Nucleophilic addition to silyl-protected five-membered ring oxocarbenium ions governed by stereoelectronic effects

Article abstract of DOI:10.1021/jo400945j

A series of fused-bicyclic acetals containing a disiloxane ring was investigated to evaluate the source of selectivity in silyl-protected 2-deoxyribose systems. The disiloxane ring unexpectedly enables the diaxial conformer of the cation to be stabilized by an electronegative atom at C-3. This low energy conformer subsequently undergoes stereoelectronically controlled nucleophilic addition to give substituted tetrahydrofurans with high diastereoselectivity.

Full text of DOI:10.1021/jo400945j

Article
pubs.acs.org/joc
Nucleophilic Addition to Silyl-Protected Five-Membered Ring
Oxocarbenium Ions Governed by Stereoelectronic Effects
Vi Tuong Tran and K. A. Woerpel*
Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States
S
* Supporting Information
ABSTRACT: A series of fused-bicyclic acetals containing a disiloxane ring was investigated to evaluate the source of selectivity
in silyl-protected 2-deoxyribose systems. The disiloxane ring unexpectedly enables the diaxial conformer of the cation to be
stabilized by an electronegative atom at C-3. This low energy conformer subsequently undergoes stereoelectronically controlled
nucleophilic addition to give substituted tetrahydrofurans with high diastereoselectivity.
INTRODUCTION
■
The additions of nucleophiles to five-membered ring oxocar-
benium ions are common reactions for the construction of
substituted tetrahydrofurans found in furanosides and nucleo-
sides. C-Nucleosides have found use as N-nucleoside mimics,
not only to inhibit enzymes,1,2 but also to investigate the factors
controlling DNA helix stability.3−5 Furanosides have also
become popular synthetic targets as antibacterial6,7 and antiviral
agents.8,9 In all cases, the stereochemistry at the anomeric
position of the substituted tetrahydrofuran is crucial for the
intended activity.10 The broad applicability of substituted
Figure 1. Reactions of fused-ring oxocarbenium ions.
tetrahydrofurans as probes in chemistry and biology and as
selective inhibitors in medicinal chemistry has highlighted the
need for stereoselective methods for the synthesis of such target
compounds.
The stereochemical courses of reactions with five-membered
ring oxocarbenium ions, particularly in the case of carbon nucleo-
philes, are governed by stereoelectronic effects.11 Nucleophilic
addition to the oxocarbenium ion, which adopts an envelope
conformation, may occur from the inside face or from the out-
side face of the lowest energy envelope conformer (Figure 1).
We proposed that nucleophiles prefer to attack from the inside
face of the envelope conformer because unfavorable eclipsing
interactions are generated during the transition state associated
with outside attack. Evidence for this stereoelectronic
preference was provided by experiments involving an
oxocarbenium ion fused to an eight-membered ring, which
resulted in diastereoselectivity comparable to an unconstrained
monocyclic system (eq 1).12 Because the eight-membered ring
could not accommodate a diaxial envelope conformer (3-diaxial),
the product must have been formed by inside attack on
3-diequatorial (Figure 1).13
A powerful method for the synthesis of β-C-nucleosides has
been developed14 that cannot be readily explained by inside
attack on the oxocarbenium ion. The addition of silane to an
oxocarbenium ion formed in situ from hemiacetal 414 (eq 2)
with a fused eight-membered ring gave the product with the
opposite stereochemical sense to the all-carbon analogue shown
in eq 1. The difference in this selectivity cannot be attributed to
the presence of the substituent at the carbon atom undergoing
substitution, because selectivity is independent of substitution
Received: May 1, 2013
Published: June 5, 2013
© 2013 American Chemical Society
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system 4 could result from a diminished preference for the
diaxial conformation.
It may not be appropriate to draw an analogy between the
unconstrained oxocarbenium ion 8 (Figure 2) and the
oxocarbenium ion derived from disiloxane 4, however. The
eight-membered ring disiloxane ring may not be able to
accommodate the electrostatically stabilized diaxial conformer
9-axial (Figure 3). X-ray crystal structures of eight-five fused-
bicyclic compounds related to acetal 4 containing a
tetraisopropyldisiloxane protecting group exhibit a ring in
which the O−Si−O−Si−O linkage places all atoms nearly
coplanar with a nearly linear geometry at the central oxygen
atom (155°).18 This observation is consistent with the
suggestion that the eight-membered disiloxane ring in pro-
tected furanoses is constrained in a diequatorial orienta-
tion,19 just as observed for the all-carbon fused bicyclic
systems 1.13
Because the diaxial intermediate 9-axial may not be the
favored conformer, the trajectories of attack on the diequatorial
conformer 9-equatorial need to be considered more carefully
(Figure 3). The major product 1,3-cis-5 could also be formed
by outside attack on diequatorial conformer 9-equatorial.
Outside attack, however, is generally disfavored because
eclipsing interactions develop between the nucleophile and
the substituents at C-2 in the first-formed product.12 Because
nucleophilic attack results in significant conformational changes
in the five-membered ring, the three-dimensional preference of
the flattened disiloxane ring may alter the inherent stereo-
electronic selectivity for the inside product.13 The dihedral
angle at the ring juncture within the five-membered ring of 1,3-
trans-5 is increased as compared to the angle in the
oxocarbenium ion 9-equatorial (Figure 3). This increase in
dihedral angle could introduce torsional strain into the
disiloxane ring and lead to diminished stereoselectivity, as
was observed with the system with a cyclohexane ring fused to
the five-membered ring (10, eq 4).13 In contrast, outside attack
at C-1.15 The origin of this high selectivity has not been
explained.
In this Article, we report reactions of a series of fused-bicyclic
acetals containing a disiloxane ring to elucidate the origins of
selectivity in silyl-protected 2-deoxyribose systems such as
those shown in eq 2. The eight-membered disiloxane ring,
although not directly involved in the reaction, exerts powerful
influences on the structure and reactivity of the five-membered
ring oxocarbenium ion to which it is fused. The three-
dimensional structure of the disiloxane ring enables access to a
low energy conformer in which the electronegative atom at C-3
is close to the positively charged carbon atom of the
oxocarbenium ion.
BACKGROUND
■
Although the eight-membered ring of disiloxane 4 is necessary
to get high yields of product, it is not required to observe
1,3-cis selectivity. Nucleophilic substitution of the monocyclic
hemiacetal 6 also proceeds with the hydride adding to the same
face as the silyloxy group at C-3 (eq 3), but with higher
diastereoselectivity than was seen with bicyclic hemiacetal 4.16
The selectivity of nucleophilic addition to hemiacetal 6, unlike
disiloxane 4, can be rationalized by the inside attack model.11,12
The substituents at C-3 and C-4 adopt axial orientations to
maximize electrostatic stabilization of the oxocarbenium ion
(Figure 2). Inside attack on intermediate 8-diaxial would form
the major product.
on 9-equatorial would form the product 1,3-cis-5 with little
additional strain because the dihedral angle in the five-
membered ring is relatively unchanged (Figure 3).13
The explanation that constraints imposed by the eight-
membered disiloxane ring reverse the inherent preference for
inside attack is also unsatisfying. Selectivity was not reversed in
the case of the smaller six-membered ring fused system 10
(eq 4); it was only diminished in that example. Consequently,
neither explanation (inside attack on the conformer 9-axial or
outside attack on conformer 9-equatorial) is logical given the
systems studied.
Figure 2. The stereoselectivity for substitution reactions of acetal 6
can be explained by the inside attack model.
It is difficult to explain the selectivity observed for disiloxane
4 because different comparisons give different explanations. If
an analogy were made to the monocyclic hemiacetal 6, then
one would conclude that the fused ring exerts only minor
influences on diastereoselectivity of 2-deoxyribose-derived
acetals such as 4 (eq 2). Because the eight-membered disiloxane
ring has such a different geometry than would be expected if
only second-row elements were present in this ring,17 the eight-
membered ring disiloxane may be capable of accommodating a
diaxial orientation. Diminished selectivity for the fused ring
EXPERIMENTAL DESIGN
■
To confirm the preference of nucleophilic attack on silyl-pro-
tected 2-deoxyribose systems, we envisioned a substrate similar
to our previously studied eight-five fused-bicyclic system 1,
but replacing the cyclooctane ring with a disiloxane ring
(i.e., acetate 12, Figure 4). We hypothesized that an eight-
five fused-bicyclic system containing a disiloxane ring has
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Figure 3. Possible reaction trajectories.
to which it is fused. On the other hand, the diequatorial
form should be favored because no oxygen atom is present
at C-3 that might shift the equilibrium to the diaxial con-
former. The outcome of nucleophilic substitution of acetate
14 will reflect the inherent ability of the disiloxane to
accommodate the changing conformation of the five-
membered ring. If selectivity were high for the 1,3-trans
product, then it would indicate that the nine-membered
disiloxane ring could allow for inside attack when that ring
was fused equatorially, just as observed for the cyclooctane
ring of acetal 1 (eq 1).
Figure 4. Substrate to test the preferred approach of allyltrimethyl-
silane.
conformational preferences different from that of an eight-
five fused-bicyclic system containing a cyclooctane ring. This
hypothesis was derived by examination of X-ray crystal
structures of compounds related to bicyclic disiloxane 4
containing the tetraisopropyldisiloxane protecting group.18
Because bonds to silicon atoms are longer than bonds to
carbon atoms,17 the eight-membered ring disiloxane may
adopt a diaxial orientation.
A series of monocyclic acetates 15−17 would serve as direct
comparisons to the bicyclic acetates 12−14 (Figure 6). Without
To distinguish between the two possible reaction trajectories
for the formation of the 1,3-cis products, substrates with nine-
membered rings fused to the five-membered ring were synthesized
(Figure 5). These substrates were designed to give opposite
Figure 6. Monocyclic substrates to serve as direct comparisons to
bicyclic substrates.
a ring fusion to constrain the conformations of the five-mem-
bered ring, acetates 15−17 are expected to undergo nucleophilic
substitution in accordance with the inside attack model. Allylation
of acetates 15 and 16 should proceed with high stereoselectivity
for the 1,3-cis product because the oxocarbenium ion can be
stabilized by the silyloxy group in a pseudoaxial position.11,12
On the other hand, the cation derived from acetate 17 is
expected to favor the conformation in which the C3 substituent
resides in the pseudoequatorial position. Inside attack on this
conformer should generate 1,3-trans products with high selec-
tivity.11,12 The substitution products of acetates 12−14 and
acetates 15−17 can be correlated directly by standard
deprotection and protection reactions.
A number of experimental constraints were applied to
provide results that could be compared easily. All substitution
reactions were conducted under similar conditions to ensure
that any differences in selectivity could be correlated to
structure. Allyltrimethylsilane was used as the nucleophile in
these substitution reactions because attack of carbon π-
nucleophiles is irreversible.20 In addition, this small nucleophile
does not experience strongly destabilizing steric interactions in
the transition state for nucleophilic attack, and its reactivity is
representative of many nucleophiles.21 The Lewis acid
BF3·OEt2 was used to facilitate dissociation of the acetate
leaving group because these conditions involve reactions that
appear to proceed through oxocarbenium ions.22,23
Figure 5. Substrates to test the two possible reaction trajectories.
trends in selectivity depending upon which pathway was
preferred. If the stereoselectivity observed for acetal 4 were the
result of inside attack on a diaxial conformer, then the pre-
ference for the 1,3-cis product should improve as the fused ring
size is expanded to a nine-membered ring (i.e., acetate 13). The
larger size of the ring fusion would presumably allow for easier
access to the diaxial conformer in which the electronegative
oxygen atom at C-3 can form a favorable electrostatic
interaction with the oxocarbenium ion. Conversely, if constraints
imposed by a diequatorially fused disiloxane ring disfavored the
inside attack pathway, then nucleophilic substitution of acetate
13 with the larger ring should result in lower selectivity for the
1,3-cis product.
A related substrate was designed to probe the importance of
electrostatic effects in disiloxane-fused oxocarbenium ions (Figure 5).
Acetate 14 possesses a nine-membered ring just as acetate 13
does, so the nine-membered disiloxane ring should impose
similar conformational constraints on the five-membered ring
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a
Scheme 1
a
Reagents: (a) Br2, H2O, 68%; (b) (Cli-Pr2Si)2O, 2,6-lutidine, 28%; (c) i-Bu2AlH, pyr, DMAP, Ac2O, 76%; (d) t-BuMe2SiCl, imidazole, 78%; (e) i-
Bu2AlH, pyr, DMAP, Ac2O, 92%.
SUBSTRATE SYNTHESIS
■
The deoxy-ribose acetates 12 and 15 were prepared in a few
steps from D-deoxy-ribose 18 (Scheme 1).14,24 Acetates 13 and
16 were synthesized from 1-methoxycyclohexa-1,4-diene (22)
in several steps (Schemes 2 and 3).25 Acetates 14 and 17 were
produced following five linear steps each from cis-2-butene-1,4-
diol (30) (Scheme 4).
with observations of the corresponding acetal 1 with the
a
cyclooctane ring fused to the five-membered ring, which gave
the 1,3-trans product 2 with high diastereoselectivity (eq 1).13
The diastereoselectivity of neither reaction (eq 1 or eq 5)
depended upon the starting ratio of anomeric acetates,13 suggest-
ing that oxocarbenium ion intermediates were involved in both
cases. The use of Me3SiOTf as a Lewis acid also did not change
the diastereoselectivity, indicating that ion-pairing effects or direct
displacement reactions are not responsible for selectivity.21,22
The nucleophilic substitution reactions of bicyclic acetates 13
and 14 with fused nine-membered disiloxane rings proceeded
with high diastereoselectivity (eqs 6 and 7), therefore clarifying
Scheme 2
a
Reagents: (a) m-CPBA, MeOH, 91%; (b) H5IO6, HC(OMe)3,
MeOH, 74%; (c) Et3SiH, BF3·OEt2, 90%; (d) OsO4, NMO, 83%; (e)
BBr3, 70%.
a
Scheme 3
a
Reagents: (a) (Cli-Pr2Si)2O, 2,6-lutidine, 28%; (b) i-Bu2AlH, pyr,
the origin of diastereoselectivity in these systems. The acetate
13 possessing a nine-membered ring exhibited even higher
selectivity for the 1,3-cis product than observed for acetate 12
with an eight-membered disiloxane ring. This increased
selectivity suggests that the corresponding oxocarbenium ion
had a greater ability to adopt a diaxial conformation due to its
larger ring size. Had the selectivity decreased, then it would
have been likely that the product resulted from a diminished
preference for outside attack on the diequatorial conformer. An
important observation was that the nucleophilic substitution of
acetate 13 and acetate 14 formed products with opposite
diastereoselectivity, despite having the same size disiloxane ring.
