Stereoselective Total Synthesis of the Non-Contiguous Polyketide Natural Product (–)-Dolabriferol

Article abstract of DOI:10.1002/ejoc.201701748

The stereoselective total synthesis of the non-contiguous polypropionate dolabriferol has been accomplished in 17 steps, by an approach that is both divergent and convergent. The key reactions involved are enantioselective cross-aldol coupling, aldol dime

Full text of DOI:10.1002/ejoc.201701748

A Journal of
Accepted Article
Title: Stereoselective total synthesis of non-contiguous polyketide
natural product (-)-dolabriferol
Authors: Pabbaraja Srihari, Naresh Gantasala, and Suresh Borra
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701748
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701748
Supported by

10.1002/ejoc.201701748
European Journal of Organic Chemistry
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Stereoselective total synthesis of non-contiguous polyketide
natural product (-)-dolabriferol
Naresh Gantasala,[a,b] Suresh Borra,[a,b] Srihari Pabbaraja*[a,b]
Abstract: Stereoselective total synthesis of non-contiguous
polypropionate dolabriferol is accomplished in 17 steps following a
divergent and convergent approach. The key reactions involved are
enantioselective cross-aldol reaction, aldol dimerization reaction of
propionaldehyde, Sharpless asymmetric epoxidation, regioselective
epoxide opening and Yamaguchi esterification reaction. Noteworthy
is the effect of protecting groups on alcohol substrate for differential
reactivity towards Yamaguchi esterification.
via an energetically favorable pathway,[7] and further supported by
its total synthesis utilizing the retro-Claisen approach.[6a,b] Vogel
6c
]
et al[ have reported the first total synthesis of (-)-dolabriferol
using Paterson’s protocol of esterification wherein a polyketide
alicyclic alcohol was coupled with polyketide acid. Attempts to
couple hemi-acetal and acid fragment were unsuccessful.
However, by taking the enol acetate, the hinderdnes of the alcohol
fragment was reduced which gave a promising result for
esterification reaction. Goodman et al[6b] have utilized Evan’s aldol
approach and retro-Claisen rearrangement as the key steps for
the total synthesis of (-)-dolabriferol. Ward et al[6a] have
accomplished the total synthesis involving an aldol approach and
the regioselective retro-Claisen fragmentation approach.
Introduction
Investigation of biological and pharmacological properties of the
secondary metabolites isolated from marine natural sources has
been a subject of great importance. The polyketide natural
products attract significant attention due to their remarkable
biological and pharmacological activities such as antibiotic,
antifungal, anti-cancer, anti-inflammatory and immuno-
suppressant etc.[1] In 1996, Gavagnin et al have isolated
dolabriferol (1) from the skin of the anaspidean mollusk
Dolabrifera dolabrifera.[2] Though, this compound is assumed to
protect the shell-less mollusk from predators, the biological
properties of this molecule has not been fully explored. In 2012,
structurally related molecules dolabriferol B (2) and C (3) were
isolated from tropical sea hare Dolabrifera dolabrifera.[3]
Structurally, these natural products are embodied by two
polypropionate subunits joined via an unusual C9 acyclic ester
linkage which is also a key skeleton of other similar natural
products such as baconipyrones A-D[4] (4-7) and siserrone A[5] (8)
(Figure 1). Dolabriferol B has the similar skeleton as dolabriferol
but has an ethyl moiety inplace of isopropyl moiety at C18.
Dolabriferol C has an extended polyketide chain in acid fragment.
Though, the structure of dolabriferol was established by extensive
NMR experiments and X-ray analysis, the absolute configuration
was determined after the total synthesis of dolabriferol by Vogel
et al.[6c] The unusual ester linkage and the stereochemistry
present in dolabriferols makes it an attractive synthetic target for
the synthetic community and several contributions have been well
precedented in this regard.[6] Though it is believed that the
unusual connectivity might originate from the biosynthetic process,
[2] its isolation through a mild base-or acid-catalyzed retro-Claisen
rearrangement was not ruled out as the rearrangement proceed
Figure 1. Polyketide/polypropionate natural products.
In continuation to our research interest towards the total synthesis
of biologically active natural products,[8] we have recently
accomplished the synthesis of nhatrangin A[9] (7) wherein a
diketide motif (bearing hydroxyl functionality) is attached to 2,3-
dihydroxy valeric acid moiety through an ester linkage. Herein we
report the total synthesis of dolabriferol employing a divergent
cum convergent approach starting from propionaldehyde and
involves an esterification reaction as a key reaction.
[a]
[b]
G. Naresh, B. Suresh, Dr. P. Srihari
Division of Natural Products Chemistry
CSIR-Indian Institute of Chemical Technology
Tarnaka, Hyderabad – 500007, Telangana, India
Academy of Scientific and Innovative Research (AcSIR),
Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110001, India
E-mail: srihari@iict.res.in; homepage:
Results and Discussion
http://www.iictindia.org/staffprofiles/staffprofile.aspx?qry=1725
Supporting information for this article is given via a link at the end of
the document.
A retrosynthetic analysis of dolabriferol is delineated in Scheme
1. Assuming difficulties for desilylation at last step in earlier
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10.1002/ejoc.201701748
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approaches,[6d,f] where in deprotection of silyl moieties proved to
be cumbersome as the starting material gets decomposed during
deprotection, we slightly modified our key precursor and planned
desilylation at the earlier step to overcome such difficulties. Thus,
the target molecule 1 could be obtained from 11 by tri-TBS-
desilylation to give cyclic hemiketal, which on selective oxidation
of C3-secondary alcohol provides the target molecule 1. 11 can
be synthesized from 12 in four-step sequence i.e. by TBS
deprotection of primary alcohol, oxidation to aldehyde followed by
ethyl Grignard and further oxidation to get the ketone. 12 can be
synthesized in a convergent approach by coupling two key
fragments, acid 13 and alcohol 14 via an esterification reaction.
