Gidget C Tay1, Chloe Y Huang, Scott D Rychnovsky. 1. Department of Chemistry, 1102 Natural Sciences II, University of California-Irvine , Irvine, California 92697, United States.
Abstract
A diastereoselective synthesis of cis-2,6-disubstituted tetrahydropyran-4-ones was developed. The key step of this methodology, a silyl enol ether Prins cyclization, was promoted by a condensation reaction between a hydroxy silyl enol ether and an aldehyde to afford substituted tetrahydropyran-4-ones. The cyclization was tolerant of many functional groups, and the modular synthesis of the hydroxy silyl enol ether allowed for the formation of more than 30 new tetrahydropyran-4-ones with up to 97% yield and >95:5 dr. The cyclization step forms new carbon-carbon and carbon-oxygen bonds, as well as a quaternary center with good diastereoselectivity. The method provides a versatile route for the synthesis of substituted tetrahydropyrans.
A diastereoselective synthesis of cis-2,6-disubstituted tetrahydropyran-4-ones was developed. The key step of this methodology, a silyl enol ether Prins cyclization, was promoted by a condensation reaction between a hydroxy silyl enol ether and an aldehyde to afford substituted tetrahydropyran-4-ones. The cyclization was tolerant of many functional groups, and the modular synthesis of the hydroxy silyl enol ether allowed for the formation of more than 30 new tetrahydropyran-4-ones with up to 97% yield and >95:5 dr. The cyclization step forms new carbon-carbon and carbon-oxygen bonds, as well as a quaternary center with good diastereoselectivity. The method provides a versatile route for the synthesis of substituted tetrahydropyrans.
Substituted tetrahydropyrans
and tetrahydropyranones are a common
motif in numerous biologically active natural products (Figure 1).[1] Synthesis of tetrahydropyran-4-ones
(THPOs), followed by reduction of the ketone, has been used to form
4-hydroxytetrahydropyran rings.[2] Tetrahydropyranones
are commonly prepared with carbon–carbon or carbon–oxygen
bond forming reactions by aldol-type cyclization,[3] hetero-Diels–Alder cycloaddition,[4] Japp–Maitland reaction,[5] oxa-Michael condensation,[6] and Petasis–Ferrier
rearrangement[7] (Figure 2).[8] These various methods have
their strengths and limitations. For example, the hetero-Diels–Alder
cycloaddition requires electronic matching of the diene and dienophile.[4] The Petasis–Ferrier rearrangement precursor
is often obtained through olefination of an ester; this route would
be incompatible with other unprotected carbonyl groups in the substrate.
Because tetrahydropyrans are prevalent in natural products, the development
of flexible new routes for their synthesis is an important goal. We
present a full account of the silyl enol ether Prins cyclization for
the synthesis of tetrahydropyranones.[9]
Figure 1
Biologically
active natural products containing highly substituted
tetrahydropyran rings, such as pederin,[10] psymberin,[11] kendomycin,[12] and lasonolide A.[13]
Figure 2
Common methods for forming tetrahydropyran-4-ones and
the silyl
enol ether Prins cyclization method discussed in this paper.
Biologically
active natural products containing highly substituted
tetrahydropyran rings, such as pederin,[10] psymberin,[11] kendomycin,[12] and lasonolide A.[13]Common methods for forming tetrahydropyran-4-ones and
the silylenol ether Prins cyclization method discussed in this paper.Synthetic methods focused on the
preparation of tetrahydropyran-4-ones
with an enol ether and oxocarbenium ion have been reported.[14,15] Recently, we reported the diastereoselective synthesis of 2,6-cis-tetrahydropyran-4-ones through cyclization between a
hydroxy silyl enol ether and an aldehyde.[9] This method was used in the total synthesis of cyanolide A.[16] Intrigued by the diastereoselectivity and functional
group tolerance of this silyl enol ether Prins cyclization,[17] we decided to develop the method further by
exploring the scope with different substitution patterns. An overview
of the tetrahydropyran-4-one synthesis is shown in Scheme 1. The synthesis began with deprotonation of an acid
chloride using triethylamine to form a ketene in situ that, when reacted
with silyl keteneacetal 1,[18] produced ester 2. Ester 2 was transformed
to Weinreb amide 3.[19] Addition
of a nucleophilic organometallic reagent and subsequent reduction
of the resulting ketone afforded alcohol 4. Silyl enolether Prins cyclization of alcohol 4 with a Lewis acid
activated aldehyde produced the desired THPO 5 with high
diastereoselectivity. The thermodynamically favored cyclization is
very effective for introducing quaternary centers at the C-3 position
of the THPO. This method allows for the formation of highly functionalized
tetrahydropyran-4-ones with substituents at each carbon atom of the
THPO core.
Scheme 1
General Overview of This Method for Diastereoselective
THPO Synthesis[20]
Results
The syntheses of a variety of Weinreb amides
are presented in Table 1. The formation of
ester 7 occurred
in satisfactory yields by reacting the ketene, prepared in situ by
deprotonation of the acid chloride, with silyl ketene acetal 6.[21] Dimethyl ketene (entry 2),
which comes from the least acidic acid chloride, was prepared by zinc
reduction of 2-bromo-2-methylpropionyl bromide.[22] In entry 3, no desired ester was observed due to the instability
of the unsubstituted silyl enol ether product. The acid chloride precursors
from entries 5 and 6 were prepared from the nonsteroidal anti-inflammatory
drugs, ibuprofen and naproxen, respectively, demonstrating that motifs
present in biologically active molecules can be incorporated into
the THPO using this method. Acid chlorides with an aryl group for
R2 and a proton for R3 generally led to low
yields of ester 7 (entry 7); these esters were not taken
further in the sequence. The transformation to ester 7 was highly diastereoselective; keteneacetal 6 underwent
nucleophilic addition at the less hindered face of the ketene. Only
a single alkene isomer of Weinreb amide 8 was isolated.
The configuration with the larger R2 substituent cis to the −OTBS group was favored in each case.
Table 1
Preparation of Weinreb Amides 9–13
The dimethylketene
reagent was prepared
in situ by zinc reduction of 2-bromo-2-methylpropionyl bromide.
The dimethylketene
reagent was prepared
in situ by zinc reduction of 2-bromo-2-methylpropionyl bromide.Weinreb amide 10 underwent nucleophilic addition with
a variety of Grignard and organolithium reagents to yield ketone 14 (Table 2). Direct reduction of the
crude allylic ketone (entry 1) was necessary to prevent isomerization
of the double bond into conjugation with the ketone. Reduction of
a vinyl ketone (entry 6) could be achieved in high yields with a Luche
reduction or enantioselectively with a CBS reduction.[23] The β-oxy-alkyllithium reagent[24] from entry 4 was enantioenriched and syn-selective reduction[25] of the ketone resulted
in diol 19 as a single diastereomer. Tertiary alcohol 20 was obtained by double addition of methylmagnesium bromide
into ester 7 (R2 and R3 = Me).
