A bidirectional approach to the synthesis of polypropionates: Synthesis of C1-C13 fragment of zincophorin and related isomers

Article abstract of DOI:10.1021/jo2013884

The structure-activity study of a bioactive natural product containing polypropionate subunits requires that its stereoisomers also be evaluated. Therefore, a general approach to synthesize these motifs is necessary. We describe herein the synthesis of the C1 - C13 polypropionate subunit of zincophorin and isomers there of using a two-reaction sequence: an aldol reaction using a mixture of tetrasubstituted enoxysilanes and a hydrogen-transfer reaction, both under Lewis acid control. Selection of the appropriate Lewis acid dictates the stereochemical outcome of these reactions. From a tactical standpoint, this study shows how a polypropionate sequence can be read and constructed in two directions, either the east-west or the west-east approaches. The choice of the optimal route is influenced by the number of complexation sites that can interfere in the aldol step under bidentate Lewis acid control.

Full text of DOI:10.1021/jo2013884

FEATURED ARTICLE
pubs.acs.org/joc
A Bidirectional Approach to the Synthesis of Polypropionates:
Synthesis of C1ÀC13 Fragment of Zincophorin and Related Isomers
Philippe Mochirian,†,‡ Franc-ois Godin,†,‡ Ioannis Katsoulis,|| Isabelle Fontaine,†,‡ Jean-Franc-ois Brazeau,^
and Yvan Guindon*,†,‡,§
†(IRCM), Bio-organic Chemistry Laboratory, Institut de Recherches Cliniques de Montrꢀeal, 110 Avenue des Pins Ouest, Montrꢀeal,
Quꢀebec, Canada H2W 1R7
‡Dꢀepartement de Chimie, Universitꢀe de Montrꢀeal, C.P. 6128, succursale Centre-ville, Montrꢀeal, Quꢀebec, Canada H3C 3J7
§Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montrꢀeal, Quꢀebec, Canada, H3A 2K6
NCSR “Demokritos”, Institute of Physical Chemistry, Agia Paraskevi, GR 15310, Greece
^Department of Chemistry, University of California, 619 Latimer Hall, Berkeley, California, 94720, United States
S Supporting Information
b
ABSTRACT: The structureÀactivity study of a bioactive natural product
containing polypropionate subunits requires that its stereoisomers also be
evaluated. Therefore, a general approach to synthesize these motifs is
necessary. We describe herein the synthesis of the C1ÀC13 polypropionate
subunit of zincophorin and isomers thereof using a two-reaction sequence:
an aldol reaction using a mixture of tetrasubstituted enoxysilanes and a
hydrogen-transfer reaction, both under Lewis acid control. Selection of the
appropriate Lewis acid dictates the stereochemical outcome of these
reactions. From a tactical standpoint, this study shows how a polypropionate sequence can be read and constructed in two
directions, either the eastÀwest or the westÀeast approaches. The choice of the optimal route is influenced by the number of
complexation sites that can interfere in the aldol step under bidentate Lewis acid control.
’ INTRODUCTION
For decades, ionophores have been of great interest for both
their biological properties and their architectural complexity.1
Their capacity to affect ion-exchange processes of monovalent
(Na+, K+) or divalent cations (Ca2+, Zn2+, Mg2+, etc.) across cell
membranes by forming lipophilic complexes explains their anti-
fungal and antibiotic activities.2 Recently, some polyketide
members of this family such as zincophorin 1, narasin 3, and
salinomycin 4 (Figure 1) have drawn increased attention after
the discovery of their potential anticancer activity.3,4 Zincophor-
in 1 was isolated from Streptomyces griseus and has demonstrated
a strong activity against Gram-positive bacteria and Clostridium
welchii.5 Its methyl ester 2 (Figure 1) was reported to have
strong inhibitory properties against influenza WSN virus and
reduced host cell toxicity compared to the free acid.6 Narasin 3
has recently been identified as an inhibitor of the NF-kB
signaling pathway.7 Constitutive activity of NF-kB signaling in
tumor cells is involved in cellular proliferation, blocking apop-
tosis, promotion of angiogenesis, and metastasis.8 Although the
mechanism of action of salinomycin 4 is not well understood, it
has demonstrated a unique activity against cancer stem cells
(CSCs).9 It has been shown that these cells play a critical role in
the growth of some tumors. CSCs are also resistant to che-
motherapy and radiation, justifying the interest of the biomedical
community to identify and develop novel molecules that would
target them.10,11
Figure 1. Representative polyketide ionophores.
These polyketides are natural products which have been bio-
synthesized by various organisms in response to environmental
stress. The biological activities described above are unlikely
correlated with their natural functions that have been selected
through evolution. These molecules could therefore be con-
sidered as “chemical leads” that could be optimized for their
potency, selectivity, and “druglike” properties. From a medicinal
Received: July 11, 2011
Published: August 24, 2011
r
2011 American Chemical Society
7654
dx.doi.org/10.1021/jo2013884 J. Org. Chem. 2011, 76, 7654–7676
|

The Journal of Organic Chemistry
FEATURED ARTICLE
chemistry standpoint, pharmacophores will need to be identified.
This could be done notably by deleting or inverting the stereo-
centers present to evaluate the impact of these changes on the
biological profiles and conformation of parent molecules.12,13
The selection of a strategy to synthesize a molecule such as
zincophorin should therefore take into account the flexibility
needed to also prepare some of its epimers while allowing
the synthesis of the 8,9-anti-9,10-anti-10,11-anti-11,12-anti
(C8ÀC12) polypropionate motif known for its synthetic
challenge.
Many groups have been inspired by the stereochemical
complexity and challenges associated with the synthesis of these
chains of consecutive carbon centers bearing methyl and hydrox-
yl substituents.14 As a consequence, a number of approaches
to the stereoselective synthesis of polypropionates have been
described in the last decades.15À22 These contributions have
advanced considerably our collective knowledge in organic
chemistry. Our group has been interested, during this period,
in developing a general substrate-controlled strategy for the syn-
thesis of polypropionates,23 avoiding some of the mismatched
scenarios noted in reagent-controlled strategies involving chiral
substrates.
used in the aldol step are a mixture of stereoisomers (Z and E).
Since a free radical is formed at the carbon α to the ester in the
second step of the reaction sequence, there is no need to control
the stereochemistry of the C2 precursors in the aldol step. Con-
sequently, stereodefined tetrasubstituted enoxysilanes do not
need to be made, thus removing a significant roadblock from a
practical standpoint.
The polypropionate motifs can be constructed in two different
directions. In the case of zincophorin, the C5ÀC13 sequence
could be elaborated from the C6 stereocenter with introduction
of the other chiral centers using the series of reactions described
before. This is referred to as the westÀeast approach. Alterna-
tively, the synthesis can start with the C12 stereocenter (e.g.,
from C12 to C1) and is termed the eastÀwest approach. From a
tactical standpoint, these two approaches may provide different
challenges that would need to be considered prior to synthesis. In
order to make such decisions easier in the future, both directions
will be evaluated in this study in the context of the C1ÀC13
zincophorin fragment synthesis. Finally, as stated before, our
approach should also allow for the preparation of various isomers
in a predictable and controlled fashion.
This study emphasizes the need to control the number of
complexing sites in planning the aldol step while also demon-
strating long distance disturbances in the course of a hydrogen-
transfer step. More importantly, it illustrates how, depending on
the stereochemistry sought after, any polypropionate chain can
be stereoselectively constructed by identifying the nature of the
Lewis acid needed in each reaction sequence to induce the
desired stereocenters.
In the present study, we aim to synthesize the C1ÀC13
portion of zincophorin (Figure 1). Stereocenters bearing a
hydroxyl moiety at C3 will be created using a Mukaiyama aldol
reaction on a β-hydroxy-α-methyl aldehyde (Figure 2). The
methyl substituent at C2 will originate from a stereocontrolled
hydrogen-transfer reaction to a carbon-centered free radical as
illustrated in Figure 2.
These reactions are remarkable in three aspects. First, our pre-
vious results indicated that the stereospecifity of both reactions
depends uniquely on 1,2-induction with no opposing 1,3-induc-
tion observed. Second, diastereoselectivity in both reactions
depends on the choice of Lewis acid used. Third, the enoxysilanes
’ RESULTS AND DISCUSSION
During the past decade, our group studied the synthesis of
polypropionate motifs using a highly selective tandem reaction
sequence consisting of a Mukaiyama aldol reaction combined
with a radical reduction, as illustrated in Figure 3. The aldoliza-
tion reaction is performed using a mixture of tetrasubstituted
ketene silylated acetals (KSA) bearing a heteroatom (X = Br,
SePh). Depending on the nature of the Lewis acid (monodentate
or bidentate), we can expect to generate either a 3,4-syn or anti
relationship. A monodentate Lewis acid (BF3 OEt2) will lead
to a 3,4-syn relationship through a FelkinÀAnh transition state,
3
Figure 2. General strategy to the synthesis of polypropionates.
Figure 3. Mukaiyama and free-radical hydrogen-transfer approach to polypropionate formation.
7655
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
Scheme 1. Radical Reduction Strategies
Figure 4. Stereochemistry as a function of Lewis acids.
2,3-anti relative disubstituted aldehydes (Cram chelate con-
trolled aldols) are often problematic, leading to poor diastereos-
electivities. Nevertheless, such complications were not detected
in our aldolizations.23bÀd
Figure 4 summarizes our previous results and can be used for
the planning of any synthesis. Depending on the relative stereo-
chemistry sought after in each reaction, a Lewis acid is suggested
to create each stereocenter in a stepwise process. Armed with this
tool, the synthesis of zincophorin was initiated.
Zincophorin’s architectural complexity has elicited consider-
able synthetic interest. Four total syntheses were completed by
Danishefsky,27 Cossy,28 Myashita,29 and Leighton,22c while syn-
theses ofvarious fragments wereprovided by Hsung,30 Marshall,20a
Roush,18b,d Burke,31 Holzapfel,32 Kallmerten,33 and our group.34
A first retrosynthetic disconnection of zincophorin 1 was envi-
sioned at the C16ÀC17 olefin. A JuliaÀKocienski coupling35
would occur between the aldehyde 5 and a sulfobenzotetrazole
bearing the C17ÀC25 fragment. The aldehyde 5 could in turn
be obtained from a carbonÀcarbon bond-forming reaction at
C12ÀC13, the primary alcohol 6 serving as precursor. The 3,7-
trans trisubstituted tetrahydropyran could be constructed step-
wise by first reacting our brominated tetrasubstituted enoxysilane
7a with aldehyde 8 (precursor of a six-membered oxonium)
using slightly modified Evans conditions36 that should lead to a
C3ÀC7 trans-selective stereochemistry and tertiary bromides at
C2. Interestingly, we recognized that the C2ÀC3 anti stereo-
chemistry could also be accessed from a radical reaction. The
resulting mixture of C2 tertiary bromides could then be reduced
by a hydrogen-transfer reaction taking advantage of the exocyclic
effect, illustrated in Scheme 1, which allows for a high C2ÀC3
anti ratio. Finally, aldehyde 8 could originate from a chain
extension starting from the generic stereoheptad 9 bearing the
requisite polypropionate sequence sought after. Synthon 9 could
be conceptually envisioned in two directions as illustrated in
Scheme 2. The sequence could be “read” from eastÀwest starting
from C12, the starting stereogenic center. Creation of the stereo-
genic center at C11 would necessitate a stepwise anti aldol
followed by an anti hydrogen transfer at C10 to create the first
propionate unit. Repeating the sequence will then require an anti
aldol to generate C9, an anti hydrogen transfer (C8), followed by
a syn aldol (C7) and an anti hydrogen transfer (C6). Lewis acids
needed to achieve this sequence of reactions and the correspond-
ing stereochemistry can be decrypted using Figure 4. The
tetrahydropyran would then be constructed to create the stereo-
genic center at C2, as previously described (vide supra).
while a bidentate Lewis acid (TiCl4 or TiCl3OiPr) will lead to a
3,4-anti relationship through a Cram chelate transition state. In
both cases, a mixture of stereoisomers at C2 was obtained.
Our group and others have shown that some radical processes
on acyclic substrates can be domesticated.24 We demonstrated
that hydrogen-transfer reactions on carbon-centered free radi-
cals, flanked on one side by an ester and on the other by a
stereogenic center bearing an electronegative group such
as a hydroxyl, are controlled through the use of Lewis acids.25
The 2,3-anti relationship (Figure 3) is achieved by reacting the
tertiary halide aldol products with Bu2BOTf or Et2BOTf. First, a
borinate intermediate is formed at C3 which eliminates hydrogen
bonding between the parent hydroxyl and ester. Transition state
A, illustrated in Scheme 1, rationalizes predominance for the
2,3-anti product in the hydrogen-transfer reaction, termed
the “acyclic effect”. Minimization of allylic-1,3 strain and dipoleÀ
dipole effects are critical factors resulting in the lower energy of
this transition state. The 2,3-syn relationship is generated when
the radical precursors are first complexed with a bidentate Lewis
acid (e.g., MgBr2 OEt2 or AlMe3) followed by hydrogen trans-
3
fer. The resulting “endocyclic effect”, the radical being embedded
in a temporary ring, favors transition state B, leading predomi-
nantly to the 2,3-syn product. Given that polypropionates are a
continuing sequence of hydroxyl and methyl groups, our set of
reactions was repeated using the resulting β-benzyloxy-α-methyl
aldehydes (Figure 3) derived from the propionate motifs as
described in Figure 2. Recently, this strategy led to the synthesis
of all possible 16 stereopentads starting from a single stereo-
center in the starting material.23e Fifteen out of the 16 hydrogen-
transfer reactions demonstrated both high stereocontrol and
yield.23d In one case, we had to take advantage of the “exocyclic
effect” in order to obtain a high anti ratio (C2ÀC3). The pre-
sence of a cycle α to the carbon-centered radical generally led to
higher anti stereoselectivity (Scheme 1, transition state C).25b,e
In the context of the Mukaiyama reaction, the presence of two
stereogenic centers at C2 and C3 of the starting aldehyde is
known to be a potential complicating factor in aldol reactions due
to opposing 1,2- and 1,3-inductions.26 Indeed, 2,3-syn relative
disubstituted aldehydes (in FelkinÀAnh controlled aldols) and
Similarly, the westÀeast approach can be considered starting
from the stereogenic center at C6. In this case, as illustrated in
Scheme 2, three anti aldol reactions will be needed, along with a
7656
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
Scheme 2. Retrosynthetic Analysis of Zincophorin and of Its Polypropionate Chain
first hydrogen transfer to establish a syn relationship (C5ÀC6)
followed by two anti hydrogen transfers. In this direction,
construction of the tetrahydropyran ring will be completed
earlier in the synthesis.
A one-pot procedure was also developed where a mixture of
phenylselenated enoxysilanes 7b was used with Et2BOTf as the
sole Lewis acid for both steps.23e The 2,3-anti-3,4-anti propionate
11 was obtained in excellent yield, and high diastereoselectivity
was noted for both steps (>20:1). The C3 alcohol of 11 was then
protected as a benzyl ether (S2) and the ester converted to
aldehyde as in 12 (88% over three steps).
Are both reaction sequences equivalent? As stated before, the
westÀeast approach would require an anti aldol to create the
hydroxyl at C11 in the third iteration. This requires the formation
of a Cram chelate intermediate in the presence of many benzyl
ethers which show a high affinity for titanium Lewis acids. The
eastÀwest approach, however, suggests the use of a syn aldol in
the third iteration, thus requiring a simple monodentate activa-
tion of the carbonyl. The sequence of hydrogen-transfer reac-
tions only differs slightly. In the westÀeast approach, a syn
hydrogen transfer is needed in the first iteration that will involve
a chelated intermediate. The next iterations require anti selective
hydrogen transfers. Both reaction sequences were studied.
We also planned to vary the stereoisomers (C9ÀC12) using
the westÀeast approach, their stereocontrolled synthesis having
been proven difficult.
EastÀWest Approach. Our first approach to the synthesis of
the C1ÀC13 fragment of zincophorin is illustrated in Scheme 3.
The aldehyde 11 derived from the (S)-Roche ester was used as a
starting material. This stereocenter will become C12 (using the
zincophorin numbering) of the final product, and from it eight
other stereogenic centers will be generated.
Stereopentad 13 was the next target. The 3,4-anti relative
stereochemistry (C9ÀC10 in 1) required use of a bidentate
Lewis acid (TiCl4) in the aldol step (S4a, S4b) while dibutylbor-
on triflate can be used for the hydrogen-transfer step to obtain a
2,3-anti relative stereochemistry (C8ÀC9 in 1). Stereopentad
13 was obtained in a 76% yield from 12 with excellent diaster-
eoselectivity. As stated before, aldehydes bearing α and β
substituents are known to induce, in certain cases, opposing
stereochemistry in many aldol reactions, leading to poor diaster-
eoselectivities. Considering product 12, the 2,3-anti relative
stereochemistry could cause mismatch scenarios under chelation
control (1,2- and 1,3- opposing inductions). However, we
obtained a greater than 20:1 ratio (3,4-anti versus 3,4-syn; as
measured by 1H NMR on crude reaction mixtures) in the aldol
step, testifying to the synthetic usefulness of our sterically encum-
bered tetrasubstituted enoxysilanes 7, 1,2-induction being the
dominant paradigm in our reactions. These results are impressive
considering the known difficulties of inducing the anti,anti motif
in polypropionates.
Aldehyde 10 was first reacted with bromoenoxysilanes 7a in
the presence of TiCl4 at À78 ꢀC, as depicted in Figure 3.
Resulting tertiary bromides S1a and S1b were then treated with
dibutylboron triflate at À78 ꢀC in the presence of DIEA prior
to the hydrogen-transfer step. This was followed by addition of
tributyltin hydride and Et3B to the reaction mixture. The free-
radical chain is simply initiated by air injection with a syringe.
A second iteration of our reaction sequence was then carried
out to synthesize stereoheptad 15 (Scheme 3). First, free-alcohol
13 was protected as a benzyl ether (S5) and the ester converted
in two steps to aldehyde 14 (72% overall yield). The 3,4-syn
relative stereochemistry (C7ÀC8 in 1) of S7 now required a
Mukaiyama reaction under control of a monodentate Lewis acid
7657
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
Scheme 3. EastÀWest Synthesis of C1ÀC13 Fragment 20 of Zincophorina
a Key:(a) Et2BOTf, 7b, CH2Cl2, À78 ꢀCthenBu3SnH, BEt3, air, CH2Cl2, À78 ꢀC;(b) TiCl4, 7a, CH2Cl2, 78ꢀC;(c) Bu2BOTf, DIEA, CH2Cl2, À78 ꢀCthen
Bu3SnH, BEt3, air, CH2Cl2, À78 ꢀC; (d) BnOCdNHCCl3, TfOH, c-Hex/CH2Cl2, 0 ꢀC; (e) DIBAL-H, CH2Cl2, À40 ꢀC; (f) (COCl)2, DMSO, CH2Cl2,
À78 ꢀC then NEt3, À78 ꢀC; (g) BF3 OEt2, 7a, CH2Cl2, À78 ꢀC; (h) TESOTf, 2,6-lutidine, CH2Cl2, 0 ꢀC; (i) (EtO)2POCH2CO2Et, DBU, LiCl, MeCN,
3
0 ꢀC; (j) H2, PdÀC, pyridine, MeOH, rt; (k) BiBr3, 7a, CH2Cl2/MeCN, À78 ꢀC; (l) Ph3SnH, BEt3, air, toluene, À78 ꢀC; (m) TBDPSCl, imidazole,
CH2Cl2, rt; (n) Pd(OH)2, H2, THF, rt; (o) PivCl, NEt3, CH2Cl2, rt.
such as BF3 OEt2 (Figure 4). The 2,3-anti relative stereochem-
ester to the corresponding alcohol (S13) and further elaboration
of fragment C1ÀC13.
3
istry (C6ÀC7 in 1) requires once again a hydrogen-transfer
reaction under acyclic control as previously described (i.e.,
Bu2BOTf). The stereoheptad 15 was obtained in a 70% yield
from aldehyde 14 with excellent diastereoselectivities for both
steps (>20:1). With the C5ÀC13 fragment in hand, we con-
sidered the synthesis of the C3ÀC7 trans tetrahydropyran. The
secondary alcohol of 15 was first protected with a triethylsilyl
group (TES; S8), and the ester reduced to aldehyde 16 (73%
over three steps). Chain extension was performed by a HornerÀ
WadsworthÀEmmons olefination (S10) followed by a chemo-
selective hydrogenation of the olefin in presence of benzyl groups
(S11).37
The resulting ester was reduced to aldehyde 17 (65% overall
yield from 16) which was reacted with bromoenoxysilanes 7a in
the presence of BiBr3 as suggested in the Evans protocol,36 with
slight modifications (Scheme 3). The cyclization took place in a
3,7-trans stereoselective manner with a 1:1 ratio of C2 epimeric
tertiary bromides 18a and 18b obtained in excellent yield (84%).
The hydrogen-transfer reaction was then performed on 18 to
give in excellent yield the expected C2ÀC3 anti product 19a, but
with a disappointing isomeric ratio of 3.5:1. This result was very
intriguing to us, having in the past achieved many radical
reductions with an adjacent tetrahydropyran or tetrahydrofuran
flanking the carbon-centered radical with excellent anti-selective
ratios.25,34,38 Nevertheless, the 2,3-anti diastereoisomer was
easily separated by flash chromatography after reduction of the
This result provided one more reason to evaluate the other
approach (i.e., westÀeast) described before. The planned second
synthesis dictates that the tetrahydropyran ring be built earlier,
thus shedding light on the impact of a shorter side chain at
C7 of the tetrahydropyran on the reduction of the tertiary
bromides at C2.
WestÀEast Approach. Alternatively, the C1ÀC13 fragment
21 could originate through two successive iterations of our
reaction sequence on aldehydes 22 and 23 (Scheme 4). These
successive iterations would install the all-anti core of zincophorin
(C8ÀC12) that was previously proven very challenging to
synthesize (vide infra). The aldehyde 23 bearing the requisite
3,7-trans tetrahydropyran could be obtained from a cycloether-
ification process on aldehyde 24 as previously described
(Scheme 3). Finally, the latter would come from an extension
of propionate motif 25 (C5ÀC9).
Synthesis of the substituted tetrahydropyran ring is depicted in
Scheme 5.39 The first propionate unit 27 targeted has a 3,4-syn
relative stereochemistry (C7ÀC8 of 1). This was achieved
through a Mukaiyama aldol reaction on aldehyde 26 with
enoxysilane 7a under BF3 OEt2 control (Figure 4). A FelkinÀ
3
Anh transition state had to be favored; therefore, the presence of
a large protecting group on the primary hydroxyl (TBDPS) was
needed to increase the diastereoselectivity of this reaction (ratio
of 11:1 favoring the 3,4-syn relative isomer S16). The 2,3-anti
7658
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
stereochemistry (C6ÀC7 of 1) was secured by an anti-selective
hydrogen-transfer reaction as described before. This sequence
was also developed as a one-pot reaction using phenylselenated
enoxysilanes 7b.23e A similar sequence of reactions was followed
in order to successively convert propionate motif 27 to aldehyde
28 (through S17 and S18; 84% over three steps) and then to
aldehyde 29 (56% over four steps). The latter was subjected to
cycloetherification to form stereoselectively the 3,7-trans tetra-
hydropyran tertiary bromides 30a and 30b as a C2 epimeric
mixture, in good yield. These bromides were then reduced under
radical conditions. The C2ÀC3 anti product 31 was obtained
in good yield and ratio (12:1). The major product (2,3-anti) 31a
obtained was identical (1H, 13C NMR and [α]D) to the one
reported by Cossy et al.28c Interestingly, the 2,3-anti ratio
observed for 31 is significantly improved as compared to its
extended analogue 19 (12:1 versus 3.5:1; Scheme 3). This result
might point to long distance disturbance of the acyclic substi-
tuted side-chain attached at C7, a hypothesis currently being
evaluated in a separate study.
used a similar aldehyde and various chiral reagents or approaches
(chiral boron enolates; crotyl titanate and allenyl zinc), in their
remarkable study.25c They were hoping to overcome the oppos-
ing inductions of substituents at C7 and C8, in the context of
the nucleophilic additions on their aldehyde at C9. The diaster-
eoselectivities observed were modest (4:1 at most) or nonexis-
tent in spite of the demonstrated usefulness of these well-crafted
chiral reagents toward polypropionate synthesis. In the case of
our substrate-controlled approach, the desired anti relative
stereochemistry at C8ÀC9 of 1 required formation of a Cram
chelate bicyclic intermediate between the carbonyl of the alde-
hyde (C9) and the tetrahydropyran oxygen. In addition, we
sought to stereoselectively prepare the four possible isomers at
C9 and C10 to test the versatility of our approach.
Different Lewis acids were screened for the Mukaiyama aldol
reaction (Table 1). Monodentate Lewis acid, such as BF3 OEt2
3
(entry 1), led to very good ratios favoring the 8,9-syn adduct 34
with an excellent yield. TiCl4, a bidentate Lewis acid, was ineffi-
cient to promote a diastereoselective Cram chelate aldol reaction
using either 1.3 equiv (entry 2) or 2.5 equiv (entry 3) although
good yields of aldol products were recovered. Switching from
TiCl4 to 1.3 equiv of TiCl3(OiPr) led to a reversal of the
diastereoselectivity toward FelkinÀAnh adducts (entry 4). How-
ever, 8,9-anti Cram chelate adducts 33 were obtained selectively
by increasing the amount of Lewis acid to 2.5 equiv (entry 5). As
well, we obtained good selectivity toward the 8,9-anti products
Ester 31 was reduced to the corresponding primary alcohol
S22 and the 2,3-anti isomer easily separated by chromatography
(Scheme 5). The alcohol at C1 was protected by a benzyl group
(S23) followed by TBDPS group deprotection (S24) and sub-
sequent oxidation of the resulting primary alcohol to aldehyde 32
(68% overall yield from 31).
