Mild and chemoselective lactone ring-opening with (TMS)ONa. Mechanistic studies and application to sweroside derivatives

Article abstract of DOI:10.1021/jo500220h

Mild and chemoselective opening of lactones with sodium trimethylsilanolate in high yields and aprotic solvents is described. Kinetic studies demonstrate that the B_Ac2 mechanistic pathway is followed. Nucleophilic attack of silanolate onto the carbonyl of the lactone moiety is the rate-determining step. NaOH present as an impurity accelerates the reaction. The method was further applied to the base-sensitive and stable lactones derived from highly functionalized iridoid derivatives.

Full text of DOI:10.1021/jo500220h

Article
pubs.acs.org/joc
Mild and Chemoselective Lactone Ring-Opening with (TMS)ONa.
Mechanistic Studies and Application to Sweroside Derivatives
Hugues Lemoine, Dean Markovic, and Brigitte Deguin*
́
Laboratoire de Pharmacognosie, Faculte
́ ́
des Sciences Pharmaceutiques et Biologiques, Universite Paris Descartes, Sorbonne Paris
Cite, UMR/CNRS No. 8638, 4 Avenue de l’Observatoire, F-75006 Paris, France
́
S
* Supporting Information
ABSTRACT: Mild and chemoselective opening of lactones with sodium
trimethylsilanolate in high yields and aprotic solvents is described. Kinetic studies
demonstrate that the BAc2 mechanistic pathway is followed. Nucleophilic attack
of silanolate onto the carbonyl of the lactone moiety is the rate-determining step.
NaOH present as an impurity accelerates the reaction. The method was further
applied to the base-sensitive and stable lactones derived from highly
functionalized iridoid derivatives.
Ester cleavage in an aprotic medium has been studied by
several groups.21−24 For example, Nicolaou25 utilized toxic
trimethyltin hydroxide in large excess and elevated reaction
INTRODUCTION
■
Hydroxy acids have found numerous applications in the
agrochemical, pharmaceutical, and cosmetic industries.1,2 Chiral
hydroxy acids, common in nature, are renewable sources of
biologically active products and synthetically useful synthons.3
Stable and unreactive lactones with diverse architecture and
varying degrees of complexity are frequent secondary
metabolites.4 Lactone ring-opening (LRO) under mild and
selective conditions would, thus, be a straightforward strategy
to access a large variety of polyfunctional hydroxy carboxylic
acids.5
temperatures. Laganis26 and Vinkovic27
employed potassium
́
and sodium trimethylsilanolates for the hydrolysis of methyl
esters and acyl chlorides. These conditions have been
successfully applied in the synthesis of antifungal agent FR-
900084828 and angiotensin II antagonist telmisartan29 and in
the large-scale production of the RAR-γ agonist BMS-270394.30
Our group has described the first example of LRO employing
silanolates.31 We used 2 equiv of (TMS)ONa to open and to
induce the rearrangement of epimeric iodolactones 2, arriving
from aucubin (1) as shown in Scheme 1. Basicity and
A variety of functional groups are incompatible with LRO
procedures, which limits their use in organic syntheses. Current
LRO methods confront several severe problems, including
selectivity of ester cleavage, elimination reactions under basic
conditions, and solubility in aprotic solvents. The LRO
methods generally imply hydrolysis of the lactone6 induced
by strong bases7−9 or acids,10−12 usually in protic media.
Various types of hydroxy carboxylic acid derivatives can be
obtained by LRO employing N-, S-, or Se-nucleophiles.3
Alternatively, reduction with hydrides or alkylation with
organometallic compounds in the absence or presence of
(TMS)X (X = halides, sulfonates)3,13 may furnish interesting
derivatives. The facility of the LRO can be correlated to the size
of the lactone. Five-membered ring systems are favored over
the open chain compounds, while six-membered lactones
equilibrate with the hydroxy acid counterpart. For obvious
reasons of ring strain release, LRO of small (three- and four-
membered ring lactones) and medium (seven-, eight-, nine-,
and ten-membered ring lactones) is easier than that of five- and
six-membered rings.14,15 Moreover, lactones that are annulated
with other rings may resist LRO because of a too small entropy
gain of the ring-opening. This may also be the case for
polysubstituted lactones that are isomerized into hydroxy
carboxylic acids. They lack full entropy of rotation due to
partially blocked C−C rotation because of gauche steric
interactions between the substituents.3,14−20
Scheme 1. (TMS)ONa-Induced Rearrangement of
Iodolactones 2 to Diastereoselectively Enriched
(1S,4R,5R,6R)-Bicyclo[3.1.0]hexene (3)
nucleophilicity of (TMS)ONa were demonstrated in the
dynamic epimerization at the α-position of lactones 2, giving
thermodynamically favored (1S,4R,5R,6R)-bicyclo[3.1.0]-
hexene (3) with high diastereoselectivity. Following our report,
(TMS)OK was found to cleave chiral 1,3-oxazolidinones.32
However, the use of silanolates for LRO has not yet been a
subject of comprehensive studies.
Herein, we describe the scope and the mechanism of mild
and selective LRO reactions with (TMS)ONa in high yields.
Interestingly, by following the reactions with 1H and 13C NMR,
Received: January 28, 2014
Published: April 16, 2014
© 2014 American Chemical Society
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we have found that NaOH present as an impurity accelerates
LRO. To demonstrate the potential of our method, we have
applied it to chemoselective ring-opening of highly stable
natural secoiridoid lactones with various sensitive chemical
functions.
Table 2. Variation of Ring Sizes and Substitutions in LRO
Using (TMS)ONa (1 M, CH2Cl2)
RESULTS AND DISCUSSION
■
To define the best possible reaction conditions, we studied the
reaction of γ-butyrolactone (4) with (TMS)ONa (commercial
1 M solution in CH2Cl2) in different solvents at rt. Our results
are summarized in Table 1. Complete conversion required 1.2
Table 1. LRO of γ-Butyrolactone ([4] = 0.2 M) with
(TMS)ONa (1 M, CH2Cl2) in Different Solvents at rt
entry
substrate
n
R1
R2
product (yield, %)
1
2
6
4
0
Me
H
H
H
H
H
H
H
H
H
Me
(polymerization)
5 (85)
1
1
3
7
Me
H
17 (75)
a
4
8
2
18 (77)
time (TMS)ONa
conversion
isolated
yield (%)
entry
solvent
THF
(h)
(equiv)
(1H NMR) (%)
5
9
2
Me
19 (86)
6
10
11
12
13
14
15
16
2
(CH2)6CH3
20 (82)
1
2
3
4
5
6
6
4
4
3
1.0
1.2
1.0
1.2
1.2
87
100
90
74
7
3
H
21 (80)
THF
83
75
85
not
isolated
not
isolated
a
8
12
1
H
22 (78)
CH2Cl2
CH2Cl2
DMSO-d6
b
9
Me
23 (86)
100
100
10
11
12
24 (82)
25 (89)
26 (84)
bc
,
H
6
DMF-d7
3
1.2
100
OMe
c
a
b
Isolated as the hydroxy acid. (TMS)ONa 2.4 equiv, reflux.
a
b
(TMS)ONa contains approximately 10% NaOH. Partial deuteration
c
1
at C2 was observed by H NMR. PhCl is the internal reference.
(TMS)2O in a 1/9 ratio. The latter arises from the reaction
(TMS)ONa + (TMS)OH(D) → NaOH(D) + (TMS)2O.33,34
(TMS)OH(D) can be formed either in the reaction with traces
of water present in the reactants and solvent or by the
enolization of lactone 4. The quantity of water in 4 was
established as 5 mol % and that of dry DMSO-d6 as 8−16 mol
% with regard to 4. With progress of the reaction, the chemical
shift of the averaged signal of (TMS)ONa and (TMS)OH(D)
varied to become that of pure (TMS)OH(D).35 The solution
of (TMS)ONa also contains small amounts of (TMS)2O as
equiv of (TMS)ONa regardless of the solvent (compare entries
1 and 3 with entries 2 and 4). In THF and CH2Cl2, the sodium
salt 5 precipitated and could be isolated by simple filtration of
the crude. In contrast, 5 at 0.2 M was completely soluble in
DMSO. In aprotic polar solvents (DMF or DMSO), the LRO
reaction was somewhat accelerated (entries 5 and 6). Under the
employed conditions, for all substrates investigated, the
instability of trimethylsilyl ether and/or ester did not permit
their detection (1H and 13C NMR).
1
established by H NMR and NaOH (5−22 mol % with regard
to 4) as measured by back-titration.36
We then turned to the primary lactones: δ-lactone 8, ε-
lactone 11, and 15-pentadecanolactone 12 and the secondary
lactones: β-lactone 6, γ-lactone 7, and δ-lactones 9 and 10
(Table 2). Except for 6, which polymerized, all other lactones
were easily converted into the corresponding hydroxy
carboxylate salts in high yields (75−86%) regardless of the
substitution and ring size. Encouraged by these results, we
tested sterically hindered 2,2-dimethylbutyrolactone (13) and
1(S)-camphanic acid (14). The corresponding hydroxy
carboxylic acid of gem-dimethyl lactone 13 experiences the
Thorpe−Ingold effect and cyclizes readily. However, under
standard conditions, 13 gave hydroxy carboxylate 23 in 86%
yield, whereas the lactone 14 furnished a similar yield of 24
(82%). Finally, the natural furanocoumarins psoralen (15) and
bergapten (16) with a rigid benzopyranone unit were
transformed without E/Z-isomerization into (Z)-25 (89%)
and (Z)-26 (84%), respectively.
Scheme 2 shows the BAl2 and BAc2 mechanistic pathways for
LRO. For ester cleavage with (TMS)ONa, the BAl2 mechanism
Scheme 2. BAl2 and BAc2 Pathways of LRO with (TMS)ONa
was proposed via the nucleophilic attack of silanolate on the
methylene group (SN2 type).27 LRO reaction may follow the
BAc2 pathway proceeding through an addition of (TMS)ONa
to the carbonyl of the lactone, leading to the formation of the
trimethylsilyl ester 28 after ring-opening (Scheme 2).
The mechanism of LRO with (TMS)ONa was elucidated by
1
The H NMR studies of LRO reaction with γ-butyrolactone
kinetic studies using γ-butyrolactone (4) or γ-valerolactone (7)
1
(4) were conducted in DMSO-d6, the only solvent that
solubilizes the reactants and hydroxy acid salt 5 ([4] ≤ 0.1 M).
