A Concise Stereoselective Total Synthesis of Methoxyl Citreochlorols and Their Structural Revisions

Article abstract of DOI:10.1002/ejoc.202001563

A concise, stereoselective and protecting group free approaches for the total synthesis of (?)-(2S,4R)- and (+)-(2R,4S)-3′-methoxyl citreochlorols and their stereoisomers are demonstrated. All four stereoisomers were synthesized to establish the absolute stereochemistry of the reported structures and the structures were revised accordingly. The approach involves chelation controlled regioselective reduction of a diester, silyl iodide promoted ring-opening iodo esterification of lactones, highly chemo- and regioselective ring-opening of an epoxy ester, dichloromethylation of a carboxyl group, and syn- and anti-selective reduction of the resulted β-hydroxy ketone as key steps.

Full text of DOI:10.1002/ejoc.202001563

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A Concise Stereoselective Total Synthesis of Methoxyl
Citreochlorols and Their Structural Revisions
Ranganayakulu Sunnapu[a] and Goreti Rajendar*[a]
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A concise, stereoselective and protecting group free approaches
for the total synthesis of (À )-(2S,4R)- and (+)-(2R,4S)-3’-methoxyl
citreochlorols and their stereoisomers are demonstrated. All
four stereoisomers were synthesized to establish the absolute
stereochemistry of the reported structures and the structures
were revised accordingly. The approach involves chelation
controlled regioselective reduction of a diester, silyl iodide
promoted ring-opening iodo esterification of lactones, highly
chemo- and regioselective ring-opening of an epoxy ester,
dichloromethylation of a carboxyl group, and syn- and anti-
selective reduction of the resulted β-hydroxy ketone as key
steps.
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Introduction
Halogen-containing small molecules are continually being
isolated from nature and becoming very attractive day by day.
These small molecules possess fascinating architectures and
show exceptionally diverse biological activities.[1] Especially,
chlorinated secondary metabolites display a range of biological
activities like anticancer, antibiotic, antimalarial, anti-HIV, etc.[2]
Pencillium based fungal metabolites are an excellent source of
halogenated compounds, especially for chlorinated compounds.
Exceptional class of organohalogens having gem-dichlorometh-
yl and trichloromethyl functional groups have been isolated
from several fungal sources.[3] Citreovirone[4] and citreochlorol[5]
are a class of polyketides with geminal dichloromethyl moiety
isolated from Penicillium Citreoviride B. In 2017, Yong‘s group
isolated several aromatic polyketide moieties having dichloro-
methide functional group, namely 3’-methoxyl citreochlorol and
their analogs from a fungal species Penicillium Sp. that grows on
Pinellia Ternata.[6] Structures of citreochlorols (Figure 1) were
established based on exhaustive NMR and mass spectral
studies. The absolute stereochemistry was determined by
[Rh2(OCOCF3)4]-induced ECD experiments and NMR spectral
analysis of their MTPA esters. Citreochlorols are moderately
active against several human pathogenic microorganisms like
E.coli and S-aureus (MIC 62.6 and 76.6 μg/ml).
Figure 1. Representative structures of methoxyl citreochlorol and its analogs.
they are enantiomers and should possess identical spectral
characteristics with opposite optical rotation signs. But the NMR
spectral data and specific rotations of both the isomers show
small variations and are not identical. Moreover, the absolute
stereochemistry of 1 was confirmed by us using X-ray analysis,
and it was identical with the reported structure 1 (Figure 2).[7]
Whereas, the synthetic syn-diol[7] 3 showed identical spectral
and optical rotation data as for the reported compound 2 which
was proposed as an anti-diol. To gain more insights on the
absolute stereochemistry of proposed structure 2, we had
decided to synthesize all the four stereoisomers of methoxyl
citreochlorols (1, 2, 3, and 4) to establish their absolute
configuration.
We recently reported the first stereoselective total synthesis
of (2S,4R)-3’-methoxyl citreochlorol 1 and its stereoisomer 3
using an auxiliary assisted aldol reaction strategy.[7] Careful
analysis of Yong‘s report[6] illustrates that compounds 1 and 2
were isolated from the ethyl acetate extract of Penicillium
species by a preparative HPLC technique on an achiral column.
The reported structures of compounds 1 and 2 suggest that
In this article, we present a new synthetic approach that
uses both D- and L-malic acids as chiral reagents to synthesize
[a] R. Sunnapu, Dr. G. Rajendar
School of Chemistry,
Indian Institute of Science Education and Research Thiruvananthapuram
Vithura 2209, Trivandrum, Kerala, 695551, India
E-mail: rajendar@iisertvm.ac.in
http://www.iisertvm.ac.in/faculty/rajendar
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001563
Figure 2. ORTEP structure of (2S, 4R)-3’-methoxy citreochlorol 1.
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all the four isomers of compound 1. Enantiomerically pure malic
iodohydrin was then reacted with silver (I) oxide which gave
the epoxide 8 in 86% yield.[12]
1
2
3
4
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8
9
acids are commercial, economically viable, and are excellent
chiral sources in total syntheses.[8] Accordingly, two identical
synthetic routes were established, one from L-malic acid for the
synthesis of compounds 1 and 3, and the second from D-malic
acid for the synthesis of 2 and 4.