Both the fragments, acid 13 and alcohol 14 were planned to be
independently synthesized starting from readily available
propionaldehyde in a divergent fashion. Acid fragment 13 can be
synthesized from the corresponding epoxy alcohol 15 through an
epoxide ring opening reaction to get 1,3-diol followed by oxidation
of primary alcohol to acid functionality with appropriate protection
of secondary alcohol. The epoxy alcohol 15 could be derived from
α,β-unsaturated ester 16 in two steps i.e ester reduction followed
by Sharpless asymmetric epoxidation of allyl alcohol.
opening reaction to yield 1,3-diol followed by TBS protection. The
compound 18 can be synthesized from 19 in two steps i.e ester
reduction and Sharpless asymmetric epoxidation reaction. The
ester 19 in turn can be obtained from aldehyde 20 which could be
accessed by a cross-aldol reaction of propionaldehyde and
isobutyraldehyde.
With a strategy of divergent cum convergent approach in mind,
the synthesis of acid fragment 13 began with an enantioselective
D-proline catalyzed self-aldol addition of propionaldehyde[10] to
get the corresponding known α-methyl,β-hydroxyvaleraldehyde
17 as an inseparable (anti:syn 4.5:1) mixture (as analysed by
GCMS, see Supporting Information). With the intention of getting
the minor diastereomer separated in the future steps, we
proceeded further with the mixture aldehyde 17 embodying a free
hydroxyl functionality for
a
2C-Wittig homologation with
carbethoxy-methylenetriphenylphosphorane to provide α,β-
unsaturated ester 21,[16] which was further treated with TBSOTf to
provide the corresponding silyl ether 16. Reduction of ester 16
with DIBAL-H provided allyl alcohol 22 which was further
subjected to Sharpless asymmetric epoxidation[11] reaction to
yield the chiral epoxy alcohol 15. The epoxide ring in 15 was
opened with methylmagnesium bromide in presence of copper
iodide[12] to provide 1,3-diol 23 which was further masked to its
corresponding tri-TBS ether 24 with TBSOTf and 2,6-lutidine.
Exposure of trisilylated ether 24 to HF-pyridine afforded primary
alcohol 25, which was oxidized under BAIB and TEMPO
conditions[13] to furnish the acid fragment 13 in 78% yield (Scheme
2).
Scheme 2. Synthesis of acid 12.
Scheme 1. Retrosynthetic analysis of dolabriferol.
The synthesis of alcohol 14 commenced with a L-proline
catalyzed enantioselective cross-aldol reaction[10a] between
isobutyraldehyde and propionaldehyde to obtain the
corresponding aldol product 20 as an inseparable mixture of
anti:syn mixture in 24.7:1 ratio (as analysed by GCMS, see
Ester 16 can be synthesized from aldehyde 17, which in turn can
be obtained enantioselectively via a self-aldol dimerization of
propionaldehyde. The other key fragment alcohol 14 was planned
to be synthesized from the epoxy alcohol 18 through a ring
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10.1002/ejoc.201701748
European Journal of Organic Chemistry
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Supporting Information). The aldehyde mixture without further
purification was subjected to 2C-homologation reaction to provide
α,β-unsaturated ester 26[17] via a C2-Wittig olefination reaction.
The free 2o alcohol was masked as the corresponding TBS ether
19 and then the ester functionality was reduced with DIBAL-H to
provide allyl alcohol 27. Sharpless asymmetric epoxidation of allyl
alcohol 27 with Ti(OiPr)4 and L-(+)-DIPT with TBHP as oxidizing
agent afforded epoxy alcohol 18. Opening of the epoxy alcohol
with methyl magnesium bromide in presence of CuI furnished the
methylated 1,3-diol 28. The primary hydroxyl group of 28 was
selectively protected as TBS ether with TBSCl in the presence of
imidazole to deliver the key intermediate alcohol fragment 14 in
95% yield (Scheme 3).
substrate remained intact. Also, after the workup, we could
recover back only alcohol 14. Attempts under various reaction
conditions (See Table 1, entry 1-6) by changing several
procedures for the coupling reaction did not yield fruitful results.
Even under Mitsunobu conditions, to check if the esterification
occurs with inversion, it was observed that both the substrates
remained intact at room temperature while at 90 oC, both the acid
and alcohol fragments gets decomposed. The non-reactivity of
alcohol may be attributed to the presence of two bulky TBS
moieties which might be hindering the nucleophilic attack of the
hydroxyl group onto the active ester. Assuming the reactivity of
acid substrate and non-reactivity of alcohol substrate 14, we
focused our attention to investigate further by modifying the
protective group of alcohol. Towards this, the compound 28 was
converted to pivaloyl ester 29 and treated with acid 13 for an
esterification reaction under various conditions (Scheme 4, Table
1, entry 1-5). However, the coupling reaction did not proceed to
our expectations and ended up with the recovery of alcohol
fragment 29. We proceeded further to reduce the steric hindrance
in alcohol by converting 28 into the known advanced ketone
intermediate 30[6e] which can be used directly for coupling reaction.
Our attempts to couple the acid 13 with alcohol 30 were also not
fruitful and ended up with either recovery of alcohol or
decomposition of both acid and alcohol (Table 1 entry 1-6).
Scheme 3. Synthesis of alcohol 13.
Scheme 4. Synthesis of alcohols 29 and 30. Coupling of acid 13 with alcohols
14 / 29 / 30.
With both the acid 13 and alcohol 14 in hand, the stage was set
for an esterification reaction. In our initial attempts under
Yamaguchi conditions, when the acid 13 was treated with 2,4,6-
trichlorobenzoyl chloride in presence of triethyl amine, a non-polar
spot was observed which we believed to be the mixed anhydride
(inferring the reactivity of acid functionality). However, after the
formation of non-polar spot, when alcohol was added to the
reaction mixture, the reaction ended up with disappearance of
non-polar spot while the spot corresponding to the alcohol
Table 1. Conditions attempted for esterification reaction of acid 13 with
alcohol 14/29/30
Sl.
no
1
Reagents /solvent / temperature
Time
10 h
10 h
Remarks
DCC, DMAP, CH2Cl2, 0 oC-rt
Alcohol
recovered
Alcohol
2
3
EDCI, HOBT, CH2Cl2, DIPEA, 0 oC-rt
recovered
2,4,6-trichlorobenzoyl chloride, NEt3,
DMAP, toluene, 0 oC- rt-70 oC
(Yamaguchi conditions)
4-10 h Alcohol
recovered
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4
5
6
2-methyl nitrobenzoic acid, DMAP,
10 h
24 h
Alcohol
recovered
Alcohol
alpha carbon (C7) to carboxylic acid functionality due to exposure
to basic conditions (characterized by H NMR, See Supporting
Information).