We were then ready to synthesize subsequent propionate units
following the west to east direction. Interestingly, Cossy et al.28
34 using MgBr2 OEt2, albeit with a lower yield (entry 6).
3
These results are interesting in many aspects. We demon-
strated for the first time, the feasibility of our approach to
successfully achieve an aldolization step in presence of a co-
ordinating functionality embedded in a ring (tetrahydropyran).
Increased rigidity of the corresponding Cram chelate intermedi-
ate could potentially increase the energy of the transition states.
However, we were pleased to note high ratios and good yield.
The second point of interest is the importance of the stoichiom-
etry of TiCl3(OiPr) to obtain a high 8,9-anti ratio. We did
observe a similar requirement in our recent study on the syn-
thesis of stereopentads and suggested that an “ate” complex was
involved. Our rationale was based on NMR studies and Gau’s
previous reports on titanium complexes where he ranked the
affinity of various ligands to titanium (iPrOÀ > ClÀ > THF >
Scheme 4. Retrosynthetic Analysis of WestÀEast Modified
Approach
Scheme 5. Synthesis of Tetrahydropyran Fragment 32a
a Key: (a) BF3 OEt2, 7a, CH2Cl2, À78 ꢀC; (b) Bu2BOTf, DIEA, CH2Cl2, À78 ꢀC then Bu3SnH, BEt3, air, CH2Cl2, À78 ꢀC; (c) TESOTf, 2,6-lutidine,
3
CH2Cl2, 0 ꢀC; (d) DIBAL-H, CH2Cl2, À40 ꢀC; separation; (e) (COCl)2, DMSO, CH2Cl2, À78 ꢀC then NEt3, À78 ꢀC; (f) Ph3PC(H)dCO2Me,
toluene, reflux; (g) H2, PdÀC, pyridine, EtOAc, rt; (h) DMP, NaHCO3, CH2Cl2, rt; (i) BiBr3, 7a, CH2Cl2/MeCN, À78 ꢀC; (j) Ph3SnH, BEt3, air,
toluene, À78 ꢀC; (k) BnOCdNHCCl3, TfOH, c-Hex/CH2Cl2, 0 ꢀC; (l) TBAF, THF, 0 ꢀC to rt.
7659
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
Table 1. Iterative Mukaiyama aldolization on aldehyde 32
entry
Lewis acid
(equiv)
yieldc (%)
selectivityd 33:34
a
1
2
3
4
5
6
BF3 OEt2
(1.5)
(1.3)
(2.5)
(1.3)
(2.5)
(5.0)
quante
89
1:>20
1:1
3
b
TiCl4
b
TiCl4
82
6:1
TiCl3(OiPr)b
TiCl3(OiPr)b
77
1:3
71
>20:1
>20:1
b
MgBr2.OEt2
53
a Reactions were conducted with 2.0 equiv of enoxysilane 7a followed by the Lewis acid in CH2Cl2 (0.1 M) at À78 ꢀC for 2 h. b Aldehydes were
precomplexed with the Lewis acid followed by the addition of 2.0 equiv of enoxysilane 7a in CH2Cl2 (0.1 M) at À78 ꢀC for 2 h. c Isolated yields over two
steps: oxidation then aldol reaction. d 8,9-anti/8,9-syn. Product ratios were determined by 1H NMR analysis of the crude reaction mixture. e NMR-based
yield since the products could not be separated from the C-silylated ester.
Et2O > PhCHO > RCO2Me).40 Our 13C NMR studies showed,
Scheme 6
as well, that in presence of an excess of TiCl3(OiPr), two benzyl
ethers and the aldehyde of an acyclic polypropionate were
involved in a three-point chelation complex.23a The results of
entry 5 (Table 1) suggest that a similar complex is at work.
As illustrated in Scheme 6, one could suggest that complex A
would be significantly populated, both the oxygen of the benzyl
ether and that of the substituted tetrahydropyran being better
ligands to titanium. This is, however, a nonreactive complex
where the carbonyl is not activated by the Lewis acid. A priori,
applying the CurtinÀHammet principle, this should be of little
consequence, the equilibrium allowing for B to be involved in a
Cram chelate transition state. Yet, poor ratios were obtained
(entry 4; Table 1). This is therefore suggestive that an unidenti-
fied monodentate complex such as C or D be present and also
involved in a FelkinÀAnh addition. Similarly, this suggests that
both transition states leading to 8,9-anti and 8,9-syn products (33
and 34, respectively) are close in energy.
This scenario may be altered by formation of a thermodyna-
mically preferred complex in which the oxygens of the benzyl
ether, the tetrahydropyran and the aldehyde are implicated. In
order to accommodate three ligands, a chloride has been dis-
placed creating a cationic species stabilized by its counterion, as
in the “ate” complex E which would also have a slow rate of
equilibrium compared to the other possible complexes depicted
before. Once the rigid three-point chelate is formed, the stere-
ochemical outcome of the aldol reaction will be controlled by 1,2-
induction due to the steric hindrance of enoxysilane 7a. Inter-
estingly, this “ate” complex may not be obtained if another
oxygen, such as an additional benzyl ether, was present in the
molecule. This hypothesis will be tested in a further iteration of
this approach (vide infra).
Zincophorin possesses a C8ÀC9 anti and a C9ÀC10 anti
relative stereochemistry. The major Cram chelate adducts 33a
and 33b were thus reduced under an acyclic stereocontrol.
Excellent yield and 2,3-anti diastereoselectivity (35) were indeed
observed using these conditions (entry 1, Table 2). Other
isomers of the C1ÀC11 fragment of zincophorin were also
prepared, attesting to the flexibility of our approach. From Cram
chelate adducts 33, the complementary C9ÀC10 syn product
36 was efficiently obtained by using a bidentate Lewis acid
(MgBr2 OEt2) in the hydrogen-transfer step (entry 2, Table 2).
3
The C8ÀC9 syn isomer (FelkinÀAnh adduct 34) achieved as the
result of the Mukaiyama reaction in the presence of BF3 OEt2
3
(entry 1, Table 1), was submitted to the same hydrogen-transfer
reactions to give, respectively, the C9ÀC10 anti product 37
(entry 3; Table 2) and syn 38 (entry 4; Table 2) with excellent
diastereoselectivity in both cases.
In order to converge to a C1ÀC11 fragment of Miyashita’s
total synthesis, the resulting propionate 35 was debenzylated to
intermediate S25 (Scheme 7) and reprotected by a TIPS group
(S26), prior to the reduction to the corresponding diol 39. Diol
39 was found identical to that reported by Miyashita (1H NMR,
13C NMR and [α]D).29
7660
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
Table 2. Stereoselective Hydrogen Transfer Reactions on C1ÀC11 Aldol Adducts 33 and 34
a Conditions A: Substrates (0.1 M) were pretreated with i-Pr2NEt (1.5 equiv) and Bu2BOTf (1.5 equiv) at À78 ꢀC for 1 h. Addition of Bu3SnH
(1.5 equiv) was followed by Et3B (0.2 equiv) and air (injections of Et3B and air were repeated every 30 min until the reaction was complete by TLC).
Conditions B: Substrates (0.1 M) were pretreated with AlMe3 (3.0 equiv) for 1 h at À78 ꢀC. Addition of Bu3SnH (1.5 equiv) was followed by Et3B
(0.2 equiv) and air (injections of Et3B and air were repeated every 30 min until the reaction was complete by TLC). b Isolated yields. c 9,10-syn/9,10-anti.
Product ratios were determined by 1H NMR analysis of the crude reaction mixture.
Scheme 7a
Scheme 8. Synthesis of Aldehyde 40a
a Key: (a) BnOCdNHCCl3, TfOH, 0 ꢀC; (b) DIBAL-H, CH2Cl2,
À40 ꢀC; (c) DessÀMartin periodinane, NaHCO3, CH2Cl2, rt.
a Key: (a) PdÀC, H2, MeOH, rt; (b) TIPSOTf, 2,6-lutidine, CH2Cl2, rt;
(c) DIBAL-H, CH2Cl2, À40 ꢀC.
A final iteration (westÀeast approach) was then considered
using aldehyde 40 as a starting material (Scheme 8). The ester
35 was first protected with a benzyl group (S27) before being
transformed to the corresponding aldehyde 40 (85% over three
steps).
were provided for compounds 43À45 by hydrogenolysis of the
benzyl groups and cyclization to their corresponding lactone
(47, 48, and 49, respectively). As illustrated in Scheme 9, the
relative stereochemistry of the two newly created stereogenic
centers was determined by 1H NMR analysis using both coupling
constants and NOE studies.
As predicted, the presence of additional oxygen in 40 (as
compared to 32) has provided another potential chelation site to
titanium that could explain the low ratios noted (entries 5 and
6, Table 3). Formation of the “ate” complex described before
(Scheme 6) was not favored. Both reaction pathways (FelkinÀ
Anh and CramÀchelate) are now at play, resulting in a poor ratio
for the aldol reaction. We reasoned that removing or blocking
one of the chelation sites of 40 may solve the problem. Therefore,
our synthesis was modified to replace the benzyl group on the
C1-primary alcohol of 35 by a bulky silyl group (TBDPS; 55%
over four steps), as illustrated in Scheme 10. The Mukaiyama
aldol reactions were then performed on the corresponding
aldehyde 50 and the results reported in Table 5. Once again,
The structure of the natural product (Scheme 1) dictated that
a C10ÀC11 anti aldol and a C11ÀC12 anti hydrogen transfer
be performed. To test the robustness and limitations of our
approach, we also planned to synthesize the corresponding three
other isomers C1ÀC13 (Table 3).
FelkinÀAnh adduct 42 (C10ÀC11 syn) was efficiently ob-
tained using BF3 OEt2 (entry 1, Table 3). The diastereoselective
3
synthesis of the C10ÀC11 anti adducts 41 was, however, pro-
blematic. The first Lewis acid used, MgBr2 OEt2, was inefficient
3
in promoting the reaction (entry 2). Titanium-based Lewis acids
(entries 3À5) gave good yields of coupling adducts, albeit with
no significant diastereoselectivities as opposed to our previous
results. Only a large excess of TiCl4 (entry 6) led, in a poor yield,
to a 5:1 ratio of the desired isomer 41. After separation, both the
C10ÀC11 anti-41 and syn-42 isomers were submitted to the
hydrogen-transfer step (Table 4).
BF3 OEt2, as a monodentate Lewis acid, gave an excellent ratio
3
and yield, favoring the C11ÀC12 syn isomer 52. We were also
pleased to note that adding 4 equiv of TiCl3(OiPr) provided
high ratios of the C11ÀC12 anti product 51 in excellent yield
(entry 2). These results support our three-point chelation “ate”
complex with TiCl3(OiPr) described herein. Furthermore, in the
context of the synthesis of polyketide-like molecules, they high-
light the necessity during the aldol step to limit the number of
potential chelation sites to meet the “ate” complex requirement (three
ligands at most).
Acyclic-controlled reduction (anti hydrogen transfer) of Cram
chelate adducts 41 gave the C11ÀC12 anti product 43 with
excellent diastereoselectivity (entry 1). The complementary
C11ÀC12 syn product 44 was also obtained diastereoselectively
using the endocyclic effect (syn hydrogen transfer) by inducing
formation of the cyclic complex with AlMe3 (entry 2). The C10À
C11 syn aldol isomer 42 (FelkinÀAnh adduct) was reduced
stereoselectively, as well (entries 3 and 4). Proofs of structure
7661
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
Table 3. Iterative Mukaiyama Aldolization on Aldehyde 40
entry
Lewis acid
(equiv)
yieldc (%)
selectivityd 41:42
a
1
2
3
4
5
6
BF3 OEt2
(1.5)
(5.0)
(2.5)
(4.0)
(2.5)
(4.0)
68
10
62
72
77
32e
1:>20
ND
1:1
3
b
MgBr2 OEt2
3
TiCl3(OiPr)b
TiCl3(OiPr)b
1:1
b
TiCl4
2:1
b
TiCl4
5:1
a Reactions were conducted with 2.0 equiv of enoxysilane 7a followed by the Lewis acid in CH2Cl2 (0.1 M) at À78 ꢀC for 2 h. b Aldehydes were
precomplexed with the Lewis acid at À78 ꢀC, followed by the addition of 2.0 equiv of enoxysilane 7a in CH2Cl2 (0.1 M) at À78 ꢀC for 2 h. c Isolated
yields over two steps: oxidation then aldolization. d 10,11-anti/10,11-syn. Product ratios were determined by 1H NMR analysis of the crude reaction
mixture. e Secondary debenzylation product observed.
Table 4. Stereoselective Hydrogen-Transfer Reactions on C1ÀC13 Aldol Adducts
a Conditions A: Substrates (0.1 M) were pretreated with i-Pr2NEt (1.5 equiv) and Bu2BOTf (1.5 equiv) at À78 ꢀC for 1 h. Addition of Bu3SnH
(1.5 equiv) was followed by Et3B (0.2 equiv) and air (injections of Et3B and air were repeated every 30 min until the reaction was complete by TLC).
Conditions B: Substrates (0.1 M) were pretreated with AlMe3 (3.0 equiv) for 1 h at À78 ꢀC. Addition of Bu3SnH (1.5 equiv) was followed by Et3B
(0.2 equiv) and air (injections of Et3B and air were repeated every 30 min until the reaction was complete by TLC). b Isolated yields. c 11,12-anti/11,12-
syn. Product ratios were determined by 1H NMR analysis of the crude reaction mixture.
’ CONCLUSION
to originate from the polysubstituted chain attached at C7, a
surprising result to us. The three-dimensional structures of the
acyclic polypropionate may be at the source of this disturbance, a
hypothesis that will be verified in a separate study. Neverthe-
less, in all other examples, these hydrogen-transfer reactions
were shown to be extremely reliable in terms of diastereocontrol
and yield.
Finally, our study also suggests the presence of tricyclic “ate”
complexes and their role in Cram chelate controlled Mukaiyama
aldolizations in the synthesis of the C1ÀC13 fragment of zinco-
phorin. In addition, it emphasizes the importance of a protecting
group strategy (chelating versus nonchelating) considering their
potential impact during the course of anti aldolizations using
titanium-based Lewis acids. In this context, exceeding two ether-
like sites of chelation is more likely to be troublesome. Consider-
ing that polyketide synthesis could be envisioned in a bidirectional
The present study provides evidence that it is possible using a
substrate-based approach to synthesize complex polyketide
molecules, fragments, and isomers thereof as illustrated herein
in the case of zincophorin. We demonstrated that a bidirectional
approach to these syntheses can be considered. Central to our
approach is the optimization of two Lewis acid controlled
reactions: a Mukaiyama aldol reaction and a free-radical-based
hydrogen transfer. These processes allow creation of each
stereocenter with high levels of 1,2-induction. Synthetic planning
of targets and analogues thereof are highly simplified, rendering it
accessible to organic and medicinal chemists interested in
deciphering the origin of the biological activities of this family
of natural products.
We reported a long distance disturbance during the course of
one free-radical reduction (exocyclic control) at C2. It is likely
7662
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
Scheme 9. Proof of Structure for Compounds 43, 44 and 45
Scheme 10. Synthesis of Aldehyde 50a
either through electrospray ionization (ESI) or electron impact (EI) on
an instrument operating at 70 eV, and FAB mass spectra were recorded
with or without ionization.
General Experimental Method for Mukaiyama Aldol Re-
action: FelkinÀAnh Control (A1). To a cold (À78 ꢀC) solution of
aldehyde 14 (8.50 g) in dry CH2Cl2 (0.1 M, 179 mL) were added
successively silylated enol ether 7a (3 equiv, 9.9 mL) and BF3 OEt2
3
(1.5 equiv, 3.4 mL), followed by stirring for 1 h at À78 ꢀC. The reaction
mixture was treated with a saturated aqueous solution of NH4Cl, fol-
lowed by separation of the organic phase at room temperature. The
aqueous layer was extracted with CH2Cl2 (3Â), and the combined
organic fractions were dried (MgSO4), filtered, and concentrated in
vacuo to a pale yellow oil. The crude product yielded an inseparable
mixture of 3,4-syn bromide adducts S7a and S7b in a >20:1 ratio of
products 3,4-syn/3,4-anti which was used without further purification.
(À)-(3R,4R,5R,6S,7S,8S)-Methyl 5,7,9-tris(benzyloxy)-2-bro-
mo-3-hydroxy-2,4,6,8-tetramethylnonanoate (S7a, S7b): Rf =
0.23 (hexanes/EtOAc, 80:20); formula C35H45BrO6; MW 641.63 g/mol;
[α]D À27.1 (c 0.35, CHCl3); IR (neat) νmax 3461, 2876, 1730, 1453, 1252,
a Key: (a) (i) H2, PdÀC, MeOH, rt; (ii) TBDPSCl, NEt3, DMAP, CH2-
Cl2; (b) BnOCdNHCCl3, TfOH, c-Hex/CH2Cl2, 0 ꢀC; (c) DIBAL-H,
CH2Cl2, À40 ꢀC; (d) DessÀMartin periodinane, NaHCO3, CH2Cl2, rt.
fashion, these mechanistic insights are extremely valuable to help
design the most efficient route of synthesis.
’ EXPERIMENTAL SECTION
General Comments. Silylated enol ethers 7a (X = Br) and 7b
(X = SePh) were prepared according to the procedure already described
by our group.23a Experimental methods and physical characterization of
products S1a, S1b, and 1123b and products S2, S3, 12, S4a, S4b, and
1323e have already been reported by our group. All procedures requiring
anhydrous conditions were carried out under a positive argon atmo-
sphere in oven-dried glassware. All solvents were purified by standard
methods. 1H (400 or 500 MHz) and 13C spectra (100 or 125 MHz) were
referenced to residual solvent peaks, and ratios of products were
735 cmÀ1 13C NMR (100 MHz, CDCl3) δ 171.2, 139.0, 138.7, 138.0,
;
128.5, 128.27, 128.24, 127.78, 127.75, 127.50, 127.40, 127.34, 87.9, 84.1,
74.8, 74.4, 74.1, 73.0, 72.6, 53.1, 37.3, 36.9, 36.4, 24.7, 16.3, 14.8, 13.6 ppm;
MS (ESI) m/z 663.2 (M + Na+, 30), 583.2 (100); HRMS calcd for
C35H45BrO6Na [M + Na+] 663.2297, found 663.2308 (1.6 ppm).
General Experimental Method for Mukaiyama Aldol Re-
action: Cram Chelate Control (A2). To a cold (À78 ꢀC) solution
of aldehyde 32 (213 mg) in dry CH2Cl2 (0.1 M, 7 mL) was added a 1 M
solution of TiCl3(OiPr) in CH2Cl2 (2.5 equiv, 1.75 mL), followed by
stirring for 5 min at À78 ꢀC. To the mixture was added silylated enol
ether 7a (3 equiv, 0.39 mL), followed by stirring for 1 h at À78 ꢀC. The
reaction mixture was treated with the addition of a saturated aqueous
1
measured from crude H spectra. 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
7663
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
Table 5. Iterative Mukaiyama Aldolization on Aldehyde 50
entry
Lewis acid
equiv
product
yieldc (%)
selectivityd51:52
a
1
2
BF3 OEt2
1.5
4.0
52
51
quant
93
1:>20
>20:1
3
TiCl3(OiPr)b
a Reaction was conducted with 2.0 equiv of enoxysilane 7a followed by the Lewis acid in CH2Cl2 (0.1 M) at À78 ꢀC for 2 h. b Aldehyde was
precomplexed with the Lewis acid at À78 ꢀC followed by the addition of 2.0 equiv of enoxysilane 7a in CH2Cl2 (0.1 M) at À78 ꢀC for 2 h. c Isolated
yields over two steps: oxidation then aldolization. d 10,11-anti/10,11-syn. Product ratios were determined by 1H NMR analysis of the crude reaction
mixture.
solution of NH4Cl into the mixture followed by separation of the organic
phase at room temperature. The aqueous layer was extracted with
CH2Cl2 (3Â), and the combined organic fractions were dried (MgSO4),
filtered, and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (hexanes/EtOAc, 85:15) to give
a ∼1: 1 mixture of bromide adducts 33a and 33b as a pale yellow oil
(271 mg, yield =71% over two steps) in a >20:1 ratio of products 3,4-anti
(33a,b):3,4-syn (34). The purified mixture of bromide adducts was
found to be contaminated by unreactive C-silylated product from enol
ether 7a.
BEt3 in CH2Cl2 (0.2 equiv, 280 μL), and air (syringe). The reaction
mixture was maintained at À78 ꢀC as supplementary addition of BEt3
solution (0.2 equiv, 280 μL) and air was realized each 30 min, until the
reaction was judged complete by TLC (3À4 h). The reaction was
treated with the addition of 1,4-dinitrobenzene (0.2 equiv, 47 mg) and
stirring of the mixture for 15 min at À78 ꢀC. Once at room temperature,
the reaction was concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (hexanes/EtOAc, 90:10) to give
an inseparable mixture of reduced product 19a and 19b as a pale yellow
oil (0.813 g, yield = 92%) in a 3.5:1 ratio of products 2,3-anti (19a)/
2,3-syn (19b).
(()-(3R,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(Benzyloxy)pro-
pan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-2-bromo-3-
hydroxy-2-methylpentanoate (33a and 33b). 33a: Rf = 0.40
(hexanes/EtOAc, 85:15); formula C23H35BrO5; MW 471.43 g/mol; IR
(neat) νmax 3407, 2952, 2927, 2856, 1738, 1453, 1378, 1258, 1117, 1097,
1039, 1019, 962, 915, 738, 698 cmÀ1; 1H NMR (500 MHz, CDCl3) δ
7.39À7.26 (m, 5H), 4.58 (d, J = 12.4 Hz, 1H), 4.55 (d, J = 12.4 Hz, 1H),
4.25 (d, J = 8.3 Hz, 1H), 3.75 (s, 3H), 3.71 (dd, J = 1.7 Hz, 9.9 Hz, 1H),
3.63 (dd, J = 4.4 Hz, 9.1 Hz, 1H), 3.65À3.59 (m, 1H), 3.57À3.51 (m,
1H), 3.35 (dd, J = 6.7 Hz, 9.1 Hz, 1H), 2.41À2.31 (m, 1H), 1.86 (s, 3H),
1.84À1.75 (m, 1H), 1.73À1.61 (m, 2H), 1.33À1.21 (m, 3H), 0.89 (d,
J = 6.8 Hz, 3H), 0.79 (d, J = 6.4 Hz, 3H), 0.75 (d, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 171.5, 138.7, 128.4, 127.5, 127.5, 75.5,
75.4, 75.3, 73.9, 73.1, 69.4, 52.9, 37.4, 31.8, 31.4, 30.9, 27.7, 26.2, 21.8,
17.7, 14.8 ppm; MS (ESI) m/z 149.1 (11), 233.2 (22), 263.0 (100),
283.2 (15), 345.1 (12), 373.2 (9), 471.2 (79Br; M + H+, 34); HRMS
calcd for C23H36O579Br [M + H+] 471.17409, found 471.1741 (0.1
ppm). 33b: Rf = 0.31 (hexanes/EtOAc, 85:15); formula C23H35BrO5;
MW 471.43 g/mol; IR (neat) νmax 3405, 3029, 2952, 2930, 2860, 1741,
1453, 1379, 1253, 1098, 1070, 1017, 963, 739, 700 cmÀ1; 1H NMR (500
MHz, CDCl3) δ 7.36À7.26 (m, 5H), 4.57 (d, J = 4.4 Hz, 1H), 4.53 (d,
J = 12.2 Hz, 1H), 4.50 (d, J = 12.2 Hz, 1H), 4.14À4.10 (m, 1H),
3.81À3.78 (m, 1H), 3.76 (s, 3H), 3.71À3.66 (m, 1H), 3.56 (dd, J =
4.7 Hz, 9.1 Hz, 1H), 3.37 (dd, J = 6.0 Hz, 9.1 Hz, 1H), 2.38À2.26 (m,
1H), 2.17 (ddq, J = 1.7 Hz, 5.4 Hz, 7.1 Hz, 1H), 1.94 (s, 3H), 1.73À1.64
(m, 3H), 1.63À1.54 (m, 1H), 1.30À1.20 (m, 1H), 1.06 (d, J = 7.2 Hz,
3H), 0.87 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 171.6, 138.4, 128.3, 127.7, 127.5, 78.1, 76.2, 75.7,
74.3, 73.1, 65.9, 53.1, 36.7, 32.1, 31.5, 27.4, 26.1, 25.1, 18.0, 14.8, 12.7
ppm; MS (ESI) m/z 413.2 (8), 471.2 (79Br; M + H+, 20), 493.2 (79Br;
M + Na+, 100), 495.2 (81Br; M + Na+, 99); HRMS calcd for C23H36-
O579Br [M + H+] 471.1741, found 471.1739 (À0.3 ppm); calcd for
C23H35O579BrNa [M + Na+] 493.1560, found 493.1555 (À1.1 ppm).