Modest yields were observed with smaller nucleophiles (entry 7), possibly
due to deprotection of the product by nucleophilic attack on the silyl
group.[26] A wide variety of hydroxy silyl
enol ethers were prepared by this sequence.
Table 2
Preparation
of Hydroxy Silyl Enol
Ether from Amide 10
Crude ketone was directly reduced
with DIBAL-H. The alcohol was obtained through a:
NaBH4 reduction,
NaBH4 reduction with
Et2B(OMe) additive,
double addition to ester 7,
Luche reduction,
CBS reduction.
Crude ketone was directly reduced
with DIBAL-H. The alcohol was obtained through a:NaBH4 reduction,NaBH4 reduction with
Et2B(OMe) additive,double addition to ester 7,Luche reduction,CBS reduction.Transformation of Weinreb amides with varying R2 and
R3 substituents to the corresponding alcohols is shown
in Table 3. Addition of Grignard or organolithium
reagents to Weinreb amide 8 gave the desired ketone 23. When treated with organolithium reagents, isomerization
of less substituted silyl enol ether 9 to form the conjugated
silyl enol ether was observed as a side reaction. Reduction of ketone 23 with sodium borohydride occurred in good yield to give
racemic hydroxyl silyl enol ethers 25–32.
Table 3
Preparation of the Hydroxy Silyl Enol
Ether with Varying R2 and R3 Substituents
NaBH4 reduction.
NaBH4 reduction.In our previous
publication, cyclization of hydroxyl silyl enol
ethers with aromatic and conjugated aldehydes was shown to be most
effective with BF3·OEt2, while TMSOTf was
necessary for aliphatic aldehydes.[9] A new
optimization of the THPO cyclization reaction was performed with hydroxyl
silyl enol ether 17, benzaldehyde, and BF3·OEt2 (Table 4). It was determined
that a polar solvent was necessary for reactivity (entries 1–3).
No product was observed when the reaction was run in toluene (entry
2). Dichloromethane (DCM) or acetonitrile (MeCN) as the solvent resulted
in similar yields, 66% and 65%, respectively, after 4 h. Dichloromethane
was selected as the solvent of choice due to its ease of removal after
the cyclization. Reaction concentrations were also examined, with
concentrations of 0.1, 0.4, and 1.0 M of alcohol 17 evaluated
(entries 4–6). It was found that the most concentrated mixture,
1.0 M, gave the highest yield of 69%. Optimization of temperature,
equivalents of the aldehyde, and equivalents of Lewis acid were conducted
using design of experiments (DoE).[27] Yields
were improved at lower temperatures: reactions at −95 °C
gave the slightly higher yields but were much slower. Cyclization
reactions shown herein were conducted at −78 °C for ease
of operation. Excess BF3·OEt2 relative
to the aldehyde lowered yields (entry 10), and a 1:1 molar ratio was
found to be optimal. It was found that a large excess of both BF3·OEt2 and aldehyde minimally affected the
yields (entry 9). Dropwise addition of hydroxyl silyl enol ether 17 to a solution of aldehyde and Lewis acid lowered yields
(entry 16). In the optimized conditions for the cyclization reaction,
it was run at −78 °C in 1.0 M dichloromethane with 1.5
equiv of both the Lewis acid and the aldehyde relative to the alcohol.
Table 4
Optimization of the THPO Cyclization
Reaction
entry
temp (°C)
equiv of PhCHO
equiv of BF3·OEt2
solvent
conc (M)
% yielda
1
–78
3.0
3.0
DCM
0.4
66
2
–78
3.0
3.0
toluene
0.4
no rxn
3
–78
3.0
3.0
MeCN
0.4
65
4
–95
3.0
2.0
DCM
1.0
69
5
–95
3.0
2.0
DCM
0.5
46
6
–95
3.0
2.0
DCM
0.1
48
7
–95
4.5
1.5
DCM
0.4
71
8
–95
1.5
1.5
DCM
0.4
71
9
–95
4.5
4.5
DCM
0.4
74
10
–95
1.5
4.5
DCM
0.4
63
11
–40
4.5
1.5
DCM
0.4
51
12
–40
1.5
1.5
DCM
0.4
49
13
–40
4.5
4.5
DCM
0.4
50
14
–40
1.5
4.5
DCM
0.4
62
15
–78
1.5
1.5
DCM
1.0
69
16b
–78
1.5
1.5
DCM
0.5
48
Yields were determined
by 1H NMR spectroscopy with respect to mesitylene internal
standard.
A diluted solution
of silyl enol
ether was added dropwise to a solution of aldehyde and BF3·OEt2 at −78 °C.
Yields were determined
by 1H NMR spectroscopy with respect to mesitylene internal
standard.A diluted solution
of silyl enolether was added dropwise to a solution of aldehyde and BF3·OEt2 at −78 °C.The tetrahydropyran-4-one synthesis with aromatic
aldehydes is
shown in Table 5. Electron-rich aldehydes gave
higher yields than electron-poor aldehydes (entries 1–4), possibly
due to enhanced stabilization of oxocarbenium ion intermediate 33. This cyclization reaction is compatible with heterocycles
such as furans (entry 6) and benzothiophenes (entry 7), but no reaction
occurred with sulfonate-protected indole carboxaldehyde[28] (entry 5). Indole carboxaldehyde[29] and 2-pyridinecarboxaldehyde were also
tested as the aldehyde partner in the cyclization, but only starting
material was recovered. Irreversible binding of the Lewis acid to
the nitrogen atom may cause the lack of reactivity. The reaction conditions
are tolerant of free aliphatic and aromatic alcohols (entries 8 and
9), esters (entry 4), and aryl halides (entry 3). Only the THPO2,6-cis diastereomer was observed when starting with hydroxyl
silyl enol ether 15.
Table 5
Scope of the Tetrahydropyran-4-one
Synthesis with Hydroxyl Silyl Enol Ether 15 and Aromatic
Aldehydes[20]
The cyclization
reaction also was compatible with aliphatic and
conjugated aldehydes (Table 6). Conjugated
aldehydes are especially good substrates and generated clean products
in high yields (entries 3 and 6). These aldehydes are expected to
form resonance stabilized oxocarbenium ion intermediates, which appear
to facilitate the cyclization. The difference between aliphatic and
conjugated aldehydes is especially apparent when comparing entries
5 and 6. The reaction is tolerant of Boc-protected amines (entry 2).