With the success of coupling reaction, the rest was to proceed
further for the chain extension and ring formation reaction.
Towards this, the compound 33 (diastereomeric mixture) was
treated with DIBAL-H for pivaloyl deprotection to yield the desired
alcohol 34, which was easily separated from the other
CH2Cl2, 0 oC-rt
1
TPP, DIAD, THF, rt
recovered
TPP, DIAD, THF + toluene (1:1), 90 oC
4-10 h Alcohol and
acid
decomposed
Owing to unsuccessful results from the coupling reaction of acid
13 with alcohols 14 / 29 / 30, and the positive esterification
reaction from the results of Vogel et al[6c] and later by Toste et
al,[6d] we further turned our attention for modification of protection
group on secondary alcohol (hydroxyl moiety on C18) of 14 to
overcome the challenge of esterification reaction. We now
investigated through replacement of the secondary silyl moiety
with PMB functionality, anticipating in keeping the bulky moiety
little farther through a methylene moiety without altering the
primary TBS protection at C12. Thus, compound 26 was treated
with PMB-imidate to provide the corresponding PMB-ether 19a in
85% yield. Compound 19a was treated with DIBAL-H to yield allyl
alcohol 27a and subjected to Sharpless asymmetric epoxidation
to provide epoxy alcohol 18a. Ring opening reaction of 18a with
methylmagnesium bromide in presence of copper iodide
furnished the mixture of inseparable 1,2- and 1,3-diols which was
further treated with sodium metaperiodate to provide 1,3-diol 28a
(See Scheme 3). Compound 28a on treatment with TBSCl in
presence of imidazole provided the corresponding TBS ether 31,
which was utilized for esterification reaction with acid 13 (Scheme
5). However, once again the reaction was fruitless and ended up
with the recovery of alcohol substrate 31.
diastereomer
(minor
diastereomer)
through
column
chromatography. Alcohol 34 was oxidized under IBX conditions to
yield aldehyde and was treated with ethyl magnesium bromide to
yield the secondary alcohol, which was further oxidized under IBX
conditions to yield the corresponding ketone 35. The silyl
deprotection at this stage was difficult with TBAF as the reaction
resulted in decomposition of the starting material. However, the
deprotection challenge was successfully overcome with HF-
pyridine to yield diol 36 in 76% yield. Exposure of diol 36 to Dess-
Martin periodinane (DMP) provided us the known precursor 37.[6b]
One-pot PMB deprotection and hemiketalization of 37 was easily
achieved with DDQ[6b] to furnish the polyketide dolabriferol 1
(Scheme 6).
The spectroscopic data of the synthesized
compound was found to be identical with that of the reported
data.[2]
Scheme 6. Total synthesis of dolabriferol (1).
Conclusions
In conclusion, we have accomplished the total synthesis of (-)-
dolabriferol in 24 overall steps and seventeen steps in convergent
approach starting from commercially available propionaldehyde
with 3.0% overall yield (convergent approach). Both the key
fragments, acid 13 and alcohol 32 were obtained from
propionaldehyde in a divergent fashion. Enantioselective self-
aldol dimerization and cross-aldol addition reactions have been
successfully employed to secure two chiral centers. Sharpless
asymmetric epoxidation reaction has been used to secure third
chiral center. The protection groups on alcohol substrate have
been found to be crucial towards the esterification reaction.
Dolabriferol B (structurally similar molecule) can also be efficiently
synthesized employing the above strategy and the efforts for the
same are now currently underway in the laboratory.
Scheme 5. Coupling of acid 13 with alcohols 31 / 32 and synthesis of 33
In further attempt, the primary hydroxyl moiety (C12 hydroxyl) of
28a was masked with pivaloyl moiety to yield 32 and then the
esterification reaction was attempted. Gratifyingly, the
esterification reaction of acid 13 with alcohol 32 proceeded
smoothly under Yamaguchi conditions[14,6d] providing the ester 33
(9:1 inseparable diastereomers) in 71% yield.[15] The
diastereomer was presumed to be obtained by epimerization at
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10.1002/ejoc.201701748
European Journal of Organic Chemistry
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concentrated under reduced pressure. The crude product was
purified by column chromatography over silica gel using
petroleum ether/EtOAc (9.5:0.5) to afford TBS ether 16 as a
Experimental Section
General Information. All the reagents were used as received
from commercial sources unless otherwise noted. All air and
moisture sensitive reactions were conducted under a nitrogen or
argon atmosphere using flame-dried or oven-dried glassware with
magnetic stirring. CH2Cl2 was stirred over CaH2 and distilled prior
to use. Tetrahydrofuran (THF) was dried over Na, benzophenone
and distilled prior to use. Toluene was freshly distilled from CaH2
and used. Reactions were monitored by thin-layer
chromatography which was carried out on silica plates (silica gel
60 F254, Merck) using UV-light, iodine and p-anisaldehyde for
visualization. Column chromatography was carried out using
silica gel (60-120 mesh or 100- 200 mesh) packed in glass
columns. Technical grade ethyl acetate and petroleum ether were
used for column chromatography and were distilled prior to use.
1H NMR and 13C NMR spectra were recorded in CDCl3 as solvent
on 300 MHz or 400 MHz or 500 MHz spectrometer at ambient
temperature. The coupling constant J is given in Hz. The chemical
shifts (δ) are reported in ppm on scale downfield from TMS and
using the residual solvent peak in CDCl3 (H: δ = 7.26 and C: δ =
77.0 ppm) or TMS (δ = 0.0) as internal standard and signal
patterns are indicated as follows: s = singlet, d = doublet, dd =
doublet of doublet, dt = doublet of triplet, t = triplet, q = quartet, qd
= quartet of doublet, m = multiplet, br = broad, tt = triplet of triplet.
IR spectra were recorded on a Bruker Infrared spectrophotometer
and are reported as cm-1. High-resolution mass spectra (HRMS)
were recorded on a Waters-TOF spectrometer.