The hydroxy acid 5 does not contain the TMS group and is
partially deuterated at the α-position (Table 1, entry 5). The
major coproducts of the reaction are (TMS)OH(D) and
under pseudo-first-order conditions by H NMR in DMSO-d6.
The fact that the reaction rate of LRO with 4 using NaOH
instead of (TMS)ONa considerably decreases (see the
Supporting Information) confirms that (TMS)ONa is respon-
sible for lactone-opening. The rate law of the LRO of 4 was
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first-order in both reactants (TMS)ONa and 4: k((TMS)ONa)
= 4.8 × 10−3 0.2 × 10−3 M−1 s−1 and k(4) = 4.6 × 10−3 0.1
× 10−3 M−1 s−1 at 25 °C. The half-life of secondary lactone 7 in
LRO reaction conditions (τ1/2 = 3670 190 s) is nearly the
same as that of primary lactone 4 (τ1/2 = 1980 110 s) (Figure
1). This is inconsistent with a BAl2 mechanism in which
interfere with the mechanism. The consumption of NaOH
during the reaction shifts equilibrium 2 toward (TMS)2O, and
these two compounds were observed as major coproducts by
1H NMR.
To further confirm the proposed mechanism, we measured
the initial rate interpolated as pseudo-first-order for LRO of 4 +
NaOH (30 mol %) and compared it to the rates for 4 and 7
employing previously described conditions (Figure 1). The
addition of 30 mol % NaOH increased the rate of LRO for 4 by
a factor of 1.8 (τ1/2 = 1150 40 s), suggesting the accelerating
role of NaOH. The existence of the equilibria described in eqs
1 and 3 is confirmed by the difference in the ratio [(TMS)2O]/
([(TMS)ONa] + [(TMS)OH]), 1.7 vs 7.7 for the LRO of 4
without and with NaOH (30 mol %) after 1 h and 40 min.
Some iridoids are abundant in nature and can be extracted
readily from various plants.3 We have used them as chiral green
bioresources. Indeed, they constitute valuable starting materials
for the synthesis of bioactive compounds.31,40−43 Our group has
developed new chiral scaffolds and building blocks starting
from aucubin (1), leading to the construction of new
heterocyclic systems via their pyran ring contraction or
expansion, generating a wide skeletal and chemodiversity. In
particular, this has allowed us to prepare new amino acids,44
enoxysilanes,43 and aminocyclopentanol glucosidase inhibi-
tors.31 We also have obtained a new series of cytotoxic
cyclopentenone glucosides45,46 and polyaminoiridoids structur-
ally related to aminoside antibiotics.47
To enlarge the scope of our original chiral building blocks
available from renewable phytomaterial,48−50 we applied our
LRO method to open lactones of secoiridoids with a fully
protected glycosyl moiety. Except for the semisynthesis of
alkaloid indolomonoterpenes,51−57 secoiridoids were rarely
used as chiral starting materials.58−61 The lactone ring of
pyrano[3,4-c]pyranone is known to be very stable, and thus, its
LRO is difficult.48−50,53 Sweroside (30) was readily extracted
from Lonicera tatarica (Caprifoliaceae).52 Its glucoside unit was
fully protected in 85% yield (31, Scheme 4). Stereoisomers 32a
Figure 1. Initial rates interpolated as pseudo-first-order for LRO of γ-
valerolactone (7), γ-butyrolactone (4), and 4 + NaOH (30 mol %).
[lactone]o = 0.09 M, [(TMS)ONa]o = 0.09 M, and t = 20 °C.
(TMS)ONa would have displaced the CH(Me)−OCO group
of 7 and the CH2−OCO group of 4. Because of the steric
hindrance in the secondary lactone 7, the latter is expected to
react at least 1000 times slower than 4.37 The order of the
reaction (TMS)ONa + 4 and this finding are consistent with a
BAc2 mechanism, with the rate-determining step being the
addition of (TMS)ONa to the carbonyl of the lactone.
Scheme 4. Syntheses of Sweroside Derivatives 31−34
The cleavage of the Si group can be interpreted in terms of
the mechanism shown in Scheme 3. Intermediate 27 generated
Scheme 3. TMS Group Cleavage in LRO with (TMS)ONa
and 32b were obtained by epoxidation53,58,59 of 31 with m-
CPBA in 47% and 18% yields, respectively. The inseparable
mixture of diols 33a and 33b (8R/8S) was obtained in 73%
yield by catalytic dihydroxylation of 31 with OsO4 (2.5 mol
%)/NMO.59 Acetonides 34a and 34b were isolated in 63% and
34% yields, respectively, after flash chromatography.
by LRO undergoes a fast transfer of the TMS group from the
trimethylsilyl ester to alkoxide (pKa,DMSO(RCOOH) = 12.638
and pKa,DMSO(RCH2OH) = 2839) and produces the more stable
trimethylsilyl ether 28. In the presence of NaOH, ester 27 or
ether 28 may be cleaved into 29 + (TMS)OH, which
equilibrates with 4-hydroxybutyrate (5) and (TMS)ONa
(Scheme 3). The small quantity of NaOH remains enough to
To demonstrate the utility of (TMS)ONa for LRO, NaOH,
LiOH, MeONa, and Me3SnOH were tested. NaOH or LiOH
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cleaved the ester protections of 31 without opening the lactone
moiety. With MeONa, 31 underwent a concomitant 1,4-
addition of MeOH to its ene ester moiety, and pivaloyl ester
groups were also cleaved. However, an excess of Me3SnOH (10
equiv) in 1,2-DCE at 80 °C led to less than 30% conversion to
hydroxy acid 35 after 24 h. When we applied our new LRO
methodology, no concurrent reactions were observed. The
lactone 31 was chemoselectively opened with 2 equiv of
(TMS)ONa in CH2Cl2 at rt. After neutralization with SiO2,
perpivaloylsecologanol 35 was isolated in 88% yield (Table 3,
entry 1).
(8S)-37b is probably due to steric interactions between the
acetonide and pyrano[3,4-c]pyranone parts. Protection of diol
33 is necessary as the latter compound did not undergo LRO
with a 5-fold excess of (TMS)ONa (Table 3, entry 4).
In conclusion, we have developed a mild and chemoselective
LRO reaction that uses (TMS)ONa in an aprotic solvent.
Kinetic studies using NMR confirmed a BAc2 mechanism of the
reaction. NaOH present as an impurity has an important role as
it increases the rate of LRO. This chemoselective method has
been efficiently applied to LRO of complex natural products,
providing the hydroxy acids in high yields. In particular, new
secoiridoid-based chiral building blocks have been obtained by
that chemistry. Further studies will explore their use in
semisynthesis of compounds with biological interest.
Table 3. LRO of Sweroside Derivatives 31−34 with
(TMS)ONa
EXPERIMENTAL SECTION
■
General Information. Optical rotations were measured (c, g/L).
NMR spectra were recorded on 400 and/or 300 MHz spectrometers,
and chemical shifts are expressed in parts per million downfield from
TMS. When necessary, all structures of the novel compounds were
ensured and the signals unambiguously assigned by 2D NMR
1
1
techniques: 1H−1H COSY, H−1H NOESY, H−13C HMQC, and
1H−13C HMBC. These experiments were performed using standard
microprograms. Chemical shifts are corrected to δH 7.26 for CDCl3, δH
4.79 for D2O, or δH 2.50 for DMSO-d6 as the internal reference and to
δC 77.00 for CDCl3 or δC 39.52 for DMSO-d6 as the internal reference.
Splitting patterns in the 1H NMR spectra are designated as s = singlet,
d = doublet, dd = doublet of doublets, t = triplet, q = quartet, quin =
quintuplet, sext = sextuplet, m = multiplet, and br = broad. DMSO-d6
was dried over calcium hydride, distilled, and stored over 4 Å
molecular sieves. ESI-MS and HR-ESI-MS were performed on QTOF
apparatuses equipped with an ESI-Z spray source. TLC was performed
on silica gel 60 F254 aluminum sheets using vanillin/H2SO4 as the
spray reagent. Column chromatographies were conducted using silica
gel [20−45 or 35−70 μm (flash)] with an overpressure of 300 mbar.
Dichloromethane was dried over calcium hydride and distilled. Yields
refer to chromatographically and spectroscopically pure compounds.
Trivial nomenclature of iridoids was employed. (TMS)ONa was
purchased as a 1 M solution in dichloromethane.
a
1
The yield was evaluated by H NMR.
To our delight, the LRO reactions of the sweroside
derivatives 32−34 with (TMS)ONa were also highly chemo-
selective (Table 3). The reaction of 32b (entry 3, 48 h)
proceeded in 87% yield, and epimer 32a was converted into
1
General Procedure GP01 for Lactone Ring-Opening of
Commercial Lactone Exemplified by the Synthesis of Sodium
4-Hydroxybutyrate (5). To a solution of γ-butyrolactone (4) (86
mg, 1.0 mmol, 1 equiv) in anhydrous CH2Cl2 (5 mL) was added a
commercial solution of (TMS)ONa (1 M) in CH2Cl2 (1.2 mL, 1.2
mmol, 1.2 equiv). The mixture was stirred under a nitrogen
atmosphere at room temperature for 4 h, filtered, and washed by
pentane (4 × 20 mL). The white solid was dried in vacuo to furnish 5
(107 mg, 85%). 1H NMR (400 MHz, D2O): δ 3.54 (2H, t, 3J4−3 = 6.5
Hz, H4), 2.18 (2H, t, 3J2−3 = 6.5 Hz, H2), 1.74 (2H, quint, 3J3−2 = 3J3−4
= 6.5 Hz, H3); 13C NMR (100 MHz, D2O): δ 183.1 (C1), 61.4 (C4),
33.9 (C2), 28.3 (C3); IR (ATR): ν 3317, 2960, 1555 (COO−), 1407,
1065, 1053, 1014, 946, 920, 888, 685 cm−1; MS (ESI−): m/z 103 [M
− Na]−. HRMS (ESI−): m/z for C4H7O3 [M − Na]−, calcd 103.0401,
found 103.0401. Spectral data were consistent with the literature.62−64
Sodium 4-Hydroxypentanoate (17). General procedure GP01
was applied using γ-valerolactone (7) (100 mg, 1.0 mmol, 1 equiv) and
(TMS)ONa (1 M) in CH2Cl2 (1.2 mL, 1.2 mmol, 1.2 equiv) for 6 h.
