H23BrO3; MW
307.22 g/mol; IR (neat) νmax 2957, 2872, 1741, 1450, 1265, 1058 cm−1;
1H NMR (500 MHz, CDCl3) δ 3.91 (dd, J = 2.9 Hz, 11.5 Hz, 1H), 3.78
(s, 3H), 3.12 (d, J = 10.3 Hz, 1H), 2.21−2.11 (m, 1H), 1.87 (s, 3H),
1.86−1.80 (m, 2H), 1.70 (ddd, J = 4.4 Hz, 12.6 Hz, 24.7 Hz, 1H), 1.48−
1.43 (m, 1H), 1.34 (ddd, J = 3.2 Hz, 6.7 Hz, 12.7 Hz, 1H), 1.12 (d, J = 7.0
Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 171.3, 85.7, 74.1, 65.8, 53.4, 27.0, 26.9, 24.3,
24.2, 20.9, 20.1, 19.6, 18.8 ppm; MS (ESI-IT) m/z 209.2 (11), 307.1 (M
+ H+, 60), 329.1 (M + Na+, 100), 332.1 (94), 637.2 (54); HRMS calcd
for C13H24BrO3 [M + H+] 307.0903, found 307.0912 (2.9 ppm); calcd
for C13H23BrNaO3 [M + Na+] 329.0728, found 329.0733 (3.0 ppm).
Product S23 was obtained as a colorless oil from α,β-unsaturated ester
S22 (1.06 g) following general procedure A2 and was used as crude
without further purification: Rf = 0.51 (hexanes/EtOAc, 80:20); formula
C16H34O3Si; MW 302.53 g/mol; IR (neat) νmax 2957, 2913, 2878, 1743,
1
1461, 1172, 1052, 737 cm−1; H NMR (500 MHz, CDCl3) δ 3.68 (s,
3H), 3.24 (app t, J = 5.0 Hz, 1H), 2.41 (ddd, J = 5.5 Hz, 9.8 Hz, 15.4 Hz,
1H), 2.26 (ddd, J = 6.9 Hz, 9.5 Hz, 15.8 Hz, 1H), 1.90 (dddd, J = 3.5 Hz,
6.9 Hz, 10.1 Hz, 13.4 Hz, 1H), 1.78 (dq, J = 13.4 Hz, 6.7 Hz, 1H), 1.64−
1.57 (m, 1H), 1.46−1.35 (m, 1H), 0.98 (t, J = 7.9 Hz, 9H), 0.90 (d, J =
6.7 Hz, 3H), 0.895 (d, J = 6.8 Hz, 3H), 0.887 (d, J = 6.6 Hz, 3H), 0.64 (q,
J = 7.9 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 174.7, 82.4, 51.7,
36.5, 32.6, 31.4, 27.1, 20.6, 18.4, 16.9, 7.4, 5.8 ppm; MS (ESI-IT) m/z
171.1 (10), 211.1 (27), 303.2 (M + H+, 98), 325.2 (M + Na+, 100);
HRMS calcd for C16H35O3Si [M + H+] 303.2350, found 303.2339 (−3.6
ppm); calcd for C16H34O3NaSi [M + Na+] 325.2175, found 325.2159
(−3.2 ppm).
(
)-(4S,5R)-4,6-Dimethyl-5-(triethylsilyloxy)heptan-1-ol
(S24).
Primary alcohol S24 (0.76 g, yield = 78% over two steps) was obtained
as a colorless oil from crude ester S23 (1.07 g) following general
procedure A4 and purification by flash chromatography on silica gel
(CH2Cl2/Et2O, 95:5): Rf = 0.18 (CH2Cl2/Et2O, 95:5); formula
C15H34O2Si; MW 274.51 g/mol; IR (neat) νmax 3332, 2957, 2913,
(
)-(S)-Methyl 2-((2S,5S,6R)-6-Isopropyl-5-methyltetrahy-
dro-2H-pyran-2-yl)propanoate (25a) and ( )-(R)-Methyl 2-
((2S,5S,6R)-6-Isopropyl-5-methyltetrahydro-2H-pyran-2-yl)
propanoate (25b).
1
2877, 1462, 1056, 1009, 736 cm−1; H NMR (500 MHz, CDCl3) δ
3.65−3.62 (m, 2H), 3.23 (app t, J = 4.9 Hz, 1H), 1.80−1.64 (m, 3H),
1.61−1.54 (m, 2H), 1.51−1.42 (m, 1H), 1.12−1.04 (m, 1H), 0.97 (t, J =
8.0 Hz, 9H), 0.89 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.87 (d, J
= 6.6 Hz, 3H), 0.62 (q, J = 8.0 Hz, 6H) ppm; 13C NMR (125 MHz,
CDCl3) δ 82.5, 63.6, 37.2, 31.19, 31.18, 28.2, 20.9, 18.1, 17.0, 7.4, 5.8
ppm; MS (ESI-IT) m/z 143.1 (60), 183.1 (100), 261.1 (11), 297.2 (M +
Na+, 11), 343.3 (8), 421.2 (8); HRMS calcd for C15H34O2NaSi [M +
Na+] 297.2226, found 297.2229 (2.9 ppm).
Products 25a and 25b (58 mg, yield = 76%) were obtained as pale yellow
oils from a mixture of bromides 17a and 17b (103 mg) following general
procedure A1 and purification by flash chromatography on silica gel
(hexanes/EtOAc 90:10). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 17:1 ratio of
products 2,3-anti (25a):2,3-syn (25b). The reaction performed on a
mixture of bromides 17a and 17b (15 mg) according to general
procedure A1 with Ph3SnH in CH2Cl2 led to the formation of product
2,3-anti (25a) and 2,3-syn (25b) in a 3:1 ratio of products (11 mg, yield
= 98%) as verified by 1H NMR analysis of the crude mixture.
( )-(4S,5R)-4,6-Dimethyl-5-(triethylsilyloxy)heptanal (S25).
Product S25 (0.66 g, yield = 91%) was obtained as a pale yellow oil from
alcohol S24 (0.73 g) following general procedure A14 and purification
by flash chromatography on silica gel (hexanes/EtOAc 85:15): Rf = 0.56
(hexanes/EtOAc, 80:20); formula C15H32O2Si; MW 272.50 g/mol; IR
(neat) νmax 2958, 2912, 2878, 2714, 1728, 1101, 1054, 1009, 736 cm−1;
1H NMR (500 MHz, CDCl3) δ 9.79 (app t, J = 1.8 Hz, 1H), 3.25 (app t, J
= 5.0 Hz, 1H), 2.51 (dddd, J = 1.6 Hz, 5.6 Hz, 9.6 Hz, 15.3 Hz, 1H),
2.41−2.34 (m, 1H), 1.92 (dddd, J = 13.4 Hz, 9.8 Hz, 6.5 Hz, 3.5 Hz, 1H),
1.79 (dq, J = 13.4 Hz, 6.7 Hz, 1H), 1.65−1.57 (m, 1H), 1.44−1.35 (m,
1H), 0.99 (t, J = 7.9 Hz, 9H), 0.905 (d, J = 6.5 Hz, 3H), 0.903 (d, J = 6.7
Hz, 3H), 0.89 (d, J = 6.2 Hz, 3H), 0.64 (q, J = 7.9 Hz, 6H) ppm; 13C
NMR (125 MHz, CDCl3) δ 203.2, 82.4, 42.5, 36.5, 31.5, 24.3, 20.6, 18.2,
17.1, 7.4, 5.8 ppm; MS (ESI-IT) m/z 157.1 (30), 271.2 (M − H+, 76),
403.3 (100), 778.6 (5); HRMS calcd for C15H31O2Si [M − H+]
271.2088, found 271.2088 (−0.04 ppm).
25a: Rf = 0.25 (hexanes/EtOAc, 90:10); formula C13H24O3; MW
228.33 g/mol; IR (neat) νmax 2955, 2933, 2875, 1740 cm−1; 1H NMR
(500 MHz, CDCl3) δ 3.84 (dt, J = 10.2 Hz, 5.3 Hz, 1H), 3.70 (s, 3H),
3.09 (app t, J = 5.9 Hz, 1H), 2.85 (dq, J = 9.7 Hz, 6.9 Hz, 1H), 1.99 (qd, J
= 6.7 Hz, 13.3 Hz, 1H), 1.72−1.54 (m, 4H), 1.36−1.30 (m, 1H), 1.09 (d,
J = 7.0 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.861 (d, J = 6.7 Hz, 3H), 0.858
(d, J = 6.8 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 176.1, 82.2,
73.7, 51.8, 42.7, 30.1, 27.9, 26.5, 24.4, 20.2, 18.4, 16.6, 14.3 ppm; MS
(ESI-IT) m/z 229.2 (M + H+, 12), 251.2 (M + Na+, 100), 252.2 (14);
HRMS calcd for C13H25O3 [M + H+] 229.1798, found 229.1794 (−2.1
ppm); calcd for C13H24NaO3 [M + Na+] 251.1618, found 251.1613
(−1.7 ppm).
25b: Rf = 0.29 (hexanes/EtOAc, 90:10); formula C13H24O3; MW
228.33 g/mol; IR (neat) νmax 2927, 2861, 1733, 1461, 1277, 1123, 1072
cm−1; 1H NMR (500 MHz, CDCl3) δ 3.80 (dt, J = 9.4 Hz, 5.3 Hz, 1H),
3.69 (s, 3H), 2.95 (app t, J = 5.9 Hz, 1H), 2.83 (dq, J = 9.2 Hz, 6.9 Hz,
M
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1H), 2.02 (dq, J = 13.3 Hz, 6.6 Hz, 1H), 1.74−1.47 (m, 4H), 1.46−1.30
(m, 1H), 1.24 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.94 (d, J =
6.8 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 176.0, 82.0, 72.8, 51.8, 42.2, 30.1, 27.9, 26.7, 26.2, 20.6, 18.4,
16.7, 13.9 ppm; MS (ESI-IT) m/z 118.1 (62), 141.0 (20), 251.2 (28),
338.3 (45), 360.3 (54), 391.3 (25), 413.3 (100); HRMS calcd for
C13H24NaO3 [M + Na+] 251.1618, found 251.1615 (−1.2 ppm).
( )-(2R,3S,6S)-6-((R)-1-(Benzyloxy)propan-2-yl)-2-isopropyl-
3-methyltetrahydro-2H-pyran (S8).
(
)-(2S,3R)-5-(Benzyloxy)-2-methyl-3-(triethylsilyloxy)-
pentan-1-ol (S28a).
An inseparable mixture of product 2,3-anti (S28a):2,3-syn (S28b) was
obtained as a colorless oil (2.32 g, yield = 81% over two steps) from an
inseparable 9:1 mixture (2.37 g) of product 2,3-anti (S27a):2,3-syn
(S27b) following general procedure A4 and purification by flash
chromatography on silica gel (hexanes/EtOAc 70:30). 1H NMR
spectroscopic analysis of the unpurified product indicated a pair of
diastereomers in a 9:1 ratio of products 2,3-anti (S28a):2,3-syn (S28b).
S28a: Rf = 0.38 (hexanes/EtOAc, 70:30); formula C19H34O3Si; MW
338.56 g/mol; IR (neat) νmax 3435, 2956, 2877, 1100, 1012, 734 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 4.51 (d, J = 11.9 Hz,
1H), 4.47 (d, J = 11.9 Hz, 1H), 3.91 (dd, J = 5.7 Hz, 10.4 Hz, 1H), 3.74
(dd, J = 3.8 Hz, 11.0 Hz, 1H), 3.53 (app t, J = 6.6 Hz, 3H), 2.62 (bs, 1H),
1.90−1.84 (m, 1H), 1.78−1.71 (m, 1H), 0.99 (d, J = 7.0 Hz, 3H), 0.96
(t, J = 7.9 Hz, 9H), 0.62 (q, J = 7.8 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3) δ 138.5, 128.6, 127.9, 127.8, 74.6, 73.3, 67.0, 65.8, 39.3, 35.0,
14.3, 7.1, 5.2 ppm; MS (ESI-IT) m/z 339.2 (M + H+, 100), 438.3 (11),
453.3 (34); HRMS calcd for C19H35O3Si [M + H+] 339.2350, found
339.2357 (2.0 ppm).
Primary alcohol was obtained as a colorless oil from ester 25a (10 mg)
following general procedure A4 and was used as crude without further
purification. To a cold (0 °C) solution of crude alcohol in dry CH2Cl2
(0.1 M, 435 μL) were added successively a 60% w/w dispersion of NaH
in mineral oil (1.3 equiv, 2 mg) and benzyl bromide (1.5 equiv, 8 μL).
The reaction mixture was stirred for 1 h at 0 °C followed by stirring for
18 h at room temperature. The reaction mixture was then treated with a
saturated aqueous solution of NH4Cl, followed by separation of the
organic phase at room temperature. The aqueous layer was extracted
with Et2O (3×), and combined organic fractions were dried (MgSO4),
filtered, and concentrated in vacuo. Product S8 (8.8 mg, 69% over two
steps) was obtained as a colorless oil after purification by flash
chromatography on silica gel (hexanes/EtOAc 90:10). 1H and 13C
NMR chemical shift were identical to those previously reported for
product S8 synthesized from S76d (vide supra).
(
)-(4S,5R,E)-Methyl 7-(Benzyloxy)-4-methyl-5-
(triethylsilyloxy)hept-2-enoate (S30a).
An inseparable mixture of aldehyde 2,3-anti (S29a):2,3-syn (S29b) was
obtained as a pale yellow oil from an inseparable 9:1 mixture (1.01 g) of
product 2,3-anti (S28a):2,3-syn (S28b) following general procedure
A11 and was used as crude without further purification. An inseparable
mixture of product 4,5-anti (S30a); 4,5-syn (S30b) was obtained as a
colorless oil (0.947 g, yield = 81% over two steps) from an inseparable
mixture of aldehyde following general procedure A6 and purification by
1
flash chromatography on silica gel (hexanes/EtOAc 80:20). H NMR
spectroscopic analysis of the unpurified product indicated a pair of
diastereomers in a 9:1 ratio of products 4,5-anti (S30a):4,5-syn (S30b).
S30a: Rf = 0.43 (hexanes/EtOAc, 80:20); formula C22H36O4Si; MW
392.60 g/mol; IR (neat) νmax 2955, 2873, 1725, 1274, 1103, 1011, 734
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.23 (m, 5H), 6.95 (dd, J =
7.8 Hz, 15.8 Hz, 1H), 5.80 (dd, J = 1.2 Hz, 15.8 Hz, 1H), 4.50 (d, J = 11.9
Hz, 1H), 4.45 (d, J = 11.9 Hz, 1H), 3.87 (td, J = 4.8 Hz, 7.3 Hz, 1H), 3.73
(s, 3H), 3.50 (app t, J = 6.5 Hz, 2H), 2.48−2.42 (m, 1H), 1.73−1.65 (m,
2H), 1.06 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.9 Hz,
6H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.2, 151.4, 138.6, 128.6,
127.9, 127.8, 121.3, 73.2, 72.4, 67.1, 51.6, 42.7, 34.4, 14.9, 7.2, 5.3 ppm;
MS (ESI-IT) m/z 169.1 (6), 229.1 (16), 261.1 (16), 393.2 (M + H+,
100), 492.4 (8), 507.3 (11); HRMS calcd for C22H37O4Si [M + H+]
393.2456, found 393.2468 (3.0 ppm).
(
)-(2R, 3R)-Methyl 5-(Benzyloxy)-2-methyl-3-
(triethylsilyloxy)pentanoate (S27a).
An inseparable mixture of product 2,3-anti (S27a):2,3-syn (S27b) was
obtained as a pale yellow oil from an inseparable 9:1 mixture (1.97 g) of
alcohol 2,3-anti (S26a) and 2,3-syn (S26b)10 following general
procedure A3. Crude product as a mixture was used without further
purification. 1H NMR spectroscopic analysis of the unpurified product
indicated a pair of diastereomers in a 9:1 ratio of products 2,3-anti
(S27a); 2,3-syn (S27b).
(
)-(4S,5R)-Methyl 7-(Benzyloxy)-4-methyl-5-
(triethylsilyloxy)heptanoate (S31a).
S27a: Rf = 0.66 (hexanes/EtOAc, 70:30); formula C20H34O4Si; MW
366.56 g/mol IR (neat) νmax 2853, 2878, 1740, 1440, 1108, 734 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.34−7.25 (m, 5H), 4.50 (d, J = 12.0 Hz,
1H), 4.47 (d, J = 12.1 Hz, 1H), 4.15 (dt, J = 5.7 Hz, 5.7 Hz, 1H), 3.65 (s,
3H), 3.56 (app t, J = 6.6 Hz, 2H), 2.65 (dq, J = 6.9 Hz, 6.9 Hz, 1H), 1.77
(q, J = 6.4 Hz, 2H), 1.12 (d, J = 7.1 Hz, 3H), 0.93 (t, J = 7.9 Hz, 9H), 0.58
(q, J = 7.9 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.3, 138.7,
128.5, 127.8, 127.7, 73.1, 71.0, 66.8, 51.7, 46.2, 33.6, 12.1, 7.1, 5.2 ppm;
MS (ESI-IT) m/z 259.2 (11), 335.2 (51), 367.2 (M + H+, 100), 481.3
(15); HRMS calcd for C20H35O4Si [M + H+] 367.2299, found 367.2302
(0.6 ppm).
An inseparable mixture of product 4,5-anti (S31a):4,5-syn (S31b) was
obtained as a colorless oil (0.86 g, yield = 83%) from an inseparable 9:1
mixture (1.03 g) of product 4,5-anti (S30a):4,5-syn (S30b) following
general procedure A2 to which was added pyridine29 (1.5 equiv, 0.26
mL) before the gas atmosphere was changed to H2. 1H NMR
spectroscopic analysis of the unpurified product indicated a pair of
diastereomers in a 9:1 ratio of products 4,5-anti (S31a):4,5-syn (S31b).
S31a: Rf = 0.43 (hexanes/EtOAc, 80:20); formula C22H38O4Si; MW
394.62 g/mol; IR (neat) νmax 2955, 2877, 1741, 1456, 1240, 1101, 1010,
735 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.22 (m, 5H), 4.51 (d, J
= 11.8 Hz, 1H), 4.47 (d, J = 11.8 Hz, 1H), 3.76 (dt, J = 8.3 Hz, 3.3 Hz,
1H), 3.66 (s, 3H), 3.54 (app t, J = 6.2 Hz, 2H), 2.42−2.33 (m, 1H),
N
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2.31−2.22 (m, 1H), 1.73−1.62 (m, 3H), 1.60−1.48 (m, 1H), 1.44−1.37
(m, 1H), 0.94 (t, J = 7.9 Hz, 9H), 0.88 (d, J = 6.7 Hz, 3H), 0.57 (q, J = 7.9
Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.5, 138.8, 128.6,
127.9, 127.7, 73.2, 72.8, 67.7, 51.8, 38.7, 32.5, 28.1, 14.2, 7.2, 5.3 ppm;
MS (ESI-IT) m/z 141.1 (16), 213.1 (9), 231.1 (18), 263.2 (100), 363.2
(6), 395.3 (M + H+, 16); HRMS calcd for C22H39O4Si [M + H+]
395.2612, found 395.2610 (−0.5 ppm).
73.3, 73.2, 67.5, 61.7, 53.2, 31.7, 30.8, 25.0, 22.3, 20.0, 18.6 ppm; MS
(ESI-IT) m/z 338.3 (7), 399.1 (M + H+, 100), 421.1 (M + Na+, 96),
458.2 (9); HRMS calcd for C19H28BrO4 [M + H+] 399.1165, found
399.1166 (0.2 ppm); calcd for C19H27BrNaO4 [M + Na+] 421.0990,
found 421.0987 (0.4 ppm).
( )-(S)-Methyl 2-((2S,5S,6R)-6-(2-(Benzyloxy)ethyl)-5-meth-
yltetrahydro-2H-pyran-2-yl)propanoate (26a) and ( )-(R)-
Methyl 2-((2S,5S,6R)-6-(2-(Benzyloxy)ethyl)-5-methyltetrahy-
dro-2H-pyran-2-yl)propanoate (26b).
(
)-(5S,6R)-6-(2-(Benzyloxy)ethyl)-5-methyltetrahydro-2H-
pyran-2-yl acetate (S33a).
An inseparable mixture of lactone 4,5-anti (S32a):4,5-syn (S32b) was
obtained as a colorless oil from an inseparable 9:1 mixture (453 mg) of
product 4,5-anti (S31a):4,5-syn (S31b) following general procedure A8.
An inseparable mixture of product 4,5-anti (S33a,b):4,5-syn (S33c,d)
(156 mg, yield = 79% over three steps) was obtained as a colorless oil
from an inseparable mixture of crude lactone 4,5-anti (S32a):4,5-syn
(S32b) following general procedure A9 and purification by flash
chromatography on silica gel (hexanes/EtOAc 95:5). 1H NMR
spectroscopic analysis of the unpurified product indicated a pair of
diastereomers in a 9:1 ratio of products 4,5-anti (S33a,b):4,5-syn
(S33c,d).