DMAP, Ac2O, 88%; (c) t-BuMe2SiCl, imidazole, 75%; (d) i-Bu2AlH,
pyr, DMAP, Ac2O, 93%.
RESULTS
■
Initial experiments verified that the use of allyltrimethylsilane as
a nucleophile gave results similar to those observed for hydride
attack (eq 2). The sense of selectivity exhibited by the hydride
addition is shared by addition of allyltrimethylsilane: nucleo-
philic substitution of the bicyclic acetate 12 proceeded with 1,3-
cis selectivity (eq 5). This observation provides a direct contrast
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a
Scheme 4
a
Reagents: (a) (Cli-Pr2Si)2O, 2,6-lutidine, 60%; (b) m-CPBA, 98%; (c) allylMgBr, 92%; (d) OsO4, NMO, NaIO4, 92%; (e) Ac2O, Et3N, 99%; (f) t-
BuMe2SiCl, imidazole, 96%; (g) m-CPBA, 97%; (h) allylMgBr, 97%; (i) OsO4, NMO, NaIO4, 87%; (j) Ac2O, Et3N, 94%.
While the substitution of both acetate 13 and acetate 14 pro-
ceeded through the preferred inside attack pathway, the nucleo-
phile must have encountered different oxocarbenium ion envelope
conformers to form the products of opposite diastereoselectiv-
ity. This result is consistent with observations of unconstrained
systems that require the two different oxocarbenium ions to
adopt different low energy conformations (diaxial for the cation
derived from acetate 13, and diequatorial for the cation derived
from acetate 14).12
acetate 16. The diminished 1,3-cis stereoselectivity observed for
acetate 12 (eq 5) suggests that the eight-membered ring disiloxane
ring had a decreased preference for the diaxial conformation.
X-RAY CRYSTALLOGRAPHIC DATA
■
Crystallographic data were necessary to confirm the relative
configurations of the substitution products 37−42 because the
nuclear Overhauser effect for five-membered rings is too small
to be conclusive. Each substitution product was derivatized
to provide a solid that could be recrystallized for X-ray diffrac-
tion studies (Schemes 5−7). The bicyclic substitution prod-
ucts 37−39 underwent additional transformations for chemical
correlation to the corresponding monocyclic substitution products
40−42.
The nucleophilic substitution reactions of the monocyclic
acetals 15−17 analogous to acetates 12−14 also resulted in
similar diastereoselectivity, respectively (eqs 8−10). The high
DISCUSSION
■
The results presented here indicate that there are significant
differences in the conformational preferences between the two
eight-five fused bicyclic substrates 1 and 12. In the all-carbon
substrate 1, the cyclooctane ring can adopt several low-energy
conformations, but all of these possibilities orient the fused ring
equatorially.26 On the other hand, the disiloxane rings of
acetate 12 and the nine-five fused system 13, which possess an
electronegative oxygen atom at C-3 that can engage in stabiliz-
ing electrostatic interactions with the oxocarbenium ion inter-
mediate,12 enable the cation to accommodate the diaxial conformer.
Preliminary computational analysis of the low energy con-
formers of the oxocarbenium ions derived from acetates 12 and
13 indicates that there are low-energy conformers that resemble
the diaxial conformer, although the five-membered ring is
somewhat flattened as compared to unconstrained substrates
(Figure 7). Eligible low-energy conformers were found by a
systematic search of the conformational space using semi-
empirical methods (PM3) in Spartan10,27 and energies were
minimized with low-level ab initio methods (HF/3-21G).
Conformations within 10 kcal/mol of the lowest energy
diastereoselectivity obtained in all of these substitution reactions is
consistent with inside attack on the cations. It is important to
note that the level of stereoselectivity of substitution of bicyclic
acetate 13 is similar to that observed for the unconstrained
a
Scheme 5
a
Reagents: (a) n-Bu4NF, 86%; (b) n-Bu4NF, 99%; (c) OsO4, NMO, 92%; (d) NaIO4, 88%; (e) C6H3(NO2)2NHNH2, 83%.
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a
Scheme 6
a
Reagents: (a) n-Bu4NF, 97%; (b) t-BuMe2SiCl, imidazole, 56%; (c) O3, PPh3, 83%; (d) C6H3(NO2)2NHNH2, 96%.
a
Scheme 7
a
Reagents: (a) n-Bu4NF, 99%; (b) n-Bu4NF, 99%; (c) O3, PPh3, 93%; (d) C6H3(NO2)2NHNH2, 92%.
combination with more shallow vibrational and torsional minima,17
enables the cation to adopt a low-energy envelope confor-
mation in which the electronegative atom at C-3 provides a stabiliz-
ing interaction. Expansion of the eight-membered disiloxane
ring to a nine-membered ring increases the preference for the
diaxial conformer, leading to an increase in diastereoselectivity.
Without the electronegative oxygen atom at C-3, however, the
nine-membered ring disiloxane biases the five-membered ring
oxocarbenium ion to the diequatorial conformer.
EXPERIMENTAL SECTION
■
(4S,5R)-4-Hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-
one 19. To a solution of 2-deoxy-D-ribose (1.0 g, 7.5 mmol) in
distilled water (6 mL) was added Br2 (2.0 mL, 39 mmol) by syringe.
The reaction was allowed to stir at room temperature for 5 days.
Excess bromine was extracted from the reaction mixture with Et2O
until the yellow color faded. The pH of the aqueous layer was adjusted
to pH 7 with the addition of Ag2CO3. The aqueous layer was then
filtered and concentrated in vacuo to afford a brown oil.24 The product
was purified by flash column chromatography on silica gel (1:1
Figure 7. Calculated (B3LYP/6-31G*) energies of fused-bicyclic
oxocarbenium ions.
conformer were selected to undergo further optimization, first
using a larger basis set (HF/6-31G*) and later using density
functional methods (B3LYP/6-31G*). The relative energy
difference between the lowest energy diaxial conformer 49-axial
and the lowest energy diequatorial conformer 49-equatorial for
the oxocarbenium ion derived from acetate 12 was too small
(0.3 kcal/mol) to draw any significant conclusion. Instead, the
presence of multiple low-energy conformers within 1 kcal/mol
implies a low preference for any particular conformation.
Because nucleophiles can react with any of these low-energy
conformers, the major product could be the product of a
conformation that is not the lowest energy oxocarbenium ion.28
By expanding the eight-membered disiloxane ring to the nine-
membered one, however, the lowest energy diaxial conformer
50-axial was favored over the lowest energy diequatorial
conformer 50-equatorial by 5.2 kcal/mol, suggesting a
potential for high selectivity. Although preliminary, these
calculations support the stereoselectivity seen in our exper-
imental results.
acetone:hexanes) to give 19 as a light brown oil (0.68 g, 68%):
1
[α]24 +4.11 (c 1.61, MeOH); H NMR (400 MHz, CD3OD) δ
D
4.43 (dt, J = 6.7, 2.3, 1H), 4.37 (dd, J = 5.5, 3.3, 1H), 3.76 (dd, J =
12.4, 3.3, 1H), 3.69 (dd, J = 12.4, 3.6, 1H), 2.92 (dd, J = 18.0, 6.8,
1H), 2.37 (dd, J = 18.0, 2.5, 1H); 13C NMR (125 MHz, CD3OD) δ
178.9, 90.2, 69.8, 62.5, 39.1; IR (thin film) 3383, 2941, 1767 cm−1
;
HRMS (TOF MS ES+) m/z calcd for C5H8NaO4 (M + Na)+
155.0320, found 155.0315.
(6aR,9aS)-2,2,4,4-Tetraisopropyltetrahydro-8H-furo[3,2-f ]-
[1,3,5,2,4]trioxadisilocin-8-one 20. To a solution of 2-deoxy-D-ribo-
nolactone 19 (0.062 g, 0.47 mmol) and imidazole (0.080 g, 1.2 mmol)
in DMF (1.5 mL) was added 1,3-dichlorotetraisopropyldisiloxane
(0.23 mL, 0.71 mmol) dropwise. The reaction mixture was stirred
overnight at room temperature. The reaction mixture was then
extracted with Et2O (2 × 10 mL) and washed with distilled water
(10 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo to give a colorless oil.14
The product was purified by flash column chromatography on silica
gel (15:85 EtOAc:hexanes) to afford 20 as a colorless oil (0.049 g,
28%). The spectral data obtained matched the reported values
for this compound:14 [α]24 +16.7 (c 1.87, MeOH); 1H NMR
D
(500 MHz, CDCl3) δ 4.64 (app q, J = 8.0, 1H), 4.22 (td, J = 6.7, 3.6,
1H), 4.14 (dd, J = 12.3, 3.6, 1H), 3.93 (dd, J = 12.3, 6.6, 1H), 2.86
(dd, J = 17.3, 8.0, 1H), 2.72 (dd, J = 17.3, 9.2, 1H), 1.11−0.93
(m, 28H); 13C NMR (125 MHz, CDCl3) δ 173.2, 85.0, 69.8, 62.5,
38.0, 17.6, 17.51, 17.48, 17.4, 17.2, 17.1, 17.0, 13.5, 13.3, 13.0, 12.7;
IR (thin film) 2943, 2870, 1795, 1034 cm−1; HRMS (TOF MS
ES+) m/z calcd for C17H34NaO5Si2 (M + Na)+ 397.1843, found
397.1849.
CONCLUSION
■
Experiments with closely related substrates indicate that the
disiloxane ring permits greater flexibility to a ring to which it is
fused than does its all-carbon analogue. The shape of the
tetraisopropyldisiloxane protecting group, likely the longer
bond lengths as compared to an all-carbon system in
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(6aR,9aS)-2,2,4,4-Tetraisopropyltetrahydro-6H-furo[3,2-f ]-
[1,3,5,2,4]trioxadisilocin-8-yl Acetate 12. A solution of protected
ribonolactone 20 (0.51 g, 1.4 mmol) in CH2Cl2 (8 mL) was cooled to
−78 °C. Diisobutylaluminum hydride (1.5 M in toluene, 1.8 mL,
2.7 mmol) was added dropwise by syringe. After the reaction mixture
was stirred for 6 h at −78 °C, a solution of dimethylaminopyridine
(0.33 g, 2.7 mmol) in dry CH2Cl2 (3 mL), pyridine (0.33 mL,
4.1 mmol), and acetic anhydride (0.77 mL, 8.1 mmol) was added
sequentially by syringe. The reaction mixture was left to stir overnight
and warm to room temperature. After the reaction mixture was cooled
to 0 °C, saturated aqueous NH4Cl (8 mL) and saturated aqueous
sodium potassium tartrate (8 mL) were added. The mixture was
allowed to warm to room temperature and was stirred until the layers
were completely separated. The reaction mixture was extracted with
CH2Cl2 (2 × 10 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (10 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo to give a dark yellow oil.29 The crude
mixture was purified by flash column chromatography on silica gel
(1:7:92 Et3N:EtOAc:hexanes) to afford 12 as a colorless oil (0.43 g,
76% yield). 1H and 13C NMR of a 30:70 (1,3-cis-12:1,3-trans-12) mix-
ture of diastereomers are given. IR, HRMS, and elemental analysis of a
58:42 (1,3-cis-12:1,3-trans-12) mixture of diastereomers is provided:
1H NMR (500 MHz, C6D6) δ 6.33 (dd, J = 5.6, 2.6, 1H), 4.74 (dt, J =
stirred until the layers were completely separated. The reaction
mixture was extracted with CH2Cl2 (2 × 10 mL). The combined
organic layers were washed with saturated aqueous NaHCO3 (10 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude
mixture was purified by flash column chromatography on silica gel
(1:9:90 Et3N:EtOAc:hexanes) to afford 15 as a colorless oil (0.39 g,
92% yield). Characterization was performed on a 28:72 (1,3-cis-15:1,3-
trans-15) mixture of diastereomers. The spectral data obtained matched
the reported values for this compound:31 [α]24 0.165 (c 4.45,
D
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 6.28 (dd, J = 5.2, 2.8,
0.72H), 6.24 (dd, J = 5.6, 1.0, 0.28H), 4.45 (td, J = 6.1, 4.6, 0.72H),
4.33 (dt, J = 6.7, 2.7, 0.28H), 4.10 (dt, J = 4.2, 3.4, 0.28H), 3.87 (q, J =
4.7, 0.72H), 3.67−3.56 (m, 2H), 2.30 (ddd, J = 14.0, 6.7, 5.8, 0.28H),
2.20−2.11 (m, 1.44H), 2.02 (s, 0.84H), 2.00 (s, 2.16H), 1.95 (ddd, J =
14.0, 2.2, 1.1, 0.28H), 0.88−0.86 (m, 18H), 0.05−0.02 (m, 12H); 13C
NMR (125 MHz, CDCl3) δ 170.7, 170.3, 99.3, 98.4, 88.7, 87.9, 71.6,
71.2, 62.9, 62.8, 41.5, 41.2, 26.00, 25.97, 25.81, 25.75, 21.5, 18.5, 18.4,
18.03, 17.95, −4.6, −4.67, −4.71, −4.8, −5.25, −5.31, −5.33, −5.4; IR
(thin film) 2943, 1741, 1240 cm−1; HRMS (TOF MS ES+) m/z calcd
for C19H40NaO5Si2 (M + Na)+ 427.2312, found 427.2307. Anal. Calcd
for C19H40O5Si2: C, 56.39; H, 9.96. Found: C, 56.88; H, 10.01. Two
attempts to obtain satisfactory combustion analysis data were
unsuccessful, likely because minor impurities were present that could
1
not be detected by H NMR spectroscopy.