The title compound 17 was obtained as a white solid (105 mg, 75%).
36a in 86% yield without epoxide ring-opening. The H NMR
of the crude 36a confirmed high selectivity of the reaction.
However, during the purification on silica, 36a was partially
rearranged into 38 resulting from a favorable intramolecular
nucleophilic attack of alkoxide on C8 of its epoxide moiety
(Scheme 5). The structure of the tetrahydropyran ring was
Scheme 5. Formation of Morroniside-Type Structure 38
3
3
1H NMR (300 MHz, D2O): δ 3.75 (1H, sext, J4−5 = J4−3 = 6.5 Hz,
established by the 3JH−H coupling constant between the H5, H6,
H8, and H9 protons. In particular, the relative configuration of
C8 was given by JH −H = JH −H = 6.0 Hz, which proved the
synperiplanar stereochemistry of protons H8, H9, and H5.
Further NOESY correlation between H10 and H1 confirmed the
8R configuration. The reaction of (TMS)ONa with acetonides
34a and 34b led to the hydroxy acids 37a (65%) and 37b
(84%) (entries 5 and 6). The lower yield for the formation of
H4), 2.19 (1H, dt, 2J2a−2b = 20.0 Hz, 3J2−3 = 7.5 Hz, H2a), 2.14 (1H, dt,
2J2b−2a = 20.0 Hz, J2−3 = 7.5 Hz, H2b), 1.64 (2H, td, J3−2 = 7.5 Hz,
3
3
3
3
8
9
9
5
3
3J3−4 = 6.5 Hz, H3), 1.11 (3H, d, J5−4 = 6.5 Hz, H5); 13C NMR (75
MHz, D2O): δ 183.2 (C1), 67.5 (C4), 34.6 (C3), 33.8 (C2), 21.5
(C5); IR (ATR): ν 2947, 1565 (COO−), 1439, 1413, 1237, 1130,
1072, 946, 818, 737, 665 cm−1; MS (ESI−): m/z 117 [M − Na]−.
HRMS (ESI−): m/z for C5H9O3 [M − Na]−, calcd 117.0557, found
117.0556. Spectral data were consistent with the literature.65
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Sodium 5-Hydroxypentanoate (18). General procedure GP01
was applied using δ-valerolactone (8) (100 mg, 1.0 mmol, 1 equiv)
and (TMS)ONa (1 M) in CH2Cl2 (1.2 mL, 1.2 mmol, 1.2 equiv) for 6
h. The title compound 18 was obtained as a white solid (107 mg,
MHz, D2O): δ 3.47 (t, 3J3−4 = 7.5 Hz, 2H, H4), 1.63 (t, 3J3−4 = 7.5 Hz,
2H, H3), 0.99 (s, 6H, 2 × CH3). 13C NMR (100.6 MHz, D2O): δ
187.1 (C1), 59.2 (C4), 42.4 (C3), 41.9 (C2), 25.7 (2 × CH3). IR
(ATR): ν 3330, 2980, 2950, 2900, 2920, 1660, 1520, 1400, 1070. MS
(ESI): m/z [M+] 154. Mp: 180.2−183.5 °C. HRMS (ESI): m/z for
C6H11NaO3, calcd C6H12NaO3 [M + H]+ 155.0684, found 155.0681.
1,3-Disodium (1S,3R)-1-Hydroxy-2,2,3-trimethylcyclopen-
tane-1,3-dicarboxylate (24). To a solution of camphanic acid
(14) (198 mg, 1.0 mmol, 1 equiv) in anhydrous CH2Cl2 (5 mL) was
added a commercial solution of (TMS)ONa (1 M) in CH2Cl2 (2.4
mL, 2.4 mmol, 2.4 equiv). The mixture was stirred at reflux for 6 h and
then diluted at rt with CH2Cl2 (15 mL). To the solution was added
water (20 mL), and the solution was washed by CH2Cl2 (2 × 20 mL).
The water was evaporated under reduced pressure to give 22 as a
white solid (213 mg, 78%). [α]D = −25.2 (c = 3.0 in H2O); 1H NMR
3
77%). 1H NMR (300 MHz, D2O): δ 3.57 (2H, t, J5−4 = 6.5 Hz, H5),
2.16 (2H, t, 3J2−3 = 6.5 Hz, H2), 1.61−1.47 (4H, m, H3, H4); 13C NMR
(75 MHz, D2O): δ 183.7 (C1), 61.4 (C5), 37.1 (C2), 31.1 (C4), 22.1
(C3); IR (ATR): ν 3432, 2941, 1734, 1561 (COO−), 1444, 1420,
1249, 1166, 1064, 922, 838 cm−1; MS (ESI−): m/z 117 [M − Na]−.
HRMS (ESI−): m/z for C5H9O3 [M − Na]−, calcd 117.0557, found
117.0558. Spectral data were consistent with the literature.67,68
Sodium 5-Hydroxyhexanoate (19). General procedure GP01
was applied using δ-caprolactone (9) (114 mg, 1.0 mmol, 1 equiv) and
(TMS)ONa (1 M) in CH2Cl2 (1.2 mL, 1.2 mmol, 1.2 equiv) for 16 h.
The title compound 19 was obtained as a white solid (132 mg, 86%).
2
3
3
3
1H NMR (300 MHz, D2O): δ 3.80 (1H, sext, J5−4 = J5−6 = 6.0 Hz,
H5), 2.16 (2H, t, 3J2−3 = 7.0 Hz, H2), 1.67−1.35 (4H, m, H3, H4), 1.13
(3H, d, 3J6−5 = 6.0 Hz, H6); 13C NMR (75 MHz, D2O): δ 183.7 (C1),
67.6 (C5), 37.6 (C2), 37.3 (C4), 22.0 (C3), 21.7 (C6); IR (ATR): ν
3336, 2964, 2930, 1705, 1559 (COO−), 1404, 1373, 1252, 1130, 1088,
1027, 946, 883, 749 cm−1; MS (ESI−): m/z 131 [M − Na]−. HRMS
(ESI−): m/z for C6H11O3 [M − Na]−, calcd 131.0714, found
131.0716.
(400 MHz, D2O): δ 2.53 (ddd, J5a−5b = 14.0 Hz, J5a−4a = 9.0 Hz,
3J5a−4b= 5.0 Hz, 1H, H5a), 2.17 (ddd, 2J4a−4b = 13.5 Hz, 3J4a−5a = 9.0 Hz,
2
3
3J4a−5b = 3.5 Hz, 1H, H4a), 1.66 (ddd, J5a−5b = 14.0 Hz, J5b−4b = 9.0
3
2
3
Hz, J5b−4a = 3.5 Hz, 1H, H5b), 1.50 (ddd, J4a−4b = 13.5 Hz, J4b−5b
=
3
9.0 Hz, J4b−5a = 5.0 Hz, 1H, H4b), 0.96 (s, 3H, CH3−C(3)), 0.86 (s,
3H, CH3−C(2)), 0.75 (s, 3H, CH3−C(2)). 13C NMR (100.6 MHz,
D2O): δ 187.9; 180.5 (C1, C2); 90.3 (C1); 57.0 (C3); 49.1 (C2);
35.5; 35.1 (C4, C5); 23.5 (CH3−C(3)); 21.7 (CH3−C(2)); 19.2
(CH3−C(2)). IR (ATR): ν 3450, 3030, 3020, 3000, 2950, 2240, 2120,
1980, 1740, 1550, 1430, 1670, 1230, 1220, 1070, 900. MS (ESI): m/z
[M + Na]+ 283. Mp: 311−314 °C. HRMS (ESI): m/z for
C10H14Na2O5, calcd [M + H]+ C10H15Na2O5 261.0709, found
261.0710.
Sodium 5-Hydroxydodecanoate (20). General procedure GP01
was applied using δ-dodecalactone (10) (114 mg, 1.0 mmol, 1 equiv)
and (TMS)ONa (1 M) in CH2Cl2 (1.2 mL, 1.2 mmol, 1.2 equiv) for
16 h. The title compound 20 was obtained as a white solid (195 mg,
82%). 1H NMR (300 MHz, D2O): δ 3.54 (1H, tt, 3J5−4 = 7.0 Hz, 3J5−6
3
= 5.0 Hz, H5), 2.06 (2H, t, J2−3 = 7.5 Hz, H2), 1.61−1.07 (16 H, m,
Sodium (2Z)-3-(6′-Hydroxy-1′-benzofuran-5′-yl)prop-2-
enoate (25). General procedure GP01 was applied using psoralen
(15) (186 mg, 1.0 mmol, 1 equiv) and (TMS)ONa (1 M) in CH2Cl2
(1.2 mL, 1.2 mmol, 1.2 equiv) for 12 h. Compound 25 was obtained as
H3, H4, H6, H7, H8, H9, H10, H11), 0.74 (3H, t, 3J12−11 = 7.0 Hz, H12);
13C NMR (75 MHz, D2O): δ 183.7 (C1), 71.4 (C5), 37.4 (C2), 35.8,
35.7, 31.1, 28.7, 28.3, 24.6, 22.0, 21.9 (8 CH2), 13.3 (C12); IR (ATR):
ν 3310, 2954, 2920, 2848, 1704, 1564 (COO−), 1459, 1409, 1130,
1094, 912, 887, 723 cm−1; MS (ESI−): m/z 215 [M − Na]−. HRMS
(ESI−): m/z for C12H23O3 [M − Na]−, calcd 215.1653, found
215.1651.