Products 26a and 26b (28 mg, yield = 70%) were obtained as pale yellow
oils from a mixture of bromides 18a and 18b (50 mg) following general
procedure A1 and purification by flash chromatography on silica gel
(hexanes/EtOAc 80:20). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 17:1 ratio of
products 2,3-anti (26a):2,3-syn (26b).
26a: Rf = 0.26 (hexanes/EtOAc, 80:20); formula C19H28O4; MW
320.42 g/mol; IR (neat) νmax 3026, 2950, 2935, 2868, 1738, 1456, 1196,
1
1092, 738 cm−1; H NMR (500 MHz, CDCl3) δ 7.36−7.26 (m, 5H),
4.53 (d, J = 11.9 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 3.85 (td, J = 4.9 Hz,
10.0 Hz, 1H), 3.62 (s, 3H), 3.57−3.45 (m, 3H), 2.86 (dq, J = 10.0 Hz,
6.9 Hz, 1H), 1.92−1.80 (m, 2H), 1.73−1.56 (m, 3H), 1.49−1.42 (m,
1H), 1.36−1.29 (m, 1H), 1.08 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.8 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 176.0, 138.9, 128.6, 127.9,
127.7, 74.8, 73.7, 73.3, 67.9, 51.7, 42.3, 33.8, 33.0, 26.4, 24.6, 18.5, 14.2
ppm; MS (ESI-IT) m/z 321.2 (M + H+, 100), 343.2 (M + Na+, 22),
380.3 (8); HRMS calcd for C19H29O4 [M + H+] 321.2060, found
321.2058 (−0.8 ppm); calcd for C19H28NaO4 [M + Na+] 343.1885,
found 343.1881 (0.3 ppm).
S33a: Rf = 0.21 (hexanes/Acetone, 95:5); formula C17H24O4; MW
292.37 g/mol; IR (neat) νmax 3068, 3032, 2956, 2930, 2866, 1746, 1456,
1
1221, 951, 737 cm−1; H NMR (500 MHz, CDCl3) δ 7.37−7.27 (m,
5H), 6.13 (bs, 1H), 4.52 (d, J = 11.8 Hz, 1H), 4.50 (d, J = 12.1 Hz, 1H),
3.65−3.56 (m, 3H), 2.06−1.99 (m, 1H), 2.05 (s, 3H), 1.85−1.74 (m,
2H), 1.66−1.59 (m, 2H), 1.56−1.45 (m, 2H), 0.91 (d, J = 6.0 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 170.1, 139.0, 128.6, 127.74,
127.65, 92.3, 73.9, 73.3, 67.0, 34.9, 33.3, 29.3, 27.0, 21.5, 18.2 ppm; MS
+
(ESI-IT) m/z 233.2 (38), 273.2 (9), 310.2 (M + NH4 , 11), 315.2 (M +
Na+, 100), 392.3 (4), 607.3 (13); HRMS calcd for C17H28O4N [M +
26b: Rf = 0.31 (hexanes/EtOAc, 80:20); formula C19H28O4; MW
320.42 g/mol; IR (neat) νmax 3062, 3030, 2950, 2932, 2861, 1736, 1455,
1112, 1048, 738 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.27 (m,
5H), 4.53 (d, J = 11.8 Hz, 1H), 4.49 (d, J = 11.9 Hz, 1H), 3.84 (td, J = 4.2
Hz, 9.0 Hz, 1H), 3.68 (s, 3H), 3.65−3.56 (m, 2H), 3.39−3.33 (m, 1H),
2.92 (dq, J = 9.6 Hz, 6.9 Hz, 1H), 1.98−1.89 (m, 1H), 1.81−1.72 (m,
1H), 1.72−1.63 (m, 2H), 1.54−1.35 (m, 3H), 1.20 (d, J = 6.9 Hz, 3H),
0.95 (d, J = 6.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.9,
138.8, 128.6, 128.0, 127.8, 73.5, 73.3, 73.2, 67.3, 51.9, 41.1, 34.3, 33.3,
27.0, 26.6, 18.4, 14.1 ppm; MS (ESI-IT) m/z 321.2 (M + H+, 47), 343.2
(M + Na+, 100); HRMS calcd for C19H29O4 [M + H+] 321.2060, found
321.2056 (−1.4 ppm); calcd for C19H28NaO4 [M + Na+] 343.1885,
found 343.1872 (−2.2 ppm).
+
NH4 ] 310.2013, found 310.2011 (−0.5 ppm); calcd for C17H24NaO4
[M + Na+] 315.1572, found 315.1564 (−0.8 ppm).
( )-Methyl 2-((2S,5S,6R)-6-(2-(Benzyloxy)ethyl)-5-methylte-
trahydro-2H-pyran-2-yl)-2-bromopropanoate (18a; 18b).
Products 18a and 18b (120 mg, yield = 83%) were obtained as pale
yellow oils from an inseparable mixture (106 mg) of product 4,5-anti
(S33a,b):4,5-syn (S33c,d) following general procedure A10 and
purification by flash chromatography on silica gel (hexanes/EtOAc
80:20). 1H NMR spectroscopic analysis of the unpurified product
indicated a pair of 2,3-diastereomers in a ∼1:1 ratio of products 18a:18b.
18a: Rf = 0.36 (hexanes/EtOAc, 80:20); formula C19H27BrO4; MW
399.32 g/mol; IR (neat) νmax 3056, 3030, 2953, 2867, 1738, 1452, 1267,
1113, 1058, 738 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.27 (m,
5H), 4.56 (d, J = 11.9 Hz, 1H), 4.52 (d, J = 11.9 Hz, 1H), 3.97 (dd, J = 2.8
Hz, 11.5 Hz, 1H), 3.86 (dd, J = 1.8 Hz, 9.9 Hz, 1H), 3.78 (s, 3H), 3.66−
3.61 (m, 1H), 2.29−2.21 (m, 1H), 1.95−1.87 (m, 1H), 1.86 (s, 3H),
1.75−1.67 (m, 2H), 1.64−1.57 (m, 1H), 1.53−1.46 (m, 1H), 1.42−1.35
(m, 1H), 1.13 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
171.2, 138.8, 128.6, 128.0, 127.8, 75.6, 73.8, 73.4, 67.6, 65.5, 53.4, 31.6,
30.7, 24.8, 23.9, 21.4, 18.6 ppm; MS (ESI-IT) m/z 399.1 (M + H+, 30),
423.1 (M + Na+, 100); HRMS calcd for C19H28BrO4 [M + H+]
399.1165, found 399.1162 (−1.0 ppm); calcd for C19H27BrNaO4 [M +
Na+] 423.0990, found 423.0979 (−1.5 ppm).
(
)-(5R,6S,E)-Methyl 7-(Benzyloxy)-6-methyl-5-
(triethylsilyloxy)hept-2-enoate (S37).
18b: Rf = 0.41 (hexanes/EtOAc, 80:20); formula C19H27BrO4; MW
399.32 g/mol; IR (neat) νmax 2953, 2867, 1742, 1451, 1264, 1096, 1049,
738 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.27 (m, 5H), 4.52 (d, J
= 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.16 (dd, J = 3.0 Hz, 11.5 Hz,
1H), 3.77−3.72 (m, 1H), 3.73 (s, 3H), 3.55−3.47 (m, 2H), 2.21−2.12
(m, 1H), 1.95−1.88 (m, 1H), 1.89 (s, 3H), 1.82−1.77 (m, 1H), 1.74−
1.68 (m, 2H), 1.61−1.52 (m, 2H), 1.10 (d, J = 7.0 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 171.6, 138.7, 128.6, 127.83, 127.77, 76.9,
Product 35 as a pale yellow oil was obtained from alcohol S3430 (1.33 g)
following general procedure A3 and was used as crude without further
purification. To a solution at room temperature of crude product in a
solvent mixture of 1,4-dioxane and H2O (3:1, 0.1 M, 60 mL) were added
successively 2,6-lutidine (2 equiv, 1.40 mL), OsO4 (0.2 equiv, 0.74 mL),
and NaIO4 (4 equiv, 5.17 g). The reaction mixture was stirred for 1.5 h at
O
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room temperature before filtration onto a pad of Celite and washing
with Et2O. The filtrate was then treated with a saturated aqueous
solution of Na2S2O3, followed by stirring overnight at room temperature
before separation of the organic phase. The aqueous layer was extracted
with Et2O (3×), and combined organic fractions were dried (MgSO4),
filtered, and concentrated in vacuo. Product S37 (1.64 g, yield =78%
over three steps) was obtained as a colorless oil from crude aldehyde S36
following general procedure A6 and purification by flash chromatog-
raphy on silica gel (hexanes/EtOAc 80:20): Rf = 0.44 (hexanes/EtOAc,
80:20); formula C22H36O4Si; MW 392.60 g/mol; IR (neat) νmax 3065,
3027, 2954, 2877, 1726, 1657, 1456, 1269, 1078 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.37−7.25 (m, 5H), 7.01 (td, J = 7.4 Hz, 15.4 Hz, 1H),
5.84 (d, J = 15.7 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 12.1 Hz,
1H), 3.86 (dd, J = 5.5 Hz, 11.1 Hz, 1H), 3.73 (s, 3H), 3.44 (dd, J = 6.1
Hz, 9.2 Hz, 1H), 3.34 (dd, J = 6.2 Hz, 9.2 Hz, 1H), 2.34−2.32 (m, 2H),
1.95 (hept, J = 6.3 Hz, 1H), 0.94 (t, J = 7.9 Hz, 9H), 0.92 (d, J = 6.9 Hz,
3H), 0.58 (q, J = 7.9 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ
167.0, 146.9, 138.8, 128.5, 127.72, 127.70, 123.0, 73.2, 72.8, 72.4, 51.6,
39.4, 36.8, 13.1, 7.2, 5.2 ppm; MS (ESI-IT) m/z 193.1 (52), 393.2 (M +
H+, 100), 507.3 (10); HRMS calcd for C22H37O4Si [M + H+] 393.2456,
found 393.2450 (−1.4 ppm).
(
)-(2S,3S)-1-(Benzyloxy)-7-methoxy-2-methyl-7-oxohep-
tan-3-yl 4-nitrobenzoate (S40).
To a solution at room temperature of alcohol S39 (0.26 g) in dry THF
(0.1 M, 9.30 mL) were added successively p-nitrobenzoic acid (2 equiv,
310 mg), PPh3 (2 equiv, 486 mg), and DEAD (2 equiv, 292 μL). The
reaction mixture was stirred overnight at room temperature before
concentration in vacuo. The crude mixture was purified by flash
chromatography on silica gel (hexanes/EtOAc, 80:20 to 65:35) to afford
product S40 as a pale yellow oil (287 mg, yield = 72%): Rf = 0.53
(hexanes/EtOAc, 50:50); formula C23H27O7N; MW 429.46 g/mol; IR
(neat) νmax 3111, 3060, 3030, 2952, 2866, 1729, 1529, 1348, 1276, 1102,
721 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 2H), 8.16
(d, J = 8.8 Hz, 2H), 7.29−7.22 (m, 5H), 5.40 (td, J = 3.9 Hz, 8.0 Hz, 1H),
4.47 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.8 Hz, 1H), 3.67 (s, 3H), 3.40
(dd, J = 1.9 Hz, 6.3 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H), 2.17 (dh, J = 4.0 Hz,
6.9 Hz, 1H), 1.87−1.78 (m, 1H), 1.76−1.65 (m, 3H), 1.08 (d, J = 7.0 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 173.8, 164.5, 150.6, 138.4,
136.1, 130.9, 128.5, 127.9, 127.7, 123.7, 76.1, 73.4, 72.5, 51.8, 37.3, 33.8,
31.4, 21.3, 11.9 ppm; MS (ESI-IT) m/z 263.2 (7), 452.2 (M + Na+,
100); HRMS calcd for C23H28O7N [M + H+] 430.1860, found 430.1851
(−2.1 ppm); calcd for C23H27NaO7N [M + Na+] 452.1685, found
452.1673 (−1.6 ppm).
(
)-(5R, 6S)-Methyl 7-(Benzyloxy)-6-methyl-5-
(triethylsilyloxy)heptanoate (S38).
(
)-(S)-6-((S)-1-(Benzyloxy)propan-2-yl)tetrahydro-2H-
Product S38 (1.41 g, yield = 86%) was obtained as a colorless oil from
α,β-unsaturated ester S37 (1.63 g) following general procedure A2 and
purification by flash chromatography on silica gel (hexanes/EtOAc
80:20): Rf = 0.44 (hexanes/EtOAc, 80:20); formula C22H38O4Si; MW
394.62 g/mol; IR (neat) νmax 3065, 3030, 2954, 2911, 2876, 1741, 1456,
1242, 1089 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.29 (m, 5H),
4.52 (d, J = 12.1 Hz, 1H), 4.47 (d, J = 12.1 Hz, 1H), 3.76 (td, J = 4.7 Hz,
6.8 Hz, 1H), 3.68 (s, 3H), 3.46 (dd, J = 6.0 Hz, 9.2 Hz, 1H), 3.31 (dd, J =
6.7 Hz, 9.1 Hz, 1H), 2.31 (dt, J = 1.9 Hz, 7.6 Hz, 2H), 1.99 (hept, J = 6.3
Hz, 1H), 1.80−1.71 (m, 1H), 1.68−1.59 (m, 1H), 1.48−1.35 (m, 2H),
0.97 (t, J = 7.9 Hz, 9H), 0.93 (d, J = 6.9 Hz, 3H), 0.61 (q, J = 7.9 Hz, 6H)
ppm; 13C NMR (100 MHz, CDCl3) δ 174.3, 139.0, 128.5, 127.7, 127.6,
73.4, 73.2, 72.9, 51.7, 39.1, 34.5, 32.6, 21.1, 13.0, 7.2, 5.4 ppm; MS (ESI-
IT) m/z 192.6 (21), 263.2 (79), 303.2 (75), 395.3 (M + H+, 76), 417.2
(M + Na+, 100), 433.2 (5), 590.9 (8); HRMS calcd for C22H39O4Si [M +
H+] 395.2612, found 395.2614 (0.3 ppm); calcd for C22H38NaO4Si [M
+ Na+] 417.2432, found 417.2433 (0.3 ppm).
pyran-2-one (S41).
To a cold (0 °C) solution of product S40 (0.27 g, 0.63 mmol) in dry
MeOH (0.1 M, 6.0 mL) was added a freshly prepared 1 M solution of
MeONa in MeOH (1.1 equiv, 0.69 mL), followed by stirring overnight
at 0 °C. The reaction mixture was treated with solid NH4Cl and filtered
onto a pad of silica (hexanes/EtOAc, 50:50) and the filtrate
concentrated in vacuo. Product S41 as a colorless oil (45 mg, yield =
30% over two steps) was obtained from crude product following general
procedure A8 and purification by flash chromatography on silica gel
(hexanes/EtOAc 70:30 to 50:50): Rf = 0.36 (hexanes/EtOAc, 50:50);
formula C15H20O3; MW 248.32 g/mol; IR (neat) νmax 3061, 3030, 2941,
2870, 1731, 1453, 1240, 1102 cm−1; H NMR (500 MHz, CDCl3) δ
1
7.36−7.27 (m, 5H), 4.53 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H),
4.48 (dt, J = 3.4 Hz, 11.6 Hz, 1H), 3.54 (dd, J = 7.7 Hz, 9.1 Hz, 1H), 3.42
(dd, J = 5.3 Hz, 9.2 Hz, 1H), 2.60 (ddd, J = 5.0 Hz, 7.1 Hz, 17.8 Hz, 1H),
2.42 (ddd, J = 7.4 Hz, 9.1 Hz, 17.6 Hz, 1H), 2.02−1.78 (m, 4H), 1.66
(dtd, J = 6.3 Hz, 11.8 Hz, 13.7 Hz, 1H), 1.00 (d, J = 7.0 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 172.4, 138.5, 128.6, 127.9, 127.8, 80.7,
73.5, 71.9, 38.4, 29.8, 25.6, 18.9, 11.4 ppm; MS (ESI-IT) m/z 249.1 (M
+ H+, 5), 271.1 (M + Na+, 100); HRMS calcd for C15H21O3 [M + H+]
249.1485, found 249.1488 (1.1 ppm); calcd for C15H20NaO3 [M + Na+]
271.1310, found 271.1309 (1.5 ppm).
( )-(5R,6S)-Methyl 7-(Benzyloxy)-5-hydroxy-6-methylhepta-
noate (S39).
To a cold (0 °C) solution of ester S38 (50 mg) in dry MeCN (0.1 M,
1.30 mL) was added BF3·OEt2 (2 equiv, 28 μL), followed by stirring at
0 °C for 1 h. The reaction mixture was treated with solid NaHCO3,
filtered onto a pad of Celite, and washed with Et2O and the filtrate
concentrated in vacuo. The crude mixture was purified by flash
chromatography on silica gel (hexanes/EtOAc, 80:20 to 70:30) to afford
product S39 as a colorless oil (29 mg, yield = 80%): Rf = 0.16 (hexanes/
EtOAc 60:40); formula C16H24O4; MW 280.36 g/mol; IR (neat) νmax
(
)-(S)-6-((S)-1-(Benzyloxy)propan-2-yl)tetrahydro-2H-
pyran-2-yl acetate (S42a,b).
1
3486, 3062, 3030, 2952, 2872, 1737, 1454, 1097, 739 cm−1; H NMR
(500 MHz, CDCl3) δ 7.38−7.30 (m, 5H), 4.55 (d, J = 11.9 Hz, 1H), 4.52
(d, J = 12.1 Hz, 1H), 3.68 (s, 3H), 3.63 (dd, J = 4.1 Hz, 9.2 Hz, 1H), 3.55
(ddd, J = 3.4 Hz, 7.7 Hz, 11.2 Hz, 1H), 3.48 (dd, J = 7.6 Hz, 9.1 Hz, 1H),
3.41 (d, J = 3.7 Hz, 1H), 2.37 (t, J = 7.5 Hz, 2H), 1.91−1.82 (m, 2H),
1.78−1.69 (m, 1H), 1.60−1.53 (m, 1H), 1.45 (dddd, J = 5.0 Hz, 8.8 Hz,
10.0 Hz, 13.7 Hz, 1H), 0.92 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 174.5, 137.9, 128.7, 128.0, 127.9, 76.0, 75.5, 73.7, 51.7,
38.4, 34.4, 34.2, 21.0, 14.2 ppm; MS (ESI-IT) m/z 201.1 (100), 213.1
(61), 231.1 (48), 244.3 (13), 281.2 (M + H+, 9), 535.9 (7), 591.5 (13);
HRMS calcd for C16H25O4 [M + H+] 281.1747, found 281.1789 (0.5
ppm).
An inseparable 4:1 mixture of product S42a,b (38 mg, yield = 60% over
two steps, based on recovery of starting material) was obtained as a pale
yellow oil from lactone S41 (64 mg) following general procedure A9 and
purification by flash chromatography on silica gel (hexanes/EtOAc
70:30): Rf = 0.39 (hexanes/EtOAc, 70:30); formula C17H24O4; MW
292.37 g/mol; IR (neat) νmax 3063, 3030, 2944, 2863, 1750, 1455, 1236,
1101, 1035, 738 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.29 (m,
5Ha+5Hb), 6.14 (bs, 1Hb), 5.64 (dd, J = 2.2 Hz, 9.8 Hz, 1Ha), 4.54 (d, J =
12.0 Hz, 1Ha), 4.52 (d, J = 11.9 Hz, 1Hb), 4.49 (d, J = 12.0 Hz, 1Ha), 4.48
(d, J = 12.0 Hz, 1Hb), 3.98 (td, J = 3.4 Hz, 11.2 Hz, 1Hb), 3.62 (ddd, J =
P
dx.doi.org/10.1021/jo400721e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.9 Hz, 4.9 Hz, 11.4 Hz, 1Ha), 3.50 (dd, J = 6.4 Hz, 9.1 Hz, 1Ha), 3.46
(dd, J = 7.4 Hz, 9.0 Hz, 1Hb), 3.38 (dd, J = 5.9 Hz, 9.1 Hz, 1Ha), 3.34 (dd,
J = 5.9 Hz, 9.0 Hz, 1Hb), 2.12 (s, 3Ha), 2.05 (s, 3Hb), 1.95−1.78 (m,
2Ha+3Hb), 1.73−1.68 (m, 1Ha), 1.65−1.41 (m, 3Ha+3Hb), 1.35 (ddd, J
= 4.1 Hz, 12.9 Hz, 24.7 Hz, 1Ha), 1.29−1.20 (m, 1Hb), 1.01 (d, J = 6.9
Hz, 3Ha), 0.94 (d, J = 6.9 Hz, 3Hb) ppm; 13C NMR (100 MHz, CDCl3)
δ 170.1b, 169.5a, 138.80b, 138.77a, 128.4a+b, 127.7a+b, 127.59a, 127.56b,
95.4a, 92.8b, 78.0a, 73.3a, 73.2b, 72.53a, 72.48b, 71.0b, 38.5a, 38.2b, 30.2a,
28.8b, 27.7b, 27.5a, 22.1a, 21.45a, 21.37b, 18.2b, 12.5a, 11.7b ppm; MS
(ESI-IT) m/z 172.9 (9), 255.1 (13), 273.1 (33), 315.2 (M + Na+, 100);
HRMS calcd for C17H24NaO4 [M + Na+] 315.1572, found 315.1564
(−0.8 ppm).