20
colourless oil (7.95 g, 93%, diastereoselectivity 82:18); [α]D = -
23.1 (c 1.7, CHCl3); IR (Neat): 2958, 2857, 1721, 1652, 1465,
1368, 1253, 1152, 1033, 986, 834, 772, 667 cm-1; 1H NMR (400
MHz, CDCl3): δ 6.96 (dd, J = 15.7, 7.9 Hz, 1H), 5.79 (dd, J = 15.7,
1.1 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.57-3.49 (m, 1H), 2.52-2.41
(m, 1H), 1.52-1.35 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.03 (d, J =
6.8 Hz, 3H), 0.89 (s, 9H), 0.87-0.81 (m, 3H), 0.04 (bs, 6H); 13C
NMR (125 MHz, CDCl3): δ 166.7, 151.5, 121.0, 76.5, 60.1, 41.3,
26.8, 25.8, 18.1, 15.1, 14.2, 9.5, -4.3, -4.6; ESI-HRMS: Calcd m/z,
for C16H32O3SiNa: 323.2018 (M+Na)+, found 323.2023.
(4R,5R,E)-5-((tert-Butyldimethylsilyl)oxy)-4-methylhept-2-en-
1-ol (22)
A solution of 16 (6.5 g, 21.66 mmol, 1.0 eq.) in CH2Cl2 (65 mL)
was cooled to 0 °C, and treated with DIBAL-H (54.16 mmol, 31.8
mL, 1.7 M solution in toluene). After 20 min, the reaction was
diluted with CH2Cl2 (40 mL) at 0 °C, and the mixture was allowed
to warm to room temperature and then quenched with saturated
aqueous sodium potassium tartrate solution (40 mL). The
resulting mixture was vigorously stirred until a clear separation of
both organic and aqueous phase occurred. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (20 x
3 mL); The combined organic extracts were washed with
saturated aqueous NaCl solution (20 mL), dried over anhydrous
Na2SO4, and the solvents were evaporated. The crude was
purified by silica gel column chromatography using petroleum
ether/EtOAc (8:2) to give allyl alcohol 22 (5.03 g, 90%,
diastereoselectivity 82:18) as a clear oil. Rf = 0.5 (SiO2, 30%
EtOAc/hexane); [α]D20 = - 12.4 (c 1.8, CHCl3); IR (neat): 3330,
2930, 1462, 1376, 1253, 1079, 1059, 927, 938, 863, 790, 771,
666 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.75-5.57 (m, 2H), 4.11
(bs, 2H), 3.49-3.41 (m, 1H), 2.37-2.28 (m, 1H), 1.50-1.35 (m, 2H),
0.99 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.85 (t, J = 7.4 Hz, 3H), 0.04
(bs, 6H); 13C NMR (125 MHz, CDCl3): δ 135.2, 128.8, 77.1, 63.8,
41.2, 26.4, 25.8, 18.1, 16.0, 10.0, -4.3, -4.5; ESI-HRMS: Calcd
m/z, for C14H30O2NaSi: 281.1907 (M+Na)+, found 281.1904.
(4S,5R,E)-5-Hydroxy-4-methylhept-2-enoate (21)
To
a
stirred
solution
of
(ethoxycarbonylmethylene)triphenylphosphorane (22.52 g, 64.65
mmol) in toluene (75 mL) under reflux condition was added (2S,
3S)-3-hydroxy-2,4-dimethylpentanal 17 (5.0 g, 43.103 mmol) in
toluene (15 mL) and the resulting mixture was heated at reflux for
2 h. After the reaction was complete, the solvent was removed
under reduced pressure to yield crude product, which was then
purified by silica gel column chromatography using petroleum
ether/EtOAc (7:3) to give α,β unsaturated ester 21[16] (7.53 g,
78%, diastereoselectivity 81:19) as a colorless oil. [α]D20 = -23.4
(c 1.54, CHCl3); IR (Neat): 3447, 2934, 2877, 1702, 1650, 1459,
((2R,3R)-3-((2S,3R)-3-((tert-Butyldimethylsilyl)oxy)pentan-2-
yl)oxiran-2-yl)methanol (15)
1370, 1269, 1182, 1097, 975, 865, 754 cm-1; H NMR (500 MHz,
1
To a solution of Ti(OiPr)4 (0.75 mL, 2.55 mmol) and 4Å molecular
sieves (1.4 g) in CH2Cl2 (45 mL), (+)-DIPT (0.53 mL, 2.55 mmol)
was added at -20 °C. After 30 min. at this temperature, the
solution of allyl alcohol 22 (3.3 g, 12.79 mmol) in dry CH2Cl2 (6
mL) was added dropwise. The stirring was continued for
additional 30 min and TBHP (7.0 mL, 28.13 mmol, 4M solution in
toluene) was added at -20 °C. The mixture was stirred for 10 h at
this temperature and filtered. The filtrate was diluted with water
(15 mL), 20% aq NaOH Solution (2.5 mL) was added and stirring
was continued for 6 h. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 X 10 mL). The
combined organic layers were washed with water (2 X 10 mL),
dried over anhydrous Na2SO4, and evaporated. The crude was
purified by silica gel column chromatography using
Hexanes/EtOAc (7.5:2.5) to give epoxy alcohol 15 as a clear oil
CDCl3): δ 6.95 (dd, J = 15.6, 8.2 Hz, 1H), 5.86 (dd, J = 15.7, 1.0
Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.52–3.42 (m, 1H), 2.47-2.36
(m, 1H), 1.54-1.49 (m, 1H), 1.46-1.35 (m, 1H), 1.28 (t, J = 7.1 Hz,
3H), 1.10 (d, J = 6.9 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 166.5, 150.2, 122.1, 76.1, 60.3, 42.1, 27.4,
15.8, 14.2, 10.0; ESI-HRMS: Calcd m/z, for C10H18O3Na:
209.1148 (M+Na)+, found 209.1153.
Ethyl (4S,5R,E)-5-((tert-butyldimethylsilyl)oxy)-4-methylhept-
2-enoate (16)
To a cold stirred solution of alcohol 21 (5.3 g, 28.49 mmol), in dry
CH2Cl2 (75 mL) 2,6-lutidine (9.9 mL, 85.48 mmol) and TBSOTf
(7.85 mL, 34.19 mmol) were added. After 1 h, the reaction was
quenched with sat. NH4Cl (20 x 3 mL), and the mixture was
extracted with CH2Cl2 (10 x 3 mL), dried with Na2SO4, and
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10.1002/ejoc.201701748
European Journal of Organic Chemistry
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(3.15 g, 90%, diastereoselectivity 83:17). Rf = 0.4 (SiO2, 30%
EtOAc/hexane); [α]D20 = + 15.4 (c 2.3, CHCl3); IR (neat): 3436,
2932, 1464, 1254, 1102, 1010, 939, 835, 760, 668 cm-1; 1H NMR
(400 MHz, CDCl3): δ 3.96-3.88 (m, 1H), 3.65-3.56 (m, 2H), 2.99
(dd, J = 7.4, 2.4 Hz, 1H), 2.92-2.89 (m, 1H), 1.87-1.77 (m, 1H),
1.68-1.61 (m, 1H), 1.57-1.50 (m, 1H), 0.94-0.81 (m, 18H), 0.09-
0.02 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 75.9, 62.0, 56.7, 56.3,
39.6, 26.9, 25.8, 18.1, 12.3, 10.1, -4.2, -4.6; ESI-HRMS: Calcd
m/z, for C14H30O3NaSi: 297.1862 (M+Na)+, found 297.1862.
