Construction of chiral tertiary alcohol stereocenters via the [2,3]- meisenheimer rearrangement: Enantioselective synthesis of the side-chain acids of homoharringtonine and harringtonine

Article abstract of DOI:10.1021/jo302203g

For the first time, the [2,3]-Meisenheimer rearrangement has been developed into a general strategy for the construction of chiral tertiary alcohols. The effectiveness and practicality of this methodology are illustrated by the successful synthesis of (R)-20 and (R)-30, the side chain acids of homoharringtonine and harringtonine, respectively.

Full text of DOI:10.1021/jo302203g

Article
pubs.acs.org/joc
Construction of Chiral Tertiary Alcohol Stereocenters via the [2,3]-
Meisenheimer Rearrangement: Enantioselective Synthesis of the
Side-Chain Acids of Homoharringtonine and Harringtonine
Hua Yang,* Moran Sun, Shuguang Zhao, Ming Zhu, Yangla Xie, Changling Niu, and Chunlin Li
School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, 450001, China
S
* Supporting Information
ABSTRACT: For the first time, the [2,3]-Meisenheimer
rearrangement has been developed into a general strategy for
the construction of chiral tertiary alcohols. The effectiveness
and practicality of this methodology are illustrated by the
successful synthesis of (R)-20 and (R)-30, the side chain acids
of homoharringtonine and harringtonine, respectively.
the best of our knowledge, in spite of the significant progress
made in the synthesis of chiral secondary alcohol via the [2,3]-
Meisenheimer rearrangement,7 no substantial efforts were made
to construct the chiral tertiary alcohols via the [2, 3]-
Meisenheimer rearrangement. Despite the unfavorable factors
(Scheme 1, eq 1, −50 °C, 2 days) encountered during the
synthesis of chiral secondary alcohols, we decided to modify
Reetz’s system, which uses a disubstituted alkene, to use a
trisubstituted alkene for the construction of chiral tertiary
alcohol.
INTRODUCTION
■
The construction of chiral tertiary alcohol functionalities is a
continuing challenge in the synthesis of complex bioactive
molecules.1 Although successful strategies for the construction
of chiral tertiary alcohols have been developed over the past
three decades, there is still a strong demand for new strategies
due to the complexity and diversity of bioactive molecules.
Successful strategies include the following: (a) the Sharpless
asymmetric dihydroxylation, Sharpless asymmetric epoxidation,
Jacobsen asymmetric epoxidation, Shi asymmetric epoxidation
of trisubstituted olefins,1 (b) a most exciting discovery in 2008
of the 1,2-metalate rearrangement of boronate complexes,2 (c)
the kinetic resolution of tertiary alcohols derived from aldol
reactions of ketones, which is efficient and suitable for large-
scale preparation,3 (d) the catalytic asymmetric additions of
organometallic reagents to ketones,1 (e) a variety of aldol-type
reactions catalyzed by chiral Lewis acid, Lewis base or chiral
copper reagents,1 and (f) a variety of other types of reactions.1
In connection with our interest in the enantioselective synthesis
of the side chain acids of homoharringtonine and harringtonine,
we intended to create a new strategy based on the [2,3]-
Meisenheimer rearrangement (Figure 1), which we hypothe-
sized would be able to satisfy the requirements of the
complexity and diversity of bioactive molecules.
While the Meisenheimer rearrangement is a 90-year-old
reaction, it was not efficiently utilized for the construction of
chiral secondary alcohol stereocenters until 1991 when Reetz et
al.4 used it with a self-immolative method. In the ensuing 10
years, Enders, Coldham, Micouin, and Guarna each studied the
chiral auxiliary method for carrying out this transformation.5
Unfortunately, only moderate diastereoselectivities were
achieved (de < 73%). However, Davies and Micouin reached
excellent diastereoselectivities (de >95%) using a combination
of the self-immolative and chiral auxiliary methods.5 After
another decade, Tambar and co-workers6 achieved a milestone
for developing the first catalyzed enantioselective [2,3]-
Meisenheimer rearrangement with high ee values (>87%). To
RESULTS AND DISCUSSION
■
Trisubstituted alkene 38 (Scheme 1) was chosen as a substrate
for model studies. We hoped to observe 100% transfer of
chirality in the transformation of 3→4 as observed by Reetz
and Lauterbach4 in the transformation of 1 → 2. To our great
delight, after oxidation with m-CPBA, 3 immediately took a
spontaneous [2,3]-Meisenheimer rearrangement to form an
unstable compound, 4, which slowly underwent a [1,3]-transfer
to yield compound 5 when allowed to stand at room
temperature or during purification using silica gel column
chromatography.9 As such, the reaction mixture was washed
with 10% NaOH aqueous solution to yield crude compound 4,
which was immediately hydrogenated at 10 °C to afford 6 in
which the N−O bond could be cleaved at 60 °C to afford the
chiral tertiary alcohol 7. The transformation of 3 → 4 → 5 was
difficult to monitor by TLC because compounds 3−5 had
identical Rf values. The 100% transfer of chirality of 3 → 4 was
confirmed by comparing the ee values of 3 and 6 (75% ee vs
75% ee). We propose that transition state 3a leads to the
observed S-configured products 4, as opposed to the sterically
less favorable transition state, 3b, which would provide the R-
configured analogues of 4 (not observed).10 Next, the
Received: October 7, 2012
Published: December 5, 2012
© 2012 American Chemical Society
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Figure 1. [2,3]-Meisenheimer rearrangement has the potential to be a general strategy for the construction of chiral tertiary alcohol stereocenters.
trisubstituted alkene 8 (E/Z = 1:0.52) was prepared.11 It
rearranged with the same ease as 3 to afford compound 9,
which was more unstable than compound 4 and necessitated
hydrogenation at −10 °C.12 The configuration of chiral carbon
atom in product 9 was expected to be both S and R because
compound 8 was a mixture of cis- and trans-olefins. With the
success of these model studies, we decided to undertake the
enantioselective synthesis of side chain acids of homoharring-
tonine and harringtonine.