4.5 Hz, 5.2 Hz, 9.9 Hz, 1H), 3.67 (s, 3H), 3.63 (dt, J = 3.2 Hz, 7.6 Hz,
1H), 3.40 (dd, J = 4.8 Hz, 9.2 Hz, 1H), 3.28 (dd, J = 6.4 Hz, 9.2 Hz, 1H),
2.86 (qd, J = 6.9 Hz, 10.0 Hz, 1H), 2.04−1.96 (m, 1H), 1.73−1.56 (m,
4H), 1.55−1.43 (m, 2H), 1.09 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.8 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 176.0, 138.8, 128.4, 127.58,
127.56, 74.0, 73.7, 73.4, 73.2, 51.6, 42.6, 36.1, 27.7, 26.6, 18.6, 14.1, 13.5
ppm; MS (ESI-IT) m/z 289.2 (6), 321.2 (M + H+, 100); HRMS calcd
for C19H29O4 [M + H+] 321.2060, found 321.2066 (1.8 ppm).
27b: Rf = 0.54 (hexanes/EtOAc, 70:30); formula C19H28O4; MW
320.42 g/mol; IR (neat) νmax 3062, 3030, 2963, 2938, 2861, 1736, 1454,
1
1039, 737 cm−1; H NMR (500 MHz, CDCl3) δ 7.38−7.30 (m, 5H),
4.52 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 3.85 (dt, J = 8.3 Hz,
3.8 Hz, 1H), 3.69 (s, 3H), 3.55 (ddd, J = 3.4 Hz, 6.7 Hz, 9.5 Hz, 1H),
3.46 (dd, J = 6.2 Hz, 9.1 Hz, 1H), 3.33 (dd, J = 5.7 Hz, 9.1 Hz, 1H), 2.95
(qd, J = 6.9 Hz, 9.6 Hz, 1H), 1.96 (hept, J = 6.4 Hz, 1H), 1.70−1.63 (m,
3H), 1.55−1.47 (m, 2H), 1.44−1.36 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H),
1.00 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 176.0,
138.8, 128.6, 127.81, 127.74, 73.5, 73.4, 73.1, 71.8, 51.8, 41.3, 37.0,
28.13, 28.07, 19.0, 14.1, 13.0 ppm; MS (ESI-IT) m/z 321.2 (M + H+,
10), 343.2 (M + Na+, 100); HRMS calcd for C19H29O4 [M + H+]
321.2060, found 321.2066 (1.6 ppm); calcd for C19H28NaO4 [M + Na+]
343.1880, found 343.1885 (1.5 ppm).
(
)-Methyl 2-((2S,6S)-6-((S)-1-(Benzyloxy)propan-2-yl)-
tetrahydro-2H-pyran-2-yl)-2-bromopropanoate (19a, 19b).
Products 19a and 19b (43 mg, yield = 90%) were obtained as pale yellow
oils from a mixture of product S42a,b (35 mg) following general
procedure A10 and purification by flash chromatography on silica gel
1
(hexanes/EtOAc 80:20 to 70:30). H NMR spectroscopic analysis of
the unpurified product indicated a pair of 2,3-diastereomers in a ∼1:1
ratio of products 19a:19b.
19a: Rf = 0.24 (hexanes/EtOAc, 80:20); formula C19H27BrO4; MW
399.32 g/mol; IR (neat) νmax 3063, 3029, 2950, 2866, 1742, 1450, 1261,
1
1098, 738 cm−1; H NMR (500 MHz, CDCl3) δ 7.37−7.30 (m, 5H),
4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 4.15 (dd, J = 2.6 Hz,
11.4 Hz, 1H), 3.79 (s, 3H), 3.71 (ddd, J = 2.4 Hz, 4.5 Hz, 7.5 Hz, 1H),
3.36 (dd, J = 5.0 Hz, 9.3 Hz, 1H), 3.30 (dd, J = 5.3 Hz, 9.3 Hz, 1H),
2.31−2.23 (m, 1H), 2.02 (ddd, J = 2.9 Hz, 5.1 Hz, 9.5 Hz, 1H), 1.89 (s,
3H), 1.75−1.60 (m, 4H), 1.48 (dq, J = 4.6 Hz, 11.7 Hz, 1H), 0.99 (d, J =
6.7 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.6, 138.6, 128.4,
127.6, 127.5, 76.9, 73.9, 73.3, 73.2, 61.9, 53.1, 32.8, 26.1, 25.0, 22.5, 18.6,
14.4 ppm; MS (ESI-IT) m/z 399.1 (M + H+, 6), 421.1 (M + Na+, 100);
HRMS calcd for C19H28BrO4 [M + H+] 399.1165, found 399.1159
(−1.6 ppm); calcd for C19H27NaBrO4 [M + Na+] 421.0985, found
421.0977 (−1.8 ppm).
19b: Rf = 0.18 (hexanes/EtOAc, 80:20); formula C19H27BrO4; MW
399.32 g/mol; IR (neat) νmax 3062, 3026, 2949, 2865, 1738, 1450, 1263,
1110, 1054, 738 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.29 (m,
5H), 4.51 (d, J = 12.1 Hz, 1H), 4.47 (d, J = 12.1 Hz, 1H), 3.96 (dd, J = 2.5
Hz, 11.1 Hz, 1H), 3.82−3.78 (m, 1H), 3.80 (s, 3H), 3.39 (dd, J = 5.0 Hz,
9.3 Hz, 1H), 3.32 (dd, J = 5.3 Hz, 9.3 Hz, 1H), 2.34 (ddd, J = 5.2 Hz, 10.5
Hz, 11.8 Hz, 1H), 1.87 (s, 3H), 1.76−1.66 (m, 4H), 1.62−1.57 (m, 1H),
1.53−1.44 (m, 1H), 1.13 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 171.2, 138.6, 128.5, 127.6, 127.5, 77.4, 74.3, 73.5, 73.2, 65.5,
53.4, 32.5, 26.4, 26.0, 24.1, 18.5, 14.7 ppm; MS (ESI-IT) m/z 229.1 (6),
321.2 (7), 399.1 (M + H+, 100); HRMS calcd for C19H28BrO4 [M + H+]
399.1165, found 399.1173 (2.0 ppm).
( )-6-(2-(Benzyloxy)ethyl)tetrahydro-2H-pyran-2-yl acetate
(S44a, S44b).
Product S44a and S44b (593 mg, yield = 95%) were obtained as pale
yellow oils from lactone S4331 (525 mg) following general procedure A9
and purification by flash chromatography on silica gel (hexanes/EtOAc
1
( )-(S)-Methyl 2-((2S,6S)-6-((S)-1-(Benzyloxy)propan-2-yl)-
tetrahydro-2H-pyran-2-yl) propanoate (27a) and ( )-(R)-Meth-
yl 2-((2S,6S)-6-((S)-1-(Benzyloxy)propan-2-yl) tetrahydro-2H-
pyran-2-yl)propanoate (27b).
80:20 to 70:30). H NMR spectroscopic analysis of the unpurified
product indicated a pair of diastereomers in a 2:1 ratio of products
S44a:S44b.
S44a: Rf = 0.52 (hexanes/EtOAc, 70:30); formula C16H22O4; MW
278.34 g/mol; IR (neat) νmax 3063, 3030, 2945, 2863, 1751, 1234, 1038
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.39−7.28 (m, 5H), 5.67 (dd, J =
2.3 Hz, 9.7 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H),
3.77−3.71 (m, 1H), 3.65−3.54 (m, 2H), 2.12 (s, 3H), 1.95−1.85 (m,
2H), 1.85−1.77 (m, 2H), 1.64−1.56 (m, 2H), 1.54−1.43 (m, 1H),
1.32−1.21 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 169.2, 138.5,
128.3, 127.6, 127.4, 94.8, 74.2, 73.0, 66.5, 36.0, 30.3, 29.9, 21.6, 21.2
ppm; MS (ESI-IT) m/z 219.1 (42), 273.1 (24), 301.1 (M + Na+, 100),
378.3 (7), 477.3 (10); HRMS calcd for C16H22NaO4 [M + Na+]
301.1410, found 301.1419 (2.8 ppm).
Products 27a and product 27b (72 mg, yield = 75%) were obtained as
pale yellow oils from a mixture of bromides 19a and 19b (120 mg)
following general procedure A1 and purification by flash chromatog-
raphy on silica gel (hexanes/EtOAc 70:30). H NMR spectroscopic
analysis of the unpurified product indicated a pair of diastereomers in a
1
S44b: Rf = 0.44 (hexanes/EtOAc, 70:30); formula C16H22O4; MW
278.34 g/mol; 1H NMR (500 MHz, CDCl3) δ 7.36−7.26 (m, 5H), 6.13
(app s, 1H), 4.50 (d, J = 11.8 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.00 (dt,
J = 5.6 Hz, 11.4 Hz, 1H), 3.60−3.50 (m, 2H), 2.05 (s, 3H), 1.87−1.77
(m, 1H), 1.77−1.62 (m, 6H), 1.41−1.31 (m, 1H) ppm.
12:1 ratio of products 2,3-anti (27a):2,3-syn (27b).
27a: Rf = 0.46 (hexanes/EtOAc, 70:30); formula C19H28O4; MW
320.42 g/mol; IR (neat) νmax 3063, 3029, 2944, 2935, 2864, 1738, 1455,
1108, 1039, 737 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.29 (m,
5H), 4.52 (d, J = 12.1 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 3.84 (ddd, J =
Q
dx.doi.org/10.1021/jo400721e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
( )-Methyl 2-((2S,6S)-6-(2-(Benzyloxy)ethyl)tetrahydro-2H-
pyran-2-yl)-2-bromopropanoate (20a, 20b).
(ESI-IT) m/z 307.2 (M + H+, 36), 329.2 (M + Na+, 100), 635.4 (4);
HRMS calcd for C18H27O4 [M + H+] 307.1904, found 307.1901 (−0.9
ppm); calcd for C18H26NaO4 [M + Na+] 329.1723, found 329.1720
(−0.9 ppm).
(
)-(R)-2-((2S,6S)-6-(2-(Benzyloxy)ethyl)tetrahydro-2H-
pyran-2-yl)propyl (4-Bromophenyl)carbamate (S45).
Products 20a and 20b (744 mg, yield = 90%) were obtained as pale
yellow oils from a mixture of product S44a,b (597 mg) following general
procedure A10 and purification by flash chromatography on silica gel
(hexanes/EtOAc 85:15). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of 2,3-diastereomers in a ∼1:1
ratio of products 20a:20b.
A primary alcohol as a colorless oil was obtained from ester 28a (48 mg)
following general procedure A4. To a cold (0 °C) solution of crude
alcohol in dry CH2Cl2 (0.1 M, 1.0 mL) were added successively Et3N
(1.1 equiv, 14 μL) and p-bromophenyl isocyanate (1.1 equiv, 21 mg).
The reaction mixture was stirred for 3 h at 0 °C before the reaction
mixture was treated with a saturated aqueous solution of NaHCO3
followed by separation of the organic phase at room temperature. The
aqueous layer was extracted with EtOAc (3×), and combined organic
fractions were dried (MgSO4), filtered, and concentrated in vacuo. The
crude mixture was purified by flash chromatography on silica gel
(hexanes/EtOAc, 90:10 to 80:20) to afford product S45 as a white solid
(48 mg, yield = 64% over two steps), for which structural assignment
was confirmed by X-ray analysis (cf. Supporting Information, part III, X-
ray): Rf = 0.19 (hexanes/EtOAc, 80:20); formula C24H30BrNO4; MW
476.40 g/mol; IR (neat) νmax 3304, 3068, 2937, 2855, 1726, 1708, 1594,
20a: Rf = 0.54 (hexanes/EtOAc, 80:20); formula C18H25BrO4; MW
385.29 g/mol; IR (neat) νmax 3062, 3029, 3001, 2945, 2861, 1742, 1263,
1097, 1046 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.26 (m, 5H),
4.50 (d, J = 11.6 Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.14 (dd, J = 2.2 Hz,
11.5 Hz, 2H), 3.70 (s, 3H), 3.53−3.45 (m, 2H), 2.22−2.12 (m, 1H),
2.05−1.98 (m, 1H), 1.83 (s, 3H), 1.79−1.61 (m, 4H), 1.47−1.34 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.3, 138.5, 128.4, 127.53,
127.52, 73.09, 73.05, 71.2, 67.2, 61.3, 52.9, 30.4, 28.4, 25.2, 22.0, 18.5
ppm; MS (ESI-IT) m/z 385.1 (M + H+, 100); HRMS calcd for
C18H26BrO4 [M + H +] 385.1009, found 385.1005 (−0.9 ppm).
20b: Rf = 0.46 (hexanes/EtOAc, 80:20); formula C18H25BrO4; MW
385.29 g/mol; IR (neat) νmax 3062, 3031, 2946, 2866, 1738, 1267, 1112,
1053 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.26 (m, 5H), 4.50 (d,
J = 11.6 Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.14 (dd, J = 2.2 Hz, 11.5 Hz,
2H), 3.70 (s, 3H), 3.53−3.45 (m, 2H), 2.22−2.12 (m, 1H), 2.05−1.98
(m, 1H), 1.83 (s, 3H), 1.79−1.61 (m, 4H), 1.47−1.34 (m, 2H) ppm; 13C
NMR (125 MHz, CDCl3) δ 170.7, 138.4, 128.2, 127.5, 127.3, 73.5, 73.0,
70.7, 67.1, 64.8, 53.0, 30.1, 28.0, 26.4, 23.5, 18.2 ppm; MS (ESI-IT) m/z
385.1 (M + H+, 100); HRMS calcd for C18H26BrO4 [M + H+] 385.1009,
found 385.1003 (−1.6 ppm).
1
1530, 1400, 1307, 1220, 1077, 1042, 824, 733 cm−1; H NMR (500
MHz, CDCl3) δ 7.41−7.20 (m, 9H), 6.76 (s, 1H), 4.53 (d, J = 11.8 Hz,
1H), 4.46 (d, J = 11.8 Hz, 1H), 4.28 (dd, J = 4.2 Hz, 10.5 Hz, 1H), 4.10
(dd, J = 6.1 Hz, 10.5 Hz, 1H), 3.97−3.91 (m, 1H), 3.62 (ddd, J = 6.0 Hz,
8.2 Hz, 8.9 Hz, 1H), 3.57−3.49 (m, 2H), 2.21−2.11 (m, 1H), 1.96 (tdd,
J = 5.5 Hz, 9.5 Hz, 14.6 Hz, 1H), 1.72−1.60 (m, 5H), 1.52−1.44 (m,
1H), 1.38−1.30 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 153.5, 138.4, 137.2, 131.9, 128.3, 127.7, 127.5, 120.1,
115.6, 73.0, 72.8, 68.2, 67.7, 67.0, 34.5, 33.6, 30.3, 27.2, 18.6, 14.1 ppm;
MS (ESI-IT) m/z 476.1 (M + H+, 49), 498.1 (M + Na+, 100), 975.3
(20); HRMS calcd for C24H31O4NBr [M + H+] 476.1431, found
476.1434 (0.6 ppm); calcd for C24H30NaO4NBr [M + Na+] 498.1250,
found 498.1254 (0.7 ppm).
( )-(S)-Methyl 2-((2S,6S)-6-(2-(Benzyloxy)ethyl)tetrahydro-
2H-pyran-2-yl)propanoate (28a) and ( )-(R)-Methyl 2-((2S,6S)-
6-(2-(Benzyloxy)ethyl)tetrahydro-2H-pyran-2-yl)propanoate
(28b).
(
)-Methyl 7-(Benzyloxy)-5-((triethylsilyl)oxy)heptanoate
(S47).
Products 28a and product 28b (80 mg, yield = 82%) were obtained as
pale yellow oils from a mixture of bromides 20a and 20b (122 mg)
following general procedure A1 and purification by flash chromatog-
raphy on silica gel (hexanes/EtOAc 80:20 to 70:30). 1H NMR
spectroscopic analysis of the unpurified product indicated a pair of
diastereomers in a 14:1 ratio of products 2,3-anti (28a):2,3-syn (28b).
28a: Rf = 0.13 (hexanes/EtOAc, 80:20); formula C18H26O4; MW
306.40 g/mol; IR (neat) νmax 3056, 3029, 2942, 2860, 1738, 1203, 1162,
1102, 1040 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.26 (m, 5H),
4.51 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 11.9 Hz, 1H), 4.00 (dq, J = 9.3 Hz,
4.5 Hz, 1H), 3.77 (ddd, J = 3.4 Hz, 8.1 Hz, 9.8 Hz, 1H), 3.63 (s, 3H),
3.56−3.45 (m, 2H), 2.70 (dq, J = 9.4 Hz, 7.0 Hz, 1H), 2.10−2.01 (m,
1H), 1.76−1.66 (m, 2H), 1.66−1.58 (m, 3H), 1.40−1.32 (m, 2H), 1.07
(d, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.8, 138.6,
128.3, 127.6, 127.4, 73.1, 72.7, 69.2, 67.3, 51.5, 43.6, 32.5, 29.6, 27.2,
18.3, 13.7 ppm; MS (ESI-IT) m/z 307.2 (M + H+, 37), 329.2 (M + Na+,
100), 635.4 (8); HRMS calcd for C18H27O4 [M + H+] 307.1904, found
307.1909 (1.7 ppm); calcd for C18H26NaO4 [M + Na+] 329.1723, found
329.1730 (1.9 ppm).
Product S47 was obtained as a pale yellow oil from alcohol S4631 (1.50
g) following general procedure A3 and was used as crude without further
purification. A small quantity (∼100 mg) of crude product S47 was
purified by flash chromatography on silica gel (hexanes/EtOAc, 90:10 to
80:20) for characterization: Rf = 0.58 (hexanes/EtOAc, 80:20); formula
C21H36O4Si; MW 380.59 g/mol; IR (neat) νmax 3086, 3068, 3030, 2953,
1
2913, 2876, 1741, 1456, 1241, 1163, 1100, 1009, 738 cm−1; H NMR
(500 MHz, CDCl3) δ 7.36−7.26 (m, 5H), 4.51 (d, J = 11.9 Hz, 1H), 4.46
(d, J = 11.9 Hz, 1H), 3.86 (tt, J = 5.6 Hz, 5.7 Hz, 1H), 3.66 (s, 3H), 3.58−
3.49 (m, 2H), 2.30 (t, J = 7.5 Hz, 2H), 1.82−1.72 (m, 2H), 1.72−1.60
(m, 2H), 1.51−1.43 (m, 2H), 0.95 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.9 Hz,
6H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.0, 138.5, 128.3, 127.6,
127.5, 72.9, 69.0, 67.0, 51.4, 36.96, 36.87, 34.1, 20.6, 6.9, 5.0 ppm; MS
(ESI-IT) m/z 141.1 (65), 171.1 (22), 187.1 (42), 199.1 (75), 217.1
(100), 249.1 (79); HRMS calcd for C21H37O4Si [M + H+] 381.2456,
found 381.2450 (−1.4 ppm).
28b: Rf = 0.22 (hexanes/EtOAc, 80:20); formula C18H26O4; MW
( )-7-(Benzyloxy)-5-((triethylsilyl)oxy)heptan-1-ol (S48).
306.40 g/mol; IR (neat) νmax 3063, 3030, 2940, 2864, 1736, 1455, 1258,
1
1201, 1166, 1106, 1038, 738 cm−1; H NMR (500 MHz, CDCl3) δ
7.37−7.26 (m, 5H), 4.51 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H),
3.82 (ddd, J = 3.5 Hz, 7.2 Hz, 12.5 Hz, 2H), 3.66 (s, 3H), 3.61−3.50 (m,
2H), 2.80 (dq, J = 6.9 Hz, 8.6 Hz, 1H), 1.95 (dq, J = 5.3 Hz, 10.2 Hz,
1H), 1.73−1.59 (m, 5H), 1.41−1.30 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 175.6, 138.4, 128.3, 127.7, 127.5,
73.1, 72.4, 68.0, 66.9, 51.6, 42.0, 33.6, 30.1, 28.1, 18.6, 13.5 ppm; MS
Product S48 was obtained as a colorless oil from crude ester S47
following general procedure A4 and was used as crude without further
purification. A small quantity (∼100 mg) of crude product S48 was
purified by flash chromatography on silica gel (hexanes/EtOAc, 80:20)
for characterization: Rf = 0.30 (hexanes/EtOAc, 80:20); formula
R
dx.doi.org/10.1021/jo400721e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C20H36O3Si; MW 352.58 g/mol; IR (neat) νmax 3392, 3056, 3031, 2950,
( )-Methyl 2-((2S,6R)-6-(2-(Benzyloxy)ethyl)tetrahydro-2H-
pyran-2-yl)-2-bromopropanoate (21a).