Tertiary alcohol 20 resulted in THPO 50 with
two tetrasubstituted carbons (entry 8). A silyl-protected alcohol
(entry 1) was partially deprotected under the cyclization reaction
conditions. Optimized procedures were found to allow for deprotection
or retention of the silyl-protected alcohols. Full deprotection of
the silyl group was achieved by removing the reaction mixture from
its −78 °C bath and stirring for a few minutes before
quenching with sodium bicarbonate. Retention of the silyl group was
achieved by adding a bulky base additive, 2,6-di-tert-butyl-4-methylpyridine, to neutralize the triflic acid formed
during the reaction. Cyclization of hydroxy silyl enol ether 22 with crotonaldehyde led to a 4.1:1.0 ratio of the 2,6-cis and 2,6-trans THPO product. Cyclizations
with a variety of aldehydes and alcohols 16–21 resulted in only a single diastereomer. The origin of the
diastereoselectivity in the cyclization with hydroxy silyl enol ether 22 will be considered in the Discussion section.
Table 6
Scope of the Tetrahydropyran-4-one
Synthesis with Hydroxy Silyl Enol Ether 15 and Conjugated
and Aliphatic Aldehydes[20]
TMSOTf was used as the Lewis acid
instead of BF3·OEt2.
TMSOTf was used as the Lewis acid
instead of BF3·OEt2.Enantiomerically enriched THPOs
can be synthesized using this route
(Scheme 2).[9] THPO 48 was synthesized from enantiomerically enriched alcohol
precursor 19. The enantiomeric ratio of thioether 53, obtained from epoxide opening with thiophenol, was 98.0:2.0.
The enantiomeric ratio of THPO 48 was 97.9:2.1, and the
enantiospecificity of the reaction was >99%, demonstrating that
essentially
no optical activity was lost during the cyclization reaction.[30]
Scheme 2
Enantiomeric Ratio Is Retained Throughout
the Cyclization
The scalability of
the cyclization reaction was explored with alcohol 17 (eq 1). Reacting crotonaldehyde with
1.9 g (6.7 mmol) of alcohol 17 produced THPO 46 in 73% yield as a single diastereomer. The reaction was completed
after 4 h at −78 °C. This result indicates that no significant
loss in yield was observed at a scale useful in multistep syntheses.The tetrahydropyran-4-ones described to this
point have been dimethyl
substituted at the C-3 position. Table 7 shows
examples with a variety of different substituents on the silyl enolether. These silyl enol ethers often resulted in a mixture of 2,6-cis and 2,6-trans diastereomers; when the
C-3 was dimethyl substituted, usually only a single diastereomer was
observed by 1H NMR. The cyclization reactions with unsymmetric
silyl enol ethers form two new stereocenters during the cyclizations,
one of them at a quaternary carbon. Substituents R3 = methyl
and R2 = hydrogen (entries 1–4) were examined because
many THP(O) natural products contain a single methyl group at the
C-3 position.[1] Lower THPO yields were obtained
with hydroxy silyl enol ether 25 because this monosubstituted
silyl enol ether underwent the competitive intermolecular Mukaiyama
aldol addition, presumably because 25 is less sterically
hindered at the enol ether moiety than other hydroxy silyl enol ether
cyclization partners. The cyclization was compatible with ester groups
(entry 3). Alkene geometries were unchanged under the cyclization
reaction conditions even though a conjugated oxocarbenium ion was
formed. THPO 62 was synthesized with a 5:1 Z:E mixture of the aldehyde,[31] and the same Z:E ratio was obtained
after the reaction. Similar to THPO 52 (Table 6, entry 10), the small alkyne substituent on the
alcohol led to a loss of cis/trans diastereoselectivity (Table 7, entry 9).
Hydroxy silyl enol ethers with substituted aromatic rings underwent
cyclization successfully (entries 10 and 11).
Table 7
Scope of
the Tetrahydropyran-4-one
Synthesis with Different Aldehydes and Alcohols, with Varying Substituents
at the C-3 Position
TMSOTf
was used as the Lewis acid
instead of BF3·OEt2. Abbreviation: PMP
= p-methoxyphenyl.
TMSOTf
was used as the Lewis acid
instead of BF3·OEt2. Abbreviation: PMP
= p-methoxyphenyl.The stereoselective outcome of the THPO cyclization
reaction was
further examined with substitution at C-5. The hydroxy silyl enolether synthesis is shown in Scheme 3. The synthesis
began with zinc reduction of 2-bromo-2-methylpropionyl bromide to
form dimethyl ketene in situ.[22] Dimethylketene added to silyl ketene acetal 66 to afford ester 67, which was transformed to Weinreb amide 68. Addition of n-butyllithium resulted in ketone 69, and diastereoselective reduction of 69 with
L-selectride produced a mixture of anti-alcohol 70 (major) and syn-alcohol 71 (minor). The two diastereomers were isolated and used in separate
THPO forming reactions.
Scheme 3
Formation of the Hydroxy Silyl Enol Ether
with R1 = Methyl
for Substitution at C-5 in the Resulting Tetrahydropyran-4-one
Alcohol 70 underwent
cyclization with crotonaldehyde
to afford THPO 72 as a single diastereomer in 50% yield.
All four substituents on the six-membered ring occupied pseudo-equatorial
positions in THPO 72 (Scheme 4). Cyclization of cis-alcohol 71 with
crotonaldehyde resulted in a mixture of diastereomers, THPO 73c and 73t. This cyclization was the first in which the 2,6-trans THPO was the major product and the 2,6-cis THPO
was the minor product. An explanation for this reversal of selectivity
is presented in the Discussion section.
Scheme 4
Tetrahydropyran-4-one Synthesis with Substitution at C-5
Discussion
The
proposed mechanism for the silyl enol ether cyclization is
outlined in Scheme 5. The reaction begins with
formation of the hemiacetal 74 from the alcohol and the
aldehyde, followed by expulsion of the leaving group, to generate
the key oxocarbenium ion intermediate 76. These steps
are presumably promoted by the Lewis acid. Irreversible[32] nucleophilic attack of the silyl enol ether
onto the oxocarbenium ion forms the desired THPO 54.
A chairlike conformation with E-configuration at
the oxocarbenium[33] is expected in the cyclization
transition state. The configuration of the major product is consistent
with this transition state geometry. Placement of the R4 groups in the pseudo-equatorial position favors one of the two possible
chairlike transitions states. The quaternary stereocenter at C-3 arises
from the Z-configuration of the enol ether in the
chairlike transition state. The sterically biased ketene addition
(Table 3) results in the less bulky substituent
at R3 in enol ether 24; the cyclization reactions
place this substituent in the axial position at C-3 in the new tetrahydropyran-4-one
ring. The stereochemical outcome of the silyl enol ether Prins cyclization
is consistent with the expected chairlike transition state.