1
a brown powder (201 mg, 89%). H NMR (400 MHz, D2O): δ 7.43
(br s, 1H, H4′), 7.36 (d, 3J1′−2′ = 2.5 Hz, 1H, H1′), 6.71 (d, 3J2−3 = 12.5
Hz, 5J7′−3 = 0.5 Hz, 1H, H3), 6.62 (br d, 5J7′−3 = 0.5 Hz, 5J7′−2′ = 1 Hz,
3
5
1H, H7′), 6.59 (dd, J1′−2′ = 2.5 Hz, J2′−7′ = 1 Hz, 1H, H2′), 5.82 (d,
3J2−3 = 12.5 Hz, 1H, H2). 13C NMR (100.6 MHz, D2O): δ 178.2 (C1),
Sodium 6-Hydroxyhexanoate (21). General procedure GP01
was applied using ε-caprolactone (11) (114 mg, 1.0 mmol, 1 equiv)
and (TMS)ONa (1 M) in CH2Cl2 (1.2 mL, 1.2 mmol, 1.2 equiv) for
16 h. The title compound 21 was obtained as a white solid (123 mg,
163.1 (C8′), 157.0 (C6′), 142.5 (C1′), 130.0 (C3), 123.4 (C3′), 123.3
(C2), 120.0 (C4′), 115.4 (C5′), 106.5 (C2′), 99.3 (C7′). IR (ATR): ν
3190, 3030, 3020, 2950, 2240, 2150, 1740, 1580, 1550, 1420, 1350,
1220, 1160, 1030 cm−1; UV (H2O): λmax (log ε) 201 nm (1.55), 245
(1.31), 299 (0.64); MS (ESI): m/z [M + Na]+ 249. HRMS (ESI): m/z
for C11H7NaO4, calcd [M + H]+ C11H8NaO4 227.0314, found
227.0317.
3
80%). 1H NMR (300 MHz, D2O): δ 3.54 (2H, t, J6−5 = 6.5 Hz, H6),
2.13 (2H, t, 3J2−3 = 7.5 Hz, H2), 1.56−1.45 (4H, m, H3, H5), 1.33−1.23
(2H, m, H4); 13C NMR (75 MHz, D2O): δ 184.0 (C1), 61.6 (C6),
37.4 (C2), 31.0 (C5), 25.5 (C3), 24.9 (C4); IR (ATR): ν 3303, 2939,
1558 (COO−), 1443, 1416, 1253, 1071, 1049, 958, 840 cm−1; MS
(ESI−): m/z 131 [M − Na]−. HRMS (ESI−): m/z for C6H11O3 [M −
Na]−, calcd 131.0714, found 131.0712.
Sodium (2Z)-3-(6′-Hydroxy-4′-methoxy-1′-benzofuran-5′-
yl)prop-2-enoate (26). General procedure GP01 was applied using
bergapten (16) (216 mg, 1.0 mmol, 1 equiv) and (TMS)ONa (1 M)
in CH2Cl2 (1.2 mL, 1.2 mmol, 1.2 equiv) for 12 h. Compound 26 was
15-Hydroxypentanoic Acid (22). To a solution of 15-
pentadecanolactone (12) (240 mg, 1.0 mmol, 1 equiv) in anhydrous
CH2Cl2 (5 mL) was added a commercial solution of (TMS)ONa (1
M) in CH2Cl2 (1.2 mL, 1.2 mmol, 1.2 equiv). The mixture was stirred
at room temperature for 16 h, then diluted with CH2Cl2 (15 mL), and
neutralized with an aqueous solution of HCl (10%) at 0 °C. The
organic layer was washed by water (2 × 20 mL) and brine (1 × 20
mL), dried over MgSO4, and evaporated in vacuo to give 22 as a white
1
obtained as a brown powder (214 mg, 84%). H NMR (400 MHz,
D2O): δ 7.32 (d, 3J1′−2′ = 2.5 Hz, 1H, H1′), 6.79 (br d, 3J1′−2′ = 2.5 Hz,
1H, H2′), 6.46 (d, 3J2−3 = 12.5 Hz, 1H, H3), 6.38 (br s, 1H, H7′), 5.91
3
(d, J2−3 = 12.5 Hz, 1H, H2), 3.82 (s, 3H, OCH3). 13C NMR (100.6
MHz, D2O): δ 176.9 (C1), 164.5 (C8′), 157.7 (C6′), 149.7 (C4′),
141.0 (C1′), 129.0 (C3); 126.7 (C2); 114.6 (C5′); 106.4 (C3′), 104.8
(C2′), 94.7 (C7′); 59.0 (OCH3). IR (ATR): ν 3290, 3020, 3005, 2970,
2240, 2130, 1740, 1730, 1550, 1370, 1220, 1160, 970. UV: λmax (log ε)
198 nm (1.44), 251 (1.26), 308 (0.63); MS (ESI): m/z [M+] 256 [2M
+ Na]+ 535. HRMS (ESI): m/z for C12H9NaO5, calcd [M + Na]+
C12H9Na2O5 279.0239, found 279.0235.
Perpivaloylsweroside (31). To a solution of sweroside (30)
(4.85 g, 13.5 mmol, 1 equiv) in a mixture of anhydrous pyridine and
CH2Cl2 (90 mL/90 mL), cooled with an ice bath, was added pivaloyl
chloride (19.8 mL, 162 mmol, 12 equiv) followed by 4-DMAP (992
mg, 8.12 mmol, 0.6 equiv). The mixture was agitated at room
temperature for 14 days and then quenched with 10 g of ice and 30
mL of water. The resulting mixture was extracted by CH2Cl2 (3 × 70
mL), and the combined organic layers were neutralized at 0 °C by
addition of aqueous HCl (10%) until the pH of the aqueous layer
remained acidic (pH 2). The organic layer was then washed by water
(2 × 50 mL) and brine (3 × 50 mL), dried over MgSO4, filtered, and
1
solid (201 mg, 78%). H NMR (300 MHz, CDCl3): δ 3.38 (2H, t,
3J15−14 = 6.0 Hz, H15), 2.07 (2H, t, 3J2−3 = 7.5 Hz, H2), 1.44−1.23 (4H,
m, H3, H14), 1.14−0.94 (20H, m, H4, H5, H6, H7, H8, H9, H10, H11,
H12, H13); 13C NMR (75 MHz, CDCl3): δ 178.9 (C1), 63.1 (C15),
33.9 (C2), 32.7 (C14), 29.53, 29.51, 29.48, 29.45, 29.37, 29.34, 29.25,
29.16, 28.99, 25.7, 24.7 (C3, C4, C5, C6, C7, C8, C9, C10, C11, C12,
C13); IR (ATR): ν 2915, 2849, 1737, 1691, 1470, 1413, 1221, 1197,
1178, 1058, 971, 718 cm−1; MS (ESI−): m/z 257 [M− − H]. HRMS
(ESI−): m/z for C15H29O3 [M− − H], calcd 257.2122, found
257.2118. Spectral data were consistent with the literature.66,67
Sodium 4-Hydroxy-2,2-dimethylbutanoate (23). General
procedure GP01 was applied using α,α-dimethyl-γ-butyrolactone
(13) (114 mg, 1.0 mmol, 1 equiv) and (TMS)ONa (1 M) in
CH2Cl2 (1.2 mL, 1.2 mmol, 1.2 equiv) for 12 h. The title compound
1
23 was obtained as a white powder (133 mg, 86%). H NMR (400
4362
dx.doi.org/10.1021/jo500220h | J. Org. Chem. 2014, 79, 4358−4366

The Journal of Organic Chemistry
Article
2
3
evaporated under reduced pressure. The crude was then purified by
flash chromatography (cyclohexane/AcOEt, 99/1 to 90/10) to give 31
(7.97 g, 11.5 mmol, 85%) as a white powder. [α]D = −76.5 (c = 0.2 in
CH2Cl2); 1H NMR (300 MHz, CDCl3): δ 7.55 (1H, d, 4J3−5 = 2.5 Hz,
2.96−2.83 (1H, m, H5), 2.77 (1H, br dd, J10a−10b = 4.5 Hz, J10a−8
4.0 Hz, H10a), 2.73 (1H, ddd, 3J8−9 = 8.5 Hz, 3J8−10a = 4.0 Hz, 3J8−10b
=
=
2
3
2.5 Hz, H8), 2.58 (1H, dd, J10b−10a = 4.5 Hz, J10b−8 = 2.5 Hz, H10b),
2.15−1.90 (2H, m, H6), 1.64 (1H, ddd, 3J9−8 = 8.5 Hz, 3J9−5 = 5.0 Hz,
3
3
3
3J9−1 = 1.5 Hz, H9), 1.22, 1.15, 1.10, 1.09 (36H, 4s, COC(CH3)3); 13
C
H3), 5.43 (1H, dt, J8−10a = 17.5 Hz, J8−10b = J8−9 = 10.0 Hz, H8),
5.35 (1H, d, 3J1−9 = 1.5 Hz, H1), 5.34 (1H, t, 3J3′−2′ = 3J3′−4′ = 9.5 Hz,
NMR (75 MHz, CDCl3): δ 177.8, 177.4, 177.0, 176.5 (4C,
COC(CH3)3), 164.6 (C11), 151.5 (C3), 105.3 (C4), 95.6 (C1′),
93.6 (C1), 72.6 (C5′), 71.8 (C3′), 70.6 (C2′), 68.5 (C7), 67.8 (C4′),
61.6 (C6′), 48.0 (C8), 44.3 (C10), 40.1 (C9), 38.9, 38.8 (4C,
C(CH3)3), 27.8(C5), 27.0, 26.9 (4C, C(CH3)3), 24.8 (C6); IR (ATR):
ν 2973, 1737 (CO), 1625, 1480, 1398, 1368, 1271, 1131, 1068, 985,
838, 761 cm−1; UV (CH2Cl2): λmax (log ε) 222 (4.14), 240 (4.32); MS
(ESI+): m/z 733 [M + Na]+. HRMS (ESI+): m/z for C36H54NaO14 [M
+ Na]+, calcd 733.3400, found 733.3402.