1
2914, 2875, 1456, 1414, 1371, 1238, 1100, 1060, 1008, 734 cm−1; H
NMR (500 MHz, CDCl3) δ 7.37−7.27 (m, 5H), 4.51 (d, J = 11.9 Hz,
1H), 4.46 (d, J = 11.9 Hz, 1H), 3.85 (tt, J = 5.6 Hz, 5.8 Hz, 1H), 3.63 (dd,
J = 6.2 Hz, 11.3 Hz, 2H), 3.58−3.50 (m, 2H), 1.82−1.68 (m, 2H), 1.59−
1.51 (m, 1H), 1.51−1.44 (m, 2H), 1.44−1.35 (m, 2H), 1.26−1.20 (m,
1H), 0.95 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.9 Hz, 6H) ppm; OH signal
missing possibly due to exchange in CDCl3; 13C NMR (100 MHz, CDCl3)
δ 138.4, 128.3, 127.6, 127.5, 72.9, 69.4, 67.1, 62.8, 37.3, 37.0, 32.8, 21.3,
6.9, 5.0 ppm; MS (ESI-IT) m/z 221.2 (26), 239.2 (23), 353.3 (M + H+,
100), 467.3 (17); HRMS calcd for C20H37O3Si [M + H+] 353.2506,
found 353.2505 (−0.4 ppm).
To a cold (−78 °C) solution of ketone S50a (98 mg) in dry CH2Cl2 (0.1
M, 1.9 mL) was added dropwise a solution of BiBr3 (1 equiv, 87 mg) in
dry MeCN (0.5 M, 0.4 mL), followed by Et3SiH (2.0 equiv, 62 μL). The
mixture was stirred for 0.5 h at −78 °C, followed by warming to room
temperature and stirring for 18 h. The reaction mixture was treated with
a saturated aqueous solution of NH4Cl followed by separation of the
organic phase. The aqueous layer was extracted with CH2Cl2 (3×), and
combined organic fractions were dried (MgSO4), filtered, and
concentrated in vacuo. The crude mixture was purified by flash
chromatography on silica gel (hexanes/EtOAc 95:5 to 80:20) to yield
product 21a as a pale yellow oil (16 mg, 22%). 1H NMR spectroscopic
analysis of the unpurified product indicated the sole formation (>20:1)
of one diastereoisomer product (21a): Rf = 0.38 (hexanes/EtOAc,
80:20); formula C18H25O4Br; MW 385.29 g/mol; IR (neat) νmax 3030,
( )-7-(Benzyloxy)-5-((triethylsilyl)oxy)heptanal (S49).
Product S49 (1.10 g, yield = 51% over three steps) was obtained as a pale
yellow oil from crude alcohol S48 (0.73 g) following general procedure
A14 and purification by flash chromatography on silica gel (hexanes/
EtOAc 95:5 to 85:15): Rf = 0.50 (hexanes/EtOAc, 60:40); formula
C20H34O3Si; MW 350.57 g/mol; IR (neat) νmax 3064, 3031, 2953, 2913,
1
2876, 2717, 1726, 1456, 1413, 1375, 1239, 1101, 1008, 738 cm−1; H
NMR (500 MHz, CDCl3) δ 9.75 (t, J = 1.5 Hz, 1H), 7.37−7.26 (m, 5H),
4.51 (d, J = 11.9 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 3.87 (tt, J = 5.7 Hz,
5.8 Hz, 1H), 3.58−3.49 (m, 2H), 2.41 (dt, J = 1.4 Hz, 7.3 Hz, 2H), 1.81−
1.72 (m, 2H), 1.73−1.60 (m, 2H), 1.53−1.40 (m, 2H), 0.95 (t, J = 7.9
Hz, 9H), 0.59 (q, J = 7.9 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ
202.8, 138.7, 128.6, 127.9, 127.8, 73.2, 69.3, 67.2, 44.2, 37.3, 37.1, 18.0,
7.2, 5.3 ppm; MS (ESI-IT) m/z 127.1 (40), 217.1 (48), 235.1 (37),
259.2 (10), 349.2 (M − H+, 100), 363.2 (13); HRMS calcd for
C20H33O3Si [M − H+] 349.2204, found 349.2199 (1.6 ppm).
2943, 2860, 1743, 1449, 1264, 1098, 1055, 738 cm−1; H NMR (500
1
MHz, CDCl3) δ 7.37−7.26 (m, 5H), 4.47 (d, J = 12.3 Hz, 1H), 4.45 (d, J
= 12.3 Hz, 1H), 3.93 (dd, J = 1.5 Hz, 11.3 Hz, 1H), 3.71 (s, 3H), 3.56−
3.49 (m, 1H), 3.47 (t, J = 6.4 Hz, 2H), 2.00 (app d, J = 12.7 Hz, 1H),
1.96−1.89 (m, 1H), 1.82 (s, 3H), 1.74−1.66 (m, 2H), 1.62−1.53 (m,
2H), 1.33 (dq, J = 3.9 Hz, 12.7 Hz, 1H), 1.19 (dq, J = 4.2 Hz, 13.3 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.4, 138.5, 128.4, 127.6,
127.5, 81.1, 77.2, 75.7, 73.1, 66.8, 60.3, 36.3, 31.4, 24.8, 23.4, 22.1 ppm;
MS (ESI-IT) m/z 385.1 (M + H+, 13), 387.1 (13), 407.1 (M + Na+,
100), 409.1 (97); HRMS calcd for C18H26O4Br [M + H+] 385.1009,
found 385.1009 (0.07 ppm); calcd for C18H25O4BrNa [M + Na+]
(
)-Methyl 9-(Benzyloxy)-2-bromo-2-methyl-3-oxo-7-
((triethylsilyl)oxy)nonanoate (S50a).
407.0828, found 407.0829 (0.02 ppm).
( )-(S)-Methyl 2-((2S,6R)-6-(2-(Benzyloxy)ethyl)tetrahydro-
2H-pyran-2-yl)propanoate (29a).
To a cold (−40 °C) solution of aldehyde S49 (400 mg) in dry CH2Cl2
(0.1 M, 11.5 mL) were added successively silylated enol ether 2 (2.5
equiv, 526 μL) and MgBr2·OEt2 (7.0 equiv, 2.06 g). The reaction
mixture was stirred for 1 h at −40 °C before treatment with a saturated
aqueous solution of NH4Cl and separation of the organic phase at room
temperature. The aqueous layer was extracted with CH2Cl2 (3×), and
combined organic fractions were dried (MgSO4), filtered, and
concentrated in vacuo. The crude mixture was purified by flash
chromatography on silica gel (hexanes/EtOAc, 85:15) to afford an
inseparable mixture of bromide adducts as a colorless oil. Product S50a
(535 mg, 91%) was obtained as a pale yellow oil from the mixture of
bromide adducts following general procedure A5 and purification by
Product 29a (80 mg, yield = 83%) was obtained as a yellow oil from
bromide 21a (121 mg) following to general procedure A1 with Bu3SnH
instead of Ph3SnH and purification by flash chromatography on silica gel
(hexanes/EtOAc 95:5). 1H NMR spectroscopic analysis of the
unpurified product indicated the sole formation (>20:1) of 2,3-anti
product (29a): Rf = 0.32 (hexanes/EtOAc, 80:20); formula C18H26O4;
MW 306.40 g/mol; IR (neat) νmax 3026, 2941, 2857, 1739, 1456, 1360,
1198, 1090, 738 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.39−7.24 (m,
5H), 4.50 (d, J = 11.9 Hz, 1H), 4.45 (d, J = 11.9 Hz, 1H), 3.62 (s, 3H),
3.52 (t, J = 6.5 Hz, 2H), 3.45 (ddd, J = 1.7 Hz, 8.9 Hz, 10.9 Hz, 2H), 2.50
(dq, J = 14.2, 7.1 Hz, 1H), 1.89−1.81 (m, 1H), 1.75−1.64 (m, 3H),
1.57−1.45 (m, 2H), 1.27−1.12 (m, 2H), 1.09 (d, J = 7.0 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 175.8, 138.6, 128.3, 127.6, 127.5, 79.5,
75.0, 73.1, 67.0, 51.4, 45.8, 36.5, 31.5, 28.3, 23.4, 13.1 ppm; MS (ESI-IT)
m/z 307.2 (M + H+, 14), 329.2 (M + Na+, 100); HRMS calcd for
C18H27O4 [M + H+] 307.1904, found 307.1898 (−2.0 ppm); calcd for
C18H26O4Na [M + Na+] 329.1723, found 329.1714 (−2.8 ppm).
1
flash chromatography on silica gel (hexanes/EtOAc 95:5). H NMR
spectroscopic analysis of the unpurified product indicated the sole
formation (>20:1) of one diastereoisomer product (S50a): Rf = 0.35
(hexanes/EtOAc, 80:20); formula C24H39O5BrSi; MW 515.55 g/mol;
IR (neat) νmax 3064, 3030, 2953, 2913, 2876, 1753, 1728, 1453, 1375,
1245, 1118, 1009, 739 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.27
(m, 5H), 4.51 (d, J = 11.9 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 3.87 (tt, J =
5.8 Hz, 5.9 Hz, 1H), 3.80 (s, 3H), 3.58−3.49 (m, 2H), 2.89−2.78 (m,
1H), 2.75−2.64 (m, 1H), 1.98 (s, 3H), 1.82−1.62 (m, 4H), 1.52−1.39
(m, 2H), 0.95 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.8 Hz, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 200.5, 168.9, 138.5, 128.3, 127.6, 127.5,
73.0, 69.2, 67.0, 62.5, 53.8, 38.1, 37.0, 36.6, 25.5, 20.2, 6.9, 5.0 ppm; MS
(ESI-IT) m/z 181.1 (9), 383.1 (16), 423.1 (100), 515.2 (M + H+, 5),
517.2 (5), 537.2 (M + Na+, 20), 539.2 (20), 825.2 (16); HRMS calcd for
C24H40O5BrSi [M + H+] 515.1823, found 515.1830 (1.3 ppm); calcd for
C24H39O5BrNaSi [M + Na+] 537.1642, found 537.1653 (2.0 ppm).
S
dx.doi.org/10.1021/jo400721e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
( − ) - ( 4 S , 5 R , 6 S ) - 7 - ( B e n z y l o x y ) - 4 , 6 - d i m e t h y l - 5 -
(triethylsilyloxy)heptan-1-ol (S57).
Product S56 was obtained as a colorless oil from α,β-unsaturated ester
S55 (860 mg) following general procedure A2 and was used as crude
without further purification. Primary alcohol S57 (702 mg, yield = 88%
over two steps) was obtained as a colorless oil from crude ester S56
following general procedure A4 and purification by flash chromatog-
raphy on silica gel (hexanes/EtOAc 80:20): Rf = 0.25 (hexanes/EtOAc,
80:20); [α]25D −13.8 (c 1.1, CHCl3); formula C22H40O3Si; MW 380.64
g/mol; IR (neat) νmax 3357, 2956, 2876, 1456, 1100, 1062, 1009, 735
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−7.26 (m, 5H), 4.51 (d, J =
12.0 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 3.61 (app t, J = 6.3 Hz, 1H), 3.55
(dd, J = 4.4 Hz, 8.9 Hz, 1H), 3.47 (dd, J = 3.4 Hz, 6.5 Hz, 1H), 3.29 (dd, J
= 7.3 Hz, 9.0 Hz, 1H), 1.97−1.90 (m, 1H), 1.64−1.56 (m, 1H), 1.54−
1.47 (m, 1H), 1.46−1.37 (m, 2H), 1.31−1.25 (m, 1H), 1.24−1.14 (m,
1H), 0.95 (d, J = 6.9 Hz, 3H), 0.94 (t, J = 6.9 Hz, 9H), 0.85 (d, J = 6.8 Hz,
3H), 0.58 (q, J = 7.9 Hz, 6H) ppm; OH signal missing possibly due to
exchange in CDCl3; 13C NMR (100 MHz, CDCl3) δ 139.0, 128.5, 127.8,
127.6, 78.4, 73.3, 73.2, 63.3, 37.8, 36.2, 31.1, 30.5, 15.6, 14.3, 7.4, 5.7
ppm; MS (ESI-IT) m/z 403.3 (M + Na+, 72), 289.2 (100); HRMS calcd
for C22H40O3NaSi [M + Na]+ 403.2644, found 403.2648 (0.9 ppm).
( − ) - ( 2 S , 3 R , 4 S ) - 5 - ( B e n z y l o x y ) - 2 , 4 - d i m e t h y l - 3 -
(triethylsilyloxy)pentan-1-ol (S53).
Product S52 was obtained as a pale yellow oil from alcohol S406a (509
mg) following general procedure A3 and was used as crude without
further purification. Product S53 (656 mg, yield = 97% over two steps)
was obtained as a colorless oil from crude ester S52 following general
procedure A4 and purification by flash chromatography on silica gel
(
) - ( 4 S , 5 R , 6 S ) - 7 - ( B e n z y l o x y ) - 4 , 6 - d i m e t h y l - 5 -
(triethylsilyloxy)heptanal (S58).
(hexanes/EtOAc 90:10): Rf = 0.20 (hexanes/EtOAc, 90:10); [α]25
D
−7.4 (c 1.2, CHCl3); formula C20H36O3Si; MW 352.58 g/mol; IR (neat)
Aldehyde S58 (500 mg, yield = 88%) was obtained as a colorless oil from
alcohol S57 (573 mg) following general procedure A5 and purification
by flash chromatography on silica gel (hexanes/EtOAc 85:15): Rf = 0.38
(hexanes/EtOAc, 85:15); formula C22H38O3Si; MW 378.62 g/mol; IR
1
νmax 3412, 3031, 2957, 1456 cm−1; H NMR (500 MHz, CDCl3) δ
7.36−7.26 (m, 5H), 4.52 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H),
3.74 (dd, J = 3.2 Hz, 6.3 Hz, 1H), 3.59−3.54 (m, 2H), 3.50 (dd, J = 5.6
Hz, 10.5 Hz, 1H), 3.33 (dd, J = 6.9 Hz, 9.0 Hz, 1H), 2.07−1.97 (m, 1H),
1.93−1.83 (m, 1H), 0.97 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.9 Hz, 9H),
0.86 (d, J = 6.8 Hz, 3H), 0.60 (q, J = 7.9 Hz, 6H) ppm; OH signal missing
possibly due to exchange in CDCl3; 13C NMR (100 MHz, CDCl3) δ 138.6,
128.4, 127.7, 127.6, 75.2, 73.2, 73.0, 66.2, 38.9, 37.6, 15.2, 11.6, 7.1, 5.4
ppm; MS (ESI-IT) m/z 261.1 (M − TES+Na+, 100), 239.1 (65);
HRMS calcd for C14H22O3Na [M + TES+Na+] 261.1467, found
261.1467 (−1.0 ppm).
1
(neat) νmax 3056, 2958, 2877, 1726, 1455, 1095, 1068, 734 cm−1; H
NMR (500 MHz, CDCl3) δ 9.77 (t, J = 1.8 Hz, 1H), 7.36−7.26 (m, 5H),
4.53 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.55 (dd, J = 4.6 Hz,
8.9 Hz, 1H), 3.54 (dd, J = 2.9 Hz, 6.3 Hz, 1H), 3.34 (dd, J = 7.1 Hz, 9.0
Hz, 1H), 2.52−2.26 (m, 2H), 1.99−1.90 (m, 1H), 1.77−1.70 (m, 1H),
1.64−1.56 (m, 1H), 1.54−1.46 (m, 1H), 0.97 (d, J = 7.3 Hz, 3H), 0.96
(t, J = 7.9 Hz, 9H), 0.87 (d, J = 6.7 Hz, 3H), 0.61 (q, J = 7.9 Hz, 6H)
ppm; 13C NMR (100 MHz, CDCl3) δ 202.9, 138.9, 128.5, 127.8, 127.7,
77.9, 73.3, 73.1, 42.5, 38.0, 36.0, 27.0, 15.3, 13.9, 7.4, 5.7 ppm.
(−)-(4S,5R,6S,E)-Methyl 7-(Benzyloxy)-4,6-dimethyl-5-
(triethylsilyloxy)hept-2-enoate (S55).
(
)-(6S,7R,8S,E)-Ethyl 9-(Benzyloxy)-2,6,8-trimethyl-7-
(triethylsilyloxy)non-2-enoate (S59).
Aldehyde S54 was obtained as a pale yellow oil from alcohol S53 (1.00
g) following general procedure A11 and was used as crude without
further purification. Product S55 (1.05 g, yield = 91% over two steps)
was obtained as a colorless oil from crude aldehyde S54 following
general procedure A6 and purification by flash chromatography on silica
To a solution of crude aldehyde S58 (37 mg) in dry CH2Cl2 (0.1 M, 1.05
mL) was added ethyl 2-(triphenylphosphoranylidene)propanoate (1.5
equiv, 57 mg), and the resulting solution was heated to reflux overnight.
The mixture was cooled to room temperature and then concentrated in
vacuo. The crude mixture was purified by flash chromatography on silica
gel (hexanes/EtOAc, 90:10) to afford (E)-α,β-unsaturated ester S59 as a
colorless oil (40 mg, yield =82% over two steps): Rf = 0.42 (hexanes/
EtOAc, 80:20); formula C27H46O4Si; MW 462.73 g/mol; IR (neat) νmax
gel (hexanes/EtOAc 90:10): Rf = 0.39 (hexanes/EtOAc, 90:10); [α]25
D
−16.8 (c 1.2, CHCl3); formula C23H38O4Si; MW 406.63 g/mol; IR
1
(neat) νmax 3031, 2956, 2877, 1726, 1456, 1097, 1011, 735 cm−1; H
NMR (500 MHz, CDCl3) δ 7.35−7.25 (m, 5H), 6.96 (dd, J = 7.9 Hz,
15.8 Hz, 1H), 5.80 (dd, J = 1.2 Hz, 15.8 Hz, 1H), 4.48 (d, J = 12.0 Hz,
1H), 4.45 (d, J = 12.1 Hz, 1H), 3.73 (s, 3H), 3.62 (t, J = 5.4 Hz, 1H), 3.51
(dd, J = 4.8 Hz, 9.1 Hz, 1H), 3.30 (dd, J = 7.2 Hz, 9.1 Hz, 1H), 2.59−2.49
(m, 1H), 1.97−1.88 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 7.0
Hz, 3H), 0.93 (t, J = 7.9 Hz, 9H), 0.58 (q, J = 7.9 Hz, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 167.3, 153.1, 138.8, 128.5, 127.7, 127.6,
120.5, 77.6, 73.2, 72.3, 51.7, 40.7, 38.2, 15.2, 14.6, 7.3, 5.5 ppm; MS (ESI-
IT) m/z 293.2 (33), 315.2 (100), 407.3 (M + H+, 15), 429.3 (M + Na+,
60), 585.4 (23); HRMS calcd for C23H39O4Si [M + H]+ 407.2618, found
407.2633 (3.8 ppm).
1
3030, 2958, 2877, 1712, 1456, 1267, 1098, 737 cm−1; H NMR (500
MHz, CDCl3) δ 7.37−7.27 (m, 5H), 6.75 (dt, J = 1.1 Hz, 7.5 Hz, 1H),
4.52 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.21 (q, J = 7.1 Hz,
2H), 3.56 (dd, J = 4.2 Hz, 8.9 Hz, 1H), 3.52 (dd, J = 3.1 Hz, 6.7 Hz, 1H),
3.33 (dd, J = 7.5 Hz, 8.8 Hz, 1H), 2.26−2.10 (m, 2H), 1.98−1.89 (m,
1H), 1.84 (s, 3H), 1.66−1.58 (m, 1H), 1.55−1.49 (m, 1H), 1.35−1.28
(m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.96 (t, J = 7.9
Hz, 9H), 0.88 (d, J = 6.8 Hz, 3H), 0.59 (q, J = 7.9 Hz, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 168.5, 142.5, 139.0, 128.5, 128.0, 127.8,
127.6, 78.0, 73.3, 73.2, 60.6, 38.0, 36.3, 33.4, 27.1, 15.5, 14.5, 14.1, 12.6,
7.4, 5.8 ppm; MS (ESI-IT) m/z 193.8 (3), 285.2 (3), 331.2 (10), 349.2
T
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(24), 371.2 (50), 448.3 (17), 463.3 (M + H+, 56), 485.3 (M + Na+, 100),
499.3 (6), 562.4 (20); HRMS calcd for C27H47O4Si [M + H+] 463.3238,
found 463.3234 (−1.0 ppm); calcd for C27H46NaO4Si [M + Na+]
485.3063, found 485.3051 (−1.4 ppm).
(
)-(R)-2-((2S,5S,6R)-6-((S)-1-(Benzyloxy)propan-2-yl)-5-
methyltetrahydro-2H-pyran-2-yl)propyl 4-bromophenylcarba-
mate (S60).