Homoharringtonine (HHT) and its homologue harringto-
nine (HT) have potent antileukemic activities. In particular,
HHT has reached phase III clinical trials in the United States
against chronic myelogenous leukemia, while in China, it is
used as a front-line therapy for acute myeloid leukemia and
shows activity against the chloroquinine-resistant Plasmodium
falciparum malaria parasite in vitro.13c Because the inactive
cephalotaxine (Figure 1) can compose as much as ca. 50% of
total alkaloid extracts, the most practical path for obtaining
large quantities of HHT and HT at the present time is through
semisynthesis by coupling the carboxyl group of the respective
ester side chain to the C-3 hydroxyl group of cephalotaxine.
Several groups have reported enantioselective syntheses of the
side chains of HHT and HT.13 In this paper, we present a new
route for synthesizing these side chains and elucidate the
important role that the [2,3]-Meisenheimer rearrangement
plays in the construction of chiral tertiary alcohol motif (vide
infra).
As shown in Scheme 2, side chain acid 20 of HHT was
synthesized from methyl 3(S)-[(tert-butoxycarbonyl)amino]-4-
hydroxybutanoate 11, which was commercially available and
also easily prepared from L-aspartic acid according to the
literature procedure.14 Treatment of ester 11 with MeMgI
afforded 1,4-diol 12 in 85% yield.15 Attempted oxidation of 12
using PCC or PDC led to the undesired lactone. Swern
oxidation of 12 resulted in decomposition of the starting
material. However, to our delight, the employment of IBX as an
oxidizing reagent furnished lactol 13 as a 1:1 diastereomeric
mixture in almost quantitative yield.16 Next, Witting coupling
between lactol 13 and 1-butyrolactonylidene triphenylphos-
phorane 14 provided exclusively the desired (E)-olefin 15 in
85% yield.17,18 Deprotection of olefin 15 and subsequent benzyl
bromide alkylation of the resulting TFA salt in the presence of
K2CO3 provided allylamine 16, the precursor for the [2,3]-
Meisenheimer rearrangement, in 80% yield. Allylamine 16 was
treated with m-CPBA, while the reaction was cooled in an ice
bath to provide 17 as an unstable [2,3]-Meisenheimer product.
After the reaction mixtures were washed with 10% NaOH
aqueous solution, the concentrated residues were hydrogenated
without further purification first at 5−20 °C to saturate the
double bonds and then at 60 °C to cleave the N−O bond to
furnish 18 and 19 in a 7:3 ratio (column chromatographic
separation).19 After surveying a large number of oxidation
methods, including Jones oxidation,19 PDC−DMF oxidation,20
CrO3−H5IO6 oxidation,21 KMnO4 oxidation,19 etc., we found
that oxidation with the TEMPO−NaClO−NaClO2 system gave
diacid 20 cleanly and in excellent yield.22 The overall yield for
11 → 20 was 36.2% over eight linear steps. However, the NMR
spectra, optical rotation, and solubility in CHCl3 for diacid 20
were not identical to those reported by Tietze et al.13d,23 To
confirm the structure, we further converted 20 to its diester 21
with 2,2-dimethoxypropane in the presence of TMSCl.24 The
NMR data, optical rotations, EIMS, IR, and melting point of
diester 21 are completely identical with the data reported by
d’Angelo et al.13f and Powell et al.25 Therefore, the structure
assigned to 20 by Tietze et al. is most likely mis-assigned. In
addition, the very small difference between the [α]20D −17.5 (c
= 0.7, CHCl3) of our own material and the [α]20 −18.0 (c =
D
0.7, CHCl3) for the methanolysis of natural HHT25 indicated a
perfect chirality transfer of 16 → 17 at 5 °C (using an ice bath)
during the [2,3]-Meisenheimer rearrangement.
To the best of our knowledge, the construction of a chiral
quaternary carbon through a [2,3]-Meisenheimer rearrange-
ment has never been developed as a general and viable
strategy.1 Our enantioselective synthesis of the side chain acid
of homoharringtonine serves as the first illustrative example of
this strategy.4−7 To improve the practicality and effectiveness of
this strategy, the double bond must be left intact during the N−
O bond cleavage, which would allow for further elaboration of
the rearranged side chain of chiral quaternary carbon. This is
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Scheme 1. Model Studies of the [2,3]-Meisenheimer Rearrangement
illustrated in the synthesis of side chain acid HT, 30 (Scheme
3).
TMSI31 proved fruitless. Compound 26 is a versatile chiral
building block because any of the carbon chains from the chiral
stereocenter are suitable for further elaboration to achieve
desired functionalities. Compound 26 was easily transformed
into the side chain acid of HT, 30, by successive manipulation
involving a MnO2 oxidation,32 a selective Grignard reaction
with the enone,33 double-bond hydrogenation, a TEMPO-
mediated oxidation of the lactone, and the formation of a new
6-membered lactone.34 The total yield was 34.7% over nine
linear steps.