769, 668 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.82 (ddd, J = 8.1,
5.2, 3.1 Hz, 1H), 3.71 (dd, J = 9.9, 5.8 Hz, 1H), 3.66 (dd, J = 7.3,
3.6 Hz, 1H), 3.39 (dd, J = 9.9, 8.1 Hz, 1H), 1.95 – 1.80 (m, 2H),
1.46-1.30 (m, 2H), 0.95 (d, J = 7.1 Hz, 3H), 0.91-0.86 (m, 30H),
0.82 (d, J = 7.2 Hz, 3H), 0.09-0.01 (m, 18H); 13C NMR (125 MHz,
CDCl3): δ 75.1, 73.5, 65.2, 43.0, 40.3, 26.1, 26.0, 25.9, 24.0, 18.3,
18.2, 18.1, 14.2, 10.2, 9.5, -4.0, -4.0, -4.2, -4.3, -5.3, -5.4; ESI-
HRMS: Calcd m/z, For C27H62O3NaSi3 (M+Na)+: 541.3904, found
541.3907.
(2S,3S,4S,5R)-5-((tert-Butyldimethylsilyl)oxy)-2,4-
dimethylheptane-1,3-diol (23)
(2S,3S,4R,5R)-3,5-bis((tert-Butyldimethylsilyl)oxy)-2,4-
dimethylheptan-1-ol (25)
To a suspension of CuI (0.521 g, 2.73 mmol) in 20 mL of THF at
-20 °C was added methyl magnesium bromide in THF (18.24 mL,
27.37 mmol, 1.5 M solution in THF, 3.0 eq.). The resulting yellow-
lemon precipitate was cooled to -25 °C and stirring continued for
30 min. Then a solution of epoxide 15 (2.5 g, 9.12 mmol) in THF
(6 mL) was added drop wise. The mixture was stirred for 1 h at -
25 °C and then warmed to 0 °C and further stirred continuously
for 14 h. The reaction was quenched at 0 °C by the careful
addition of aqueous NH4Cl + NH4OH (1:1 mixture, 18 mL) until the
precipitate turned grey and gas evolution was no longer observed.
The solids were removed by filtration, rinsed with ethyl acetate,
and the combined filtrates were treated with additional saturated
aqueous solutions of NH4Cl + NH4OH (1:1 ratio, 8 mL) until the
aqueous washes were no longer blue in colour. The aqueous
phase was then separated, the organic phase was extracted with
EtOAc (4 x 8 mL), dried over anhydrous Na2SO4, filtered and the
solvents were evaporated. The crude was purified by silica gel
column chromatography using petroleum ether/EtOAc (7:3) to
give the diol 23 as a colorless viscous oil (2.11 g, 80%); Rf = 0.5
(SiO2, 40% EtOAc/hexane); [α]D20 = - 5.7 (c 2.46, CHCl3). Lit. for
A solution of HF/pyridine (1.2 mL) was added to a stirred solution
of tri TBS ether 24 (2.5 g, 4.82 mmol) in THF (50 mL) at 0 °C. The
reaction mixture was stirred at ambient temperature for 12 h and
then cooled to 0o C and to this was added powdered NaHCO3
portion wise until pH = 7 was attained. After 10 min, the reaction
mixture was filtered and concentrated. The crude was purified by
silica gel column chromatography using petroleum ether/EtOAc
(9:1) to afford 25 as a colorless oil (1.55 g, 80% yield). [α]D20 = –
2.0 (c 2.49, CHCl3); IR(neat): 3446, 2932, 2858, 1466, 1383,
1255, 1005, 938, 832, 755, 668 cm-1; 1H NMR (500 MHz, CDCl3):
δ 3.87 (dd, J = 6.1, 3.2 Hz, 1H), 3.81 (dt, J = 10.8, 3.2 Hz, 1H),
3.75-3.70 (m, 1H), 3.60-3.53 (m, 1H), 2.80 (bs, H), 1.99-1.93 (m,
1H), 1.93-1.87 (m, 1H), 1.50-1.42 (m, 2H), 1.07 (d, J = 7.1 Hz,
3H), 0.93-0.86 (m, 24H), 0.11 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H),
0.04 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 78.1, 73.6, 66.2, 43.4,
36.2, 26.0, 25.9, 25.1, 18.1, 18.1, 16.7, 8.2, -4.0, -4.1, -4.3, -4.6;
ESI-HRMS: Calcd m/z, For C21H48O3NaSi2 (M+Na)+: 427.3040,
found 427.3103.
(2R,3R,4R,5R)-3,5-bis((tert-Butyldimethylsilyl)oxy)-2,4-
dimethylheptanoic acid (13)
20
diastereomer of 23 [α]D = +10.2 (c 2.5, CHCl3)[6g]; IR (neat):
3354, 2958, 2931, 2851, 1462, 1381, 1255, 1052, 1007, 973, 861,
833, 791, 772, 663 cm-1; 1H NMR (500 MHz, CDCl3): δ 4.21 (bs,
1H), 3.91 (dd, J = 10.9, 2.7 Hz, 1H), 3.73 (q, J = 5.3 Hz, 1H), 3.57
(d, J = 10.5 Hz, 1H), 3.49 (dd, J = 7.9, 3.6 Hz, 1H), 3.34 (bs, 1H),
1.96-1.85 (m, 1H), 1.86-1.79 (m, 1H), 1.67-1.60 (m, 1H), 1.60-
1.53 (m, 1H) 1.11 (d, J = 7.0 Hz, 3H), 0.93-0.88 (m, 12H), 0.84 (d,
J = 7.0 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 81.1, 78.8, 65.4, 39.5, 36.0, 27.4, 25.8, 18.0, 15.3, 14.7,
8.9, -4.3, -4.7; ESI-HRMS: Calcd m/z, for C15H35O3Si (M+H)+:
291.2355, found 291.2361.