Scheme 5
Proposed
Mechanism for the Silyl Enol Ether Prins Cyclization
Silyl enol ether 22 (Table 6, entry 10) leads to a large amount of the 2,6-trans THPO product in the cyclization with crotonaldehyde.
The diastereoselectivity
of the major product in the cyclization results from the alkyne and
crotonaldehydealkene being placed in the lower energy pseudo-equatorial
position in the chairlike reactive conformer 77 (Scheme 6). When the R4 substituent is sterically
small, in this case an alkyne, the energetic cost for it to occupy
a pseudo-axial position in the reactive conformation 78 is modest, and the cyclization results in a significant amount of
the 2,6-trans diastereomer 2t. For relative size comparison,
an alkyne group has an A value of 0.41 kcal/mol and
a methyl group has an A value of 1.7 kcal/mol in
a cyclohexane ring.[34] The 2,6-trans diastereomer was obtained when the small alkyne substituent occupied
a pseudo-axial position in the chairlike transition state.
Scheme 6
Small R4 Groups Resulted in Diminished Diastereoselectivity
during Cyclization
The 2,6-cis/trans selectivity
was influenced by the substituents on the C-3 position. The data are
summarized in Figure 3. When the substituents
on C-3 are identical, THPO 46 was observed as a single
diastereomer with a 2,6-cis configuration. When there
was a methyl group and proton on C-3, a 7.0:1.0 cis:trans diastereomeric ratio was obtained. With aryl
and methyl substitution on C-3, diastereoselectivity further diminished
to about a 3:1 ratio of cis:trans diastereomers. Note that, in all of these examples, the larger group
occupied the equatorial position at C-3 in the 2,6-cis product. Interestingly, the minor diastereomer in this cyclization
reaction is not the same one reported for similar cyclizations, an
oxonia-cope Prins reaction.[35] Dalgard and
Rychnovsky reported[14] the C-3 epimer of
the 2,6-cis product as the minor diastereomer in
their systems and suggest that the minor product could arise from E/Z isomerization of the starting silylenol ether[36] or a competing chair–boat
cyclization.[1a] Our minor diastereomer had
a different relative stereochemical relationship between C-2 and C-6
and retained relative stereochemistry between C-2 and C-3; we proposed
that the minor diastereomer would arise through the diastereomeric
chairlike transition state 80 (Figure 3). One would expect that, as the size of the R2 group increases, the steric interactions between the R2 substituent and the −OTBS and crotyl groups in TS 79 would increase. TS 80 places the R2 substituent
axial, relieving steric interactions between the crotyl group, and
becomes more favorable as the size of the R2 substituent
relative to the R3 substituent increases. Thus, increasing
the difference in size between the large R2 and small R3 subsitutents would lead to more of the 2,6-trans diastereomer, which is the observed outcome in this series.
Figure 3
Diastereoselective
trend caused by varying the substituents at
C-3 is shown with the major 2,6-cis isomer drawn.
The minor diastereomer has a 2,6-trans relationship.
The relative stereochemistry between C-2 and C-3 remained the same
for both diastereomers.
Diastereoselective
trend caused by varying the substituents at
C-3 is shown with the major 2,6-cis isomer drawn.
The minor diastereomer has a 2,6-trans relationship.
The relative stereochemistry between C-2 and C-3 remained the same
for both diastereomers.Introducing a new stereogenic center at C-5 influenced the
selectivity
of the cyclization (Scheme 4 and Figure 4). When alcohol 70 reacted with crotonaldehyde,
it likely proceeded through chairlike transition state 81 where all possible substituents adopted pseudo-equatorial positions
(Figure 4). In contrast, the cyclization geometry
from the reaction of alcohol 71 and crotonaldehyde must
have at least one substituent axial. Disfavored transition state 82 has the C-5 methyl group in an axial configuration with
a 1,3-diaxial orientation to a C-3 methyl group. In the preferred
transition state 83, the n-butyl group
at C-6 occupies an axial position. Both of these transition states
have destabilizing interactions, and the result is modest selectivity
in the cyclization for 73t. Apparently,
placing the n-butyl group axial is preferable to
the diaxial interaction between the methyl groups in the transition
state, leading to 73c. The lowest energy
chair conformer for each is product shown in Figure 4.[37]
Figure 4
Proposed chairlike transition
states to explain the diastereoselectivity
of THPO 72, 73c, and 73t. Full reaction conditions are shown in
Scheme 4.
Proposed chairlike transition
states to explain the diastereoselectivity
of THPO 72, 73c, and 73t. Full reaction conditions are shown in
Scheme 4.
Conclusion
The silyl enol ether Prins reaction is highly
diastereoselective
with most substrates, and the major products are consistent with cyclizations
through chairlike transition states. The reaction is tolerant of a
variety of functional groups and can form a quaternary center on the
THPO with good diastereoselectivity. This method allows
for the synthesis of substituted THPOs with substitution demonstrated
at every carbon atom in the ring. The flexibility of this silyl enolether Prins method makes it a useful tool for synthesizing diverse
THPO cores found in natural products or medicinal chemistry targets.
Experimental Section
General Information
All air- and moisture-sensitive
reactions were carried out in flame- or oven-dried flasks equipped
with a magnetic stir bar under an argon atmosphere. All commercially
available reagents were used as received unless stated otherwise.
Zinc dust was activated by sequential washing with 1 M HCl, water,
and ethanol and was then dried under reduced pressure. BF3·OEt2 was distilled neat under an argon atmosphere.
TMSOTf was distilled over CaH2 under reduced pressure.
Thin-layer chromatography (TLC) was performed on 250 μm layer
silica gel plates, and developed plates were visualized by UV light, p-anisaldehyde, potassium permanganate, or vanillin.1H NMR spectra were recorded at 500 MHz, and 13C NMR spectra were recorded at 126 MHz. Chemical shifts (δ)
were referenced to either TMS or the residual solvent peak. The 1H NMR spectra data are presented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, app. = apparent, br. = broad), coupling constant(s)
in hertz (Hz), and integration. Infrared spectra were recorded on
NaCl plates. High-resolution mass spectrometry was performed using
ESI-TOF. Structures not numbered in the article were numbered consecutively
starting with 101. Compounds 101–104, 10, 16–20, 35–39, 41, 44, 47, 48, 50, and 53 were formed using known procedures.[9]
General Procedures to Form Ester 7
Triethylamine
(1.7 equiv) was added dropwise to a solution of acid chloride (1.7
equiv) in dry THF (0.6 M relative to 6) at 0 °C.