(
)-Ethyl 2-((2S,5S,6R)-6-((S)-1-(Benzyloxy)propan-2-yl)-5-
methyltetrahydro-2H-pyran-2-yl)-2-iodopropanoate (22a,b).
Primary alcohol as a colorless oil was obtained from ester 30a (13 mg)
following general procedure A4. To a cold (0 °C) solution of crude
alcohol in dry CH2Cl2 (0.1 M, 0.4 mL) were added successively Et3N
(1.1 equiv, 6 μL) and p-bromophenyl isocyanate (1.1 equiv, 8 mg). The
reaction mixture was stirred for 3 h at 0 °C before the reaction mixture
was treated with a saturated aqueous solution of NaHCO3 and
separation of the organic phase at room temperature. The aqueous layer
was extracted with EtOAc (3×), and the combined organic fractions
were dried (MgSO4), filtered, and concentrated in vacuo. The crude
mixture was purified by flash chromatography on silica gel (hexanes/
EtOAc, 90:10) to afford product S60 as a white solid (14 mg, yield =
76% over two steps), for which structural assignment was confirmed by
X-ray analysis (cf. Supporting Information, part III, X-ray): Rf = 0.53
(hexanes/EtOAc, 80:20); formula C26H34BrNO4; MW 504.46 g/mol;
IR (neat) νmax 3319, 2965, 2926, 2855, 1707, 1595, 1532, 1491, 1399,
To a solution at room temperature of product S59 (40 mg) in dry
MeCN (0.1 M, 0.86 mL) was added I2 (2.9 equiv, 66 mg). The reaction
mixture was stirred for 5 h at room temperature before addition of
AgOTf (1.4 equiv, 33 mg) and stirring overnight at room temperature.
The reaction mixture was diluted with EtOAc and then treated with a
saturated aqueous solution of Na2S2O3. The resulting mixture was
stirred for 1 h at room temperature before separation of the organic
phase. The aqueous layer was extracted with Et2O (3×), and the
combined organic fractions were dried (MgSO4), filtered, and
concentrated in vacuo. 1H NMR spectroscopic analysis of the unpurified
product indicated a pair of diastereomers in a 6:1 mixture of 3,7-cis
(22a,b):3,7-trans products. The two diastereoisomers were separated by
flash chromatography on silica gel (hexanes/EtOAc, 95:5) to afford an
inseparable mixture of 2,3-iodides 22a,b as a colorless oil (22 mg, yield =
54%).
1
1307, 1221, 1075, 1059, 825, 735, 697 cm−1; H NMR (500 MHz,
CDCl3) δ 7.43−7.21 (m, 9H), 6.52 (bs, 1H), 4.51 (d, J = 12.0 Hz, 1H),
4.47 (d, J = 12.0 Hz, 1H), 4.31 (dd, J = 4.0 Hz, 10.4 Hz, 1H), 4.17 (dd, J =
6.4 Hz, 10.4 Hz, 1H), 3.62 (dd, J = 2.8 Hz, 8.7 Hz, 1H), 3.49 (dd, J = 6.4
Hz, 8.6 Hz, 1H), 3.22 (dd, J = 1.3 Hz, 10.2 Hz, 1H), 3.16 (dd, J = 7.5 Hz,
13.9 Hz, 1H), 1.93−1.85 (m, 1H), 1.84−1.76 (m, 2H), 1.76−1.69 (m,
2H), 1.48−1.42 (m, 2H), 0.97 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 7.2 Hz,
3H), 0.93 (d, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
153.8, 139.4, 137.4, 132.2, 128.5, 127.6, 127.5, 120.3, 115.9, 81.2, 79.7,
73.3, 73.1, 67.6, 38.8, 36.3, 31.5, 28.1, 24.1, 13.8, 13.5, 11.5 ppm; MS
(ESI-IT) m/z 360.3 (7), 504.2 (15, M + H+), 528.2 (100), 865.5 (8),
1031.3 (24); HRMS calcd for C26H35BrNO4 [M + H+] 504.1544, found
504.1734 (−2.0 ppm); calcd for C26H34BrNO4Na [M + Na+] 526.1563,
found 526.1550 (−2.5 ppm).
22a: Rf = 0.25 (hexanes/EtOAc, 80:20); formula C21H31IO4; MW
474.37 g/mol; IR (neat) νmax 3062, 3026, 2964, 2857, 1732, 1453, 1253,
1094, 1055, 736 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.26 (m,
5H), 4.49 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.21 (dq, J =
10.7 Hz, 7.1 Hz, 1H), 4.05 (dq, J = 10.7 Hz, 7.1 Hz, 1H), 3.88 (dd, J = 2.0
Hz, 11.6 Hz, 1H), 3.55 (dd, J = 3.2 Hz, 8.8 Hz, 1H), 3.22−3.16 (m, 2H),
2.05 (s, 3H), 1.98−1.93 (m, 1H), 1.86−1.75 (m, 3H), 1.74−1.67 (m,
1H), 1.66−1.56 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.7 Hz,
3H), 0.91 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
172.5, 139.1, 128.5, 127.65, 127.59, 82.8, 82.3, 73.3, 73.2, 62.0, 42.6,
35.9, 31.5, 27.7, 24.9, 21.2, 14.0, 13.3, 11.5 ppm; MS (ESI-IT) m/z 365.2
(5), 387.2 (10), 403.2 (16), 442.3 (14), 475.1 (M + H+, 67), 497.1 (M +
Na+, 100), 536.2 (4), 749.4 (5); HRMS calcd for C21H32IO4 [M + H+]
475.1334, found 475.1334 (−1.2 ppm); calcd for C21H31INaO4 [M +
Na+] 497.1151, found 497.1151 (−1.7 ppm).
( )-Methyl 2-((2R,5S,6R)-6-((S)-1-(Benzyloxy)propan-2-yl)-5-
methyltetrahydro-2H-pyran-2-yl)-2-bromopropanoate (31a,
31b).
( )-(S)-Ethyl 2-((2S,5S,6R)-6-((S)-1-(Benzyloxy)propan-2-yl)-
5-methyltetrahydro-2H-pyran-2-yl)propanoate (30a).
Products 31a and 31b (32 mg, yield = 73%) were obtained as pale yellow
oils from aldehyde S58 (40 mg) following general procedure A7 and
purification by flash chromatography on silica gel (hexanes/EtOAc 95:5
1
to 90:10). H NMR spectroscopic analysis of the unpurified product
indicated a pair of 2,3-diastereomers in a ∼1:1 ratio of products 31a:31b.
31a: Rf = 0.56 (hexanes/EtOAc, 90:10); formula C20H29BrO4; MW
413.35 g/mol; IR (neat) νmax 2953, 2861, 1736, 1455 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.39−7.26 (m, 5H), 4.55 (d, J = 11.9 Hz, 1H), 4.45
(d, J = 11.9 Hz, 1H), 4.33 (dd, J = 4.8 Hz, 10.4 Hz, 1H), 3.78 (s, 3H),
3.67 (dd, J = 3.7 Hz, 9.9 Hz, 1H), 3.53 (dd, J = 3.1 Hz, 8.7 Hz, 1H), 3.41
(dd, J = 6.3 Hz, 8.7 Hz, 1H), 2.10−2.02 (m, 1H), 1.97−1.89 (m, 2H),
1.91 (s, 3H), 1.88−1.76 (m, 2H), 1.36−1.26 (m, 1H), 0.95 (d, J = 6.8
Hz, 3H), 0.94 (d, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
171.7, 139.1, 128.5, 127.8, 127.6, 77.1, 75.3, 73.2, 72.5, 62.9, 53.3, 35.1,
29.0, 27.9, 23.1, 20.5, 15.7, 14.2 ppm; MS (ESI-IT) m/z 413.1 (M + H+,
87), 416.1 (22), 432.2 (23), 435.1 (M + Na+, 100), 438.1 (25); HRMS
calcd for C20H30BrO4 [M + H+] 413.1327, found 413.1324 (0.4 ppm);
calcd for C20H29O4BrNa [M + Na+] 435.1141, found 435.1142 (0.08
ppm).
Product 30a (13 mg, yield = 87%) was obtained as a colorless oil from a
mixture of iodides 22a,b (20 mg) following general procedure A1 and
purification by flash chromatography on silica gel (hexanes/EtOAc
70:30). 1H NMR spectroscopic analysis of the unpurified product
indicated exclusively (>20:1) product 2,3-anti (30a): Rf = 0.15
(hexanes/EtOAc, 80:20); formula C21H32O4; MW 348.48 g/mol; IR
(neat) νmax 3062, 3026, 2970, 2856, 1735, 1454, 1176, 1067, 736 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.36−7.25 (m, 5H), 4.50 (d, J = 12.1 Hz,
1H), 4.47 (d, J = 12.0 Hz, 1H), 4.14−4.04 (m, 2H), 3.62 (dd, J = 3.2 Hz,
8.9 Hz, 1H), 3.46 (ddd, J = 3.5 Hz, 8.9 Hz, 12.1 Hz, 1H), 3.31 (dd, J = 7.7
Hz, 8.6 Hz, 1H), 3.16 (dd, J = 1.9 Hz, 10.2 Hz, 1H), 2.53−2.45 (m, 1H),
1.87−1.76 (m, 2H), 1.75−1.69 (m, 2H), 1.52−1.36 (m, 2H), 1.25 (t, J =
7.1 Hz, 3H), 1.10 (d, J = 7.1 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.92 (d, J
= 6.7 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.6, 139.4, 128.5,
127.7, 127.5, 81.5, 80.3, 73.32, 73.29, 60.4, 46.1, 36.0, 31.3, 28.1, 23.4,
14.6, 13.4, 13.3, 11.5 ppm; MS (ESI-IT) m/z 349.2 (M + H+, 45), 371.2
(M + Na+, 100), 372.2 (22), 448.3 (6); HRMS calcd for C21H33O4 [M +
H+] 349.2366, found 349.2366 (−2.0 ppm); calcd for C21H32NaO4 [M
+ Na+] 371.2182, found 371.2182 (−2.8 ppm).
31b: Rf = 0.46 (hexanes/EtOAc, 90:10); formula C20H29BrO4; MW
413.35 g/mol; IR (neat) νmax 2928, 2867, 1736, 1455, 1165, 741 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.39−7.26 (m, 5H), 4.57 (d, J = 11.9 Hz,
1H), 4.52 (d, J = 12.0 Hz, 1H), 4.13 (dd, J = 4.5 Hz, 10.6 Hz, 1H), 3.76
(s, 3H), 3.74−3.70 (m, 2H), 3.51 (dd, J = 7.2 Hz, 8.9 Hz, 1H), 2.09−
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1.92 (m, 3H), 1.86 (s, 3H), 1.78−1.69 (m, 1H), 1.67−1.60 (m, 1H),
1.37−1.26 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 171.3, 139.1, 128.5, 127.8, 127.6,
77.4, 76.2, 73.3, 73.0, 66.1, 53.4, 34.5, 30.2, 27.6, 24.5, 22.8, 16.5, 14.7;
MS (ESI-IT) m/z 413.1 (98), 415.1 (100), 427.1 (27), 430.2 (10), 432.2
(11), 435.1 (58), 438.1 (16); HRMS calcd for C20H30BrO4 [M + H+]
413.1327, found 413.1313 (−2.3 ppm); calcd for C20H29O4BrNa [M +
Na+] 435.1141, found 435.1136 (−1.1 ppm).
( )-(R)-Methyl 2-((2R,5S,6R)-6-((S)-1-(Benzyloxy)propan-2-
yl)-5-methyltetrahydro-2H-pyran-2-yl)propanoate (34a) and
( )-(S)-Methyl 2-((2R,5S,6R)-6-((S)-1-(Benzyloxy)propan-2-yl)-
5-methyltetrahydro-2H-pyran-2-yl)propanoate (34b).
To a cold (0 °C) solution of alcohol 106a (6.89 g) in dry CH2Cl2 (0.1 M,
166 mL) were added successively 2,6-lutidine (1.2 equiv, 2.3 mL) and
TESOTf (1.1 equiv, 4.1 mL). The reaction mixture was stirred for 1.5 h
at 0 °C or until alcohol was completely consumed, as verified by TLC
(hexanes/EtOAc, 85:15). The reaction mixture was then treated with a
saturated aqueous solution of NH4Cl, followed by separation of the
organic phase at room temperature. The aqueous layer was extracted
with CH2Cl2 (3×), and combined organic fractions were dried
(MgSO4), filtered, and concentrated in vacuo. The crude mixture was
purified by flash chromatography on silica gel (hexanes/EtOAc, 95:5) to
afford protected alcohol S1 as a colorless oil (8.00 g, yield = 91%): Rf =
0.75 (hexanes/EtOAc, 85:15); formula C30H48O4Si2; MW 528.87 g/
mol; IR (neat) νmax 3071, 3050, 2955, 2878, 1739, 1590, 1461, 1429,
1388, 1363, 1246, 1195, 1140, 1110, 1057, 1010, 941, 822, 739, 704, 614
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.68−7.62 (m, 4H), 7.46−7.34
(m, 6H), 4.19 (dd, J = 4.0 Hz, 6.4 Hz, 1H), 3.66 (s, 3H), 3.54 (dd, J = 7.0
Hz, 10.1 Hz, 1H), 3.44 (dd, J = 5.9 Hz, 10.1 Hz, 1H), 2.69−2.59 (m,
1H), 1.76−1.67 (m, 1H), 1.15 (d, J = 7.0 Hz, 3H), 1.06 (s, 9H), 0.93 (t, J
= 7.9 Hz, 9H), 0.86 (d, J = 6.9 Hz, 3H), 0.61−0.54 (m, 6H) ppm; 13C
NMR (125 MHz, CDCl3) δ 175.7, 135.61, 135.58, 133.8, 133.7, 129.6,
129.5, 127.59, 127.58, 73.7, 66.3, 51.5, 44.1, 40.1, 26.8, 19.2, 13.0, 11.5,
7.0, 5.3 ppm; MS (ESI-IT) m/z 273.2 (51), 451.3 (32), 529.3 (M + H+,
100); HRMS calcd for C30H49O4Si2 [M + H+] 529.3164, found
529.3168 (0.7 ppm).
Products 34a and 34b (20 mg, yield = 83%) were obtained as colorless
oils from a mixture of bromides 31a and 31b (30 mg) following general
procedure A1 and purification by flash chromatography on silica gel
(hexanes/EtOAc 95:5 to 85:15). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 2:1 ratio of
products 2,3-anti (34a):2,3-syn (34b).
34a: Rf = 0.48 (hexanes/EtOAc, 85:15); formula C20H30O4; MW
334.45 g/mol; IR (neat) νmax 2953, 2870, 1739, 1455, 1165, 741 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.37−7.23 (m, 5H), 4.52 (d, J = 12.1 Hz,
1H), 4.48 (d, J = 12.1 Hz, 1H), 3.96 (dd, J = 5.8 Hz, 10.9 Hz, 1H), 3.62
(dd, J = 3.4 Hz, 8.9 Hz, 1H), 3.56 (s, 3H), 3.39 (dd, J = 2.3 Hz, 10.0 Hz,
1H), 3.15−3.05 (m, 2H), 1.98−1.89 (m, 1H), 1.89−1.81 (m, 2H),
1.80−1.72 (m, 1H), 1.48 (ddd, J = 3.6 Hz, 7.2 Hz, 13.3 Hz, 1H), 1.44−
1.38 (m, 1H), 1.07 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.93 (d, J
= 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.7, 139.2, 128.5,
127.7 127.5, 75.7, 74.3, 73.7, 73.3, 51.6, 39.9, 36.0, 28.4, 26.2, 19.7, 15.0,
13.4, 11.5 ppm; MS (ESI-IT) m/z 335.2 (M + H+, 30), 357.2 (M + Na+,
100), 359.2 (13); HRMS calcd for C20H31O4 [M + H+] 335.2222, found
335.2210 (−2.1 ppm); calcd for C20H30O4Na [M + Na+] 357.2036,
found 357.2033 (−0.9 ppm).
34b: Rf = 0.54 (hexanes/EtOAc, 85:15); formula C20H30O4; MW
334.45 g/mol; IR (neat) νmax 2938, 1737, 1455, 1165, 1043, 737 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.38−7.26 (m, 5H), 4.51 (d, J = 11.9 Hz,
1H), 4.46 (d, J = 11.9 Hz, 1H), 3.90 (dd, J = 5.5 Hz, 10.8 Hz, 1H), 3.67
(s, 3H), 3.55 (dq, J = 4.4 Hz, 8.6 Hz, 2H), 3.36 (dd, J = 2.3 Hz, 10.1 Hz,
1H), 3.17−3.10 (m, 1H), 2.00−1.86 (m, 2H), 1.86−1.75 (m, 2H),
1.52−1.46 (m, 1H), 1.24−1.18 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 0.97
(d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 176.1, 139.0, 128.5, 127.8, 127.6, 75.0, 73.3, 72.6, 72.4, 51.9,
39.3, 36.2, 28.2, 26.6, 21.9, 14.5, 13.5, 11.3 ppm; MS (ESI-IT) m/z 335.2
(M + H+, 100), 357.2 (M + Na+, 77); HRMS calcd for C20H31O4 [M +
H+] 335.2222, found 335.2210 (−2.1 ppm); calcd for C20H30O4Na [M
+ Na+] 357.2036, found 357.2027 (−2.6 ppm).
( )-(2R,3S,4S)-5-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-3-
(triethylsilyloxy)pentan-1-ol (S2).
To a cold (−40 °C) solution of ester S1 (1.51 g) in dry CH2Cl2 (0.1 M,
29 mL) was added a 1.0 M solution of DIBAL-H in hexanes (3 equiv, 8.6
mL). The mixture was stirred for 1 h at −40 °C or until ester was
completely consumed, as verified by TLC (hexanes/EtOAc, 85:15). The
reaction mixture was treated first with the dropwise addition of MeOH
at −40 °C until gas evolution ceased, followed by a saturated potassium
sodium tartrate solution (Rochelle’s salt). The mixture was stirred for 1
h at room temperature (or until clarification of phases) followed by
separation of the organic phase. The aqueous layer was extracted with
Et2O (3×), and the combined organic fractions were dried (MgSO4),
filtered, and concentrated in vacuo. The crude mixture was purified by
flash chromatography on silica gel (hexanes/EtOAc, 85:15) to afford
primary alcohol S2 as a colorless oil (1.32 g, yield = 92%): Rf = 0.43
(hexanes/EtOAc, 85:15); formula C29H48O3Si2; MW 500.86 g/mol; IR
(neat) νmax 3382, 3071, 3050, 2957, 2934, 2877, 1590, 1463, 1427, 1388,
1
1239, 1109, 1030, 968, 912, 823, 738, 703, 613 cm−1; H NMR (500
MHz, CDCl3) δ 7.72−7.64 (m, 4H), 7.47−7.36 (m, 6H), 4.03−3.99 (m,
1H), 3.71−3.65 (m, 1H), 3.56−3.43 (m, 3H), 2.39 (bs, 1H), 2.03−1.93
(m, 1H), 1.93−1.83 (m, 1H), 1.08 (s, 9H), 0.96 (t, J = 7.9 Hz, 9H), 0.92
(d, J = 6.9 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H), 0.67−0.58 (m, 6H) ppm;
13C NMR (100 MHz, CDCl3) δ 135.9, 135.8, 134.02, 133.99, 129.9,
127.9, 74.7, 67.0, 66.6, 40.5, 37.8, 27.1, 19.4, 13.2, 12.5, 7.2, 5.4 ppm; MS
(ESI-IT) m/z 227.2 (19), 291.2 (63), 351.2 (26), 423.3 (29), 501.3 (M
+ H+, 100), 600.4 (19); HRMS calcd for C29H49O3Si2 [M + H+]
501.3215, found 501.3226 (2.2 ppm).
( )-(2S,3R,4S)-5-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-3-
(triethylsilyloxy)pentanal (11).
To a cold (−78 °C) solution of oxalyl chloride (1.2 equiv, 0.26 mL) in
dry CH2Cl2 (0.1 M, 25 mL) was added dropwise anhydrous DMSO (2.4
equiv, 0.43 mL), and the mixture was stirred for 10 min at −78 °C. A
solution of the alcohol S2 (6.58 g) in dry CH2Cl2 (0.5 M, 5 mL) was
cannulated into the reaction flask and the mixture was allowed to stir for
an additional 30 min at −78 °C before addition of dry Et3N (5 equiv,
1.75 mL). The mixture was stirred 1 h at −78 °C and then treated with a
saturated aqueous solution of NH4Cl followed by separation of organic
phase at room temperature. The aqueous layer was extracted with Et2O
( )-(2S,3R,4S)-Methyl 5-(tert-butyldiphenylsilyloxy)-2,4-di-
methyl-3-(triethylsilyloxy)pentanoate (S1).