Mixture of (8R,10)-Dihydroxy-2′,3′,4′,6′-O-tetrapivaloyls-
weroside (33a) and (8S,10)-Dihydroxy-2′,3′,4′,6′-O-tetrapiva-
loylsweroside (33b). To a solution of perpivaloylsweroside (31)
(1.389 g, 2.0 mmol, 1 equiv) in THF/H2O (42 mL/14 mL) were
added NMO (407 mg, 3.0 mmol, 1.5 equiv) and a 2.5% solution of
OsO4 in tert-butyl alcohol (1.25 mL, 0.1 mmol, 0.05 equiv). The
reaction was agitated at room temperature for 96 h and quenched by
addition of 10 mL of a solution of NaHSO3 (1 g/L). The mixture was
filtered through Celite. THF was evaporated, and the residual aqueous
phase was extracted by CH2Cl2 (3 × 100 mL). The combined organic
extracts were washed with 5% HCl aqueous solution (2 × 50 mL), 5%
NaHCO3 aqueous solution (2 × 50 mL), and brine (2 × 50 mL),
dried (MgSO4), and evaporated in vacuo. The crude product was
purified by flash chromatography (CH2Cl2/MeOH, 98/2) to give a
mixture (4/3) of inseparable compounds (33a and 33b) as a white
solid (1.053 g, 73%). The absolute configurations of the two
diastereoisomers were determined by comparison with the liter-
ature.59,68 1H NMR (300 MHz, CDCl3, 33a = A, 33b = B): δ 7.59
(1H, d, 4J3A−5A = 2.5 Hz, H3A), 7.50 (1H, d, 4J3B−5B = 2.5 Hz, H3B) 5.84
3
3
H3′), 5.31−5.22 (2H, m, H10), 5.10 (1H, t, J4′−3′ = J4′−5′ = 9.5 Hz,
H4′), 5.02 (1H, dd, 3J2′−3′ = 9.5 Hz, 3J2′−1′ = 8.0 Hz, H2′), 4.91 (1H, d,
3J1′−2′ = 8.0 Hz, H1′), 4.42 (1H, dt, 2J7a−7b = 11.5 Hz, 3J7a−6b = 3J7a−6a
=
3.0 Hz, H7a), 4.21 (1H, ddd, 2J7b−7a = 11.5 Hz, 3J7a−6a = 8.5 Hz, 3J7a−6b
2
3
= 6.0 Hz, H7b), 4.17 (1H, dd, J6′a−6′b = 12.5 Hz, J6′a−5′ = 2.0 Hz,
2
3
H6′a), 4.09 (1H, dd, J6′b−6′a = 12.5 Hz, J6′b−5′ = 6.0 Hz, H6′b), 3.80
3
3
3
(1H, ddd, J5′−4′ = 9.5 Hz, J5′−6′b = 6.0 Hz, J5−6a′ = 2.0 Hz, H5′),
2.86−2.76 (1H, m, H5), 2.62 (1H, ddd, 3J9−8 = 10.0 Hz, 3J9−5 = 5.5 Hz,
3J9−1 = 1.5 Hz, H9), 1.73−1.64 (2H, m, H6), 1.19, 1.13, 1.09, 1.08
(36H, 4s, COC(CH3)3); 13C NMR (75 MHz, CDCl3): δ 178.1, 177.1,
176.8, 176.6 (4C, COC(CH3)3), 164.8 (C11), 152.0 (C3), 131.1
(C8), 120.9 (C10), 105.0 (C4), 95.9 (C1′), 95.7 (C1), 72.6 (C5′),
72.1 (C3′), 70.8 (C2′), 68.2 (C7), 68.1 (C4′), 61.9 (C6′), 42.2 (C9),
39.8, 38.7, 38.6 (4C, C(CH3)3), 27.5 (C5), 27.3, 27.2, 27.1, 27.0 (4C,
C(CH3)3), 24.7 (C6); IR (ATR): ν 2972, 1737 (CO), 1624, 1480,
1275, 1131, 1064, 981, 843, 761 cm−1; UV (CH2Cl2): λmax (log ε) 242
nm (4.01); MS (ESI+): m/z 717 [M + Na]+. HRMS (ESI+): m/z for
C36H54O13Na [M + Na]+, calcd 717.3456, found 717.3454.
9-((8S)-Epoxy)perpivaloylsweroside (32a) and 9-((R)-Epoxy)-
perpivaloylsweroside (32b). To a solution of 31 (585 mg, 0.842
mmol, 1 equiv) in dry toluene (15 mL), was added m-CPBA (207 mg,
0.842 mmol, 1 equiv), and the mixture was stirred at 50 °C for 24 h.
Then an additional 2 equiv of m-CPBA (414 mg, 1.684 mmol) was
added, and the mixture was stirred for 48 h at 50 °C. The reaction was
then diluted by CH2Cl2 (50 mL) and washed by 5% aqueous NaOH
solution (2 × 20 mL) and brine (3 × 20 mL). The organic layer was
dried (MgSO4) and evaporated in vacuo. The crude product was
purified by flash chromatography (cyclohexane/AcOEt, 80/20) to
give, in order of elution, the recovered starting material 31 (57 mg,
10%), the minor compound (R)-32b as a white solid (108.3 mg, 18%),
and compound (S)-32a as a white solid (278.5 mg, 47%). The
absolute configurations of the two diastereoisomers were determined
by comparison with the literature.58
3
3
(1H, d, J1A−9A = 1.5 Hz, H1A), 5.55 (1H, d, J1B−9B = 1.0 Hz, H1B),
5.32 (2H, t, J3′−2′ = 3J3′−4′ = 9.5 Hz, H3′A, H3′B), 5.01 (2H, t, J4′−3′
=
3
3
3J4′−5′ = 9.5 Hz, H4′A, H4′B), 5.03−4.94 (2H, m, H2′A, H2′B), 4.91 (1H,
d, 3J1′A−2′A = 8.0 Hz, H1′A), 4.87 (1H, d, 3J1′B−2′B = 8.0 Hz, H1′B), 4.49−
4.38 (2H, m, H7aA, H7aB), 4.28 (1H, dd, J6′aB−6′bB = 12.5 Hz, 3J6′aB−5′B
3
= 2.0 Hz, H6′aB), 4.21 (1H, dd, 3J6′aA−6′bA = 12.5 Hz, 3J6′aA−5′A = 2.0 Hz,
H6′aA), 4.20−4.10 (2H, m, H7bB, H7bA), 4.06 (1H, dd, 2J6′bA−6′aA = 12.5
Major Compound: 9-((8S)-Epoxy)perpivaloylsweroside (32a).
1
3
2
[α]D = −86.0 (c = 0.18, CH2Cl2); H NMR (300 MHz, CDCl3): δ
Hz, J6′bA−5′A = 5.5 Hz, H6′bA), 4.00 (1H, dd, J6′bB−6′aB = 12.5 Hz,
3J6′bB−5′B = 5.5 Hz, H6′bB), 3.82−3.73 (2H, m, H5′B, H5′A), 3.69−3.41
7.62 (1H, d, 4J3−5 = 2.5 Hz, H3), 5.69 (1H, d, 3J1−9 = 1.5 Hz, H1), 5.35
(1H, t, 3J3′−2′ = 3J3′−4′ = 9.5 Hz, H3′), 5.10 (1H, t, 3J4′−3′ = 3J4′−5′ = 9.5
(6H, m, H10B, H10A, H8B, H8A), 3.01−2.71 (2H, m, H5B, H5A), 2.70
(4H, br s, 4 OH), 2.20−2.13 (1H, m, H9A), 2.11−1.68 (5H, m, H6A,
H6B, H9B), 1.20, 1.13, 1.08, 1.05 (72H, 4s, COC(CH3)3); 13C NMR
(75 MHz, CDCl3): δ 178.3, 178.2, 177.0, 176.7, 176.6, 176.4 (8C,
COC(CH3)3), 165.3 (2C, C11B, C11A), 153.5 (C3A), 152.0 (C3B),
106.0 (C4A), 104.7 (C4B), 96.0 (C1′A), 95.6 (C1′B), 93.6 (C1A), 92.9
(C1B), 72.5 (C5′B), 72.4 (C5′A), 71.9 (2C, C3′B, C3′A), 70.7 (2C,
C2′B,C2′A), 68.8 (2C C8B, C8A), 68.3 (C7A,), 68.2 (C7B), 67.7 (2C,
C4′B, C4′A), 66.3 (C10A), 63.8 (C10B), 61.5 (C6′A), 61.4 (C6′B), 39.9
(C9B), 38.8, 38.7, 38.6 (8C, C(CH3)3), 37.7 (C9A), 27.8 (C5B), 27.3
(C5A), 27.0, 26.9 (8C, C(CH3)3), 25.3 (C6B), 24.8 (C6A); IR (ATR):
ν 2971, 1727 (CO), 1617, 1480, 1398, 1278, 1140, 1068, 1024, 938,
840, 762 cm−1; UV (CH2Cl2): λmax (log ε) 222 (4.01), 239 (4.01); MS
(ESI+): m/z 751 [M + Na]+. HRMS (ESI+): m/z for C36H56NaO15 [M
+ Na]+, calcd 751.3510, found 751.3510.
3
3
Hz, H4′), 5.01 (1H, br dd, J2′−3′ = 9.5 Hz, J2′2−1′ = 8.0 Hz, H2′), 4.95
3
(1H, d, J1′−2′ = 8.0 Hz, H1′), 4.48 (1H, dm, J7a−7b = 11.0 Hz, H7a),
2
4.24 (1H, m, J7a−7b = 11.0 Hz, H7b), 4.16−4.11 (2H, m, H6′), 3.85−
3.77 (1H, m, H5′), 2.96−2.88 (1H, m, H5), 2.86 (1H, br dd, 2J10a−10b
5.0 Hz, 3J10a−8 = 4.0 Hz, H10a), 2.70 (1H, ddd, 3J8−9 = 9.5 Hz, 3J8−10a
=
=
=
4.0 Hz, 3J8−10b = 2.5 Hz, H8), 2.55 (1H, dd, 2J10b−10a = 5.0 Hz, 3J10b−8
3
2.5 Hz, H10b), 1.91−1.80 (2H, m, H6), 1.62 (1H, ddd, J9−8 = 9.5 Hz,
3J9−5 = 5.5 Hz, J9−1 = 1.5 Hz, H9), 1.23, 1.14, 1.09, 1.08 (36H, 4s,
3
COC(CH3)3); 13C NMR (75 MHz, CDCl3): δ 178.0, 176.9, 176.7,
176.4 (4C, COC(CH3)3), 164.2 (C11), 152.4 (C3), 104.7 (C4), 96.0
(C1′), 93.8 (C1), 72.5 (C5′), 71.9 (C3′), 70.7 (C2′), 68.1 (C7), 67.8
(C4′), 61.7 (C6′), 48.1 (C8), 47.4 (C10), 40.7 (C9), 38.8, 38.7, 38.6
(4C, C(CH3)3), 27.1, 27.0 (4C, C(CH3)3), 26.9 (C5), 24.6 (C6); IR
(ATR): ν 2973, 1737 (CO), 1625, 1480, 1398, 1368, 1271, 1131,
1068, 985, 838, 761 cm−1; UV (CH2Cl2): λmax (log ε) 222 (4.14), 240
(4.32); MS (ESI+): m/z 733 [M + Na]+. HRMS (ESI+): m/z for
C36H54NaO14 [M + Na]+, calcd 733.3400, found 733.3402.