8.9, 6.8, 0.3H), 4.29 (dt, J = 8.6, 5.6, 0.7H), 4.20−4.16 (m, 0.7H), 4.12
(dd, J = 11.3, 3.8, 0.3H), 4.07 (dd, J = 11.7, 3.6, 0.7H), 4.01−3.97 (m,
0.3H), 3.88 (dd, J = 11.2, 8.8, 0.3H), 3.70 (dd, J = 11.7, 7.9, 0.7H),
2.20−2.13 (m, 1H), 2.06−2.01 (m, 1H), 1.65 (s, 2.1H), 1.58 (s, 0.9H),
1.14−0.90 (m, 28H); 13C NMR (125 MHz, C6D6) δ 169.8, 169.2,
97.6, 97.4, 85.9, 85.3, 73.9, 73.8, 66.2, 64.2, 41.7, 41.3, 21.18, 21.15,
18.13, 18.10, 18.05, 18.02, 18.00, 17.96, 17.9, 17.71, 17.68, 17.60,
17.57, 14.1, 14.0, 13.9, 13.7, 13.6, 13.4, 13.3; IR (thin film) 2943, 1738,
1035 cm−1; HRMS (TOF MS ES+) m/z calcd for C19H38NaO6Si2 (M
+ Na)+ 441.2105, found 441.2107. Anal. Calcd for C19H38O6Si2: C,
54.51; H, 9.15. Found: C, 54.67; H, 9.16. A 44:56 (1,3-cis-12:1,3-trans-
6,6-Dimethoxycyclohex-3-en-1-ol 23. To a solution of 1-meth-
oxycyclohexa-1,4-diene (1.00 g, 9.11 mmol) in MeOH (30 mL) at
−10 °C was added dropwise a solution of m-chloroperoxybenzoic acid
(2.1 g, 75%, 9.1 mmol) in MeOH (20 mL). The mixture was stirred at
−10 °C for 1 h, then at room temperature for 4 h. The reaction mixture
was washed with saturated aqueous NaHCO3 (80 mL) and extracted
with CH2Cl2 (4 × 80 mL). The combined organic layers were filtered
through a cotton plug and concentrated in vacuo to give an amber oil.
The product was purified by flash column chromatography on silica gel
(40:60 ether:hexanes) to give 23 as a colorless oil (1.3 g, 91%). The
spectral data obtained matched the reported values for this com-
pound:25 1H NMR (400 MHz, CDCl3) δ 5.63−5.54 (m, 2H), 4.02 (s,
1H), 3.30 (s, 3H), 3.25 (s, 3H), 2.47−2.23 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 123.7, 122.8, 100.4, 66.8, 48.6, 48.2, 31.2, 29.8; IR
(thin film) 3454, 3030, 2944, 1658, 1422 cm−1; HRMS (TOF MS ES+)
m/z calcd for C8H14NaO3 (M + Na)+ 181.0841, found 181.0839. Anal.
Calcd for C8H14O3: C, 60.74; H, 8.92. Found: C, 60.82; H, 9.06.
Methyl (Z)-6,6-Dimethoxyhex-3-enoate 24. To a solution of
23 (0.41 g, 2.6 mmol) in MeOH (9 mL) at −10 °C was added
dropwise a solution of periodic acid (0.70 g, 3.1 mmol) in MeOH
(4 mL). The reaction mixture was stirred at −10 °C for 1 h, then at
room temperature for 5 h. Trimethyl orthoformate (0.84 mL, 7.7 mmol)
was added all at once, and the reaction mixture was left to stir
overnight. The reaction mixture was washed with brine (50 mL) and
extracted with EtOAc (2 × 40 mL). The combined organic layers were
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo to give a yellow oil. The product was purified by flash column
chromatography on silica gel (25:75 EtOAc:hexanes) to afford 24 as a
yellow oil (0.36 g, 74%). The spectral data obtained matched the
reported values for this compound:25 1H NMR (600 MHz, CDCl3) δ
5.70 (dtt, J = 10.6, 7.2, 1.6, 1H), 5.60 (dtt, J = 10.5, 7.2, 1.6, 1H), 4.39
(t, J = 5.7, 1H), 3.69 (s, 3H), 3.34 (s, 3H and s, 3H), 3.12 (dt, J = 7.2,
0.7, 2H), 2.38 (tt, J = 6.4, 0.8, 2H); 13C NMR (150 MHz, CDCl3) δ
172.2, 127.4, 123.6, 104.0, 53.3, 52.0, 33.1, 31.4; IR (thin film) 3032,
2953, 1741, 1661, 1437 cm−1; HRMS (TOF MS ES+) m/z calcd for
C9H16NaO4 (M + Na)+ 211.0947, found 211.0945. Anal. Calcd for
C9H16O4: C, 57.43; H, 8.57. Found: C, 57.14; H, 8.42.
12) mixture of diastereomers gave [α]24 −11.3 (c 1.74, MeOH). A
D
36:64 (1,3-cis-12:1,3-trans-12) mixture of diastereomers gave [α]24
D
−0.485 (c 2.99, MeOH). The optical rotation of the pure diastereomer
1,3-cis-12 was calculated to be −86.8, and the optical rotation of the
pure diastereomer 1,3-trans-12 was calculated to be +48.1.
(4S,5R)-4-((tert-Butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)dihydrofuran-2(3H)-one 21. To a solution of
2-deoxy-D-ribonolactone 19 (0.112 g, 0.848 mmol) in DMF (4 mL) at
0 °C were added imidazole (0.289 g, 4.24 mmol) and tert-butyl-
dimethylsilyl chloride (0.268 g, 1.78 mmol). The reaction mixture was
stirred overnight at room temperature. The reaction mixture was then
extracted with EtOAc (2 × 20 mL) and washed with distilled water
(10 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo to give a colorless oil. The
product was purified by flash column chromatography on silica gel
(10:90 EtOAc:hexanes) to afford 21 as a white solid (0.238 g, 78%).
The spectral data obtained matched the reported values for this
compound:30 1H NMR (500 MHz, CDCl3) δ 4.49 (dt, J = 6.5, 2.2,
1H), 4.32 (dt, J = 2.5, 2.3, 1H), 3.80 (dd, J = 11.6, 3.3, 1H), 3.75 (dd,
J = 11.5, 2.5, 1H), 2.81 (dd, J = 17.7, 6.7, 1H), 2.37 (dd, J = 17.7, 2.5,
1H), 0.87 (s, 18H), 0.08 (s, 6H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 176.0, 88.3, 69.8, 62.7, 39.2, 26.0, 25.8, 18.4,
18.1, −4.56, −4.64, −5.3, −5.5.
(4S,5R)-4-((tert-Butyldimethylsilyl)oxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)tetrahydrofuran-2-yl Acetate 15. A solution of
bis-TBS protected ribonolactone 21 (0.377 g, 1.04 mmol) in CH2Cl2
(10 mL) was cooled to −78 °C. Diisobutylaluminum hydride (1.5 M
in toluene, 2.1 mL, 3.1 mmol) was added dropwise by syringe. After
the reaction mixture was stirred for 1 h at −78 °C, a solution of
dimethylaminopyridine (0.255 g, 2.09 mmol) in dry CH2Cl2 (3 mL),
pyridine (0.253 mL, 3.13 mmol), and acetic anhydride (0.592 mL,
6.26 mmol) was added sequentially by syringe. The reaction mixture
was left to stir overnight and warm to room temperature. After the
reaction mixture was cooled to 0 °C, saturated aqueous NH4Cl (5 mL)
and saturated aqueous sodium potassium tartrate (5 mL) were added.
The mixture was allowed to warm to room temperature and was
Methyl (Z)-6-Methoxyhex-3-enoate 25. To a solution of 24
(0.788 g, 4.19 mmol) in CH2Cl2 (42 mL) at −78 °C were added
triethylsilane (2.68 mL, 16.8 mmol) and boron trifluoride diethyl
etherate (0.620 mL, 5.02 mmol). After 6 h, saturated aqueous sodium
bicarbonate (100 mL) was added. The reaction mixture was extracted
with CH2Cl2 (2 × 100 mL). The combined organic layers were filtered
through a cotton plug and concentrated in vacuo to give a colorless oil.
The product was purified by flash column chromatography on silica gel
(10:90 EtOAc:hexanes) to afford 25 as a colorless oil (0.598 g, 90%):
6615
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Article
1H NMR (600 MHz, CDCl3) δ 5.67 (dtt, J = 10.7, 7.1, 1.5, 1H), 5.61
(dtt, J = 10.4, 7.1, 1.5, 1H), 3.69 (s, 3H), 3.41 (t, J = 6.8, 2H), 3.34 (s,
3H), 3.12 (dd, J = 7.1, 1.3, 2H), 2.34 (qd, J = 6.8, 1.3, 2H); 13C NMR
(150 MHz, CDCl3) δ 172.4, 129.6, 123.1, 72.1, 58.9, 52.1, 33.1, 28.2;
IR (ATR) 3028, 2927, 1737, 1436 cm−1; HRMS (TOF MS ES+) m/z
calcd for C8H14NaO3 (M + Na)+ 181.0841, found 181.0840. Two
attempts to obtain satisfactory combustion analysis data were
unsuccessful, likely because minor impurities were present that could
reaction mixture was warmed to 0 °C, and saturated aqueous sodium
potassium tartrate (1 mL) and saturated aqueous ammonium chloride
(1 mL) were added. The mixture was allowed to warm to room tem-
perature and was stirred until the layers were completely separated.
The reaction mixture was extracted with CH2Cl2 (2 × 15 mL). The
combined organic layers were filtered through a cotton plug
and concentrated in vacuo to give a colorless oil. The product
was purified by flash column chromatography on silica gel (1:5:94
1
1
Et3N:EtOAc:hexanes) to give 13 as a colorless oil (0.14 g, 88%). H
not be detected by H NMR spectroscopy.
and 13C NMR spectra of the separated diastereomers are given. IR,
HRMS, and elemental analysis of a mixture of diastereomers are given.
(4R*,5S*)-4-Hydroxy-5-(2-methoxyethyl)dihydrofuran-
2(3H)-one 26. To a solution of 25 (0.341 g, 2.15 mmol) in acetone
and water (1:1, 22 mL) was added 4-methylmorpholine N-oxide
(0.757 g, 6.46 mmol). The reaction mixture was cooled to 0 °C, and
osmium tetroxide (4.0% in H2O, 0.68 mL, 0.11 mmol) was added by
syringe. The reaction mixture was allowed to warm to room tem-
perature overnight, then was extracted with EtOAc (6 × 100 mL).
The combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to give a gray oil. The product was
purified by flash column chromatography on silica gel (EtOAc) to
afford 26 as a colorless oil (0.32 g, 83%): 1H NMR (500 MHz,
CDCl3) δ 4.28−4.23 (m, 2H), 3.59 (dd, J = 3.8, 0.6, 1H), 3.58 (d, J =
3.9, 1H), 3.56 (br s, 1H), 3.40 (s, 3H), 2.84 (dd, J = 17.6, 7.0, 1H),
2.60 (dd, J = 17.5, 7.8, 1H), 2.08−1.95 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 174.3, 85.8, 72.7, 69.2, 59.2, 37.3, 33.5; IR (thin film) 3419,
2930, 1778 cm−1; HRMS (TOF MS ES+) m/z calcd for C7H12NaO4
(M + Na)+ 183.0633, found 183.0638. Two attempts to obtain
satisfactory combustion analysis data were unsuccessful, likely because
minor impurities were present that could not be detected by 1H NMR
spectroscopy.
1
High Rf diastereomer: H NMR (600 MHz, CDCl3) δ 6.31 (dd, J =
5.2, 1.2, 1H), 4.71 (td, J = 6.9, 4.0, 1H), 4.19 (dt, J = 11.5, 4.0, 1H),
3.99−3.91 (m, 2H), 2.38 (ddd, J = 13.7, 7.5, 1.2, 1H), 2.25 (ddd, J =
13.7, 6.4, 5.3, 1H), 2.19 (ddt, J = 13.7, 9.5, 3.9, 1H), 2.03 (s, 3H), 1.63
(dddd, J = 13.9, 11.5, 5.3, 2.3, 1H), 1.10−0.90 (m, 28H); 13C NMR
(150 MHz, CDCl3) δ 170.4, 98.8, 86.7, 73.6, 59.2, 42.5, 37.6, 21.6,
17.7, 17.6, 17.51, 17.46, 17.40, 17.38, 17.37, 13.6, 13.4, 13.1, 13.0. Low
Rf diastereomer: 1H NMR (600 MHz, CDCl3) δ 6.25 (d, J = 5.0, 1H),
4.49 (ddd, J = 7.5, 3.0, 1.6, 1H), 4.34 (dt, J = 11.5, 3.4, 1H), 3.96−3.94
(m, 2H), 2.33 (ddd, J = 14.3, 7.6, 5.2, 1H), 2.17−2.09 (m, 2H), 2.05
(s, 3H), 1.49−1.43 (m, 1H), 1.18−0.90 (m, 28H); 13C NMR (150
MHz, CDCl3) δ 171.0, 98.6, 87.4, 73.3, 59.5, 41.7, 35.8, 21.5, 17.7,
17.6, 17.5, 17.43, 17.38, 17.3, 13.61, 13.56, 13.10, 13.06; IR (ATR)
2944, 1746, 1464, 1086 cm−1; HRMS (TOF MS ES+) m/z calcd for
C20H40NaO6Si2 (M + Na)+ 455.2261, found 455.2264. Anal. Calcd for
C20H40O6Si2: C, 55.52; H, 9.32. Found: C, 55.79; H, 9.45.
