Relative stereochemical determination and synthesis of the C17-C25 δ-lactone fragment of hemicalide

Article abstract of DOI:10.1021/jo302440a

Hemicalide is a novel marine metabolite polyketide distinguished by a unique mechanism of action. Because of insufficient quantities of purified material, this natural product has evaded complete stereochemical assignments. Recently, we have determined th

Full text of DOI:10.1021/jo302440a

Article
pubs.acs.org/joc
Relative Stereochemical Determination and Synthesis of the C17−
C25 δ‑Lactone Fragment of Hemicalide
Etienne Fleury,† Geoffroy Sorin,† Elise Prost,† Ange Pancrazi,† Francois Sautel,‡ Georges Massiot,‡
̧
Marie-Isabelle Lannou,† and Janick Ardisson*,†
†CNRS UMR 8638, Faculte
́
de Pharmacie, Universite
́
Paris Descartes, 4 avenue de l’observatoire, 75270 Paris Cedex 06, France
eloppement Pierre Fabre, 3 avenue Hubert Curien, 31035 Toulouse
‡CNRS/Pierre Fabre USR 3388, Centre de Recherche et Dev
́
Cedex 01, France
S
* Supporting Information
ABSTRACT: Hemicalide is a novel marine metabolite polyketide
distinguished by a unique mechanism of action. Because of insufficient
quantities of purified material, this natural product has evaded
complete stereochemical assignments. Recently, we have determined
the relative stereochemistry of the C8−C13 hexad by synthesizing the
C1−C13 fragment. Presently, we report the assignment of the C17−
C25 δ-lactone fragment. NMR analysis of authentic hemicalide along
with a computational conformation study allowed us to reduce the
number of putative relative isomers from 16 to 4. Concise syntheses
of the four candidate diastereomers were achieved using a common
strategy based on a Dias aldehyde allylation reaction, an intra-
molecular Horner−Wadsworth−Emmons olefination, and a dihy-
droxylation reaction. Finally, thorough NMR comparisons enabled us
to deduce the relative stereochemistry of the C1−C17 fragment with high certainty.
INTRODUCTION
■
A new complex polyketide was recently isolated from extracts
of the marine sponge Hemimycale sp., collected in deep water
around Torres Islands (Vanuatu) in the south Pacific, by
French researchers of the CNRS-Pierre Fabre Laboratories
joint unit in association with Institut de Recherche pour le
Dev
́
eloppement (IRD).1 This new natural product, called
hemicalide, was found to be a potent mitotic blocker and to
display high antiproliferative potency against a panel of cancer
cell lines at subnanomolar concentrations (IC50 values ranging
from 0.1 to 1 nM). Importantly, immunocytochemistry studies
revealed that hemicalide acts by destabilizing the α/β
microtubule network but the mechanism seems to be different
from that observed with known antimitotic antitubulin agents.
However, the remaining amount of hemicalide was not
sufficient to support complementary pharmacological evalua-
tion, and since harvesting the natural raw material is difficult
and uncertain, chemical synthesis remained the only alternative
way to pursue the research.
The planar structure of hemicalide 1 was fully elucidated
through intensive NMR experiments.1 The natural product
comprises a 46-carbon backbone punctuated by 21 stereo-
centers (Figure 1). However, the stereochemical information
was highly limited, since the very low extraction yield prevented
any derivatization or degradation (less than 1 mg was isolated).
The relative configurations of the stereogenic centers were
therefore not assigned.
Figure 1. Structure of hemicalide 1.
Recently, we achieved the relative stereochemical determi-
nation of the six contiguous stereogenic centers of the C8−C13
segment of hemicalide 1 by means of initial NMR analysis and
subsequent synthesis of the six putative stereoisomers of model
2, structurally close enough to the natural compound to allow
NMR comparison (Figure 2).2 A combination of these works
led to the assignment of the C8−C13 motif as a syn-anti-anti-
syn-syn stereohexad.3
Herein we report the relative structural determination of the
C17−C25 α,β-dihydroxy-δ-lactone core appended with side
arms substituted by methyl groups, with a high level of
confidence. This work associates preliminary NMR experiments
on the natural product, computational conformational analysis,
Received: July 26, 2012
Published: January 9, 2013
© 2013 American Chemical Society
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Figure 2. Model compound 2 and relative assignment of the C8−C13
stereocenters.2.
and final synthesis of the appropriate four putative δ-lactone
models.
Figure 4. Structure of δ-lactone models 4.
RESULTS AND DISCUSSION
■
In order to establish the relative configuration of the five
stereocenters of the C17−C25 δ-lactone framework of 1, NMR
experiments were considered (Figure 3). NOESY analysis and
Scheme 1. δ-Lactone Models 4: Retrosynthetic Strategy
diastereoselective key Dias allylation reaction of aldehyde 5
by allylic silane 6 was selected.
To set up δ-lactone stereocenters, we opted for a
stereocontrolled tin-mediated allylation reaction. Initially
reported by Dias, this reaction involves chiral aldehydes and
a chiral allylic silane bearing an ethereal functionality as
coupling partners and provides 1,4-syn homoallylic alcohols
through 1,4-asymmetric induction.5
The preparation of diastereomeric homoallylic alcohols 7a,b,
precursors of lactones 4a,b, is detailed in Scheme 2. (S)-and
(R)-Roche esters were respectively converted into aldehydes
(S)-5 and (R)-5, by standard silylation of the hydroxy function,
ester reduction, and subsequent Swern oxidation.6 In the
meantime, chiral allylsilane (S)-6 was synthesized in a three-
step sequence from (R)-Roche ester.7 The organocerium
Figure 3. C17−C25 δ-lactone framework of 1: determination of the
putative structures.
3
the characteristic J(H19−H20) coupling constant (11.3 Hz)
Scheme 2. Synthesis of Homoallylic Alcohols 7a,b
were consistent with a chair conformation of this δ-lactone with
both hydroxy functions at C21 and C22 positions in a cis
relationship and the chain at C19 in a relative trans orientation.
Computational conformational analysis (Quenched Molecular
Dynamic, Sybyl software) from model 3 did confirm this chair
conformation.4 As a result of these considerations, only 4
relative δ-lactone diastereomers out of the 16 initially
envisioned could potentially correspond to natural product 1
(Figure 3).
Therefore, we set out to synthesize the four δ-lactone models
(4a−d) in order to determine the relative stereochemistry of
the C17−C25 δ-lactone framework of hemicalide 1 (Figure 4).
As previously done for the C8−C13 segment, these models
were designed to be close enough to the natural compound to
permit accurate NMR comparison.
The designed synthetic strategy could efficiently deliver the
four isomers (4a−d) using common intermediates and
featuring a limited number of steps (Scheme 1). The formation
of these δ-lactones was envisioned from corresponding α,β-
unsaturated lactones 8 by means of a syn-dihydroxylation
reaction. Lactones 8 would be constructed from homoallylic
alcohol 7. For the synthesis of this intermediate and
simultaneous control of the C19 stereocenter, a highly
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reagent generated from CeCl3 and ((trimethylsilyl)methyl)
magnesium chloride reacted with benzyl-protected (R)-Roche
ester to afford the corresponding bis(silylmethyl)carbinol as an
intermediate, which, after treatment with Amberlyst-15, led to
the desired allylsilane (S)-6 in 51% overall yield.8 Then, to
ensure transmetalation of allylsilane, (S)-6 and SnCl4 were
mixed before addition of aldehydes (S)-5 and (R)-5,
respectively, providing expected homoallylic alcohols 7a,b in
high yields (74−85%) and diastereoselectivities (up to 90%
de).7
Scheme 5. H-W-E Approach: Synthesis of δ-Lactone 4a
To obtain homoallylic alcohols 7c,d, precursors of lactones
4c,d, alcohols 7a,b were subjected to an inversion of
configuration at C19 under Mitsunobu conditions (Scheme
3).9,10
Scheme 3. Synthesis of Homoallylic Alcohols 7c,d
Table 1. Optimization of the Intramolecular H-W-E
Reaction from 11a
entry
base (equiv)
temp, °C
8a:12a
1
NaH (0.9)15a−c
0, room temp, or 40
20:80
4
K2CO3 (1.5)15d
room temp
room temp
room temp
−10
starting material
starting material
starting material
0:100
With access to the required homoallylic alcohols 7a−d now
reliable, the stage was set for the synthesis of lactones 4a−d. As
illustrated in Scheme 4, a ring closure metathesis (RCM) was
5
Ba(OH)2 (1.5)15e
LiClO4/DBU (1.5)15f,g
LiHMDS (1.0)15h
NaHMDS (1.0)
n-BuLi (1.0)15h
6
7
8
−10
40
0:100
Scheme 4. RCM Approach: Synthesis of Unsaturated δ-
Lactone 8a
9
starting material
b
10
t-BuOLi (0.9)15g
40
80:20
a
b
1
Determined by H NMR analysis of crude mixtures. 8a isolated
yield: 70%.
Finally, while the deprotonation was performed with freshly
prepared lithium tert-butoxide in THF, lactone 8a was isolated
in a satisfactory 70% yield; however, side reactions could not be
totally suppressed, since 17% of α,β-unsaturated ketone 12a
was still observed (Table 1 entry 10).15g
The final point of the sequence was the dihydroxylation of
α,β-unsaturated lactone 8a to lead to dihydroxylactone 4a with
both cis hydroxy functions at C21 and C22 in relative trans
positions to the chain at C19. A diastereoselective dihydrox-
ylation reaction in the presence of osmium tetroxide afforded
the expected lactone 4a in 97% yield (Scheme 5).16 Lactone 4a
was obtained in 45.7% overall yield for eight steps.
Following a similar sequence, lactones 4b−d were elaborated
in 23.6−55.8% overall yield for 8 or 10 steps (due to
Mitsunobu inversion of configuration at C19). Yields in key
intermediates, phosphonates 11b−d, and α,β-unsaturated
lactones 8b−d are highlighted in Scheme 6.
first examined. This strategy would provide α,β-unsaturated δ-
lactone 8a from acrylate ester 9 (obtained by esterification of
7a). Unfortunately, despite several attempts, the best
conditions, i.e. slow addition of Hoveyda−Grubbs second-
generation catalyst in refluxing toluene, afforded lactone 8a
with a mere conversion of 15%.11 This modest performance
could be attributed to steric considerations.12
Therefore, an alternative approach was suggested on the
basis of an intramolecular Horner−Wadsworth−Emmons
reaction. Synthesis of phosphonate 10a under Steglich
conditions13 and subsequent ozonolysis to obtain ketone 11a
were achieved in high yields (Scheme 5).