9-((8R)-12,12-Dimethyl-8,10-dioxolanyl)perpivaloylswero-
side (34a) and 9-((8S)-12,12-Dimethyl-8,10-dioxolanyl)-
perpivaloylsweroside (34b). To a solution of 33 (1.07 g, 1.48
mmol, 1 equiv) in acetone (20 mL) was added camphorsulfonic acid
(CSA) (68.8 mg, 0.296 mmol, 0.2 equiv), and the mixture was agitated
at room temperature for 24 h. Then silica was added, and the solvent
was evaporated in vacuo. The crude product was purified by flash
chromatography (cyclohexane/AcOEt, 70/30) to give, in order of
elution, the minor compound (S)-34b as a white solid (386.3 mg,
34%) and compound (R)-34a as a white solid (717.5 mg, 63%).
Major Compound: 9-((8R)-12,12-Dimethyl-8,10-dioxolanyl)-
Minor Compound: 9-((8R)-Epoxy)perpivaloylsweroside (32b).
1
[α]D = −64.5 (c = 0.31, CH2Cl2); H NMR (300 MHz, CDCl3): δ
7.58 (1H, d, 4J3−5 = 2.5 Hz, H3), 5.47 (1H, d, 3J1−9 = 1.5 Hz, H1), 5.35
(1H, t, 3J3′−2′ = 3J3′−4′ = 9.5 Hz, H3′), 5.11 (1H, t, 3J4′−3′ = 3J4′−5′ = 9.5
3
3
Hz, H4′), 5.01 (1H, dd, J2′−3′ = 9.5 Hz, J2′−1′ = 8.0 Hz, H2′), 4.92
(1H, d, 3J1′−2′ = 8.0 Hz, H1′), 4.51 (1H, ddd, 2J7a−7b = 11.0 Hz, 3J7a−6b
=
4.0 Hz, 3J7a−6a = 2.5 Hz, H7a), 4.24 (1H, td, 2J7a−7b = 3J7b−6a = 11.0 Hz,
3J7b−6b = 2.5 Hz, H7b), 4.23 (1H, dd, J6′a−6′b = 12.0 Hz, J6′a−5′ = 2.0
2
3
1
Hz, H6′a), 4.07 (1H, dd, 2J6′b−6′a = 12.0 Hz, 3J6′b−5′ = 5.5 Hz, H6′b), 3.80
perpivaloylsweroside (34a). [α]D = −111.5 (c = 0.23, CH2Cl2); H
NMR (300 MHz, CDCl3): δ 7.59 (1H, d, J3−5 = 2.5 Hz, H3), 5.82
3
3
3
4
(1H, ddd, J5′−4′ = 9.5 Hz, J5′−6′b = 5.5 Hz, J5′−6a′ = 2.0 Hz, H5′),
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(1H, d, 3J1−9 = 1.5 Hz, H1), 5.32 (1H, t, 3J3′−2′ = 3J3′−4′ = 9.5 Hz, H3′),
1.08 (36H, 4s, COC(CH3)3); 13C NMR (75 MHz, CDCl3): δ 177.9,
177.1, 176.5, 176.4 (4C, COC(CH3)3), 172.5 (C11), 154.7 (C3),
133.1 (C8), 119.2 (C10), 109.5 (C4), 96.9 (C1′), 96.5 (C1), 72.4
(C5′), 72.0 (C3′), 70.6 (C2′), 67.7 (C4′), 61.6 (C6′), 59.7 (C7), 43.6
(C9), 38.8, 38.7, 38.6 (4C, C(CH3)3), 33.2 (C6), 29.6 (C5), 27.1,
27.0, 26.9 (4C, C(CH3)3); IR (ATR): ν 2917, 2874, 1740, 1680, 1631,
1480, 1460, 1398, 1278, 1133, 1067, 1035, 915, 733 cm−1; MS (ESI+):
m/z 735 [M + Na]+. HRMS (ESI+): m/z for C36H56NaO14 [M + Na]+,
calcd 735.3568, found 735.3560.
7-Deoxy-10-hydroxy-11-demethyl-(2′,3′,4′,6′-O-tetra-
pivaloyl)morroniside (38) and 9-((8S)-Epoxy)-11-demethyl-
(2′,3′,4′,6′-O-tetrapivaloyl)secologanol (36a). The title com-
pounds were synthesized using general procedure GP02 with 32a
(35 mg, 0.05 mmol, 1 equiv) and (TMS)ONa (1 M) in CH2Cl2 (100
μL, 0.1 mmol, 2 equiv) for 24 h. The general procedure afforded after
purification by flash chromatography, in order of elution, compound
38 as a white solid (12.0 mg, 32%) and compound 36a as a white solid
(19.6 mg, 54%).
3
3
3
5.06 (1H, t, J4′−5′ = J4′−3′ = 9.5 Hz, H4′), 4.98 (1H, dd, J2′−3′ = 9.5
Hz, 3J2′−1′ = 8.0 Hz, H2′), 4.89 (1H, d, 3J1′−2′ = 8.0 Hz, H1′), 4.41 (1H,
dm, 2J7a−7b = 11.0 Hz, H7a), 4.21 (1H, dd, 3J6′a−6′b = 12.5 Hz, 3J6′a−5′
=
2
2.0 Hz, H6′a), 4.19−4.11 (1H, m, H7b), 4.08 (1H, dd, J10a−10b = 7.5
2
Hz, 3J10a−8 = 6.5 Hz, H10a), 3.99 (1H, dd, J6′b−6′a = 12.5 Hz, 3J6′b−5′
=
6.0 Hz, H6′b), 3.85 (1H, dt, 3J8−9 = 10.0 Hz, 3J8−10a = 3J8−10b = 6.5 Hz,
H8), 3.76 (1H, ddd, 3J5′−4′ = 9.5 Hz, 3J5′3−6′b = 6.0 Hz, 3J5−6a′ = 2.0 Hz,
2
H5′), 3.56 (1H, dd, J10b−10a = 7.5 Hz, J10b−8 = 6.5 Hz, H10b), 2.97−
2.85 (1H, m, H5), 2.10 (1H, ddd, 3J9−8 = 10.0 Hz, 3J9−5 = 6.0 Hz, 3J9−1
2
= 1.5 Hz, H9), 1.75 (1H, dm, J6a−6b = 13.0 Hz, H6a), 1.45 (1H, qd,
3
2
3
3J6b−7b = J6b−5 = J6b−6a = 13.0 Hz, J6b−7a = 3.5 Hz, H6b), 1.36, 1.28
(6H, 2s, CCH3); 1.18, 1.12, 1.06, 1.05 (36H, 4s, COC(CH3)3); 13C
NMR (75 MHz, CDCl3): δ 177.8, 176.8, 176.6, 176.4 (4C,
COC(CH3)3), 164.4 (C11), 152.9 (C3), 108.7 ((CH3)2C)) 104.3
(C4), 95.8 (C1′), 93.4 (C1), 72.4 (C5′), 71.8 (C8), 71.6 (C3′), 70.7
(C2′), 69.5 (C10), 67.9 (C7), 67.8 (C4′), 61.7 (C6′), 41.2 (C9), 38.7,
38.6, 38,5 (4C, C(CH3)3), 27.0, 26.9 (4C, C(CH3)3), 26.8 (C5), 26.4
(CH3), 25.2 (C6), 24.9 (CH3); IR (ATR): ν 2974, 1738 (CO),
1625, 1480, 1398, 1270, 1132, 1066, 970, 893 cm−1; UV (CH2Cl2):
λmax (log ε) 222 (4.21), 241 (4.13); MS (ESI+): m/z 791 [M + Na]+.
HRMS (ESI+): m/z for C39H60NaO15 [M + Na]+, calcd 791.3824,
found 791.3823.
9-((8S)-Epoxy)-11-demethyl-(2′,3′,4′,6′-O-tetrapivaloyl)-
1
secologanol (36a). Note that 36a relactonizes to 32a in solution. H
NMR (300 MHz, CDCl3): δ 7.58 (1H, br s, H3), 5.50 (1H, d, 3J1−9
7.0 Hz, H1), 5.35 (1H, t, J3′−2′ = J3′−4′ = 9.5 Hz, H3′), 5.14 (1H, t,
=
3
3
3
3
3
3J4′−3′ = J4′−5′ = 9.5 Hz, H4′), 5.07 (1H, dd, J2′−3′ = 9.5 Hz, J2′−1′
=
=
8.0 Hz, H2′), 4.99 (1H, d, 3J1′−2′ = 8.0 Hz, H1′), 4.23 (1H, dd, 2J6′a−6′b
Minor Compound: 9-((8S)-12,12-Dimethyl-8,10-dioxolanyl)-
3
2
1
12.5 Hz, J6′a−5′ = 2.0 Hz, H6′a), 4.07 (1H, dd, J6′b−6′a = 12.5 Hz,
3J6′b−5′ = 5.5 Hz, H6′b), 3.78 (1H, ddd, 3J5′−4′ = 9.5 Hz, 3J5′−6′b = 5.5 Hz,
3J5′−6′a = 2.0 Hz, H5′), 3.71−3.63 (1H, m, H7a), 3.62−3.54 (1H, m,
H7b), 3.35 (1H, br s, OH), 2.96−2.88 (2H, m, H5, H8), 2.81 (1H, dd,
2J10a−10b = 4.5 Hz, 3J10a−8 = 3.0 Hz, H10a), 2.75 (1H, t, 2J10b−10a = 3J10b−8
perpivaloylsweroside (34b). [α]D = −110.4 (c = 0.28, CH2Cl2); H
4
NMR (300 MHz, CDCl3): δ 7.48 (1H, d, J3−5 = 2.5 Hz, H3), 5.29
(1H, t, 3J3′−2′ = 3J3′−4′ = 9.5 Hz, H3′), 5.40 (1H, d, 3J1−9 = 1.0 Hz, H1),
5.03 (1H, t, 3J4′−5′ = 3J4′−3′ = 9.5 Hz, H4′), 4.96 (1H, br dd, 3J2′−3′ = 9.5
Hz, 3J2′−1′ = 8.0 Hz, H2′), 4.85 (1H, d, 3J1′−2′ = 8.0 Hz, H1′), 4.41 (1H,
dm, 2J7a−7b = 11.0 Hz, H7a), 4.21 (1H, dd, 2J6′a−6′b = 12.0 Hz, 3J6′a−5′
=
= 4.5 Hz, H10b), 2.07−1.95 (1H, m, H6a), 1.88−1.80 (1H, m, H9),
1.75−1.63 (1H, m, H6b), 1.22, 1.15, 1.11, 1.10 (36H, 4s, COC-
(CH3)3); 13C NMR (75 MHz, CDCl3): δ 178.0, 177.1, 176.4 (4C,
COC(CH3)3), 171.8 (C11), 154.8 (C3), 109.2 (C4), 96.9 (C1′), 95.3
(C1), 72.5 (C5′), 71.8 (C3′), 70.7 (C2′), 67.7 (C4′), 61.5 (C6′), 59.9
(C7), 50.6 (C8), 45.2 (C10), 41.4 (C9), 38.8, 38.7, 38.6 (4C,
C(CH3)3), 33.2 (C6), 28.5 (C5), 27.1, 27.0, 26.9 (4C, C(CH3)3); IR
(ATR): ν 2972, 1741, 1626, 1480, 1267, 1133, 1068, 940, 733 cm−1;
MS (ESI+): m/z 751 [M + Na]+. HRMS (ESI+): m/z for C36H56NaO15
[M + Na]+, calcd 751.3511, found 751.3507.