General Experimental Method for Radical Reduction:
Exocyclic Effect Control (A3). To a cold (À78 ꢀC) solution of a
mixture of bromides 18a and 18b (0.99 g) in dry toluene (0.1 M, 14 mL)
were added successively Ph3SnH (2 equiv, 0.72 mL), a 1 M solution of
(+)-Methyl 2-((2S,5S,6S)-5-methyl-6-((2S,3S,4S,5S,6S)-3,5,7-
tris(benzyloxy)-4,6-dimethylheptan-2-yl)tetrahydro-2H-
pyran-2-yl)propanoate (19a, 19b): Rf = 0.27 (hexanes/EtOAc,
85:15); formula C40H54O6; MW 630.85 g/mol; [α]D +28.6 (c 0.39,
CHCl3); IR (neat) νmax 2949, 1737, 1455, 1376, 966, 734, 698 cmÀ1; 1H
NMR (400 MHz, CDCl3) δ 7.37À7.19 (m, 15H19a,19b), 4.72À4.37 (m,
6H19a,19b), 3.90À3.83 (m, 1H19a), 3.82À3.75 (m, 1H19b), 3.68 (dd, J =
9.2 Hz, 4.4 Hz, 1H19a), 3.64 (s, 3H19b), 3.61 (s, 3H19a), 3.59À3.50 (m,
2H19a, 3H19b), 3.46À3.38 (m, 2H19a,19b), 2.88À2.79 (m, 1H19b), 2.73À
2.64 (m, 1H19a), 2.34À2.04 (m, 3H19a,19b), 1.76À1.38 (m, 4H19a,19b),
1.29À1.18 (m, 1H19a,19b), 1.14 (d, J = 6.8 Hz, 3H19b), 1.10 (d, J = 7.0 Hz,
3H19b), 1.08À0.99 (m, 9H19a, 3H19b), 0.96 (d, J = 7.1 Hz, 3H19b), 0.92
(d, J = 7.0 Hz, 3H19a), 0.75 (d, J = 6.6 Hz, 3H19a), 0.72 (d, J = 6.3 Hz,
3H19b) ppm; 13C NMR [19a] (100 MHz, CDCl3) δ 176.0, 139.7, 139.5,
138.8, 128.3, 128.13, 128.07, 127.5, 127.3, 127.04, 126.99, 84.1, 83.5,
77.7, 73.3, 73.2, 73.0, 72.7, 72.5, 51.5, 43.2, 37.7, 37.2, 36.3, 29.3, 26.2,
24.2, 18.2, 16.7, 15.2, 13.9, 11.8 ppm; MS (ESI) m/z 631.4 (M + H+, 25),
415.3 (80), 325.2 (35), 185.1 (100); HRMS calcd for C40H56O6 [M +
H+] 631.3999, found 631.3974 (3.9 ppm). Anal. Calcd for C40H54O6: C,
76.16; H, 8.63. Found: C, 76.50; H, 8.63.
General Experimental Method for Radical Reduction:
Acyclic Stereoselection Control (A4). To a cold (À78 ꢀC)
solution of a mixture of bromides S7a and S7b (4.30 g) in dry CH2Cl2
(0.1 M, 67 mL) were added successively DIEA (1.5 equiv, 1.75 mL) and
a 1 M solution of Bu2BOTf in CH2Cl2 (1.3 equiv, 8.70 mL) followed by
stirring for 1.5 h at À78 ꢀC. The mixture was then successively treated
with Bu3SnH (2 equiv, 3.60 mL), a 1 M solution of BEt3 in CH2Cl2
(0.2 equiv, 1.35 mL), and air (syringe). Supplementary addition of BEt3
solution (0.2 equiv, 1.35 mL) and air was realized each 30 min until
reaction was judged completed by TLC (3À4 h). The reaction was
treated with the addition of 1,4-dinitrobenzene (0.2 equiv, 227 mg) and
stirring of the mixture for 15 min at À78 ꢀ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
(3Â). Combined organic fractions were washed (2Â) with a saturated
aqueous solution of KF and brine before being dried (MgSO4). The
7664
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
filtrate was concentrated to a residue which was solubilized in MeOH
and cooled to 0 ꢀC before being treated by a 35% w/w of H2O2 in water
(3 equiv, 1.77 mL). The solution was stirred for 2 h at 0 ꢀC and then
treated with addition of water before extraction with Et2O (3Â). Com-
bined organic fractions were washed with a saturated brine solution, then
dried (MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (hexanes/EtOAc,
85:15) to give 2,3-anti product 15 (3.09 g, yield = 82%) in a >20:1 ratio
of product 2,3-anti/2,3-syn as a pale yellow oil.
(À)-(2R,3R,4R,5R,6S,7S,8S)-Methyl 5,7,9-tris(benzyloxy)-
3-hydroxy-2,4,6,8-tetramethylnonanoate (15): Rf = 0.25
(hexanes/EtOAc, 75:25); formula C35H46O6; MW 562.74 g/mol;
[α]D À41.7 (c 0.23, CHCl3); IR (neat) νmax 3494, 3030, 2969, 1737,
1455 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.34À7.20 (m, 15H), 4.67
(d, J = 10.9 Hz, 1H), 4.58 (d, J = 11.4 Hz, 1H), 4.53 (d, J = 10.4 Hz,
1H), 4.48 (d, J = 7.4 Hz, 1H), 4.44 (s, 2H), 4.18 (d, J = 10.1 Hz, 1H),
3.80 (d, J = 0.8 Hz, 1H), 3.71 (s, 3H), 3.70À3.67 (m, 1H), 3.60À3.49
(m, 3H), 2.61À2.51 (m, 1H), 2.44À2.35 (m, 1H), 2.20À2.09 (m,
1H), 2.01À1.91 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 7.0 Hz,
3H), 1.05 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 176.6, 138.8, 138.7, 137.7, 128.4, 128.3,
127.8, 127.6, 127.5, 127.41, 127.37, 86.7, 83.6, 74.7, 73.9, 73.0,
72.9, 72.6, 51.8, 43.6, 37.5, 36.9, 34.2, 16.3, 14.3, 13.6, 11.8 ppm;
MS (FAB) m/z 563.2 (M + H+, 24), 181.1 (100), 154.0 (35); HRMS
calcd for C31H40O4Na [M + Na+] 499.2824, found 499.2824 (0.7
ppm). Anal. Calcd for C35H46O6: C, 74.70; H, 8.24. Found: C, 74.74;
H, 7.92.
(0.1 M, 340 μL) was added a 2 M solution of AlMe3 in hexanes (2.5 equiv,
52 μL). The reaction mixture was stirred at À78 ꢀC for 1 h before
successive additions of Bu3SnH (2 equiv, 18 μL), a 1 M solution of BEt3 in
CH2Cl2 (0.2 equiv, 7 μL), and air (syringe). Supplementary addition of
BEt3 solution (0.2 equiv, 7 μL) and air was realized each 30 min until the
reactionwasjudgedcompletedbyTLC(3À4 h). Thereactionwas treated
with the addition of 1,4-dinitrobenzene (0.2 equiv, 1 mg) and stirring
of the mixture for 15 min at À78 ꢀC. The mixture was treated first with
the dropwise addition of MeOH at À78 ꢀC until gas evolution ceased,
followed by a saturated aqueous solution of potassium sodium tartrate
(Rochelle’s salt). The mixture was stirred overnight at room temperature
followed by separation of the organic phase. The organic phase was
separated at room temperature, and the aqueous layer was extracted with
Et2O (3Â). The combinedorganic fractions were washed with a saturated
aqueous solution of KF. The combined organic fractions were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (hexanes/EtOAc, 85:15) to
give product 44 as a pale yellow oil (10.1 mg, yield = 55%) in a >20:1 ratio
of products 2,3-syn (44)/2,3-anti (43).
(()-(2S,3R,4S,5S,6S)-Methyl 5-(benzyloxy)-6-((2S,3S,6S)-
6-((R)-1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyr-
an-2-yl)-3-hydroxy-2,4-dimethylheptanoate (44): Rf = 0.18
(hexanes/EtOAc, 85:15); formula C33H48O6; MW 540.73 g/mol; IR
(neat) νmax 3515, 3029, 2952, 2927, 1735, 1495, 1455, 1379, 1201, 1092,
1
1066, 1025, 969, 735, 698 cmÀ1; H NMR (500 MHz, CDCl3) δ
7.35À7.23 (m, 10H), 4.63 (d, J = 11.3 Hz, 1H), 4.58 (d, J = 11.3 Hz,
1H), 4.48À4.43 (m, 2H), 4.09 (dd, J = 2.9 Hz, 9.3 Hz, 1H), 3.70 (s, 3H),
3.63 (dd, J = 3.7 Hz, 8.7 Hz, 1H), 3.56À3.50 (m, 2H), 3.48 (dd, J =
4.9 Hz, 6.4 Hz, 2H), 3.36 (dd, J = 7.1 Hz, 8.6 Hz, 1H), 2.63 (dq, J =
2.8 Hz, 7.0 Hz, 1H), 2.25À2.15 (m, 1H), 2.09À2.00 (m, 1H), 1.99À
1.90 (m, 1H), 1.79À1.47 (m, 5H), 1.16 (d, J = 7.1 Hz, 3H), 0.99 (d, J =
7.0 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 7.1 Hz, 3H), 0.89 (d, J =
6.6 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 176.2, 138.8, 138.3,
128.4, 128.2, 127.6, 127.6, 127.5, 127.3, 86.4, 76.6, 74.1, 74.0, 73.1, 72.9,
72.4, 51.8, 42.1, 37.9, 35.6, 29.8, 27.8, 26.8, 26.6, 24.7, 18.4, 15.8, 14.0,
11.9, 9.0 ppm; MS (ESI) m/z 541.4 (M + H+, 12), 563.3 (M + Na+, 100),
653.4 (10); HRMS calcd for C33H49O6 [M + H+] 541.3524, found
541.3517 (À1.2 ppm); calcd for C33H48O6Na [M + Na+] 563.3343,
found 563.3340 (À0.5 ppm).
General Experimental Method for Radical Reduction:
Endocyclic Effect Control with MgBr2 OEt2 (A5). To a cold
3
(0 ꢀC) solution of a mixture of bromides 33a and 33b (14.1 mg) in dry
CH2Cl2 (0.1 M, 300 μL) was added MgBr2 OEt2 (3 equiv, 23 mg). The
3
reaction mixture was stirred at 0 ꢀC for 1 h and then cooled to À78 ꢀC
before successive additions of Bu3SnH (2 equiv, 16 μL), a 1 M solution
of BEt3 in CH2Cl2 (0.2 equiv, 6 μL), and air (syringe). Supplementary
addition of BEt3 solution (0.2 equiv, 6 μL) and air was realized each
30 min until the reaction was judged completed by TLC (3À4 h). The
reaction was treated with the addition of 1,4-dinitrobenzene (0.2 equiv,
1 mg) and stirring of the mixture for 15 min at À78 ꢀ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 CH2Cl2 (3Â). The combined organic fractions were dried
(MgSO4), filtered and concentrated in vacuo to a pale yellow oil. The
crude product was purified by flash chromatography on silica gel
(hexanes/EtOAc, 90:10) to give product 36 (9.8 mg, yield =83%) in a
>20:1 ratio of product 2,3-syn (36): 2,3-anti (35) as a pale yellow oil.
(()-(2S,3R,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(benzyloxy)-
propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-
2-methylpentanoate (36): Rf = 0.27 (hexanes/EtOAc, 85:15); for-
mula C23H36O5; MW 392.53 g/mol; IR (neat) νmax 3452, 2930, 2859,
1736, 1456, 1379, 1246, 1201, 1072, 1017, 962, 913, 735, 698 cmÀ1; 1H
NMR (500 MHz, CDCl3) δ 7.37À7.25 (m, 5H), 4.53 (d, J = 12.1 Hz,
1H), 4.49 (d, J = 12.1 Hz, 1H), 3.84À3.78 (m, 1H), 3.78À3.72 (m, 2H),
3.68À3.63 (m, 1H), 3.65 (s, 3H), 3.61 (dd, J = 3.6 Hz, 9.0 Hz, 1H), 3.37
(dd, J = 6.8 Hz, 8.8 Hz, 1H), 2.70 (dq, J = 7.0 Hz, 7.0 Hz, 1H), 2.45À2.35
(m, 1H), 1.75À1.65 (m, 3H), 1.65À1.52 (m, 2H), 1.32À1.21 (m, 1H),
1.26 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.1 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H),
0.76 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 176.4,
138.6, 128.3, 127.5, 127.4, 75.8, 75.4, 75.0, 73.6, 73.2, 51.5, 43.3, 35.4,
31.8, 31.6, 27.2, 26.1, 17.6, 14.9, 12.6, 10.6 ppm; MS (ESI) m/z 393.3
(M + H+, 100); HRMS calcd for C23H37O5 [M + H+] 393.2636, found
393.2624 (À3.0 ppm).
General Experimental Method for Protection of Alcohol
with Benzyl Ether (A7). To a cold (0 ꢀC) solution of alcohol 13
(10.16 g) in c-Hex/CH2Cl2 (2: 1, 0.1 M, 245 mL) were added
successively 2,2,2-benzyltrichloroacetimidate (1.5 equiv, 6.83 mL) and
TfOH (0.1 equiv, 0.22 mL), followed by overnight stirring at 0 ꢀC. The
reaction mixture was treated with NEt3 (0.15 equiv, 0.40 mL) and then
concentrated in vacuo. The crude product was dissolved in hexanes and
filtered onto a pad of Celite. The filtrate was concentrated and purified
by flash chromatography on silica gel (hexanes/EtOAc, 85:15) to give
product S5 as a colorless oil (10.01 g, yield = 81%).
(+)-(2S,3S,4S,5S,6S)-Methyl 3,5,7-tris(benzyloxy)-2,4,6-tri-
methylheptanoate (S5): Rf = 0.25 (hexanes/EtOAc, 85:15); for-
mula C32H40O5; MW 504.66 g/mol; [α]D +12.2 (c 0.45, CHCl3); IR
(neat) νmax 3087, 3063, 3029, 2879, 1735, 1454 cmÀ1 1H NMR
;
(400 MHz, CDCl3) δ 7.38À7.13 (m, 15H), 4.65 (d, J = 11.3 Hz,
1H), 4.54 (s, 2H), 4.47 (d, J = 11.3 Hz, 1H), 4.44 (d, J = 1.6 Hz, 2H),
3.86 (t, J = 5.3 Hz, 1H), 3.62 (s, 3H), 3.62À3.59 (m, 1H), 3.55 (dd, J =
10.5 Hz, 4.7 Hz, 1H), 3.42 (dd, J = 9.1 Hz, 7.0 Hz, 1H), 2.98 (dq, J =
6.9 Hz, 6.9 Hz, 1H), 2.28À2.18 (m, 1H), 2.18À2.09 (m, 1H), 1.16 (d,
J = 7.1 Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 175.7, 139.0, 138.77, 138.73, 128.3,
128.2, 127.6, 127.46, 127.41, 127.35, 127.29, 83.4, 83.0, 73.5, 73.0,
72.5, 51.5, 42.4, 37.5, 36.4, 16.2, 13.8, 13.0 ppm; MS (ESI) m/z 519.3
(M + H+, 100), 541.2 (M + Na+, 55), 181.1 (100); HRMS calcd for
C33H43O5 [M + H+] 519.3111, found 519.3095 (À1.8 ppm).
General Experimental Method for Radical Reduction:
Endocyclic Effect Control with AlMe3 (A6). To a cold (À78 ꢀC)
solution of a mixture of bromide 41a and 41b (21.1 mg) in dry CH2Cl2
7665
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
General Experimental Method for Protection of Alcohol
with Trialkylsilyl Trifluoromethanesulfonate Reagents (A8).
To a cold (0 ꢀC) solution of alcohol 15 (2.25 g) in dry CH2Cl2 (0.1 M,
40 mL) were added successively 2,6-lutidine (1.2 equiv, 0.56 mL) and
TESOTf (1.1 equiv, 1.00 mL). 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 tem-
perature. The aqueous layer was extracted with CH2Cl2 (3Â), and the
combined organic fractions were dried (MgSO4), filtered, and concen-
trated in vacuo. The crude product was purified by flash chromatography
on silica gel (hexanes/EtOAc, 95:5) to give the desired protected alcohol
S8 as a colorless oil (2.74 g, quantitative yield).
chloride (1.3 equiv, 1.52 mL) in dry CH2Cl2 (0.1 M, 138 mL) was added
dropwise anhydrous DMSO (2.2 equiv, 2.16 mL), and the mixture was
stirred for 10 min at À78 ꢀC. A solution of the alcohol S6 (6.58 g) in dry
CH2Cl2 (0.2 M, 69 mL) was cannulated into the reaction flask, and the
mixture was allowed to stir for an additional 30 min at À78 ꢀC before
addition of dry NEt3 (5 equiv, 9.62 mL). The mixture was then stirred
for 1 h at À78 ꢀC and quenched by the addition of a saturated aqueous
solution of NH4Cl followed by separation of organic phase at room
temperature. The aqueous layer was extracted with Et2O (3Â), and the
combined organic fractions were washed with a saturated brine solution
and then dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (hexanes/
EtOAc, 85:15) to give the desired aldehyde 14 as a colorless oil (5.89 g,
yield = 90%).
(+)-(2R,3R,4S,5S,6S,7S,8S)-Methyl 5,7,9-tris(benzyloxy)-
2,4,6,8-tetramethyl-3-(triethylsilyloxy)nonanoate (S8): Rf =
0.19 (hexanes/EtOAc, 90:10); formula C41H60O6Si; MW 677.00
g/mol; [α]D +18.2 (c 0.22, CHCl3); IR (neat) νmax 2954, 2877, 1738,
1455, 734 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.39À7.22 (m, 15H),
4.74 (d, J = 3.9 Hz, 1H), 4.71 (d, J = 4.0 Hz, 1H), 4.60 (d, J = 21.0 Hz,
1H), 4.57 (d, J = 21.0 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J =
12.0 Hz, 1H), 4.23 (dd, J = 7.4 Hz, 1.7 Hz, 1H), 3.72 (dd, J = 9.2 Hz, 5.0
Hz, 1H), 3.61À3.54 (m, 1H), 3.56 (s, 3H), 3.46À3.39 (m, 2H), 2.61À
2.51 (m, 1H), 2.37À2.27 (m, 1H), 2.27À2.15 (m, 1H), 2.03À1.92 (m,
1H), 1.10 (d, J = 4.7 Hz, 3H), 1.08 (d, J = 5.0 Hz, 3H), 0.92À0.86 (m,
12H), 0.84 (d, J = 7.0 Hz, 3H), 0.64À0.47 (m, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ 175.6, 139.4, 139.3, 138.7, 128.3, 128.2, 128.1, 127.5,
127.4, 127.12, 127.06, 127.0, 126.6, 84.9, 83.5, 74.1, 73.40, 73.36, 73.0,
72.3, 51.3, 45.8, 39.3, 37.3, 36.3, 16.5, 15.9, 13.7, 11.7, 7.0, 5.6 ppm; MS
(ESI) m/z 699.4 (M + Na+, 100), 591.3 (10), 435.2 (12); HRMS calcd
for C41H60O6NaSi [M + Na+] 699.4057, found 699.4059 (0.3 ppm).
Anal. Calcd for C41H60O6Si: C, 72.74; H, 8.93. Found: C, 72.72; H, 8.83.
General Experimental Method for Reduction of Ester to
Primary Alcohol with DIBAL-H (A9). To a cold (À40 ꢀC) solution
of ester S5 (1.67 g) in dry CH2Cl2 (0.1 M, 33 mL) was added a 1.0 M
solution of DIBAL-H in hexanes (3 equiv, 9.9 mL). The mixture was
stirred for 1 h at À40 ꢀC or until ester was completely consumed as
verified by TLC. The reaction mixture was treated first with the dropwise
addition of MeOH at À40 ꢀ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 (3Â), and the combined organic fractions
were dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (hexanes/
EtOAc, 75:25) to give the desired primary alcohol S6 as a colorless oil
(1.46 g, yield = 93%).
(À)-(2R,3R,4R,5S,6S)-3,5,7-Tris(benzyloxy)-2,4,6-trimethyl-
heptan-1-ol (S6): Rf = 0.19 (hexanes/EtOAc, 75:25); formula
C31H40O4; MW 476.65 g/mol; [α]D À10.0 (c 0.39, CHCl3); IR
(neat) νmax 3451, 3063, 3030, 1495, 1455 cmÀ1; 1H NMR (400 MHz,
CDCl3) δ 7.35À7.24 (m, 15H), 4.65 (d, J = 11.1 Hz, 1H), 4.55 (d, J = 1.5
Hz, 2H), 4.48 (d, J = 10.4 Hz, 1H), 4.47 (s, 2H), 3.81 (ddd, J = 11.1 Hz,
4.8 Hz, 3.3 Hz, 1H), 3.64À3.58 (m, 2H), 3.57À3.46 (m, 3H), 2.86 (dd,
J = 6.7 Hz, 4.8 Hz, 1H), 2.36À2.26 (m, 1H), 2.25À2.14 (m, 1H),
2.06À1.96 (m, 1H), 1.11 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H),
1.05 (d, J = 6.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 138.9,
138.7, 138.1, 129.0, 128.4, 128.29, 128.26, 127.8, 127.7, 127.5, 127.41,
127.35, 86.1, 83.6, 73.9, 73.6, 73.1, 72.4, 66.0, 38.2, 36.6, 36.4, 16.5, 16.1,
13.7 ppm; MS (ESI) m/z 499.2 (M + Na+, 100), 477.2 (M + H+, 30),
369.2 (10); HRMS calcd for C31H40O4Na [M + Na+] 499.2824, found
499.2828 (0.7 ppm). Anal. Calcd for C31H40O4: C, 78.11; H, 8.46.
Found: C, 78.27; H, 8.55.
(+)-(2S,3S,4S,5S,6S)-3,5,7-Tris(benzyloxy)-2,4,6-trimethyl-
heptanal (14): Rf = 0.32 (hexanes/EtOAc, 80:20); formula C31-
H38O4; MW 474.63 g/mol; [α]D +10.2 (c 0.38, CHCl3); IR (neat)
νmax 3030, 1720, 1454, 736 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.79
(d, J = 2.7 Hz, 1H), 7.40À7.22 (m, 15H), 4.62À4.38 (m, 6H), 3.84 (dd,
J = 5.4 Hz, 3.3 Hz, 1H), 3.59 (dd, J = 9.0 Hz, 4.5 Hz, 1H), 3.47 (ddd, J =
7.4 Hz, 7.0 Hz, 1.6 Hz, 2H), 2.81À2.71 (m, 1H), 2.38À2.24 (m, 1H),
2.21À2.07 (m, 1H), 1.10 (d, J = 3.9 Hz, 3H), 1.08 (d, J = 3.8 Hz, 3H),
0.99 (d, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 205.2,
138.7, 138.6, 138.3, 128.9, 128.4, 128.3, 127.5, 127.4, 83.6, 82.1,
74.2, 73.1, 72.4, 72.3, 48.3, 37.6, 36.5, 15.9, 13.4, 12.5 ppm; MS (ESI)
m/z 497.2 (M + Na+, 100), 345.2 (60), 237.1 (30). Anal. Calcd for
C31H38O4: C, 78.45; H, 8.07. Found: C, 78.48; H, 8.28.
General Experimental Method for Oxidation of Primary
Alcohol with DessÀMartin Periodinane (A11). To a solution of
alcohol S21 (1.96 g) in dry CH2Cl2 (0.1 M, 37 mL) were added
successively NaHCO3 (10 equiv, 3.11 g) and DessÀMartin periodinane
(1.5 equiv, 2.35 g). The mixture was stirred for 1 h at room temperature
and then concentrated. Product was digested from white solid residue in
hexanes and filtered onto a pad of Celite. The filtrate was concentrated in
vacuo and purified by flash chromatography on silica gel (hexanes/
EtOAc, 85:15) to give the desired aldehyde 29 as a colorless oil (1.70 g,
yield = 87%).
(À)-(4R,5S,6S)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-
5-(triethylsilyloxy)heptanal (29): Rf = 0.65 (hexanes/EtOAc,
85:15); formula C31H50O3Si2; MW 526.90 g/mol; [α]D À0.5 (c 0.98,
CHCl3); IR (neat) νmax 3017, 2957, 2934, 2877, 2714, 1727, 1436, 1427,
1
1387, 1239, 1109, 1054, 1008, 823, 738, 703, 613 cmÀ1; H NMR
(500 MHz, CDCl3) δ 9.72 (dd, J = 1.7 Hz, 1.7 Hz, 1H), 7.68À7.62 (m,
4H), 7.45À7.35 (m, 6H), 3.70 (dd, J = 3.0 Hz, 6.0 Hz, 1H), 3.53 (dd, J =
7.5 Hz, 9.9 Hz, 1H), 3.42 (dd, J = 6.0 Hz, 10.0 Hz, 1H), 2.50À2.41 (m,
1H), 2.37À2.28 (m, 1H), 1.90À1.75 (m, 2H), 1.58À1.50 (m, 1H),
1.39À1.23 (m, 2H), 1.06 (s, 9H), 0.92 (t, J = 7.9 Hz, 9H), 0.85 (d, J =
6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H), 0.62À0.53 (m, 6H) ppm; 13C NMR
(100 MHz, CDCl3) δ 202.8, 135.6, 133.83, 133.79, 129.6, 127.6, 75.8,
66.9, 42.2, 38.3, 37.3, 26.8, 24.9, 19.2, 16.2, 11.3, 7.1, 5.4 ppm; MS (ESI)
m/z 139.1 (38), 239.1 (12), 285.2 (26), 317.2 (40), 395.2 (100), 435.2
(8), 527.3 (M + H+, 30), 549.3 (M + Na+, 24), 581.3 (61); HRMS calcd
for C31H51O3Si2 [M + H+] 527.3371, found 527.3376 (0.9 ppm); calcd
for C31H50O3Si2Na [M + Na+] 549.3191, found 549.3194 (0.6 ppm).
General Experimental Method for Hydrogenolysis with
Palladium (A12). To a solution of α,β-unsaturated ester S10 (1.40 g)
in MeOH (0.1 M, 19.5 mL) at room temperature was added 10 wt % Pd
on activated carbon (0.1 equiv, 208 mg). Inert gas atmosphere was
purged by three cycles of vacuum/H2 gas, and the reaction mixture was
stirred until the reaction was judged completed 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 (hexanes/EtOAc, 85:15) to give the desired product S11 as
a colorless oil (1.36 g, yield = 97%).