However, an intramolecular Horner−Wadsworth−Emmons
reaction from 11a was impeded by difficulties associated with β-
elimination as a competing side reaction, leading to a mixture of
the desired lactone 8a and α,β-unsaturated ketone 12a.14
Experimentally, several attempts were made to overcome this
unfavorable elimination reaction, using different bases in THF
(see Table 1).15
The relative structure of lactones 4a−d (i.e., both hydroxy
functions at C21 and C22 positions in a cis relationship and the
chain at C19 in a relative trans orientation) was confirmed by
NMR experiments (NOESY analysis and 3J(H19−H20) coupling
constant values; see Figure 5 and the Supporting Information).
A direct NMR comparison between natural product 1 and
the four synthesized lactones 4a−d was performed.
1
A H NMR study was essential to discriminate the four
lactones. The differences in the 1H NMR spectra are
1
highlighted in Table 2 and Figure 6. In fact, H NMR data of
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1
Scheme 6. Synthesis of δ-Lactones 4b−d
Table 2. Comparison of H NMR Data (d4-Methanol, 500
MHz) for Hemicalide 1 and Isomers 4a−d
3
δ(H), mult, J (Hz)
H−C19
H−C22
hemicalide 1
isomer 4a
isomer 4b
isomer 4c
isomer 4d
4.42, ddd, 11.5, 7.5, 3.5
4.76, dt, 12.0, 3.9
4.27, s
4.23, s
4.24, s
4.15, s
4.14, s
4.62, ddd, 10.7, 6.7, 4.9
4.63, ddd, 11.3, 6.7, 4.4
4.77, dt, 11.9, 3.9
1
Figure 6. Comparison of the H NMR spectra for hemicalide 1 and
isomers 4a−d.
the two protons at the C20 position of the hemicalide are not
accurately available and there is no proton at C21 (tertiary
alcohol). Therefore, comparison was mainly localized at both
C19 and C22 significant positions, the chemical shift of protons
at these places being particularly dependent on the orientation
1
of the δ-lactone substituents. H NMR data of protons at C22
and C19 are given for hemicalide 1 and δ-lactones 4a−d in
Table 2. The position at C22 is not affected by structural
differences between the δ-lactone models and hemicalide 1;
therefore, the chemical shift of this proton can be considered as
significant data to discriminate between different isomers. Thus,
isomers 4a,b (with a cis relationship between the C19 and C24
centers) are closest to hemicalide.
Concerning the H−C19 position, a direct comparison of
chemical shifts seems irrelevant, given the structural differences
between the natural molecule and models in this region. In
contrast, the coupling constants at this level carry information
on the relative configuration of different groups. Similarity in
3
terms of multiplicity (ddd) and JH−H values between isomers
4b,c (with an anti relationship between C18 and C19 centers)
and hemicalide 1 could be observed, the other isomers 4a,d
having different multiplicities (dt).
Thus, it appeared that lactone 4b, with a cis relationship
between C19 and C24 and an anti orientation between C19
and C18, most closely matches the authentic natural product.
Comparison of 13C NMR data between isomers 4a−d and
hemicalide 1 was also performed but proved to be inconclusive
(Figure 7). An initial comparison brings out differences of more
Figure 5. NMR analysis of δ-lactones 4a−d: NOESY spectrum of δ-
lactone 4d.
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h, the mixture was warmed to 20 °C and stirred for 2 days. The
solution was filtered through a pad of Celite and concentrated in
vacuo. The residue was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 90/10) to give the expected (R)-methyl 3-
(benzyloxy)-2-methylpropanoate (15.8 g, 85%) as a yellow oil. 1H
NMR (400 MHz, CDCl3): δ 7.37−7.27 (m, 5H), 4.52 (s, 2H), 3.69 (s,
3H), 3.65 (dd, 1H, J = 9.3, 1.7 Hz), 3.49 (dd, 1H, J = 9.3, 4.9 Hz), 2.79
(qdd, 1H, J = 7.1, 4.9, 1.7 Hz), 1.18 (d, 3H, J = 7.1 Hz). 13C NMR
(100 MHz, CDCl3): δ 175.3 (C), 138.1 (C), 128.3 (CH), 127.6 (CH),
127.5 (CH), 73.0 (CH2), 71.9 (CH2), 51.7 (CH3), 40.1 (CH), 13.9
(CH3).
In a three-neck 500 mL round-bottom flask, powdered CeCl3·7H2O
(17.9 g, 48 mmol) was heated under vacuum (∼3 mmHg) at 160 °C
for 9 h with vigorous stirring, resulting in the formation of a white
mobile solid. The reaction flask was then flushed with argon and
cooled to room temperature before addition of THF (96 mL). The
resulting uniform white suspension was stirred overnight at room
temperature. After this time, this suspension was cooled to −78 °C
and (trimethylsilyl)methylmagnesium chloride (1.3 M solution in
THF, 37 mL, 48 mmol) was added dropwise, forming a brown-yellow
suspension which was stirred at −78 °C for 1 h. The (R)-methyl 3-
(benzyloxy)-2-methylpropanoate obtained above (2.0 g, 9.6 mmol) in
THF (10 mL) was then added dropwise, and the resulting mixture was
warmed gradually to room temperature. Upon complete consumption
of starting material, the gray solution was cooled to 0 °C and
quenched by addition of a saturated aqueous NH4Cl solution. The
organic layer was separated, and the aqueous layer was further
extracted with diethyl ether (2×). The combined organic extracts were
washed with saturated aqueous NaCl, dried over MgSO4, filtered, and
concentrated in vacuo, affording the crude (R)-4-(benzyloxy)-3-
methyl-1-(trimethylsilyl)-2-((trimethylsilyl)methyl)butan-2-ol (2.27 g,
67% yield). 1H NMR (300 MHz, CDCl3): δ 7.29−7.38 (m, 5H), 4.53
(s, 2H), 3.47 (dd, 1H, J = 9.1, 4.8 Hz), 3.21 (dd, 1H, J = 9.1, 8.1 Hz),
2.35−2.25 (m, 1H), 0.90−0.70 (m, 4H), 1.12 (d, 3H, J = 7.1 Hz), 0.02
(s, 18H).
To a solution of the above alcohol (2.3 g, 6.5 mmol) in hexane (15
mL) at room temperature was added Amberlyst-15 (∼0.5 equiv). The
mixture was stirred until complete consumption of the starting
material (maximum 1 h) before being filtered. The solvent was
removed under reduced pressure, and the residue was purified by flash
chromatography on silica gel (cyclohexane/diethyl ether 98/2) to
afford allylsilane (S)-6 (1.54 g, 90%). 1H NMR (300 MHz, CDCl3): δ
7.38−7.29 (m, 5H), 4.64 (s, 1H), 4.62 (s, 1H), 4.53 (s, 2H), 3.54 (dd,
1H, J = 9.2, 4.8 Hz), 3.26 (dd, 1H, J = 9.2, 8.1 Hz), 2.34−2.22 (m,
1H), 1.57 (m, 2H), 1.12 (d, 3H, J = 6.6 Hz), 0.03 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ 149.9 (C), 138.8 (C), 128.4 (CH), 127.6 (CH),
127.5 (CH), 106.5 (CH2), 75.0 (CH2), 72.9 (CH2), 40.9 (CH), 26.6
(CH2), 17.0 (CH3), −1.5 (CH3). HRMS (TOF MS ES+): calcd m/z
for C16H26OSi (M + Na+) 285.1651, found 285.1640. [α]2D2 = −12.5°
(c = 1.3, CHCl3). IR (film, cm−1): ν 3066, 2957, 2856, 1631, 1496,
1454, 1420, 1364, 1248, 1158, 1099, 958, 854, 735.
(2S,3S,6S)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-methyleneheptan-3-ol (7a). See ref 5a,b for the synthesis of
corresponding enantiomer ent-7a. Tin(IV) chloride (1.7 mL, 14.5
mmol) was slowly added to a cooled (−78 °C) solution of allylsilane 6
(3.8 g, 14.5 mmol) in CH2Cl2 (100 mL). The mixture was then stirred
at −78 °C for 1 h. After this time, a solution of aldehyde 56 (2.9 g, 14.5
mmol) in CH2Cl2 (5 mL) was added dropwise. The solution was
stirred for 50 min at −78 °C and quenched by addition of
triethylamine (∼3 mL). The mixture was partitioned between
CH2Cl2 and a saturated aqueous NaCl solution. The organic layer
was dried over MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 97.5/2.5 to 90/10) in order to yield the
desired homoallylic alcohol 7a (4.1 g, 74% yield) as a colorless oil. 1H
NMR (300 MHz, CDCl3): δ 7.35−7.27 (m, 5H), 4.93 (s, 1H), 4.91 (s,
1H), 4.51 (s, 2H), 3.97 (ddd, 1H, J = 8.7, 5.8, 2.9 Hz), 3.68 (dd, 1H, J
= 9.8, 4.9 Hz), 3.64 (dd, 1H, J = 9.8, 6.2 Hz), 3.50 (dd, 1H, J = 9.1, 7.1
Hz), 3.35 (dd, 1H, J = 9.1, 6.8 Hz), 2.50 (dqd, 1H, J = 7.1, 6.9, 6.8
Hz), 2.23−2.17 (m, 2H), 1.72 (qddd, 1H, J = 7.1, 6.2, 5.8, 4.9 Hz),
Figure 7. Δδ13C (ppm) between hemicalide 1 and lactones 20, 23, 26,
and 29 for carbons 19−24.
than 2.5 ppm in the chemical shift of C19 between 1 and δ-
lactone models. This phenomenon could be explained by the
C16−C17 double bond present in the natural molecule and
absent in the models. Differences in chemical shifts at C20,
C21, C22, and C23 between lactones 4a−d and hemicalide 1
are shown in the figure. However, the Δδ values are not
significant (most often less than 1 ppm); the four isomers have
quite similar profiles.
CONCLUSION
■
Despite significant technical challenges, the relative stereo-
chemistry of the C17−C25 δ-lactone fragment of hemicalide 1
has been elucidated. Prescreening of 16 putative stereoisomers
by NMR analysis and computational conformation studies
allowed us to focus our synthetic efforts on four likely
candidates. A common and concise strategy involving Dias
aldehyde allylation, Horner−Wadsworth−Emmons olefination,
and dihydroxylation reaction was used to synthesize the four
diastereomers of interest. On the basis of direct NMR spectral
comparisons with the natural product, the best correlations
were observed for δ-lactone 4b. The total synthesis of
hemicalide using intermediate 4b is ongoing and will be
reported in due course.