The epoxide 8 was then subjected to a chemoselective and
regioselective ring-opening reaction with aryl magnesium
bromide. A freshly generated 3,5-dimethoxyphenyl magnesium
bromide reacted with epoxide 8 in the presence of copper(I)
iodide to provide a highly regioselective ring-opening product
14 in 81% yield.[13] The ester 14 was then directly treated with
dichloromethyl lithium, which is generated in situ from di-
Results and Discussion
chloromethane and
a base (Table 1, entry 3) to provide
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The retrosynthetic analysis of compounds 1 and 3 is given in
Scheme 1. We hypothesized that both syn- and anti-diols of
methoxyl citreochlorols could be obtained from a common key
intermediate ketone 7 by selective reduction methods. Ketone 7
dichloromethyl ketone 7 in 54% along with recovered ester
(20%).[14,15] To improve the yield, ester 14 was converted to
Weinreb amide 15 in 93% yield[7] which upon reaction with
dichloromethyl lithium produced compound 7 in 58% yield
along with recovered amide (24%) (Table 1, entry 6). Overall,
the alternative method that uses two steps provided only 53%
yield. Several other conditions to improve the yields were
unsuccessful; hence we further proceeded with ester 14 to
procure the intermediate 7 (Scheme 3).
The key intermediate 7 is equipped with the required
carbon skeleton, including the dichloromethide group. The
stereoselective reduction β-hydroxy ketone was conducted
using both syn- and anti-selective protocols. At first, the ketone
was subjected to anti-selective reduction using tetrameth-
ylammonium triacetoxyborohydride to provide the desired anti-
diol, i.e. (2S,4R)-3’-methoxyl citreochlorol 1 in 96% yield along
with its syn-diastereomer in 3%.[16] The synthetic compound 1
was found to be identical with the natural product 1. The NMR
spectral data and specific rotation are in good agreement with
the reported values (Table 2). Also, the absolute configuration
of synthetic compound 1 was established based on X-ray
analysis (Figure 2).[7,17]
can be synthesized from epoxide
8 in two steps using
regioselective ring opening of epoxide, with 3,5-dimethoxy
phenylmagnesium bromide followed by dichloromethyl addition
to the carboxyl group. Epoxide 8 in turn can be prepared from
lactone 9 by ring-opening, haloesterification, and epoxidation
methods. The lactone 9 can be easily prepared from commercial
L-malic acid in three steps using esterification, regioselective
reduction of the ester moiety followed by lactonization.
We started the synthesis aiming at the natural product 1
and its synthetic isomer 3 starting from L-malic acid (Scheme 2).
L–Malic acid was first converted to its diester by refluxing it in
ethanol in the presence of H2SO4 to provide 11 in 95% yield.
Subsequently, diester 11 was subjected to chelation controlled
regioselective reduction using borane in the presence of
catalytic NaBH4 to give diol 12 in 98% yield.[9] The diol was
immediately treated with trifluoroacitic acid to obtain the
lactone 9 as the sole product in 95% yield. The lactone was
then subjected to a selective ring-opening reaction by the
nucleophilic substitution and esterification method using a
modified protocol.[10] When lactone 9 was treated with 2
equivalents of TMSCl, KI, and 2 equivalents of ethanol in
dichloromethane it provided iodohydrin 13 in 76% yield.[11] The
Table 1. Conditions for the addition of dichloromethyl lithium to ester and
amide.
S.
No.
Compound Conditions
Yield
[%]
1.
14
n-BuLi, CH2Cl2, THF:Hexane (1:1), À 94 to
–
°
À 78 C, 1 h
°
2.
3.
4.
5.
14
14
15
15
LDA, CH2Cl2,THF,À 78 C, 1 h
41%
54%
–
°
Cy2NLi, CH2Cl2, THF, À 78 C, 2 h
°
n-BuLi, CH2Cl2, THF, À 78 C, 2 h
n-BuLi, CH2Cl2, THF: Et2O:Hexane (4:1:1),
–
°
À 110 C, 2 h
°
6.
15
Cy2NLi, CH2Cl2, THF, À 78 C, 2 h
58%
Scheme 1. Retrosynthetic analysis of methoxyl citreochlorols.
Scheme 2. Preparation of epoxy ester 8 from L-malic acid.
Scheme 3. Preparation of key intermediate 7 from epoxide 8.
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Similarly, a syn-selective reduction of ketone 7 in the presence
citreochlorol
conditions.[7]
5
was unsuccessful under several reaction
1
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3
4
5
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7
8
9
of catechol borane provided a mixture of isomeric diols in 96%
yield (Scheme 4).[18] The less polar diastereomer 3 was isolated in
82% yield showing lower chemical shift (δH =5.69 ppm) value for
C1-H proton and the more polar anti-isomer 1 was isolated in 14%
with a higher chemical shift (δH =5.76 ppm) for C1-H proton.[19]
The syn-diol has identical δH-values (4.16 ppm) and anti-diol has
different δH-values (4.16 and 4.27) for C2 and C4 methines. Similarly,
two diastereotropic methylene protons at C3 were clearly
distinguishable in H-NMR, syn-diol showing two signals at 1.80
and 2.06 ppm and anti-diol gives a single multiplet at 1.88 ppm.
Also, 13C-NMR spectra of both syn- and anti-diols were differ-
entiated only from the chemical shift values of C2 and C4 positions.