The synthesis of 30 began from N-Boc-aldehyde 22, which
was conveniently prepared from L-threonine according to the
literature procedure.26 Protected aldehyde 22 was transformed
into E-substituted alkene 24 by successive manipulation
involving the Wittig reaction, deprotection, and N-bisbenzyla-
tion. Upon treating 24 with m-CPBA in CH2C12 at 5 °C,
hydroxylamine 25 was formed as the sole product. After the
reaction system was washed with 10% NaOH aqueous solution,
the concentrated residues were dissolved in concentrated HCl−
MeOH solution without further purification, and zinc powder
was added under vigorous stirring. TLC indicated a complete
reaction after 20 min, and the reaction was quenched with a
cold saturated ammonium hydroxide solution. Extraction and
column chromatographic separation afforded 26 in 75% total
yield.27 Attempts to improve the reduction yield by using other
reductants, including Al (Hg),28 Na (liq NH3),29 CuSO4,30 and
CONCLUSIONS
■
In conclusion, we have developed a highly enantioselective
process for the synthesis of the side-chain acids of
homoharringtonine and harringtonine. This study expands
the usefulness of the [2,3]-Meisenheimer rearrangement to
include the efficient synthesis of chiral tertiary alcohols for the
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Scheme 2. Synthesis of the Side-Chain Acid of HHT, 20
Scheme 3. Synthesis of the Side Chain Acid HT, 30
first time. This strategy has the potential for enabling the brief
syntheses of a large number of complex bioactive molecules
bearing chiral tertiary alcohol functionalities. Further inves-
tigations into the substrate scopes and Wittig reagents used and
the application of this strategy to the synthesis of fostriecin,
erythronolide A, and integerrimine are underway, and the
results will be reported in due course.
EXPERIMENTAL SECTION
■
General Methods. For product purification by flash column
chromatography, silica gel (200−300 mesh) and petroleum ether (bp
60−90 °C)are used. All solvents were purified and dried by standard
techniques and distilled prior to use. All organic extracts were dried
over MgSO4, unless otherwise noted. IR spectra were recorded using
KBr disks in the 400−4000 cm−1 region. Optical rotations were
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1
measured using a polarimeter. HR-MS was obtained by ESI (positive
ion mode) on TOF mass analyzer. Melting points were determined
without correction. 1H and 13C NMR spectra were recorded with TMS
as an internal standard and CDCl3 or CD3COCD3 as solvent.
General Procedure for N-Boc Deprotection with TFA and N-
Bisbenzylation with BnBr To Yield Products 16 and 24. To a
solution of N-Boc olefin (8.53 mmol) in dry dichloromethane (20
mL) was added TFA (42.65 mmol). The mixture was stirred at reflux
for 3 h, after which time it was evaporated to give a white solid. To a
solution of the white solid in dry acetonitrile (100 mL) was added
K2CO3 (42.65 mmol), followed by BnBr (12 mmol). The reaction
mixture was stirred at reflux for 3 h, at which point most of the solvent
was evaporated under reduced pressure. The residue was diluted with
water, and the mixture was extracted with EtOAc (3 × 80 mL). The
combined extracts were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The product was purified by
chromatography on silica gel to afford the N-bisbenzylated olefin.
Greater than 80% yield could be stably achieved using the strictly dry
TFA, DCM, BnBr, and CH3CN.
General Procedure for the Oxidation of Allyl Tertiary
Amines 3, 8, 16, and 24 To Yield the Crude [2,3]-Meisenheimer
Rearrangement Products 4, 9, 17, and 25, Respectively. To a
solution of allylic tertiary amine (14.40 mmol) in CH2Cl2 (50 mL) was
added m-CPBA (75%, 3.66 g, 15.91 mmol) at 5 °C. The reaction
mixture was stirred at this temperature for 10 min. Then, the
suspension was filtered, and the filtrate was washed with 10% NaOH
(3 × 10 mL), saturated NaHCO3 (2 × 10 mL), and saturated NaCl (2
× 10 mL), dried over MgSO4, filtered, and concentrated at 30 °C
under reduced pressure to give an oily residue (crude 4, 9, 17, and 25,
respectively), which was used in the next step without further
purification.
(E)-3-(2-((Dibenzylamino)oxy)propylidene)dihydrofuran-
2(3H)-one (5). Crude 4 (289 mg, 0.86 mmol) decomposed into the
compound 5 and other impurities during purification by chromatog-
raphy on silica gel. Pure 5 (183 mg, 63% yield) was obtained as a
colorless oil via purification using a second silica gel column
(petroleum ether−EtOAc, 8:1): IR (KBr) 1769 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.37−7.23 (m, 10H), 6.27 (d, J = 9.0 Hz, 1H),
4.27 (m, 2H), 3.87 (d, J = 12.84 Hz, 2H), 3.83−3.79 (m, 1H), 3.80 (d,
J = 12.84 Hz, 2H), 2.70−2.50 (m, 2H), 0.94 (d, J = 6.52 Hz, 3H); 13C
NMR (DEPT) (100 MHz, CDCl3) δ 170.9 (C), 140.7 (CH), 137.5
(C), 129.8 (CH), 128.2 (CH), 127.5 (CH), 125.2 (C), 75.9 (CH),
65.4 (CH2), 63.4 (CH2), 25.0 (CH2), 18.4 (CH3); HRMS (ESI-TOF)
m/z [M + Na]+, calcd for C21H23NNaO3 360.1576, found 360.1573.