EXPERIMENTAL SECTION
■
General Considerations. All commercially available reagents and
solvents were used without further purification. For reactions requiring
anhydrous conditions, dry solvents were bought or freshly distillated
prior to use (THF and Et2O over the sodium/benzophenone system,
DCM and DMSO over calcium hydride, and MeOH and EtOH over
magnesium). Unless otherwise noted, experiments were carried out
under argon. Reactions were monitored by TLC (silica gel 60 F254
plates) with detection by use of UV light (254 and 366 nm) or a
phosphomolybdic acid solution in EtOH (5%) followed by heating at
100−110 °C. Purifications were performed by flash chromatography
on silica gel (silica gel 60, 40−63 μm). 1H NMR spectra were recorded
at 300, 400, and 500 MHz. Chemical shifts are given in ppm relative to
1
the residual H solvent signal (CDCl3, δ 7.26 ppm; CD3OD, δ 3.31
1
ppm) as the internal reference. H NMR assignments were confirmed
by 2D COSY spectra. The multiplicities given reflect apparent signal
patterns. 13C NMR spectra were recorded at 100 and 125 MHz.
Chemical shifts are given in ppm relative to the residual 13C solvent
signal (CDCl3, δ 77.0 ppm; CD3OD, δ 49.0 ppm). 13C NMR
assignments were confirmed by 2D HSQC spectra. Coupling
constants (J) are given in Hz for all NMR spectroscopic data. IR
spectra were recorded with a FT-IR spectrometer. Mass spectra were
recorded with ESI-MS and ESI-TOF-HRMS instruments.
δ-Lactone 4a. (S)-(4-(Benzyloxy)-3-methyl-2-methylenebutyl)-
trimethylsilane ((S)-6). See ref 5a,b for the synthesis of the
corresponding enantiomer (R)-6. A solution of methyl (R)-
(−)-methyl D-β-hydroxyisobutyrate (10 mL, 90.2 mmol) in an
anhydrous mixture of CH2Cl2 and cyclohexane (1/2, 120 mL) was
cooled to 0 °C and treated with crude benzyl trichloroimidate (27.3 g,
108.1 mmol) and triflic acid (800 μL, 9.0 mmol) over 10 min. After 3
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1.06 (d, 3H, J = 6.9 Hz), 0.93 (d, 3H, J = 7.1 Hz), 0.90 (s, 9H), 0.06
(s, 6H). 13C NMR (75 MHz, CDCl3): δ 149.3 (C), 138.4 (C), 128.3
(2CH), 127.6 (2CH), 127.5 (CH), 111.6 (CH2,), 74.6 (CH2), 73.0
(CH2), 71.2 (CH), 67.4 (CH2), 40.7 (CH2), 39.2 (CH), 39.1 (CH),
25.9 (3CH3), 18.2 (C), 17.5 (CH3), 10.5 (CH3), −5.5 (CH3), −5.6
(CH3). HRMS (TOF MS ES+): calcd m/z for C23H40O3Si (M + Na+)
415.2644, found 415.2662. [α]2D2 = +8.5° (c = 0.9, CHCl3). IR (film): ν
3482, 2955, 2928, 2856, 1639, 1472, 1389, 1255, 1093, 894, 735 cm−1.
(2S,3S,6S)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-methyleneheptan-3-yl Acrylate (9). Alcohol 7a (500 mg,
1.27 mmol) was dissolved in anhydrous CH2Cl2 (5 mL) at 0 °C. To
this solution were added successively triethylamine (355 μL, 2.55
mmol) and acryloyl chloride (154 μL, 1.91 mmol). The mixture was
warmed to room temperature, and the reaction was monitored by thin-
layer chromatography. Upon total consumption of the starting
material, the mixture was partitioned between CH2Cl2 (3×) and an
saturated aqueous NH4Cl solution. The combined organics were dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (cyclohexane/diethyl
ether 100/0 to 80/20) to afford ester 9 as a colorless oil (568 mg, 99%
yield). 1H NMR (300 MHz, CDCl3): δ 7.37−7.26 (m, 5H), 6.37 (dd,
1H, J = 17.2, 1.6 Hz), 6.10 (dd, 1H, J = 17.2, 10.4 Hz), 5.80 (dd, 1H, J
= 10.4, 1.6 Hz), 5.30 (td, 1H, J = 7.0, 3.4 Hz), 4.88 (m, 2H), 4.56 (d,
1H, J = 12.1 Hz), 4.51 (d, 1H, J = 12.1 Hz), 3.51 (dd, 1H, J = 9.3, 5.5
Hz), 3.50−3.42 (m, 2H), 3.36 (dd, 1H, J = 9.3, 7.5 Hz), 2.53 (dqd,
1H, J = 7.5, 7.0, 5.5 Hz), 2.41−2.35 (m, 2H), 1.99−1.88 (m, 1H), 1.12
(d, 3H, J = 7.0 Hz), 0.95 (d, 3H, J = 7.0 Hz), 0.90 (s, 9H), 0.03 (s,
6H). 13C NMR (75 MHz, CDCl3): δ 165.6 (C), 147.8 (C), 138.7 (C),
130.1 (CH2), 128.9 (2CH), 128.3 (2CH), 127.5 (CH), 127.4 (CH),
112.1 (CH2), 74.5 (CH2), 72.8 (CH2), 72.6 (CH), 64.9 (CH2), 39.1
(CH), 38.4 (CH), 37.6 (CH2), 25.9 (3CH3), 18.2 (C), 17.1 (CH3),
10.9 (CH3), −5.5 (2CH3). HRMS (TOF MS ES+) calcd m/z for
C26H42O4Si (M + Na+) 469.2750, found 469.2764. [α]2D2 = +2.2° (c =
1.1, CHCl3). IR (film): ν 2929, 1723, 1193, 1095, 837 cm−1.
temperature overnight. The solvent was removed under reduced
pressure, and the crude mixture was purified by flash chromatography
on silica gel (cyclohexane/ethyl acetate 60/40 to 40/60) to afford
ketone 11a as a colorless oil (3.11 g, 91% yield). 1H NMR (300 MHz,
CDCl3): δ 7.34−7.26 (m, 5H), 5.43 (ddd, 1H, J = 9.8, 7.1, 4.1 Hz),
4.49 (d, 1H, J = 11.9 Hz), 4.44 (d, 1H, J = 11.9 Hz), 4.20−4.07 (m,
4H), 3.58 (dd, 1H, J = 9.0, 7.8 Hz), 3.55−3.44 (m, 3H), 2.90−2.75
(m, 5H), 1.96−1.87 (m, 1H), 1.32 (m, 6H), 1.06 (d, 3H, J = 7.0 Hz),
0.89 (d, 3H, J = 6.9 Hz), 0.88 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H). 13C
2
NMR (75 MHz, CDCl3): δ 209.7 (C), 164.9 (d, C, JC−P = 6.4 Hz),
138.0 (C), 128.3 (2CH), 127.7 (2CH), 127.6 (CH), 73.3 (CH2), 72.2
2
(CH2), 71.9 (CH), 64.5 (CH2), 62.6 (d, 2CH2, JC−P = 6.4 Hz), 46.5
(CH), 44.1 (CH2), 38.7 (CH), 34.3 (d, CH2, 1JC−P = 133.7 Hz), 25.8
3
(3CH3), 18.2 (C), 16.3 (d, 2CH3, JC−P = 7.5 Hz), 13.2 (CH3), 11.3
(CH3), −5.5 (2CH3). HRMS (TOF MS ES+): calcd m/z for
C28H49O8PSi (M + Na+) 595.2832, found 595.2864. [α]2D2 = −15.6°
(c = 2.6, CHCl3). IR (film): ν 2931, 2856, 1736, 1259, 1098, 1027,
972, 837 cm−1.
(S)-4-((S)-1-(Benzyloxy)propan-2-yl)-6-((S)-1-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-5,6-dihydropyran-2-one (8a).
Ketone 11a (500 mg, 0.87 mmol) was dissolved in THF (20 mL)
at 40 °C, and freshly prepared lithium tert-butoxide (0.5 M solution in
THF, 1.57 mL, 0.79 mmol) was added very slowly. After the addition,
the mixture was stirred for 15 min at 30−40 °C, before being
quenched by addition of saturated aqueous NH4Cl. The mixture was
extracted with ethyl acetate (2×), the combined organic layers were
dried over MgSO4, and the solvent was removed in vacuo. The crude
product was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 95/5 to 80/20) to yield lactone 8a (256
1
mg, 70% yield) as a colorless oil. H NMR (300 MHz, CDCl3): δ
7.37−7.26 (m, 5H), 5.83 (d, 1H, J = 2.3 Hz), 4.51 (d, 1H, J = 12.0
Hz), 4.46 (d, 1H, J = 12.0 Hz), 4.42 (ddd, 1H, J = 12.5, 4.4, 3.7 Hz),
3.63 (dd, 1H, J = 10.2, 6.6 Hz), 3.58 (dd, 1H, J = 10.2, 5.5 Hz), 3.48−
3.44 (m, 2H), 2.73−2.61 (m, 1H), 2.42 (ddd, 1H, J = 17.4, 12.5, 2.3
Hz), 2.20 (dd, 1H, J = 17.4, 3.7 Hz), 1.87 (m, 1H), 1.12 (d, 3H, J = 7.0
Hz), 0.99 (d, 3H, J = 7.0 Hz), 0.87 (s, 9H), 0.04 (s, 6H). 13C NMR
(75 MHz, CDCl3): δ 165.9 (C), 163.5 (C), 137.8 (C), 128.5 (2CH),
127.8 (2CH), 127.7 (CH), 115.6 (CH), 77.9 (CH), 73.2 (CH2), 72.6
(CH2), 64.2 (CH2), 40.4 (CH), 39.5 (CH), 29.4 (CH2), 25.9 (3CH3),
18.2 (C), 15.6 (CH3), 11.6 (CH3), −5.5 (2CH3). HRMS (TOF MS
ES+): calcd m/z for C24H38O4Si (M + Na+) 441.2437, found 441.2442.
[α]2D2 = −42.7° (c = 0.6, CHCl3). IR (film): ν 2928, 2855, 1720, 1454,
1250, 1097, 836 cm−1.