While the syn-diol showed signals at δc 75.5 and 72.2, the anti-diol
produced signals at δc 73.7 and 69.3 for C2 and C4. Though the
absolute stereochemistry of anti-isomer 1 was confirmed using X-
ray analysis, the stereochemistry of its corresponding syn-diaster-
eomer 3 was further established by standard NMR methods. For
that, the diol 3 was protected with acetonide group to obtain
compound 17. The 13C-NMR of compound 17 showed well
resolved signals for two methyl groups of acetonide which
appeared at δc 19.9 and 31.2 ppm, clearly confirming the syn-
relation of diol in compound 3.[20] Unfortunately, selective
deprotection of methoxy group of syn-diol 3 for the synthesis of
After careful analysis, it was confirmed that the spectral data
of synthetic 3, is completely matching with the reported natural
product[6] (see Table 2). Hence, the stereochemistry of proposed
structure 2 was reassigned as syn-diol 3. To gain more insight
regarding the absolute stereochemistry of the anti-isomer 2, we
decided to synthesize both the enantiomers of compounds 1
and 3 namely anti-isomer 2 and its corresponding diastereomer
4 from D-malic acid (Scheme 5).
Our synthesis began with the conversion of D-malic acid
10D to the key intermediate 7D following similar synthetic
protocols used for the preparation of compound 7. Then
compound 7D was selectively reduced to diol 2 by treating it
with tetramethylammonium triacetoxyborohydride to provide
the desired anti-diol, i.e. (2R,4S)-3’-methoxyl citreochlorol 2 in
94% as the major isomer. The spectral data of compound 2 was
not matching with the reported data for the natural product 2
but it exactly matched with the data of compound 1, also
showed opposite optical rotation. This clearly confirmed that
compound 2 is an enantiomer of compound 1 and does not
match with the isolated natural product. Likewise, the syn-
selective reduction of 7D with catecholborane provided syn-diol
4 in 82% yield along with anti-diol 2 in 14% yield. The NMR
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Table 2. H-NMR and specific rotation of reported and synthetic methoxyl citreochlorols.
S. No
Reported 1
(À )-isomer
(δH ppm)
Reported and
revised (+)-isomer 3
(δH ppm)
Synthetic 1
(δH ppm)
Synthetic 3
(δH ppm)
Synthetic 2
(δH ppm)
Synthetic 4
(δH ppm)
C1
C2
5.75 (d, 4.4)
4.25 (m)
1.88 (m)
5.72 (d, 4.0)
4.17 (m)
1.80 (m)
5.76 (d, 4.3)
4.26 (dd,5, 11.1)
1.9 (m)
5.69 (d, 4.2)
4.15 (m)
1.82 (m)
2.06 (m)
4.15 (m)
2.70 (dd, 9, 13.3)
2.81 (dd, 3.9, 13.4)
6.37 (br s)
3.79 (s)
6.37 (br s)
3.79 (s)
5.76 (d, 4.3)
4.26 (dd, 5, 11.1)
1.9 (m)
5.69 (d, 4.2)
4.15 (m)
1.82 (m)
C3a
C3b
1.89 (m)
4.17 (m)
2.04 (m)
4.12 (m)
1.9 (m)
4.18 (m)
1.9 (m)
2.06 (m)
C4
4.18 (m)
4.15 (m)
C5a
C5b
2.67 (dd, 8.9, 13.4)
2.81 (dd, 4.1, 13.4)
6.37 (br s)
3.78 (s)
2.69 (dd, 4.4, 13.5),
2.82 (dd, 8.5, 13.5)
6.36 (br s)
3.78 (s)
6.36 (br s)
2.67 (dd, 5, 11.1)
2.80 (dd, 4, 13.4)
6.37 (br s)
3.79 (s)
6.37 (br s)
2.67 (dd, 5, 11.1)
2.80 (dd, 4, 13.4)
6.37 (br s)
2.70 (dd, 9, 13.3)
2.81 (dd, 3.9, 13.4)
6.37 (br s)
3.79 (s)
C7
C8(OMe)
C9
3.79 (s)
6.36 (br s)
6.37 (br s)
3.79 (s)
6.37 (br s)
3.79 (s)
C10(OMe)
C11
Specific Rotation:
3.78 (s)
3.78 (s)
3.79 (s)
6.37 (br s)
[α]25D =À 2.3
(c 0.16, MeOH)
6.36 (br s)
6.37 (br s)
6.37 (br s)
[α]22D = +4.6
(c 0.16, MeOH)
6.37 (br s)
6.37 (br s)
[α]22D =À 6.0
(c 0.05, MeOH)
[α]25D = +4.6
(c 0.13, MeOH)
[α]22D =À 5.6
(c 0.05, MeOH)
[α]22D = +4.3
(c 0.16, MeOH)
Scheme 4. Preparation of methoxyl citreochlorols 1 and 3 from L-malic acid.
Scheme 5. Preparation of methoxyl citreochlorols 2 and 4 from D-malic acid.
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and brine. The organic phase was dried over anhydrous Na2SO4 and
spectral data of 4 was found to be in good agreement with
compound 3 except for the opposite optical rotation.
From Table 2, it is clear that the spectral data of natural
product 1 was identical to synthetic 1, and natural product 3
(previously proposed as anti-isomer 2)[6] was identical to
synthetic syn-isomer 3. The remaining two isomers obtained
from D-malic acid, i.e., synthetic compounds 2 and 4, are non-
natural stereoisomers, and they are epimers of natural com-
pounds 1 and 3.