(R)-3-((Dibenzylamino)oxy)-3-propyldihydrofuran-2(3H)-
one (6). To a solution of crude 4 (500 mg, 1.48 mmol) in MeOH (30
mL) was added 10% Pd/C (25 mg) at 0 °C. The mixture was stirred
under a hydrogen atmosphere (60 psi) at 10 °C for 3 h. After the
reaction was complete, the catalyst was removed by filtration over
Celite and washed with MeOH (3 × 6 mL). The filtrate was
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether−EtOAc, 5:1) to yield 6
(465 mg, 93%) as a colorless oil: IR (KBr) 1756 cm−1; 1H NMR (400
MHz,CDCl3) δ 7.36−7.15 (m, 10H), 4.41 (d, J = 12.72 Hz, 1H),
4.22−4.16 (m, 1H), 4.06−4.00 (m, 1H), 3.90−3.52 (m, 2H), 3.57 (d, J
= 13.36 Hz, 1H), 1.80−1.60 (m, 3H), 1.58−1.38 (m, 2H), 1.22−1.18
(m, 1H), 0.90 (t, J = 7.20 Hz, 3H); 13C NMR (DEPT) (100 MHz,
CDCl3) δ 176.1 (C), 137.1 (C), 136.7 (C), 130.5 (CH2), 129.9
(CH2), 128.3 (CH2), 128.2 (CH2), 127.7 (CH2), 127.5 (CH2), 83.0
(C), 66.0 (CH2), 63.4 (CH2), 61.9 (CH2), 37.9 (CH2), 30.6 (CH2),
16.8 (CH2),16.4 (CH3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C21H25NO3Na 362.1732, found 362.1730.
oil: IR (KBr) 1756 cm−1; H NMR (400 MHz, CDCl3) δ 4.43−4.37
(m, 1H), 4.26−4.20 (m, 1H), 3.30−3.10 (brs, 1H), 2.40−2.28 (m,
2H), 1.81−1.72 (m, 1H), 1.72−1.60 (m,1H), 1.60−1.48 (m, 1H),
1.48−1.38 (m, 1H), 0.98 (t, J = 7.32 Hz, 3H); 13C NMR (DEPT)
(100 MHz, CDCl3) δ 179.3 (C), 74.8 (C), 65.4 (CH2), 38.7 (CH2),
34.4 (CH2), 16.6 (CH2), 14.2 (CH3); HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C7H12 O3Na 167.0684, found 167.0685.
(S)-Dimethyl 2-(2-(Dibenzylamino)propylidene)succinate
(8). To a solution of diethyl phosphite (967 mg, 7.00 mmol) in
EtOH (35 mL) was added NaH (168 mg, 7.00 mmol) at 0 °C. The
mixture was allowed to reach room temperature and stirred for 30 min.
After the addition of diethyl maleate (1.21 g, 7.00 mmol), stirring was
continued for 1 h. (S)-2-(Dibenzylamino)propanal (1.77 g, 7.00
mmol) was added, and the mixture was stirred for 4 h. After the
addition of aq NH4Cl (25 mL), the mixture was extracted with EtOAc
(4 × 30 mL). The combined extracts were washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The residue
was purified by chromatography on silica gel (petroleum ether−
EtOAc, 8:1) to afford 8 (E/Z = 1:0.52) (2.24 g, 83%) as a colorless oil.
Dimethyl 2-((Dibenzylamino)oxy)-2-propylsuccinate (10).
To a solution of 9 (397 mg, 1 mmol) in MeOH (30 mL) was
added 10% Pd/C (20 mg). The mixture was stirred under a hydrogen
atmosphere (60 psi) at −10 °C for 3 h. After the reaction was
complete, the catalyst was removed by filtration over Celite and
washed with MeOH (3 × 6 mL). The filtrate was concentrated under
reduced pressure. Because pure 10 was difficult to obtain via column
chromatography, crude 10 was reduced with LiAlH4 in THF. The
obtained product proved to be 2-((dibenzylamino)oxy)-2-propylbu-
tane-1,4-diol (216 mg, 65% from 8) after purification by column
chromatography: 1H NMR (400 MHz, CDCl3) δ 7.40−7.25 (m,
10H), 4.01 (d, J = 13.0 Hz, 1H), 3.95−3.80 (m, 3H), 3.75−3.65 (m,
1H), 3.65−3.55 (m, 1H), 3.29 (d, 1H, J = 12.4 Hz, 1H), 3.20 (d, J =
12.4 Hz, 1H), 2.60−2.40 (brs, 1H), 1.80−1.60 (m, 4H), 1.50−1.40
(m, 1H), 1.40−1.20 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR
(DEPT) (100 MHz, CDCl3) δ 136.3 (C), 130.1 (CH), 129.9 (CH),
128.5 (CH), 127.9 (CH), 85.1 (C), 67.6 (CH2), 63.8 (CH2), 63.2
(CH2), 58.7 (CH2), 36.3 (CH2), 36.2 (CH2), 17.2 (CH2), 14.7
(CH3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C21H29NO3Na
366.2045, found 366.2046.