(2S,3S,6S)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-methyleneheptan-3-yl 2-(Diethoxyphosphoryl)acetate
(10a). Diethylphosphonoacetic acid (205 μL, 1.27 mmol), DMAP
(62 mg, 0.51 mmol), and DCC (263 mg, 1.27 mmol) were
successively added to a solution of alcohol 7a (200 mg, 0.51 mmol)
in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for
30 min and then concentrated in vacuo. The residue was taken up in a
1/1 mixture of n-hexane/diethyl ether and then filtered through a pad
of Celite. The resulting yellow liquid was concentrated under reduced
pressure. The crude ester was purified by flash chromatography on
silica gel (cyclohexane/ethyl acetate 80/20 to 20/80) to afford
(2R,6R,E)-1-(Benzyloxy)-7-((tert-butyldimethylsilyl)oxy)-2,6-dime-
1
thylhept-4-en-3-one (12a). H NMR (300 MHz, CDCl3): δ 7.35−
1
phosphonate 17 (291 mg, 100% yield) as a yellow oil. H NMR (300
7.26 (m, 5H), 6.85 (dd, 1H, J = 15.9, 7.3 Hz), 6.19 (dd, 1H, J = 15.9,
1.3 Hz), 4.52 (d, 1H, J = 12.2 Hz), 4.47 (d, 1H, J = 12.2 Hz), 3,71 (dd,
1H, J = 9.1, 7.2 Hz), 3.55 (dd, 1H, J = 9.6, 6.4 Hz), 3.52 (dd, 1H, J =
9.6, 6.3 Hz), 3.45 (dd, 1H, J = 9.1, 6.0 Hz), 3.21−3.09 (m, 1H), 2.56−
2.45 (m, 1H), 1.12 (d, 3H, J = 7.0 Hz), 1.05 (d, 3H, J = 6.8 Hz), 0.88
(s, 9H), 0.03 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 202.3 (C), 150.0
(CH), 138.2 (C), 128.7 (CH), 128.3 (2CH), 127.6 (3CH), 73.2
(CH2), 72.1 (CH2), 66.9 (CH2), 43.9 (CH), 39.4 (CH), 25.8 (CH3),
18.3 (C), 15.6 (CH3), 14.2 (CH3), −5.4 (2CH3). HRMS (TOF MS
ES+): calcd m/z for C22H36O3Si (M + Na+) 399.2331, found 399.2320.
(3R,4S,6S)-4-((R)-1-(Benzyloxy)propan-2-yl)-6-((S)-1-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-3,4-dihydroxy-tetrahydropyr-
an-2-one (4a). Potassium osmate(VI) dihydrate (11 mg, 0.03 mmol)
was added to a solution of lactone 8a (250 mg, 0.60 mmol) in acetone
(2 mL) and H2O (2 mL) at room temperature. After stirring for 10
min, NMO (161 mg, 1.37 mmol) was added and the mixture was
stirred overnight at room temperature. After this time, the dark brown
solution was partitioned between ethyl acetate and saturated aqueous
NaCl. The organic layer was dried over MgSO4 and concentrated
under reduced pressure. Purification by flash chromatography on silica
gel (cyclohexane/ethyl acetate 90:10 to 50:50) afforded required diol
MHz, CDCl3): δ 7.34−7.27 (m, 5H), 5.27 (td, 1H, J = 7.0, 3.2 Hz),
4.88−4.85 (m, 2H), 4.53 (d, 1H, J = 12.2 Hz), 4.48 (d, 1H, J = 12.2
Hz), 4.20−4.03 (m, 4H), 3.48 (dd, 1H, J = 9.2, 5.6 Hz), 3.47 (dd, 1H,
J = 10.0, 7.2 Hz), 3.43 (dd, 1H, J = 10.0, 6.2 Hz), 3.34 (dd, 1H, J = 9.2,
7.4 Hz), 2.92 (dd, 1H, J = 14.4 Hz, 1JP−H = 21.6 Hz), 2.89 (dd, 1H, J =
14.4 Hz, 1JP−H = 21.6 Hz), 2.48 (dqd, 1H, J = 7.4, 6.9, 5.6 Hz), 2.35 (d,
2H, J = 7.0 Hz), 1.87 (m, 1H), 1.33 (t, 6H, J = 7.1 Hz), 1.09 (d, 3H, J
= 6.9 Hz), 0.92 (d, 3H, J = 6.9 Hz), 0.87 (s, 9H), 0.01 (s, 6H). 13C
2
NMR (75 MHz, CDCl3): δ 165.2 (d, C, JC−P = 6.2 Hz), 147.6 (C),
128.3 (2CH), 127.5 (2CH), 127.4 (CH), 112.1 (CH2), 74.5 (CH2),
2
73.7 (CH), 72.8 (CH2), 64.8 (CH2), 62.5 (d, 2CH2, JC−P = 6.1 Hz),
1
39.0 (CH), 38.3 (CH), 37.6 (CH2), 34.4 (d, CH2, JC−P = 134.2 Hz),
3
25.8 (3CH3), 18.2 (C), 17.1 (CH3), 16.3 (d, 2CH3, JC−P = 6.2 Hz),
10.6 (CH3), −5.5 (2CH3). HRMS (TOF MS ES+): calcd m/z for
C29H51O7PSi (M + Na+) 593.3039, found 593.3052. [α]2D2 = +2.4° (c =
2.2, CHCl3). IR (film): ν 2930, 2856, 1735, 1271, 1098, 1027, 971,
832 cm−1.
(2S,3S,6R)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-oxoheptan-3-yl 2-(Diethoxyphosphoryl)acetate (11a). A
stream of ozone was bubbled to a cooled (−78 °C) solution of
phosphonate 10a (3.43 g, 6.01 mmol) and Sudan III (small amount)
in CH2Cl2 (80 mL) until the pink solution became colorless (ca. 5−10
min). Triphenylphosphine (2.36 g, 9.01 mmol) was then cautiously
added, the cold bath was removed, and the mixture was stirred at room
1
4a (263 mg, 97% yield) as a slightly yellow oil. H NMR (500 MHz,
CD3OD): δ 7.34−7.27 (m, 5H), 4.76 (dt, 1H, J = 12.0, 3.9 Hz), 4.49
(s, 2H), 4.23 (s, 1H), 3.61 (dd, 1H, J = 10.1, 7.1 Hz), 3.58 (dd, 1H, J =
10.1, 6.5 Hz), 3.56 (dd, 1H, J = 9.7, 5.8 Hz), 3.51 (dd, 1H, J = 9.7, 5.5
860
dx.doi.org/10.1021/jo302440a | J. Org. Chem. 2013, 78, 855−864

The Journal of Organic Chemistry
Article
Hz), 2.31 (qdd, 1H, J = 7.0, 5.8, 5.5 Hz), 1.98 (dd, 1H, J = 14.5, 12.0
Hz), 1.84 (dd, 1H, J = 14.5, 3.9 Hz), 1.76 (m, 1H), 1.05 (d, 3H, J = 7.0
Hz), 0.91 (d, 3H, J = 6.9 Hz), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR
(125 MHz, CD3OD): δ 176.8 (C), 139.6 (C), 129.4 (2CH), 128.9
(2CH), 128.7 (CH), 78.9 (CH), 75.4 (C), 74.3 (CH2), 73.4 (CH2),
73.2 (CH), 65.7 (CH2), 41.3 (CH), 40.2 (CH), 33.6 (CH2), 26.4
(3CH3), 19.1 (C), 12.1 (CH3), 11.4 (CH3), −5.3 (2CH3). HRMS
(TOF MS ES+): calcd m/z for C24H40O6Si (M + Na+) 475.2492,
found 475.2482. [α]2D2 = +15.1° (c = 3.7, CHCl3). IR (film): ν 3448,
2955, 2928, 2856, 1729, 1471, 1462, 1252, 1102, 857, 777 cm−1.
δ-Lactone 4b. (2R,3S,6S)-7-(Benzyloxy)-1-((tert-
butyldimethylsilyl)oxy)-2,6-dimethyl-5-methyleneheptan-3-ol (7b).
See ref 5a,b for the synthesis of corresponding enantiomer ent-7b.
Tin(IV) chloride (117 μL, 1.0 mmol) was slowly added to a cooled
(−78 °C) solution of allylsilane (S)-6 (262 mg, 1.0 mmol) in CH2Cl2
(8 mL). The mixture was then stirred at −78 °C for 60 min. After this
time, a solution of aldehyde (R)-56 (202 mg, 1.0 mmol, 1.0 equiv) in
CH2Cl2 (3 mL) was added dropwise. The solution was stirred for 50
min at −78 °C and quenched by addition of triethylamine (∼0.5 mL).
The mixture was partitioned between CH2Cl2 and a saturated aqueous
NaCl solution. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel (cyclohexane/ethyl acetate 97.5/
2.5 to 90/10) in order to yield homoallylic alcohol 7b (334 mg, 85%
a cooled (−78 °C) solution of the preceding phosphonate 10b (2.18 g,
3.82 mmol) and Sudan III (small amount) in CH2Cl2 (55 mL) was
bubbled a stream of ozone until the pink solution became colorless
(ca. 5−10 min). Triphenylphosphine (1.50 g, 5.73 mmol) was then
cautiously added, the cold bath was removed, and the mixture was
stirred at room temperature overnight. The solvent was removed
under reduced pressure, and the crude mixture was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 60/40 to 40/
60) to afford the desired ketone 11b as a colorless oil (2.14 g, 98%
1
yield). H NMR (300 MHz, CDCl3): δ 7.36−7.25 (m, 5H), 5.44 (dt,
1H, J = 7.4, 4.8 Hz), 4.49 (d, 1H, J = 12.2 Hz), 4.44 (d, 1H, J = 12.2
Hz), 4.19−4.08 (m, 4H), 3.60 (dd, 1H, J = 9.2, 7.7 Hz), 3.57 (dd, 1H,
J = 10.2, 6.1 Hz), 3.47 (dd, 1H, J = 10.2, 5.8 Hz), 3.44 (dd, 1H, J = 9.2,
5.6 Hz), 2.90−2.80 (m, 5H), 2.04 (m, 1H), 1.33 (t, 6H, J = 7.0 Hz),
1.06 (d, 3H, J = 7.0 Hz), 0.91 (d, 3H, J = 7.0 Hz), 0.87 (s, 9H), 0.02
(s, 6H). 13C NMR (75 MHz, CDCl3): δ 209.5 (C), 164.8 (d, C, 2JC−P
= 6.4 Hz), 138.0 (C), 128.4 (2CH), 127.6 (3CH), 73.2 (CH2), 72.8
2
(CH), 71.9 (CH2), 64.5 (CH2), 62.5 (d, 2CH2, JC−P = 6.4 Hz), 46.7
(CH), 43.2 (CH2), 38.6 (CH), 34.3 (d, CH2, 1JC−P = 133.6 Hz), 25.8
3
(3CH3), 18.2 (C), 16.3 (d, 2CH3, JC−P = 7.6 Hz), 13.3 (CH3), 12.4
(CH3), −5.5 (CH3), −5.6 (CH3). HRMS (TOF MS ES+): calcd m/z
for C28H49O8PSi (M + Na+) 595.2832, found 595.2821. [α]2D2
=
−11.2° (c = 1.7, CHCl3). IR (film): ν 2931, 2925, 2856, 1734, 1259,
1096, 1027, 972, 841, 734 cm−1.