2.0 Hz, H6′a), 4.12 (1H, tm, 2J7b−7a = 3J7b−6b = 12.0 Hz, H7b), 3.96 (1H,
dd, 2J6′b−6′a = 12.0 Hz, 3J6′b−5′ = 6.0 Hz, H6′b), 3.93 (1H, dd, 2J10a−10b
=
3
3
3
8.0 Hz, J10a−8 = 5.5 Hz, H10a), 3.83 (1H, td, J8−10b = J8−9 = 8.0 Hz,
3J8−10a = 5.5 Hz, H8), 3.74 (1H, ddd, 3J5′−4′ = 9.5 Hz, 3J5′−6′b = 6.0 Hz,
3J5−6a′ = 2.0 Hz, H5′), 3.58 (1H, t, J10b−10a = J10b−8 = 8.0 Hz, H10b),
2
3
2.89 (1H, dtd, 3J5−6a = 13.0 Hz, 3J5−9 = 3J5−6b = 5.0 Hz, 4J5−3 = 2.5 Hz,
H5), 2.14 (1H, ddd, 3J9−8 = 8.0 Hz, 3J9−5 = 5.0 Hz, 3J9−1 = 1.0 Hz, H9),
2.05 (1H, qd, 3J6a−7a = 3J6a−5 = 2J6a−6b = 13.0 Hz, 3J6a−7b = 3.5 Hz, H6a),
1.85 (1H, dm, 2J6b−6a = 13.0 Hz, H6b), 1.31, 1.26 (6H, 2s, CCH3), 1.17,
1.10, 1.04, 1.03 (36H, 4s, COC(CH3)3); 13C NMR (75 MHz, CDCl3):
δ 177.7, 176.8, 176.5, 176.4 (4C, COC(CH3)3), 164.6 (C11), 151.4
(C3), 109.1 ((CH3)2C), 105.9 (C4), 95.3 (C1′), 92.8 (C1), 72.5
(C5′), 71.8 (C8), 71.7 (C3′), 70.5 (C2′), 68.6 (C7), 67.8 (C4′), 67.2
(C10), 61.7 (C6′), 40.1 (C9), 38.7, 38.6, 38.5 (4C, C(CH3)3), 28.1
(C5), 27.0, 26.9, 26.7 (4C, C(CH3)3), 26.5, 26.0 (2C, CH3), 25.4
(C6); IR (ATR): ν 2974, 1738 (CO), 1625, 1480, 1398, 1270,
1132, 1066, 970, 893 cm−1; UV (CH2Cl2): λmax (log ε) 222 (4.21),
241 (4.13); MS (ESI+): m/z 791 [M + Na]+. HRMS (ESI+): m/z for
C39H60NaO15 [M + Na]+, calcd 791.3824, found 791.3823.
9-((8R)-Epoxy)-11-demethyl-(2′,3′,4′,6′-O-tetrapivaloyl)-
secologanol (36b). The title compound was synthesized using general
procedure GP02 with 32b (35.5 mg, 0.05 mmol, 1 equiv) and
(TMS)ONa (1 M) in CH2Cl2 (100 μL, 0.1 mmol, 2 equiv) for 48 h.
The general procedure afforded compound 36b as a white solid (31.7
1
mg, 87%). [α]D = −58.5 (c = 0.95, CH2Cl2); H NMR (400 MHz,
3
CDCl3): δ 7.55 (1H, s, H3), 5.43 (1H, d, J1−9 = 9.0 Hz, H1), 5.35
(1H, t, 3J3′−2′ = 3J3′−4′ = 9.5 Hz, H3′), 5.13 (1H, t, 3J4′−3′ = 3J4′−5′ = 9.5
3
3
Hz, H4′), 5.04 (1H, dd, J2′−3′ = 9.5 Hz, J2′−1′ = 8.0 Hz, H2′), 4.96
(1H, d, 3J1′−2′ = 8.0 Hz, H1′), 4.24 (1H, dd, 2J6′a−6′b = 12.0 Hz, 3J6′a−5′
=
2.0 Hz, H6′a), 4.04 (1H, dd, 2J6′b−6′a = 12.0 Hz, 3J6′b−5′ = 5.0 Hz, H6′b),
General Procedure GP02 for Lactone Ring-Opening of
Secoiridoids Exemplified by the Synthesis of 11-Demethyl-
(2,3′,4′,6′-O-tetrapivaloyl)secologanol (35). To a solution of 31
(50 mg, 0.072 mmol, 1 equiv) in anhydrous CH2Cl2 (5 mL) was
added a commercial solution of (TMS)ONa (1 M) in CH2Cl2 (140
μL, 0.14 mmol, 2 equiv). The reaction was stirred at room temperature
for 2 h and quenched by addition of silica. After 15 min of stirring, the
suspension was evaporated in vacuo. The crude product was purified
by flash chromatography (CH2Cl2/MeOH, 97/3) to give 35 as a white
3.77 (1H, ddd, 3J5′−4′ = 9.5 Hz, 3J5′−6′b = 5.0 Hz, 3J5′−6′a = 2.0 Hz, H5′),
2
3
3
3.70 (1H, dt, J7a−7b = 11.5 Hz, J7a−6a = J7a−6b = 5.5 Hz, H7a), 3.63
(1H, ddd, J7b−7a = 11.5 Hz, J7b−6a = 9.0 Hz, J7b−6b = 4.0 Hz, H7b),
2
3
3
3
3
3
3.02 (1H, dt, J5−6b = 9.0 Hz, J5−9 = J5−6a = 5.0 Hz, H5), 2.95−2.90
2
(1H, m, H8), 2.91−2.87 (1H, m, H10a), 2.59 (1H, dd, J10b−10a = 4.5
Hz, 3J10b−8 = 2.0 Hz, H10b), 2.13 (1H, dddd, 2J6a−6b = 14.0 Hz, 3J6a−7b
9.0 Hz, 3J6a−7a = 5.5 Hz, 3J6a−5 = 5.0 Hz H6a), 1.54 (1H, dddd, 2J6b−6a
=
=
3
3
14.0 Hz, J6b−5 = 9.0 Hz, J6b−7a = 5.5 Hz, 3J6b−7b = 4.0 Hz, H6b), 1.48
1
3
3
3
solid (45 mg, 88%). Note that 35 relactonizes to 31 in solution. H
(1H, td, J9−8 = J9−1 = 9.0 Hz, J9−5 = 5.0 Hz, H9), 1.20, 1.14, 1.11,
1.10 (36H, 4s, COC(CH3)3); 13C NMR (100 MHz, CDCl3): δ 177.9,
177.1, 176.6, 176.4 (4C, COC(CH3)3); 172.2 (C11), 154.3 (C3),
109.3 (C4), 96.7 (C1′), 94.7 (C1), 72.6 (C5′), 71.7 (C3′), 70.5 (C2′),
67.6 (C4′), 61.5 (C6′), 59.7 (C7), 49.7 (C8), 48.6 (C10), 44.1 (C9),
38.8, 38.7, 38.8 (4C, C(CH3)3), 33.9 (C6), 27.8 (C5), 27.1, 27.0, 26.9
(4C, C(CH3)3); IR (ATR): ν 2971, 1741, 1629, 1481, 1277, 1134,
1067, 911, 732 cm−1; UV (CH2Cl2): λmax (log ε) 222 (3.66), 241
(3.99); MS (ESI+): m/z 751 [M + Na]+. HRMS (ESI+): m/z for
C36H56NaO15 [M + Na]+, calcd 751.3511, found 751.3510.
NMR (300 MHz, CDCl3): δ 7.55 (1H, s, H3), 5.65 (1H, ddd, 3J8−10a
=
17.5 Hz, 3J8−10b = 10.5 Hz, 3J8−9 = 7.5 Hz, H8), 5.36 (1H, d, 3J1−9 = 8.0
Hz, H1), 5.33 (1H, t, 3J3′−2′ = 3J3′−4′ = 9.5 Hz, H3′), 5.28−5.19 (2H, m,
3J10a−8 = 17.5 Hz, 3J10b−8 = 10.5 Hz, H10), 5.13 (1H, t, 3J4′−3′ = 3J4′−5′
=
9.5 Hz, H4′), 5.04 (1H, dd, 3J2′−3′ = 9.5 Hz, 3J2′−1′ = 8.0 Hz, H2′), 4.96
(1H, d, 3J1′−2′ = 8.0 Hz, H1′), 4.24 (1H, dd, 2J6′a−6′b = 12.0 Hz, 3J6′a−5′
=
2.0 Hz, H6′a), 4.05 (1H, dd, 2J6′b−6′a = 12.0 Hz, 3J6′b−5′ = 5.5 Hz, H6′b),
3.76 (1H, ddd, 3J5′−4′ = 9.5 Hz, 3J5′−6′b = 5.5 Hz, 3J5′−6a′ = 2.0 Hz, H5′),
3
3
3
3.66−3.50 (2H, m, H7), 2.82 (1H, dt, J5−9 = 9.0 Hz, J5−6a = J5−6b
=
5.0 Hz, H5), 2.50 (1H, br td, 3J9−5 = 3J9−1 = 8.0 Hz, 3J9−8 = 5.0 Hz, H9),
1.97−1.84 (1H, m, H6a), 1.50−1.40 (1H, m, H6b), 1.19, 1.13, 1.09,
7-Deoxy-10-hydroxy-11-demethyl-(2′,3′,4′,6′-O-tetrapivaloyl)-
morroniside (38). [α]D20 = −27.2 (c = 0.58, CH2Cl2); H NMR (300
1
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Article
MHz, CDCl3): δ 7.50 (1H, br s, H3), 5.42 (1H, t, 3J3′−2′ = 3J3′−4′ = 9.5
39.8, 38.7 (4C, C(CH3)3), 34.1 (C6), 30.2 (C5), 27.1, 27.0 (4C,
C(CH3)3), 26.3, 25.4 (2C, CH3); IR (ATR): ν 2973, 1741, 1635, 1480,
1277, 1132, 1064, 892, 852, 736 cm−1; UV (CH2Cl2): λmax (log ε) 222
(3.98), 241 (4.06); MS (ESI+): m/z 809 [M + Na]+. HRMS (ESI+):
m/z for C39H62NaO16 [M + Na]+, calcd 809.3936, found 809.3953.