General Experimental Method for Swern Oxidation of
Primary Alcohols (A10). To a cold (À78 ꢀC) solution of oxalyl
7666
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
(+)-(4S,5S,6S,7S,8S,9S,10S)-Ethyl 7,9,11-tris(benzyloxy)-
4,6,8,10-tetramethyl-5-(triethylsilyloxy)undecanoate (S11):
Rf = 0.23 (hexanes/EtOAc, 90:10); formula C44H66O6Si; MW 719.08 g/
mol; [α]D +25.0 (c 0.12, CHCl3); IR (neat) νmax 2957, 2875, 1734,
1455, 1090 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.34À7.20 (m, 15H),
4.71 (d, J = 8.8 Hz, 1H), 4.68 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 3.2 Hz, 1H),
4.54 (d, J = 3.4 Hz, 1H), 4.49 (d, J = 11.9 Hz, 1H), 4.45 (d, J = 11.9 Hz,
1H), 4.07 (q, J = 7.1 Hz, 2H), 3.79 (dd, J = 4.7 Hz, 2.6 Hz, 1H), 3.70 (dd,
J = 9.2 Hz, 4.7 Hz, 1H), 3.57 (dd, J = 7.9 Hz, 3.3 Hz, 1H), 3.45À3.38 (m,
2H), 2.34À2.06 (m, 4H), 2.01À1.88 (m, 1H), 1.76À1.64 (m, 1H),
1.54À1.42 (m, 1H), 1.30À1.16 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.09
(d, J = 7.0 Hz, 3H), 1.06 (d, J = 7.2 Hz, 3H), 0.93À0.86 (m, 12H), 0.72
(d, J = 6.8 Hz, 3H), 0.55 (q, J = 8.1 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3) δ 173.9, 139.4, 139.3, 138.8, 128.3, 128.21, 128.16, 128.07,
127.5, 127.3, 127.1, 126.9, 126.7, 85.1, 83.5, 75.9, 73.3, 73.2, 73.0, 72.4,
60.1, 39.0, 38.7, 37.4, 36.3, 32.5, 27.4, 16.5, 15.7, 15.3, 14.2, 12.7, 7.1, 5.6
ppm; MS (ESI) m/z 627.3 (M + H+ À TES + Na+, 100), 605.3 (M + H+
À TES, 18), 437.2 (100), 283.1 (50); HRMS calcd for C38H52O6Na
[M + H+ À TES + Na+] 627.3662, found 627.3670 (1.3 ppm). Anal.
Calcd for C44H64O6Si: C, 73.49; H, 9.25. Found: C, 73.62; H, 9.01.
General Experimental Method for Cycloetherification Re-
action (A13). To a cold (À78 ꢀC) solution of aldehyde 17 (3.44 g) in
dry CH2Cl2 (0.1 M, 51 mL) was added dropwise a solution of BiBr3
(1 equiv, 2.29 g) in dry MeCN (0.5 M, 10.2 mL), followed by silylated
enol ether 7a (1.5 equiv, 1.41 mL). The mixture was stirred for 1.5 h at
À78 ꢀC or until aldehyde was completely consumed as verified by TLC.
The reaction mixture was treated with the addition of a saturated
aqueous solution of NH4Cl into the mixture at À40 ꢀC followed by
separation of the organic phase at room temperature. The aqueous layer
was extracted with CH2Cl2 (3Â), and the combined organic fractions
were dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (hexanes/
EtOAc, 90:10) to give a mixture of bromide adducts 18a and 18b in a
∼1:1 ratio as a pale yellow oil (2.96 g, yield = 82%).
NMR (100 MHz, CDCl3) δ 171.0, 139.3, 139.2, 138.8, 128.3, 128.2,
128.1, 127.5, 127.32, 127.28, 127.24, 127.14, 127.08, 84.0, 83.4, 80.1,
74.0, 73.3, 73.2, 73.0, 72.7, 65.8, 53.2, 38.0, 36.3, 36.2, 27.4, 25.3, 24.0,
21.7, 18.0, 16.7, 14.8, 12.7 ppm; MS (ESI) m/z 731.1 (M + Na+, 100),
651.3 (50); HRMS calcd for C40H52O6 [M À HBr] 628.3777, found
628.3763 (2.1 ppm). Anal. Calcd for C40H53BrO6: C, 67.69; H, 7.53.
Found: C, 67.98; H, 7.49.
(+)-(2S,3S,4S,5S,6S,7S,8S)-5,7,9-Tris(benzyloxy)-2,4,6,8-
tetramethyl-3-(triethylsilyloxy)nonan-1-ol (S9). Primary alco-
hol S9 as a colorless oil (6.95 g, quantitative yield) was obtained from
ester S8 (6.97 g) according to general procedure A9: Rf = 0.25 (hexanes/
EtOAc, 80:20); formula C40H60O5Si; MW 648.99 g/mol; [α]D +36.4
(c 0.22; CHCl3); IR (neat) νmax 3466, 2957, 2876, 1455 cmÀ1; 1H NMR
(400 MHz, CDCl3) δ 7.36À7.20 (m, 15H), 4.69 (d, J = 10.8 Hz, 1H),
4.58À4.48 (m, 3H), 4.45 (s, 2H), 4.15 (s, 1H), 3.89 (d, J = 9.7 Hz, 1H),
3.73À3.60 (m, 3H), 3.60À3.47 (m, 3H), 2.41À2.30 (m, 1H), 2.21À
2.09 (m, 1H), 2.00À1.90 (m, 1H), 1.90À1.77 (m, 1H), 2.61À2.51 (m,
1H), 2.37À2.27 (m, 1H), 2.27À2.15 (m, 1H), 1.10 (d, J = 4.7 Hz, 3H),
1.08 (d, J = 5.0 Hz, 3H), 0.92À0.86 (m, 12H), 0.84 (d, J = 7.0 Hz, 3H),
0.64À0.47 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 139.4, 138.9,
138.5, 129.2, 128.6, 128.5, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 127.3,
126.9, 85.0, 83.7, 77.4, 75.3, 73.7, 73.3, 73.2, 72.4, 65.8, 41.3, 38.7, 37.8,
36.5, 16.5, 14.8, 13.3, 13.2, 7.2, 5.6, 5.5 ppm; MS (ESI) m/z 649.4 (M +
H+, 55), 541.3 (30), 433.3 (50), 301.2 (70), 203.1 (100); HRMS calcd
for C40H60O5NaSi [M + Na+] 671.4108, found 671.4095 (1.9 ppm).
Anal. Calcd for C40H60O5Si: C, 74.03; H, 9.32. Found: C, 74.17; H, 9.62.
(+)-(2R,3R,4S,5S,6S,7S,8S)-5,7,9-Tris(benzyloxy)-2,4,6,8-
tetramethyl-3-(triethylsilyloxy)nonanal (16). Aldehyde 16 as a
colorless oil (6.28 g, quantitative yield) was obtained from primary
alcohol S9 (6.17 g) according to general procedure A10: Rf = 0.39
(hexanes/EtOAc, 85:15); formula C40H58O5Si; MW 646.97 g/mol;
[α]D +16.9 (c 0.13, CHCl3); IR (neat) νmax 2959, 2876, 1726,
1455 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 2.3 Hz, 1H),
7.35À7.20 (m, 15H), 4.74 (d, J = 11.7 Hz, 1H), 4.68 (d, J = 11.8 Hz,
1H), 4.59 (d, J = 11.8 Hz, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.49 (s, 1H),
4.48 (s, 1H), 4.16 (dd, J = 5.8 Hz, 3.0 Hz, 1H), 3.70 (dd, J = 9.2 Hz, 5.0
Hz, 1H), 3.56 (dd, J = 8.2 Hz, 3.3 Hz, 1H), 3.48 (dd, J = 8.2 Hz, 3.1 Hz,
1H), 3.44 (dd, J = 9.1 Hz, 7.4 Hz, 1H), 2.50À2.40 (m, 1H), 2.40À2.28
(m, 1H), 2.28À2.12 (m, 1H), 2.06À1.94 (m, 1H), 1.10 (d, J = 7.0 Hz,
3H), 1.08 (d, J = 7.3 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H), 0.88 (t, J = 7.9 Hz,
9H), 0.82 (d, J = 7.0 Hz, 3H), 0.53 (q, J = 8.0 Hz, 6H) ppm; 13C NMR
(100 MHz, CDCl3) δ 205.2, 139.2, 139.0, 138.7, 128.27, 128.26, 128.1,
127.5, 127.4, 127.3, 127.0, 126.7, 84.7, 83.6, 74.3, 73.5, 73.2, 73.1, 72.3,
52.0, 40.5, 37.5, 36.4, 16.4, 15.6, 12.4, 11.2, 7.0, 5.5 ppm; MS (FAB) m/z
647.4 (M + H+, 15), 201.1 (50), 181.1 (100); HRMS calcd for C40H58-
O5NaSi [M + Na+] 669.3951, found 669.3962 (1.6 ppm). Anal. Calcd
for C40H58O5Si: C, 74.26; H, 9.04. Found: C, 74.49; H, 9.31.
(+)-(4S,5S,6S,7S,8S,9S,10S,E)-Ethyl 7,9,11-Tris(benzyloxy)-
4,6,8,10-tetramethyl-5-(triethylsilyloxy)undec-2-enoate (S10).
To a cold (0 ꢀC) solution of vacuum-dried LiCl (5.6 equiv, 2.23 g) in
MeCN (1 M, 53 mL) under argon gas were added successively triethyl
phosphonoacetate (1.3 equiv, 2.42 mL) and DBU (1.25 equiv, 1.76 mL)
before the solution was stirred for 30 min at room temperature. The
mixture was then cooled to 0 ꢀC before being treated dropwise with a
solution of aldehyde 16 (1 equiv, 6.08 g) in MeCN (0.2 M, 47 mL). The
reaction was stirred for 4 h at 0 ꢀC before being treated with a saturated
aqueous solution of NH4Cl and separation of the organic phase at room
temperature. The aqueous layer was extracted with Et2O (3Â), and the
combined organic fractions were washed with a saturated brine solution
and then dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (hexanes/
EtOAc, 90:10) to give the desired (E)-α,β-unsaturated ester S10 (6.07 g,
yield = 90%): Rf = 0.22 (hexanes/EtOAc, 90:10); formula C44H64O6Si;
MW 717.06 g/mol; [α]D +6.0 (c 0.15, CHCl3); IR (neat) νmax 2960, 2876,
(+)-Methyl 2-Bromo-2-((2S,5S,6S)-5-methyl-6-((2S,3S,4S,
5S,6S)-3,5,7-tris(benzyloxy)-4,6-dimethylheptan-2-yl)tetra-
hydro-2H-pyran-2-yl)propanoate (18a, 18b). 18a: Rf = 0.38
(hexanes/EtOAc, 85:15); formula C40H53BrO6; MW 709.75 g/mol;
[α]D +19.0 (c 0.20, CHCl3); IR (neat) νmax 2960, 2873, 1741, 1453,
1377, 1262, 966, 735, 699 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.35À
7.20 (m, 15H), 4.65 (d, J = 11.8 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H), 4.52
(d, J = 25.6 Hz, 1H), 4.49 (d, J = 25.9 Hz, 1H), 4.45 (d, J = 2.44 Hz, 2H),
4.15 (dd, J = 11.0 Hz, 2.8 Hz, 1H), 3.75 (s, 3H), 3.67À3.60 (m, 2H),
3.60À3.54 (m, 1H), 3.44À3.32 (m, 2H), 2.30À2.06 (m, 3H), 1.94À
1.60 (m, 4H), 1.84 (s, 3H), 1.41À1.32 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H),
1.00 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 171.4, 139.32, 139.26, 138.8,
128.3, 128.2, 128.1, 127.3, 127.19, 127.16, 127.08, 84.2, 83.4, 80.2, 73.6,
73.5, 73.2, 73.0, 72.6, 62.0, 52.9, 37.8, 36.5, 36.3, 27.4, 25.7, 22.4, 20.6,
17.8, 16.7, 15.3, 11.9 ppm; MS (FAB) m/z 709.3 (M + H+, 20), 307.0
(20), 264.9 (80), 181.1 (90), 154.0 (100), 136.0 (75); HRMS calcd for
C40H54BrO6 [M + H+] 709.3103, found 709.3069 (4.8 ppm). Anal.
Calcd for C40H53BrO6: C, 67.69; H, 7.53. Found: C, 68.05; H, 7.71. 18b:
Rf = 0.32 (hexanes/EtOAc, 85:15); formula C40H53BrO6; MW 709.75
g/mol; [α]D +19.0 (c 0.20, CHCl3); IR (neat) νmax 2959, 2873, 1739,
1453, 1264, 735, 698 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.37À7.23
(m, 15H), 4.69 (d, J = 11.5 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 4.54 (d,
J = 11.5 Hz, 1H), 4.48 (d, J = 11.7 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H),
4.43 (d, J = 12.0 Hz, 1H), 3.95 (dd, J = 10.9 Hz, 3.2 Hz, 1H), 3.77 (s,
3H), 3.71 (dd, J = 7.5 Hz, 4.8 Hz, 1H), 3.66 (dd, J = 9.0 Hz, 4.0 Hz, 1H),
3.62À3.57 (m, 1H), 3.52À3.47 (m, 1H), 3.42 (dd, J = 9.1 Hz, 7.3 Hz,
1H), 2.38À2.08 (m, 3H), 1.98À1.88 (m, 1H), 1.83 (s, 3H), 1.81À1.62
(m, 2H), 1.47À1.32 (m, 2H), 1.053 (d, J = 6.9 Hz, 3H), 1.049 (d, J = 6.9
Hz, 3H), 1.02 (d, J = 7.2 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H) ppm; 13C
7667
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
1718, 1455 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.35À7.23 (m, 15H),
6.95 (dd, J = 8.3 Hz, 15.8 Hz, 1H), 5.70 (dd, J = 1.1 Hz, 15.8 Hz, 1H), 4.68
(d, J = 11.9 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H),
4.53 (d, J = 11.7 Hz, 1H), 4.49 (d, J = 11.9 Hz, 1H), 4.45 (d, J = 11.9 Hz,
1H), 4.16(q, J=7.1 Hz, 2H), 3.89 (dd, J=3.2 Hz, 5.2 Hz, 1H), 3.69 (dd, J=
4.7 Hz, 9.2 Hz, 1H), 3.56 (dd, J = 3.7 Hz, 7.7 Hz, 1H), 3.46À3.38 (m, 2H),
2.43À2.33 (m, 1H), 2.34À2.24 (m, 1H), 2.24À2.13 (m, 1H), 1.97À1.87
(m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H), 1.06 (d, J =
7.3 Hz, 3H), 1.92À1.86 (m, 15H), 0.85 (d, J = 6.9 Hz, 3H), 0.58À0.51 (m,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 166.6, 152.1, 139.3, 139.2,
138.8, 128.3, 128.2, 128.1, 127.5, 127.4, 127.1, 127.0, 127.0, 126.8, 121.0,
84.7, 83.5, 75.9, 73.4, 73.2, 73.0, 72.4, 60.0, 42.6, 40.3, 37.4, 36.4, 16.56,
16.50, 15.5, 14.3, 12.3, 7.1, 5.7 ppm; MS (FAB) m/z 717.1 (M + H+, 38),
501.2 (25), 271.1 (100), 181.1 (90); HRMS calcd for C44H64O6NaSi
[M + Na+] 739.4370, found 739.4351 (2.6 ppm). Anal. Calcd for C44H64-
O6Si: C, 73.70; H, 9.00. Found: C, 73.87; H, 9.06.
2,3-syn (S13b) as a colorless oil (0.304 g, yield = 70% for S13a) was
obtained from a mixture of esters 19a and 19b (0.454 g) according to
general procedure A9. S13a: Rf = 0.22 (hexanes/EtOAc, 75:25); formula
C39H54O5; MW 602.84 g/mol; [α]D +5.9 (c 0.17, CHCl3); IR (neat)
1
νmax 3468, 2961, 1455, 1378, 734, 697 cmÀ1; H NMR (400 MHz,
CDCl3) δ 7.36À7.20 (m, 15H), 4.68 (d, J = 11.7 Hz, 1H), 4.62 (d, J = 2.3
Hz, 2H), 4.50 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 2.6 Hz, 2H), 3.67 (dd, J =
9.1 Hz, 4.1 Hz, 1H), 3.61 (dd, J = 6.1 Hz, 3.8 Hz, 1H), 3.59 (dd, J = 5.1
Hz, 3.8 Hz, 1H), 3.54À3.45 (m, 4H), 3.42 (dd, J = 9.1 Hz, 7.4 Hz, 1H),
3.10 (bs, 1H), 2.34À2.25 (m, 1H), 2.25À2.06 (m, 2H), 1.97À1.84 (m,
1H), 1.88À1.67 (m, 1H), 1.68À1.47 (m, 3H), 1.35À1.22 (m, 1H), 1.06
(d, J = 7.0 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.1 Hz, 3H), 0.81
(d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 139.4, 139.2, 138.8, 128.3, 128.2, 128.1, 127.5, 127.33, 127.26,
127.16, 127.09, 84.3, 83.1, 77.2, 77.0, 73.4, 73.1, 73.0, 72.6, 68.0, 37.9,
36.8, 36.3, 36.29, 29.9, 26.3, 25.7, 18.4, 16.7, 14.3, 13.9, 12.5 ppm; MS
(ESI) m/z 625.3 (M + Na+, 100), 603.3 (M + H+, 10), 437.1 (20);
HRMS calcd for C39H54O5Na [M + Na+] 625.3869, found 625.3887 (2.9
ppm). Anal. Calcd for C39H54O5: C, 77.70; H, 9.03. Found: C, 77.36; H,
9.26. S13b: Rf = 0.16 (hexanes/EtOAc, 75:25); formula C39H54O5; MW
602.84 g/mol; IR (neat) νmax 3457, 3029, 1495, 1455, 1378, 1090, 734,
697 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.40À7.20 (m, 15H), 4.65 (d,
J = 11.6 Hz, 1H), 4.58 (s, 2H), 4.50 (d, J = 11.6 Hz, 1H), 4.45 (d, J =
3.1 Hz, 2H), 3.72À3.48 (m, 7H), 3.42 (dd, J =9.0 Hz, 7.5Hz, 1H), 2.51 (t,
J = 5.3 Hz, 1H), 2.34À2.20 (m, 2H), 2.20À2.08 (m, 1H), 1.94À1.77 (m,
2H), 1.77À1.65 (m, 2H), 1.45À1.27 (m, 2H), 1.06 (d, J = 6.9 Hz, 3H),
1.03 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H),
0.85 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 139.3,
139.2, 138.8, 128.3, 128.2, 128.1, 127.5, 127.3, 127.2, 127.12, 127.07, 83.6,
83.4, 78.2, 77.2, 73.8, 73.3, 73.0, 72.6, 66.3, 38.0, 37.5, 36.3, 36.1, 28.7, 26.0,
23.0, 18.2, 16.6, 14.4, 12.5, 12.3 ppm; MS (ESI) m/z 625.3 (M + Na+,
100), 603.4 (M + H+, 80), 495.3 (20); HRMS calcd for C39H55O5 [M +
H+] 603.4050, found 603.4038 (1.9 ppm).
(+)-(4S,5S,6S,7S,8S,9S,10S)-7,9,11-Tris(benzyloxy)-4,6,8,10-
tetramethyl-5-(triethylsilyloxy)undecan-1-ol (S12). Primary
alcohol S12 as a colorless oil (7.55 g, quantitative yield) was obtained
from ester S11 (7.98 g) according to general procedure A9: Rf = 0.30
(hexanes/EtOAc, 75:25); formula C42H64O5Si; MW 677.04 g/mol;
[α]D +23.6 (c 0.33, CHCl3); IR (neat) νmax 3431, 2956, 2912, 2875,
1455, 1090, 1066, 733 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.34À7.22
(m, 15H), 4.73 (d, J = 11.8 Hz, 1H), 4.70 (d, J = 11.3 Hz, 1H), 4.56 (d,
J = 12.8 Hz, 1H), 4.53 (d, J = 11.5 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H),
4.46 (d, J = 12.0 Hz, 1H), 3.82 (dd, J = 4.3 Hz, 2.7 Hz, 1H), 3.72 (dd, J =
9.2 Hz, 4.7 Hz, 1H), 3.59 (dd, J = 8.0 Hz, 3.3 Hz, 1H), 3.47À3.35 (m,
4H), 2.38À2.26 (m, 1H), 2.26À2.14 (m, 1H), 2.02À1.90 (m, 1H),
1.54À1.38 (m, 2H), 1.38À1.22 (m, 2H), 1.10 (d, J = 7.2 Hz, 3H), 1.08
(d, J = 7.7 Hz, 3H), 0.95À0.88 (m, 14H), 0.75 (d, J = 6.8 Hz, 3H), 0.56
(q, J = 7.5 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 139.5, 139.3,
138.8, 128.3, 128.2, 128.1, 127.5, 127.4, 127.2, 126.9, 126.7, 85.3, 83.6,
77.2, 75.8, 73.3, 73.1, 72.4, 63.2, 39.3, 38.6, 37.4, 36.4, 30.8, 28.2, 16.6,
15.8, 15.4, 12.8, 7.1, 5.7 ppm; MS (FAB) m/z 677.3 (M + H+, 10), 231.2
(28), 201.2 (27), 181.2 (100); HRMS calcd for C36H50O5Na
[M + H+ À TES + Na+] 585.3556, found 585.3564 (1.4 ppm). Anal.
Calcd for C42H64O5Si: C, 74.51; H, 9.53; found: C, 74.27; H, 9.71.
(+)-(4S,5S,6S,7S,8S,9S,10S)-7,9,11-Tris(benzyloxy)-4,6,8,10-
tetramethyl-5-(triethylsilyloxy)undecanal (17). Aldehyde 17 as
a colorless oil (602 mg, yield = 92%) was obtained from primary alcohol
S12 (660 mg) according to general procedure A10: Rf = 0.33 (hexanes/
EtOAc, 85:15); formula C42H62O5Si; MW 675.02 g/mol; [α]D +26.9
(+)-tert-Butyl((R)-2-((2S,5S,6S)-5-methyl-6-((2S,3S,4S,5S,6S)-
3,5,7-tris(benzyloxy)-4,6-dimethylheptan-2-yl)tetrahydro-
2H-pyran-2-yl)propoxy)diphenylsilane (S14). Product S14 was
obtained from a cold (0 ꢀC) solution of primary alcohol S13a (0.70 g) in
dry CH2Cl2 (0.2 M, 5.8 mL) to which were successively added imidazole
(2.2 equiv, 0.17 g) and TBDPSCl (2.2 equiv, 0.66 g) before the mixture
was stirred overnight at room temperature. The reaction mixture was
then treated with the addition of a saturated aqueous solution of NH4Cl
into the mixture followed by solvent evaporation in vacuo. The residue
was extracted with Et2O (3Â), and the combined organic fractions were
dried (MgSO4), filtered, and concentrated in vacuo to a colorless oil
used as crude without further purification: Rf = 0.25 (hexanes/EtOAc,
90:10); formula C55H72O5Si; MW 841.24 g/mol; [α]D +27.7 (c 0.13,
(c 0.23, CHCl3); IR (neat) νmax 3030, 2716, 1726, 1455, 734, 698 cmÀ1
;
1H NMR (400 MHz, CDCl3) δ 9.51 (t, J = 1.6 Hz, 1H), 7.40À7.20 (m,
15H), 4.73 (d, J = 11.5 Hz, 1H), 4.72 (d, J = 11.9 Hz, 1H), 4.59 (d, J =
11.9 Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H), 4.46
(d, J = 12.1 Hz, 1H), 3.80 (dd, J = 2.4 Hz, 4.4 Hz, 1H), 3.72 (dd, J = 5.0
Hz, 9.2 Hz, 1H), 3.57 (dd, J = 3.2 Hz, 8.2 Hz, 1H), 3.44 (dd, J = 7.6 Hz,
9.1 Hz, 1H), 3.40 (dd, J = 3.1 Hz, 9.0 Hz, 1H), 2.41À2.25 (m, 1H),
2.25À2.10 (m, 3H), 2.00À1.89 (m, 1H), 1.62À1.51 (m, 1H), 1.51À
1.40 (m, 1H), 1.13À1.06 (m, 6H), 0.95À0.86 (m, 12H), 0.71 (d, J = 6.9
Hz, 3H), 0.55 (q, J = 8.0 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ
202.9, 139.4, 139.2, 138.8, 128.3, 128.2, 128.1, 127.5, 127.4, 127.22,
127.15, 126.9, 126.6, 85.6, 83.6, 75.5, 73.4, 73.3, 73.1, 72.3, 42.1, 39.0,
38.9, 37.3, 36.4, 24.4, 16.5, 15.7, 15.6, 12.8, 7.1, 5.6 ppm; MS (ESI) m/z
675.4 (M + H+, 100), 435.2 (30), 343.2 (32), 229.1 (27); HRMS calcd
for C42H62O5NaSi [M + Na+] 697.4264, found 697.4270 (0.8 ppm).
Anal. Calcd for C42H62O5Si: C, 74.73; H, 9.26. Found: C, 74.49; H, 9.31.