1
yield) as a colorless oil. H NMR (300 MHz, CDCl3): δ 7.35−7.27
(S)-4-((S)-1-(Benzyloxy)propan-2-yl)-6-((R)-1-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-5,6-dihydropyran-2-one (8b).
Ketone 11b (500 mg, 0.87 mmol) was dissolved in THF (20 mL)
at 40 °C, and freshly prepared lithium tert-butoxide (0.5 M solution in
THF, 1.57 mL, 0.79 mmol) was added very slowly. After the addition,
the mixture was stirred for 15 min at 30−40 °C, before being
quenched by addition of saturated aqueous NH4Cl. The mixture was
extracted with ethyl acetate (2×), the combined organic layers were
dried over MgSO4, and the solvent was removed in vacuo. The crude
product was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 95/5 to 80/20), and lactone 8b (263
(m, 5H), 4.95 (s, 1H), 4.92 (s, 1H), 4.51 (s, 2H), 3.76−3.71 (m, 1H),
3.71 (dd, 1H, J = 10.1, 3.7 Hz), 3.64 (dd, 1H, J = 10.1, 5.9 Hz), 3.51
(dd, 1H, J = 9.1, 7.4 Hz), 3.37 (dd, 1H, J = 9.1, 6.6 Hz), 2.49 (dqd, 1H,
J = 7.4, 6.9, 6.6 Hz), 2.32 (dd, 1H, J = 14.0, 3.3 Hz), 2.10 (dd, 1H, J =
14.0, 9.3 Hz), 1.80−1.69 (m, 1H), 1.06 (d, 3H, J = 6.9 Hz), 0.92 (d,
3H, J = 7.0 Hz), 0.90 (s, 9H), 0.06 (s, 6H). 13C NMR (75 MHz,
CDCl3): δ 149.5 (C), 138.7 (C), 128.3 (2CH), 127.6 (2CH), 127.5
(CH), 111.7 (CH2), 74.6 (CH2), 73.0 (CH2), 72.2 (CH), 66.4 (CH2),
41.2 (CH2), 40.1 (CH), 38.9 (CH), 25.9 (3CH3), 18.2 (C), 17.6
(CH3), 13.6 (CH3), −5.5 (2CH3). HRMS (TOF MS ES+): calcd m/z
for C23H40O3Si (M + Na+) 415.2644, found 415.2632. [α]2D2 = +8.8° (c
= 0.6, CHCl3). IR (film): ν 3482, 2954, 2928, 2856, 1640, 1472, 1392,
1328, 1255, 1093, 894 cm−1.
1
mg, 72% yield) was obtained as a colorless oil. H NMR (300 MHz,
CDCl3): δ 7.37−7.26 (m, 5H), 5.83 (d, 1H, J = 1.9 Hz), 4.51 (d, 1H, J
= 12.1 Hz), 4.47 (d, 1H, J = 12.1 Hz), 4.35 (ddd, 1H, J = 11.9, 6.5, 4.3
Hz), 3.68 (dd, 1H, J = 9.8, 5.2. Hz), 3.62 (dd, 1H, J = 9.8, 5.5 Hz),
3.50−3.43 (m, 2H), 2.71−2.62 (m, 1H), 2.35 (ddd, 1H, J = 17.4, 11.9,
1.9 Hz), 2.20 (dd, 1H, J = 17.4, 4.3 Hz), 2.02 (qddd, 1H, J = 7.0, 6.5,
5.5, 5.2 Hz), 1.11 (d, 3H, J = 7.0 Hz), 0.95 (d, 3H, J = 7.0 Hz), 0.87 (s,
9H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 165.6
(C), 163.2 (C), 137.8 (C), 128.5 (2CH), 127.8 (2CH), 127.7 (CH),
115.6 (CH), 78.7 (CH), 73.2 (CH2), 72.6 (CH2), 63.9 (CH2), 40.4
(CH), 39.3 (CH), 28.4 (CH2), 25.9 (3CH3), 18.2 (C), 15.6 (CH3),
12.4 (CH3), −5.5 (2CH3). HRMS (TOF MS ES+): calcd m/z for
C24H38O4Si (M + Na+) 441.2437, found 441.2452. [α]2D2 = +35.1° (c =
0.1, CHCl3). IR (film): ν 2932, 2848, 1725, 1718, 1455, 1250, 1097,
937, 836 cm−1.
(2R,3S,6S)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-methyleneheptan-3-yl 2-(Diethoxyphosphoryl)acetate
(10b). Diethylphosphonoacetic acid (1.54 mL, 9.55 mol), DMAP
(0.47 g, 3.82 mmol) and DCC (1.97 g, 9.55 mmol) were successively
added to a solution of alcohol 7b (1.50 g, 3.82 mmol) in CH2Cl2 (50
mL) at room temperature. The mixture was stirred for 30 min and
then concentrated in vacuo. The residue was taken up in a 1/1 mixture
of n-hexane and diethyl ether and the solution then filtered through a
pad of Celite. The resulting yellow liquid was concentrated under
reduced pressure. The crude ester was purified by flash chromatog-
raphy on silica gel (cyclohexane/ethyl acetate 80:20 to 20:80) to afford
desired diethoxyphosphorylacetate 10b (2.18 g, 100% yield) as a
1
yellow oil. H NMR (300 MHz, CDCl3): δ 7.35−7.27 (m, 5H), 5.18
(3R,4S,6S)-4-((R)-1-(Benzyloxy)propan-2-yl)-6-((R)-1-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-3,4-dihydroxytetrahydropyran-
2-one (4b). Potassium osmate(VI) dihydrate (11 mg, 0.03 mmol) was
added to a solution of lactone 8b (250 mg, 0.60 mmol) in acetone (2
mL) and H2O (2 mL) at room temperature. After the mixture was
stirred for 10 min, NMO (160 mg, 1.37 mmol) was added and the
mixture was stirred overnight at room temperature. After this time, the
dark brown solution was partitioned between ethyl acetate (2×) and
saturated aqueous NaCl. The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. Purification by flash
chromatography on silica gel (cyclohexane/ethyl acetate 90/10 to 50/
50) afforded the desired diol 4b (251 mg, 93% yield) as a slightly
yellow oil. 1H NMR (500 MHz, CD3OD): δ 7.34−7.26 (m, 5H), 4.62
(ddd, 1H, J = 10.7, 6.7, 4.9 Hz), 4.49 (s, 2H), 4.24 (s, 1H), 3.68 (dd,
1H, J = 10.1, 5.2 Hz), 3.64 (dd, 1H, J = 10.1, 5.2 Hz), 3.57 (dd, 1H, J =
9.7, 5.8 Hz), 3.49 (dd, 1H, J = 9.7, 5.5 Hz), 2.34−2.28 (m, 1H), 1.93−
1.84 (m, 3H), 1.04 (d, 3H, J = 7.1 Hz), 0.92 (d, 3H, J = 7.0 Hz), 0.90
(s, 9H), 0.06 (s, 6H). 13C NMR (125 MHz, CD3OD): δ 176.7 (C),
139.6 (C), 129.4 (2CH), 128.9 (2CH), 128.7 (CH), 80.0 (CH), 75.3
(C), 74.2 (CH2), 73.4 (CH2), 73.2 (CH), 65.2 (CH2), 41.6 (CH),
(ddd, 1H, J = 8.9, 5.4, 3.2 Hz), 4.85 (s, 1H), 4.83 (s, 1H), 4.53 (d, 1H,
J = 11.9 Hz), 4.48 (d, 1H, J = 11.9 Hz), 4.19−4.09 (m, 4H), 3.61 (dd,
1H, J = 10.1, 6.2 Hz), 3.48 (dd, 1H, J = 9.3, 5.7 Hz), 3.46 (dd, 1H, J =
10.1, 4.7 Hz), 3.32 (dd, 1H, J = 9.3, 7.5 Hz), 2.92 (dd, 1H, J = 14.4 Hz,
1
1JP−H = 21.4 Hz), 2.87 (dd, 1H, J = 14.4 Hz, JP−H = 21.4 Hz), 2.46
(dqd, 1H, J = 7.5, 7.0, 5.7 Hz), 2.38 (dd, 1H, J = 14.8, 3.2 Hz), 2.24
(dd, 1H, J = 14.8, 8.9 Hz), 2.00 (m, 1H), 1.33 (t, 6H, J = 7.1 Hz), 1.08
(d, 3H, J = 7.0 Hz), 0.93 (d, 3H, J = 7.0 Hz), 0.89 (s, 9H), 0.04 (s,
3H), 0.02 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 165.1 (d, C, 2JC−P
=
6.3 Hz), 147.8 (C), 138.6 (C), 128.3 (2CH), 127.5 (2CH), 127.4
(CH), 111.7 (CH2), 75.5 (CH), 74.4 (CH2), 72.8 (CH2), 64.4 (CH2),
2
62.5 (d, 2CH2, JC−P = 6.3 Hz), 39.4 (CH), 39.0 (CH), 36.1 (CH2),
34.3 (d, CH2, 1JC−P = 134.3 Hz), 25.9 (3CH3), 18.2 (C), 17.2 (CH3),
3
16.3 (d, 2CH3, JC−P = 6.4 Hz), 12.6 (CH3), −5.5 (2CH3). HRMS
(TOF MS ES+): calcd m/z for C29H51O7PSi (M + Na+) 593.3039,
found 593.3022. [α]2D2 = −1.5° (c = 0.8, CHCl3). IR (film): ν 2930,
2925, 2856, 1736, 1271, 1098, 1012, 971, 832, 735 cm−1.
(2R,3S,6R)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-oxoheptan-3-yl 2-(Diethoxyphosphoryl)acetate (11b). To
861
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Article
40.2 (CH), 32.9 (CH2), 26.4 (3CH3), 19.1 (C), 12.6 (CH3), 12.1
(CH3), −5.3 (CH3), −5.4 (CH3). HRMS (TOF MS ES+): calcd m/z
for C24H40O6Si (M + Na+) 475.2492, found 475.2487. [α]2D2 = +7.8° (c
= 1.2, CHCl3). IR (film): ν 3445, 2955, 2925, 2855, 1729, 1471, 1461,
1252, 1104, 854, 777, 734 cm−1.
(qddd, 1H, J = 6.9, 6.6, 6.0, 5.0 Hz), 2.37 (dd, 1H, J = 14.3, 3.6 Hz),
2.25 (dd, 1H, J = 14.3, 9.7 Hz), 1.96 (m, 1H), 1.35−1.30 (m, 6H),
1.06 (d, 3H, J = 6.9 Hz), 0.90 (d, 3H, J = 6.9 Hz), 0.88 (s, 9H), 0.02
(s, 6H). 13C NMR (75 MHz, CDCl3): δ 165.0 (d, C, 2JC−P = 6.3 Hz),
147.9 (C), 138.5 (C), 128.3 (2CH), 127.5 (2CH), 127.4 (CH), 111.9
(CH2), 75.0 (CH), 74.9 (CH), 72.9 (CH2), 64.4 (CH2), 62.4 (d,
δ-Lactone 4c. (2S,3R,6S)-7-(Benzyloxy)-1-((tert-
butyldimethylsilyl)oxy)-2,6-dimethyl-5-methyleneheptan-3-ol (7c).