The mixture turned into a white sludge due to the formation of Et3NCl salt. Silyl ketene acetal 6 (1.0 equiv) was
added to the mixture, and the solution was stirred overnight, slowly
warming from 0 °C to room temperature. The reaction was quenched
with saturated aqueous NaHCO3, and the mixture was extracted
with Et2O (3×). The organic layer was dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. Purification
by column chromatography of the crude residue produced ethyl ester 7.
Triethylamine (0.31 mL, 2.22 mmol, 1.70
equiv) was added dropwise to a solution of 2-(6-methoxynaphthalen-2-yl)propanoyl
chloride (552 mg, 2.22 mmol, 1.70 equiv) in dry THF (0.6 M relative
to 6) at 0 °C. The mixture turned into a white sludge
due to the formation of Et3N·HCl salt. Silyl keteneacetal 6 (264 mg, 1.30 mmol, 1.00 equiv) was added to
the mixture, and the solution was stirred overnight slowly, warming
from 0 °C to room temperature. A second portion of triethylamine
(0.31 mL, 2.22 mmol, 1.70 equiv) was added dropwise to the solution
at rt. The reaction was monitored by TLC, and once starting material
was consumed, the reaction was quenched with saturated aqueous NaHCO3 (10 mL). The mixture was extracted with Et2O (3
× 10 mL). The organic layers were combined, dried over anhydrous
MgSO4, and filtered, and the resulting solution was concentrated
in vacuo. Purification by column chromatography (10:1:89 EtOAc:Et3N:hexanes) of the crude residue afforded 108 as
a clear colorless oil (471 mg. 87%): R = 0.7 (10% EtOAc/hexanes); 1H NMR (500
MHz, CDCl3) δ 7.70 (br. s, 1H), 7.65 (dd, J = 9.0, 7.0 Hz, 2H), 7.44 (dd, J = 8.5,
1.5 Hz, 1H), 7.11–7.09 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.34 (s, 2H), 2.04 (s, 3H), 1.32 (t, J = 7.25 Hz, 3H), 0.71 (s, 9H), −0.30 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 170.8, 157.7, 140.3,
137.3, 133.4, 129.7, 129.1, 128.8, 127.9, 126.3, 118.8, 118.1, 105.9,
61.2, 55.6, 40.2, 26.0, 19.8, 18.3, 14.7, −4.2; IR (thin film)
2931, 2956, 2897, 2857, 1739, 1605 cm–1; HRMS (ES/MeOH) m/z calcd for C24H34O4SiNa [M + Na]+ 437.2124, found 437.2112.
A sample of silyl ketene acetal 6 (200 mg, 1.00 mmol) and phenylacetyl chloride (260 mg, 1.68
mmol) was converted to 109 following the general procedures
for ester 7 formation. Purification by column chromatography
(20:1:79 EtOAc:Et3N:hexanes) of the crude residue afforded 109 as a clear colorless oil (98 mg, 31%): R = 0.65 (20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 7.5 Hz, 2H), 7.25 (app. t, J = 7.8 Hz, 2H), 7.13
(app. t, J = 7.5 Hz, 1H), 5.58 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.2 (s, 2H), 1.29 (t, J = 7.0 Hz, 3H), 0.92 (s, 9H), 0.06 (s, 6H); 13C NMR (126
MHz, CDCl3) δ 170.2, 145.5, 136.0, 128.7, 127.9,
126.0, 111.6, 61.0, 43.8, 25.8, 18.3, 14.3, −3.8; IR (thin
film) 2931, 2858, 1740, 1654 cm–1; HRMS (ES/MeOH) m/z calcd for C18H28O3SiNa [M + Na]+ 343.1705, found 343.1712.
General Procedures To Form Weinreb Amide 8(19)
A solution of 2.0 M i-PrMgCl (2.4 equiv) in dry THF was added dropwise to a solution of
ethyl ester 7 (1.0 equiv) and Me(MeO)NH·HCl
(1.2 equiv) in dry THF (0.12 M relative to 7) at −20
°C. The mixture was stirred at −20 °C for 2 h, and
the reaction was then quenched with saturated aqueous NH4Cl. The mixture was extracted with Et2O (3×). The
organic layers were combined, dried over anhydrous MgSO4, and filtered, and the resulting solution was concentrated in vacuo.
Purification by column chromatography of the crude residue afforded
Weinreb amide 8.
A solution of 2.0 M i-PrMgCl
(0.30 mL, 0.60 mmol, 2.0 equiv) in dry THF was added dropwise to a
two-neck flask containing ethyl ester 107 (116 mg, 0.30
mmol, 1.0 equiv) and Me(MeO)NH·HCl (29 mg, 0.30
mmol, 1.0 equiv) in dry THF (1.25 mL) and dry toluene (1.25 mL) at
rt. The mixture was stirred for 6 h at rt. Four portions of 2.0 M i-PrMgCl (each portion: 0.30 mL, 0.60 mmol, 2.0 equiv) in
dry THF and Me(MeO)NH·HCl (each portion: 29 mg,
0.30 mmol, 1.0 equiv) were added to the solution at rt in 6 h intervals.
The reaction was monitored by TLC, and once starting material was
consumed, the reaction was quenched with saturated aqueous NH4Cl (3 mL). The mixture was extracted with Et2O
(3 × 5 mL). The organic layers were combined, dried over anhydrous
MgSO4, and filtered, and the resulting solution was concentrated
in vacuo. Purification by column chromatography (15:1:84 EtOAc:Et3N:hexanes) of the crude residue afforded Weinreb amide 12 as a clear colorless oil (92 mg. 76%): R = 0.17 (15% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 3.74 (s,
3H), 3.43 (s, 2H), 3.22 (s, 3H), 2.43 (d, J = 7.2
Hz, 2H), 1.94 (s, 3H), 1.83 (app. septet, J = 6.7
Hz, 1H), 0.89 (d, J = 6.6 Hz, 6H), 0.73 (s, 9H),
−0.24 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 171.5, 140.0, 139.4 (2), 129.1, 128.6, 117.7, 61.4, 45.3,
38.3, 32.6, 30.4, 25.9, 22.4, 19.5, 18.1, −4.4; IR (thin film)
2954, 2930, 2857, 1677 cm–1; HRMS (ES/MeOH) m/z calcd for C23H39NO3SiNa [M + Na]+ 428.2597, found 428.2599.