(S)-tert-Butyl (1,4-Dihydroxy-4-methylpentan-2-yl)-
carbamate (12). A three-necked, round-bottomed flask equipped
with a reflux condenser and a dropping funnel was charged with
magnesium turnings (1.44 g, 58.4 mmol) and anhydrous ethyl ether
(20 mL). A solution of iodomethane (3.35 mL, 40.7 mmol) in
anhydrous ethyl ether (40 mL) was added dropwise to this suspension,
maintaining slight boiling, and the suspension was stirred for an
additional 90 min at ca. 20 °C. A solution of 11 (2.1 g, 9.05 mmol) in
anhydrous ethyl ether (20 mL) was added dropwise at 5 °C to the
Grignard reagent. The dropping funnel was rinsed with THF (10 mL),
and the white suspension was stirred at ca. 20 °C for a further 90 min.
The reaction mixture was cooled to 0 °C, cautiously quenched by
addition of ether (40 mL) and 1 N HCl (20 mL), and poured into a
separating funnel. The aqueous phase was extracted with ethyl ether (3
× 70 mL). The combined extracts were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (petroleum ether−EtOAc,
3:2) to afford 12 (1.78 g 85%) as a colorless oil: IR (KBr) 3430, 1717,
1682 cm−1; [α]25 = −15.1 (c 1.45, EtOH); H NMR (400 MHz,
1
D
CDCl3) δ 3.82−3.73 (m, 1H), 3.70−3.61 (m, 1H), 3.61−3.55 (m,
1H), 2.78 (brs, OH, 2H), 1.69−1.66 (m, 2H), 1.44 (s, 9H), 1.29(s,
6H); 13C NMR (100 MHz, CDCl3) δ 156.6, 79.8, 70.3, 66.6, 50.1,
44.2, 30.0, 28.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C11H23NO4Na 256.1525, found 256.1526.
(R)-3-Hydroxy-3-propyldihydrofuran-2(3H)-one (7). To a
solution of crude 6 (300 mg, 0.89 mmol) in MeOH (30 mL) was
added 10% Pd/C (15 mg). The mixture was stirred under a hydrogen
atmosphere (60 psi) at 60 °C for 3 h. After the reaction was complete,
the catalyst was removed by filtration over Celite and washed with
MeOH (3 × 5 mL). The filtrate was concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
(petroleum ether−EtOAc, 3:1) to yield 6 (108 mg, 85%) as a colorless
tert-Butyl ((3S)-2-Hydroxy-5,5-dimethyltetrahydrofuran-3-
yl)carbamate (13). To a solution of 12 (3.00 g, 12.9 mmol) in
dimethyl sulfoxide (30 mL) was added o-iodoxybenzoic acid (4.33 g,
15.5 mmol). The mixture was stirred at room temperature for 10 h.
Then, the reaction mixture was quenched with water (5 mL). The
suspension was filtered over Celite and washed with EtOAc. The
filtrate was extracted with methylene chloride (3 × 50 mL). The
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combined extracts were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether−EtOAc, 2:1) to afford
13 (2.76g, 93%) as a white solid: Rf 0.21 (1:1 EtOAc−petroleum
ether); mp 129.0−129.8 °C (EtOAc); IR (KBr) 3442, 1717, 1691
cm−1; 1H NMR (400 MHz, CDCl3) δ 5.27−5.24 (m, 1H), 5.16−5.08
(m, 1H), 4.39−4.20 (m, 1H), 4.20−3.90 (m, 1H), 2.35−2.30 (m,
0.6H), 2.20−2.10 (m, 1H), 1.71 (t, 1H, J = 11.7 Hz), 1.50−1.40 (m,
2H), 1.43 (s, 9H), 1.39 (s, 3H), 1.21 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 155.5, 102.4, 95.4, 82.5, 81.2, 79.9, 79.5, 58.8, 53.4, 43.0,
41.4, 31.0, 30.4, 29.2, 28.4, 28.3; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C11H21NO4Na 254.1368, found 254.1364.
CDCl3) δ 177.0, 77.5, 70.8, 59.1, 52.8, 43.62, 40.4, 40.1, 29.3, 29.1,
18.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C11H22O5Na
257.1365, found 257.1364.
(R)-2-Hydroxy-2-(4-hydroxy-4-methylpentyl)succinic Acid
(20). Compounds 18 (1.23 g, 6.09 mmol) and 19 (0.30 g, 1.28
mmol) were stirred for 20 min with 2.8 mL of 5 M NaOH. Sodium
phosphate buffer (30 mL, 0.67 M) was added, and the pH was
adjusted to 6.8 (5 M HCl). Acetonitrile (37.0 mL) and TEMPO (452
mg, 2.90 mmol) were added, and the mixture was heated to 35 °C.
Over a period of 5 h, sodium hypochlorite solution (9.24 mL in 51 mL
of H2O, 0.24 M) and NaClO2 (1.68 g, 18.7 mmol in 7.28 mL H2O)
were added dropwise from separate syringes at 35 °C with stirring.
(Caution: Do not mix sodium hypochlorite solution and NaClO2
before adding to the reaction!) At room temperature, the pH was
adjusted to 8.5 with 5 M NaOH. The mixture was quenched with
Na2SO3 (37.7 mL, 6.72 g in 112 mL water) at 0 °C, and the resulting
solution was stirred at room temperature for 0.5 h (pH 8.5−9.0). After
acidification to pH 1, most of the water was removed under reduced
pressure. The mixture was extracted with EtOAc (5 × 60 mL). The
combined extracts were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether−EtOAc, 1:5) to afford
20 (1.55 g, 90%) as a white crystalline solid: mp 112.1−112.9 °C
tert-Butyl (4-Hydroxy-4-methyl-1-(2-oxodihydrofuran-3-
ylidene)pentan-2-yl)carbamate (15). To a solution of lactol 13
(2.76 g, 11.9 mmol) in dry toluene (50 mL) was added 1-
butyrolactonylidene triphenylphosphorane 14 (4.53 g, 13.1 mmol).