(4R*,5S*)-4-((tert-Butyldimethylsilyl)oxy)-5-(2-((tert-
butyldimethylsilyl)oxy)ethyl)dihydrofuran-2(3H)-one 29. To a
solution of 27 (0.046 g, 0.20 mmol) in DMF (1 mL) at 0 °C were
added imidazole (0.067 g, 0.99 mmol) and tert-butyldimethylsilyl
chloride (0.075 g, 0.49 mmol). The reaction mixture was allowed to
warm to room temperature overnight before being concentrated in
vacuo to give a yellow oil. The product was purified by flash column
chromatography on silica gel (10:90 EtOAc:hexanes) to give 29 as a
colorless oil (0.056 g, 75%): 1H NMR (600 MHz, CDCl3) δ 4.46 (dt,
J = 8.8, 3.9, 1H), 4.28 (ddd, J = 6.5, 4.0, 3.6, 1H), 3.78−3.66 (m, 2H),
2.76 (dd, J = 17.6, 6.6, 1H), 2.44 (dd, J = 17.6, 4.1, 1H), 1.87 (dddd,
J = 14.1, 8.0, 6.1, 4.1, 1H), 1.70 (ddt, J = 14.1, 9.0, 4.9, 1H), 0.89
(s, 9H), 0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 175.3, 85.2, 72.6, 58.9, 38.3,
36.3, 26.1, 25.8, 18.4, 18.1, −4.5, −4.6, −5.21, −5.22; IR (ATR) 2929,
1784, 1078 cm−1; HRMS (TOF MS ES+) m/z calcd for C18H39O4Si2
(M + H)+ 375.2386, found 375.2387. Anal. Calcd for C18H38O4Si2: C,
57.70; H, 10.22. Found: C, 58.00; H, 10.22.
(4R*,5S*)-4-Hydroxy-5-(2-hydroxyethyl)dihydrofuran-2(3H)-
one 27. To a solution of 26 (0.26 g, 1.5 mmol) in CH2Cl2 (15 mL) at
−78 °C was added boron tribromide (0.41 mL, 4.4 mmol). The reac-
tion mixture was allowed to warm to room temperature overnight. The
reaction mixture was cooled to −78 °C before adding MeOH (1 mL)
and concentrating in vacuo to give a brown oil. The product was puri-
fied by flash column chromatography on silica gel (2.5:97.5 MeOH:EtOAc)
1
to give 27 as a colorless oil (0.15 g, 70%): H NMR (400 MHz,
CD3OD) δ 4.48 (ddd, J = 8.8, 4.8, 2.8, 1H), 4.27 (ddd, J = 6.4, 3.4, 2.9,
1H), 3.74−3.65 (m, 2H), 2.90 (dd, J = 17.9, 6.5, 1H), 2.40 (dd, J =
17.9, 3.5, 1H), 1.90 (dddd, J = 14.3, 7.9, 6.5, 4.9, 1H), 1.77 (ddt, J =
14.3, 9.0, 5.3, 1H); 13C NMR (100 MHz, CD3OD) δ 178.1, 87.0, 72.5,
59.0, 38.1, 36.9; IR (ATR) 3360, 2925, 1748 cm−1; HRMS (TOF MS
ES+) m/z calcd for C6H10NaO4 (M + Na)+ 169.0477, found 169.0477.
Two attempts to obtain satisfactory combustion analysis data were
unsuccessful, likely because minor impurities were present that could
1
not be detected by H NMR spectroscopy.
(4R*,5S*)-4-((tert-Butyldimethylsilyl)oxy)-5-(2-((tert-butyldi-
methylsilyl)oxy)ethyl)tetrahydrofuran-2-yl Acetate 16. To a
solution of 29 (0.151 g, 0.403 mmol) in CH2Cl2 (4 mL) at −78 °C
was added diisobutylaluminum hydride (0.81 mL, 1.0 M in toluene,
0.81 mmol). After 1 h at −78 °C, a solution of dimethylaminopyridine
(0.098 g, 0.81 mmol) in CH2Cl2 (1 mL), pyridine (0.098 mL, 1.2 mmol),
and acetic anhydride (0.228 mL, 2.42 mmol) was added sequentially,
and the reaction mixture was allowed to warm to room temperature
overnight. The reaction mixture was cooled to 0 °C before saturated
aqueous sodium potassium tartrate (2 mL) and saturated aqueous
ammonium chloride (2 mL) were added. The reaction mixture was
allowed to warm to room temperature and was stirred until the layers
were completely separated. The reaction mixture was extracted with
CH2Cl2 (3 × 20 mL), and the combined organic layers were filtered
through a cotton plug and concentrated in vacuo to give a colorless oil.
The product was purified by flash column chromatography on silica gel
(1:5:94 Et3N:EtOAc:hexanes) to give 16 as a colorless oil (0.15 g,
93%). Characterization was performed on a 44:56 mixture of dia-
(7aR*,10aS*)-2,2,4,4-Tetraisopropyltetrahydrofuro[3,2-f ]-
[1,3,5,2,4]trioxadisilonin-9(6H)-one 28. To a solution of 27 (0.186
g, 1.27 mmol) in dichloroethane (13 mL) at 0 °C was added 2,6-
lutidine (0.592 mL, 5.09 mmol) and 1,3-dichloro-1,1,3,3-tetraisopro-
pyldisiloxane (0.813 mL, 2.54 mmol). The reaction mixture was stirred
at room temperature overnight, then concentrated in vacuo. The
product was purified by flash column chromatography on silica gel
(10:90 EtOAc/hexanes) to give 28 as a colorless oil (0.137 g, 28%):
1H NMR (600 MHz, CDCl3) δ 4.67 (dt, J = 7.4, 3.3, 1H), 4.57 (ddd, J
= 11.8, 3.5, 2.9, 1H), 4.02−3.96 (m, 2H), 2.87 (dd, J = 18.3, 7.7, 1H),
2.59 (dd, J = 18.3, 3.5, 1H), 2.23−2.21 (m, 1H), 1.63−1.57 (m, 1H),
1.17−0.91 (m, 28H); 13C NMR (150 MHz, CDCl3) δ 175.3, 87.7,
70.3, 58.6, 37.8, 35.2, 17.6, 17.53, 17.46, 17.4, 17.28, 17.26, 17.24,
17.19, 13.6, 13.5, 13.3, 13.0; IR (ATR) 2945, 1782, 1464, 1081 cm−1;
HRMS (TOF MS ES+) m/z calcd for C18H37O5Si2 (M + H)+
389.2179, found 389.2174. Anal. Calcd for C18H36O5Si2: C, 55.63;
H, 9.34. Found: C, 55.45; H, 9.51.
(7aR*,10aS*)-2,2,4,4-Tetraisopropylhexahydrofuro[3,2-f ]-
[1,3,5,2,4]trioxadisilonin-9-yl acetate 13. To a solution of 28
(0.137 g, 0.352 mmol) in CH2Cl2 at −78 °C was added diisobutyl-
aluminum hydride (1.0 M in toluene, 0.70 mL, 0.70 mmol). After 2 h
at −78 °C, a solution of dimethylaminopyridine (0.086 g, 0.70 mmol)
in CH2Cl2 (0.5 mL), pyridine (0.0854 mL, 1.06 mmol), and acetic
anhydride (0.200 mL, 2.11 mmol) was added. After 2 h at −78 °C, the
1
stereomers: H NMR (600 MHz, CDCl3) δ 6.29 (dd, J = 5.3, 2.0,
0.56H), 6.22 (dd, J = 5.8, 2.0, 0.44H), 4.23 (td, J = 6.4, 4.7, 0.56H),
4.09 (dt, J = 8.5, 4.5, 0.44H), 4.03 (ddd, J = 7.5, 5.0, 4.4, 0.44H), 3.96
(dt, J = 9.1, 4.4, 0.56H), 3.76−3.68 (m, 2H), 2.45 (ddd, J = 13.9, 7.4,
5.8, 0.44H), 2.21 (ddd, J = 13.5, 6.4, 2.0, 0.56H), 2.15 (ddd, J = 13.5,
6.3, 5.5, 0.56H), 2.05 (s, 1.32H), 2.03 (s, 1.68H), 1.94 (ddd, J = 14.1,
4.2, 2.0, 0.44H), 1.87−1.80 (m, 1H), 1.70 (dddd, J = 13.9, 9.1, 6.5, 5.0,
6616
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0.56H), 1.63 (ddt, J = 13.9, 8.5, 5.7, 0.44H), 0.89−0.88 (m, 18H),
0.08−0.05 (m, 12H); 13C NMR (150 MHz, CDCl3) δ 170.9, 170.4,
98.8, 98.3, 84.5, 83.4, 75.4, 75.2, 60.2, 60.0, 41.7, 41.4, 38.0, 36.4, 26.1,
25.91, 25.88, 21.62, 21.56, 18.5, 18.14, 18.09, −4.41, −4.42, −4.6,
−5.11, −5.13, −5.14, −5.15; IR (thin film) 2954, 1750, 1251, 1089
cm−1; HRMS (TOF MS ES+) m/z calcd for C20H42NaO5Si2 (M +
Na)+ 441.2467, found 441.2462. Anal. Calcd for C20H42O5Si2: C,
57.37; H, 10.11. Found: C, 57.62; H, 10.18.
mixture was stirred overnight at room temperature before adding
sodium periodate (0.562 g, 2.63 mmol). The reaction mixture was
stirred overnight before washing with saturated aqueous sodium
bicarbonate (60 mL). The aqueous layer was extracted with CH2Cl2
(2 × 40 mL). The combined organic layers were filtered through a
cotton plug and concentrated in vacuo to give a gray oil. The product
was purified by flash column chromatography on silica gel (20:80
EtOAc:hexanes) to give a lactol as a colorless oil (0.47 g, 92%). Char-
1
(Z)-2,2,4,4-Tetraisopropyl-6,9-dihydro-1,3,5,2,4-trioxadisilo-
nine 31. To a solution of cis-2-butene-1,4-diol (0.214 g, 2.43 mmol)
in CH2Cl2 (48 mL) at 0 °C were added 2,6-lutidine (0.850 mL, 7.30 mmol)
and 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (0.778 mL, 2.43 mmol).
The reaction mixture was stirred overnight at room temperature, then
was washed with saturated aqueous sodium bicarbonate (100 mL).
The aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic layers were filtered through a cotton plug and
concentrated in vacuo. The product was purified by flash column
chromatography on silica gel (5:95 EtOAc:hexanes) to give 31 as a
acterization was performed on a 56:44 mixture of diastereomers: H
NMR (600 MHz, CDCl3) δ 5.56 (dt, J = 5.5, 3.5, 0.44H), 5.40 (t, J =
4.9, 0.56H), 4.18 (dd, J = 11.3, 3.7, 0.56H), 4.13−4.09 (m, 1.32H),
4.06 (dd, J = 11.8, 2.3, 0.56H), 4.00 (dd, J = 11.8, 3.2, 0.56H), 3.98−
3.94 (m, 1H), 3.75 (dd, J = 11.3, 9.9, 0.44H), 3.66 (dd, J = 11.3, 9.8,
0.56H), 3.00 (d, J = 3.4, 0.44H), 2.88 (d, J = 5.0, 0.56H), 2.87−2.82
(m, 0.56H), 2.58 (ttd, J = 9.5, 9.2, 3.8, 0.44H), 2.28 (ddd, J = 13.4, 9.2,
5.5, 0.44H), 1.92 (dd, J = 12.2, 6.5, 0.56H), 1.68 (td, J = 12.3, 4.6,
0.56H), 1.52 (ddd, J = 13.2, 9.5, 3.7, 0.44H), 1.12−0.92 (m, 28H); 13C
NMR (150 MHz, CDCl3) δ 97.9, 97.5, 85.3, 82.7, 65.43, 65.39, 64.1,
63.5, 41.6, 38.8, 37.8, 37.1, 17.67, 17.66, 17.62, 17.61, 17.59, 17.55,
17.51, 17.48, 17.47, 17.44, 17.42, 17.40, 13.74, 13.69, 13.29, 13.27,
13.01, 12.96, 12.9; IR (ATR) 3419, 2944, 1464, 1040 cm−1; HRMS
(TOF MS ES+) m/z calcd for C18H42NO5Si2 (M + NH4)+ 408.2601,
found 408.2605. Two attempts to obtain satisfactory combustion
analysis data were unsuccessful, likely because minor impurities were
1
colorless oil (0.484 g, 60%): H NMR (600 MHz, CDCl3) δ 5.82
(ddd, J = 6.7, 4.8, 1.9, 2H), 4.39 (d, J = 6.7, 2H and dd, J = 4.8, 1.9,
2H), 1.06−1.04 (m, 24H), 1.00−0.94 (m, 4H); 13C NMR (150 MHz,
CDCl3) δ 130.8, 57.9, 17.6, 17.5, 13.7; IR (ATR) 3023, 2943, 1464,
1082 cm−1; HRMS (TOF MS ES+) m/z calcd for C16H35O3Si2 (M +
H)+ 331.2124, found 331.2125. Anal. Calcd for C16H34O3Si2: C, 58.13;
H, 10.37. Found: C, 58.38; H, 10.31.