A solution of 2.0 M i-PrMgCl (0.48 mL, 0.96 mmol,
2.0 equiv) in dry THF was added dropwise to a two-neck flask containing
ethyl ester 108 (200 mg, 0.48 mmol, 1.0 equiv) and Me(MeO)NH·HCl
(47 mg, 0.48 mmol, 1.0 equiv) in dry THF (2 mL) and dry toluene (2
mL) at 0 °C. The mixture was stirred for 7 h, slowly warming
to rt. A second portion of 2.0 M i-PrMgCl (0.48 mL,
0.96 mmol, 2.0 equiv) in dry THF and Me(MeO)NH·HCl (47
mg, 0.48 mmol, 1.0 equiv) was added to the solution and stirred overnight
at rt. A third portion of 2.0 M i-PrMgCl (0.48 mL,
0.96 mmol, 2.0 equiv) in dry THF and Me(MeO)NH·HCl (47
mg, 0.48 mmol, 1.0 equiv) was added to the solution. The reaction
was monitored by TLC, and once starting material was consumed, the
reaction was quenched with saturated aqueous NH4Cl (20
mL). The mixture was extracted with EtOAc (5 × 20 mL). The organic
layers were combined, dried over anhydrous MgSO4, and filtered,
and the resulting solution was concentrated in vacuo. Purification
by column chromatography (20:1:79 EtOAc:Et3N:hexanes) of
the crude residue afforded Weinreb amide 13 as a clear
colorless oil (183 mg. 90%): R = 0.55 (20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.74 (br. s, 1H), 7.65 (app. dd, J = 8.8, 6.1 Hz, 2H), 7.5 (app. d, J = 8.5 Hz, 1H),
7.12–7.07 (m, 2H), 3.91 (s, 3H), 3.77 (s, 3H), 3.49 (s, 2H),
3.24 (s, 3H), 2.04 (s, 3H), 0.72 (s, 9H), 0.29 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 171.1, 157.3, 140.5, 137.2,
133.0, 129.4, 128.8, 128.6, 127.7, 126.0, 118.5, 117.6, 105.6, 77.4,
61.4, 55.3, 38.2, 25.8, 19.4, 18.1, −4.3; IR (thin film) 2954,
2932, 2856, 2896, 1674, 1604 cm–1; HRMS (ES/MeOH) m/z calcd for C24H35NO4SiNa [M + Na]+ 452.2233, found 452.2219.
General Procedures to Form Ketone 14/23 with an Organolithium Reagent
To a flask containing Weinrebamide 8/10 (1.0 equiv) and dry THF (0.3 M) was added
an organolithium reagent (1.5 equiv) dropwise at −78 °C.
The mixture was stirred for 5 h at −78 °C, and the reaction
was quenched with saturated aqueous NH4Cl. The solution
was extracted with DCM (4×). The organic layers were combined,
dried with anhydrous MgSO4, filtered, and concentrated
in vacuo. Purification by column chromatography of the crude residue
afforded ketone 14/23.
General Procedures
to Form Ketone 14/23 with a Grignard Reagent
A Grignard reagent (1.5 equiv)
was added dropwise to a solution of Weinreb amide 8/10 (1.0 equiv) in dry THF (0.3 M) at 0 °C. The mixture was stirred
overnight, slowly warming to room temperature. The reaction was quenched
with saturated aqueous NH4Cl. The mixture was extracted
with EtOAc (4×). The organic layers were combined and dried over
anhydrous Na2SO4, filtered, and concentrated
in vacuo. Purification by column chromatography of the crude residue
afforded ketone 14/23.
n-BuLi (2.27 M in hexanes,
0.22 mL) was added to a solution of phenyl acetylene (57 μL,
0.52 mmol) in dry THF (1.2 mL) at −78 °C. The mixture
was stirred for 1 h; then Weinreb amide 10 (100 mg, 0.35
mmol) was added. The solution was stirred for 4 h, slowly warming
to rt. The reaction was quenched with saturated aqueous NH4Cl (2 mL), and the mixture was extracted with EtOAc (3 × 5 mL).
The organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography
(5% EtOAc/hexanes) of the crude residue afforded ketone 111 as a yellow oil (45 mg, 39%): R = 0.62 (10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.56–7.54 (m, 2H), 7.45–7.43 (m, 1H),
7.40–7.36 (m, 2H), 3.46 (s, 2H), 1.72 (s, 3H), 1.71 (s, 3H),
0.94 (s, 9H), 0.14 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 184.8, 137.1, 133.3, 130.8, 128.7, 120.3, 115.0,
91.2, 88.0, 49.5, 30.0, 19.6, 18.4, 18.3, −3.7; IR (thin film)
2957, 2929, 2858, 1667 cm–1; HRMS (ES/MeOH) m/z calcd for C20H28O2SiNa [M + Na]+ 351.1756, found 351.1754.
Ethyl acetate (0.09 mL, 0.88 mmol) was
added dropwise to a freshly made solution of LDA (0.5 M in THF, 1.8
mL) over 5 min at −78 °C. The mixture was stirred for
1 h. DMPU (0.13 mL, 1.10 mmol) and Weinreb amide 9 (200
mg, 0.82 mmol) were added to the solution, and the mixture was stirred
for 28 h at −78 °C. The reaction was quenched with saturated
aqueous NH4Cl (2 mL), and the mixture was extracted with
EtOAc (3 × 10 mL). The organic layers were combined, dried with
anhydrous MgSO4, filtered, and concentrated in vacuo. Purification
by column chromatography (10% EtOAc:hexanes) of the crude residue
afforded ketone 113 as a clear colorless oil (129 mg,
59%): R = 0.44 (10%
EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ
4.71 (q, J = 6.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.54 (s, 2H), 3.18 (s, 2H), 1.57 (d, J = 6.8 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 0.93 (s,
9H), 0.13 (s, 6H); 13C NMR (126 MHz, CDCl3)
δ 201.0, 167.6, 144.4, 108.3, 61.4, 51.8, 47.5, 25.8, 18.3,
14.2, 11.3, −3.9; IR (thin film) 2932, 2957, 2859, 2897, 1748,
1721, 1676 cm–1; HRMS (ES/MeOH) m/z calcd for C15H28O4SiNa [M + Na]+ 323.1655, found 323.1652.
n-BuLi (2.27 M in hexanes,
0.28 mL) was added to a solution of phenyl acetylene (70 μL,
0.63 mmol) in dry THF (1.9 mL) at −78 °C. The mixture
was stirred for 1.5 h; then Weinreb amide 11 (200 mg,
0.57 mmol) was added. The solution was stirred for 2.5 h at −78
°C, warmed to 0 °C, and stirred for an additional 2 h. The
reaction was quenched with saturated aqueous NaHCO3 (3
mL), and the mixture was extracted with EtOAc (3 × 10 mL). The
organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography
(15% EtOAc/hexanes) of the crude residue afforded ketone 117 as a yellow oil (130 mg, 58%): R = 0.76 (15% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.58 (dd, J = 8.2, 1.1 Hz, 2H),
7.47–7.44 (m, 1H), 7.39–7.34 (m, 4H), 7.28 (app. t, J = 8.3 Hz, 2H), 7.19–7.16 (m, 1H), 3.56 (s, 2H),
2.07 (s, 3H), 0.73 (s, 9H), −0.23 (s, 6H); 13C NMR
(126 MHz, CDCl3) δ 184.4, 141.8, 139.5, 133.3, 130.9,
129.3, 128.8, 128.0, 126.3, 120.2, 120.0, 91.4, 87.9, 50.3, 25.7,
19.9, 18.1, −4.4; IR (thin film) 2954, 2928, 2856, 1673 cm–1; HRMS (ES/MeOH) m/z calcd for C25H30O2SiNa [M
+ Na]+ 413.1913, found 413.1923.