Hz, H3′), 5.26 (1H, d, 3J1−9 = 9.5 Hz, H1), 5.16 (1H, t, 3J4′−3′ = 3J4′−5′
=
9.5 Hz, H4′), 5.11 (1H, dd, 3J2′−3′ = 9.5 Hz, 3J2′−1′ = 8.0 Hz, H2′), 5.03
(1H, d, 3J1′−2′ = 8.0 Hz, H1′), 4.27 (1H, dd, 2J6′a−6′b = 12.5 Hz, 3J6′a−5′
=
1.5 Hz, H6′a), 4.07 (1H, dd, 2J6′b−6′a = 12.5 Hz, 3J6′b−5′ = 5.5 Hz, H6′b),
3
3.97−3.86 (3H, m, H7a, H8, H10a), 3.81 (1H, ddd, J5′−4′ = 9.5 Hz,
3J5′−6′b = 5.5 Hz, J5′−6′a = 1.5 Hz, H5′), 3.66 (1H, dd, J10b−10a = 12.5
3
2
ASSOCIATED CONTENT
■
Hz, 3J10b−8 = 8.5 Hz, H10b), 3.05 (1H, br t, J7b−7a = 3J7b−6b = 12.5 Hz,
2
S
H7b), 3.04 (1H, dd, 3J5−6b = 10.0 Hz, 3J5−9 = 6.0 Hz, H5), 1.92 (1H, dt,
* Supporting Information
Description of the experimental kinetic studies and 1H and 13
C
3
3
2
3J9−1 = 9.5 Hz, J9−5 = J9−8 = 6.0 Hz, H9), 1.82 (1H, br d, J6a−6b
=
2
3
NMR spectra of the compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
14.5 Hz, H6a), 1.51 (1H, dddd, J6b−6a = 14,5 Hz, J6b−7b = 12.5 Hz,
3J6b−5 = 10.0 Hz, 3J6b−7a = 2.5 Hz, H6b), 1.22, 1.16, 1.14, 1.11 (36H, 4s,
COC(CH3)3); 13C NMR (75 MHz, CDCl3): δ 178.0, 177.7, 177.0,
176.4 (4C, COC(CH3)3), 170.4 (C11), 152.8 (C3), 110.0 (C4), 96.2
(C1′), 96.0 (C1), 72.8 (C5′), 71.9 (C10), 71.7 (C7), 71.6 (C8), 71.2
(C3′), 70.7 (C2′), 67.7 (C4′), 61.5 (C6′), 47.0 (C9), 38.9, 38.8 (4C,
C(CH3)3), 35.2 (C6), 32.8 (C5), 27.1, 27.0, 26.9 (4C, C(CH3)3); IR
(ATR): ν 2971, 1739, 1633, 1480, 1277, 1132, 1068, 940, 737 cm−1;
UV (CH2Cl2): λmax (log ε) 222 (3.58), 234 (3.70); MS (ESI+): m/z
751 [M + Na]+. HRMS (ESI+): m/z for C36H56NaO15 [M + Na]+,
calcd 751.3511, found 751.3507.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: +33 01 40 46 96 58. E-mail: brigitte.deguin@
parisdescartes.fr.
Notes
The authors declare no competing financial interest.
9-((8S)-12,12-Dimethyl-8,10-dioxolanyl)-11-demethyl-
(2′,3′,4′,6′-O-tetrapivaloyl)secologanol (37b). The title com-
pound was synthesized using general procedure GP02 with 34b (76
mg, 0.1 mmol, 1 equiv) and (TMS)ONa (1 M) in CH2Cl2 (200 μL,
0.2 mmol, 2 equiv) for 24 h. The general procedure afforded 37b as a
white solid (66 mg, 84%). [α]D = −73.1 (c = 0.42, CH2Cl2); 1H NMR
(400 MHz, CDCl3): δ 7.54 (1H, br s, H3), 5.34 (1H, t, 3J3′−2′ = 3J3′−4′
ACKNOWLEDGMENTS
■
We gratefully acknowledge Prof. Pierre Vogel for fruitful
discussions. We thank the Agence Nationale de la Recherche
(Grant ANR-09-CP2D-09-01) and Minister
̀
e de l’Enseigne-
ment Superieur et de la Recherche for financial support.
́
3
3
= 9.5 Hz, H3′), 5.28 (1H, d, J1−9 = 9.0 Hz, H1), 5.13 (1H, t, J4′−3′
=
3
3
3J4′−5′ = 9.5 Hz, H4′), 5.00 (1H, dd, J2′−3′= 9.5 Hz, J2′−1′ = 8.0 Hz,
REFERENCES
■
3
2
H2′), 4.92 (1H, d, J1′−2′ = 8.0 Hz, H1′), 4.25 (1H, dd, J6′a−6′b = 12.0
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3
2
3
Hz, J6′a−5′ = 2.0 Hz, H6′a), 4.17 (1H, dd, J10a−10b = 8.5 Hz, J10a−8
=
6.0 Hz, H10a), 4.02 (1H, dd, 2J6′b−6′a = 12.0 Hz, 3J6′b−5′ = 5.0 Hz, H6′b),
3
3
4.10−3.92 (1H, m, H8), 3.75 (1H, dd, J5′−4′ = 9.5 Hz, J5′−6′b = 5.0
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3
3
H5), 2.15−2.04 (1H, m, H6a), 1.87 (1H, ddd, J9−1 = J9−5 = 9.0 Hz,
3J9−8 = 5.0 Hz, H9), 1.35, 1.33 (6H, 2s, CH3), 1.33−1.25 (1H, m, H6b),
1.20, 1.14, 1.12, 1.10 (36H, 4s, COC(CH3)3); 13C NMR (100 MHz,
CDCl3): δ 177.9, 177.1, 176.4, 176.3 (4C, COC(CH3)3), 172.5 (C11),
154.6 (C3), 109.9 (C4), 108.1 ((CH3)2C), 97.1 (C1′), 95.9 (C1), 73.0
(C8), 72.6 (C5′), 71.6 (C3′), 70.4 (C2′), 70.2 (C10), 67.5 (C4′), 61.4
(C6′), 59.9 (C7), 44.6 (C9), 38.8, 38.7, 38.6 (4C, C(CH3)3), 34.3
(C6), 27.8 (C5), 27.1, 27.0, 26.9 (4C, C(CH3)3), 26.5 (CH3), 25.5
(CH3); IR (ATR): ν 2973, 1741, 1633, 1480, 1277, 1132, 1060, 932,
761 cm−1; UV (CH2Cl2): λmax (log ε) 222 (3.98), 241 (4.06); MS
(ESI+): m/z 809 [M + Na]+. HRMS (ESI+): m/z for C39H62NaO16 [M
+ Na]+, calcd 809.3936, found 809.3953.
9-((8R)-12,12-Dimethyl-8,10-dioxolanyl)-11-demethyl-
(2′,3′,4′,6′-O-tetrapivaloyl)secologanol (37a). The title com-
pound was synthesized using general procedure GP02 with 34a (76
mg, 0.1 mmol, 1 equiv) and (TMS)ONa (1 M) in CH2Cl2 (200 μL,
0.2 mmol, 2 equiv) for 39 h. The general procedure afforded 37a as a
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1
white solid (51 mg, 65%). [α]D = −110.4 (c = 0.28, CH2Cl2); H
́
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3
3
9.0 Hz, H1), 5.35 (1H, t, J3′−2′ = J3′−4′ = 9.5 Hz, H3′), 5.14 (1H, t,
3J4′−3′ = 3J4′−5′ = 9.5 Hz, H4′), 5.08 (1H, br dd, 3J2′−3′ = 9.5 Hz, 3J2′−1′
8.0 Hz, H2′), 5.03 (1H, d, 3J1′−2′ = 8.0 Hz, H1′), 4.22 (1H, br t, 3J8−10
=
=
7.5 Hz, H8), 4.17−4.10 (2H, m, H6′), 3.96−3.88 (2H, m, H10), 3.78
3
2
(1H, dm, J5′−4′ = 9.5 Hz, H5′), 3.64 (1H, br dt, J7a−7b = 11.0 Hz,
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3
2
3J7b−6a = 10.0 Hz, 3J7b−6b = 2.0 Hz, H7b), 2.85 (1H, br ddd, 3J5−6b = 11.0
3
3
2
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=
14.0 Hz, 3J6a−7b = 10.0 Hz, 3J6a−5 = 5.0 Hz, 3J6a−7a = 4.0 Hz, H6a), 1.95
3
3
(1H, br dd, J9−1 = 9.0 Hz, J9−5 = 4.0 Hz, H9), 1.32, 1.21 (6H, 2s,
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COC(CH3)3); 13C NMR (100 MHz, CDCl3): δ 178.0, 177.1, 176.4,
176.3 (4C, COC(CH3)3), 172.8 (C11), 154.3 (C3), 109.6 (C4), 109.3
((CH3)2C), 96.0 (C1′), 95.0 (C1), 75.5 (C8), 72.6 (C5′), 71.9 (C3′),
70.6 (C2′), 67.7 (C10), 67.6 (C4′), 61.7 (C6′), 59.5 (C7), 40.1 (C9),
4365
dx.doi.org/10.1021/jo500220h | J. Org. Chem. 2014, 79, 4358−4366

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