1
2
3
4
5
6
7
8
9
evaporated under vacuum to give ester 11 (6.7 g, 95%) as colour-
less oil. [α]D22 =À 6.2 (c 3, CHCl3) Rf =0.6 (100% EtOAc); 1H NMR
(500 MHz, CDCl3) δ 4.48 (t, J=5,1H), 4.29 (q, J=5, 2 H), 4.25 (q, J=
5, 2H), 2.87–2.76 (m, 2H), 2.47 (bs, 1 H), 1.31 (t, J=5, 3H), 1.27 (t, J=
5, 3 H); 13C NMR (125 MHz, CDCl3) δ 173.4, 170.5, 67.3, 62.1, 61.0,
38.7, 14.1; IR (neat, cmÀ 1): 3396, 2971, 1779, 1450, 1378, 1296, 1179,
1050; HRMS (ESI-quadrupole) m/z: [M+Na]+ Calcd for C8H14O5Na
213.1829; Found 213.0734.
Compound 11D obtained in 95% yield as a colorless oil. [α]D
+5.9 (c 3, CHCl3)
=
22
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Preparation of ethyl (R)-3,4-dihydroxybutanoate (12): To a stirred
solution of malate ester 11 (5.8 g, 35.8 mmol) in THF (40 mL) was
added borane dimethyl sulfide (3.4 mL, 35.8 mmol) drop wise. After
Conclusion
°
1 hour the reaction mixture was cooled to 0 C and added NaBH4
In conclusion, we have synthesized all the four stereoisomers of
methoxyl citreochlorols from L- and D-malic acids. The absolute
configuration of isolated compounds was established by compar-
ing the spectral and optical rotation data of synthesized
compounds. The structures of isolated natural products i.e. the
(À )-methoxyl citreochlorol was confirmed as anti-diol 1, and
(+)-methoxyl citreochlorol was confirmed as syn-diol 3. Both the
compounds 1 and 3 (similarly 2 and 4) were synthesized in a
concise, and protecting group free manner from a chiral pool
starting material. Lactone opening by halo esterification, chemo-
and regioselective ring opening of epoxide, the addition of
dichloromethyl lithium to amide, and syn- and anti-selective
reduction of β-hydroxy ketone were used as crucial steps. The final
product‘s overall yields after eight-step synthesis are obtained as
24.2% and 21.5% from commercially available malic acids.
(0.135 g, 3.58 mmol). The reaction mixture was continued to stir at
room temperature for 12 hours. Completion of the reaction was
confirmed by TLC analysis. The reaction mixture was carefully
°
treated with MeOH at 0 C. The solvents were evaporated under
vacuum and the residue was purified by column chromatography
(Silica gel, EtOAc:hexane 1.5:1) to afford the product 12 (5.2 g,
1
98%) as colorless oil. [α]D22 =À 22.3 (c 2, CHCl3). H NMR (500 MHz,
CDCl3) δ 4.16 (q, J=5 Hz, 2H), 4.13–4.10 (m, 1H), 3.66 (dd, J=5,
15 Hz, 1 H), 3.52 (dd, J=5, 10 Hz, 1H), 2.87 (bs, 2H), 2.60–2.46 (m,
2H) 1.26 (t, J=10 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 172.7, 68.6,
65.7, 60.9, 37.6, 14.1; IR (neat, cmÀ 1): 3346, 2972, 1745, 1447, 1375,
1282, 1177, 1052. HRMS (ESI-quadrupole) m/z: [M+Na]+ Calcd for
C6H12O4Na 171.0736; Found 171.0628.
Compound 12d obtained in 98% as colourless oil: [α]D22 = +28.4
(c 1.2, CHCl3).
Preparation of 3-(S)-hydroxy-4-butanolide (9): To a stirred solution
of diol 12 (3g, 20.2mmol) in CH2Cl2 (30 mL) was added trifluoro-
°
acetic acid (0.6 mL, 7.08 mmol) at 0 C. The reaction mixture was
°
Experimental Section
stirred at 25 C and the reaction progress was closely monitored by
TLC. Once the starting material disappeared, solvents were
removed under reduced pressure and the residue was purified by
column chromatography (Silica gel, EtOAc: hexane 1:1) to afford
the product 9 (1.95 g, 95%) as colorless oil. [α]D22 =À 66.6 (c 1,
General Techniques: All the reactions utilizing air- or moisture-
sensitive reagents were performed under an atmosphere of argon or
nitrogen. Tetrahydrofuran (THF) and diethyl ether were double
distilled from LAH, and dichloromethane (DCM) was distilled from
CaH2 before use. Pyridine and i-Pr2NH were distilled from CaH2 and
dried over 4 Å molecular sieves. Commercially available reagents were
used as received. Reactions using heating conditions were conducted
in an oil bath. Reactions were monitored by thin-layer chromatog-
raphy (TLC) carried out on 0.25 mm silica gel glass plates (60-F254)
that were analyzed by fluorescence upon 254 nm irradiation or by
staining with p-anisaldeyde/AcOH/H2SO4/EtOH, (NH4)6Mo7O24 ·4H2O/
H2SO4. The products were purified by open chromatography on a silica
gel (spherical, neutral, 100–230 μm) column. NMR spectra were
recorded with an Avance III-500 (Bruker) (1H: 500 MHz, 13C{1H}:
125 MHz) or a 700 MHz (1H: 700 MHz, 13 C{1H}: 175 MHz) spectrom-
eter and referenced to the solvent peak at 7.26 ppm (1H) and
77.00 ppm (13 C{1H}) for CDCl3. Infrared spectra were recorded with a
Bruker-Alpha (ATR-ZnSe) spectrometer and are reported as wave-
number (cmÀ 1). Single-crystal X-ray intensity data were collected on a
Bruker KAPPA APEX-II diffractometer in omega and phi scan mode,
Mo Kα=0.71073 Å at 298 K. A Q-Exactive benchtop HRMS was used
for the high-resolution mass analysis.