1
present that could not be detected by H NMR spectroscopy.
4,4,6,6-Tetraisopropyl-3,5,7,10-tetraoxa-4,6-disilabicyclo-
[7.1.0]decane 32. To a solution of 31 (0.484 g, 1.47 mmol) in
CH2Cl2 (15 mL) at 0 °C was added m-chloroperoxybenzoic acid (0.66 g,
77%, 2.9 mmol). The reaction mixture was stirred at room
temperature overnight before being washed sequentially with saturated
sodium bisulfite (50 mL) and saturated aqueous sodium bicarbonate
(100 mL) and extracting with CH2Cl2 (4 × 50 mL). The combined
organic layers were filtered through a cotton plug and concentrated in
vacuo. The product was purified by flash column chromatography on
silica gel to give 32 as a colorless oil (0.50 g, 98%): 1H NMR
(600 MHz, CDCl3) δ 4.17−4.15 (m, 2H), 3.65−3.61 (m, 2H), 3.22−
3.19 (m, 2H), 1.08−0.91 (m, 28H); 13C NMR (150 MHz, CDCl3) δ
58.8, 55.8, 17.6, 17.38, 17.37, 17.3, 13.5, 13.3; IR (ATR) 2944, 1464,
1083 cm−1; HRMS (TOF MS ES+) m/z calcd for C16H35O4Si2
(M + H)+ 347.2073, found 347.2075. Two attempts to obtain
satisfactory combustion analysis data were unsuccessful, likely because
minor impurities were present that could not be detected by 1H NMR
spectroscopy.
(7R*,8S*)-8-Allyl-2,2,4,4-tetraisopropyl-1,3,5,2,4-trioxadisi-
lonan-7-ol 33. To a solution of 32 (0.495 g, 1.43 mmol) in Et2O
(15 mL) at 0 °C was added allylmagnesium bromide (4.3 mL, 1.0 M in
Et2O, 0.43 mmol). After 2 h at room temperature, saturated aqueous
ammonium chloride (50 mL) was added, and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 40 mL).
The combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to give a light yellow oil. The
product was purified by flash column chromatography on silica gel
(1:5:94 Et3N:EtOAc:hexanes) to give 33 as a light yellow oil (0.51 g,
92%): 1H NMR (600 MHz, CDCl3) δ 5.81 (dddd, J = 17.0, 10.1, 7.5,
6.7, 1H), 5.08 (ddt, J = 17.0, 2.0, 1.5, 1H), 5.03 (ddt, J = 10.1, 2.0, 1.0,
1H), 4.27 (dd, J = 10.6, 1.1, 1H), 4.01 (dd, J = 11.4, 2.5, 1H), 3.93 (dd,
J = 10.7, 4.1, 1H), 3.69 (dd, J = 11.5, 8.4, 1H), 3.45 (dddd, J = 9.1, 7.3,
4.1, 1.1, 1H), 2.85 (d, J = 9.2, 1H), 2.33 (dddt, J = 14.0, 6.1, 4.6, 1.4,
1H), 2.03 (dddt, J = 14.0, 8.7, 7.6, 1.1, 1H), 1.95 (tddd, J = 8.6, 7.2,
4.5, 2.5, 1H), 1.09−0.92 (m, 28H); 13C NMR (150 MHz, CDCl3) δ
136.8, 116.8, 73.9, 64.3, 64.2, 44.1, 33.5, 17.70, 17.67, 17.59, 17.56,
17.53, 17.50, 13.8, 13.4, 13.2, 12.8; IR (ATR) 3452, 3077, 2944, 1640,
1464, 1025 cm−1; HRMS (TOF MS ES+) m/z calcd for
C19H40NaO4Si2 (M + Na)+ 411.2362, found 411.2359. Anal. Calcd
for C19H40O4Si2: C, 58.71; H, 10.37. Found: C, 58.56; H, 10.33.
(3aR*,10aS*)-6,6,8,8-Tetraisopropylhexahydrofuro[2,3-g]-
[1,3,5,2,4]trioxadisilonin-2-yl Acetate 14. To a solution of 33
(0.511 g, 1.31 mmol) in acetone and water (10:1, 13.2 mL) at 0 °C
were added 4-methylmorpholine N-oxide (0.500 g, 4.27 mmol) and
osmium tetroxide (0.42 mL, 4.0% in water, 0.066 mmol). The reaction
To a solution of the lactol (0.134 g, 0.344 mmol) in CH2Cl2
(1.4 mL) at 0 °C were added triethylamine (0.288 mL, 2.06 mmol)
and acetic anhydride (0.0651 mL, 0.689 mmol). The reaction mixture
was stirred at room temperature overnight before being washed with
saturated aqueous sodium bicarbonate (20 mL). The layers were
separated and the aqueous layer was extracted with CH2Cl2 (2 ×
10 mL). The combined organic layers were filtered through a cotton
plug and concentrated in vacuo. The product was purified by flash
column chromatography on silica gel (1:10:89 Et3N:EtOAc:hexanes)
1
to give 14 as a colorless oil (0.148 g, 99%). H and 13C NMR spectra
of the separated diastereomers are given. IR, HRMS, and elemental
analysis of a mixture of diastereomers are given. High Rf diastereomer:
1H NMR (500 MHz, CDCl3) δ 6.26 (dd, J = 5.9, 2.9, 1H), 4.16 (ddd, J
= 8.3, 5.3, 2.9, 1H), 4.14−4.11 (m, 2H), 3.91 (dd, J = 11.6, 5.3, 1H),
3.78 (dd, J = 11.4, 8.6, 1H), 2.55 (quintd, J = 8.8, 3.6, 1H), 2.42 (ddd, J
= 13.7, 9.7, 5.9, 1H), 2.04 (s, 3H), 1.75 (ddd, J = 13.7, 8.6, 3.0, 1H),
1.10−0.92 (m, 28H); 13C NMR (100 MHz, CDCl3) δ 170.6, 98.2,
82.9, 64.3, 63.8, 42.2, 35.5, 21.5, 17.62, 17.58, 17.54, 17.51, 17.46, 17.4,
1
13.5, 13.21, 13.16, 13.0. Low Rf diastereomer: H NMR (600 MHz,
CDCl3) δ 6.22 (d, J = 4.9, 1H), 4.18 (dd, J = 11.4, 3.8, 1H), 4.09 (dd, J
= 11.9, 2.5, 1H), 4.03 (dd, J = 11.9, 3.8, 1H), 3.98 (ddd, J = 9.3, 3.5,
2.8, 1H), 3.66 (dd, J = 11.4, 9.2, 1H), 2.81 (dtdd, J = 12.5, 9.4, 6.4, 3.7,
1H), 2.03 (s, 3H), 2.01 (dd, J = 13.1, 6.4, 1H), 1.87 (td, J = 12.8, 4.9,
1H), 1.13−0.93 (m, 28H); 13C NMR (150 MHz, CDCl3) δ 170.7,
97.8, 86.1, 64.7, 63.8, 39.3, 36.2, 21.7, 17.63, 17.61, 17.56, 17.5, 17.43,
17.38, 13.6, 13.3, 13.0, 12.9; IR (ATR) 2944, 1748, 1464, 1040 cm−1;
HRMS (TOF MS ES+) m/z calcd for C20H40NaO6Si2 (M + Na)+
455.2261, found 455.2259. Anal. Calcd for C20H40O6Si2: C, 55.52; H,
9.32. Found: C, 55.64; H, 9.24.
(Z)-2,2,3,3,10,10,11,11-Octamethyl-4,9-dioxa-3,10-disilado-
dec-6-ene 34. To a solution of cis-2-butene-1,4-diol (0.429 g, 4.87
mmol) and imidazole (1.66 g, 24.3 mmol) in DMF (10 mL) at 0 °C
was added tert-butyldimethylchlorosilane (1.83 g, 12.2 mmol). The
reaction mixture was stirred at room temperature overnight before
being washed with saturated aqueous sodium bicarbonate (40 mL)
and extracted with EtOAc (2 × 40 mL). The combined organic layers
were dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo. The product was purified by flash column chromatography
on silica gel (1:99 EtOAc:hexanes) to give 34 as a colorless oil (1.48 g,
96%). The spectral data obtained matched the reported values for this
compound:32 1H NMR (600 MHz, CDCl3) δ 5.55 (t, J = 4.2, 2H),
4.23 (d, J = 4.2, 4H), 0.90 (s, 18H), 0.07 (s, 12H); 13C NMR (150
MHz, CDCl3) δ 130.4, 59.9, 26.2, 18.6, −5.0; HRMS (TOF MS ES+)
m/z calcd for C16H37O2Si2 (M + H)+ 317.2332, found 317.2327.
6617
dx.doi.org/10.1021/jo400945j | J. Org. Chem. 2013, 78, 6609−6621

The Journal of Organic Chemistry
Article
2,3-Bis(((tert-butyldimethylsilyl)oxy)methyl)oxirane 35. To a
solution of 34 (1.47 g, 4.66 mmol) in CH2Cl2 (47 mL) at 0 °C was
added m-chloroperoxybenzoic acid (2.1 g, 77%, 9.2 mmol). The
reaction mixture was stirred at room temperature overnight before
being washed sequentially with saturated aqueous sodium bisulfite
(150 mL) and saturated aqueous sodium bicarbonate (200 mL) and
being extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were filtered through a cotton plug and concentrated in vacuo.
The product was purified by flash column chromatography on silica gel
(1:5:94 Et3N:EtOAc:hexanes) to give 35 as a colorless oil (1.5 g,
97%). The spectral data obtained matched the reported values for this
compound:32 1H NMR (600 MHz, CDCl3) δ 3.80 (dd, J = 11.8, 4.2,
2H), 3.72 (dd, J = 11.8, 6.1, 2H), 3.15−3.12 (m, 2H), 0.91 (s, 18H),
0.09 (s, 6H), 0.08 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 62.0, 57.1,
26.1, 18.5, −5.0, −5.2; HRMS (TOF MS ES+) m/z calcd for
C16H37O3Si2 (M + H)+ 333.2281, found 333.2284.
sodium bicarbonate (20 mL) and extracting with CH2Cl2 (2 × 20
mL). The combined organic layers were filtered through a cotton plug
and concentrated in vacuo. The product was purified by flash column
chromatography on silica gel (1:5:94 Et3N:EtOAc:hexanes) to give 17
as a colorless oil (0.21 g, 94%). The spectral data obtained matched
the reported values for this compound.33 Characterization was
performed on a 50:50 mixture of diastereomers: 1H NMR (400
MHz, CDCl3) δ 6.29 (dd, J = 5.4, 1.0, 0.5H), 6.24 (d, J = 4.7, 0.5H),
4.07 (app q, J = 4.2, 0.5H), 3.93 (dt, J = 7.7, 5.5, 0.5H), 3.77−3.60 (m,
4H), 2.46−2.36 (m, 1H), 2.29 (ddd, J = 13.7, 10.0, 5.4, 0.5H), 2.11−
1.96 (m, 1H), 2.03 (s, 1.5H), 2.02 (s, 1.5H), 1.85 (ddd, J = 13.7, 3.4,
1.0, 0.5H), 0.90 (s, 9H), 0.89 (s, 9H), 0.06 (s, 3H and s, 3H), 0.05 (s,
3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 99.8, 99.2,
83.9, 83.8, 66.4, 65.1, 65.0, 63.9, 41.8, 41.7, 36.2, 35.2, 26.14, 26.10,
21.7, 21.6, 18.6, 18.5, −5.10, −5.13, −5.17, −5.19, −5.22, −5.24; IR
(ATR) 2929, 1750, 1092 cm−1; HRMS (TOF MS ES+) m/z calcd for
C20H42NaO5Si2 (M + Na)+ 441.2469, found 441.2467. Anal. Calcd for
C20H42O5Si2: C, 57.37; H, 10.11. Found: C, 57.38; H, 9.90.
General Procedure for Allyltrimethylsilane Addition to
Bicyclic Acetates. A solution of acetate (0.10 M) in dry CH2Cl2
was cooled to −78 °C. Allyltrimethylsilane (4 equiv) was added to the
reaction mixture, followed by dropwise addition of boron trifluoride
etherate (1.6 equiv). The reaction mixture was allowed to come slowly
to room temperature overnight. A solution of 1:1:1 dry
CH2Cl2:MeOH:Et3N was added to the reaction mixture at −78 °C.
The reaction mixture was extracted with CH2Cl2. The combined
organic layers were washed with saturated aqueous NaHCO3, dried
over anhydrous Na2SO4, and concentrated in vacuo.