BAIB (2.87 g, 8.91 mmol), TEMPO (46.4 mg, 0.29 mmol) were
added sequentially to the stirred solution of compound 25 (1.20 g,
2.97 mmol) in acetonitrile buffer solution (PH = 7) (1:1, 30 mL) at
rt and stirred for 4 h. After completion of the reaction, saturated
Na2S2O3 solution (20 mL) and Et2O (50 mL) was added and the
organic layer was separated. The separated organic phase was
washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to yield
the acid 13 (0.968 g, 78% yield) as clear oil. [α]D20 = +1.1 (c 0.8,
CHCl3); IR(neat): 3405, 2929, 2857, 1706, 1462, 1382, 1252,
1052, 1004, 943, 832, 770, 672 cm-1; 1H NMR (400 MHz, CDCl3):
δ 4.20 (dd, J = 4.2, 1.3 Hz, 1H), 3.63 (dt, J = 8.6, 4.0 Hz, 1H), 2.62
(qd, J = 7.3, 1.3, 7.2 Hz, 1H), 2.00-1.89 (m, 1H), 1.55-1.50 (m,
2H), 1.32 (d, J = 7.3 Hz, 3H), 0.96 (s, 9H), 0.90 (s, 9H), 0.86-0.82
(m, 6H), 0.17 (s, 6H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 176.6, 75.8, 73.1, 42.5, 40.1, 25.8, 25.7, 25.6,
18.0, 17.9, 17.2, 9.1, 6.5, -4.0, -4.3, -4.8, -4.8; ESI-HRMS: Calcd
m/z, For C21H46O4NaSi2 (M+Na)+: 441.2832, found 441.2811.
(5R,6R,7S,8S)-7-((tert-Butyldimethylsilyl)oxy)-5-ethyl-
2,2,3,3,6,8,11,11,12,12-decamethyl-4,10-dioxa-3,11
disilatridecane (24)
To a cold stirred solution of diol 23 (1.7 g, 5.86 mmol), 2,6-lutidine
(4.07 mL, 35.17 mmol) in dry CH2Cl2 (20 mL) and TBSOTf (4.03
mL, 17.58 mmol) were added. After 1 h, the reaction was
quenched with sat. NH4Cl (20 x1 mL), and the mixture was
extracted with CH2Cl2 (5 x 3 mL), dried with (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified by column chromatography over silica gel using
petroleum ether/EtOAc (9.5:0.5) to afford tri TBS ether 24 as a
Ethyl (4R,5S,E)-5-hydroxy-4,6-dimethylhept-2-enoate(26)
To
a
stirred
solution
of
20
colourless oil (2.79 g, 92%); [α]D = +3.0 (c 1.86, CHCl3); IR
(ethoxycarbonylmethylene)triphenylphosphorane (8.03 g, 23.07
(neat): 2955, 2931, 2888, 2858, 1467, 1253, 1048, 1007, 832,
mmol) in toluene (40 mL) under reflux condition was added (2S,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701748
European Journal of Organic Chemistry
FULL PAPER
3S)-3-hydroxy-2,4-dimethylpentanal 20 in toluene (2.0 g, 15.38
mmol) and the resulting mixture was heated at reflux for 2 h. After
the reaction was complete, the solvent was removed under
reduced pressure to yield crude product, which was then purified
by silica gel column chromatography using petroleum
1183, 1052, 1005, 974, 834, 769, 671 cm-1 1H NMR (500 MHz,
;
CDCl3): δ 5.77-5.71 (m, 1H), 5.62-5.55 (m, 1H), 4.10 (t, J = 5.1
Hz, 2H), 3.28 (dd, J = 5.1, 4.1 Hz, 1H), 2.42-2.34 (m, 1H), 1.77-
1.69 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.87 (dd, J =
6.7, 5.7 Hz, 6H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 136.4, 128.1, 80.9, 64.0, 40.6, 32.1, 26.1, 20.0, 18.4,
ether/EtOAc (7:3) to give α,β-unsaturated ester 26[17] (2.95 g,
20
82%) as a colorless oil. [α]D20 = +23.5 (c 0.2, CHCl3), Lit. [α]D
=
18.3,
-3.7,
-3.7;
ESI-HRMS:
Calcd
m/z,
for
+19.1 (c 1.04, CHCl3)[17]; IR (Neat): 3503, 2970, 1711, 1650,
1460, 1373, 1241, 1181, 1100, 1041, 987, 862, 729 cm-1; 1H NMR
(400 MHz, CDCl3): δ 7.00 (dd, J = 15.8, 8.5 Hz, 1H), 5.88 (dd, J =
15.9, 0.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.20 (dd, J = 10.0, 5.1
Hz, 1H), 2.54 (tq, J = 13.9, 6.9 Hz, 1H), 1.73 (td, J = 13.2, 6.6 Hz,
1H), 1.29 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H), 0.94 (d, J =
6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 166.5, 150.4, 122.1,
79.8, 60.2, 39.8, 30.9, 19.5, 17.0, 16.8, 14.2; ESI-HRMS: Calcd
m/z for C11H21O3(M+H)+; 201.1493, found 201.1485.
C15H32O2NaSi:295.2069 (M+Na)+, found 295.2063.