Alcohol 7a (2.0 g, 5.1 mmol) was dissolved in THF (60 mL) at 0
°C. Triphenylphosphine (2.7 g, 10.2 mmol), p-nitrobenzoic acid (1.7
g, 10.2 mmol), and DIAD (2.0 mL, 10.2 mmol) were successively
added to the solution. The mixture was stirred at 0 °C for 30 min then
at room temperature for 2 days. After this time, saturated aqueous
NH4Cl was added and the mixture was extracted with CH2Cl2 (2×).
The combined organics were dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography on silica gel (cyclo-
hexane/diethyl ether 100/0 to 95/5) provided (2S,3R,6S)-7-
(benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-dimethyl-5-methyle-
neheptan-3-yl 4-nitrobenzoate (1.6 g, 58% yield). 1H NMR (400 MHz,
CDCl3): δ 8.25 (d, 2H, J = 8.6 Hz), 8.15 (d, 2H, J = 8.6 Hz), 7.35−
7.26 (m, 5H), 5.43 (ddd, 1H, J = 10.1, 5.4, 3.1 Hz), 4.85 (s, 1H), 4.81
(s, 1H), 4.47 (s, 2H), 3.61 (dd, 1H, J = 10.2, 6.2 Hz), 3.55 (dd, 1H, J =
10.2, 5.9 Hz), 3.50 (dd, 1H, J = 9.0, 6.0 Hz), 3.42 (dd, 1H, J = 9.0, 6.1
Hz), 2.56−2.49 (m, 2H), 2.41 (dd, 1H, J = 14.5, 10.1 Hz), 2.10 (qddd,
1H, J = 7.0, 6.2, 5.9, 5.4 Hz), 1.06 (d, 3H, J = 6.8 Hz), 0.98 (d, 3H, J =
7.0 Hz), 0.88 (s, 9H,), 0.02 (s, 6H). 13C NMR (75 MHz, CDCl3): δ
163.9 (C), 150.3 (C), 148.0 (C), 138.5 (C), 136.2 (C), 130.6 (2CH),
128.3 (2CH), 127.5 (2CH), 127.4 (CH), 123.5 (2CH), 112.3 (CH2),
75.3 (CH), 75.1 (CH2), 72.9 (CH2), 64.6 (CH2), 39.7 (CH), 38.9
(CH), 37.5 (CH2), 25.9 (3CH3), 18.2 (C), 16.9 (CH3), 12.9 (CH3),
−5.5 (2CH3). HRMS (TOF MS ES+): calcd m/z for C30H43NO6Si (M
+ Na+) 564.2757, found 564.2768. [α]D22 = +1.9° (c = 1.4, CHCl3). IR
(film): ν 2929, 2856, 1735, 1704, 1652, 1257, 1097, 834 cm−1.
Potassium carbonate (319 mg, 2.31 mmol) was added to a solution
of the previous ester (1.25 g, 2.31 mmol) in methanol (40 mL) at
room temperature. The mixture was stirred overnight, before being
quenched by addition of saturated aqueous NH4Cl and extracted with
CH2Cl2 (2×). The combined organic layers were dried over MgSO4
and concentrated under reduced pressure. The crude alcohol 13 was
purified by flash chromatography on silica gel (cyclohexane/ethyl
acetate 97.5/2.5 to 90/10) but could not be separated from the p-
nitrobenzoic acid methyl ester byproduct.
2
2CH2, JC−P = 6.2 Hz), 39.2 (CH), 38.8 (CH), 37.1 (CH2), 34.2 (d,
1
CH2, JC−P = 134.9 Hz), 25.8 (CH3), 18.2 (C), 16.9 (CH3), 16.3 (d,
2CH3, 3JC−P = 6.2 Hz), 12.7 (CH3), −5.4 (CH3), −5.5 (CH3). HRMS
(TOF MS ES+): calcd m/z for C29H51O7PSi (M + Na+) 593.3039,
found 593.3064. [α]2D2 = −7.9° (c = 2.5, CHCl3). IR (film): ν 2930,
2927, 1732, 1274, 1098, 1012, 971, 837 cm−1.
(2S,3R,6R)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-oxoheptan-3-yl 2-(Diethoxyphosphoryl)acetate (11c). To
a cooled (−78 °C) solution of the previous phosphonate 10c (1.25 g,
2.19 mmol) and Sudan III (small amount) in CH2Cl2 (30 mL) was
bubbled a stream of ozone until the pink solution became colorless
(ca. 5−10 min). Triphenylphosphine (0.86 g, 3.29 mmol) was then
cautiously added, the cold bath was removed and the mixture was
stirred at room temperature overnight. The solvent was removed
under reduced pressure and the crude mixture was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 60/40 to 40/
1
60) to afford ketone 11c (1.1 g, 88% yield). H NMR (300 MHz,
CDCl3): δ 7.34−7.26 (m, 5H), 5.46−5.39 (m, 1H), 4.49 (d, 1H, J =
12.5 Hz), 4.44 (d, 1H, J = 12.5 Hz), 4.19−4.09 (m, 4H), 3.62−3.54
(m, 2H), 3.52−3.42 (m, 2H), 2.92−2.70 (m, 5H), 2.05−1.97 (m, 1H),
1.35−1.29 (m, 6H), 1.05 (d, 3H, J = 7.0 Hz), 0.90 (d, 3H, J = 7.1 Hz),
0.87 (s, 9H), 0.02 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 209.9 (C),
2
164.9 (d, C, JC−P = 7.0 Hz), 138.0 (C), 128.4 (2CH), 127.6 (2CH),
127.5 (CH), 73.2 (CH2), 72.9 (CH), 72.1 (CH2), 64.5 (CH2), 62.5 (d,
2
2CH2, JC−P = 6.4 Hz), 46.5 (CH), 43.2 (CH2), 38.5 (CH), 34.2 (d,
1
CH2, JC−P = 133.9 Hz), 25.8 (3CH3), 18.2 (C), 16.3 (d, 2CH3, 3JC−P
= 6.3 Hz), 13.2 (CH3), 12.4 (CH3), −5.5 (CH3), −5.6 (CH3). HRMS
(TOF MS ES+): calcd m/z for C28H49O8PSi (M + Na+) 595.2832,
found 595.2854. [α]2D2 = −4.3° (c = 1.7, CHCl3). IR (film): ν 2931,
2856, 1736, 1259, 1098, 1027, 972, 837 cm−1.
(R)-4-((S)-1-(Benzyloxy)propan-2-yl)-6-((S)-1-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-5,6-dihydropyran-2-one (8c).
Ketone 11c (500 mg, 0.87 mmol) was dissolved in THF (20 mL)
at 40 °C, and freshly prepared lithium tert-butoxide (0.5 M solution in
THF, 1.57 mL, 0.79 mmol) was added very slowly. After the addition,
the mixture was stirred for 15 min at 30−40 °C, before being
quenched by addition of saturated aqueous NH4Cl. The mixture was
extracted with ethyl acetate (2×), the combined organic layers were
dried over MgSO4, and the solvent was removed in vacuo. The crude
product was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 95/5 to 80/20), and lactone 8c (256 mg,
(2S,3R,6S)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-methyleneheptan-3-yl 2-(Diethoxyphosphoryl)acetate
(10c). Potassium carbonate (319 mg, 2.31 mmol) was added to a
solution of the previous (2S,3R,6S)-7-(benzyloxy)-1-((tert-
butyldimethylsilyl)oxy)-2,6-dimethyl-5-methyleneheptan-3-yl 4-nitro-
benzoate (1.25 g, 2.31 mmol) in methanol (40 mL) at room
temperature. The mixture was stirred overnight, before being
quenched by addition of saturated aqueous NH4Cl and extracted
with CH2Cl2 (2×). The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The crude alcohol
7c was purified by flash chromatography on silica gel (cyclohexane/
ethyl acetate 97.5/2.5 to 90/10) but could not be separated from the
p-nitrobenzoic acid methyl ester byproduct.
1
70% yield) was obtained. H NMR (300 MHz, CDCl3): δ 7.35−7.26
(m, 5H), 5.84 (d, 1H, J = 2.3 Hz), 4.51 (d, 1H, J = 12.2 Hz), 4.47 (d,
1H, J = 12.2 Hz), 4.34 (ddd, 1H, J = 12.2, 6.1, 3.5 Hz), 3.68 (dd, 1H, J
= 10.1, 5.4 Hz), 3.63 (dd, 1H, J = 10.1, 5.5 Hz), 3.48−3.43 (m, 2H),
2.72−2.63 (m, 1H), 2.40 (ddd, 1H, J = 17.6, 12.2, 2.3 Hz), 2.20 (dd,
1H, J = 17.6, 3.5 Hz), 2.02 (qddd, 1H, J = 7.0, 6.1, 5.5, 5.4 Hz), 1.12
(d, 3H, J = 6.9 Hz), 0.95 (d, 3H, J = 7.0 Hz), 0.87 (s, 9H), 0.03 (s,
3H), 0.02 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 165.6 (C), 163.1
(C), 137.8 (C), 128.4 (2CH), 127.8 (2CH), 127.6 (CH), 115.8 (CH),
78.6 (CH), 73.2 (CH2), 72.7 (CH2), 63.8 (CH2), 40.7 (CH), 39.3
(CH), 28.6 (CH2), 25.8 (3CH3), 18.2 (C), 15.0 (CH3), 12.4 (CH3),
−5.5 (CH3), −5.6 (CH3). HRMS (TOF MS ES+): calcd m/z for
C24H38O4Si (M + Na+) 441.2437, found 441.2441. [α]2D2 = +40.3° (c =
1.4, CHCl3). IR (film): ν 2926, 2855, 1720, 1454, 1250, 1097, 836
cm−1.
Diethylphosphonoacetic acid (921 μL, 5.73 mmol,), DMAP (280
mg, 2.29 mmol), and DCC (1182 mg, 5.73 mmol) were successively
added to a solution of alcohol 7c (900 mg, 2.29 mmol,) in CH2Cl2 (30
mL) at room temperature. The mixture was stirred for 30 min and
then concentrated in vacuo. The residue was taken up in a 1/1 mixture
of n-hexane and diethyl ether and then filtered through a pad of Celite.
The resulting yellow liquid was concentrated under reduced pressure.