Weinreb amide 13 (50 mg,
0.12 mmol) and n-BuLi (2.37 M in hexanes, 0.16 mL)
were converted to ketone 119 following the general procedures
for ketone 23 formation with an organolithium reagent. n-BuLi was added in two equal portions; the second portion
was added after 5 h. The mixture was stirred for an additional 1 h.
The solution was extracted with EtOAc instead of DCM. Purification
by column chromatography (10% EtOAc/hexanes) of the crude residue
afforded ketone 119 as a clear colorless oil (30 mg,
60%): R = 0.63 (10%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
7.69 (d, J = 7.4 Hz, 1H), 7.66 (dd, J = 9.0, 2.7 Hz, 2H), 7.44 (dd, J = 8.5, 1.7 Hz,
1H), 7.13–7.09 (m, 2H), 3.92 (s, 3H), 3.35 (s, 2H), 2.65 (t, J = 7.4 Hz, 2H), 2.04 (s, 3H), 1.65 (app. quintet, J = 7.5 Hz, 2H), 1.39 (app. sextet, J =
7.4 Hz, 2H), 0.96 (t, J = 3H), 0.70 (s, 9H), −0.32
(s, 6H); 13C NMR (126 MHz, CDCl3) δ 207.9,
157.5, 140.8, 136.9, 133.2, 129.4, 128.9, 128.4, 127.6, 126.2, 118.7,
118.3, 105.7, 55.4, 49.0, 41.0, 26.0, 25.8, 22.6, 19.7, 18.0, 14.0,
−4.3; IR (thin film) 2956, 2931, 2858, 1717, 1633, 1605 cm–1; HRMS (ES/MeOH) m/z calcd for C26H38O3SiNa [M
+ Na]+ 449.2488, found 449.2477.
General Procedures to Form
Alcohol 15/24
Sodium borohydride (1.1 equiv)
was added to a vial containing ketone 14/23 (1.0 equiv)
in MeOH (0.2 M relative to the ketone) at
−20 °C. The reaction was monitored by TLC, and when starting
material was consumed, the reaction was quenched with saturated aqueous
NH4Cl. The solution was extracted with EtOAc (3×),
and the organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by column
chromatography of the crude residue afforded alcohol 15/24.
A solution
of BH3·SMe2 (1.0 M in DCM, 0.23 mL), (R)-(+)-2-methyl-CBS-oxazaborolidine (1.0 M in toluene,
0.04 mL) and 3.6 mL of dry toluene was stirred for 10 min at rt, cooled
to −40 °C, and stirred for an additional 10 min. A solution
of enone 110 (91 mg, 0.36 mmol) in 0.8 mL dry toluene
was added dropwise over 5 min. The mixture was stirred overnight,
warming to 0 °C. The solution was cooled back down to −40
°C, and an additional portion of BH3·SMe2 (1.0 M in DCM, 0.23 mL) was added. The mixture was stirred
for 4.5 h, slowly warming to −20 °C. The reaction was
quenched with H2O (1 mL), and the solution was extracted
with EtOAc (3 × 2 mL). The combined organic layers were washed
with saturated aqueous NaCl (2 mL), dried with anhydrous MgSO4, filtered, and concentrated in vacuo. Purification of the
crude residue by column chromatography (10% EtOAc:hexanes) afforded
enantioenriched alcohol 21 (9.0:1.0 e.r.) as a clear colorless oil (50 mg, 60%). Racemic reduction: CeCl3·7H2O (160 mg, 0.43 mmol) was added to a vial
containing enone 110 (100 mg, 0.39 mmol) and MeOH (1.95
mL) at −78 °C. The mixture was stirred for 10 min. Then
NaBH4 (16 mg, 0.43 mmol) was added, and the solution was
stirred for an additional 20 min. The reaction was quenched with saturated
aqueous NH4Cl (10 mL) and diluted with 10 mL of saturated
aqueous NaCl. The solution was extracted with EtOAc (3 × 15 mL),
and the organic layers were combined, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification
by column chromatography (10% EtOAc:hexanes) of the crude residue
afforded racemic alcohol 21 as a clear colorless oil
(94 mg, 94%): R = 0.46
(10% EtOAc/hexanes); [α]D24 = 7.5 (c 1.97, acetone); 1H NMR (500 MHz, CDCl3) δ 5.89 (ddd, J = 17.0, 10.7, 6.0 Hz, 1H), 5.26 (d, J = 17.2 Hz, 1H), 5.10 (d, J = 10.5 Hz, 1H), 4.35–4.31
(m, 1H), 2.41 (dd, J = 14.1, 8.8 Hz, 1H), 2.27 (dd, J = 14.1, 4.1 Hz, 1H), 1.64 (app. s, 6H), 0.95 (s, 9H),
0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 140.8, 140.5, 114.4, 113.6, 71.3, 40.1, 26.0, 19.3,
18.4, 18.3, −3.67, −3.74; IR (thin film) 3417, 2958,
2930, 2859, 1681 cm–1; HRMS (ES/MeOH) m/z calcd for C14H28O2SiNa [M + Na]+ 279.1756, found 279.1762.
Ketone 119 (51 mg, 0.12 mmol)
was converted to alcohol 32 following the general procedures
for alcohol 24 formation. The mixture was stirred for
4 h at −20 °C and extracted with DCM instead of EtOAc.
Purification by column chromatography (10% EtOAc/hexanes) of the crude
residue afforded alcohol 32 as a clear light yellow oil
(40 mg, 79%): R = 0.30
(10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 7.67–7.64 (m, 3H), 7.41 (dd, J = 8.5,
1.5 Hz, 1H), 7.12–7.10 (m, 2H), 4.05–3.99 (m, 1H), 3.92
(s, 3H), 2.50–2.42 (m, 2H), 2.32 (br. s, 1H), 2.07 (s, 3H),
1.63–1.36 (m, 6H), 0.95 (t, J = 7.1 Hz, 3H),
0.72 (s, 9H), −0.29 (s, 3H), −0.35 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.4, 144.4, 137.4, 133.1,
129.4, 128.9, 128.6, 127.7, 126.1, 118.6, 117.8, 105.6, 70.9, 55.4,
40.9, 36.9, 28.1, 25.9, 22.9, 19.6, 18.1, 14.2, −4.2, −4.3;
IR (thin film) 3444, 2956, 2929, 2858, 1604 cm–1; HRMS (ES/MeOH) m/z calcd for
C26H40O3SiNa [M + Na]+ 451.2644, found 451.2645.