(6R*,7S*)-7-Allyl-2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-
3,10-disiladodecan-6-ol 36. To a solution of 35 (1.48 g, 4.44
mmol) in Et2O (44 mL) at 0 °C was added allylmagnesium bromide
(6.7 mL, 1.0 M in Et2O, 6.7 mmol). After 3.5 h at room temperature,
saturated aqueous ammonium chloride (100 mL) was added, and the
layers were separated. The aqueous layer was extracted with EtOAc
(2 × 100 mL). The combined organic layers were dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
product was purified by flash column chromatography on silica gel
1
(5:95 EtOAc:hexanes) to give 36 as a colorless oil (1.6 g, 97%): H
NMR (500 MHz, CDCl3) δ 5.80 (dddd, J = 16.9, 10.1, 8.0, 6.3, 1H),
5.08−5.00 (m, 2H), 3.82 (dtd, J = 7.4, 4.7, 2.9, 1H), 3.68−3.67 (m,
2H), 3.67 (dd, J = 10.0, 5.1, 1H), 3.60 (dd, J = 10.1, 7.3, 1H), 2.95 (d,
J = 2.9, 1H), 2.31−2.12 (m, 2H), 1.72 (tt, J = 9.0, 4.5, 1H), 0.90 (s,
9H), 0.89 (s, 9H), 0.07 (s, 6H), 0.05 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 137.6, 116.3, 73.9, 65.2, 63.6, 42.3, 30.5, 26.12, 26.06, 18.5,
18.3, −5.1, −5.4; IR (ATR) 3511, 3077, 2928, 1640, 1089 cm−1;
HRMS (TOF MS ES+) m/z calcd for C19H42NaO3Si2 (M + Na)+
397.2570, found 397.2565. Anal. Calcd for C19H42O3Si2: C, 60.90; H,
11.30. Found: C, 61.13; H, 11.16.
(6aR,8R,9aS)-8-Allyl-2,2,4,4-tetraisopropyltetrahydro-6H-
furo[3,2-f][1,3,5,2,4]trioxadisilocine 37. The general allyltrime-
thylsilane addition procedure was followed with acetate 12 (0.038 g,
0.090 mmol). Purification by flash column chromatography on silica
gel (5:95 EtOAc:hexanes) afforded 37 as a light yellow oil (0.031 g,
85%). Characterization was performed on a 84:16 (1,3-cis-37:1,3-trans-
37) mixture of diastereomers: [α]24 −10.1 (c 1.18, MeOH); 1H
D
NMR (500 MHz, C6D6) δ 5.82−5.74 (m, 1H), 5.06−5.00 (m, 2H),
4.42 (dd, J = 13.9, 7.6, 1H), 4.19 (dd, J = 11.3, 3.6, 0.16H), 4.11 (dd,
J = 11.5, 3.6, 0.84H), 4.08−4.03 (m, 0.16H), 3.95 (ddd, J = 7.7, 6.4,
3.6, 0.84H), 3.92−3.85 (m, 1H), 3.82−3.77 (m, 1H), 2.39 (dt, J =
13.9, 6.6, 0.84H), 2.27 (dt, J = 13.5, 6.8, 0.16H), 2.22−2.13 (m, 1H),
2.07 (ddd, J = 12.1, 7.2, 6.1, 0.84H), 1.94 (ddd, J = 12.8, 6.4, 3.8,
0.16H), 1.78 (dt, J = 12.1, 8.6, 0.84H), 1.67 (dt, J = 12.8, 8.2, 0.16H),
1.18−0.93 (m, 28H); 13C NMR (125 MHz, C6D6) δ 135.3, 135.2,
117.5, 117.4, 87.1, 84.1, 77.6, 77.1, 75.5, 75.3, 65.3, 65.0, 41.1, 41.00,
40.97, 40.4, 18.2, 18.09, 18.05, 18.02, 17.97, 17.82, 17.79, 17.72, 17.69,
14.3, 14.2, 14.1, 14.0, 13.8, 13.7, 13.4; IR (thin film) 3078, 2945, 1643,
1036 cm−1; HRMS (TOF MS ES+) m/z calcd for C20H40NaO4Si2 (M
+ Na)+ 423.2363, found 423.2361. Anal. Calcd for C20H40O4Si2: C,
59.95; H, 10.06. Found: C, 60.21; H, 10.15.
(4R*,5S*)-4,5-Bis(((tert-butyldimethylsilyl)oxy)methyl)-
tetrahydrofuran-2-yl Acetate 17. To a solution of 36 (1.61 g,
4.30 mmol) in acetone and water (10:1, 44 mL) at 0 °C were added
4-methylmorpholine-N-oxide (1.64 g, 14.0 mmol) and osmium
tetroxide (1.4 mL, 4.0% in water, 0.22 mmol). The reaction mixture
was stirred overnight at room temperature before sodium periodate
(1.84 g, 8.59 mmol) was added. After 8 h at room temperature, the
reaction mixture was washed with saturated aqueous sodium
bicarbonate (100 mL) and extracted with CH2Cl2 (2 × 125 mL).
The combined organic layers were filtered through a cotton plug and
concentrated in vacuo to give a gray oil. The product was purified by
flash column chromatography on silica gel (10:90 EtOAc:hexanes) to
give a lactol as a colorless oil (1.4 g, 87%). Characterization was
performed on a 50:50 mixture of diastereomers: 1H NMR (500 MHz,
CDCl3) δ 5.37 (t, J = 4.6, 0.5H), 5.35 (dd, J = 4.6, 2.4, 0.5H), 4.81 (d,
J = 10.4, 0.5H), 4.08−4.00 (m, 1.5H), 3.84 (dd, J = 10.5, 2.5, 0.5H),
3.74−3.68 (m, 2H), 3.62 (dd, J = 10.5, 2.0, 0.5H), 3.59 (dd, J = 10.4,
5.7, 0.5H), 3.51 (dd, J = 9.4, 8.4, 0.5H), 2.61−2.54 (m, 0.5H), 2.39−
2.34 (m, 0.5H), 2.25 (td, J = 11.4, 5.1, 0.5H), 1.96 (dd, J = 12.7, 7.8,
0.5H), 1.75−1.68 (m, 1H), 0.93 (s, 4.5H and s, 4.5H), 0.89 (s, 4.5H),
0.88 (s, 4.5H), 0.12 (s, 6H), 0.06 (s, 1.5H), 0.05 (s, 1.5H), 0.04 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 98.8, 98.6, 83.8, 80.2, 65.50,
65.46, 65.3, 41.3, 39.3, 38.6, 37.7, 26.13, 26.12, 26.09, 26.06, 18.7, 18.6,
18.5, 18.4, −5.1, −5.18, −5.23, −5.28, −5.30, −5.37, −5.39; IR (ATR)
3422, 2953, 1253, 1085 cm−1; HRMS (TOF MS ES+) m/z calcd for
C18H40NaO4Si2 (M + Na)+ 399.2363, found 399.2360. Anal. Calcd for
C18H40O4Si2: C, 57.40; H, 10.70. Found: C, 57.94; H, 10.77. Two
attempts to obtain satisfactory combustion analysis data were
unsuccessful, likely because minor impurities were present that could
(((2R,3S,5R)-5-Allyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-
tetrahydrofuran-3-yl)oxy)(tert-butyl)dimethylsilane 40. The
general allyltrimethylsilane addition procedure was followed with
acetate 15 (0.148 g, 0.366 mmol). Purification by flash column
chromatography on silica gel (5:95 EtOAc:hexanes) afforded 40 as a
1
colorless oil (0.129 g, 91%): [α]24 34.9 (c 1.45, CH2Cl2); H NMR
D
(500 MHz, CDCl3) δ 5.80 (ddt, J = 17.2, 10.2, 7.0, 1H), 5.10−5.03
(m, 2H), 4.35 (ddd, J = 6.4, 5.0, 4.1, 1H), 4.09 (quint, J = 6.6, 1H),
3.84 (app q, J = 4.1, 1H), 3.61 (dd, J = 10.9, 3.9, 1H), 3.56 (dd, J =
10.9, 5.0, 1H), 2.47 (dt, J = 14.0, 6.6, 1H), 2.32 (dt, J = 14.0, 7.0, 1H),
2.17 (dt, J = 12.6, 6.7, 1H), 1.66 (ddd, J = 12.7, 6.2, 5.2, 1H), 0.89 (s,
9H), 0.88 (s, 9H), 0.06 (s, 6H), 0.05 (s, 3H and s, 3H); 13C NMR
(125 MHz, CDCl3) δ 135.4, 116.9, 86.5, 78.5, 73.5, 63.7, 41.1, 40.2,
26.2, 26.0, 18.6, 18.2, −4.5, −4.6, −5.1, −5.2; IR (thin film) 3078,
2954, 1643, 1471, 1255, 1111 cm−1; HRMS (TOF MS ES+) m/z calcd
for C20H42NaO3Si2 (M + Na)+ 409.2570, found 409.2562. Anal. Calcd
for C20H42O3Si2: C, 62.12; H, 10.95. Found: C, 62.42; H, 11.07.
(7aR*,9R*,10aS*)-9-Allyl-2,2,4,4-tetraisopropylhexahydro-
furo[3,2-f][1,3,5,2,4]trioxadisilonine 38. The general allyltrime-
thylsilane addition procedure was followed with acetate 13 (0.056 g,
0.13 mmol). Purification by flash column chromatography on silica gel
1
not be detected by H NMR spectroscopy.
To a solution of the lactol (0.200 g, 0.531 mmol) in CH2Cl2 (5 mL)
at 0 °C were added triethylamine (0.89 mL, 6.4 mmol) and acetic
anhydride (0.20 mL, 2.1 mmol). The reaction mixture was stirred at
room temperature overnight before washing with saturated aqueous
6618
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The Journal of Organic Chemistry
Article
(5:95 EtOAc:hexanes) afforded 38 as a colorless oil (0.46 g, 86%): 1H
NMR (600 MHz, CDCl3) δ 5.81 (ddt, J = 17.2, 10.2, 7.0, 1H), 5.09
(ddt, J = 17.2, 2.0, 1.5, 1H), 5.06 (ddt, J = 10.2, 2.1, 1.0, 1H), 4.48 (dt,
J = 7.1, 3.9, 1H), 4.09 (dt, J = 11.3, 3.7, 1H), 4.05 (dt, J = 12.6, 6.7,
1H), 3.98−3.92 (m, 2H), 2.50 (dtt, J = 13.9, 6.8, 1.3, 1H), 2.35 (dtt,
J = 13.9, 7.1, 1.2, 1H), 2.22 (dt, J = 12.6, 7.0, 1H), 2.09−2.03 (m, 1H),
1.77 (ddd, J = 12.8, 5.8, 4.1, 1H), 1.53−1.47 (m, 1H), 1.19−0.87 (m,
28H); 13C NMR (150 MHz, CDCl3) δ 135.4, 117.1, 84.6, 77.6, 75.6,
59.5, 40.9, 39.9, 36.2, 17.8, 17.7, 17.59, 17.56, 17.47, 17.46, 17.45,
13.60, 13.57, 13.11, 13.10; IR (ATR) 2943, 2867, 1642, 1464 cm−1;
HRMS (TOF MS APCI+) m/z calcd for C21H43O4Si2 (M + H)+
415.2692, found 415.2693. Anal. Calcd for C21H42O4Si2: C, 60.82; H,
10.21. Found: C, 60.70; H, 9.99.
(((2R*,3S*,5R*)-5-Allyl-2-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)tetrahydrofuran-3-yl)oxy)(tert-butyl)dimethylsilane 41.
The general allyltrimethylsilane addition procedure was followed
with acetate 16 (0.080 g, 0.19 mmol). The products were purified by
flash column chromatography on silica gel (5:95−25:75 EtOAc:hex-
anes) to give 41 (0.031 g, 40%) and a mono-TBS protected allyl
product (0.030 g, 54%) as colorless oils: 1H NMR (600 MHz, C6D6) δ
5.85 (dddd, J = 17.2, 10.2, 7.3, 6.7, 1H), 5.09−5.02 (m, 2H), 4.07
(ddd, J = 8.9, 5.1, 3.5, 1H), 3.97 (tt, J = 6.8, 6.7, 1H), 3.91 (td, J = 6.3,
5.3, 1H), 3.84 (dd, J = 7.6, 5.4, 2H), 2.49 (dtd, J = 13.4, 6.5, 1.4, 1H),
2.29 (dtd, J = 14.0, 7.1, 1.0, 1H), 1.96 (dt, J = 12.4, 6.8, 1H), 1.89 (dtd,
J = 13.5, 7.5, 3.5, 1H), 1.67−1.59 (m, 2H), 0.99 (s, 9H), 0.95 (s, 9H),
0.10 (s, 3H), 0.09 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR
(150 MHz, C6D6) δ 135.6, 116.8, 81.5, 77.8, 77.0, 60.6, 41.3, 40.6,
37.4, 26.2, 26.0, 18.5, 18.2, −4.4, −4.6, −5.12, −5.14; IR (ATR) 3078,
2929, 1642, 1472, 1251, 1085 cm−1; HRMS (TOF MS ES+) m/z calcd
for C21H44NaO3Si2 (M + Na)+ 423.2726, found 423.2728. Anal. Calcd
for C21H44O3Si2: C, 62.94; H, 11.07. Found: C, 63.15; H, 11.01.
2-((2R*,3S*,5R*)-(5-Allyl-3-((tert-butyldimethylsilyl)oxy)-
tetrahydrofuran-2-yl)ethan-1-ol. 1H NMR (600 MHz, C6D6) δ
5.74 (ddt, J = 17.2, 10.2, 7.0, 1H), 5.05−4.99 (m, 2H), 3.92 (ddd, J =
9.2, 5.6, 3.6, 1H), 3.87 (tt, J = 7.0, 6.6, 1H), 3.80 (td, J = 6.7, 5.8, 1H),
3.73 (m, 2H), 2.47 (br s, 1H), 2.34 (dtt, J = 13.7, 6.6, 1.3, 1H), 2.17
(dtt, J = 13.9, 7.0, 1.0, 1H), 1.88 (dt, J = 12.4, 6.8, 1H), 1.69 (dtd, J =
14.0, 5.1, 3.6, 1H), 1.61−1.55 (m, 1H), 1.50 (ddd, J = 12.4, 7.3, 6.9,
1H), 0.92 (s, 9H), −0.01 (s, 3H), −0.02 (s, 3H); 13C NMR (150
MHz, C6D6) δ 135.1, 117.1, 84.2, 77.4, 77.1, 61.3, 41.0, 40.2, 35.8,
26.0, 18.1, −4.5, −4.7; IR (ATR) 3421, 3077, 2929, 1642 cm−1;
HRMS (TOF MS ES+) m/z calcd for C15H31O3Si (M + H)+
287.2042, found 287.2044. Anal. Calcd for C15H30O3Si: C, 62.89; H,
10.55. Found: C, 62.67; H, 10.35.
0.92H), 1.68−1.61 (m, 0.92H), 1.35 (dt, J = 12.1, 9.7, 0.08H), 0.90 (s,
9H), 0.89 (s, 9H), 0.06 (s, 6H), 0.04 (s, 6H); 13C NMR (100 MHz,) δ
135.4, 116.8, 82.4, 78.4, 65.9, 65.0, 43.6, 40.6, 34.4, 26.2, 18.6, 18.5,
−5.0, −5.1, −5.2; IR (ATR) 3078, 2928, 1643, 1092 cm−1; HRMS
(TOF MS ES+) m/z calcd for C21H44NaO3Si2 (M + Na)+ 423.2726,
found 423.2726. Anal. Calcd for C21H44O3Si2: C, 62.94; H, 11.07.