1
CHCl3); H NMR (500 MHz, CDCl3) δ 4.68–4.66 (m, 1H), 4.43–4.39 (m,
1H), 4.29 (d, J=10 Hz, 1H), 2.77–2.72(m, 1H), 2.52 (d, 15 Hz, 1H). 13C
NMR (125 MHz, CDCl3) δ 176.5, 76.1, 67.5, 37.8; IR (neat, cmÀ 1): 3363,
2980, 1786, 1379, 1191, 1093, 998; HRMS (ESI-quadrupole) m/z: [M
+H]+ Calcd for C4H7O3 103.0317; Found 103.0392.
Compound 9d obtained in 98% yield as colourless oil: [α]D
+63.2 (c 1, CHCl3).
=
22
Prepration of ethyl 3-(S)-hydroxy-4-iodobutanoate (13)22: To a stirred
suspension of potassium iodide (9.76 g, 58.8 mmol) in DCM (20 ml)
°
was added TMS-Cl (7.5 ml, 58.8 mmol) drop wise at 0 C. The
°
suspension was warmed to 25 C for 30 minutes until a dark brown
colour solution formed. Lactone 9 (3 g, 29.4 mmol) and absolute EtOH
(5.12 ml, 88.2 mmol) in CH2Cl2 (20 ml) was added to reaction mixture
°
drop wise manner. The reaction was continued overnight at 25 C and
the completion of the reaction was confirmed by TLC. The solvents
were removed under reduced pressure and the residue was dissolved
in diethyl ether (30 mL). The organic layer was washed with 5%
aqueous Na2S2O3 solution (3×10 mL), water, brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified
by silica gel chromatography (hexane/EtOAc=5:1 to 3:1) to afford
the product 13 (5.5 g, 76%) as pale yellow oil. [α]D22 =À 10.5 (c 1,
Preparation of diethyl (S)-2-hydroxysuccinate(11): To a stirred
solution of L-malic acid (5 g, 37.2 mmol) in 40 mL ethanol was
added concentrated sulphuric acid (4.38 g and 44.64 mmol) drop-
wise. The reaction mixture was stirred at reflux for 12 hours. The
reaction mixture was then cooled to room temperature and
concentrated under reduced pressure. The residue was diluted with
EtOAc (50 mL) and washed with saturated aqueous NaHCO3, water
1
CHCl3) H NMR (400 MHz, CDCl3) δ: 4.18 (q, J=8.0 Hz, 2H), 4.02–3.97
(m, 1H), 3.35–3.27 (m, 2H), 3.22–3.19 (m, 1H), 2.69–2.57 (m, 2H), 1.27 (t,
J=8.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 171.6, 67.4, 60.9, 40.7,
14.0, 12.1; IR (neat, cmÀ 1): 3346, 2974, 1740, 1424, 1381, 1306, 1200,
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1085; HRMS (ESI-quadrupole) m/z: [M+Na]+ Calcd for C6H11IO3Na
280.9753; Found 280.9644.
chromatography to obtain the amide 15 (195 mg, 93%) as a light
1
2
3
4
5
6
7
8
9
1
yellow oil. [α]D À 29 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3) δ 6.38
22
(d, J=1.45 Hz, 2H), 6.31 (d, J=2.1 Hz, 1H), 4.30–4.25 (m, 1H), 3.75 (s,
6H), 3.6 (s, 3H), 3.15 (s, 3H), 2.84 (dd, J=7.1, 13.5 Hz, 1H), 2.71–2.55
(m, 2H), 2.51 (dd, J=8.8, 16.4 Hz, 1H); 13C NMR (175 MHz, CDCl3) δ
173.5, 160.8, 140.5, 107.3, 98.5, 68.9, 61.2, 55.2, 43.2, 37.4, 31.8; IR
(neat, cmÀ 1): 2926, 2853, 1644, 1599, 1464, 1389, 1294, 1205,
1153, 1067, 995. HRMS (ESI-quadrupole) m/z: [M+H]+ Calcd for
C14H22NO5 284.1497; Found 284.1492.
Compound 13D obtained in 76% as pale yellow colour: [α]D
+10.2 (c 1, CHC13).
=
22
Preparation of ethyl (S)-3,4-epoxybutanoate (8): To a stirred
solution of iodo compound 13 (700 mg, 2.86 mmol) in acetonitrile
°
(15 ml) was added Ag2O (800 mg, 3.44 mmol) at 25 C. The reaction
was continued for 24 h and the completion of the reaction was
confirmed by TLC analysis. The solids were filtered off though a pad
of celite, the filtrate was concentrated under reduced pressure. The
residue was subjected to column chromatography (Silica gel,
hexane/ether=5:1 to 4:1) to afford epoxy ester 8 (320 mg, 86%)
as colorless oil. [α]D22 =À 8.4 (c 0.5, CHC13) 1H NMR (500 MHz, CDCl3)
δ: 4.19 (q, J=10 Hz, 2H), 3.30–3.27 (m, 1H), 2.84 (t, J=5 Hz, 1H),
2.57–2.54 (m, 3H), 1.28 (t, J=10 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ: 170.4, 60.9, 48.0, 46.7, 38.1, 14.2; IR (neat, cmÀ 1): 2941, 1746,
1467, 1380, 1270, 1193, 1042, 974; HRMS (ESI-quadrupole) m/z: [M
+H]+ Calcd for C6H11O3 131.1630; Found 131.0702.