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(3×), and combined organic fractions were washed with a saturated
brine solution, dried (MgSO4), filtered, and concentrated in vacuo to
afford aldehyde 11 as a colorless oil (1.26 g, quantitative yield) which
was used as crude without further purification: Rf = 0.72 (hexanes/
EtOAc, 85:15); formula C29H46O3Si2; MW 498.84 g/mol; IR (neat)
νmax 3071, 3050, 2957, 2878, 2706, 1890, 1725, 1590, 1463, 1427, 1390,
1363, 1240, 1187, 1109, 1109, 965, 942, 909, 821, 734, 709, 614 cm−1;
1H NMR (500 MHz, CDCl3) δ 9.87 (d, J = 1.0 Hz, 1H), 7.76−7.69 (m,
4H), 7.50−7.40 (m, 6H), 4.40 (app t, J = 4.6 Hz, 1H), 3.65 (dd, J = 7.0
Hz, 10.2 Hz, 1H), 3.54 (dd, J = 5.6 Hz, 10.2 Hz, 1H), 2.64−2.57 (m,
1H), 1.91−1.81 (m, 1H), 1.14 (m, 9H), 1.11 (d, J = 7.0 Hz, 3H), 1.01 (t,
J = 8.0 Hz, 9H), 0.92 (d, J = 6.9 Hz, 3H), 0.70−0.63 (m, 6H) ppm; MS
(ESI-IT) m/z 111.1 (100), 171.1 (33), 243.2 (19), 289.2 (42), 349.2
(14), 381.2 (77), 437.3 (19), 481.3 (13), 521.3 (M + Na+, 48), 598.4
(15), 629.4 (26); HRMS calcd for C29H46O3NaSi2 [M + Na+] 521.2878,
found 521.2880 (0.4 ppm).
(dd, J = 7.1 Hz, 10.0 Hz, 1H), 3.49 (dd, J = 6.0 Hz, 10.0 Hz, 1H), 2.46−
2.37 (m, 1H), 2.37−2.26 (m, 1H), 1.92−1.82 (m, 2H), 1.69−1.59 (m,
1H), 1.52−1.42 (m, 1H), 1.12 (s, 9H), 0.99 (t, J = 8.0 Hz, 9H), 0.91 (d, J
= 6.7 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.69−0.59 (m, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 174.1, 135.53, 135.52, 133.76, 133.73,
129.49, 129.48, 127.53, 127.52, 75.7, 66.8, 51.3, 38.5, 37.1, 32.2, 28.8,
26.8, 19.1, 15.1, 11.8, 7.1, 5.4 ppm; MS (ESI-IT) m/z 169.1 (100), 347.2
(81), 425.3 (73), 557.3 (M + H+, 38), 656.5 (6); HRMS calcd for
C32H53O4Si2 [M + H+] 557.3477, found 557.3485 (1.4 ppm).
( )-(4R,5S,6S)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-5-
(triethylsilyloxy)heptan-1-ol (S5).
Primary alcohol S5 as a colorless oil (1.98 g, yield = 83%) was obtained
from ester S4 (2.51 g) following general procedure A4 and purification
by flash chromatography on silica gel (hexanes/EtOAc 85:15): Rf = 0.38
(hexanes/EtOAc, 85:15); formula C31H52O3Si2; MW 528.91 g/mol; IR
(neat) νmax 3339, 3071, 3050, 2956, 2936, 2876, 2361, 2341, 1590, 1463,
1427, 1387, 1239, 1188, 1109, 1059, 1009, 968, 832, 738, 703, 613 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.71−7.64 (m, 4H), 7.46−7.36 (m, 6H),
3.73−3.69 (m, 1H), 3.65−3.59 (m, 2H), 3.56 (dd, J = 7.2 Hz, 9.6 Hz,
1H), 3.45 (dd, J = 6.1 Hz, 9.7 Hz, 1H), 1.87−1.78 (m, 1H), 1.69−1.54
(m, 2H), 1.54−1.44 (m, 2H), 1.39−1.27 (bs, 1H), 1.08 (s, 9H), 0.95 (t, J
= 7.9 Hz, 9H), 0.88 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.64−
0.56 (m, 6H) ppm; OH signal missing possibly due to exchange in CDCl3;
13C NMR (100 MHz, CDCl3) δ 135.59, 135.58, 133.89, 133.88, 129.52,
129.51, 127.55, 127.54, 75.9, 67.0, 63.4, 38.5, 37.4, 30.8, 29.5, 26.9, 19.2,
15.5, 12.0, 7.1, 5.5 ppm; MS (ESI-IT) m/z 192.7 (16), 288.3 (55), 319.2
(84), 397.3 (100), 529.4 (M + H+, 26), 608.4 (7), 628.5 (17); HRMS
calcd for C31H53O3Si2 [M + H+] 529.3528, found 529.3526 (−0.4 ppm).
( )-(4R,5S,6S)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-5-
(triethylsilyloxy)heptanal (12).
( )-(4R,5S,6S,E)-Methyl 7-(tert-Butyldiphenylsilyloxy)-4,6-di-
methyl-5-(triethylsilyloxy)hept-2-enoate (S3a,b).
To a solution of aldehyde 11 (2.44 g) in dry toluene (0.1 M, 49 mL) was
added methyl (triphenylphosphoranylidene)acetate (1.5 equiv, 2.46 g),
and the resulting solution was heated to reflux overnight. The mixture
was cooled to room temperature and then concentrated in vacuo. The
solid yellow residue was digested in hexanes and filtered onto a pad of
Celite, leading to a filtrate which was concentrated in vacuo. The crude
mixture was purified by flash chromatography on silica gel (hexanes/
EtOAc, 95:5) to afford an inseparable 10:1 mixture of (E):(Z) α,β-
unsaturated ester S3a,b as a colorless oil (2.23 g, yield = 82%): Rf = 0.55
(hexanes/EtOAc, 90:10); formula C32H50O4Si2; MW 554.91 g/mol; IR
(neat) νmax 2957, 2877, 1726, 1656, 1461, 1429, 1387, 1334, 1270, 1236,
1109, 1009, 824, 803, 736, 703, 613 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.69−7.62 (m, 4Ha + 4Hb), 7.46−7.35 (m, 6Ha+6Hb), 7.02 (dd, J = 8.4
Hz, 15.7 Hz, 1Hb), 7.00 (dd, J = 7.9 Hz, 15.8 Hz, 1Ha), 5.81 (dd, J = 1.1
Hz, 15.8 Hz, 1Ha), 5.76 (dd, J = 0.9 Hz, 15.8 Hz, 1Hb), 3.90 (dd, J = 2.7
Hz, 6.6 Hz, 1Ha), 3.85 (dd, J = 3.5 Hz, 5.8 Hz, 1Hb), 3.76 (s, 3Ha), 3.72
(s, 3Hb), 3.53 (dd, J = 7.9 Hz, 10.0 Hz, 1Ha+1Hb), 3.44 (dd, J = 5.9 Hz,
10.1 Hz, 1Hb), 3.41 (dd, J = 5.9 Hz, 10.1 Hz, 1Ha), 2.57−2.47 (m, 1Ha),
2.50−2.42 (m, 1Hb), 1.81−1.76 (m, 1Hb), 1.76−1.69 (m, 1Ha), 1.07 (s,
9Ha+9Hb), 1.06 (d, J = 7.0 Hz, 3Ha), 1.02 (d, J = 6.9 Hz, 3Hb), 0.95 (t, J =
7.9 Hz, 9Ha+9Hb), 0.83 (d, J = 6.8 Hz, 3Hb), 0.76 (d, J = 6.8 Hz, 3Ha),
0.65−0.55 (m, 6Ha), 0.56−0.49 (m, 6Hb) ppm; 13C NMR (125 MHz,
CDCl3) δ 167.0a+b, 152.6b, 152.4a, 135.59a, 135.58b, 135.57b, 135.55a,
133.83b, 133.82a, 133.67b, 133.66a, 129.59a, 129.58b, 129.56b, 129.55a,
127.59b, 127.58a, 120.6b, 120.0a, 75.5b, 74.9a, 66.5a, 66.4b, 51.4a, 51.3b,
41.6a, 41.4b, 39.2b, 38.9a, 26.85b, 26.84a, 19.19b, 19.17a, 16.7b, 15.8a, 11.3b,
10.8a, 7.0a+b, 5.36b, 5.34a ppm; MS (ESI-IT) m/z 229.1 (4), 345.2 (14),
477.3 (100), 555.3 (M + H+, 21), 654.4 (6); HRMS calcd for
C32H51O4Si2 [M + H+] 555.3320, found 555.3327 (1.1 ppm).
To a solution of alcohol S5 (1.97 g) in dry CH2Cl2 (0.1 M, 37 mL) were
added successively NaHCO3 (10 equiv, 3.08 g) and Dess−Martin
periodinane (1.5 equiv, 2.33 g). The reaction mixture was stirred for 1 h
at room temperature and then concentrated. The resulting white solid
residue was digested in hexanes and filtered onto a pad of Celite. The
filtrate was then concentrated in vacuo and purified by flash
chromatography on silica gel (hexanes/EtOAc, 90:10) to afford
aldehyde 12 as a colorless oil (1.68 g, yield = 87%): Rf = 0.74
(hexanes/EtOAc, 85:15); formula C31H50O3Si2; MW 526.90 g/mol; IR
(neat) νmax 3071, 3050, 2957, 2934, 2877, 2714, 1727, 1590, 1464, 1427,
1388, 1363, 1240, 1189, 1109, 1057, 1009, 970, 823, 739, 704, 613 cm−1;
1H NMR (500 MHz, CDCl3) δ 9.76 (dd, J = 1.8 Hz, 3.4 Hz, 1H), 7.69−
7.63 (m, 4H), 7.46−7.35 (m, 6H), 3.75−3.71 (m, 1H), 3.53 (dd, J = 7.3
Hz, 9.9 Hz, 1H), 3.44 (dd, J = 5.8 Hz, 9.9 Hz, 1H), 2.50−2.41 (m, 1H),
2.41−2.32 (m, 1H), 1.84−1.75 (m, 2H), 1.64−1.54 (m, 1H), 1.44−1.34
(m, 1H), 1.07 (s, 9H), 0.94 (t, J = 8.0 Hz, 9H), 0.86 (d, J = 6.8 Hz, 3H),
0.85 (d, J = 6.8 Hz, 3H), 0.63−0.54 (m, 6H) ppm; 13C NMR (100 MHz,
CDCl3) δ 202.7, 135.60, 135.57, 133.80, 133.79, 129.57, 129.56, 127.58,
127.57, 75.7, 66.8, 42.2, 38.5, 37.3, 26.9, 25.7, 19.2, 15.2, 12.0, 7.1, 5.4
ppm; MS (ESI-IT) m/z 111.1 (100), 171.1 (38), 245.1 (36), 289.2 (47),
359.2 (22), 381.2 (95), 439.2 (29), 521.3 (51), 553.3 (54), 581.3 (18);
HRMS calcd for C31H51O3Si2 [M + H+] 527.3371, found 527.3373 (0.3
ppm); calcd for C31H50O3Si2Na [M + Na+] 549.3191, found 549.3192
(0.3 ppm).
( )-(4R,5S,6S)-Methyl 7-(tert-Butyldiphenylsilyloxy)-4,6-di-
methyl-5-(triethylsilyloxy)heptanoate (S4).
To a solution of α,β-unsaturated ester S3a,b (1.00 g) in EtOAc (0.1 M,
10 mL) at room temperature was added 10 wt % Pd on activated carbon
(0.1 equiv, 192 mg). The inert gas atmosphere was purged by three
cycles of vacuum/H2 gas before the reaction mixture was stirred until the
reaction was judged complete by TLC (hexanes/EtOAc, 90:10). The
mixture was then filtered onto a pad of Celite and washed with hexanes.
The filtrate was concentrated in vacuo and purified by flash
chromatography on silica gel (hexanes/EtOAc, 85:15) to afford product
S4 as a colorless oil (1.02 g, quantitative yield): Rf = 0.45 (hexanes/
EtOAc, 90:10); formula C32H52O4Si2; MW 556.92 g/mol; IR (neat)
νmax 3072, 2956, 2877, 1742, 1462, 1429, 1387, 1241, 1171, 1109, 823,
739, 703, 613 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.76−7.68 (m, 4H),
7.49−7.38 (m, 6H), 3.77 (dd, J = 3.7 Hz, 5.0 Hz, 1H), 3.70 (s, 3H), 3.59
(
)-Methyl 2-Bromo-2-((2S,5R,6S)-6-((S)-1-(tert-
butyldiphenylsilyloxy)propan-2-yl)-5-methyltetrahydro-2H-
pyran-2-yl)propanoate (13a, 13b).
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To a cold (−78 °C) solution of aldehyde 12 (1.69 g) in dry CH2Cl2 (0.1
M, 32 mL) was added dropwise a solution of BiBr3 (1 equiv, 1.44 g) in
dry MeCN (0.5 M, 6.4 mL), followed by silylated enol ether 2 (1.5
equiv, 0.89 mL). The mixture was stirred for 1.5 h at −78 °C or until
aldehyde was completely consumed, as verified by TLC (hexanes/
EtOAc, 90:10). The reaction mixture was treated with a saturated
aqueous solution of NH4Cl at −40 °C, followed by separation of the
organic phase at room temperature. The aqueous layer was extracted
with CH2Cl2 (3×), and the combined organic fractions were dried
(MgSO4), filtered, and concentrated in vacuo. 1H NMR spectroscopic
analysis of the unpurified product indicated exclusive (>20:1) formation
of 3,7-trans products as a pair of 2,3-diastereomers in a ∼1:1 ratio of
products 13a:13b. The two diastereoisomers were separated by flash
chromatography on silica gel (hexanes/EtOAc, 90:10) to afford product
23a and 23b as pale yellow oils. Product yield was not calculated due to
contamination with C-silylated product from enol ether 2.
13a: Rf = 0.47 (hexanes/EtOAc, 90:10); formula C29H41BrO4Si; MW
561.62 g/mol; IR (neat) νmax 3071, 2957, 2933, 2860, 1743, 1590, 1453,
1429, 1381, 1263, 1191, 1263, 1110, 1049, 823, 704, 615 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.66−7.63 (m, 4H), 7.45−7.35 (m, 6H), 4.30 (dd,
J = 4.1 Hz, 10.3 Hz, 1H), 3.80−3.74 (m, 2H), 3.73 (s, 3H), 3.59 (dd, J =
4.4 Hz, 9.9 Hz, 1H), 3.44 (dd, J = 5.8 Hz, 9.9 Hz, 1H), 1.99−1.79 (m,
3H), 1.92 (s, 3H), 1.73−1.63 (m, 1H), 1.40−1.29 (m, 1H), 1.07 (d, J =
6.9 Hz, 3H), 1.05 (s, 9H), 0.82 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (125
MHz, CDCl3) δ 171.4, 135.57, 135.56, 133.77, 133.69, 129.57, 129.56,
127.60, 127.59, 76.2, 75.9, 66.0, 62.6, 53.0, 36.9, 30.6, 27.7, 26.8, 23.0,
22.0, 19.3, 16.3, 14.7 ppm; MS (ESI-IT) m/z 147.1 (14), 207.1 (32),
225.1 (39), 305.1 (62), 395.2 (23), 481.3 (14), 563.2 (100), 660.3 (9);
HRMS calcd for C29H42O4BrSi [M + H+] 561.2030, found 561.2036
(1.0 ppm).
ratio of products 14a:14b. The two diastereoisomers were separated by
flash chromatography on silica gel (hexanes/EtOAc, 90:10) to afford
product 14a and 14b as colorless oils (0.24 g, yield = 50%).
14a: Rf = 0.39 (toluene/EtOAc, 98:2); formula C20H29BrO4; MW
413.35 g/mol; IR (neat) νmax 2955, 2933, 2869, 1742, 1452, 1378, 1263,
1097, 1049, 736, 698 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.25
(m, 5H), 4.48 (d, J = 12.1 Hz, 1H), 4.44 (d, J = 12.1 Hz, 1H), 4.30 (dd, J
= 4.0 Hz, 10.6 Hz, 1H), 3.75 (s, 3H), 3.72 (dd, J = 4.3 Hz, 7.7 Hz, 1H),
3.39 (dd, J = 4.8 Hz, 9.2 Hz, 1H), 3.25 (dd, J = 6.2 Hz, 9.1 Hz, 1H),
2.02−1.84 (m, 4H), 1.89 (s, 3H), 1.72−1.62 (m, 1H), 1.46−1.35 (m,
1H), 1.07 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3) δ 171.4, 138.6, 128.3, 127.5, 127.4, 76.3, 76.2, 73.08,
73.05, 62.4, 53.0, 35.1, 31.0, 27.8, 22.8, 22.3, 16.4, 15.2 ppm; MS (ESI-
IT) m/z 305.1 (21), 413.1 (M + H+, 100), 503.2 (6); HRMS calcd for
C20H30O4Br [M + H+] 413.1322, found 413.1319 (−0.8 ppm).
14b: Rf = 0.32 (toluene/EtOAc, 98:2); formula C20H29BrO4; MW
413.35 g/mol; IR (neat) νmax 2954, 2933, 2873, 1739, 1665, 1452, 1379,
1
1306, 1263, 1089, 1054, 1024, 972, 827, 798, 737, 698, 649 cm−1; H
NMR (500 MHz, CDCl3) δ 7.36−7.25 (m, 5H), 4.50 (d, J = 12.1 Hz,
1H), 4.46 (d, J = 12.1 Hz, 1H), 4.07 (dd, J = 4.5 Hz, 10.2 Hz, 1H), 3.79
(dd, J = 4.7 Hz, 8.2 Hz, 1H), 3.76 (s, 3H), 3.48 (dd, J = 4.4 Hz, 9.2 Hz,
1H), 3.30 (dd, J = 6.5 Hz, 9.2 Hz, 1H), 2.07−2.00 (m, 1H), 2.00−1.91
(m, 1H), 1.89−1.81 (m, 1H), 1.86 (s, 3H), 1.74−1.62 (m, 2H), 1.45−
1.33 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 7.1 Hz, 3H) ppm; 13C
NMR (125 MHz, CDCl3) δ 171.1, 138.6, 128.3, 127.5, 127.4, 77.2, 76.2,
73.3, 73.1, 65.8, 53.2, 34.7, 31.5, 27.5, 24.8, 24.0, 16.8, 15.6 ppm; MS
(ESI-IT) m/z 305.1 (35), 337.1 (5), 413.1 (M + H+, 100), 468.0 (98);
HRMS calcd for C20H30O4Br [M + H+] 413.1322, found 413.1327 (1.3
ppm).
( )-(S)-Methyl 2-((2S,5R,6S)-6-((S)-1-(Benzyloxy)propan-2-
yl)-5-methyltetrahydro-2H-pyran-2-yl)propanoate (35a) and
( )-(R)-Methyl 2-((2S,5R,6S)-6-((S)-1-(Benzyloxy)propan-2-yl)-
5-methyltetrahydro-2H-pyran-2-yl)propanoate (35b).
13b: Rf = 0.40 (hexanes/EtOAc, 90:10); formula C29H41BrO4Si; MW
561.62 g/mol; IR (neat) νmax 3071, 2956, 2933, 2860, 1739, 1453, 1429,
1
1381, 1263, 1111, 823, 739, 704, 614 cm−1; H NMR (500 MHz,
CDCl3) δ 7.67−7.64 (m, 4H), 7.45−7.35 (m, 6H), 4.05 (dd, J = 4.3 Hz,
10.2 Hz, 1H), 3.80 (dd, J = 4.1 Hz, 8.3 Hz, 1H), 3.75 (s, 3H), 3.65 (dd, J
= 4.1 Hz, 10.0 Hz, 1H), 3.49 (dd, J = 6.2 Hz, 10.0 Hz, 1H), 1.97−1.77
(m, 3H), 1.87 (s, 3H), 1.75−1.61 (m, 2H), 1.37−1.27 (m, 1H), 1.16 (d,
J = 6.7 Hz, 3H), 1.06 (s, 9H), 0.81 (d, J = 6.9 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3) δ 171.1, 135.64, 135.61, 133.79, 133.74, 129.55,
129.54, 127.59, 127.58, 77.0, 76.0, 66.3, 65.8, 53.2, 36.5, 31.2, 27.5, 26.9,
24.8, 23.9, 19.3, 16.7, 15.1 ppm; MS (ESI-IT) m/z 229.1 (14), 305.1
(51), 395.2 (28), 563.2 (100), 662.3 (11); HRMS calcd for
C29H42O4BrSi [M + H+] 561.2030, found 561.2036 (1.1 ppm).
( )-Methyl 2-((2S,5R,6S)-6-((S)-1-(Benzyloxy)propan-2-yl)-5-
methyltetrahydro-2H-pyran-2-yl)-2-bromopropanoate (14a,
14b).