The mixture was heated at reflux for 3 h. After completing the
reaction, the solvent was removed under reduced pressure. The
residue was purified by chromatography on silica gel (petroleum
ether−EtOAc, 2:1) to yield olefin 15 (3.03 g, 85%) as a white solid:
mp 102.3−103.1 °C (EtOAc); [α]25 = −22.5 (c 8.7, CHCl3); IR
D
1
(KBr) 3401, 3322, 1725, 1682 cm−1; H NMR(400 MHz, CDCl3) δ
6.50 (d, J = 7.92 Hz, 1H), 5.66 (brs, 1H), 4.33 (brs, 1H), 4.33−4.29
(m, 2H), 3.18−3.08 (brs, 1H), 2.96−2.84 (m, 1H), 1.75−1.69 (m,
1H), 1.58−1.50 (m, 1H), 1.34 (s, 9H), 1.20 (s, 6 H); 13C NMR (100
MHz, CDCl3) δ 171.7, 155.6, 140.9, 125.0, 79.6, 70.3, 65.8, 48.1, 45.9,
30.7, 29.1, 28.4, 24.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H25N O5Na 322.1630, found 322.1631.
3-(2-(Dibenzylamino)-4-hydroxy-4-methylpentylidene)-
dihydrofuran-2(3H)-one (16). See the general procedure for
preparation: white solid; mp 141.6−142.5 °C; IR (KBr) 3596, 3481,
3298, 1751, 1675 cm−1; [α]25D = −32.6 (c 1.0, EtOH); 1H NMR (400
MHz, CDCl3) δ 7.38−7.22 (m, 10H), 7.09−6.97 (dt, 1H, J = 9.84
Hz), 5.90 (s, 1H), 4.49−4.33(m, 2H), 4.11(d, 2H, J = 12.92 Hz), 3.82
(t, J = 12.04 Hz, 1H), 3.28 (d, J = 12.92 Hz, 2H), 2.81−2.62 (m, 2H),
2.27−2.16 (m, 1H), 1.19 (s, 3H), 1.22−1.11 (m, 1H), 0.81 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.7, 137.7, 136.2, 129.4, 128.7,
(EtOAc); IR (KBr) 3569, 3456, 1709 cm−1; [α]25 = −10.5 (c 1.14,
D
1
MeOH); H NMR (400 MHz, acetone-d6) δ 1.17 (s, 6H), 1.30−1.40
(m, 1H), 1.40−1.50 (m, 2H), 1.55−1.78 (m, 3H), 2.67 (d, J = 16.0
Hz, 1H), 2.95 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, acetone-d6)
δ 18.0 (CH2), 28.7 (CH3), 28.8 (CH3), 39.5 (CH2), 42.8 (CH2), 43.8
(CH2), 69.4 (C), 74.5 (C), 171.7 (C), 175.5 (C); HRMS (ESI-TOF)
m/z [M + Na − 2H]+ calcd for C10H16O6Na 255.0845, found
255.0847.
(R)-Dimethyl 2-Hydroxy-2-(4-hydroxy-4-methylpentyl)-
succinate (21). To a solution of 20 (0.5 g, 2.14 mmol) in dry
MeOH (1.2 mL) were added 2, 2-dimethoxypropane (4.8 mL) and
TMSCl (0.076 mL, 0.6 mmol). The mixture was stirred at the room
temperature for 12 h. After the reaction was complete, the solvent was
removed under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether−EtOAc, 5:1) to afford
128.0, 127.7, 70.7, 65.4, 55.8, 54.2, 41.5, 31.5, 27.8, 25.2; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C24H29NO3Na 402.2045, found
402.2047.
21 (532 mg, 95%) as a white solid: mp 33.8−34.2 °C (EtOAc); IR
1
(KBr) 3499, 1740 cm−1; [α]20 = −17.5 (c 0.74, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 3.80 (s, 3H), 3.77 (s, 1H), 3.67 (s, 3H), 2.93 (d,
J = 16.3 Hz, 1H), 2.70 (d, J = 16.3 Hz, 1H), 1.72−1.61 (m, 2H), 1.59−
1.45 (m, 2H), 1.45−1.40 (m, 2H), 1.28−1.15 (m, 1H), 1.19 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 175.6, 171.4, 75.2, 70.8, 53.0, 51.9,
(R)-3-Hydroxy-3-(4-hydroxy-4-methylpentyl)dihydrofuran-
2(3H)-one (18), (R)-Methyl 2,6-Dihydroxy-2-(2-hydroxyethyl)-
6-methylheptanoate (19). To a solution of 16 (5.46g, 14.40 mmol)
in CH2Cl2 (50 mL) was added m-CPBA (75%, 3.66 g, 15.91 mmol) at
5 °C. The reaction mixture was stirred at this temperature for 10 min.
Then the suspension was filtered, and the filtrate was washed with 10%
NaOH (3 × 10 mL), saturated NaHCO3 (2 × 10 mL), and saturated
NaCl (2 × 10 mL), dried over MgSO4, filtered, and concentrated at 40
°C under reduced pressure to give an oily residue (crude 17), which
was used in next step without further purification. To a solution of the
crude 17 (14.40 mol) in MeOH (50 mL) was added 10% Pd/C (250
mg) at 0 °C. The mixture was stirred under a hydrogen atmosphere
(60 psi) at 10 °C for 2 h. Then the temperature was raised to 60 °C.