The crude ester was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 90/10 to 40/60) to afford the required
diethoxyphosphorylacetate 10c (1.25 g, 95% over two steps) as a
(3S,4R,6R)-4-((R)-1-(Benzyloxy)propan-2-yl)-6-((S)-1-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-3,4-dihydroxytetrahydropyran-
2-one (4c). Potassium osmate(VI) dihydrate (3 mg, 0.008 mmol) was
added to a solution of lactone 8c (50 mg, 0.12 mmol) in acetone (0.5
mL) and H2O (0.5 mL) at room temperature. After the mixture was
stirred for 10 min, NMO (33 mg, 0.28 mmol) was added and the
mixture was stirred overnight at room temperature. After this time, the
dark brown solution was partitioned between ethyl acetate and
1
yellow oil. H NMR (300 MHz, CDCl3): δ 7.34−7.29 (m, 5H), 5.16
(ddd, 1H, J = 9.7, 5.0, 3.6 Hz), 4.86 (s, 1H), 4.84 (s, 1H), 4.51 (d, 1H,
J = 12.1 Hz), 4.46 (d, 1H, J = 12.1 Hz), 4.21−4.09 (m, 4H), 3.60 (dd,
1H, J = 10.1, 6.0 Hz), 3.45 (dd, 1H, J = 10.1, 6.6 Hz), 3.42 (dd, 1H, J =
9.1, 5.9 Hz), 3.28 (dd, 1H, J = 9.1, 7.0 Hz), 2.91 (dd, 1H, J = 14.4 Hz,
1
1JP−H = 21.4 Hz), 2.86 (dd, 1H, J = 14.4 Hz, JP−H = 21.4 Hz), 2.47
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saturated aqueous NaCl. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. Purification by flash chromatog-
raphy on silica gel (cyclohexane/ethyl acetate 90/10 to 50/50)
afforded diol 4c (51 mg, 94% yield) as a pale oil. 1H NMR (500 MHz,
CD3OD): δ 7.34−7.26 (m, 5H), 4.63 (ddd, 1H, J = 11.3, 6.7, 4.4 Hz),
4.54 (d, 1H, J = 12.0 Hz), 4.50 (d, 1H, J = 12.0 Hz), 4.15 (s, 1H),
3.70−3.64 (m, 3H), 3.58 (dd, 1H, J = 9.3, 6.0 Hz), 2.38−2.31 (m,
1H), 1.95−1.85 (m, 3H), 1.01 (d, 3H, J = 7.0 Hz), 0.92 (d, 3H, J = 7.0
Hz), 0.90 (s, 9H), 0.06 (s, 6H). 13C NMR (125 MHz, CD3OD): δ
176.6 (C), 139.6 (C), 129.4 (2CH), 128.8 (2CH), 128.7 (CH), 79.9
(CH), 76.1 (C), 74.3 (CH2), 72.8 (CH2), 72.7 (CH), 65.2 (CH2),
41.5 (CH), 39.4 (CH), 32.1 (CH2), 26.4 (3CH3), 19.1 (C), 13.3
(CH3), 12.8 (CH3), −5.2 (CH3), −5.3 (CH3). HRMS (TOF MS
ES+): calcd m/z for C24H40O6Si (M + Na+) 475.2492, found 475.2494.
[α]2D2 = −15.9° (c = 0.9, CHCl3). IR (film): ν 3447, 2955, 2928, 2856,
1729, 1471, 1462, 1252, 777 cm−1.
min and then concentrated in vacuo. The residue was taken up in a 1/
1 mixture of n-hexane and diethyl ether and the solution then filtered
through a pad of Celite. The resulting yellow liquid was concentrated
under reduced pressure. The crude ester was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 80/20 to 20/
80) to afford diethoxyphosphorylacetate 10d (703 mg, 99% yield) as a
yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.35−7.26 (m, 5H), 5.29−
5.22 (m, 1H), 4.86−4.85 (m, 2H), 4.52 (d, 1H, J = 12.1 Hz), 4.47 (d,
1H, J = 12.1 Hz), 4.20−4.08 (m, 4H), 3.49 (dd, 1H, J = 9.1, 7.3 Hz),
3.49−3.40 (m, 2H), 3.30 (dd, 1H, J = 9.1, 7.1 Hz), 2.92 (dd, 1H, J =
14.4 Hz, 1JP−H = 24.1 Hz), 2.88 (dd, 1H, J = 14.4 Hz, 1JP−H = 24.1 Hz),
2.52−2.43 (m, 1H), 2.40−2.25 (m, 2H), 1.88−1.82 (m, 1H), 1.33 (t,
6H, J = 7.1 Hz), 1.08 (d, 3H, J = 6.9 Hz), 0.93 (d, 3H, J = 7.0 Hz),
0.87 (s, 9H), 0.01 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 165.1 (d,
C, 2JC−P = 6.1 Hz), 147.7 (C), 138.8 (C), 128.3 (2CH), 127.5 (2CH),
127.4 (CH), 112.1 (CH2), 74.7 (CH2), 73.7 (CH), 72.9 (CH2), 64.8
2
(CH2), 62.5 (d, 2CH2, JC−P = 6.3 Hz), 39.0 (CH), 38.8 (CH), 37.8
δ-Lactone 4d. (2R,3R,6S)-7-(Benzyloxy)-1-((tert-
butyldimethylsilyl)oxy)-2,6-dimethyl-5-methyleneheptan-3-ol (7d).
Alcohol 7b (750 mg, 1.91 mmol) was dissolved in THF (30 mL) at
0 °C. Triphenylphosphine (1 g, 3.82 mmol), p-nitrobenzoic acid (638
mg, 3.82 mmol), and DIAD (752 μL, 3.82 mmol) were successively
added to the solution. The mixture was stirred at 0 °C for 30 min and
then at room temperature for 2 days. After this time, saturated aqueous
NH4Cl was added and the mixture was extracted with CH2Cl2 (2×).
The combined organics were dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography on silica gel (cyclo-
hexane/diethyl ether 100/0 to 95/5) provided (2R,3R,6S)-7-
(benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-dimethyl-5-methyle-
(CH2), 34.0 (d, CH2, 1JC−P = 136.5 Hz), 25.8 (3CH3), 18.2 (C), 17.0
3
(CH3), 16.3 (d, 2CH3, JC−P = 6.2 Hz), 11.0 (CH3), −5.5 (2CH3).
HRMS (TOF MS ES+): calcd m/z for C29H51O7PSi (M + Na+)
593.3039, found 593.3034. [α]2D2 = −3.8° (c = 1.2, CHCl3). IR (film):
ν 2930, 2925, 2856, 1736, 1271, 1098, 1011, 971, 837, 832, 735 cm−1.
(2R,3R,6R)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-oxoheptan-3-yl 2-(Diethoxyphosphoryl)acetate (11d). A
stream of ozone was bubbled to a cooled (−78 °C) solution of the
previous ester 10d (1.18 g, 2.06 mmol) and Sudan III (small amount)
in CH2Cl2 (28 mL) until the pink solution became colorless (ca. 5−10
min). Triphenylphosphine (0.81 g, 3.09 mmol) was then cautiously
added, the cold bath was removed, and the mixture was stirred at room
temperature overnight. The solvent was removed under reduced
pressure, and the crude mixture was purified by flash chromatography
on silica gel (cyclohexane/ethyl acetate 60/40 to 40/60) to afford
1
neheptan-3-yl 4-nitrobenzoate (670 mg, 66% yield). H NMR (300
MHz, CDCl3): δ 8.27 (d, 2H, J = 8.8 Hz), 8.15 (d, 2H, J = 8.8 Hz),
7.35−7.27 (m, 5H), 5.52 (ddd, 1H, J = 8.5, 5.6, 3.8 Hz), 4.87 (s, 1H),
4.84 (s, 1H), 4.49 (s, 2H), 3.51 (d, 2H, J = 6.2 Hz), 3.46 (dd, 1H, J =
9.0, 6.0 Hz), 3.32 (dd, 1H, J = 9.0, 6.9 Hz), 2.59−2.48 (m, 2H), 2.45
(dd, 1H, J = 14.1, 5.3 Hz), 2.01 (qtd, 1H, J = 6.9, 6.2, 5.6 Hz), 1.09 (d,
3H, J = 6.9 Hz), 1.02 (d, 3H, J = 6.9 Hz), 0.87 (s, 9H), −0.01 (s, 3H),
−0.02 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 164.0 (C), 147.7 (C),
138.5 (C), 136.2 (C), 130.5 (2CH), 128.3 (2CH), 127.5 (2CH),
123.5 (2CH), 112.4 (CH2), 74.8 (CH2), 74.2 (CH), 72.9 (CH2), 65.0
(CH2), 39.0 (CH), 38.9 (CH), 38.2 (CH2), 25.8 (3CH3), 18.2 (C),
17.0 (CH3), 11.3 (CH3), −5.6 (2CH3). HRMS (TOF MS ES+): calcd
1
ketone 11d (1.07 g, 91% yield). H NMR (300 MHz, CDCl3): δ
7.35−7.26 (m, 5H), 5.43 (ddd, 1H, J = 7.5, 5.2, 4.4 Hz), 4.49 (d, 1H, J
= 11.9 Hz), 4.44 (d, 1H, J = 11.9 Hz), 4.20−4.08 (m, 4H), 3.59 (dd,
1H, J = 9.1, 7.5 Hz), 3.52 (dd, 1H, J = 10.2, 6.2 Hz), 3.48 (dd, 1H, J =
10.2, 6.0 Hz), 3.45 (dd, 1H, J = 9.1, 5.5 Hz), 2.90−2.80 (m, 5H), 1.91
(m, 1H), 1.33 (t, 6H, J = 7.0 Hz), 1.07 (d, 3H, J = 7.0 Hz), 0.92 (d,
3H, J = 6.9 Hz), 0.88 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H). 13C NMR
2
(75 MHz, CDCl3): δ 209.8 (C), 164.9 (d, C, JC−P = 6.2 Hz), 138.0
m/z for C30H43NO6Si (M + Na+) 564.2757, found 564.2749. [α]2D2
=
(C), 128.4 (2CH), 127.6 (2CH), 127.5 (CH), 73.2 (CH2), 72.1
(CH2), 72.0 (CH2), 64.5 (CH2), 62.5 (d, 2CH2, 2JC−P = 6.2 Hz), 46.6
(CH), 43.8 (CH2), 38.9 (CH), 34.3 (d, CH2, 1JC−P = 133.7 Hz), 25.8
−3.5° (c = 2.6, CHCl3). IR (film): ν 2932, 2856, 1735, 1705, 1656,
1257, 1097, 1054, 1027, 971, 837 cm−1.