(+)-(R)-2-((2S,5S,6S)-5-Methyl-6-((2S,3S,4S,5S,6S)-3,5,7-tris-
(benzyloxy)-4,6-dimethyl heptan-2-yl)tetrahydro-2H-pyran-
2-yl)propan-1-ol (S13a) and (S)-2-((2S,5S,6S)-5-Methyl-6-((2S,
3S,4S,5S,6S)-3,5,7-tris(benzyloxy)-4,6-dimethylheptan-2-yl)-
tetrahydro-2H-pyran-2-yl)propan-1-ol (S13b). A separable
mixture of their corresponding primary alcohol 2,3-anti (S13a) and
1
CHCl3); IR (neat) νmax 2857, 1455, 1091, 735, 699 cmÀ1; H NMR
(400 MHz, CDCl3) δ 7.70À7.62 (4H), 7.43À7.33 (m, 10H),
7.32À7.16 (m, 11H), 4.71 (d, J = 11.9 Hz, 1H), 4.51 (d, J = 11.9 Hz,
1H), 4.48 (d, J = 10.6 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 4.44 (d, J =
11.7 Hz, 1H), 4.38 (d, J = 11.6 Hz, 1H), 3.76À3.66 (m, 4H), 3.64 (dd,
J = 4.0 Hz, 9.5 Hz, 1H), 3.55 (dd, J = 3.4 Hz, 7.5 Hz, 1H), 3.48À3.42 (m,
1H), 3.39 (dd, J = 3.8 Hz, 7.9 Hz, 1H), 2.26À2.09 (m, 4H), 2.00À1.90
(m, 1H), 1.67À1.48 (m, 4H), 1.08 (d, J = 6.9 Hz, 3H), 1.05 (s, 9H), 0.93
(d, J = 7.2 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.65
(d, J = 6.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 139.5, 138.8,
135.7, 133.9, 129.4, 128.3, 128.0, 127.6, 127.51, 127.47, 127.3, 126.91,
126.88, 126.80, 84.9, 83.6, 76.4, 73.7, 73.3, 73.0, 72.5, 71.6, 65.7, 37.6,
37.3, 36.4, 36.3, 30.3, 30.2, 26.9, 24.7, 19.3, 18.1, 16.8, 16.2, 13.4, 11.5
ppm; MS (ESI) m/z 841.5 (M + H+, 5), 359.3 (100), 341.3 (97); HRMS
calcd for C55H73O5Si [M + H+] 841.5227, found 841.5212 (À1.0 ppm).
(+)-(2S,3S,4S,5S,6S)-6-((2S,3S,6S)-6-((R)-1-(tert-Butyldiphe-
nylsilyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-
2,4-dimethylheptane-1,3,5-triol (S15). Product S15 as a colorless
7668
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
oil (0.50 g, yield = 92%) was obtained from benzyl ether product S14
(0.80 g) according to general procedure A12 in THF (0.1 M, 9.5 mL)
with Pd(OH)2 20 wt % on activated carbon. The crude product was
purified by flash chromatography on silica gel (hexanes/EtOAc, 65:35):
Rf = 0.28 (hexanes/EtOAc, 65:35); formula C34H54O5Si; MW 570.88 g/
mol; [α]D +62.1 (c 0.14, CHCl3); IR (neat) νmax 3380, 2859, 1459,
1428, 1383, 823, 739, 702 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.67À
7.63 (m, 2H), 7.61À7.57 (m, 2H), 7.44À7.34 (m, 6H), 5.65 (s, 1H),
4.56 (d, J = 8.2 Hz, 1H), 4.16À4.09 (m, 1H), 3.92 (dd, J = 10.0 Hz, 3.0
Hz, 1H), 3.77 (dt, J = 10.9 Hz, 2.4 Hz, 1H), 3.62 (dd, J = 10.1 Hz, 2.8 Hz,
1H), 3.60 (dd, J = 10.5 Hz, 1.9 Hz, 1H), 3.53 (dd, J = 8.5 Hz, 2.4 Hz, 1H),
3.48À3.38 (m, 2H), 3.10 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 2.18À2.07 (m,
1H), 2.06À1.97 (m, 1H), 1.82À1.54 (m, 7H), 1.11 (d, J = 7.1 Hz, 3H),
1.10 (d, J = 7.1 Hz, 3H), 1.05 (s, 9H), 0.86 (d, J = 7.1 Hz, 3H), 0.79 (d, J =
6.5 Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 135.7, 135.55, 133.65, 129.6, 127.63, 127.59, 83.8, 82.5, 76.2,
73.0, 65.1, 64.4, 39.3, 35.5, 33.8, 33.5, 31.6, 27.07, 27.00, 25.6, 19.5, 17.8,
15.5, 14.1, 13.3, 11.3 ppm; MS (ESI) m/z 593.3 (M + Na+, 98), 571.3
(M + H+, 100), 493.3 (20), 365.1 (20); HRMS calcd for C34H55O5Si
[M + H+] 571.3819, found 571.3814 (0.8 ppm).
451.3 (18), 529.3 (M + H+, 100), 628.4 (6); HRMS calcd for C30H49-
O4Si2 [M + H+] 529.3164, found 529.3180 (3.0 ppm).
(+)-(2R,3S,4S)-5-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-
3-(triethylsilyloxy)pentan-1-ol (S18). Primary alcohol S18 as a
colorless oil (1.25 g, yield = 87%) was obtained from ester S17 (1.51 g)
following general procedure A9: Rf = 0.40 (hexanes/EtOAc, 85:15);
formula C29H48O3Si2; MW 500.86 g/mol; [α]D +4.2 (c 0.44, CHCl3);
IR (neat) νmax 3411, 3071, 2957, 2934, 2877, 1590, 1463, 1427, 1387,
1240, 1109, 1030, 1008, 823, 802, 738, 703, 613 cmÀ1; 1H NMR (500
MHz, CDCl3) δ 7.70À7.63 (m, 4H), 7.47À7.36 (m, 6H), 3.91À3.87
(m, 1H), 3.60 (d, J = 4.6 Hz, 2H), 3.56 (dd, J = 7.4 Hz, 10.2 Hz, 1H), 3.49
(dd, J = 6.0 Hz, 10.2 Hz, 1H), 2.59À5.53 (bs, 1H), 1.90À1.78 (m, 2H),
1.08 (s, 9H), 0.98À0.93 (m, 12H), 0.88 (d, J = 6.9 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 135.6, 133.7, 133.6, 129.6, 127.6, 77.2, 66.3,
66.2, 39.7, 38.6, 26.8, 19.2, 15.3, 11.5, 7.0, 5.2 ppm; MS (ESI) m/z 192.7
(27), 229.1 (36), 291.2 (100), 345.2 (85), 423.3 (59), 501.3 (M + H+,
61), 600.4 (32); HRMS calcd for C29H49O3Si2 [M + H+] 501.3215,
found 501.3214 (À0.1 ppm).
(()-(2S,3R,4S)-5-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-
3-(triethylsilyloxy)pentanal (28). Aldehyde 28 as a colorless oil
(1.43 g, quantitative yield) was obtained from primary alcohol S18 (1.35
g) according to general procedure A10: Rf = 0.83 (hexanes/EtOAc,
85:15); formula C29H46O3Si2; MW 498.84 g/mol; IR (neat) νmax 3072,
3051, 2957, 2936, 2878, 2710, 2361, 1889, 1728, 1590, 1463, 1427, 1389,
1363, 1240, 1187, 1110, 1046, 1009, 972, 941, 912, 829, 801, 739, 704,
(+)-(2S,3S,4S,5S,6S)-6-((2S,3S,6S)-6-((R)-1-(tert-Butyldiphen-
ylsilyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-
3,5-dihydroxy-2,4-dimethylheptyl Pivalate (20). Product 20 as
a colorless oil (0.501 g, yield = 90%) was obtained from a cold (0 ꢀC)
solution of primary alcohol S15 (0.485 g) in dry CH2Cl2 (0.1 M,
8.5 mL) to which were successively added pyridine (5 equiv, 0.34 mL)
and PivCl (2.5 equiv, 0.26 mL) before the mixture was stirred overnight
at room temperature. The reaction mixture was then treated with the
addition of a saturated NaHCO3 solution into the mixture followed by
solvent evaporation in vacuo. The residue was extracted with Et2O (3Â),
and the combined organic fractions were washed with a saturated brine
solution and then dried (MgSO4), filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography on silica gel
(hexanes/EtOAc, 85:15): Rf = 0.19 (hexanes/EtOAc, 85:15); formula
C39H62O6Si; MW 654.99 g/mol; [α]D +22.5 (c 0.12, CHCl3); IR (neat)
1
614 cmÀ1; H NMR (500 MHz, CDCl3) δ 9.81 (d, J = 2.6 Hz, 1H),
7.74À7.67 (m, 4H), 7.49À7.39 (m, 6H), 4.22 (dd, J = 3.4 Hz, 6.4 Hz,
1H), 3.63 (dd, J = 7.4 Hz, 10.2 Hz, 1H), 3.55 (dd, J = 5.8 Hz, 10.2 Hz,
1H), 2.68À2.61 (m, 1H), 1.92À1.83 (m, 1H), 1.15 (s, 9H), 1.10 (d, J =
7.0 Hz, 3H), 0.99 (t, J = 8.0 Hz, 9H), 0.92 (d, J = 6.9 Hz, 3H), 0.69À0.61
(m, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 205.1, 135.59, 135.58,
133.6, 129.7, 129.6, 127.64, 127.63, 73.8, 65.9, 50.6, 39.5, 26.9, 19.2, 11.5,
11.0, 6.9, 5.3 ppm; MS (ESI) m/z 171.1 (79), 189.1 (22), 289.2 (100),
349.2 (37), 381.2 (50), 437.3 (19), 481.3 (14), 521.3 (M + Na+, 55),
553.3 (76), 598.4 (15); HRMS calcd for C29H46O3NaSi2 [M + Na+]
521.2878, found 521.2890 (2.4 ppm).
1
νmax 3393, 2963, 2932, 1726, 1159, 1112, 1072, 1007, 703 cmÀ1; H
(À)-(4R,5S,6S,E)-Methyl 7-(tert-Butyldiphenylsilyloxy)-4,6-
dimethyl-5-(triethylsilyloxy)hept-2-enoate (S19). To a solu-
tion of aldehyde 28 (2.44 g) in toluene (0.1 M, 49 mL) was added
methyl (triphenylphosphoranylidene)acetate (1.5 equiv, 2.46 g), and
the reaction mixture 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 product
was purified by flash chromatography on silica gel (hexanes/EtOAc,
95:5) to give (E)-α,β-unsaturated ester S19 as a colorless oil (2.23 g,
yield = 82%): Rf = 0.53 (hexanes/EtOAc, 90:10); formula C32H50O4Si2;
MW 554.91 g/mol; [α]D À8.3 (c 0.40, CHCl3); IR (neat) νmax 3071,
2957, 2878, 1726, 1657, 1590, 1462, 1429, 1386, 1271, 1240, 1190, 1153,
1110, 1009, 823, 801, 738, 704, 613 cmÀ1; 1H NMR (500 MHz, CDCl3)
δ 7.67À7.63 (m, 4H), 7.46À7.35 (m, 6H), 7.01 (dd, J = 8.3 Hz, 15.8 Hz,
1H), 5.75 (dd, J = 1.0 Hz, 15.8 Hz, 1H), 3.84 (dd, J = 3.5 Hz, 5.8 Hz, 1H),
3.72 (s, 3H), 3.54 (dd, J = 7.1 Hz, 10.1 Hz, 1H), 3.43 (dd, J = 6.0 Hz, 10.1
Hz, 1H), 2.51À2.41 (m, 1H), 1.80À1.71 (m, 1H), 1.06 (s, 9H), 1.01 (d,
J = 6.9 Hz, 3H), 0.92 (t, J = 7.9 Hz, 9H), 0.83 (d, J = 6.8 Hz, 3H),
0.62À0.53 (m, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 167.0, 152.6,
135.6, 135.6, 133.8, 133.8, 129.6, 129.6, 127.6, 120.6, 75.5, 66.4, 51.3,
41.4, 39.2, 26.9, 19.2, 16.7, 11.3, 7.0, 5.4 ppm; MS (ESI) m/z 229.1 (4),
345.2 (14), 477.3 (100), 555.3 (M + H+, 21), 654.4 (6); HRMS calcd for
C32H51O4Si [M + H+] 555.3320, found 555.3327 (+1.1 ppm).
NMR (400 MHz, CDCl3) δ 7.67À7.63 (m, 2H), 7.62À7.58 (m, 2H),
7.41À7.33 (m, 6H), 4.50 (bs, 1H), 4.21 (dd, J = 10.8 Hz, 5.2 Hz, 1H),
4.10À4.03 (m, 1H), 3.93 (dd, J = 10.0 Hz, 3.1 Hz, 1H), 3.66 (dd, J = 10.8
Hz, 8.3 Hz, 1H), 3.63À3.57 (m, 2H), 3.46À3.38 (m, 2H), 2.19À2.08
(m, 1H), 2.07À1.96 (m, 2H), 1.74À1.45 (m, 7H), 1.17 (s, 9H), 1.09 (d,
J = 7.1 Hz, 3H), 1.05 (s, 9H), 1.02 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.9 Hz,
3H), 0.77 (d, J = 6.5 Hz, 3H), 0.73 (d, J = 6.7 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 178.7, 135.8, 135.6, 133.9, 133.7, 129.5, 127.61,
127.55, 83.8, 79.9, 77.2, 76.3, 73.1, 65.2, 38.9, 38.7, 34.8, 33.7, 33.5,
31.6, 27.2, 27.06, 26.99, 25.6, 19.4, 17.8, 15.6, 13.9, 13.2, 11.3 ppm; MS
(ESI) m/z 677.4 (M + Na+, 100), 655.4 (M + H+, 25), 381.3 (30);
HRMS calcd for C39H63O6Si [M + Na+] 655.4394, found 655.4377 (2.6
ppm). Anal. Calcd for C39H62O6Si: C, 71.52; H, 9.54. Found: C, 71.57;
H, 9.73.
(À)-(2S,3R,4S)-Methyl 5-(tert-Butyldiphenylsilyloxy)-2,4-
dimethyl-3-(triethylsilyloxy)pentanoate (S17). Product S17
as a colorless oil (7.81 g, yield = 89%) was obtained from alcohol 27
(6.88 g) following general procedure A8: Rf = 0.42 (hexanes/EtOAc,
90:10); formula C30H48O4Si2; MW 528.87 g/mol; [α]D À12.4 (c 0.5,
CHCl3); IR (neat) νmax 3072, 3050, 2955, 2878, 1741, 1460, 1429, 1381,
1242, 1194, 1174, 1111, 823, 807, 739, 704, 614 cmÀ1; 1H NMR (500
MHz, CDCl3) δ 7.72À7.65 (m, 4H), 7.47À7.36 (m, 6H), 4.19 (dd, J =
2.0 Hz, 8.6 Hz, 1H), 3.67 (s, 3H), 3.59 (dd, J = 7.7 Hz, 10.0 Hz, 1H), 3.45
(dd, J = 6.5 Hz, 10.0 Hz, 1H), 2.71À2.63 (m, 1H), 1.85À1.75 (m, 1H),
1.10 (s, 9H), 1.07 (d, J = 7.1 Hz, 3H), 0.91 (t, J = 8.0 Hz, 9H), 0.81 (d, J =
6.8 Hz, 3H), 0.62À0.48 (m, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ
176.1, 135.6, 135.6, 133.81, 133.76, 129.6, 129.5, 127.6, 73.3, 66.5, 51.4,
45.0, 37.9, 26.8, 19.2, 14.2, 9.6, 6.9, 5.2 ppm; MS (ESI) m/z 273.2 (28),
(À)-(4R,5S,6S)-Methyl 7-(tert-Butyldiphenylsilyloxy)-4,6-
dimethyl-5-(triethylsilyloxy)heptanoate (S20). Product S20 as
a colorless oil was obtained from α,β-unsaturated ester S19 (1.00 g)
according to general procedure A12 in EtOAc (0.1 M, 18 mL). The
7669
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
filtrate was concentrated in vacuo and used as crude without further
purification: Rf = 0.51 (hexanes/EtOAc, 90:10); formula C32H52O4Si2;
MW 556.92 g/mol; [α]D À0.5 (c 0.66, CHCl3); IR (neat) νmax 3071,
2956, 2934, 2877, 1742, 1462, 1429, 1386, 1242, 1171, 1110, 823, 739,
100), 563.2 (81Br; M + H+, 98), 660.3 (6); HRMS calcd for C29H42-
O479BrSi [M + H+] 561.2030, found 561.2040 (1.7 ppm).
(+)-(S)-Methyl 2-((2S,5S,6S)-6-((S)-1-(tert-Butyldiphenylsi-
lyloxy)propan-2-yl)-5-methyltetrahydro-2H-pyran-2-yl)pro-
panoate (31). Product 31 as a pale yellow oil (15.7 mg, yield = 81%)
was obtained from a mixture of bromides 30a and 30b (22.5 mg)
according to general procedure A3 in a 12:1 ratio of products 2,3-anti
(31)/2,3-syn: Rf = 0.44 (hexanes/EtOAc, 90:10); formula C29H42O4Si;
MW 482.73 g/mol; [α]D +34.9 (c 0.46, CHCl3); IR (neat) νmax 3071,
2952, 2931, 2857, 1740, 1460, 1429, 1379, 1361, 1267, 1194, 1167, 1110,
1967, 824, 740, 704, 612 cmÀ1; 1H NMR (500 MHz, CDCl3) δ 7.68À
7.62 (m, 4H), 7.43À7.34 (m, 6H), 3.75 (td, J = 4.9 Hz, 9.9 Hz, 1H), 3.55
(dd, J = 4.2 Hz, 9.9 Hz, 1H), 3.52À3.44 (m, 2H), 3.33 (s, 3H), 3.29 (dd,
J = 5.9 Hz, 5.9 Hz, 1H), 2.78 (qd, J = 7.1 Hz, 9.9 Hz, 1H), 2.04À1.95 (m,
1H), 1.70À1.49 (m, 5H), 1.30À1.21 (m, 1H), 1.04 (s, 9H), 1.01 (d, J =
6.9 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H) ppm; 13C
NMR (125 MHz, CDCl3) δ 176.2, 135.9, 134.4, 134.3, 129.8, 127.9,
78.5, 73.9, 67.8, 67.8, 51.6, 42.2, 36.5, 30.2, 27.2, 26.5, 24.5, 19.6, 18.3,
14.3, 11.5 ppm; MS (ESI) m/z 405.2 (46), 483.3 (M + H+, 100); HRMS
calcd for C29H43O4Si [M + H+] 483.2925, found 483.2937 (2.5 ppm).
(+)-(R)-2-((2S,5S,6S)-6-((S)-1-(tert-Butyldiphenylsilyloxy)-
propan-2-yl)-5-methyltetrahydro-2H-pyran-2-yl)propan-1-ol
(S22). Primary alcohol S22 as a colorless oil (1.40 g, yield = 81%) was
obtained from ester 31 (1.83 g) according to general procedure A9: Rf =
0.30 (hexanes/EtOAc, 75:25); formula C28H42O3Si; MW 454.72 g/mol;
[α]D +19.4 (c 0.34, CHCl3); IR(neat) νmax 3453, 3071, 2958, 2859, 1590,
1462, 1428, 1190, 1110, 1024, 823, 801, 740, 704, 614 cmÀ1; 1H NMR
(400 MHz, CDCl3) δ 7.62À7.68 (m, 4H), 7.46À7.35 (m, 6H),
3.64À3.58 (m, 3H), 3.51 (dd, J = 5.4 Hz, 10.1 Hz, 1H), 3.49À3.44 (m,
1H), 3.43 (dd, J = 4.5 Hz, 7.2 Hz, 1H), 2.93 (dd, J = 4.4 Hz, 7.2 Hz, 1H),
2.13À2.02 (m, 1H), 1.95À1.83 (m, 1H), 1.78À1.47 (m, 4H), 1.39À1.29
(m, 1H), 1.05 (s, 9H), 0.99 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H),
0.84 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 135.6,
133.7, 129.6, 127.6, 78.3, 75.9, 67.5, 66.5, 37.9, 35.3, 28.8, 26.8, 25.6, 25.0,
19.3, 18.3, 13.8, 12.4 ppm; MS (EI) m/z 55.0 (13), 69.1 (17), 95.1 (19),
135.0 (28), 163.1 (35), 183.0 (34), 199.0 (100), 229 (21), 269.0 (7),
289.0(9), 319.1 (40), 379.1(6), 397.1(17); HRMScalcd forC24H33O3Si
[M À t-Bu] 397.2199, found 397.2210 (À2.8 ppm). Anal. Calcd for
C28H42O3Si: C, 73.96; H, 9.31. Found: C, 73.92; H, 9.44.
(+)-((S)-2-((2S,3S,6S)-6-((R)-1-(Benzyloxy)propan-2-yl)-3-
methyltetrahydro-2H-pyran-2-yl)propoxy)(tert-butyl)diphenyl-
silane (S23). Protected benzyl ether product S23 as a colorless oil
(1.47 g, yield = 90%) was obtained from alcohol S22 (1.36 g) according
to general procedure A7: Rf = 0.40 (hexanes/EtOAc, 90:10); formula
C35H48O3Si; MW 544.84 g/mol; [α]D +25.8 (c 0.33, CHCl3); IR (neat)
νmax 3069, 2858, 1685, 1589, 1459, 1428, 1110, 1023, 824, 739, 703,
613 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.69À7.63 (m, 4H), 7.42À
7.33 (m, 6H), 7.32À7.27 (m, 2H), 7.26À7.22 (m, 3H), 4.37 (d, J = 12.1
Hz, 1H), 4.33 (d, J = 12.0 Hz, 1H), 3.66 (dd, J = 6.0 Hz, 9.9 Hz, 1H), 3.54
(dd, J = 6.5 Hz, 9.8 Hz, 1H), 3.51 (dd, J = 4.7 Hz, 8.4 Hz, 2H), 3.39À3.34
(m, 2H), 2.18À2.09 (m, 1H), 2.04À1.92 (m, 1H), 1.69À1.52 (m, 1H),
1.35À1.25 (m, 1H), 1.05 (s, 9H), 0.92 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.9
Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
138.9, 135.59, 135.56, 134.1, 133.9, 129.5, 128.2, 127.6, 127.4, 127.2,
76.6, 73.0, 72.8, 72.5, 67.0, 36.1, 34.3, 30.1, 26.9, 26.6, 24.8, 19.3, 18.1,
14.2, 11.1 ppm; MS (ESI) m/z 159.0 (7), 239.1 (8), 288.2 (20), 299.2
(9), 545.3 (100), 567.3 (51), 590.4 (6), 632.4 (9), 652.4 (21); HRMS
calcd for C35H49O3Si [M + H+] 545.3445, found 545.3438 (À1.3 ppm);
calcd for C35H48O3SiNa [M + Na+] 567.3265, found 567.3257 (À1.4
ppm). Anal. Calcd for C35H48O3Si: C, 77.16; H, 8.88. Found: C, 77.08;
H, 8.90.
1
703, 612 cmÀ1; H NMR (500 MHz, CDCl3) δ 7.76À7.69 (m, 4H),
7.48À7.38 (m, 6H), 3.79 (dd, J = 2.9 Hz, 5.9 Hz, 1H), 3.68 (s, 3H), 3.60
(dd, J = 7.5 Hz, 9.9 Hz, 1H), 3.49 (dd, J = 6.0 Hz, 9.9 Hz, 1H), 2.47À2.38
(m, 1H), 2.33À2.24 (m, 1H), 2.00À1.82 (m, 2H), 1.67À1.58 (m, 1H),
1.47À1.37 (m, 1H), 1.12 (s, 9H), 0.99 (t, J = 8.0 Hz, 9H), 0.92 (d, J =
6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.69À0.59 (m, 6H) ppm; 13C
NMR (125 MHz, CDCl3) δ 174.2, 135.5, 133.8, 133.8, 129.5, 127.5,
75.6, 66.9, 51.3, 38.1, 37.3, 32.3, 27.9, 26.8, 19.1, 15.9, 11.3, 7.0, 5.4 ppm;
MS (ESI) m/z 169.1 (93), 288.3 (12), 347.2 (82), 425.3 (70), 479.3 (7),
557.3 (M + H+, 100), 656.5 (10); HRMS calcd for C32H53O4Si2
[M + H+] 557.3477, found 557.3487 (1.6 ppm).
(À)-(4R,5S,6S)-7-(tert-Butyldiphenylsilyloxy)-4,6-dimethyl-
5-(triethylsilyloxy)heptan-1-ol (S21). Primary alcohol S21 as a
colorless oil (1.98 g, yield = 83% over two steps) was obtained from ester
S20 (2.51 g) according to general procedure A9: Rf = 0.33 (hexanes/
EtOAc, 85:15); formula C31H52O3Si2; MW 528.91 g/mol; [α]D À0.8
(c 0.48, CHCl3); IR (neat) νmax 3341, 3072, 3050, 2957, 2934, 2876,
1590, 1463, 1428, 1386, 1239, 1188, 1109, 1155, 1009, 970, 824, 738,
1
703, 612 cmÀ1; H NMR (500 MHz, CDCl3) δ 7.71À7.63 (m, 4H),
7.46À7.34 (m, 6H), 3.71 (dd, J = 2.2 Hz, 5.3 Hz, 1H), 3.65À3.52 (m,
3H), 3.43 (dd, J = 5.9 Hz, 9.8 Hz, 1H), 1.88À1.78 (m, 1H), 1.71À1.61
(m, 1H), 1.61À1.41 (m, 2H), 1.36À1.28 (bs, 1H), 1.08 (s, 9H), 0.94 (t,
J = 7.9 Hz, 9H), 0.88 (d, J = 6.1 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H),
0.63À0.55 (m, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 135.6, 133.9,
129.5, 127.6, 75.9, 67.1, 63.4, 38.0, 37.7, 30.9, 28.8, 26.8, 19.2, 16.1, 11.2,
7.1, 5.4 ppm; MS (ESI) m/z 141.1 (16), 192.7 (12), 241.2 (14), 288.3
(11), 319.2 (99), 397.3 (100), 415.3 (6), 529.4 (M + H+, 59), 582.5 (7),
628.5 (26); HRMS calcd for C31H52O3Si2 [M + H+] 529.3528, found
529.3529 (0.2 ppm).