((2R,3R)-3-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-4-
methylpentan-2-yl)oxiran-2-yl)methanol (18)
To a solution of Ti(OiPr)4 (0.43 mL, 1.47 mmol) and 4 Å molecular
sieves (0.8 g) in CH2Cl2 (25 mL), (+)-DIPT (0.30 mL, 1.47 mmol)
was added at -20 °C. After 30 min at this temperature, a solution
of allyl alcohol 27 (2.0 g, 7.35 mmol) in dry CH2Cl2 (4 mL) was
added drop wise. The stirring was continued for additional 30 min
and TBHP (16.17 mmol, 4.04 mL, 4M solution in toluene) was
added at -20 °C. The mixture was stirred for 10 h at this
temperature and filtered. The filtrate was diluted with water (8.6
mL), 20% aq NaOH Solution (1.5 mL) was added and stirring was
continued for 6 h. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 x 6 mL). The
combined organic layers were washed with water (2 x 5 mL), dried
over anhydrous Na2SO4, and evaporated. The crude was purified
by silica gel column chromatography using Hexanes/EtOAc (8:2)
to give epoxy alcohol 18, as a clear oil (1.8 g, 85%): Rf = 0.5 (SiO2,
(4R,5S,E)-Ethyl
5-((tert-butyldimethylsilyl)oxy)-4,6-
dimethylhept-2-enoate (19)
To a cold stirred solution of alcohol 26 (1.2 g, 6.0 mmol), 2,6-
lutidine (1.8 mL, 15.6 mmol) in anhydrous CH2Cl2 (20 mL) and
TBSOTf (1.79 mL, 7.8 mmol) were added. After 1 h, the reaction
was quenched with sat. NH4Cl (1 x 8 mL), and the mixture was
extracted with CH2Cl2 (4 x 3 mL), dried with (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified by column chromatography over silica gel using
petroleum ether/EtOAc (9.5:0.5) to afford TBS ether 19 as a
colourless oil (1.77 g, 94%); [α]D20 = + 13.3 (c 0.97, CHCl3), Lit. for
C4-epimer, [α]D25 = - 27.0 (c 1.5, CH2Cl2)[18] ; IR (Neat): 2960,
2933, 2858, 1718, 1652, 1467, 1370, 1253, 1153, 1040, 840, 758,
670 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.05 (dd, J = 15.7, 8.1 Hz,
1H), 5.77 (dd, J = 15.8, 1.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.36
(t, J = 4.7 Hz, 1H), 2.57-2.48 (m, 1H), 1.78-1.70 (m, 1H), 1.28 ( t,
J = 7.2 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 0.91(s, 9H), 0.87 (dd, J
= 6.7, 4.5 Hz, 6H), 0.04 (s, 3H), 0.04 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 166.7, 152.5, 120.4, 80.4, 60.0, 40.7, 32.2, 26.0, 19.7,
18.3, 18.0, 17.3, 14.2, -3.7, -3.8. ESI-HRMS: Calcd m/z, for
C17H34O3NaSi: 337.2175 (M+Na)+, found 337.2146.
20
30% EtOAc/hexane); [α]D = - 10.7 (c 0.58, CHCl3); IR (neat):
3419, 2957, 2932, 2858, 1466, 1384, 1253, 1105, 1050, 972, 835,
769, 672 cm-1; 1H NMR (500 MHz, CDCl3): δ 3.92 (ddd, J = 12.5,
8.0, 2.5 Hz, 1H), 3.62-3.56 (m, 1H), 3.41 (dd, J = 5.9, 3.2 Hz, 1H),
3.07 (dd, J = 7.1, 2.4 Hz, 1H), 2.92 (dq, J = 4.8, 2.5 Hz, 1H), 1.95-
1.85 ( m, 1H), 1.72-1.68 (m, 1H), 0.95 (d, J = 2.8 Hz, 3H), 0.94 (d,
J = 3.2 Hz, 3H), 0.93-0.91 (m, 12H), 0.07 (s, 3H), 0.05 (s, 3H);13
C
NMR (100 MHz, CDCl3): δ 80.0, 62.1, 56.9, 56.7, 38.9, 32.3, 26.1,
19.4, 19.0, 18.3, 14.4, -3.8, -3.9; ESI-HRMS: Calcd m/z, for
C15H32O3NaSi: 311.2022 (M+Na)+, found 311.2018.
(2S,3S,4S,5R)-5-((tert-butyldimethylsilyl)oxy)-2,4,6-
trimethylheptane-1,3-diol (28)
(4R,5S,E)-5-((tert-butyldimethylsilyl)oxy)-4,6-dimethylhept-2-
en-1-ol (27)
To a suspension of CuI (0.258 g, 1.35 mmol) in 10 mL of THF at
-20 °C was added methyl magnesium bromide in THF (13.54
mmol, 9.0 mL (1.5 M solution in THF)). The resulting yellow-lemon
precipitate was cooled to -25 °C and stirring continued for 30 min.
Then a solution of epoxide 18 (1.3 g, 4.51 mmol) in THF (4 mL)
was added dropwise. The mixture was stirred for 1 h at -25 °C and
then warmed to 0 °C and further stirred continuously for 14 h. The
reaction was quenched at 0 °C by the careful addition of aqueous
NH4CI + NH4OH (1:1 ratio, 8 mL) until the precipitate turned grey
and gas evolution was no longer in observed. The solids were
removed by filtration, rinsed with ethyl acetate, and the combined
filtrates were treated with additional aqueous NH4Cl + NH4OH (1:1
ratio, 6 mL) until the aqueous washes were no longer blue in color.
The aqueous phase was then separated, the organic phase was
extracted with EtOAc (4 x 4 mL), dried over anhydrous Na2SO4
and the solvents were evaporated, The crude was purified by
silica gel column chromatography using petroleum ether/EtOAc
(7:3) to give the diol 28 as a colorless viscous oil (1.12 g, 82%);
A solution of 19 (2.3 g, 7.32 mmol) in CH2Cl2 (25 mL) was cooled
to 0 °C, and treated with DIBAL-H (18.31 mmol, 10.77 mL, 1.7 M
solution in toluene). After 20 min, the reaction was diluted with
CH2Cl2 (18 mL) at 0 °C, and the mixture was allowed to warm to
room temperature and then quenched with saturated aqueous
Na+/K+-tartrate solution (18 mL). The resulting mixture was
vigorously stirred until a clear separation of both organic and
aqueous phase was observed. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (8 x 3 mL); The
combined organic extracts were washed with saturated aqueous
NaCl solution (8 mL), dried over anhydrous Na2SO4, and the
solvents were evaporated. The crude was purified by silica gel
column chromatography using petroleum ether/EtOAc (8:2) to
give allyl alcohol 27 (1.79 g, 90%) as a clear oil. [α]D20 = +1.6 (c
25
1.7, CHCl3). Literature for C4-epimer [α]D = +10.6 (c 0.5,
CHCl3)[19]; IR (neat): 3341, 2957, 2929, 2857, 1462, 1362, 1253,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701748
European Journal of Organic Chemistry
FULL PAPER
Rf = 0.5 (SiO2, 30% EtOAc/hexane); [α]D20 =+ 5.4 (c 0.69, CHCl3);
IR (neat): 3392, 2957, 2882, 1741, 1684, 1581, 1462, 1373, 1250,
1106, 1044, 975, 834, 771, 675, 607 cm-1; 1H NMR (500 MHz,
CDCl3): δ 3.68-3.63 (m, 3H), 3.55 (dd, J = 9.1, 1.8 Hz, 1H), 1.93-
1.88 (m, 1H), 1.86-1.80 (m, 2H), 0.94 (d, J = 4.5 Hz, 3H), 0.93 (d,
J = 4.7 Hz, 3H), 0.92 (s, 9H), 0.89 (d, J = 6.8 Hz, 3H), 0.79 (d, J
= 6.8 Hz, 3H), 0.12 (s, 3H), 0.11 (s. 3H). 13C NMR (100 MHz,
CDCl3): δ 82.0, 81.3, 68.7, 37.4, 36.4, 32.8, 29.6, 26.0, 18.6, 18.4,
13.6, 7.7, -3.2, -4.2. ESI-HRMS: Calcd m/z, for C16H36O3NaSi
(M+Na)+: 327.2333, found 327.2331.