The solution was kept under stirring for another 2 h. After completing
the reaction, the catalyst was removed by filtration over Celite and
washed with MeOH (3 × 15 mL). The filtrate was concentrated under
reduced pressure. The residue was purified by chromatography on
silica gel (petroleum ether−EtOAc, 2:1) to afford 18 (1.91 g, 66%)
and 19 (0.30 g, 9%), respectively, as a white solid. Compound 18: mp
43.5, 43.4, 39.6, 29.3, 29.1, 18.1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C12H22O6Na 285.1314, found 285. 1314.
tert-Butyl ((2R,3R,E)-3-((tert-Butyldimethylsilyl)oxy)-1-(2-ox-
odihydrofuran-3(2H)-ylidene)butan-2-yl)carbamate (23). To a
solution of 22 (8.88 g, 28.01 mmol) in dry CH2Cl2 (100 mL) was
added 1-butyrolactonylidene triphenylphosphorane 14 (10.7 g, 30.83
mmol). The mixture was heated at reflux for 3 h. After the reaction
was complete, the solvent was removed under reduced pressure. The
residue was purified by chromatography on silica gel (petroleum
ether−EtOAc, 4:1) to yield 23 (9.17 g, 85%) as an oil: IR (KBr) 3448,
1760, 1714 cm−1; [α]20D = 14.8 (c 1.348, EtOH); 1HNMR (400 MHz,
CDCl3) δ 6.65−6.54 (m, 1H), 4.98 (d, J = 8.0 Hz, 1H), 4.37 (t, J = 7.6
Hz, 2H), 4.18−4.14 (m, 1H), 3.96−3.87 (m, 1H), 3.19−3.05 (m, 1H),
2.95−2.87 (m, 1H), 1.44 (s, 9H), 1.20 (d, J = 6.0 Hz, 3H), 0.90 (s,
1H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
171.1, 155.8, 138.3, 126.8, 79.8, 69.7, 65.6, 55.9, 28.4, 25.8, 25.7, 25.2,
20.7, 18.0, 3.58, 4.45, 4.91; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C19H35NO5SiNa 408.2182, found 408.2185.
98.0−98.8 °C (EtOAc); IR (KBr) 3500, 3280, 1769 cm−1; [α]25
=
D
+13.6 (c 1.728, EtOH); 1H NMR (400 MHz, CDCl3) δ 4.43−4.37 (m,
1H), 4.26−4.20 (m, 1H), 4.10−3.90 (brs, 1H), 2.59−2.20 (brs, 1H),
2.40−2.24 (m, 2H), 1.83−1.73 (m, 1H), 1.73−1.58 (m, 2H), 1.58−
1.40 (m, 3H), 1.22 (s, 3H), 1.21 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 179.2, 74.7, 71.1, 65.5, 43.4, 36.7, 34.7, 29.3, 29.2, 17.9;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C10H18O4Na 225.1103,
found 225.1103. Compound 19: 1H NMR (400 MHz, CDCl3) δ 3.91
(s, 1H), 3.79 (s, 3H), 3.88−3.75 (m, 1H), 3.75−3.65 (m, 1H), 2.75
(brs, 1H), 2.21−2.01 (m, 1H), 2.01−1.88 (m, 1H), 1.82−1.63 (m,
3H), 1.62−1.40 (m, 3H), 1.26−1.06 (m, 7H); 13C NMR (100 MHz,
(E)-3-((2R,3R)-2-(Dibenzylamino)-3-hydroxybutylidene)-
dihydrofuran-2(3H)-one (24). See the general procedure for
preparation. The compound 24 was obtained as a white solid: mp
175.9−176.5 °C (EtOAc); IR (KBr) 3429, 1755, 1677 cm−1; [α]20
=
D
−34.9 (c 1.60, EtOH); 1H NMR (400 MHz, CDCl3) δ 7.38−7.29 (m,
10H), 6.86 (dt, J = 11.2, 2.8 Hz, 1H), 4.46−4.39 (m, 2H), 4.13 (s,
1H), 4.06 (d, J = 13.6 Hz, 2H), 4.00−3.90 (m, 1H), 3.40 (d, J = 13.6
Hz, 2H), 3.09 (dd, J = 10.0, 11.2 Hz, 1H), 2.84−2.67 (m, 2H), 1.04 (d,
344
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Article
J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 138.3, 134.0,
131.7, 128.8, 128.7, 127.6, 65.6, 65.5, 65.1, 54.2, 26.0, 19.3; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C22H25N O3Na 374.1732, found
374.1733.
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether−EtOAc, 1:3) to afford
29 (242 mg, 96%) as a white solid: mp 98.0−98.6 °C (EtOAc); IR
(KBr) 3416, 3258, 1752 cm−1; [α]20D = 18.7 (c 1.09, EtOH); 1H NMR
(400 MHz, CDCl3) δ 4.93 (brs, 1H), 4.43−4.37 (m, 1H), 4.25−4.18
(m, 1H), 2.55 (brs, 1H), 2.44−2.35 (m, 1H), 2.28−2.20 (m, 1H),
1.98−1.83 (m, 2H), 1.70 (t, J = 6.8 Hz, 2H), 1.28 (s, 3H), 1.27 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 179.2, 74.2, 70.7, 65.4, 36.9,
35.8, 31.2, 30.2, 28.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C9H16O4Na 211.0946, found 211.0947.