Found: C, 63.14; H, 11.28.
Stereochemical Proofs of Nucleophilic Substitution Reac-
tions. In all cases, the diastereoselectivities were determined by GC
analysis of the unpurified reaction mixture and confirmed by 1H NMR
spectroscopy. The relative stereochemistry of the nucleophilic sub-
stitution products was proven by X-ray structure determination of
crystalline derivatives and subsequent chemical correlation.
(E)-1-(2-((2R,4S,5R)-4-((tert-Butyldimethylsilyl)oxy)-5-(((tert-
butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-
ethylidene)-2-(2,4-dinitrophenyl)hydrazine 44. To a solution of
40 (0.102 g, 0.263 mmol) in acetone and water (2.2 mL, 10:1) at 0 °C
were added 4-methylmorpholine N-oxide (0.100 g, 0.854 mmol) and
osmium tetroxide (0.17 mL, 2.5% in H2O, 0.013 mmol). After being
stirred overnight at room temperature, the reaction mixture was washed
with saturated aqueous sodium thiosulfate (4 mL) and extracted with
Et2O (2 × 20 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The product
was purified by flash column chromatography on silica gel (Et2O) to
give a diol as a colorless oil (0.102 g, 92%). Characterization was
performed on a 50:50 mixture of diastereomers: [α]24 34.9 (c 1.35,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 4.38−4.29 (m, 2H), 3.98−
3.90 (m, 1H), 3.88−3.83 (m, 1.5H), 3.65−3.48 (m, 4H), 3.02 (d,
J = 3.8, 0.5H), 2.39−2.36 (m, 0.5H), 2.31−2.23 (m, 1.5H), 1.91−1.64
(m, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H), 0.05 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 86.5, 86.4, 78.6, 76.4, 73.1, 72.9, 71.7,
70.0, 67.0, 66.7, 63.4, 63.3, 41.5, 40.8, 39.2, 38.5, 26.0, 25.9, 18.4, 18.1,
−4.6, −4.7, −5.2, −5.3; IR (thin film) 3417, 2929, 1647, 1464 cm−1;
HRMS (TOF MS ES+) m/z calcd for C20H44NaO5Si2 (M + Na)+
443.2625, found 443.2622. Anal. Calcd for C20H44O5Si2: C, 57.09; H,
10.54. Found: C, 56.89; H, 10.60.
To a solution of the diol (0.079 g, 0.19 mmol) in acetone and water
(2 mL, 1:1) was added sodium periodate (0.048 g, 0.23 mmol). After
being stirred overnight at room temperature, the reaction mixture was
washed with saturated aqueous NaHCO3 and extracted with CH2Cl2
(3 × 15 mL). The combined organic layers were filtered through a
cotton plug and concentrated in vacuo. The product was purified by
flash column chromatography on silica gel (10:90 EtOAc:hexanes) to
give an aldehyde as a colorless oil (0.065 g, 88%): [α]24D 38.8 (c 0.98,
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 9.81 (t, J = 1.9, 1H), 4.56
(2R*,3aS*,10aR*)-2-Allyl-6,6,8,8-tetraisopropylhexahydrofuro-
[2,3-g][1,3,5,2,4]trioxadisilonine 39. The general allyltrimethylsilane
addition procedure was followed with acetate 14 (0.115 g, 0.266 mmol).
Purification by flash column chromatography on silica gel (5:95 EtOAc:
hexanes) afforded 39 as a colorless oil (0.106 g, 96%): 1H NMR (500
MHz, CDCl3) δ 5.82 (ddt, J = 17.2, 10.2, 7.0, 1H), 5.09−5.03 (m,
2H), 4.12−4.07 (m, 2H), 4.02 (tt, J = 7.2, 5.8, 1H), 3.95 (dd, J = 11.7,
4.2, 1H), 3.77 (tt, J = 3.6, 3.1, 1H), 3.64 (dd, J = 11.2, 9.8, 1H), 2.52
(quintd, J = 9.1, 3.6, 1H), 2.37 (dt, J = 13.2, 6.6, 1H), 2.23 (dt, J =
13.9, 7.0, 1H), 1.75−1.65 (m, 2H), 1.11−0.88 (m, 28H); 13C NMR
(125 MHz, CDCl3) δ 135.0, 117.2, 84.1, 77.1, 65.3, 64.1, 41.4, 41.0,
33.5, 17.69, 17.67, 17.64, 17.59, 17.50, 17.47, 13.7, 13.3, 13.1; IR (thin
film) 3076, 2945, 1642, 1465, 1045 cm−1; HRMS (TOF MS ES+) m/z
calcd for C21H46NO4Si2 (M + NH4)+ 432.2965, found 432.2962. Anal.
Calcd for C21H42O4Si2: C, 60.82; H, 10.21. Found: C, 60.85; H, 10.07.
((((2R*,3S*,5R*)-5-Allyltetrahydrofuran-2,3-diyl)bis-
(methylene))bis(oxy))bis(tert-butyldimethylsilane) 42. The gen-
eral allyltrimethylsilane addition procedure was followed with acetate
17 (0.103 g, 0.246 mmol). Purification by flash column chromatog-
raphy on silica gel (5:95 EtOAc:hexanes) afforded 42 as a colorless oil
(0.076 g, 77%). Characterization was performed on a 8:92 (1,3-cis-
42:1,3-trans-42) mixture of diastereomers: 1H NMR (400 MHz,
CDCl3) δ 5.81 (ddt, J = 17.2, 10.2, 7.0, 1H), 5.10−5.01 (m, 2H), 4.02
(ddd, J = 11.8, 9.7, 6.2, 0.08H), 3.95 (dt, J = 14.4, 6.3, 0.92H), 3.80
(dt, J = 6.8, 4.6, 0.08H), 3.72−3.54 (m, 4.92H), 2.39−2.18 (m, 3H),
2.07 (ddd, J = 12.5, 7.7, 5.4, 0.08H), 1.81 (ddd, J = 12.4, 6.3, 4.6,
(tt, J = 7.3, 5.4, 1H), 4.38 (tt, J = 3.4, 3.0, 1H), 3.90 (dt, J = 5.4, 3.7,
1H), 3.61 (dd, J = 10.8, 3.9, 1H), 3.51 (dd, J = 10.8, 5.4, 1H), 2.90
(ddd, J = 16.7, 7.3, 2.2, 1H), 2.66 (ddd, J = 16.7, 5.5, 1.6, 1H), 2.32 (tt,
J = 7.2, 6.2, 1H), 1.67 (ddd, J = 12.7, 4.8, 3.9, 1H), 0.89 (s, 9H), 0.88
(s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H and s, 3H); 13C NMR
(125 MHz, CDCl3) δ 201.9, 87.1, 74.1, 73.7, 63.7, 50.6, 40.6, 26.1,
25.9, 18.5, 18.1, −4.65, −4.68, −5.2, −5.3; IR (thin film) 2954, 2719,
1728, 1471 cm−1; HRMS (TOF MS ES+) m/z calcd for
C19H40NaO4Si2 (M + Na)+ 411.2363, found 411.2359. Anal. Calcd
for C19H40O4Si2: C, 58.71; H, 10.37. Found: C, 58.80; H, 10.46.
To a solution of aldehyde (0.041 g, 0.11 mmol) in EtOH (1 mL)
was added 2,4-dinitrophenylhydrazine (0.020 g 0.10 mmol). The reac-
tion mixture was stirred at 80 °C overnight, then concentrated in vacuo to
give an orange oil. The product was purified by flash column chro-
matography on silica gel (10:90 EtOAc/hexanes) to give hydrazone 44
1
as an orange oil (0.050 g, 83%): [α]24 +24 (c 0.55, CH2Cl2); H
D
NMR (500 MHz, CDCl3) δ 11.45 (s, 0.27H), 11.05 (s, 0.73H), 9.12
(d, J = 2.6, 0.27H), 9.11 (d, J = 2.6, 0.73H), 8.31 (d, J = 2.5, 0.27H),
8.28 (dd, J = 9.8, 2.5, 0.73H), 7.95 (d, J = 9.7, 0.27H), 7.92 (d, J = 9.6,
0.73H), 7.60 (t, J = 5.6, 0.73H), 7.15 (t, J = 5.8, 0.27H), 4.46−4.36 (m,
2H), 4.05 (dt, J = 4.6, 3.5, 0.27H), 3.94 (dt, J = 4.5, 3.7, 0.73H), 3.63
(dd, J = 10.9, 3.9, 1H), 3.57−3.53 (m, 1H), 2.89−2.80 (m, 1H), 2.68
(dt, J = 15.0, 5.4, 0.73H), 2.56 (ddd, J = 15.6, 5.4, 3.5, 0.27H), 2.40−
2.30 (m, 1H), 1.80−1.72 (m, 1H), 0.90 (s, 6.57H), 0.89 (s, 6.57H),
0.88 (s, 2.43H), 0.86 (s, 2.43H), 0.08 (s, 3H and s, 3H), 0.06
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Article
(s, 2.19H), 0.05 (s, 2.19H), 0.04 (s, 0.81H), 0.03 (s, 0.81H); 13C
NMR (125 MHz, CDCl3) δ 150.6, 149.0, 145.8, 145.3, 138.3, 138.0,
130.1, 129.9, 129.0, 124.7, 123.7, 123.6, 116.9, 116.7, 87.4, 87.3, 77.4,
76.5, 73.9, 73.4, 63.8, 63.5, 40.9, 40.5, 39.6, 35.3, 26.12, 26.08, 25.98,
25.95, 18.5, 18.2, −4.55, −4.58, −4.61, −5.1, −5.19, −5.22, −5.3; IR
(thin film) 3302, 3109, 2954, 1620 cm−1; HRMS (TOF MS ES+) m/z
calcd for C25H44N4NaO7Si2 (M + Na)+ 591.2646, found 591.2643.
Anal. Calcd for C25H44N4O7Si2: C, 52.79; H, 7.80. Found: C, 53.08; H,
7.89.
1H), 4.13 (dd, J = 11.4, 3.8, 1H), 4.08 (dd, J = 11.8, 2.6, 1H), 3.97 (dd,
J = 11.8, 3.9, 1H), 3.79 (ddd, J = 8.8, 3.7, 2.7, 1H), 3.66 (dd, J = 11.4,
9.5, 1H), 2.77 (ddd, J = 16.6, 6.7, 1.9, 1H), 2.60−2.53 (m, 2H), 1.87
(ddd, J = 12.7, 9.5, 8.3, 1H), 1.71 (ddd, J = 12.6, 8.9, 4.8, 1H), 1.11−
0.92 (m, 28H); 13C NMR (150 MHz, CDCl3) δ 201.4, 84.6, 72.7,
65.2, 63.8, 50.5, 41.1, 34.5, 17.67, 17.66, 17.64, 17.62, 17.58, 17.56,
17.52, 17.45, 13.7, 13.3, 13.07, 13.05; IR (ATR) 2955, 2725, 1726,
1464, 1040 cm−1; HRMS (TOF MS ES+) m/z calcd for C20H41O5Si2
(M + H)+ 417.2493, found 417.2489. Anal. Calcd for C20H40O5Si2: C,
57.65; H, 9.68. Found: C, 57.38; H, 9.71.
(E)-1-(2-((2R*,4S*,5R*)-4-((tert-Butyldimethylsilyl)oxy)-5-(2-
((tert-butyldimethylsilyl)oxy)ethyl)tetrahydrofuran-2-yl)-
ethylidene)-2-(2,4-dinitrophenyl)hydrazine 46. To a solution of
41 (0.051 g, 0.13 mmol) in CH2Cl2 (2 mL) at −78 °C was added a
stream of ozone until a blue color persisted. The reaction mixture was purged
with oxygen for 30 min, and triphenylphosphine (0.066 g, 0.25 mmol)
was added. The reaction mixture was stirred at room temperature
overnight before being concentrated in vacuo. The product was purified
by flash column chromatography on silica gel (10:90 EtOAc:hexanes)
To a solution of the aldehyde (0.091 g, 0.22 mmol) in EtOH
(2 mL) was added 2,4-dinitrophenylhydrazine (0.042 g, 0.21 mmol). The
reaction mixture was heated at 80 °C overnight and cooled to room
temperature before being concentrated in vacuo to give an orange
solid. The product was purified by flash column chromatography on
silica gel (15:85 EtOAc:hexanes) to give 48 as an orange solid (0.114
1
g, 92%): mp 116−120 °C; H NMR (600 MHz, CDCl3) δ 11.05 (s,
1H), 9.12 (d, J = 2.5, 1H), 8.30 (ddd, J = 9.5, 2.6, 0.6, 1H), 7.92 (d, J =
9.6, 1H), 7.60 (t, J = 5.5, 1H), 4.26 (tt, J = 7.6, 4.9, 1H), 4.15 (dd, J =
11.4, 3.7, 1H), 4.11 (dd, J = 11.9, 2.5, 1H), 3.99 (dd, J = 11.8, 3.7, 1H),
3.81 (ddd, J = 8.9, 3.5, 2.7, 1H), 3.67 (dd, J = 11.3, 9.5, 1H), 2.70−2.57
(m, 3H), 1.85 (ddd, J = 12.6, 9.7, 8.2, 1H), 1.80 (ddd, J = 12.5, 8.9, 4.7,
1H), 1.11−0.91 (m, 28H); 13C NMR (150 MHz, CDCl3) δ 150.0,
145.3, 138.1, 130.1, 129.1, 123.7, 116.7, 84.8, 75.4, 65.2, 63.7, 41.1,
39.5, 34.2, 17.67, 17.65, 17.62, 17.55, 17.4, 13.7, 13.3, 13.1, 13.0, 12.8;
IR (ATR) 3303, 2941, 1611, 1320, 1037 cm−1; HRMS (TOF MS ES
+) m/z calcd for C26H45N4O8Si2 (M + H)+ 597.2776, found 597.2776.