Compound 15D obtained in 93% yield as pale yellow colour oil:
[α]D22 = +23.7 (c 0.5, CHC13).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Preparation of (R)-1,1-Dichloro-5-(3,5-dimethoxyphenyl)-4-hy-
droxypentan-2-one (7): To a stirred solution of ester 14 (400 mg,
°
1.49 mmol) in CH2Cl2 (0.5 mL) and THF (10 mL) at À 78 C under a N2
atmosphere was added lithium dicyclohexylamide in THF (gener-
ated by treating n-BuLi (21 mL, 0.7 M, 14.9 mmol) and dicyclohexyl-
°
amine (3 mL, 14.9 mmol) in THF at 0 C for 15 min) slowly over 1 h
using a syringe pump. The reaction mixture was stirred for
additional 1 h, and completion of the reaction was confirmed by
TLC. The reaction mixture was treated with saturated NH4Cl
solution. The organic layer was separated, the aqueous layer was
extracted with EtOAc (3×10 mL). The combined organic layers
were washed with water, 2 N oxalic acid, brine, dried over
anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by column chromatography (silica gel, 10%
EtOAc/hexane) to give 7 (251 mg, 54%) as a colorless oil along with
recovery of the starting ester (53 mg, 13%). Rf =0.6 (30% EtOAc in
Compound 8D obtained in 76% as colourless oil: [α]D22 = +9.1 (c 1,
CHC13).
Praparation of ethyl (R)-4-(3,5-dimethoxyphenyl)-3-hydroxybuta-
noate (14): To a stirred suspension of Mg (923 mg, 38 mmol) in Et2O
(10 ml) under N2 atmosphere was added dimethoxy bromobenzene
°
(4.16 g, 19.21 mmol) in Et2O (10 ml) dropwise manner at 40 C. After
2 h the reaction mixture was allowed cool to room temperature. The
Grignard solution was then added to a stirred suspension of CuI
petroleum ether); [α]D À 7.0 (c 0.1, CHCl3); 1H NMR (700 MHz,
°
20
(724 mg, 3.8 mmol) in THF at À 40 C. After 30 min a solution of
CDCl3) δ 6.39–6.36 (m, 3H), 5.88 (s, 1H), 4.39–4.33 (m, 1H), 3.78 (s,
6H), 3.05–2.96 (m, 2H), 2.77 (d, J=6.3 Hz, 2H). 13C{1H} NMR
(175 MHz, CDCl3) δ 196.4, 161.0, 139.5, 107.4, 98.8 70.0, 68.6, 55.3,
43.4, 41.8, ; IR (neat): 2926, 2853, 1734, 1653, 1597, 1449, 1205,
1152, 1070, 994 cmÀ 1. (ESI-quadrupole) m/z: [M+H]+ Calcd for
C13H17O4Cl2 307.0503; Found 307.0498.
epoxide 8 (500 mg, 3.8 mmol) was added in THF (5 ml) dropwise over
1 h using syringe pump at same temperature. The reaction mixture
was slowly warmed to room temperature and stirred for 12 h.
Completion of the reaction was confirmed by TLC analysis. The
reaction mixture was carefully treated with saturated ammonium
°
chloride solution at 0 C. The residue was extracted with EtOAC
(20 ml×3), the combined organic layer was washed with water, brine,
dried over anhydrous Na2SO4 and concentrated under vacuum. The
crude compound was purified by column chromatography (silica gel;
petroleum ether/ethyl acetate (8:2) to afford the ester 14 (825 mg,
81%). [α]D20 À 4.6 (c 0.5, CHCl3), 1H NMR(500 MHz, CDCl3) δ: 6.33 (d, J=
2.2 Hz, 2H) 6.29 (t, J=4.3 Hz,1H), 4.25–4.20 (m, 1H), 4.18–4.14 (m, 1H),
3.77 (s, 6H), 2.80 (dd, J=7.15, 13.5 Hz, 1H), 2.68 (dd, J=6.15, 13.5 Hz,
1H), 2.49 (dd, J=3.55, 16.35 Hz, 1H), 2.41 (dd, J=8.7, 16.4 Hz, 1H), 1.28
(t, J=8.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 172.7, 160.9, 139.9,
107.4, 98.6, 68.9, 60.7, 55.2, 43.2, 40.5, 14.1; IR (neat, cmÀ 1): 3433, 2940,
1723, 1595, 1460, 1295, 1149, 1058, 834: HRMS (ESI-quadrupole) m/z:
[M+H]+ Calcd for C14H21O5 269.1389; Found 269.1375.