(+)-Methyl2-Bromo-2-((2S,5S,6S)-6-((S)-1-(tert-butyldiphe-
nylsilyloxy)propan-2-yl)-5-methyltetrahydro-2H-pyran-2-yl)-
propanoate (30a, 30b). A mixture of bromide adducts 30a and 30b in
a ∼1:1 ratio as a pale yellow oil (1.98 g, quantitative yield) was obtained
from aldehyde 29 (1.69 g) according to general procedure A13. A quan-
titative yield was calculated due to contamination with C-silylated product
from enol ether 7a. 30a: Rf = 0.43 (hexanes/EtOAc, 90:10); formula
C29H41BrO4Si; MW 561.62 g/mol; [α]D +4.49 (c 0.54, CHCl3); IR
(neat) νmax 3070, 2956, 2932, 2860, 1744, 1589, 1458, 1429, 1378, 1263,
1
1200, 1142, 1110, 1044, 1005, 859, 823, 804, 740, 704, 613 cmÀ1; H
NMR (500 MHz, CDCl3) δ 7.67À7.62 (m, 4H), 7.46À7.36 (m, 6H),
4.08 (dd, J = 3.2 Hz, 10.2 Hz, 1H), 3.76 (s, 3H), 3.55 (dd, J = 4.6 Hz,
10.1 Hz, 1H), 3.50 (dd, J = 4.9 Hz, 10.2 Hz, 1H), 3.46 (d, J = 9.2 Hz, 1H),
2.17À2.07 (m, 1H), 1.91 (s, 3H), 1.89À1.81 (m, 1H), 1.80À1.71 (m,
3H), 1.48À1.41 (m, 1H), 1.06 (d, J = 7.2 Hz, 3H), 1.04 (s, 9H), 0.96 (d,
J = 6.6 Hz, 3H) ppm;13C NMR (125 MHz, CDCl3) δ 171.5, 135.6, 135.6,
133.6, 129.6, 127.6, 81.4, 73.6, 66.4, 62.2, 53.0, 34.8, 26.9, 26.8, 24.7, 22.5,
19.6, 19.3, 18.2, 13.5 ppm; MS (ESI) m/z 225.1 (11), 305.1 (10), 395.2
(7), 485.2 (15), 561.2 (79Br; M + H+, 100), 563.2 (81Br; M + H+, 99),
662.3 (6); HRMS calcd for C29H42O479BrSi [M + H+] 561.2030, found
561.2037 (1.2 ppm). 30b: Rf = 0.33 (hexanes/EtOAc, 90:10); formula
C29H41BrO4Si; MW 561.62 g/mol; IR (neat) νmax 3071, 2956, 2933,
2860, 1740, 1590, 1452, 1429, 1379, 1265, 1190, 1159, 1111, 1055, 1034,
908, 861, 829, 704, 614 cmÀ1; 1H NMR (500 MHz, CDCl3) δ 7.68À7.62
(m, 4H), 7.46À7.35 (m, 6H), 3.89 (dd, J = 2.2 Hz, 11.0 Hz, 1H), 3.78 (s,
3H), 3.61À3.51 (m, 3H), 2.22À2.13 (m, 1H), 1.90À1.84 (bs, 1H), 1.87
(s, 3H), 1.82À1.65 (m, 3H), 1.47À1.29 (m, 2H), 1.11 (d, J = 7.0 Hz, 3H),
1.10 (d, J = 6.4 Hz, 3H), 1.05 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3)
δ 171.1, 135.60, 135.56, 133.59, 133.57, 129.6, 127.6, 81.3, 74.0, 66.6,
65.6, 53.2, 34.7, 26.9, 26.8, 24.3, 24.0, 20.7, 19.3, 18.3, 14.0 ppm; MS(ESI)
m/z 161.1 (18), 305.1 (9), 395.2 (11), 485.2 (10), 561.2 (79Br; M + H+,
(+)-(S)-2-((2S,3S,6S)-6-((R)-1-(Benzyloxy)propan-2-yl)-3-
methyltetrahydro-2H-pyran-2-yl)propan-1-ol (S24). To a cold
(0 ꢀC) solution of product S23 (1.63 g) in dry THF (0.1 M, 30 mL) was
7670
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
added dropwise a 1 M solution of TBAF in THF (1.2 equiv, 3.6 mL),
followed by overnight stirring at room temperature. The reaction mix-
ture was treated with the addition of a saturated aqueous solution of
NH4Cl and then concentrated in vacuo. The product was extracted with
Et2O (3Â), and the combined organic fractions were washed with a
saturated brine solution and then dried (MgSO4), filtered, and concen-
trated in vacuo. The crude product was purified by flash chromatography
on silica gel (hexanes/EtOAc, 75:25) to give the desired primary alcohol
S24 as a colorless oil (0.84 g, yield = 91%): Rf = 0.22 (hexanes/EtOAc,
75:25); formula C19H30O3; MW 306.44 g/mol; [α]D +64.0 (c 0.25,
CHCl3); IR (neat) νmax 3441, 2961, 1456, 1233, 1075, 1020, 967, 737,
698 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.37À7.26 (m, 5H), 4.56 (d,
J = 12.1 Hz, 1H), 4.50 (d, J = 12.1 Hz, 1H), 3.63 (dd, J = 3.6 Hz, 8.5 Hz,
1H), 3.64À3.61 (m, 1H), 3.60 (dd, J = 3.6 Hz, 6.8 Hz, 1H), 3.55 (dd, J =
5.6 Hz, 10.7 Hz, 1H), 3.41 (dd, J = 2.9 Hz, 9.4 Hz, 1H), 3.35 (dd, J =
6.9 Hz, 9.1 Hz, 1H), 2.40À2.30 (m, 1H), 1.88À1.78 (m, 1H), 1.71À
1.65 (m, 2H), 1.60À1.52 (m, 2H), 1.33À1.21 (m, 1H), 0.95 (d, J =
7.1 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 138.7, 128.3, 127.7, 127.4, 78.6, 74.6, 73.2,
72.8, 67.5, 35.4, 32.0, 31.7, 27.1, 25.8, 17.7, 14.8, 9.4 ppm; MS (EI) m/z
41.0 (8), 55.0 (12), 81.1 (14), 91.0 (100), 121.1 (18), 139.1 (17), 157.1
(35), 200.1 (8), 247.1 (16), 288.2 (2), 306.2 (M + H+, 2); HRMS calcd
for C19H30O3 [M + H+] 306.2195, found 306.2190 (1.8 ppm). Anal.
Calcd for C19H30O3: C, 74.47; H, 9.87. Found: C, 74.17; H, 9.82.
(+)-(R)-2-((2S,3S,6S)-6-((R)-1-(Benzyloxy)propan-2-yl)-3-
methyltetrahydro-2H-pyran-2-yl)propanal (32). Aldehyde 32
as a colorless oil (0.57 g, yield = 94%) was obtained from primary alcohol
S24 (0.61 g) according to general procedure A10: Rf = 0.28 (hexanes/
EtOAc, 85:15); formula C19H28O3; MW 304.42 g/mol; [α]D +21.9 (c
1.2, CHCl3); IR (neat) νmax 2927, 2856, 1725, 1456, 1376, 1092, 1020,
738, 698 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 1.2 Hz, 1H),
7.36À7.24 (m, 5H), 4.49 (s, 2H), 3.75 (dd, J = 4.4 Hz, 8.1 Hz, 1H), 3.52
(dd, J = 3.5 Hz, 9.1 Hz, 1H), 3.53À3.46 (m, 1H), 3.24 (dd, J = 7.5 Hz,
9.0 Hz, 1H), 2.57 (ddq, J = 1.2 Hz, 4.4 Hz, 6.9 Hz, 1H), 2.32À2.19 (m,
1H), 1.73À1.55 (m, 4H), 1.43À1.29 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H),
0.93 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 204.7, 138.7, 128.3, 127.6, 127.4, 75.1, 74.0, 73.1, 72.5,
47.7, 33.1, 31.1, 26.5, 25.1, 17.8, 14.4, 7.1 ppm; MS (ESI) m/z 141.1 (3),
195.1 (6), 247.2 (12), 303.2 (34), 305.2 (M + H+, 35), 321.2 (52), 327.2
(M + Na+, 38), 359.2 (78), 375.2 (13), 389.2 (4), 557.3 (16), 573.3 (59),
647.4 (42), 663.3 (100), 679.3 (70); HRMS calcd for C19H28O3Na
[M + Na+] 327.1931, found 327.1925 (À3.5 ppm).
(()-(2R,3R,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(Benzyloxy)-
propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-
2-methylpentanoate (35). Product 35 as a pale yellow oil (0.48 g,
yield = 77%) was obtained from a mixture of bromides 33a and 33b
(0.75 g) according to general procedure A4 in a >20:1 ratio of products
2,3-anti (35)/2,3-syn (36): Rf = 0.24 (hexanes/EtOAc, 85:15); formula
C23H36O5; MW 392.53 g/mol; IR (neat) νmax 3463, 3030, 2950, 2931,
2859, 1740, 1457, 1379, 1362, 1272, 1249, 1196, 1169, 1097, 1071, 1016,
985, 737, 698 cmÀ1; 1H NMR (500 MHz, CDCl3) δ 7.41À7.25 (m, 5H),
4.63 (d, J = 11.9 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 3.78À3.65 (m, 4H),
3.72 (s, 3H), 3.63 (dd, J = 1.7 Hz, 10.2 Hz, 1H), 3.43 (dd, J = 7.1 Hz,
9.0 Hz, 1H), 2.83À2.76 (m, 1H), 2.46À2.36 (m, 1H), 1.92À1.84 (m,
1H), 1.78À1.54 (m, 4H), 1.33À1.22 (m, 1H), 1.13 (d, J = 7.0 Hz, 3H),
1.07 (d, J = 7.1 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 176.1, 138.8, 128.2, 127.6, 127.2,
77.6, 75.3, 74.6, 73.2, 72.9, 51.4, 43.7, 34.3, 31.7, 31.6, 26.9, 25.8, 17.7,
14.7, 14.6, 10.8 ppm; MS (ESI) m/z 185.1 (100), 235.2 (47), 267.2 (22),
325.2 (38), 393.3 (M + H+, 42); HRMS calcd for C23H37O5 [M + H+]
393.2636, found 393.2634 (À0.4 ppm).
(()-(2S,3S,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(Benzyloxy)-
propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-
2-methylpentanoate (37). Product 37 as a pale yellow oil (7.2 mg,
yield = 68%) was obtained from bromide 34 (12.7 mg) according to
general procedure A4 in a >20:1 ratio of products 2,3-anti (37)/2,3-syn
(38): Rf = 0.18 (hexanes/EtOAc, 85:15); formula C23H36O5; MW
392.53 g/mol; IR (neat) νmax 3462, 2930, 2859, 1738, 1540, 1457,
1347, 1249, 1195, 1170, 1071, 1044, 1016, 965, 908, 736, 699 cmÀ1; 1H
NMR (500 MHz, CDCl3) δ 7.37À7.26 (m, 5H), 4.53 (d, J = 11.8 Hz,
1H), 4.49 (d, J = 11.8Hz, 1H), 3.96À3.91 (m, 2H), 3.72 (s, 3H), 3.68 (dt,
J = 10.3 Hz, 3.7 Hz, 1H), 3.55 (dd, J = 3.2 Hz, 9.0 Hz, 1H), 3.43 (dd, J =
2.4 Hz, 9.4 Hz, 1H), 3.42À3.38 (m, 1H), 2.63 (dq, J = 9.6 Hz, 7.1 Hz,
1H), 2.37À2.28 (m, 1H), 1.87À1.80 (m, 1H), 1.71À1.66 (m, 2H),
1.66À1.59 (m, 1H), 1.59À1.52 (m, 1H), 1.34À1.22 (m, 1H), 1.07 (d, J =
7.0 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 7.1 Hz, 3H), 0.81 (d, J =
6.6 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 176.5, 138.8, 128.9,
128.2, 127.8, 127.4, 81.8, 78.2, 74.5, 73.2, 72.4, 51.7, 43.5, 33.6, 31.8,
30.3, 26.9, 25.6, 17.6, 14.9, 14.1, 4.7 ppm; MS (ESI) m/z 393.3 (M + H+,
100); HRMS calcd for C23H37O5 [M + H+] 393.2636, found 393.2623
(À3.1 ppm).
(()-(2R,3S,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(Benzyloxy)-
propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-
2-methylpentanoate (38). Product 38 as a pale yellow oil (6.3 mg,
yield = 59%) was obtained from bromide 34 (12.7 mg) according to
general procedure A5 in a >20:1 ratio of products 2,3-syn (38)/2,3-anti
(37): Rf = 0.25 (hexanes/EtOAc, 85:15); formula C23H36O5; MW
392.53 g/mol; IR (neat) νmax 3470, 2955, 2927, 2871, 1736, 1456,
1433, 1360, 1314, 1232, 1197, 1160, 1117, 1074 cmÀ1; 1H NMR (500
MHz, CDCl3) δ 7.37À7.26 (m, 5H), 4.56 (d, J = 11.9 Hz, 1H), 4.50 (d,
J = 11.9 Hz, 1H), 3.85À3.79 (m, 2H), 3.73À3.67 (m, 1H), 3.66 (s, 3H),
3.58 (dd, J = 3.1 Hz, 9.0 Hz, 1H), 3.44À3.38 (m, 2H), 2.65 (dq, J = 9.2
Hz, 6.8 Hz, 1H), 2.39À2.30 (m, 1H), 1.72À1.62 (m, 3H), 1.62À1.50 (m,
2H), 1.31À1.21 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.8 Hz,
3H), 0.91 (d, J = 7.1 Hz, 3H), 0.76 (d, J = 6.4 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 175.9, 136.9, 128.3, 127.7, 127.4, 81.5, 76.6, 74.6,
73.3, 72.5, 51.5, 43.8, 43.1, 35.7, 31.7, 29.7, 26.9, 25.7, 17.5, 14.8,5.2 ppm;
MS (ESI) m/z 393.3 (M + H+, 100); HRMS calcd for C23H37O5
[M + H+] 393.2636, found 393.2626 (À2.6 ppm).
(()-(3S,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(Benzyloxy)pro-
pan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-2-bromo-3-
hydroxy-2-methylpentanoate (34). Bromide product 34 as a pale
yellow oil (72 mg, quantitative yield) was obtained from aldehyde 32
(43 mg) according to general procedure A1 in a >20:1 ratio of products
3,4-syn (34)/3,4-anti (33). The purified bromide product 34 was found
to be contaminated by unreactive C-silylated product from enol ether
7a: Rf = 0.29 (hexanes/EtOAc, 85:15); formula C23H35BrO5; MW
471.43 g/mol; IR (neat) νmax 3464, 2951, 2930, 2859, 1737, 1453, 1378,
1
1313, 1261, 1100, 1051, 1016, 967, 919, 738, 699 cmÀ1; H NMR
(500 MHz, CDCl3) δ 7.40À7.24 (m, 5H), 4.58 (d, J = 12.2 Hz, 1H),
4.55 (d, J = 12.2 Hz, 1H), 4.35 (s, 1H), 3.80 (s, 3H), 3.66 (ddd, J =
3.2 Hz, 4.7 Hz, 10.4 Hz, 1H), 3.61 (dd, J = 3.3 Hz, 9.1 Hz, 1H), 3.42 (dd,
J = 6.8 Hz, 9.0 Hz, 1H), 3.33 (dd, J = 3.1 Hz, 9.1 Hz, 2H), 2.37À2.27 (m,
1H), 1.95 (s, 3H), 1.93À1.87 (m, 1H), 1.74À1.51 (m, 4H), 1.33À1.18
(m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.80 (d, J =
6.4 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 171.2, 138.7, 128.3,
127.7, 127.4, 82.2, 79.5, 74.4, 73.3, 72.8, 65.8, 53.0, 35.0, 32.3, 30.9, 26.7,
25.5, 23.9, 17.5, 14.7, 6.6 ppm; MS (ESI) m/z 185.2 (55), 233.2 (78),
283.2 (87), 345.1 (32), 363.1 (13), 453.2 (8), 471.2 (79Br; M + H+, 100),
570.3 (7); HRMS calcd for C23H36O579Br [M + H+] 471.1741, found
471.1739 (À0.3 ppm).
(()-(2R,3R,4S)-Methyl 3-Hydroxy-4-((2S,3S,6S)-6-((R)-1-
hydroxypropan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-2-
methylpentanoate (S25). Product S25 as a colorless oil was
obtained from benzyl ether 35 (90 mg) according to general procedure
A12. The crude product was used as crude without further purification:
Rf = 0.05 (hexanes/EtOAc, 85:15); formula C16H30O5; MW 302.41 g/mol;
1H NMR (500 MHz, CDCl3) δ 3.85À3.76 (m, 2H), 3.69 (s, 3H), 3.64
7671
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
(dd, J = 1.5 Hz, 9.9 Hz, 1H), 3.59À3.53 (m, 2H), 3.44 (dd, J = 6.2 Hz,
10.5 Hz, 1H), 3.12 (sl, 1H), 2.75 (dq, J = 7.0 Hz, 7.0 Hz, 1H), 2.28À2.17
(m, 1H), 1.85À1.76 (m, 1H), 1.73À1.64 (m, 2H), 1.64À1.52 (m, 2H),
1.29À1.18 (m, 1H), 1.15 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 7.1 Hz, 3H),
0.85 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.4 Hz, 3H) ppm.
yield = 95%) was obtained from ester S27 (246 mg) according to general
procedure A9: Rf = 0.33 (hexanes/EtOAc, 80:20); formula C29H42O4;
MW 454.64 g/mol; IR (neat) νmax 3440, 3063, 3030, 2962, 2927, 2876,
1495, 1455, 1379, 1207, 1093, 1070, 1025, 966, 909, 735, 698 cmÀ1; 1H
NMR (500 MHz, CDCl3) δ 7.34À7.23 (m, 10H), 4.63 (d, J = 11.0 Hz,
1H), 4.52 (d, J = 11.0 Hz, 1H), 4.48 (d, J = 11.9 Hz, 1H), 4.45 (d, J =
11.9 Hz, 1H), 3.83 (dt, J = 10.8 Hz, 3.7 Hz, 1H), 3.68 (dd, J = 3.6 Hz,
8.8 Hz, 1H), 3.59À3.52 (m, 2H), 3.50 (dd, J = 4.3 Hz, 7.2 Hz, 1H), 3.41
(dd, J = 3.9 Hz, 7.2 Hz, 1H), 3.34 (dd, J = 7.5 Hz, 8.5 Hz, 1H), 2.88 (dd, J =
4.3 Hz, 7.1 Hz, 1H), 2.20À2.12 (m, 1H), 2.12À2.03 (m, 1H), 1.96À1.87
(m, 1H), 1.75À1.53 (m, 4H), 1.35À1.23 (m, 1H), 1.11 (d, J= 7.1 Hz, 3H),
0.93 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 138.7, 138.3, 128.4, 128.3, 127.7,
127.6, 127.5, 127.4, 87.0, 76.4, 74.8, 73.2, 73.1, 72.6, 65.3, 37.0, 36.3, 35.2,
30.0, 26.7, 24.9, 18.4, 16.3, 14.1, 11.0 ppm; MS (ESI) m/z 347.3 (6), 455.3
(M + H+, 100), 456.3 (30), 545.4 (20); HRMS calcd for C29H43O4 [M +
H+] 455.3156, found 455.3153 (À0.6 ppm).
(()-(2R,3R,4S)-Methyl 3-Hydroxy-2-methyl-4-((2S,3S,6S)-
3-methyl-6-((R)-1-(triisopropylsilyloxy)propan-2-yl)tetrahy-
dro-2H-pyran-2-yl)pentanoate (S26). Product S26 as a colorless
oil (96 mg, yield = 77% over two steps) was obtained from crude alcohol
S25 according to general procedure A8 with TIPSOTf (1.1 equiv,
68 μL): Rf = 0.21 (hexanes/EtOAc, 95:5); formula C25H50O5Si; MW
458.75 g/mol; IR (neat) νmax 3521, 2942, 2866, 1742, 1719, 1461, 1381,
1250, 1196, 1170, 1095, 1068, 1013, 883, 838, 777, 682, 660 cmÀ1; 1H
NMR (500 MHz, CDCl3) δ 3.86À3.79 (m, 2H), 3.74 (dd, J = 3.1 Hz,
9.6 Hz, 1H), 3.67 (s, 3H), 3.65À3.54 (m, 2H), 3.43 (d, J = 9.4 Hz, 1H),
2.65 (dq, J = 7.0 Hz, 7.1 Hz, 1H), 2.24À2.15 (m, 1H), 1.82À1.74 (m,
1H), 1.71À1.65 (m, 2H), 1.65À1.51 (m, 2H), 1.28À1.18 (m, 1H), 1.13
(d, J = 7.1 Hz, 3H), 1.10À1.06 (m, 3H), 1.06À1.02 (m, 18H), 0.98 (d,
J = 7.1 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.5 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3) δ 176.4, 76.7, 75.1, 73.3, 64.7, 51.5, 43.2,
35.4, 33.3, 31.7, 27.4, 25.9, 18.01, 17.98, 17.8, 14.8, 14.1, 11.9, 10.6 ppm;
MS (ESI) m/z 459.4 (M + H+, 100); HRMS calcd for C25H51O5Si [M +
H+] 459.3500, found 459.3503 (0.5 ppm).
(()-(2S,3S,4S)-2-Methyl-4-((2S,3S,6S)-3-methyl-6-((R)-1-(tri-
isopropylsilyloxy)propan-2-yl)tetrahydro-2H-pyran-2-yl)pen-
tane-1,3-diol (39)29. Primary alcohol 39 as a colorless oil (69 mg,
yield = 76%) was obtained from ester S26 (96 mg) according to general
procedure A9: Rf = 0.23 (hexanes/EtOAc, 85:15); formula C24H50O4Si;
MW 430.74 g/mol; IR (neat) νmax 3416, 2959, 2940, 2866, 1461, 1382,
1235, 1096, 1074, 1012, 883, 836, 775, 682 cmÀ1; 1H NMR (500 MHz,
CDCl3) δ 4.29 (d, J = 7.9 Hz, 1H), 3.90 (ddd, J = 3.7 Hz, 3.7 Hz, 9.3 Hz,
1H), 3.80 (dd, J = 4.4 Hz, 9.6 Hz, 1H), 3.75 (dd, J = 3.1 Hz, 9.6 Hz, 1H),
3.73À3.62 (m, 4H), 3.43 (ddd, J = 3.2 Hz, 9.2 Hz, 9.1 Hz, 1H), 2.24À
2.14 (m, 1H), 1.97À1.90 (m, 1H), 1.90À1.81 (m, 1H), 1.72À1.61 (m,
3H), 1.61À1.53 (m, 1H), 1.30À1.16 (m, 1H), 1.13À1.06 (m, 3H), 1.08
(d, J = 7.2 Hz, 3H), 1.06À1.02 (m, 18H), 0.91 (d, J = 6.9 Hz, 3H), 0.80
(d, J = 6.5 Hz, 3H), 0.76 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 83.2, 76.1, 73.4, 68.9, 65.1, 38.0, 34.0, 33.7, 31.8, 27.0, 25.9,
18.03, 17.99, 17.9, 14.2, 13.7, 11.9, 11.3 ppm; MS (ESI) m/z 159.1 (67),
244.3 (83), 288.3 (32), 339.1 (27), 431.4 (M + H+, 100), 663.5 (66);
HRMS calcd for C24H51O4Si [M + H+] 431.3551, found 431.3553 (0.3
ppm).
(+)-(2R,3R,4S)-3-(Benzyloxy)-4-((2S,3S,6S)-6-((R)-1-(benzyl-
oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-2-meth-
ylpentanal (40). Aldehyde 40 as a colorless oil was obtained from
primary alcohol S28 (105 mg) according to general procedure A11: Rf =
0.65 (hexanes/EtOAc, 80:20); formula C29H40O4; MW 452.63 g/mol;
[α]D +31.0 (c 1.6, CHCl3); IR (neat) νmax 3030, 2955, 2925, 2854, 1724,
1456, 1379, 1263, 1094, 1070, 1020, 965, 802, 736, 697, 645 cmÀ1; 1H
NMR (500 MHz, CDCl3) δ 9.79 (d, J = 1.8 Hz, 1H), 7.34À7.25 (m,
10H), 4.53À4.48 (m, 2H), 4.48À4.42 (m, 2H), 3.69 (dd, J = 3.0 Hz, 7.7
Hz, 1H), 3.62À3.55 (m, 2H), 3.52 (dd, J = 3.2 Hz, 8.3 Hz, 1H), 3.33 (dd,
J = 7.2 Hz, 8.7 Hz, 1H), 2.73 (ddq, J = 2.0 Hz, 2.7 Hz, 6.9 Hz, 1H),
2.21À2.12 (m, 1H), 2.12À2.06 (m, 1H), 1.68À1.57 (m, 3H), 1.33À
1.21 (m, 2H), 1.14 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.84 (d, J =
6.5 Hz, 3H), 0.82 (d, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 204.4, 138.7, 138.4, 128.28, 128.25, 127.6, 127.42, 127.38, 127.2, 82.3,
75.6, 73.2, 73.1, 72.9, 72.5, 48.5, 36.7, 33.8, 30.6, 27.0, 25.3, 18.2, 14.3, 10.8,
9.8 ppm; MS (ES-TOF) m/z 237.2 (8), 327.2 (8), 342.3 (24), 345.2 (31),
415.2 (53), 431.2 (57), 453.3 (M + H+, 10), 475.3 (M + Na+, 100), 491.3
(81), 492.3 (30), 507.3 (26), 521.8 (8), 683.4 (5); HRMS calcd for
C29H40O4Na [M + Na+] 475.2824, found 475.2828 (0.8 ppm).
(()-(3R,4S,5S,6S)-Methyl 5-(Benzyloxy)-6-((2S,3S,6S)-6-((R)-
1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-
yl)-2-bromo-3-hydroxy-2,4-dimethylheptanoate (41a, 41b).