To a cold (−78 °C) solution of a mixture of bromides 14a and 14b (69
mg) in dry toluene (0.1 M, 1.6 mL) were added successively Ph3SnH (2
equiv, 114 mg), a 1 M solution of Et3B in CH2Cl2 (0.2 equiv, 32 μL), and
air (syringe). The reaction mixture was maintained at −78 °C as
supplementary addition of Et3B solution (0.2 equiv, 32 μL) and air were
realized each 30 min, until reaction was judged complete by TLC (3−4
h, hexanes/EtOAc, 90:10). The reaction mixture was treated with the
addition of 1,4-dinitrobenzene (0.2 equiv, 5 mg), followed by stirring of
the mixture for 15 min at −78 °C. Once at room temperature, the
reaction was concentrated in vacuo. 1H NMR spectroscopic analysis of
the unpurified product indicated a pair of diastereomers in a 5:1 ratio of
products 2,3-anti (35a):2,3-syn (35b). The two diastereoisomers were
separated by flash chromatography on silica gel (hexanes/EtOAc,
90:10) to afford product 35a and 35b as pale yellow oils (37 mg, yield =
68%).
To a cold (0 °C) solution of a mixture of products 13a and 13b (652
mg) in dry THF (0.1 M, 12 mL) was added dropwise a solution of
HF·pyridine (ca. 70% HF, 1 mL per mmol of substrate, 1.2 mL). The
reaction mixture was stirred overnight at 0 °C and then treated slowly
with a saturated aqueous solution of NaHCO3, followed by separation of
the organic phase at room temperature. The aqueous layer was extracted
with CH2Cl2 (3×), and the combined organic fractions were dried
(MgSO4), filtered, and concentrated in vacuo. The crude mixture was
purified by flash chromatography on silica gel (hexanes/EtOAc, 80:20)
to afford an inseparable mixture of bromide adducts as a colorless oil
(248 mg, yield = 66% over two steps). To a cold (0 °C) solution of crude
product (165 mg) in solvent mixture of cyclohexane and CH2Cl2 (2:1,
0.1 M, 5.1 mL) were added successively 2,2,2-benzyltrichloroacetimi-
date (1.3 equiv, 130 μL) and TfOH (0.1 equiv, 5 μL). The reaction
mixture was stirred overnight at 0 °C before treatment with Et3N (0.15
equiv, 11 μL) and then concentration in vacuo. The crude mixture was
dissolved in hexanes and filtered onto a pad of Celite, followed by
concentration in vacuo of the filtrate. 1H NMR spectroscopic analysis of
the unpurified product indicated a pair of 2,3-diastereomers in a ∼1:1
35a: Rf = 0.29 (hexanes/EtOAc, 90:10); formula C20H30O4; MW
334.45 g/mol; IR (neat) νmax 2946, 2864, 1739, 1456, 1363, 1269, 1256,
1
1212, 1162, 1086, 1053, 1021, 967, 909, 852, 828, 738, 699 cm−1; H
NMR (500 MHz, CDCl3) δ 7.37−7.25 (m, 5H), 4.49 (d, J = 12.2 Hz,
1H), 4.45 (d, J = 12.2 Hz, 1H), 3.99 (dd, J = 6.1 Hz, 10.7 Hz, 1H), 3.68
(s, 3H), 3.49 (dd, J = 2.3 Hz, 9.5 Hz, 1H), 3.37 (dd, J = 4.1 Hz, 9.2 Hz,
1H), 3.24 (dd, J = 6.4 Hz, 9.2 Hz, 1H), 3.11 (dq, J = 11.0 Hz, 6.8 Hz,
1H), 1.97−1.87 (m, 1H), 1.85−1.68 (m, 3H), 1.46−1.35 (m, 2H), 1.07
(d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 175.6, 138.6, 128.3, 127.44,
127.41, 75.5, 74.6, 73.1, 72.2, 51.5, 39.8, 35.6, 28.9, 26.2, 19.7, 14.89,
14.83, 11.9 ppm; MS (ESI-IT) m/z 227.2 (44), 335.2 (M + H+, 100);
HRMS calcd for C20H31O4 [M + H+] 335.2217, found 335.2215 (−0.7
ppm).
35b: Rf = 0.37 (hexanes/EtOAc, 90:10); formula C20H30O4; MW
334.45 g/mol; IR (neat) νmax 2938, 2867, 1736, 1455, 1376, 1254, 1194,
X
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1163, 1107, 1046, 967, 902, 856, 738, 699 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.37−7.25 (m, 5H), 4.49 (d, J = 12.2 Hz, 1H), 4.45 (d, J = 12.2
Hz, 1H), 3.90 (dd, J = 5.5 Hz, 10.6 Hz, 1H), 3.66 (s, 3H), 3.38 (dd, J =
3.9 Hz, 9.2 Hz, 1H), 3.32 (dd, J = 3.0 Hz, 9.1 Hz, 1H), 3.30 (dd, J = 5.5
Hz, 9.2 Hz, 1H), 3.12 (dq, J = 10.8 Hz, 6.8 Hz, 1H), 1.99−1.89 (m, 1H),
1.88−1.72 (m, 3H), 1.43 (dq, J = 13.1 Hz, 3.5 Hz, 1H), 1.22 (d, J = 6.8
Hz, 3H), 1.21−1.15 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.9
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.8, 138.5, 128.3,
127.51, 127.47, 74.8, 73.8, 73.1, 72.0, 51.6, 39.2, 35.8, 28.8, 26.5, 21.9,
15.4, 14.5, 11.9 ppm; MS (ESI-IT) m/z 227.2 (45), 335.2 (M + H+,
100), 434.3 (19); HRMS calcd for C20H31O4 [M + H+] 335.2217, found
335.2215 (−0.7 ppm).
301.2193, found 301.2198 (1.5 ppm); calcd for C16H32O3NaSi [M +
Na+] 323.2013, found 323.2019 (1.8 ppm).
(
)-(5R,6R)-6-Isopropyl-5-methyltetrahydro-2H-pyran-2-
one (S66).
Product S65 was obtained as a colorless oil from α,β-unsaturated ester
S64 (0.345 g) following general procedure A2 and was used as crude
without further purification. Product S6633 (0.12 g, yield = 69% over two
steps) was obtained as a colorless oil from crude ester S65 following
general procedure A8 and purification by flash chromatography on silica
gel (hexanes/EtOAc, 75:25): Rf = 0.16 (hexanes/EtOAc, 80:20);
formula C9H16O2; MW 156.22 g/mol; IR (neat) νmax 2965, 2877, 1738,
1244, 1063, 986 cm−1; 1H NMR (500 MHz, CDCl3) δ 3.82 (dd, J = 2.4
Hz, 10.0 Hz, 1H), 2.54 (dd, J = 6.3 Hz, 8.6 Hz, 2H), 2.23−2.16 (m, 1H),
2.11−2.02 (m, 1H), 1.93−1.82 (m, 1H), 1.73−1.65 (m, 1H), 1.10 (d, J =
6.4 Hz, 3H), 0.97 (d, J = 7.1 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H) ppm; 13C
NMR (125 MHz, CDCl3) δ 172.4, 88.6, 30.0, 27.1, 26.9, 26.4, 20.0, 18.3,
11.7 ppm; MS (ESI-IT) m/z 157.1 (M + H+, 95), 179.1 (M + Na+, 100),
241.1 (5), 335.2 (24), 360.3 (12); HRMS calcd for C9H17O2 [M + H+]
157.1223, found 157.1223 (0.03 ppm); calcd for C9H16NaO2 [M + Na+]
179.1043, found 179.1043 (0.3 ppm).
(
)-(2R,3R)-2,4-Dimethyl-3-(triethylsilyloxy)pentan-1-ol
(
)-(5R,6R)-6-Isopropyl-5-methyltetrahydro-2H-pyran-2-yl
(S62).
Acetate (S67).
Product S61 was obtained as a pale yellow oil from alcohol S18b32 (0.32
g) following general procedure A3 and was used as crude without further
purification. Product S62 (385 mg, yield = 78% over two steps) was
obtained as a colorless oil from ester S61 (549 mg) following general
procedure A4 and purification by flash chromatography on silica gel
(hexanes/EtOAc 80:20): Rf = 0.34 (hexanes/EtOAc, 80:20); formula
C13H30O2Si; MW 246.46 g/mol; IR (neat) νmax 3336, 2958, 2912, 2878,
1101, 1051, 1028 cm−1; 1H NMR (500 MHz, CDCl3) δ 3.62 (ddd, J =
4.8 Hz, 7.8 Hz, 10.4 Hz, 1H), 3.52 (dd, J = 3.1 Hz, 6.1 Hz, 1H), 3.48 (dd,
J = 5.7 Hz, 10.5 Hz, 1H), 1.90 (dh, J = 3.0 Hz, 7.0 Hz, 1H), 1.83 (app t, J
= 5.2 Hz, 1H), 1.78 (ddd, J = 6.8 Hz, 13.4 Hz, 20.1 Hz, 1H), 0.98 (t, J =
7.9 Hz, 9H), 0.94 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.86 (d, J
= 7.0 Hz, 3H), 0.63 (q, J = 7.9 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3) δ 79.0, 66.5, 39.3, 31.7, 20.3, 19.3, 11.7, 7.2, 5.6 ppm; MS (ESI-
IT) m/z 155.1 (100), 195.1 (17), 247.2 (M + H+, 13), 269.2 (M + Na+,
99), 360.3 (13), 421.2 (8), 638.6 (9); HRMS calcd for C13H31O2Si [M +
H+] 247.2088, found 247.2090 (0.7 ppm); calcd for C13H30NaO2Si [M
+ Na+] 269.1907, found 269.1911 (1.4 ppm).
Product S67 (0.10 g, yield = 64% over two steps) was obtained as a pale
yellow oil from lactone S66 (0.12 g) following general procedure A9 and
purification by flash chromatography on silica gel (hexanes/EtOAc
85:15): Rf = 0.49 (hexanes/EtOAc, 80:20); formula C11H20O3; MW
200.27 g/mol; IR (neat) νmax 2961, 2875, 1754, 1233, 1043, 989 cm−1;
1H NMR (500 MHz, CDCl3) δ 5.59 (dd, J = 2.6 Hz, 9.4 Hz, 1H), 3.09
(dd, J = 2.0 Hz, 9.9 Hz, 1H), 2.12 (s, 3H), 1.86−1.80 (m, 1H), 1.79−
1.67 (m, 4H), 1.63−1.59 (m, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.98 (d, J =
7.0 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 169.6, 96.0, 85.6, 29.9, 27.7, 25.3, 21.5, 20.2, 18.3, 11.5 ppm;
MS (ESI-IT) m/z 141.1 (58), 181.1 (21), 223.1 (M + Na+, 100), 281.2
(6), 321.2 (7), 423.3 (11); HRMS calcd for C11H20NaO3 [M + Na+]
223.1305, found 223.1299 (−2.6 ppm).
( )-Methyl 2-Bromo-2-((2S,5R,6R)-6-isopropyl-5-methylte-
trahydro-2H-pyran-2-yl) propanoate (32a, 32b).
( )-(4R,5R,E)-Methyl 4,6-Dimethyl-5-(triethylsilyloxy)hept-2-
enoate (S64).
Product 32a and 32b (0.25 g, yield = 93%) were obtained as pale yellow
oils from product S67 (0.18 g) following general procedure A10 and
purification by flash chromatography on silica gel (hexanes/EtOAc
85:15). 1H NMR spectroscopic analysis of the unpurified product
indicated a pair of 2,3-diastereomers in a ∼1:1 ratio of products 32a:32b.
32a: Rf = 0.57 (hexanes/EtOAc, 80:20); formula C13H23BrO3; MW
Aldehyde S63 was obtained as a pale yellow oil from alcohol S62 (0.38
g) following general procedure A14 and was used as crude without
further purification. Product S64 (0.46 g, yield = 82% over two steps)
was obtained as a colorless oil from crude aldehyde S63 following
general procedure A6 and purification by flash chromatography on silica
gel (hexanes/EtOAc 90:10): Rf = 0.55 (hexanes/EtOAc, 80:20);
formula C16H32O3Si; MW 300.51 g/mol; IR (neat) νmax 2958, 2913,
1
307.22 g/mol; IR (neat) νmax 2957, 2873, 1742, 1263, 1052 cm−1; H
NMR (500 MHz, CDCl3) δ 4.29 (dd, J = 4.3 Hz, 10.1 Hz, 1H), 3.79 (s,
3H), 3.33 (dd, J = 3.5 Hz, 9.3 Hz, 1H), 2.01−1.82 (m, 3H), 1.92 (s, 3H),
1.79−1.70 (m, 2H), 1.39−1.30 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.91
(d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 171.4, 80.5, 76.2, 63.0, 53.1, 30.0, 28.7, 27.6, 23.4, 21.3, 20.2,
19.5, 16.0 ppm; MS (ESI-IT) m/z 201.1 (38), 233.2 (88), 307.1 (M +
H+, 100); HRMS calcd for C13H24BrO3 [M + H+] 307.0903, found
307.0908 (1.6 ppm).
1
2878, 1728, 1460, 1270, 1176, 1058, 1012, 735 cm−1; H NMR (500
MHz, CDCl3) δ 6.98 (dd, J = 8.1 Hz, 15.8 Hz, 1H), 5.82 (dd, J = 0.9 Hz,
15.8 Hz, 1H), 3.75 (s, 3H), 3.41 (dd, J = 4.8 Hz, 5.5 Hz, 1H), 2.50 (h, J =
6.7 Hz, 1H), 1.76−1.66 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.98 (t, J = 7.9
Hz, 9H), 0.91 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.63 (q, J =
7.9 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 167.4, 153.3, 120.1,
80.8, 51.7, 41.2, 32.1, 20.4, 17.4, 15.3, 7.3, 5.7 ppm; MS (ESI-IT) m/z
169.1 (53), 209.1 (18), 301.2 (M + H+, 14), 323.2 (M + Na+, 100), 338.3
(15), 360.3 (10), 441.3 (6); HRMS calcd for C16H33O3Si [M + H+]
32b: Rf = 0.52 (hexanes/EtOAc, 80:20); formula C13H23BrO3; MW
1
307.22 g/mol; IR (neat) νmax 2957, 2873, 1742, 1263, 1051 cm−1; H
NMR (500 MHz, CDCl3) δ 4.05 (dd, J = 4.3 Hz, 10.6 Hz, 1H), 3.78 (s,
3H), 3.43 (dd, J = 4.0 Hz, 9.5 Hz, 1H), 2.01−1.82 (m, 3H), 1.88 (s, 3H),
1.79−1.70 (m, 1H), 1.65 (qd, J = 4.3 Hz, 13.2 Hz, 1H), 1.39−1.29 (m,
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1H), 1.02 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.6
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.1, 80.6, 76.9, 65.8,
53.1, 30.9, 28.1, 27.3, 25.0, 23.4, 20.5, 20.0, 16.8, ppm; MS (ESI-IT) m/z
209.2 (17), 233.2 (7), 307.1 (M + H+, 100), 391.3 (11); HRMS calcd for
C13H24BrO3 [M + H+] 307.0903, found 307.0912 (2.7 ppm).
further purification: Rf = 0.66 (hexanes/EtOAc, 70:30); formula
C20H34O4Si; MW 366.56 g/mol; IR (neat) νmax 2953, 2877, 1738,
1457, 1098, 738 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.34−7.23 (m,
5H), 4.51 (d, J = 11.9 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 4.20 (dd, J = 5.7
Hz, 11.2 Hz, 1H), 3.66 (s, 3H), 3.52 (app t, J = 6.5 Hz, 2H), 2.55 (dq, J =
4.8 Hz, 7.0 Hz, 1H), 1.87−1.75 (m, 2H), 1.13 (d, J = 7.0 Hz, 3H), 0.93
(t, J = 7.9 Hz, 9H), 0.57 (q, J = 7.9 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3) δ 175.5, 138.7, 128.6, 127.9, 127.7, 73.2, 71.0, 67.0, 51.7, 45.4,
35.3, 11.6, 7.1, 5.3 ppm; MS (ESI-IT) m/z 259.2 (39), 335.2 (33), 367.2
(M + H+, 100), 466.3 (6); HRMS calcd for C20H35O4Si [M + H+]
367.2299, found 367.2307 (2.1 ppm).
(
)-(S)-Methyl 2-((2S,5R,6R)-6-Isopropyl-5-methyltetrahy-
dro-2H-pyran-2-yl)propanoate (36a) and ( )-(R)-Methyl 2-
((2S,5R,6R)-6-Isopropyl-5-methyltetrahydro-2H-pyran-2-yl)-
propanoate (36b).
(
)-(2R,3R)-5-(Benzyloxy)-2-methyl-3-(triethylsilyloxy)-
pentan-1-ol (S28b).
Products 36a and 36b (26 mg, yield = 67%) were obtained as pale yellow
oils from a mixture of bromides 32a and 32b (53 mg) following general
procedure A1 and purification by flash chromatography on silica gel
(hexanes/EtOAc 90:10). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 5:1 ratio of
products 2,3-anti (36a):2,3-syn (36b). The reaction performed on a
mixture of bromides 32a and 32b (20 mg) according to general
procedure A1 with Ph3SnH in CH2Cl2 led to the formation of product
2,3-anti (36a) and 2,3-syn (36b) in a 1:2 ratio of products (15 mg,
quantitative yield) as verified by 1H NMR analysis of the crude mixture.
36a: Rf = 0.25 (hexanes/EtOAc, 90:10); formula C13H24O3; MW
228.33 g/mol; IR (neat) νmax 2952, 28.74, 1742, 1464, 1164, 1054 cm−1;
1H NMR (500 MHz, CDCl3) δ 3.99 (dd, J = 5.7 Hz, 10.9 Hz, 1H), 3.69
(s, 3H), 3.21 (dd, J = 2.5 Hz, 9.7 Hz, 1H), 3.15 (dq, J = 11.0 Hz, 6.9 Hz,
1H), 1.97−1.88 (m, 1H), 1.88−1.82 (m, 1H), 1.80−1.72 (m, 1H),
1.60−1.54 (m, 1H), 1.47 (ddd, J = 13.4 Hz, 7.3 Hz, 3.6 Hz, 1H), 1.43−
1.37 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.85 (d, J
= 6.5 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 175.8, 78.3, 75.7, 51.7, 40.0, 30.1, 28.6, 26.4, 20.2, 19.7, 18.4,
15.1, 11.5 ppm; MS (ESI-IT) m/z 229.2 (M + H+, 14), 251.2 (M + Na+,
100), 479.3 (10); HRMS calcd for C13H25O3 [M + H+] 229.1798, found
229.1794 (−2.0 ppm); calcd for C13H24NaO3 [M + Na+] 251.1618,
found 251.1613 (−1.8 ppm).
36b: Rf = 0.33 (hexanes/EtOAc, 90:10); formula C13H24O3; MW
228.33 g/mol; IR (neat) νmax 2942, 2870, 1738, 1454, 1166, 1043 cm−1;
1H NMR (500 MHz, CDCl3) δ 3.91 (dd, J = 5.2 Hz, 10.9 Hz, 1H), 3.69
(s, 3H), 3.13 (dq, J = 10.7 Hz, 6.9 Hz, 1H), 2.98 (dd, J = 2.1 Hz, 9.6 Hz,
1H), 1.99−1.92 (m, 1H), 1.90−1.83 (m, 1H), 1.68−1.58 (m, 1H),
1.50−1.45 (m, 1H), 1.28−1.27 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), 1.23−
1.18 (m, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 0.83 (d, J
= 6.7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 176.1, 77.9, 75.0,
51.8, 39.4, 30.3, 28.7, 26.8, 22.1, 20.7, 18.5, 14.7, 11.6 ppm; MS (ESI-IT)
m/z 251.2 (M + Na+, 70), 360.3 (100), 408.3 (19), 697.7 (13); HRMS
calcd for C13H24NaO3 [M + Na+] 251.1618, found 251.1619 (0.3 ppm).
Product S28b (1.83 g, yield = 89% over two steps) was obtained as a
colorless oil from ester S27b following general procedure A4 and
purification by flash chromatography on silica gel (hexanes/EtOAc
70:30): Rf = 0.36 (hexanes/EtOAc, 70:30); formula C19H34O3Si; MW
338.56 g/mol; IR (neat) νmax 3442, 2953, 2879, 1096, 1012, 736 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.37−7.24 (m, 5H), 4.51 (d, J = 11.9 Hz,
1H), 4.47 (d, J = 11.9 Hz, 1H), 3.91 (dd, J = 5.7 Hz, 10.4 Hz, 1H), 3.74
(dd, J = 3.8 Hz, 11.0 Hz, 1H), 3.53 (app t, J = 6.6 Hz, 3H), 2.62 (bs, 1H),
1.87 (q, J = 6.5 Hz, 2H), 1.79−1.70 (m, 1H), 0.99 (d, J = 7.0 Hz, 3H),
0.96 (t, J = 7.9 Hz, 9H), 0.62 (q, J = 7.8 Hz, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ 138.6, 128.6, 127.9, 127.8, 73.4, 73.3, 67.4, 66.2, 40.2,
32.5, 12.7, 7.1, 5.2 ppm; MS (ESI-IT) m/z 339.2 (M + H+, 100), 438.3
(16), 453.3 (22); HRMS calcd for C19H35O3Si [M + H+] 339.2350,
found 339.2348 (−0.5 ppm).
(
)-(4R,5R,E)-Methyl 7-(Benzyloxy)-4-methyl-5-
(triethylsilyloxy)hept-2-enoate (S30b).