Compound 7D obtained in 58% as colourless oil: [α]D20 +5.88
(c 1.02, CHCl3)
Preparation
of
(2S,4R)-1,1-Dichloro-5-(3,5-dimethoxyphenyl)
pentane-2,4-diol (1): To a stirred solution of tetramethylammonium
triacetoxyborohydride (40 mg, 0.15 mmol) in acetonitrile (0.3 mL) and
°
anhydrous acetic acid (0.3 mL) at À 40 C was added ketone 7 (10 mg,
0.0326 mmol) in acetonitrile (0.2 mL). The reaction mixture was stirred
for 18 h, and completion of the reaction was confirmed by TLC. The
reaction mixture was treated carefully with 0.5 N aqueous sodium
potassium tartrate solution (1 mL). The product was extracted with
DCM (3×5 mL), and the combined organic layers were washed with
H2O, sat. NaHCO3 solution, and brine, dried over anhydrous Na2SO4,
filtered, and evaporated under vacuum to give 3’-methoxyl citreo-
chlorol 1 (9.6 mg, 96%) as white needles along with the syn-isomer 3
(0.3 mg, 2%) (1H NMR of crude shows dr=97:3). Rf =0.4 (30% EtOAc
Compound 14D obtained in 81% as pale yellow colour oil: [α]D
+5.2 (c 1, CHC13).
=
22
Preparatio of (R)-4-(3,5-Dimethoxyphenyl)-3-hydroxy-N-methoxy-
N-methylbutanamide (15): To a stirred suspension of MeONH-
in petroleum ether); [α]D À 5.6 (c 0.05, MeOH); 1H NMR(500 MHz,
25
CDCl3) δ 6.37 (s, 3H), 5.76 (d, J=4.3 Hz, 1H), 4.26 (dd, J=5, 11.1 Hz,
1H), 4.21–4.16 (m, 1H), 3.79 (s, 6H), 2.82 (dd, J=4, 13.4 Hz, 1H), 2.67
(dd, J=9, 13.4 Hz, 1H), 2.19 (bs, 2H), 1.9 (t, J=5 Hz, 2H). 13C{1H} NMR
(125 MHz, CDCl3 +CCl4) δ 161.1, 139.9, 107.3, 98.8, 76.5, 73.7, 69.3,
55.3, 44.4, 38.2; IR (neat): 3424, 2926, 1601, 1463, 1295, 1204, 1155,
1071, 837, 780; HRMS (ESI-quadrupole) m/z: [M+Na]+ Calcd for
C13H18O4Cl2Na 331.0479; Found 331.0471.
°
Me·HCl (180 mg, 1.85 mmol) in THF (5 mL) at À 10 C was added a
solution of AlMe3 (2 M solution, 0.93 mL, 1.85 mmol) over a 15 min
period. The reaction mixture was stirred at room temperature for
45 min, then a solution of ester 14 (200 mg, 0.74 mmol) in THF
(10 mL) was added, and the resulting mixture was stirred at room
temperature for 2 h. Completion of the reaction was confirmed by
TLC, and the reaction was treated carefully with saturated NH4Cl
solution (5 mL) followed by addition of EtOAc (10 mL) and
saturated solution of Rochelle salt (5 mL). The resulting mixture was
stirred until formation clear solution (3 h). The organic layer was
separated, and the aqueous phase was extracted with EtOAc (2×
10 mL). The combined organic layer was washed with water, brine,
dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. The crude compound was purified by column
Compound 2 obtained in 85% yield (9.9 mg) as colorless oil.: [α]D
22
+4.6 (0.16, MeOH)
Preparation
of
(2S,4S)-1,1-Dichloro-5-(3,5-dimethoxyphenyl)
pentane-2,4-diol 3: To a stirred solution of 7 (10 mg, 0.033 mmol)
°
in THF (0.5 mL) at À 10 C was added catecholborane (0.021 mL,
0.195 mmol). The reaction mixture was stirred for 5 h, and
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Chem. Rev. 2006, 106, 3364–3378; c) J. Latham, E. Brandenburger, S. A.
completion of the reaction was confirmed by TLC. The reaction
mixture was treated carefully with MeOH (0.2 mL) and 0.5 N
aqueous sodium potassium tartrate solution (0.2 mL). The product
was extracted with EtOAc (3×5 mL), and the combined organic
layers were washed with 2 N NaOH (2 mL×3), water, brine, dried
over anhydrous Na2SO4, and concentrated under vacuum to give 3’-
methoxyl citreochlorol 3 (8.6 mg, 85%) as a colorless oil with along
with the anti-isomer 1 (1 mg, 9.7%) dr. Rf =0.4 (30% EtOAc in
petroleum ether); [α]D22 +4.3 (c 0.16, MeOH); 1H NMR
(500 MHz,CDCl3) δ 6.37 (bs, 1H), 5.71 (d, J=4.2 Hz, 1H), 4.17À 4.14
(m, 1H), 3.79 (s, 6H), 2.81 (dd, J=3.9, 13.4 Hz, 1H), 2.70 (dd, J=9,
13.3 Hz, 1H), 2.66À 2.45 (bm, 2H), 2.06 (d, J=14.5 Hz, 1H), 1.86–1.79
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3 +CCl4) δ 161.1, 139.5, 107.4,
98.8, 76.3, 75.5, 72.2, 55.3, 44.7, 37.1; IR (neat): 3424, 2926, 1601,
1464, 1296, 1204, 1155, 1071, 837, 780: HRMS (ESI-quadrupole) m/z:
[M+Na]+ Calcd for C13H18O4Cl2Na 331.0479; Found 331.0471.
1
2
3
4
5
6
7
8
9
Shepherd, B. R. K. Menon, J. Micklefield, Chem. Rev. 2018, 118, 232–269;
d) P. Chankhamjon, Y. Tsunematsu, M. Ishida-Ito, Y. Sasa, F. Meyer, D. B.
Schmidt, B. Urbansky, M. Klaus-Dieter, K. Scherlach, K. Watanabe, C.