A ∼1:1 mixture of bromide adducts 41a and 41b as a pale yellow oil
(45.6 mg, yield = 32% over two steps) was obtained from aldehyde 40
(104 mg) according to general procedure A2 in a 5:1 ratio of products
3,4-anti (41a,b)/3,4-syn (42) with 1 M solution of TiCl4 in CH2Cl2
(4 equiv, 0.92 mL). Purified mixture of bromide adducts was found to be
contaminated by unreactive C-silylated product from enol ether 7a. 41a:
Rf = 0.40 (hexanes/EtOAc, 85:15); formula C33H47BrO6; MW 619.63
g/mol; IR (neat) νmax 3561, 3030, 2952, 2928, 2860, 1738, 1453, 1379,
1307, 1260, 1093, 1068, 1027, 967, 913, 736, 698 cmÀ1; 1H NMR (500
MHz, CDCl3) δ 7.35À7.24 (m, 10H), 4.60À4.53 (m, 2H), 4.49 (d, J =
12.2 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.37 (d, J = 9.6 Hz, 1H), 3.78 (s,
3H), 3.65 (dd, J = 2.9 Hz, 8.6 Hz, 2H), 3.62À3.57 (m, 2H), 3.36 (dd, J =
7.3 Hz, 8.4 Hz, 1H), 3.05 (sl, 1H), 2.19À1.99 (m, 3H), 1.87 (s, 3H),
1.74À1.54 (m, 4H), 1.33À1.21 (m, 1H), 0.96 (d, J = 7.0 Hz, 3H), 0.91
(d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.2 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 171.3, 138.85, 138.84, 128.3,
128.2, 127.5, 127.34, 127.29, 127.26, 84.0, 77.2, 75.6, 75.2, 73.2, 73.14,
73.12, 73.11, 68.9, 52.8, 38.6, 37.8, 34.2, 30.4, 27.2, 25.3, 21.0, 18.4, 14.2,
10.8 ppm; MS (ESI) m/z 247.2 (5), 345.2 (9), 431.3 (7), 449.3 (61),
491.2 (6), 539.3 (11), 619.3 (79Br; M + H+, 100); HRMS calcd for
C33H48O679Br [M + H+] 619.2629, found 619.2620 (À1.5 ppm).
(()-(3S,4S,5S,6S)-Methyl 5-(Benzyloxy)-6-((2S,3S,6S)-6-((R)-
1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-
yl)-2-bromo-3-hydroxy-2,4-dimethylheptanoate (42). Bromide
(()-(2R,3R,4S)-Methyl 3-(Benzyloxy)-4-((2S,3S,6S)-6-((R)-1-
(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-
2-methylpentanoate (S27). Protected benzyl ether product S27
as a colorless oil (227 mg, yield = 92%) was obtained from alcohol 35
(200 mg) according to general procedure A7: Rf = 0.24 (hexanes/EtOAc,
90:10); formula C30H42O5; MW 482.65 g/mol; IR (neat) νmax 3064,
3030, 2949, 2929, 1737, 1496, 1455, 1379, 1359, 1205, 1094, 1069, 1026,
1
966, 736, 696 cmÀ1; H NMR (500 MHz, CDCl3) δ 7.34À7.22 (m,
10H), 4.53 (s, 2H), 4.48 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H),
3.79 (dd, J = 5.3 Hz, 7.1 Hz, 1H), 3.68À3.64 (m, 1H), 3.66 (s, 3H), 3.57
(dd, J = 3.9 Hz, 7.6 Hz, 2H), 3.35 (dd, J = 7.2 Hz, 8.8 Hz, 1H), 2.91 (dq,
J = 5.4 Hz, 7.1 Hz, 1H), 2.19À2.05 (m, 2H), 1.75À1.53 (m, 4H), 1.36À
1.26 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.89 (d,
J = 7.1 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 175.2, 138.8, 128.20, 128.15, 127.5, 127.3, 127.2, 82.7, 75.6,
73.1, 73.0, 72.8, 72.6, 51.5, 41.6, 36.2, 34.4, 30.3, 26.8, 25.0, 18.3, 14.2,
12.1, 10.1 ppm;MS (ESI) m/z 185.1 (100), 235.2 (33), 267.2 (40), 325.2
(28), 375.3 (37), 451.3 (5), 483.3 (M + H+, 22), 573.4 (8); HRMS calcd
for C30H43O5 [M + H+] 483.3105, found 483.3099 (À1.3 ppm).
(()-(2S,3S,4S)-3-(Benzyloxy)-4-((2S,3S,6S)-6-((R)-1-(benzyl-
oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-2-meth-
ylpentan-1-ol (S28). Primary alcohol S28 as a colorless oil (220 mg,
7672
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
adduct 42 as a pale yellow oil (16.9 mg, yield = 68% over two steps) was
obtained from aldehyde 40 (18.1 mg) according to general procedure A1
in a >20:1 ratio of products 3,4-syn (42)/3,4-anti (41a,b). The purified
product was found to be contaminated by unreactive C-silylated product
from enol ether 7a: Rf = 0.44 (hexanes/EtOAc, 85:15); formula C33H47-
BrO6; MW 619.63 g/mol; IR (neat) νmax 3454, 3030, 2950, 2928, 1737,
1454, 1380, 1260, 1085, 735, 699 cmÀ1; 1H NMR (500 MHz, CDCl3) δ
7.34À7.24 (m, 10H), 4.65 (d, J = 10.9 Hz, 1H), 4.52 (d, J = 10.9 Hz, 1H),
4.48 (s, 2H), 4.46 (dd, J = 1.2 Hz, 1.7 Hz, 1H), 3.78 (s, 3H), 3.73 (d, J = 2.0
Hz, 1H), 3.67 (dd, J = 3.5 Hz, 8.7 Hz, 1H), 3.60À3.56 (m, 1H), 3.56 (dd,
J = 2.8 Hz, 8.7 Hz, 1H), 3.36 (dd, J = 2.5 Hz, 8.7 Hz, 1H), 3.34 (dd, J =
7.3Hz, 8.5 Hz,1H), 2.10À2.01(m, 2H), 1.99À1.92(m, 1H),1.95 (s, 3H),
1.78À1.70 (m, 1H), 1.70À1.66 (m, 1H), 1.66À1.60 (m, 2H), 1.31À1.23
(m, 1H), 1.12 (d, J = 7.1 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (d, J =
6.5 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3)
δ 171.1, 138.6, 138.0, 128.5, 128.2, 127.7, 127.53, 127.49, 127.39, 88.4,
75.9, 75.6, 74.4, 73.20, 73.17, 72.9, 66.4, 53.1, 37.2, 35.9, 35.4, 30.0, 27.1,
25.3, 24.8, 18.5, 14.1, 13.9, 10.2 ppm; MS (ESI) m/z 329.1 (12), 619.3
(79Br; M+H+, 98), 621.3 (81Br; M+H+, 94), 636.3 (94), 641.2 (79Br; M +
Na+, 100), 643.2 (81Br; M + Na+, 95), 644.2 (36), 718.4 (89); HRMS calcd
for C33H48O679Br [M + H+] 619.2629, found 619.2637 (1.4 ppm); calcd
for C33H47O679BrNa [M + Na+] 641.2448, found 641.2458 (1.5 ppm).
(()-(2R,3R,4S,5S,6S)-Methyl 5-(Benzyloxy)-6-((2S,3S,6S)-
6-((R)-1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-
pyran-2-yl)-3-hydroxy-2,4-dimethylheptanoate (43). Product
43 as a pale yellow oil (9.9 mg, yield = 54%) was obtained from a mixture
of bromide 41a and 41b (21.1 mg) according to general procedure A4 in
a >20:1 ratio of products 2,3-anti (43)/2,3-syn (44): Rf = 0.24 (hexanes/
EtOAc, 85:15); formula C33H48O6; MW 540.73 g/mol; IR (neat) νmax
3500, 3030, 2952, 2928, 2879, 1738, 1540, 1496, 1456, 1378, 1360, 1198,
(M + H+, 26), 550.6 (30), 563.3 (M + Na+, 100), 653.4 (17); HRMS
calcd for C33H49O6 [M + H+] 541.3524, found 541.3518 (À1.0 ppm);
calcd for C33H48O6Na [M + Na+] 563.3343, found 563.3350 (1.2 ppm).
(()-(2R,3S,4S,5S,6S)-Methyl 5-(Benzyloxy)-6-((2S,3S,6S)-
6-((R)-1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-
pyran-2-yl)-3-hydroxy-2,4-dimethylheptanoate (46). Product
46 as a pale yellow oil (15 mg, yield = 66%) was obtained from bromide
42 (25 mg) according to general procedure A6 in a >20: 1 ratio of
products 2,3-syn (46)/2,3-anti (45): Rf = 0.25 (hexanes/EtOAc, 85:15);
formula C33H48O6; MW 540.73 g/mol; IR (neat) νmax 3473, 2927,
2874, 1735, 1455, 1380, 1349, 1272, 1193, 1085, 1052 cmÀ1; 1H NMR
(500 MHz, CDCl3) δ 7.33À7.21 (m, 10H), 4.60 (d, J = 10.8 Hz, 1H),
4.53 (d, J = 10.9 Hz, 1H), 4.50 (d, J = 9.7 Hz, 1H), 4.48 (d, J = 9.7 Hz,
1H), 4.04À3.98 (m, 2H), 3.71 (dd, J = 8.6, 3.3 Hz, 1H), 3.66 (s, 3H),
3.56 (dt, J = 9.4, 4.8 Hz, 1H), 3.49 (ddd, J = 19.1, 9.3, 1.7 Hz, 2H), 3.30
(dd, J = 8.4, 7.9 Hz, 1H), 2.66À2.58 (m, 1H), 2.16À2.03 (m, 2H),
1.79À1.56 (m, 6H), 1.27 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 7.2 Hz, 3H),
0.91 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.4 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 176.8, 138.7, 138.0, 128.5, 128.4,
127.83, 127.75, 127.6, 127.5, 87.5, 76.1, 75.7, 73.54, 73.49, 73.47, 72.8,
52.0, 43.7, 37.7, 34.5, 33.9, 30.7, 27.4, 25.6, 18.6, 14.5, 13.8, 12.0, 10.4
ppm; MS (ESI) m/z 360.3 (7), 541.4 (M + H+, 5), 563.3 (M + Na+,
100), 577.3 (13), 653.4 (6); HRMS calcd for C33H49O6 [M + H+]
541.3524, found 541.3515 (À1.6 ppm); calcd for C33H48O6Na
[M + Na+] 563.3343, found 563.3349 (1.1 ppm).
(()-(3R,4R,5S,6S)-4-Hydroxy-6-((R)-1-((2S,3S,6S)-6-((R)-1-
Hydroxypropan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-
ethyl)-3,5-dimethyltetrahydro-2H-pyran-2-one (47). Product
47 as a colorless oil (5.6 mg, yield = 90%) was obtained from product 43
(10.3 mg) according to general procedure A12 with 20 wt % Pd(OH)2
on activated carbon (3.5 equiv, 35 mg) in MeOH (0.1 M, 190 μL). The
crude product was purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 95:5): Rf = 0.16 (CH2Cl/MeOH, 95:5); formula
C18H32O5; MW 328.44 g/mol; IR (neat) νmax 3400, 2932, 1711, 1460,
1380, 1206, 1121, 1082, 1014, 971, 912, 732 cmÀ1; 1H NMR (500 MHz,
CDCl3) δ 4.38 (dd, J = 5.2 Hz, 9.7 Hz, 1H), 3.85 (t, J = 2.1 Hz, 1H), 3.75
(dd, J = 6.0 Hz, 10.9 Hz, 1H), 3.60 (dd, J = 4.6 Hz, 7.1 Hz, 1H), 3.54 (dt,
J = 9.5 Hz, 4.7 Hz, 1H), 3.44 (dd, J = 5.2 Hz, 10.9 Hz, 1H), 2.61 (dq, J =
2.5 Hz, 7.1 Hz, 1H), 2.17À2.03 (m, 3H), 1.75À1.57 (m, 4H), 1.37À
1.29 (m, 1H), 1.31 (d, J = 7.1 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.08 (d,
J = 7.0 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 173.6, 83.5, 76.3, 75.3, 74.0, 67.8, 41.9,
37.6, 36.5, 35.7, 30.5, 26.5, 25.6, 18.2, 15.5, 14.0, 12.6, 10.9 ppm; MS
(ESI) m/z 329.2 (M + H+, 100), 657.5 (6); HRMS calcd for C18H33O5
[M + H+] 329.2323, found 329.2315 (À2.3 ppm).
1
1170, 1095, 1067, 1025, 966, 736, 698 cmÀ1; H NMR (500 MHz,
CDCl3) δ 7.34À7.23 (m, 10H), 4.59 (d, J = 10.8 Hz, 1H), 4.55 (d, J =
10.8 Hz, 1H), 4.51 (d, J = 12.3 Hz, 1H), 4.48 (d, J = 12.3 Hz, 1H), 3.71
(sl, 1H), 3.70À3.67 (m, 1H), 3.67 (s, 3H), 3.65 (dd, J = 3.6 Hz, 8.8 Hz,
1H), 3.53 (dd, J = 4.7 Hz, 7.3 Hz, 2H), 3.49 (dd, J = 4.3 Hz, 7.1 Hz, 1H),
3.35 (dd, J = 7.2 Hz, 8.7 Hz, 1H), 2.79 (dq, J = 3.5 Hz, 7.1 Hz, 1H), 2.21
(ddq, J = 4.7 Hz, 6.9 Hz, 7.0 Hz, 1H), 2.09À2.01 (m, 2H), 1.78À1.70
(m, 1H), 1.70À1.61 (m, 1H), 1.61À1.51 (m, 2H), 1.34À1.25 (m, 1H),
1.26 (d, J = 7.1 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.1 Hz, 3H),
0.92 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (125
MHz, CDCl3) δ 176.1, 138.8, 138.6, 128.3, 128.2, 127.60, 127.56,
127.43, 127.37, 85.9, 76.7, 76.5, 74.0, 73.1, 73.0, 72.4, 51.6, 42.1, 39.2,
37.5, 35.5, 29.8, 26.7, 24.8, 18.4, 15.9, 15.0, 14.1, 11.8 ppm; MS (ESI)
m/z 433.3 (13), 541.4 (M + H+, 100); HRMS calcd for C33H49O6
[M + H+] 541.3524, found 541.3513 (À1.9 ppm).
(()-(2S,3S,4S,5S,6S)-Methyl 5-(Benzyloxy)-6-((2S,3S,6S)-6-
((R)-1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyr-
an-2-yl)-3-hydroxy-2,4-dimethylheptanoate (45). Product 45
as a pale yellow oil (17 mg, yield = 78%) was obtained from bromide 42
(25 mg) according to general procedure A4 in a >20:1 ratio of products
2,3-anti (45)/2,3-syn (46): Rf = 0.20 (hexanes/EtOAc, 85:15); formula
C33H48O6; MW 540.73 g/mol; IR (neat) νmax 3481, 2951, 2925, 1739,
1455, 1378, 1196, 1172, 1096, 1069 cmÀ1; 1H NMR (500 MHz, CDCl3)
δ 7.37À7.24 (m, 10H), 4.62 (d, J = 10.8 Hz, 1H), 4.57 (d, J = 10.9 Hz,
1H), 4.54 (d, J = 12.2 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1H), 4.15 (d, J =
10.0 Hz, 1H), 4.01 (s, 1H), 3.75À3.71 (m, 1H), 3.74 (s, 3H), 3.61 (dt,
J = 9.5, 4.7 Hz, 1H), 3.55 (t, J = 10.0 Hz, 2H), 3.35 (t, J = 8.1 Hz, 1H),
2.62 (dq, J = 9.8, 7.0 Hz, 1H), 2.19À2.09 (m, 2H), 1.91 (q, J = 7.2 Hz,
1H), 1.74À1.61 (m, 4H), 1.32À1.22 (m, 1H), 1.13 (d, J = 7.1 Hz, 3H),
1.08 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.865 (d, J = 7.0 Hz,
3H), 0.864 (d, J = 6.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ
176.8, 138.7, 138.0, 128.5, 128.4, 127.83, 127.75, 127.6, 127.5, 87.5, 76.1,
75.7, 73.54, 73.49, 73.47, 72.8, 52.0, 43.7, 37.7, 34.5, 33.9, 30.7, 27.4,
25.6, 18.6, 14.5, 13.8, 12.0, 10.4 ppm; MS (ESI) m/z 338.3 (11), 541.4
(()-(3S,4R,5S,6S)-4-Hydroxy-6-((R)-1-((2S,3S,6S)-6-((R)-1-
hydroxypropan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-
ethyl)-3,5-dimethyltetrahydro-2H-pyran-2-one (48). Product
48 as a colorless oil (5.7 mg, yield = 96%) was obtained from product 44
(9.7 mg) according to general procedure A12 with 20 wt % Pd(OH)2 on
activated carbon (3.5 equiv, 34 mg) in MeOH (0.1 M, 180 μL). The
crude product was purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 95:5): Rf = 0.14 (CH2Cl2:MeOH, 95:5); formula
C18H32O5; MW 328.44 g/mol; IR (neat) νmax 3394, 2930, 2883, 1707,
1460, 1384, 1304, 1204, 1133, 1082, 1055, 1017, 985, 910, 733 cmÀ1; 1H
NMR (500 MHz, CDCl3) δ 4.24 (dd, J = 4.1 Hz, 8.9 Hz, 1H), 3.92 (dd,
J = 3.8 Hz, 10.9 Hz, 1H), 3.83 (dd, J = 4.5 Hz, 8.4 Hz, 1H), 3.58 (dd, J =
3.1 Hz, 8.7 Hz, 1H), 3.54À3.48 (m, 1H), 3.35 (dd, J = 6.6 Hz, 10.9 Hz,
1H), 2.55 (dq, J = 7.2 Hz, 7.2 Hz, 1H), 2.30À2.23 (m, 1H), 2.20À2.11
(m, 1H), 2.00À1.89 (m, 1H), 1.73À1.56 (m, 4H), 1.36 (d, J = 7.1 Hz,
3H), 1.34À1.23 (m, 1H), 1.13 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 6.9 Hz,
3H), 0.88 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3) δ 173.8, 83.1, 75.3, 74.0, 71.0, 66.5, 40.6, 37.9, 35.1,
33.7, 31.2, 27.2, 25.8, 17.6, 14.4, 14.2, 12.3, 9.9 ppm; MS (ESI) m/z
7673
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
329.2 (M + H+, 20), 351.2 (M + Na+, 100), 679.4 (30); HRMS calcd for
C18H33O5 [M + H+] 329.2323, found 329.2317 (À1.6 ppm); calcd for
C18H32O5Na [M + Na+] 351.2142, found 351.2135 (À1.9 ppm).
(()-(3S,4S,5S,6S)-4-Hydroxy-6-((R)-1-((2S,3S,6S)-6-((R)-1-
hydroxypropan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-
ethyl)-3,5-dimethyltetrahydro-2H-pyran-2-one (49). Product
49 as a colorless oil (3.6 mg, yield = 32%) was obtained from product 45
(18.7 mg) according to general procedure A12 with 20 wt % Pd(OH)2
on activated carbon (1.5 equiv, 35 mg) in MeOH (0.05 M, 800 μL). The
crude product was purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 95:5): Rf = 0.36 (CH2Cl2/MeOH, 95:5); formula
C18H32O5; MW 328.44 g/mol; IR (neat) νmax 3414, 2927, 2878, 2858,
7.63À7.67 (m, 4H), 7.46À7.36 (m, 6H), 7.28À7.21 (m, 3H), 7.18À
7.14 (m, 2H), 4.37 (d, J = 11.6 Hz, 1H), 4.20 (d, J = 11.6 Hz, 1H),
3.81À3.77 (m, 1H), 3.77 (dd, J = 5.0 Hz, 9.6 Hz, 1H), 3.71 (dd, J = 4.5
Hz, 8.0 Hz, 1H), 3.65 (s, 3H), 3.59 (dd, J = 3.8 Hz, 9.6 Hz, 1H), 3.53 (dd,
J = 3.6 Hz, 7.6 Hz, 1H), 2.87 (dq, J = 4.9 Hz, 7.0 Hz, 1H), 2.14À2.06 (m,
1H), 2.06À1.97 (m, 1H), 1.75À1.67 (m, 1H), 1.67À1.55 (m, 3H),
1.34À1.25 (m 1H), 1.16 (d, J = 7.1 Hz, 3H), 1.09 (s, 9H), 0.92 (d, J = 6.8
Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H) ppm; 13
C
NMR (125 MHz, CDCl3) δ 175.0, 138.8, 135.75, 135.69, 134.04,
134.03, 129.44, 129.42, 128.0, 127.54, 127.53, 127.03, 126.97, 82.2,
75.4, 72.2, 71.8, 65.6, 51.4, 41.3, 36.4, 35.7, 30.3, 27.0, 26.9, 24.8, 19.4,
18.3, 13.6, 12.0, 9.9 ppm; MS (ESI) m/z 631.4 (M + H+, 66), 653.4 (M +
Na+, 100), 654.4 (33), 690.5 (5); HRMS calcd for C39H55O5Si [M +
H+] 631.3813; found 631.3819 (0.9 ppm); calcd for C39H54O5SiNa [M
+ Na+] 653.3633; found 653.3640 (1.1 ppm).
1
1725, 1459, 1380, 1206 cmÀ1; H NMR (500 MHz, CD2Cl2) δ 3.84
(dd, J = 10.1, 4.5 Hz, 1H), 3.76 (dd, J = 9.7, 1.2 Hz, 1H), 3.75À3.71 (m,
1H), 3.71 (s, 1H), 3.61 (dd, J = 2.8, 0.9 Hz, 1H), 3.57 (dd, J = 11.0, 8.5
Hz, 1H), 3.50 (dd, J = 11.0, 4.8 Hz, 1H), 3.45 (s, 1H), 2.64 (qd, J = 6.8,
3.0 Hz, 1H), 2.44À2.34 (m, 1H), 2.30 (td, J = 14.1, 6.9 Hz, 1H), 2.09À
2.01 (m, 1H), 1.81À1.58 (m, 4H), 1.38À1.30 (m, 1H), 1.25 (d, J =
6.8 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H), 1.06 (d, J = 7.1 Hz, 3H), 0.88 (d, J =
6.4 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 174.5, 85.0, 79.0, 76.7, 73.8, 69.6, 39.2, 39.1, 35.5, 32.0, 31.9,
27.5, 26.6, 18.4, 17.3, 13.6, 11.8, 10.9 ppm; MS (ESI) m/z 329.2 (M +
H+, 19), 351.2 (M + Na+, 100), 383.2 (7), 550.6 (20), 679.4 (23);
HRMS calcd for C18H33O5 [M + H+] 329.2323, found 329.2319 (À1.2
ppm); calcd for C18H32O5Na [M + Na+] 351.2142, found 351.2140
(À0.5 ppm).
(()-(2S,3S,4S)-3-(Benzyloxy)-4-((2S,3S,6S)-6-((R)-1-(tert-but-
yldiphenylsilyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-
2-yl)-2-methylpentan-1-ol (S31). Primary alcohol S31 as a color-
less oil (173 mg, yield = 82%) was obtained from ester S30 (221 mg)
according to general procedure A9: Rf = 0.18 (hexanes/EtOAc, 85:15);
formula C38H54O4Si; MW 602.92 g/mol; IR (neat) νmax 3442, 3069,
2959, 2929, 2859, 1460, 1428, 1385, 1110, 1092, 1028, 966, 823, 738,
1
703, 615 cmÀ1; H NMR (500 MHz, CDCl3) δ 7.74À7.68 (m, 4H),
7.47À7.37 (m, 6H), 7.34À7.25 (m, 3H), 7.25À7.21 (m, 2H), 4.45 (d,
J = 11.2 Hz, 1H), 4.42 (d, J = 11.2 Hz, 1H), 3.85 (dd, J = 1.8 Hz, 10.8 Hz,
1H), 3.79À3.74 (m, 2H), 3.73 (dt, J = 3.9 Hz, 9.5 Hz, 1H), 3.58À3.50
(m, 1H), 3.47 (dd, J = 3.4 Hz, 7.8 Hz, 1H), 3.35 (dd, J = 3.1 Hz, 8.0 Hz,
1H), 2.93À2.85 (bs, 1H), 2.13 (ddq, J = 3.9 Hz, 7.1 Hz, 7.0 Hz, 1H),
2.06À1.96 (m, 1H), 1.91À1.84 (m, 1H), 1.77À1.56 (m, 4H), 1.34À
1.24 (m, 1H), 1.08 (s, 9H), 1.06 (d, J = 7.1 Hz, 3H), 0.95 (d, J = 6.8 Hz,
3H), 0.91 (d, J = 7.5 Hz, 3H), 0.90 (d, J = 7.4 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3) δ 138.3, 135.69, 135.66, 133.90, 133.83, 129.52,
129.46, 128.3, 127.55, 127.51, 127.3, 86.7, 76.0, 74.9, 71.9, 65.7, 64.8,
37.4, 36.4, 36.1, 30.2, 26.94, 26.88, 24.8, 19.3, 18.4, 16.3, 13.5, 10.7 ppm;
MS (ESI) m/z 307.1 (6), 525.3 (21), 603.4 (M + H+, 100), 693.4 (5);
HRMS calcd for C38H55O4Si [M + H+] 603.3864, found 603.3861
(À0.5 ppm).