Anal. Calcd for C26H44N4O8Si2: C, 52.32; H, 7.43. Found: C, 52.50; H,
7.58.
1
to give an aldehyde as a colorless oil (0.043 g, 83%): H NMR (600
MHz, CDCl3) δ 9.81 (t, J = 2.0, 1H), 4.52 (tt, J = 7.4, 5.6, 1H), 4.09
(dt, J = 6.2, 4.1, 1H), 3.92 (dd, J = 8.8, 4.0, 1H), 3.72 (ddd, J = 10.2,
7.0, 5.2, 1H), 3.67 (ddd, J = 10.2, 7.7, 6.1, 1H), 2.88 (ddd, J = 16.7, 7.3,
2.2, 1H), 2.65 (ddd, J = 16.7, 5.7, 1.8, 1H), 2.34 (ddd, J = 12.9, 7.4, 6.3,
1H), 1.71 (dtd, J = 13.7, 7.3, 4.3, 1H), 1.63 (ddd, J = 13.0, 5.6, 4.4,
1H), 1.57 (dddd, J = 13.9, 8.8, 6.1, 5.2, 1H), 0.89 (s, 9H), 0.88 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H and s, 3H and s, 3H); 13C NMR (150 MHz,
CDCl3) δ 201.9, 82.8, 77.1, 72.8, 60.2, 50.6, 40.7, 36.9, 26.1, 26.0, 18.5,
18.1, −4.5, −4.6, −5.1; IR (ATR) 2929, 2722, 1726, 1084 cm−1; HRMS
(TOF MS ES+) m/z calcd for C20H43O4Si2 (M + H)+ 403.2699, found
403.2699. Two attempts to obtain satisfactory combustion analysis
data were unsuccessful, likely because minor impurities were present
General Procedure for Deprotection. A solution of silyl-
protected diol was dissolved in tetrahydrofuran (0.1 M). Tetrabutyl-
ammonium fluoride (3 equiv) was added dropwise at room
temperature, and the reaction mixture was allowed to stir overnight.
Aqueous NH4HCO3 (5%, 3 mL) was added to the reaction mixture,
which was then extracted with EtOAc (2 × 10 mL). The combined
organic layers were washed with brine (10 mL), dried over Na2SO4,
and concentrated in vacuo.
1
that could not be detected by H NMR spectroscopy.
To a solution of the aldehyde (0.035 g, 0.088 mmol) in EtOH
(1 mL) was added 2,4-dinitrophenylhydrazine (0.017 g, 0.083 mmol).
The reaction mixture was heated at 80 °C overnight, then concen-
trated in vacuo. The product was purified by flash column chromato-
graphy (5:95 EtOAc:hexanes) to give 46 as a yellow solid (0.049 g,
1
96%): mp 116−128 °C; H NMR (600 MHz, CDCl3) δ 11.4 (s,
(2R,3S,5R)-5-Allyl-2-(hydroxymethyl)tetrahydrofuran-3-ol
43. The general deprotection procedure was followed with compound
37 (0.15 g, 0.38 mmol). The resulting oil was purified by flash column
chromatography on silica gel (4:1 EtOAc:hexanes) to afford diol 43 as
a light yellow oil (0.053 g, 86%). Characterization was performed on a
0.2H), 11.1 (s, 0.8H), 9.13 (d, J = 2.6, 0.2H), 9.12 (d, J = 2.6, 0.8H),
8.31 (ddd, J = 9.6, 2.6, 0.6, 0.2H), 8.29 (ddd, J = 9.6, 2.6, 0.8, 0.8H),
7.96 (d, J = 9.5, 0.2H), 7.92 (d, J = 9.5, 0.8H), 7.60 (t, J = 5.5, 0.8H),
7.16 (t, J = 5.7, 0.2H), 4.38 (tdd, J = 7.7, 6.0, 3.8, 0.2H), 4.34 (tt, J =
7.4, 5.2, 0.8H), 4.15 (ddd, J = 6.1, 4.4, 3.8, 0.2H), 4.12 (dt, J = 6.3, 3.9,
0.8H), 4.05 (dt, J = 8.5, 4.1, 0.2H), 3.97 (dt, J = 8.6, 4.0, 0.8H), 3.73
(ddd, J = 10.2, 6.8, 5.3, 1H), 3.69 (ddd, J = 10.2, 7.7, 6.1, 0.8H), 3.65
(ddd, J = 10.3, 7.4, 6.5, 0.2H), 2.83 (ddd, J = 14.9, 7.5, 5.3, 0.8H), 2.79
(ddd, J = 15.6, 8.0, 5.9, 0.2H), 2.68 (dt, J = 14.9, 5.5, 0.8H), 2.59 (ddd,
J = 15.7, 5.5, 3.9, 0.2H), 2.36 (ddd, J = 13.1, 7.3, 6.2, 0.2H), 2.33 (ddd,
J = 13.1, 7.4, 6.4, 0.8H), 1.76−1.69 (m, 2H), 1.61−1.57 (m, 1H), 0.90
(s, 7.2H), 0.89 (s, 7.2H), 0.88 (s, 1.8H), 0.86 (s, 1.8H), 0.08 (s, 2.4H
and s, 1.2H), 0.07 (s, 2.4H), 0.06 (s, 2.4H), 0.05 (s, 2.4H), 0.02 (s,
0.6H), 0.01 (s, 0.6H); 13C NMR (150 MHz, CDCl3) δ 150.6, 145.3,
138.1, 130.1, 123.7, 116.7, 83.1, 77.1, 75.5, 60.2, 40.4, 39.4, 36.8, 35.0,
26.2, 26.1, 26.0, 25.9, 18.5, 18.2, −4.45, −4.51, −5.1; IR 3282, 3062,
2951, 1615, 1095 cm−1; HRMS (TOF MS ES+) m/z calcd for
C26H47N4O7Si2 (M + H)+ 583.2983, found 583.2986. Two attempts to
obtain satisfactory combustion analysis data were unsuccessful, likely
because minor impurities were present that could not be detected by
1H NMR spectroscopy.
86:14 (1,3-cis-43:1,3-trans-43) mixture of diastereomers: [α]24 +34
D
1
(c 0.89, MeOH); H NMR (500 MHz, CD3OD) δ 5.89−5.78 (m,
1H), 5.09 (dd, J = 7.2, 1.6, 1H), 5.03 (dt, J = 10.3, 1.0, 1H), 4.22−4.10
(m, 1.16H), 4.09 (tt, J = 7.0, 6.5, 0.84H), 3.79−3.75 (m, 1H), 3.61
(dd, J = 11.7, 3.8, 0.84H), 3.53 (dd, J = 11.5, 5.3, 1.16H), 2.46−2.26
(m, 2.86H), 1.88 (dd, J = 13.2, 5.4, 0.14H), 1.74−1.63 (m, 1H); 13C
NMR (125 MHz, CD3OD) δ 136.2, 136.1, 117.54, 117.49, 88.8, 86.9,
79.4, 79.2, 74.2, 73.5, 64.2, 63.5, 41.8, 41.4, 41.04, 40.95; IR (thin film)
3375, 3078, 2931, 1643 cm1; HRMS (TOF MS ES+) m/z calcd for
C8H14NaO3 (M + Na)+ 181.0841, found 181.0837.
(2R*,3S*,5R*)-5-Allyl-2-(2-hydroxyethyl)tetrahydrofuran-3-
ol 45. The general deprotection procedure was followed with com-
pound 38 (0.046 g, 0.11 mmol). The resulting oil was purified by flash
column chromatography on silica gel (EtOAc) to afford diol 45 as a
1
colorless oil (0.018 g, 97%): H NMR (600 MHz, CD3OD) δ 5.82
(ddt, J = 17.2, 10.3, 7.0, 1H), 5.11−5.03 (m, 2H), 4.05 (tt, J = 7.7, 6.5,
1H), 4.01 (td, J = 6.7, 5.3, 1H), 3.80 (dt, J = 8.4, 5.0, 1H), 3.69 (ddd,
J = 10.8, 6.9, 5.4, 1H), 3.64 (ddd, J = 10.8, 7.6, 6.3, 1H), 2.41 (dtt, J =
13.5, 7.0, 1.3, 1H), 2.33−2.27 (m, 2H), 1.78 (dddd, J = 13.9, 7.6, 7.0,
4.8, 1H), 1.67 (dddd, J = 14.0, 8.3, 6.3, 5.4, 1H), 1.62 (ddd, J = 12.7,
7.7, 6.6, 1H); 13C NMR (150 MHz, CD3OD) δ 136.0, 117.4, 83.2,
78.0, 77.2, 60.3, 41.7, 40.5, 37.1; IR (thin film) 3351, 3077, 2923, 1642,
1050 cm−1; HRMS (TOF MS ES+) m/z calcd for C9H16NaO3 (M +
Na)+ 195.0998, found 195.1001. Two attempts to obtain satisfactory
combustion analysis data were unsuccessful, likely because minor
impurities were present that could not be detected by 1H NMR
spectroscopy.
(E)-1-(2,4-Dinitrophenyl)-2-(2-((2R*,3aR*,10aS*)-6,6,8,8-
tetraisopropylhexahydrofuro[2,3-g][1,3,5,2,4]trioxadisilonin-
2-yl)ethylidene)hydrazine 48. To a solution of 39 (0.162 g,
0.390 mmol) in CH2Cl2 (4 mL) at −78 °C was added a stream of
ozone until a blue color persisted. The reaction mixture was purged
with oxygen for 30 min, and triphenylphosphine (0.205 g, 0.780 mmol)
was added. The reaction mixture was stirred at room temperature
overnight before concentrating in vacuo. The product was purified
by flash column chromatography on silica gel (10:90 EtOAc:hexanes)
to give an aldehyde as a colorless oil (0.151 g, 93%): 1H NMR
(600 MHz, CDCl3) δ 9.81 (t, J = 1.9, 1H), 4.42 (dtd, J = 8.2, 6.3, 4.9,
6620
dx.doi.org/10.1021/jo400945j | J. Org. Chem. 2013, 78, 6609−6621

The Journal of Organic Chemistry
Article
((2R*,3S*,5R*)-(5-Allyltetrahydrofuran-2,3-diyl)dimethanol
47. The general deprotection procedure was followed with compound
42 (0.071 g, 0.18 mmol). The resulting oil was purified by flash
column chromatography on silica gel (EtOAc) to afford diol 47 as a
colorless oil (0.030 g, 99%). Characterization was performed on a 8:92
(1,3-cis-47:1,3-trans-47) mixture of diastereomers: 1H NMR (600
MHz, MeOD) δ 5.87−5.80 (m, 1H), 5.10−5.02 (m, 2H), 4.05 (dq, J =
9.7, 6.0, 0.1H), 3.97 (dq, J = 7.7, 6.4, 0.9H), 3.79 (ddd, J = 7.3, 5.6, 4.3,
0.1H), 3.68 (td, J = 6.0, 4.4, 0.9H), 3.62 (dd, J = 11.3, 4.4, 0.9H),
3.59−3.54 (m, 2.2H), 3.52 (dd, J = 10.8, 7.0, 0.9H), 2.38−2.33 (m,
1H), 2.26−2.21 (m, 1.1H), 2.20−2.16 (m, 0.9H), 2.13 (ddd, J = 12.8,
7.6, 5.5, 0.1H), 1.82 (ddd, J = 12.5, 6.5, 5.2, 0.9H), 1.72 (ddd, J = 12.6,
9.2, 7.9, 0.9H), 1.37 (dt, J = 12.2, 9.8, 0.1H); 13C NMR (150 MHz,
MeOD) δ 136.3, 117.4, 84.5, 79.7, 65.7, 64.8, 44.8, 41.5, 35.3; IR
(ATR) 3335, 3076, 2929, 1641 cm−1; HRMS (TOF MS ES+) m/z
calcd for C9H16NaO3 (M + Na)+ 195.0997, found 195.0995. Two
attempts to obtain satisfactory combustion analysis data were
unsuccessful, likely because minor impurities were present that could
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1
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ASSOCIATED CONTENT
■
S
* Supporting Information
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kwoerpel@nyu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Institutes of
Health, National Institute of General Medical Sciences (GM-
61066). We thank Dr. Phil Dennison (University of California,
Irvine) and Dr. Chin Lin (NYU) for assistance with NMR
spectroscopy, Dr. John Greaves (UCI) and Ms. Shirin
Sorooshian (UCI) for mass spectrometric data, and Dr. Joe
Ziller (UCI) and Dr. Chunhua Hu (NYU) for the X-ray
crystallographic analysis. We also thank the Molecular Design
Institute of NYU for purchasing a single-crystal diffractometer.
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