(S)-3-Hydroxy-3-((R,E)-3-hydroxybut-1-en-1-yl)-
dihydrofuran-2(3H)-one (26). To a solution of 24 (5.05 g, 14.38
mmol) in CH2Cl2 (50 mL) was added m-CPBA (75%, 3.66 g, 15.91
mmol) at 5 °C. The reaction mixture was stirred at this temperature
for 20 min. Then the suspension was filtered, and the filtrate was
washed with 10% NaOH (3 × 10 mL), saturated NaHCO3 (2 × 10
mL), and saturated NaCl (2 × 10 mL), dried over MgSO4, filtered,
and concentrated at 30 °C under reduced pressure to give an oily
residue (crude 25) that was used in the next step without further
purification. To a solution of crude 25 (14.38 mol) in MeOH (24 mL)
were added concd HCl (1.2 mL) and Zn powder (9 g, 140 mmol) at 5
°C. The reaction mixture was stirred at this temperature for 20 min.
Then the suspension was filtered and washed with MeOH, and the
filtrate was neutralized with a 25% ammonium hydroxide solution to
pH = 8. The mixture was extracted with EtOAc (5 × 60 mL).The
combined extracts were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether−EtOAc, 1:1) to afford
(R)-2-(3-Hydroxy-6,6-dimethyl-2-oxotetrahydro-2H-pyran-3-
yl)acetic Acid (30). The experimental procedure was the same as that
described for the preparation of compound 20. The compound 30 was
obtained as a white solid: mp 133.1−133.7 °C (EtOAc); IR (KBr)
3350−3000 (broad peak), 1715, 1693 cm−1; [α]20 = +25.5 (c 1.30,
D
1
MeOH); H NMR (400 MHz, acetone-d6) δ 1.41 (s, 3H), 1.45 (s,
3H), 1.78 (dt, J = 14.0, 4.28, 4.00 Hz, 1H), 1.87 (dt, J = 14.0, 3.64,
4.44 Hz, 1H), 2.20 (td, J = 13.44, 3.32 Hz, 1H), 2.44 (td, J = 13.5, 3.64
Hz, 1H), 2.65 (d, J = 16.56 Hz, 1H), 3.10 (d, J = 16.56 Hz, 1H);
13CNMR (100 MHz, acetone-d6) δ 26.3, 29.6, 29.7, 30.2, 69.2, 82.8,
171.6, 171.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C9H14O5Na
225.0739, found 225.0736.
26 (1.86 g, 75%) as a colorless oil: IR (KBr) 3405, 1767 cm−1; [α]20
D
= +22.0 (c, 0.55, MeOH); 1H NMR (400 MHz, CDCl3) δ 5.94 (dd, J
= 5.48, 15.84 Hz, 1H), 5.82 (d, J = 15.84 Hz, 1H), 4.65 (brs, 1H),
4.50−4.32 (m, 2H), 4.23 (q, J = 7.88 Hz, 1H), 3.53 (brs, 1H), 2.50−
2.38 (m, 2H), 1.27 (d, J = 6.48 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 178.0, 136.8, 126.8, 74.8, 67.5, 65.5, 36.2, 22.8; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C8H12O4Na 195.0633, found
195.0635.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra for compounds 5−8,
12−16, 18−21, 23, 24, and 26−30. This material is available
free of charge via the Internet at http://pubs.acs.org.
3-Hydroxy-3-(3-oxobut-1-en-1-yl)dihydrofuran-2(3H)-one
(27). To a solution of 26 (850 mg, 5 mmol) in 30 mL of CH2Cl2 was
added activated MnO2 (85 wt.%, 4.35g, 50 mmol) at 0 °C. The
reaction mixture was stirred at this temperature for 20 min. Then the
reaction mixture was allowed to reach room temperature. The reaction
mixture was further stirred at room temperature overnight. The
mixture was filtered over Celite and washed with CH2Cl2. The filtrate
was concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether−EtOAc, 1:1) to afford
enone 27 (798 mg, 95%) as a colorless oil: IR (KBr) 3475, 1775, 1715,
1677, 1629 cm−1; [α]20D = −4.1 (c 1.50, MeOH); 1HNMR (400 MHz,
CDCl3) δ 6.79 (d, J = 15.9 Hz, 1H), 6.45 (d, J = 15.9 Hz, 1H), 4.54−
4.48 (m, 1H), 4.36−4.30 (m, 1H), 4.15−4.08 (brm, 1H), 2.59−2.46
(m, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.0, 176.1,
141.2, 130.3, 74.9, 65.4, 36.2, 28.2; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C8H10O4Na 193.0477, found 193.0478.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yanghua@zzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation
(20502023) for financial support.
REFERENCES
■
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D
1
0.85, MeOH); H NMR (400 MHz, CDCl3) δ 5.99 (d, J = 15.82 Hz,
1H), 5.85 (d, J = 15.88 Hz, 1H), 4.46−4.41 (m, 1H), 4.24−4.18 (m,
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while in Tietze’s paper, the 1H NMR experiment of 19b (i.e., 20) was
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= 1.0, MeOH), while in Tietze’s paper, the optical rotation of 19b (i.e.,
20) was [α]20 = −5.8 (c = 1.0, MeOH).
D
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