(()-(2R,3R,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(tert-Butyldi-
phenylsilyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-
yl)-3-hydroxy-2-methylpentanoate (S29). Product 35 (200 mg)
was deprotected according to general procedure A12. The crude prod-
uct was dissolved in dry CH2Cl2 (0.1 M, 5.1 mL) and cooled to 0 ꢀC
before being successively treated with TBDPSCl (1.1 equiv, 146 μL),
Et3N (1.3 equiv, 92 μL), and DMAP (0.2 equiv, 13 mg). The mixture
was stirred overnight at 0 ꢀC before being treated with the addition of a
saturated aqueous solution of NH4Cl followed by separation of the
organic phase at room temperature. The aqueous layer was extracted
with CH2Cl2 (3Â), and the combined organic fractions were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (hexanes/EtOAc, 90:10)
to give product S29 as a colorless oil (257 mg, yield = 93% over two
steps): Rf = 0.47 (hexanes/EtOAc, 85:15); formula C32H48O5Si; MW
540.81 g/mol; IR (neat) νmax 3474, 3071, 2957, 2931, 2857, 1739, 1717,
1460, 1429, 1382, 1361, 1196, 1171, 1112, 1011, 822, 740, 704,
610 cmÀ1; 1H NMR (500 MHz, CDCl3) δ 7.70À7.64 (m, 4H), 7.43À
7.33 (m, 6H), 3.92À3.86 (m, 1H), 3.86 (dd, J = 4.8 Hz, 9.9 Hz, 1H), 3.72
(dd, J = 3.2 Hz, 9.9 Hz, 1H), 3.55À3.50 (m, 1H), 3.52 (s, 3H), 3.48 (dt,
J = 6.4 Hz, 9.3 Hz, 1H), 3.12 (d, J = 9.4 Hz, 1H), 2.57 (dq, J = 7.0 Hz,
7.0 Hz, 1H), 2.27À2.16 (m, 1H), 1.76À1.65 (m, 3H), 1.65À1.53 (m,
2H), 1.29À1.15 (m, 1H), 1.05 (s, 9H), 1.01 (d, J = 7.1 Hz, 3H), 0.95 (d,
J = 7.1 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.4 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3) δ 176.4, 135.71, 135.70, 134.17, 134.09,
129.42, 129.36, 127.5, 77.2, 76.2, 75.0, 73.4, 65.4, 51.4, 42.7, 36.2, 33.4,
31.6, 27.5, 26.94, 26.92, 26.90, 25.9, 19.4 ppm; MS (ESI) m/z 161.1 (5),
189.2 (10), 217.2 (15), 249.2 (66), 385.2 (49), 463.3 (11), 541.3 (M +
H+, 100), 543.3 (37); HRMS calcd for C32H49O5Si [M + H+] 541.3344,
found 541.3333 (À2.0 ppm).
(2R,3R,4S)-3-(Benzyloxy)-4-((2S,3S,6S)-6-((R)-1-(tert-butyl-
diphenylsilyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-
2-yl)-2-methylpentanal (50). Aldehyde 50 as a colorless oil was
obtained from primary alcohol S31 (20 mg) according to general pro-
cedure A11. The crude product was used without further purification:
Rf = 0.55 (hexanes/EtOAc, 85:15); formula C38H52O4Si; MW 600.90 g/
mol; 1H NMR (500 MHz, CDCl3) δ 9.68 (d, J = 1.4 Hz, 1H), 7.75À7.61
(m, 4H), 7.47À7.33 (m, 6H), 7.32À7.19 (m, 3H), 7.19À7.08 (m, 2H),
4.24 (d, J = 11.6 Hz, 1H), 4.15 (d, J = 11.6 Hz, 1H), 3.81À3.75 (m, 1H),
3.72 (dd, J = 9.5, 5.2 Hz, 1H), 3.59 (dd, J = 9.5, 3.5 Hz, 1H), 3.54 (dd, J =
8.2, 2.6 Hz, 1H), 3.44 (dd, J = 8.6, 2.4 Hz, 1H), 2.61 (q, J = 6.7 Hz, 1H),
2.11À1.96 (m, 2H), 1.78À1.68 (m, 1H), 1.68À1.56 (m, 3H), 1.55À
1.48 (m, 1H), 1.05 (s, 9H), 1.01 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.8 Hz,
3H), 0.81 (d, J = 6.3 Hz, 3H), 0.78 (d, J = 7.1 Hz, 3H) ppm.
(()-(3R,4S,5S,6S)-Methyl 5-(Benzyloxy)-2-bromo-6-((2S,
3S,6S)-6-((R)-1-(tert-butyldiphenylsilyloxy)propan-2-yl)-3-
methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-2,4-dimethyl-
heptanoate (51). Bromide adduct 51 as a pale yellow oil (23.7 mg,
yield = 93% over two steps) was obtained from aldehyde 50 (19.9 mg)
according to general procedure A2 in a >20:1 ratio of products 3,4-anti
(51)/3,4-syn (52): Rf = 0.31 (hexanes/EtOAc, 85:15); formula
C42H59BrO6Si; MW 767.90 g/mol; IR (neat) νmax 3558, 2953, 2929,
2857, 1745, 1728, 1428, 1384, 1259, 1112, 1063 cmÀ1; 1H NMR (500
MHz, CDCl3) δ 7.69À7.63 (m, 4H), 7.44À7.33 (m, 6H), 7.29À7.23
(m, 3H), 7.19À7.14 (m, 2H), 4.41 (d, J = 11.4 Hz, 1H), 4.37 (d, J = 11.3
Hz, 1H), 4.05 (dd, J = 8.4, 4.9 Hz, 1H), 3.75 (s, 3H), 3.75À3.68 (m, 2H),
3.58 (dd, J = 9.6, 4.0 Hz, 1H), 3.51 (dd, J = 7.7, 3.8 Hz, 1H), 3.42 (d,
(()-(2R,3R,4S)-Methyl 3-(Benzyloxy)-4-((2S,3S,6S)-6-((R)-
1-(tert-butyldiphenylsilyloxy)propan-2-yl)-3-methyltetra-
hydro-2H-pyran-2-yl)-2-methylpentanoate (S30). Protected
product S30 as a colorless oil (yield = 78%) was obtained from alcohol
S29 (254 mg) according to general procedure A7: Rf = 0.57 (hexanes/
EtOAc, 85:15); formula C39H54O5Si; MW 630.93 g/mol; IR (neat) νmax
3069, 2952, 2930, 2858, 1737, 1460, 1429, 1384, 1205, 1110, 1091, 1028,
1013, 823, 738, 703, 615 cmÀ1 1H NMR (500 MHz, CDCl3) δ
;
7674
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
J = 4.9 Hz, 1H), 3.36 (dd, J = 8.0, 3.5 Hz, 1H), 2.19À2.07 (m, 2H),
1.98À1.89 (m, 1H), 1.91 (s, 3H), 1.75À1.53 (m, 4H), 1.31À1.21 (m,
1H), 1.03 (s, 9H), 0.97 (d, J = 7.6 Hz, 3H), 0.96 (d, J = 7.4 Hz, 3H), 0.89
(d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 171.8, 138.4, 135.93, 135.89, 134.2, 134.1, 129.7, 129.6, 128.5,
127.74, 127.68, 127.66, 127.5, 86.4, 77.8, 76.1, 74.1, 71.8, 65.82, 65.77,
53.3, 39.5, 38.2, 36.9, 30.1, 27.14, 27.06, 25.9, 24.8, 19.5, 18.6, 17.6, 13.5,
11.5 ppm; MS (ESI) m/z 251.1 (42), 360.3 (42), 408.3 (24), 550.6 (22),
619.3 (100), 709.4 (95), 789.3 (79Br; M + Na+, 80), 791.3 (81Br;
M + Na+, 80); HRMS calcd for C42H60O6Si79Br [M + H+] 767.3337,
found 767.3329 (À1.1 ppm); calcd for C42H59O6Si79BrNa [M + Na+]
789.3156, found 789.3153 (À0.5 ppm).
(d) Dutton, C. J.; Banks, B. J.; Cooper, C. B. Nat. Prod. Rep. 1995,
12, 165.
(3) Ding, W.-Q.; Lind, S. E. Life Sciences. Part 2, Biochem., Gen. Mol.
Biol. 2009, 61, 1013.
(4) Monensin, another ionophore, has been recently shown to be
among the most potent and cancer-specific inhibitors of prostate cell
growth among all the tested known drugs and druglike molecules:
(a) Ketola, K.; Vainio, P.; Vidal, F.; Kallioniemi, O.; Iljin, K. Mol. Cancer
Ther. 2010, 9, 3175. (b) Iljin, K.; Ketola, K.; Vainio, P.; Halonen, P.;
Kohonen, P.; Fey, V.; Grafst€orm, R. C.; Per€al€a, M.; Kallioniemi, O. Clin.
Cancer Res. 2010, 15, 6070.
(5) (a) Gr€afe, U.; Schade, W.; Roth, M.; Radics, L.; Incze, M.;
Ujszaszy, K. J. Antibiot. 1984, 37, 836. (b) Brooks, H. A.; Gardner, D.;
Poyser, J. P.; King, T. J. J. Antibiot. 1984, 37, 1501.
(()-(3S,4S,5S,6S)-Methyl 5-(Benzyloxy)-2-bromo-6-((2S,
3S,6S)-6-((R)-1-(tert-butyldiphenylsilyloxy)propan-2-yl)-3-
methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-2,4-dimethyl-
heptanoate (52). Bromide product 52 as a pale yellow oil (17.6 mg,
yield = 82% over two steps) was obtained from aldehyde 50 (16.8 mg)
according to general procedure A1 in a >20:1 ratio of products 3,4-syn
(52)/3,4-anti (51): Rf = 0.30 (hexanes/EtOAc, 90:10); formula
C42H59BrO6Si; MW 767.90 g/mol; IR (neat) νmax 3455, 3069, 2954,
2930, 2859, 1737, 1458, 1429, 1385, 1259, 1109, 1087, 911, 738,
703 cmÀ1; 1H NMR (500 MHz, CDCl3) δ 7.68À7.62 (m, 4H), 7.43À
7.38 (m, 2H), 7.38À7.33 (m, 4H), 7.30À7.24 (m, 3H), 7.19À7.15 (m,
2H), 4.44 (d, J = 11.0 Hz, 1H), 4.42 (s, 1H), 4.35 (d, J = 10.9 Hz, 1H),
3.79 (d, J = 1.3 Hz, 1H), 3.78 (s, 3H), 3.74À3.66 (m, 3H), 3.49 (dd, J =
2.0 Hz, 9.0 Hz, 1H), 3.22 (dd, J = 1.3 Hz, 9.4 Hz, 1H), 2.03À1.94 (m,
2H), 1.93 (s, 3H), 1.92À1.84 (m, 1H), 1.74À1.65 (m, 2H), 1.65À1.58
(m, 2H), 1.28À1.19 (m, 1H), 1.03 (s, 9H), 0.99 (d, J = 7.1 Hz, 3H), 0.91
(d, J = 6.8 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 7.4 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 171.1, 138.0, 135.71, 135.66,
133.87, 133.86, 129.56, 129.49, 128.4, 127.68, 127.58, 127.53, 127.4,
88.6, 75.8, 75.6, 74.4, 72.2, 66.3, 65.8, 53.1, 37.4, 36.7, 35.7, 30.1, 27.3,
26.9, 25.3, 24.8, 19.3, 18.5, 14.0, 13.6, 10.1 ppm; MS (ESI) m/z 144.0
(16), 193.7 (12), 592.3 (5), 767.3 (M + H+, 70), 789.3 (M + Na+, 59),
791.3 (67), 868.4 (100), 886.4 (12); HRMS calcd for C42H60O6Si79Br
[M + H+] 767.3337, found 767.3345 (1.0 ppm); calcd for C42H59O6-
Si79BrNa [M + Na+] 789.3156, found 789.3167 (1.3 ppm).
(6) (a) Gr€afe, U.; Tonew, E.; Schade, W.; Reinhardt, G.; H€artl, A.
German Patent (East) DD 231 793, 1986. (b) Tonew, E.; Tonew, M.;
Gr€afe, U.; Zopel, P. Pharmazie 1988, 43, 717.
(7) Miller, S. C.; Huang, R.; Sakamuru, S.; Shukla, S. J.; Attene-
Ramos, M. S.; Shinn, P.; Van Leer, D.; Leister, W.; Austin, C. P.; Xia, M.
Biochem. Pharmacol. 2010, 79, 1272.
(8) (a) Amiri, K. I.; Richmond, A. Cancer Metastasis Rev. 2005,
24, 301. (b) Sch€on, M.; Wienrich, B. G.; Kneitz, S.; Sennefelder, H.;
Amschler, K.; Vohringer, V.; Weber, O.; Stiewe, T.; Ziegelbauer, K.;
Sch€on, M. P. J. Natl. Cancer Inst. 2008, 100, 862. (c) Chaturvedi, M. M.;
Sung, B.; Yadav, V. R.; Kannapan, R.; Aggarwal, B. B. Oncogene 2011,
30, 1615.
(9) (a) Gupta, P. B.; Onder, T. T.; Jiang, G.; Tao, K.; Kuperwasser,
C.; Weinberg, R. A.; Lander, E. S. Cell 2009, 138, 645. (b) Beug, H. Cell
2009, 138, 623. (c) Riccioni, R.; Dupuis, M. L.; Bernabei, M.; Pterucci,
E.; Pasquini, L.; Mariani, G.; Cianfriglia, M.; Testa, U. Blood Cells Mol.
Dis. 2010, 45, 86. (d) Fuchs, D.; Daniel, V.; Sadeghi, M.; Opelz, G.;
Naujokat, C. Biochem. Biophys. Res. Commun. 2010, 394, 1098.
(10) (a) Adell O’Brien, C.; Kreso, A.; Dick, J. E. Semin. Radiat. Oncol.
2008, 19, 71. (b) Naujokat, C; Fuchs, D.; Opelz, G. Mol. Med. Reports
2010, 3, 559.
(11) Rowan, K. J. Natl. Cancer Inst. 2009, 101, 1438.
(12) For remarkable structureÀactivity studies related to discoder-
molide, see:(a) Choy, N.; Shin, Y. S.; Nguyen, P. Q.; Curran, D. P.;
Balachandran, R.; Madiraju, C.; Day, B. W. Org. Lett. 2002, 4, 4443.
(b) Choy, N.; Shin, Y. S.; Nguyen, P. Q.; Curran, D. P.; Balachandran, R.;
Madiraju, C.; Day, B. W. J. Med. Chem. 2003, 46, 2846. (c) Smith, A. B.,
III; Xian, M. Org. Lett. 2005, 7, 5229. (d) Zhou, W.; Jimenez, M.; Jung,
W.-H.; Camarco, D. P.; Balachandran, R.; Vogt, A.; Day, B. W.; Curran,
D. P. J. Am. Chem. Soc. 2010, 132, 9175.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C spectra for com-
S
b
pounds 14À20, 28À38, 40À52, S5, S6, S10ÀS15, S17ÀS24,
and S27ÀS31. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) For an overview of discodermolide development from bench to
clinical trials, see: Molinski, T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes,
J. P. Nat. Rev. Drug Discovery 2009, 8, 69.
(14) (a) Mukaiyama, T. Org. React. 1982, 28, 103. (b) Evans, D. A.
Aldrichim. Acta 1982, 15, 23. (c) Masamune, S.; Choy, W. Aldrichim.
Acta 1982, 15, 23. (d) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl.
1987, 26, 489. (e) Hoffmann, R. W. Angew. Chem. 1987, 99, 503.
(f) Heathcock, C. H. Aldrichim. Acta 1990, 23, 99. (g) Roush, W. R.
J. Org. Chem. 1991, 56, 4151. (h) Hoffmann, R. W.; Dahmann, G.
Synthesis 1994, 629.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: yvan.guindon@ircm.qc.ca.
(15) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(b) Brown, H. C.; Bhat, K. S.; Randad, R. J. Am. Chem. Soc. 1989, 54,
1570. (c) Brown, H. C.; Racherla, U. S. J. Org. Chem. 1991, 56, 401.
(16) (a) Paterson, I. Pure Appl. Chem. 1992, 64, 1821. (b) Paterson,
I; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 35, 639.
(17) (a) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560. (b) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc.
1990, 112, 6447. (c) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990,
55, 5190. (d) Evans, D. A.; Sheppard, G. S. J. Org. Chem. 1990, 55, 5192.
(e) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard,
G. S. J. Am. Chem. Soc. 1990, 112, 866. (f) Evans, D. A.; Ng, H. P.; Clark,
J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127.
’ ACKNOWLEDGMENT
We express our gratitude to the Natural Sciences and En-
gineeringResearchCouncil ofCanada(NSERC) andtothe Fonds
Quꢀebꢀecois de la Recherche sur la Nature et les Technologies
(FQRNT) for their financial support. Fellowship support from
NSERC PGS D (F.G. and J.-F.B.) is gratefully acknowledged.
’ REFERENCES
(1) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407.
(2) (a) Dobler, M. Ionophores and their structures; Wiley: New York,
1981. (b) Westley, J. W., Ed.Polyether Antibiotics; Marcel Dekker: New
York, 1982; Vols. 1À2. (c) Westley, J. W. J. Nat. Prod. 1986, 49, 35.
(18) (a) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc.
1990, 112, 6348. (b) Roush, W. R.; Chemler, S. R. J. Org. Chem. 1998,
7675
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676

The Journal of Organic Chemistry
FEATURED ARTICLE
63, 3800. (c) Roush, W. R.; Chemler, S. R. Tetrahedron Lett. 1999, 40,
4643. (d) Roush, W. R.; Chemler, S. R. J. Org. Chem. 2003, 68, 1319.
(19) (a) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57, 5790. (b)
Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999. (c) Nareshkumar,
F. J.; Cirillo, P. F.; Schaus, J. V.; Panek, J. S. Tetrahedron Lett. 1995, 36,
8723. (d) Nareshkumar, F. J.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc.
1996, 118, 12475.
(20) (a) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 65, 1501.
(b) Marshall, J. A.; Palovich, M. J. Org. Chem. 1998, 63, 3701. (c)
Marshall, J. A.; Maxson, K. J. Org. Chem. 2000, 65, 630. (d) Marshall,
J. A.; Schaaf, G. J. Org. Chem. 2001, 66, 7825.
(29) (a) Hirai, A.; Matsui, A.; Komatsu, K.; Tanino, K.; Miyashita,
M. Chem. Commun. 2002, 17, 1970. (b) Komatsu, K.; Tanino, K.;
Miyashita, M. Angew. Chem., Int. Ed. 2004, 43, 4341.
(30) (a) Song, Z.; Hsung, R. P. Org. Lett. 2007, 9, 2199. (b) Song, Z.;
Hsung, R. P.; Lu, T.; Lohse, A. G. J. Org. Chem. 2007, 72, 9722. (c) Song
also reviewed synthetic efforts towards synthesis of zincophorin; see:
Song, Z.; Lohse, A. G.; Hsung, R. P. Nat. Prod. Rep. 2009, 26, 560.
(31) Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J. J. Org.
Chem. 1998, 63, 3160.
(32) Booysen, J. F.; Holzapfel, C. W. Synth. Commun. 1995,
25, 1473.
(21) (a) Ward, D. E.; Gillis, H. M.; Akinnusi, O. T.; Rasheed, M. A.;
Saravanan, K.; Samal, P. K. Org. Lett. 2006, 8, 2631. (b) Jheengut, V.;
Ward, D. E. J. Org. Chem. 2007, 72, 7805. (c) Ward, D. E.; Becerril-
Jiminez, F.; Zahedi, M. M. J. Org. Chem. 2009, 74, 4447. (d) Beye, G. E.;
Ward, D. E. J. Am. Chem. Soc. 2010, 132, 7210. (e) Ward, D. E.; Jheengut,
V.; Beye, G. E.; Gillis, H. M.; Karagiannis, A.; Becerril-Jiminez, F. Synlett
2011, 4, 508.
(33) (a) Balestra, M.; Wittman, M. D.; Kallmerten, J. Tetrahedron
Lett. 1988, 29, 6905. (b) Cywin, C. L.; Kallmerten, J. Tetrahedron Lett.
1993, 34, 1103.
(34) Guindon, Y.; Murtagh, L.; Caron, V.; Landry, S. R.; Jung, G.;
Bencheqroun, M.; Faucher, A.-M.; Guꢀerin, B. J. Org. Chem. 2001, 66,
5427.
(35) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
(22) (a) Wang, X.; Meng, Q.; Nation, A. J.; Leighton., J. L. J. Am.
Chem. Soc. 2002, 124, 10672. (b) Spletstoser, J. T.; Zacuto, M. J.;
Leighton, J. L. Org. Lett. 2008, 10, 5593. (c) Kim, H.; Ho, S.; Leighton,
J. L. J. Am. Chem. Soc. 2011, 133, 7308.
1998, 1, 26.
(36) Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J. J. Am. Chem.
Soc. 2003, 125, 11456.
(37) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465.
(23) (a) Guindon, Y.; Houde, K.; Prꢀevost, M.; Cardinal-David, B.;
Landry, S. R.; Daoust, B.; Bencheqroun, M.; Guꢀerin, B. J. Am. Chem. Soc.
2001, 123, 8496. (b) Guindon, Y.; Prꢀevost, M.; Mochirian, P.; Guꢀerin, B.
Org. Lett. 2002, 4, 1019. (c) Mochirian, P.; Cardinal-David, B.; Guꢀerin,
B.; Prꢀevost, M.; Guindon, Y. Tetrahedron Lett. 2002, 43, 7067. (d)
Guindon, Y.; Brazeau, J. F. Org. Lett. 2004, 6, 2599. (e) Brazeau, J. F.;
Mochirian, P.; Prꢀevost, M.; Guindon, Y. J. Org. Chem. 2009, 74, 64. (f)
Brazeau, J. F.; Guilbaut, A.-A.; Kochuparampil, J.; Mochirian, P.;
Guindon, Y. Org. Lett. 2010, 12, 36.
(38) The apparent discrepancy noted in the case of the reduction of
18 is at the origin of a comprehensive study on the effects of substituents
on the pyran in this type of reaction which is presently underway in
our group.
(39) Synthesis of propionate fragment 27 was generated herein with
the eastÀwest approach using (S)-Roche ester as a source of the C8
stereocenter following numbering of zincophorin 1. This methodology
was preferred over the westÀeast approach (starting from the C6
stereocenter) due the more expedient synthesis of the propionate
fragment displaying an appropriate positioning of the ester group
required for further elaboration of the motif.
(24) Nonexhaustive list of relevant examples: (a) Hart, D. J.; Huang,
H.-C. Tetrahedron Lett. 1985, 26, 3749. (b) Crich, D.; Davies, J. W.
Tetrahedron Lett. 1987, 27, 4205. (c) Hart, D. J.; Huang, H.-C.;
Krishnamurthy, R.; Schwartz, T. J. Am. Chem. Soc. 1989, 111, 7507.
(d) Hart, D. J.; Krishnamurthy, T. Synlett 1991, 412. (e) Giese, B.;
Bulliard, M.; Zeitz, H.-G. Synlett 1991, 425. (f) Porter, N. A.; Giese, B.;
Curran, D. P. Acc. Chem. Res. 1991, 24, 296. (g) Kopping, B.;
Chatgilialoglu, C.; Zehnder, M.; Giese, B. J. Org. Chem. 1992, 57,
3994. (h) Hart, D. J.; Krishnamurthy, R. J. Org. Chem. 1992, 57, 4457.
(i) Cha, J.-K.; Kin, N.-S. Chem. Rev. 1995, 95, 1761. (j) Sibi, M.; Ji, J.
Angew. Chem. 1996, 35, 190.(k) Renaud, P.; Sibi, M. P. Radicals in
Organic Synthesis, Vol. 2: Applications; VHC: Weinheim, 2001.
(25) (a) Durkin, K.; Liotta, D.; Rancourt, J.; Lavallꢀee, J.-F.; Boisvert,
L.; Guindon, Y. J. Am. Chem. Soc. 1992, 114, 4912. (b) Guindon, Y.;
Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme, D.; Renaud, J.;
Robinson, G.; Lavallꢀee, J.-F.; Slassi, A.; Jung, G.; Rancourt, J.; Durkin,
K.; Liotta, D. J. Org. Chem. 1994, 59, 1166. (c) Guindon, Y.; Slassi, A.;
Rancourt, J.; Bantle, G.; Bencheqroun, M.; Murtagh, M.; Ghiro, E.; Jung,
G. J. Org. Chem. 1995, 60, 288. (d) Guindon, Y.; Guꢀerin, B.; Rancourt, J.;
Chabot, C.; Mackintosh, N.; Ogilvie, W. W. Pure Appl. Chem. 1996,
(40) Gau, H. M.; Lee, C. S.; Lin, C. C.; Jiang, M.-K.; Ho, Y.-C.; Kuo,
C.-N. J. Am. Chem. Soc. 1996, 118, 2936.
ꢀ
68, 89. (e) Guindon, Y.; Faucher, A.-M.; Bourque, E.; Caron, C.; Jung,
G.; Landry, S. R. J. Org. Chem. 1997, 62, 9276. (f) Denissova, I.; Maretti,
L.; Wilkes, B. C.; Scaiano, J. C.; Guindon, Y. J. Org. Chem. 2009, 74, 2438.
(26) Evans, D. A.; Allison, B. D.; Yang, M.; Masse, C. E. J. Am. Chem.
Soc. 2001, 123, 10840.
(27) (a) Danishefsky, S.; Harvey, D. F. J. Am. Chem. Soc. 1985,
107, 6647. (b) Zelle, R. E.; DeNinno, M. P.; Selnick, H. G.; Danishefsky,
S. J. J. Org. Chem. 1986, 51, 5032. (c) Danishefsky, S. J.; DeNinno, S.;
Lartey, P. J. Am. Chem. Soc. 1987, 109, 2082. (d) Danishefsky, S. J.;
Selnick, H. G.; Zelle, R. B.; DeNinno, M. P. J. Am. Chem. Soc. 1988, 110,
4368.
(28) (a) Cossy, J.; Blanchard, N.; Defosseux, M.; Meyer, C. Angew.
Chem., Int. Ed. 2003, 41, 2144. (b) Cossy, J.; Blanchard, N.; Defosseux,
M.; Meyer, C. Org. Lett. 2003, 5, 4037. (c) Cossy, J.; Blanchard, N.;
Defosseux, M.; Meyer, C. J. Org. Chem. 2004, 69, 4626. (d) Cossy, J.;
Meyer, C.; Defosseux, M.; Blanchard, N. Pure Appl. Chem. 2005, 77,
1131.
7676
dx.doi.org/10.1021/jo2013884 |J. Org. Chem. 2011, 76, 7654–7676