3
(3CH3), 18.2 (C), 16.3 (d, 2CH3, JC−P = 6.2 Hz), 13.3 (CH3), 11.5
Potassium carbonate (171 mg, 1.24 mmol) was added to a solution
of the previous ester (670 mg, 1.24 mmol) in methanol (25 mL) at
room temperature. The mixture was stirred overnight, before being
quenched by addition of NH4Cl and extracted with CH2Cl2 (2×). The
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 97.5/2.5 to
(CH3), −5.5 (2CH3). HRMS (TOF MS ES+): calcd m/z for
C28H49O8PSi (M + Na+) 595.2832, found 595.2852. IR (film): ν
2956, 2931, 2856, 1734, 1259, 1098, 1027, 971, 837 cm−1.
(R)-4-((S)-1-(Benzyloxy)propan-2-yl)-6-((R)-1-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-5,6-dihydropyran-2-one (8d).
Ketone 11d (500 mg, 0.87 mmol) was dissolved in THF (20 mL)
at 40 °C, and freshly prepared lithium tert-butoxide (0.5 M solution in
THF, 1.57 mL, 0.79 mmol) was added very slowly. After the addition,
the mixture was stirred for 15 min at 30−40 °C, before being
quenched by addition of saturated aqueous NH4Cl. The mixture was
extracted with ethyl acetate (2×), the combined organic layers were
dried over MgSO4, and the solvent was removed in vacuo. The crude
product was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 95/5 to 80/20), and lactone 8d (254
1
90/10) to furnish alcohol 7d (453 mg, 93% yield). H NMR (300
MHz, CDCl3): δ 7.35−7.27 (m, 5H), 4.93 (s, 1H), 4.92 (s, 1H), 4.50
(s, 2H), 3.94 (m, 1H), 3.67 (dd, 1H, J = 9.8, 4.5 Hz), 3.63 (dd, 1H, J =
9.8, 4.4 Hz), 3.47 (dd, 1H, J = 9.1, 6.6 Hz), 3.33 (dd, 1H, J = 9.1, 6.9
Hz), 2.50 (quintd, 1H, J = 6.9, 6.6 Hz), 2.20 (d, 2H, J = 6.2 Hz), 1.73
(dqdd, 1H, J = 7.4, 7.0, 4.5, 4.4 Hz), 1.10 (d, 3H, J = 6.9 Hz), 0.92 (d,
3H, J = 7.0 Hz), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (75 MHz,
CDCl3): δ 149.4 (C), 138.4 (C), 128.3 (2CH), 127.6 (2CH), 127.5
(CH), 111.6 (CH2), 74.8 (CH2), 73.0 (CH2), 71.8 (CH), 67.6 (CH2),
40.7 (CH2), 39.4 (CH), 39.1 (CH), 25.9 (3CH3), 18.2 (C), 17.3
(CH3), 10.4 (CH3), −5.5 (CH3), −5.6 (CH3). HRMS (TOF MS
ES+): calcd m/z for C23H40O3Si (M + Na+) 415.2644, found 415.2654.
[α]2D2 = −1.5° (c = 2.1, CHCl3). IR (film): ν 3481, 2954, 2928, 1642,
1472, 1351, 1255, 1093 cm−1.
(2R,3R,6S)-7-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2,6-di-
methyl-5-methyleneheptan-3-yl 2-(Diethoxyphosphoryl)acetate
(10d). Diethylphosphonoacetic acid (500 μL, 3.09 mmol), DMAP
(151 mg, 1.24 mmol), and DCC (638 mg, 3.09 mmol) were
successively added to a solution of alcohol 7d (486 mg, 1.24 mmol) in
CH2Cl2 (18 mL) at room temperature. The mixture was stirred for 30
1
mg, 70% yield) was obtained. H NMR (300 MHz, CDCl3): δ 7.36−
7.25 (m, 5H), 5.84 (d, 1H, J = 2.3 Hz), 4.51 (d, 1H, J = 11.9 Hz), 4.46
(d, 1H, J = 11.9 Hz), 4.43 (ddd, 1H, J = 12.6, 4.3, 3.3 Hz), 3.64 (dd,
1H, J = 10.1, 7.0 Hz), 3.59 (dd, 1H, J = 10.1, 5.3 Hz), 3.47−3.43 (m,
2H), 2.73−2.64 (m, 1H), 2.46 (ddd, 1H, J = 17.3, 12.6, 2.3 Hz), 2.13
(dd, 1H, J = 17.3, 3.3 Hz), 1.86 (dqdd, 1H, J = 7.0, 6.9, 5.3, 4.3 Hz),
1.12 (d, 3H, J = 7.0 Hz), 0.98 (d, 3H, J = 6.9 Hz), 0.87 (s, 9H), 0.04
(s, 6H). 13C NMR (75 MHz, CDCl3): δ 165.7 (C), 163.4 (C), 137.9
(C), 128.5 (2CH), 127.8 (2CH), 127.6 (CH), 115.8 (CH), 77.8
(CH), 73.2 (CH2), 72.7 (CH2), 64.2 (CH2), 40.6 (CH), 39.5 (CH),
29.5 (CH2), 25.9 (3CH3), 18.2 (C), 15.0 (CH3), 11.5 (CH3), −5.5
(2CH3). HRMS (TOF MS ES+): calcd m/z for C24H38O4Si (M +
863
dx.doi.org/10.1021/jo302440a | J. Org. Chem. 2013, 78, 855−864

The Journal of Organic Chemistry
Article
Na+) 441.2437, found 441.2431. [α]D22 = +33.9° (c = 1.4, CHCl3). IR
(film): ν 2928, 2855, 1720, 1454, 1254, 1098, 972, 837 cm−1.
(3S,4R,6R)-4-((R)-1-(Benzyloxy)propan-2-yl)-6-((R)-1-((tert-
butyldimethylsilyl)oxy)propan-2-yl)-3,4-dihydroxytetrahydropyran-
2-one (4d). Potassium osmate(VI) dihydrate (11 mg, 0.03 mmol) was
added to a solution of lactone 8d (250 mg, 0.60 mmol) in acetone (2
mL) and H2O (2 mL) at room temperature. After the mixture was
stirred for 10 min, NMO (161 mg, 1.37 mmol) was added and the
mixture was stirred overnight at room temperature. After this time, the
dark brown solution was partitioned between ethyl acetate and
saturated aqueous NaCl. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. Purification by flash chromatog-
raphy on silica gel (cyclohexane/ethyl acetate 90/10 to 50/50)
afforded diol 4d (265 mg, 98% yield) as a slightly yellow oil. 1H NMR
(500 MHz, CD3OD): δ 7.34−7.27 (m, 5H), 4.77 (dt, 1H, J = 11.9, 3.9
Hz), 4.54 (d, 1H, J = 11.9 Hz), 4.50 (d, 1H, J = 11.9 Hz), 4.14 (s, 1H),
3.68 (dd, 1H, J = 9.4, 6.0 Hz), 3.63−3.59 (m, 2H), 3.56 (dd, 1H, J =
9.4, 6.3 Hz), 2.35 (qdd, 1H, J = 7.1, 6.3, 6.0 Hz), 1.95 (dd, 1H, J =
14.2, 11.9 Hz), 1.84 (dd, 1H, J = 14.2, 3.9 Hz), 1.79−1.74 (m, 1H),
1.01 (d, 3H, J = 7.1 Hz), 0.94 (d, 3H, J = 6.9 Hz), 0.90 (s, 9H), 0.06
(s, 6H). 13C NMR (125 MHz, CD3OD): δ 176.7 (C), 139.6 (C),
129.6 (2CH), 129.4 (2CH), 128.7 (CH), 79.0 (CH), 76.2 (C), 74.3
(CH2), 72.9 (CH), 72.8 (CH2), 65.6 (CH2), 41.2 (CH), 39.4 (CH),
32.8 (CH2), 26.4 (3CH3), 19.1 (C), 13.3 (CH3), 11.5 (CH3), −5.2
(CH3), −5.3 (CH3). HRMS (TOF MS ES+): calcd m/z for
C24H40O6Si (M + Na+) 475.2492, found 475.2490. [α]2D2 = −19.5°
(c = 0.8, CHCl3). IR (film): ν 3448, 2954, 2927, 1729, 1472, 1462,
1257, 1101, 857, 777 cm−1.
Å−1). Among all resulting conformers, only those corresponding to
local minima of energy are retained.
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(7) Confirmation of the structures of (S)-6 and 7a,b was performed
by comparison with literature data.5a,b
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(10) Alcohol 7c could not be separated from the p-nitrobenzoic acid
methyl ester byproduct by flash chromatography. The saponification
reaction seemed nearly quantitative. Therefore, 7c was engaged as the
crude product in the following reactions and the yield was calculated
from the p-nitrobenzoic acid ester of 7a.
ASSOCIATED CONTENT
(11) Yoshida, K.; Narui, R.; Imamoto, T. Chem. Eur. J. 2008, 14,
■
9706−9713. (b) Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-
S
̈
* Supporting Information
Figures giving full analyses of 13C and H NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204−2207. (c) Green, A. P.;
Hardy, S.; Thomas, E. J. Synlett 2008, 2103−2106.
(12) N.B. We have previously shown that less sterically hindered
acrylate esters similar to 9 undergo RCM to afford the expected
lactones in appreciable yields. For representative reaction conditions,
see: (a) D’Annibale, A.; Ciaralli, L.; Bassetti, M.; Pasquini, C. J. Org.
Chem. 2007, 72, 6067−6074. (b) Hansen, T. V. Tetrahedron:
Asymmetry 2002, 13, 547−550.
AUTHOR INFORMATION
Corresponding Author
*E-mail: janick.ardisson@parisdescartes.fr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17, 522−
524.
(14) Despite successful examples, the elimination may prevail: Chen,
We thank Pierre Fabre Laboratories and CNRS for a doctoral
fellowship for E.F. and the CNRS for a postdoctoral fellowship
for G.S.
X.; Wiemer, D. F. J. Org. Chem. 2003, 68, 6597−6604.
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I.; Britton, R.; Ashton, K.; Knust, H.; Stafford, J. Proc. Natl. Acad. Sci.
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Tetrahedron Lett. 1984, 25, 2183−2186. (g) Nahmany, M.; Melman, A.
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Tetrahedron Lett. 1984, 25, 2183−2186.
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(4) Computational analysis was achieved by means of Sybyl software
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relative combinations for model 3 were subjected to conformational
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the different stereoisomers are heated in silico at a given temperature
(1000 K), which allows free rotation of each bond angle. These
conditions are applied for 100 000 fs, during which time an image of
the conformation is saved every 50 fs. The resulting 2000 conformers
represent all possible conformations on the assumption that the
heating time is long enough. The energy of these structures is then
minimized (to obtain an energy gradient of less than 0.001 kcal mol−1
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