Aldehyde S29b was obtained as a pale yellow oil from alcohol S28b
(1.09 g) following general procedure A14 and was used as crude without
further purification. Product S30b (0.95 g, yield = 77% over two steps)
was obtained as a pale yellow oil from crude aldehyde S29b following
general procedure A6 and purification by flash chromatography on silica
gel (hexanes/EtOAc 80:20): Rf = 0.42 (hexanes/EtOAc, 80:20);
formula C22H36O4Si; MW 392.60 g/mol; IR (neat) νmax 2953, 2880,
1
1726, 1274, 1098, 1012, 733 cm−1; H NMR (500 MHz, CDCl3) δ
7.36−7.26 (m, 5H), 7.05 (dd, J = 7.1 Hz, 15.9 Hz, 1H), 5.81 (dd, J = 1.4
Hz, 15.9 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H),
3.85 (td, J = 4.2 Hz, 8.3 Hz, 1H), 3.73 (s, 3H), 3.53−3.50 (m, 2H),
2.50−2.43 (m, 1H), 1.79−1.73 (m, 1H), 1.66−1.58 (m, 1H), 1.03 (d, J =
6.9 Hz, 3H), 0.94 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.9 Hz, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 167.2, 151.8, 138.6, 128.6, 127.9, 127.8,
121.0, 73.2, 72.7, 67.1, 51.6, 42.6, 34.1, 14.5, 7.2, 5.3 ppm; MS (ESI-IT)
m/z 169.1 (7), 229.1 (6), 261.1 (14), 361.2 (5), 393.2 (M + H+, 100),
492.4 (8), 507.3 (12); HRMS calcd for C22H37O4Si [M + H+] 393.2456,
found 393.2469 (3.5 ppm).
(
)-(4R,5R)-Methyl 7-(Benzylo xy)-4-methyl-5-
(triethylsilyloxy)heptanoate (S31b).
Product S31b (0.906 g, yield = 90%) was obtained as a colorless oil from
α,β-unsaturated ester S30b (1.01 g) following general procedure A2 to
which was added pyridine29 (1.5 equiv, 315 μL) before the gas
atmosphere was changed to H2: Rf = 0.42 (hexanes/EtOAc, 80:20);
formula C22H38O4Si; MW 394.62 g/mol; IR (neat) νmax 2955, 2877,
1740, 1457, 1240, 1093, 909, 735 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.36−7.26 (m, 5H), 4.52 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.9 Hz, 1H),
3.77 (td, J = 3.9 Hz, 7.9 Hz, 1H), 3.67 (s, 3H), 3.53 (app t, J = 6.4 Hz,
2H), 2.39 (ddd, J = 5.7 Hz, 9.9 Hz, 15.6 Hz, 1H), 2.29 (ddd, J = 6.5 Hz,
(
)-(2S, 3R)-Methyl 5-(Benzyloxy)-2-methyl-3-
(triethylsilyloxy)pentanoate (S27b).
Product S27b was obtained as a pale yellow oil from alcohol S26b34
(1.54 g) following general procedure A3 and was used as crude without
Z
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9.6 Hz, 15.7 Hz, 1H), 1.94−1.84 (m, 1H), 1.81−1.64 (m, 2H), 1.57−
1.49 (m, 1H), 1.47−1.37 (m, 1H), 0.94 (t, J = 7.9 Hz, 9H), 0.84 (d, J =
6.8 Hz, 3H), 0.57 (q, J = 7.9 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3) δ 174.5, 138.8, 128.5, 127.9, 127.7, 73.2, 73.1, 67.7, 51.7, 38.5,
33.3, 32.8, 27.5, 14.8, 7.2, 5.4 ppm; MS (ESI-IT) m/z 155.1 (9), 213.1
(5), 231.1 (10), 263.2 (100), 395.3 (M + H+, 24); HRMS calcd for
C22H39O4Si [M + H+] 395.2612, found 395.2615 (0.6 ppm).
(hexanes/EtOAc, 80:20). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of 2,3-diastereomers in a ∼1:1
ratio of products 33a:33b.
33a: Rf = 0.36 (hexanes/EtOAc, 80:20); formula C19H27BrO4; MW
399.32 g/mol; IR (neat) νmax 3063, 3030, 2956, 2870, 1742, 1452, 1263,
1101 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.27 (m, 5H), 4.53 (d,
J = 12.2 Hz, 1H), 4.51 (d, J = 12.2 Hz, 1H), 4.10 (dd, J = 2.2 Hz, 11.2 Hz,
1H), 3.98 (ddd, J = 2.6 Hz, 5.2 Hz, 11.7 Hz, 1H), 3.70 (s, 3H), 3.58 (ddd,
J = 4.5 Hz, 8.1 Hz, 8.7 Hz, 1H), 3.50 (dt, J = 9.0 Hz, 7.5 Hz, 1H), 2.09−
2.01 (m, 2H), 1.96−1.90 (m, 1H), 1.86 (s, 3H), 1.69−1.64 (m, 1H),
1.70−1.58 (m, 1H), 1.52−1.38 (m, 2H), 0.84 (d, J = 7.0 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3) δ 171.6, 138.9, 128.6, 127.8, 127.7, 76.0,
(
)-(5R,6R)-6-(2-(Benzyloxy)ethyl)-5-methyltetrahydro-2H-
pyran-2-one (S32b).
73.3, 72.5, 67.5, 61.7, 53.1, 33.6, 26.8, 26.0, 24.8, 22.5, 17.7 ppm; MS
(ESI-IT) m/z 160.1 (6), 291.1 (6), 399.1 (M + H+, 100), 416.1 (9);
HRMS calcd for C19H28BrO4 [M + H+] 399.1165, found 399.1156
(−2.4 ppm).
To a cold (0 °C) solution of ester S31b (1.11 g) in dry MeCN (0.1 M,
28.0 mL) was added BF3·OEt2 (2 equiv, 713 μL), followed by stirring for
1 h at 0 °C. The reaction mixture was then treated with a saturated
aqueous solution of NH4Cl. The aqueous layer was extracted with Et2O
(3×), and the combined organic fractions were dried (MgSO4), filtered,
and concentrated in vacuo. The crude mixture was purified by flash
chromatography on silica gel (hexanes/EtOAc, 90:10 to 50:50) to afford
lactone S32b as a pale yellow oil (0.698 g, yield =79%): Rf = 0.26
(hexanes/EtOAc, 80:20); formula C15H20O3; MW 248.32 g/mol; IR
(neat) νmax 3030, 2961, 2877, 1734, 1455, 1365, 1241, 1205, 1109, 1078,
742, 700 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.39−7.29 (m, 5H), 4.57
(dt, J = 3.2 Hz, 9.6 Hz, 1H), 4.55 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.8
Hz, 1H), 3.72−3.64 (m, 2H), 2.56 (app t, J = 7.2 Hz, 2H), 2.10−2.03
(m, 2H), 2.00−1.91 (m, 1H), 1.87−1.81 (m, 1H), 1.72−1.65 (m, 1H),
0.99 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.1,
138.4, 128.7, 128.0, 127.9, 79.7, 73.5, 66.4, 32.8, 29.7, 27.0, 26.3, 12.9
ppm; MS (ESI-IT) m/z 141.1 (72), 231.1 (8), 249.1 (M + H+, 100),
317.2 (7), 497.3 (60), 695.3 (6); HRMS calcd for C15H21O3 [M + H+]
249.1485, found 249.1483 (−1.0 ppm).
33b: Rf = 0.31 (hexanes/EtOAc, 80:20); formula C19H27BrO4; MW
399.32 g/mol; IR (neat) νmax 3056, 3030, 2953, 2870, 1738, 1452, 1266,
1113, 1087 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.27 (m, 5H),
4.57 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.08 (ddd, J = 3.0 Hz,
5.0 Hz, 12.0 Hz, 1H), 3.94 (dd, J = 2.0 Hz, 10.8 Hz, 1H), 3.78 (s, 3H),
3.75 (dt, J = 4.5 Hz, 9.0 Hz, 1H), 3.66 (dt, J = 9.1 Hz, 7.7 Hz, 1H), 2.14−
2.04 (m, 1H), 2.01−1.92 (m, 1H), 1.84 (s, 3H), 1.68−1.54 (m, 3H),
1.50−1.38 (m, 2H), 0.84 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 171.2, 138.8, 128.6, 128.0, 127.8, 75.7, 73.5, 73.1, 67.6, 65.0,
53.4, 33.4, 27.1, 26.7, 24.7, 23.8, 17.7 ppm; MS (ESI-IT) m/z 160.1 (5),
291.1 (9), 399.1 (M + H+, 100), 401.1 (98), 402.1 (18); HRMS calcd for
C19H28BrO4 [M + H+] 399.1165, found 399.1160 (−1.4 ppm).
( )-(S)-Methyl 2-((2S,5R,6R)-6-(2-(Benzyloxy)ethyl)-5-meth-
yltetrahydro-2H-pyran-2-yl)propanoate (37a) and ( )-(R)-
Methyl 2-((2S,5R,6R)-6-(2-(Benzyloxy)ethyl)-5-methyltetrahy-
dro-2H-pyran-2-yl)propanoate (37b).
(
)-(5R,6R)-6-(2-(Benzyloxy)ethyl)-5-methyltetrahydro-2H-
pyran-2-yl acetate (S33c, S33d).
An inseparable mixture of product S33c,d (0.41 g, yield = 50%) was
obtained as a pale yellow oil from lactone S32b (2.51 g) following
general procedure A9 and purification by flash chromatography on silica
gel (hexanes/EtOAc 80:20). H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 10:1 ratio of
products S33c:S33d.
Products 37a and 37b (35 mg, yield = 85%) were obtained as pale yellow
oils from a mixture of bromides 33a and 33b (52 mg) following general
procedure A1 and purification by flash chromatography on silica gel
(hexanes/EtOAc 80:20). 1H NMR spectroscopic analysis of the
unpurified product indicated a pair of diastereomers in a 15:1 ratio of
products 2,3-anti (37a):2,3-syn (37b).
1
S33c,d: Rf = 0.44 (hexanes/EtOAc, 80:20); formula C17H24O4; MW
292.37 g/mol; IR (neat) νmax 2956, 2864, 1749, 1366, 1235, 1036 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.38−7.27 (m, 5Hc+5Hd), 6.09 (d, J =
3.3 Hz, 1Hd), 5.68 (dd, J = 2.9 Hz, 8.7 Hz, 1Hc), 4.54 (d, J = 11.9 Hz,
1Hc), 4.52 (d, J = 12.1 Hz, 1Hd), 4.49 (d, J = 12.2 Hz, 1Hd), 4.50 (d, J =
11.9 Hz, 1Hc), 4.16 (ddd, J = 2.8 Hz, 3.5 Hz, 9.6 Hz, 1Hd), 3.84 (ddd, J =
2.6 Hz, 3.8 Hz, 9.4 Hz, 1Hc), 3.65−3.60 (m, 1Hd), 3.60−3.57 (m, 2Hc),
3.56−3.54 (m, 1Hd), 2.12 (s, 3Hc), 2.06 (s, 3Hd), 1.94−1.85 (m, 1Hd),
1.93−1.84 (m, 1Hc), 1.83−1.78 (m, 1Hc+1Hd), 1.75−1.62 (m,
5Hc+5Hd), 0.99 (d, J = 6.9 Hz, 3Hc), 0.87 (d, J = 6.5 Hz, 3Hd) ppm;
37a: Rf = 0.25 (hexanes/EtOAc, 80:20); formula C19H28O4; MW
320.42 g/mol IR (neat) νmax 3062, 3030, 2950, 2872, 1738, 1456, 1201,
1089 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.27 (m, 5H), 4.54 (d,
J = 12.1 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 3.96 (ddd, J = 3.5 Hz, 4.6 Hz,
11.8 Hz, 1H), 3.68−3.58 (m, 2H), 3.64 (s, 3H), 3.52 (dt, J = 9.1 Hz, 7.5
Hz, 1H), 2.52 (dq, J = 8.9 Hz, 7.0 Hz, 1H), 2.10−2.00 (m, 1H), 1.99−
1.89 (m, 1H), 1.76 (ddd, J = 3.5 Hz, 6.7 Hz, 12.8 Hz, 1H), 1.65−1.55 (m,
2H), 1.44−1.34 (m, 1H), 1.31−1.21 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H),
0.83 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.9,
138.8, 128.4, 127.7, 127.5, 74.3, 73.3, 70.9, 67.4, 51.5, 45.4, 33.1, 28.2,
26.6, 25.3, 17.1, 13.5 ppm; MS (ESI-IT) m/z 213.1 (6), 289.2 (9), 321.2
(M + H+, 100); HRMS calcd for C19H29O4 [M + H+] 321.2060, found
321.2054 (−1.8 ppm).
37b: Rf = 0.31 (hexanes/EtOAc, 80:20); formula C19H28O4; MW
320.42 g/mol IR (neat) νmax 3062, 3030, 2951, 2873, 1737, 1455, 1258,
1199, 1093 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.28 (m, 5H),
4.54 (d, J = 11.8 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H), 3.93 (ddd, J = 3.8 Hz,
4.2 Hz, 11.6 Hz, 1H), 3.69−1.65 (m, 1H), 3.67 (s, 3H), 3.62−3.54 (m,
2H), 2.55 (dq, J = 7.0 Hz, 7.0 Hz, 1H), 2.09−1.99 (m, 1H), 1.93−1.86
(m, 1H), 1.66−1.60 (m, 3H), 1.45−1.27 (m, 2H), 1.17 (d, J = 7.0 Hz,
3H), 0.84 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ
175.6, 138.7, 128.6, 128.0, 127.8, 74.0, 73.5, 70.4, 67.6, 51.8, 44.8, 33.2,
28.8, 26.9, 26.0, 16.9, 13.5 ppm; MS (ESI-IT) m/z 213.1 (9), 289.2 (18),
321.2 (M + H+, 100); HRMS calcd for C19H29O4 [M + H+] 321.2060,
found 321.2057 (−1.1 ppm).
13C NMR (100 MHz, CDCl3) δ 170.2d, 169.6c, 138.9d, 138.8c, 128.6c+d
,
127.9c+d, 127.8c+d, 95.60c, 95.13d, 79.7d, 76.2c, 73.4c, 69.8d, 67.3c, 67.0d,
34.7d, 33.3c, 31.3d, 30.5d, 30.4c, 29.1c, 25.6c, 23.6d, 21.5c, 17.3d, 12.2c,
11.4d ppm; MS (ESI-IT) m/z 233.2 (9), 315.2 (M + Na+, 100), 607.3
(7); HRMS calcd for C17H24NaO4 [M + Na+] 315.1567, found
315.1569 (0.8 ppm).
( )-Methyl 2-((2S,5R,6R)-6-(2-(Benzyloxy)ethyl)-5-methylte-
trahydro-2H-pyran-2-yl)-2-bromopropanoate (33a; 33b).
Products 33a and 33b (0.53 g, yield = 95%) were obtained as pale yellow
oils from a mixture of product S33c,d (0.41 g) following general
procedure A10 and purification by flash chromatography on silica gel
AA
dx.doi.org/10.1021/jo400721e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
)-(R)-2-((2S,5R,6R)-6-(2-(Benzyloxy)ethyl)-5-methyltetra-
REFERENCES
■
hydro-2H-pyran-2-yl)propyl 4-bromophenylcarbamate (S68).
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Primary alcohol as a colorless oil was obtained from ester 37a (34 mg)
following general procedure A4. To a cold (0 °C) solution of crude
alcohol in dry CH2Cl2 (0.1 M, 1.1 mL) were added successively Et3N
(1.1 equiv, 16 μL) and p-bromophenyl isocyanate (1.1 equiv, 23 mg).
The reaction mixture was stirred for 3 h at 0 °C before the reaction
mixture was treated with a saturated aqueous solution of NaHCO3
followed by separation of the organic phase at room temperature. The
aqueous layer was extracted with EtOAc (3×), and the combined
organic fractions were dried (MgSO4), filtered, and concentrated in
vacuo. The crude mixture was purified by flash chromatography on silica
gel (hexanes/EtOAc, 90:10) to afford product S68 as a white solid (46
mg, yield = 90% over two steps), for which structural assignment was
confirmed by X-ray analysis (cf. Supporting Information, part III, X-
ray): Rf = 0.26 (hexanes/EtOAc, 80:20); formula C25H32BrNO4; MW
490.43 g/mol; IR (neat) νmax 3312, 2954, 2872, 1732, 1707, 1595, 1533,
1399, 1308, 1220, 1077, 1047, 824, 736, 698 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.34−7.13 (m, 9H), 6.60 (bs, 1H), 4.45 (d, J = 11.7 Hz, 1H),
4.39 (d, J = 11.8 Hz, 1H), 4.20 (dd, J = 4.0 Hz, 10.5 Hz, 1H), 4.04 (dd, J =
6.0 Hz, 10.5 Hz, 1H), 3.84 (ddd, J = 3.5 Hz, 4.3 Hz, 11.5 Hz, 1H), 3.58−
3.52 (m, 1H), 3.52−3.46 (m, 1H), 3.35−3.28 (m, 1H), 1.99−1.90 (m,
1H), 1.87−1.79 (m, 2H), 1.69−1.63 (m, 1H), 1.61−1.52 (m, 2H),
1.35−1.21 (m, 2H), 0.87 (d, J = 6.9 Hz, 3H), 0.77 (d, J = 7.0 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 153.7, 138.6, 137.4, 132.2, 128.6,
128.0, 127.8, 120.2, 115.9, 74.0, 73.4, 70.0, 67.7, 67.6, 37.6, 33.3, 28.3,
27.0, 25.8, 17.1, 14.0 ppm; MS (ESI-IT) m/z 203.0 (10), 412.2 (10),
490.2 (100, M + H+), 512.1 (68, M + Na+), 530.1 (20), 574.1 (13);
HRMS calcd for C25H33BrNO4 [M + H+] 490.1587, found 490.1589
(0.3 ppm); calcd for C25H32BrNO4Na [M + Na+] 512.1407, found
512.1410 (0.5 ppm).
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ASSOCIATED CONTENT
■
S
* Supporting Information
(7) (a) Guindon, Y.; Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme,
D.; Renaud, J.; Robinson, G.; Lavallee, J. F.; Slassi, A.; Jung, G.;
́
Rancourt, J.; Durkin, K.; Liotta, D. J. Org. Chem. 1994, 59 (5), 1166−
1178. (b) Guindon, Y.; Faucher, A. M.; Bourque, E.; Caron, V.; Jung, G.;
Landry, S. R. J. Org. Chem. 1997, 62 (26), 9276−9283 and references
therein. (c) Guindon, Y.; Liu, Z. P.; Jung, G. J. Am. Chem. Soc. 1997, 119
NMR spectra (1H and 13C) of radical precursors (13−22a,b,
31−33a,b) and reduced products (23−30a,b, 34−37a,b).
Cartesian coordinates (GS and TS) of radical intermediates for
17a,b, 32a,b, 38−39a,b,. X-ray crystallographic structural proof
for reduced products 25a (S9), 28a (S45), 30a (S60) and 37a
(S68). This material is available free of charge via the Internet at
http://pubs.acs.org.
́
(39), 9289−9290. (d) Bouvier, J. P.; Jung, G.; Liu, Z. P.; Guerin, B.;
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(8) Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J. J. Am. Chem. Soc.
2003, 125 (38), 11456−11457.
(9) Numbering of atoms throughout manuscript was attributed
according to that of ionophores 1a−c.
AUTHOR INFORMATION
■
́
(10) Godin, F.; Prevost, M.; Gorelsky, S. I.; Mochirian, P.; Nguyen, M.;
Corresponding Author
Viens, F.; Guindon, Y., Chem. Eur. J. 2013, accepted (doi: 10.1002/
chem.201300377).
*E-mail: yvan.guindon@ircm.qc.ca.
Notes
(11) The stereogenic center of the starting β-hydroxy-α-methylalde-
hyde correponds to the C8 center of zincophorin.
The authors declare no competing financial interest.
(12) Renaud, P.; Beauseigneur, A.; Brecht-Forster, A.; Becattini, B.;
Darmency, V.; Kandhasamy, S.; Montermini, F.; Ollivier, C.; Panchaud,
P.; Pozzi, D.; Scanlan, E. M.; Schaffner, A. P.; Weber, V. Pure Appl. Chem.
2007, 79 (2), 223−233.
ACKNOWLEDGMENTS
■
The authors wish to express their gratitude to the Natural
Sciences and Engineering Research Council of Canada
(NSERC) for its financial support. Fellowship support (B2)
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and-half combination of HF and Becke exchange with Lee−Yang−Parr
́ ́
from Fonds Quebecois de la Recherche sur la Nature et les
Technologies (FQRNT) to F.G. is also gratefully acknowledged.
We also thank Prof. Tom K. Woo for providing an access to the
high-performance computing facilities at the University of
Ottawa.
LYP
correlation functional: 0.5*EXHF + 0.5*EXLSDA + 0.5*ΔEXBecke88 + EC
(Gaussian 09).
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AB
dx.doi.org/10.1021/jo400721e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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