Hertweck, Angew. Chem. Int. Ed. 2016, 55, 11955–11959; Angew. Chem.
2016, 128, 12134–12138.
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Rajendar, J. Org. Chem. 2020, 85, 4103–4113.
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[8] a) L. Shipeng, H. Peiqiang, Prog. Chem. 2020, 32, 1846–1868; b) A. S. Lee,
M. D. Shair, Org. Lett. 2013, 15, 2390–2393; c) L. C. Dias, E. C. de Lucca Jr,
Org. Lett. 2015, 17, 6278–6281; d) L. C. Dias, E. C. de Lucca Jr, J. Org.
Chem. 2017, 82, 3019–3045; e) Y. Zhang, Q. Guo, X. Sun, J. Lu, Y. Cao, Q.
Pu, Z. Chu, L. Gao, Z. Song, Angew. Chem. Int. Ed. 2018, 57, 942–946;
Angew. Chem. 2018, 130, 954–958; f) I. Paterson, E. A. Anderson, S. M.
Dalby, J. H. Lim, J. Genovino, P. Maltas, C. Moessner, Angew. Chem. Int.
Ed. 2008, 47, 3016–3020; Angew. Chem. 2008, 120, 3058–3062; g) I.
Paterson, E. A. Anderson, S. M. Dalby, J. H. Lim, J. Genovino, P. Maltas, C.
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Moriwake, Chem. Lett. 1984, 13, 1389–1392; b) S. Saito, T. Ishikawa, A.
Kuroda, K. Koga, T. Moriwake, Tetrahedron 1992, 48, 4067–4086.
[10] M. Kolb, J. Barth, Synth. Commun. 1981, 11, 763–769.
[11] Improved yields were observed with in situ generation of TMSI in place
of commercial TMSI.
[12] M. Larcheveque, S. Henrot, Tetrahedron 1990, 46, 4277–4282.
[13] T. Rikuhei, H. Ken, A. Kaji, J. Chem. Soc. Chem. Commun. 1986, 836–837.
[14] Addition of excess dichloromethyl lithium provided the ketone 7 only.
We have not observed any tertiary alcohol formation by the double
addition of dichloromethyl lithium to ester group.
[15] a) J. Barluenga, L. liavona, M. Yus, J. M. Concellon, Tetrahedron 1991, 47,
7875–7886; b) R. S. Grainger, R. B. Owoare, P. Tisselli, J. W. Steed, J. Org.
Chem. 2003, 68, 7899–7902; c) T. Onishi, Y. Otake, N. Hirose, T. Nakano,
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3560–3578.
Compound 4 obtained in 85% yield (9 mg) as yellow oil. [α]D22-6.00
(c 0.05, MeOH).
Preparation of (2S,4S)-1,1-Dichloro-6-(3,5-dimethoxybenzyl)-2,2-
dimethyl-1,3-dioxane 17: To a stirred solution of 3 (50 mg, 0.16) in
°
acetone (2 mL) at 0 C was added PTSA (5 mg) and 2,2-Dimethoxy
propane (0.5 mL). The reaction mixture was stirred for 1 h at rt, and
completion of the reaction was confirmed by TLC. Solid K2CO3
(0.5 g) was added and the solids were removed by filtration and
washed with ethyl acetate (2×5 mL). The filtrate was washed with
water, brine, dried over anhydrous Na2SO4, and concentrated under
vacuum. The crude was purified by column chromatography to
give 17 (48 mg, 81%) a light yellow color oil. Rf =0.8 (30% EtOAc in
1
petroleum ether); H NMR (500 MHz, CDCl3 +CCl4) δ 6.35 (d, 5 Hz,
2H), 6.31 (s, 1H), 5.53 (d, J=5 Hz, 1H), 4.07–4.03 (m, 2H), 3.78 (s, 6H),
2.89 (dd, J=5, 10 Hz, 1H), 2.61 (dd, J=5, 10 Hz, 1H), 1.80–1.86 (m,
1H), 1.45 (s, 6H), 1.43À 1.35 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3 +
CCl4) δ 160.7, 139.7, 107.5, 99.6, 98.4, 73.9, 73.7, 69.5, 55.2, 43.1,
31.2, 29.9, 19.9; IR (neat): 2950, 1606, 1470, 1210, 1118, 1075, 839,
766: HRMS (ESI-quadrupole) m/z: 349.0973 [M+H]+ Calcd for
C16H23O4Cl2; Found 349.0969.
[17] X-ray crystallographic information for compound
1 is available.
Deposition Number 1968911 (for 1) contains the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
Acknowledgements
[18] D. A. Evans, A. H. Hoveyda, J. Org. Chem. 1990, 55, 5190–5192.
[19] H NMR spectra of A) diastereomeric mixture, (syn:anti=72:28); B) Syn-
diol 3, C) Anti-diol 1.
GR Thankful to SERB-India for Ramanujan Fellowship (D.O. No.
SB/S2/RJN-071/2015) and Ranganayakulu acknowledges DST for
INSPIRE Ph.D. fellowship.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: methoxyl citreochlorols · aromatic polyketides ·
geminal dichlomethyl groupWW · dichloromethyl lithium ·
selective reduction
[20] S. D. Rychnovsky, D. J. Skalitzky Tetrahedron Lett. 1990, 31, 945–948.
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Manuscript received: November 30, 2020
Revised manuscript received: February 18, 2021
Accepted manuscript online: February 19, 2021
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