General Procedures for THPO Formation
BF3·OEt2 (1.5 equiv) was added dropwise
to a solution
of aldehyde (1.5 equiv) and hydroxy silyl enol ether (1.0 equiv) in
DCM (1.0 M relative to the silyl enol ether) at −78 °C.
The mixture was stirred for 4 h, and the reaction was quenched with
saturated aqueous NaHCO3. The solution was extracted with
DCM (3×), and the organic layers were combined, dried with anhydrous
MgSO4, filtered, and concentrated in vacuo. Purification
by column chromatography of the crude residue afforded the desired
THP.
2-Bromo-2-methylpropionyl bromide
(1.6 g, 6.9 mmol) was added dropwise to a suspension of activated
zinc dust (0.91 g, 13.9 mmol) in dry THF (12 mL) at 0 °C. The
reaction mixture was stirred for 1 h at 0 °C and then transferred
via cannula to a solution of silyl ketene acetal 66 (0.5
g, 2.3 mmol) in dry THF (12 mL) at 0 °C. The gray-green mixture
was stirred overnight, slowly warming to room temperature. The reaction
mixture was then diluted with Et2O (25 mL) and washed with
H2O (15 mL). The aqueous layer was extracted with Et2O (20 mL × 6). The organic layers were combined, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo.
Purification by column chromatography (10:1:89 Et2O:Et3N:hexanes) of the crude residue produced ethyl ester 67 as a colorless oil (0.22 g, 33%): R = 0.57 (10% Et2O/hexanes); 1H NMR (500 MHz, CDCl3) δ 4.15–4.03
(m, 2H), 3.53 (q, J = 7.3 Hz, 1H), 1.59 (s, 3H),
1.57 (s, 3H), 1.24 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.05 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 173.9, 142.8, 111.3,
60.7, 42.6, 26.2, 19.0, 18.9, 18.8, 14.4, 14.4, −3.5, −3.8;
IR (thin film) 2956, 2932, 2905, 2859, 1736, 1675 cm–1; HRMS (ES/MeOH) m/z calcd for
C15H30O3SiNa [M + Na]+ 309.1862, found 309.1864.
A solution of 2.0 M i-PrMgCl (0.92 mL, 1.8 mmol) in dry THF was added dropwise to a solution
of ethyl ester 67 (0.22 g, 0.77 mmol) and Me(MeO)NH·HCl
(90 mg, 0.92 mmol) in dry THF (6.4 mL) at −78 °C. The
mixture was stirred for 3.5 h at −78 °C, warmed to 0 °C,
and stirred for an additional 2.5 h. A solution of 2.0 M i-PrMgCl (0.92 mL, 1.8 mmol) in dry THF and Me(MeO)NH·HCl
(90 mg, 0.92 mmol) was added to the reaction mixture and stirred for
2.5 h at 0 °C. The reaction was then quenched with saturated
aqueous NH4Cl (5 mL). The mixture was extracted with EtOAc
(3 × 10 mL). The organic layers were combined, dried over anhydrous
MgSO4, and filtered, and the resulting solution was concentrated
in vacuo. Purification by column chromatography (15% EtOAc/hexanes)
of the crude residue afforded Weinreb amide 68 as a colorless
oil (183 mg, 79%): R = 0.54 (15% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 3.73–3.62 (m, 1H), 3.59 (s, 3H), 3.14 (s,
3H), 1.59 (s, 3H), 1.58 (s, 3H), 1.24 (d, J = 7.2
Hz, 3H), 0.93 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 174.8, 143.7, 109.9, 77.4,
60.7, 41.1, 26.2, 18.9, 18.7, 18.6, 14.8, −3.3, −3.4;
IR (thin film) 2956, 2932, 2898, 2858, 1668 cm–1; HRMS (ES/MeOH) m/z calcd for
C15H31NO3SiNa [M + Na]+ 324.1971, found 324.1979.
Alcohol 71 (9 mg, 0.03 mmol) and crotonaldehyde (6 mg,
0.09 mmol) were converted to 73 following the general
procedures for THPO formation using 3.0 equiv of aldehyde and 3.0
equiv of BF3·OEt2 instead of 1.5 equiv.
The solution was run at 0.3 M instead of 1.0 M. Purification by column
chromatography (5% EtOAc/hexanes) of the crude residue afforded THPO 73 as a mixture of diastereomers (1.0:1.8 cis:trans) that was a clear colorless oil (5.2 mg,
72%). Some of the THPO 73t was separated
for characterization, but most of it was recovered as a mixture of
the two diastereomers. THPO 73c: R = 0.49 (5% EtOAc/hexanes); 13C NMR (126 MHz, CDCl3) δ 219.9, 130.4, 126.5,
85.6, 79.0, 49.3, 47.5, 31.6, 27.9, 22.8, 21.1, 21.0, 18.2, 14.2,
12.6; 13C chemical shifts were determined by taking a 13C NMR spectra of the diastereomeric mixture and subtracting
peaks that belonged to THPO 73t. THPO 73t: R = 0.42 (5% EtOAc/hexanes); 1H NMR (500
MHz, CDCl3) δ 5.72 (dq, J = 18.4,
4.3 Hz, 1H), 5.54 (dd, J = 15.3, 7.5 Hz, 1H), 4.18–4.10
(m, 1H), 3.79 (d, J = 7.4 Hz, 1H), 3.23 (app. quintet, J = 6.8 Hz, 1H), 1.75 (d, J = 6.4 Hz, 3H),
1.39–1.27 (m, 4H), 1.17 (s, 3H), 0.93 (s, 3H), 0.90 (d, J = 7.5 Hz, 3H), 0.88–0.83 (m, 5H); 13C NMR (126 MHz, CDCl3) δ 214.0, 130.6, 126.5, 79.2,
78.6, 44.5, 29.8, 27.4, 26.0, 22.6, 20.7, 19.7, 18.1, 14.2, 10.3;
IR (thin film) 2959, 2932, 2859, 1709 cm–1; HRMS
(ES/MeOH) m/z calcd for C15H30O2N [M + NH4]+ 256.2277,
found 256.2274.
Authors: George R Pettit; Jun-Ping Xu; Jean-Charles Chapuis; Robin K Pettit; Larry P Tackett; Dennis L Doubek; John N A Hooper; Jean M Schmidt Journal: J Med Chem Date: 2004-02-26 Impact factor: 7.446
Figure 1
Figure 2
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Figure 3
Figure 4