To a stirred solution of alcohol 26 (2.0 g, 10.0 mmol), freshly
prepared 4-methoxybenzyl trichloroacetimidate (4.23 g, 15.0
mmol), and CH2Cl2 (30 mL) in a 100-mL round bottom flask, under
an atmosphere of N2, was added (±)-camphor-10-sulfonic acid
(0.464 g, 2.0 mmol) in one portion at 0 °C. The reaction was
allowed to stirr for 6 h at rt. After complete consumption of starting
material, the reaction mixture was quenched with aq NaHCO3 (15
mL) and diluted with water (10 mL). The aqueous phase was then
separated, the organic phase was extracted with CH2Cl2 (2 x 10
mL) and dried over anhydrous Na2SO4), and the organic layers
were evaporated. The crude was purified by silica gel column
chromatography using petroleum ether/EtOAc (9.5:0.5) to give
PMB ether 19a (2.72 g, 85% yield) as a colorless oil. [α]D20 = +2.1
(c 1.03, CHCl3); IR (neat): 2962, 1715, 1513, 1462, 1299, 1245,
1175, 1155, 1082, 1032, 993, 801 cm-1; 1H NMR (500 MHz,
CDCl3): δ 7.30-7.24 (m, 2H), 7.08 (dd, J = 15.8, 8.4 Hz, 1H), 6.89-
6.85 (m, 2H), 5.82 (dd, J = 15.7, 0.9 Hz, 1H), 4.48 (s, 2H), 4.18
(q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.01 (dd, J = 5.9, 5.3 Hz, 1H),
2.67-2.59 (m, 1H), 1.82 (dq, J = 13.4, 6.7 Hz, 1H), 1.29 (t, J = 7.1
Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.93
(d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 166.7, 159.1,
151.6, 130.8, 129.3, 121.0, 113.7, 88.1, 74.7, 60.1, 55.2, 39.7,
31.2, 19.8, 18.0, 17.0, 14.3; ESI-HRMS: Calcd m/z for
C19H28O4Na (M+Na)+; 343.1885, found 343.1886.
(5R,6S,7S,8S)-5-isopropyl-2,2,3,3,6,8,11,11,12,12-
decamethyl-4,10-dioxa-3,11-disilatridecan-7-ol (14)
To a cold stirred solution of alcohol 28 (1.0 g, 3.28 mmol),
imidazole (0.671 g, 9.86 mmol) and TBSCl (0.743 g, 4.93 mmol)
in dry CH2Cl2 (20 mL) were added. After 4 h, the reaction was
quenched with sat. NH4Cl (10 x 1 mL), and the mixture was
extracted with CH2Cl2 (2 x 3 mL), dried with (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified by column chromatography over silica gel using
petroleum ether/EtOAc (9.5:0.5) to afford TBS ether 14 as a
colourless oil (1.23 g, 90%); [α]D20 = - 12.2 (c 2.27, CHCl3); IR
(Neat): 3504, 2956, 2885, 1470, 1362, 1256, 1042, 988, 833, 771,
669 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.75 (dd, J = 9.9, 4.2 Hz,
1H), 3.67-3.60 (m, 1H), 3.57 (dd, J = 7.7, 4.5 Hz, 1H), 3.55-3.51
(m, 2H), 1.99-1.91 (m, 1H), 1.85-1.75 (m, 1H), 1.73-1.64 (m, 1H),
0.94 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.8 Hz,, 3H), 0.91 (s, 9H),
0.90 (s, 9H), 0.85 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H),
0.08 (s, 6H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 78.9, 77.4, 68.8, 38.6, 37.6, 31.1, 26.2, 25.8, 20.4, 18.5,
18.2, 16.5, 13.3, 9.6, -3.3, -3.5, -5.5, -5.6; ESI-HRMS: Calcd m/z,
for C22H51O3Si2: 419.3377 (M+H)+, found 419.3374.
(4R,5S,E)-5-((4-Methoxybenzyl)oxy)-4,6-dimethylhept-2-en-1-
ol (27a)
A solution of 19a (2.0 g, 6.25 mmol, 1.0 eq.) in CH2Cl2 (30 mL)
was cooled to 0 °C, and treated with DIBAL-H (9.19 mL, 15.62
mmol (1.7 M solution in toluene)). After 20 min. the reaction was
diluted with CH2Cl2 (15 mL) at 0 °C, and the mixture was allowed
to warm to room temperature and then quenched with saturated
aqueous sodium potassium tartrate solution (20 mL). The
resulting mixture was vigorously stirred until a clear separation of
both organic and aqueous phase occurred. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (10 x
3 mL); The combined organic extracts were washed with
saturated aqueous NaCl solution (5 mL), dried over anhydrous
Na2SO4, and the solvents were evaporated. The crude was
purified by silica gel column chromatography using petroleum
ether/EtOAc (7.5:2.5) to give allyl alcohol 27a (1.56 g, 90%) as a
(2R,3R,4R,5S)-5-((tert-Butyldimethylsilyl)oxy)-3-hydroxy-
2,4,6-trimethylheptyl pivalate (29)
To a cooled solution of diol 28 (500 mg, 1.64 mmol) in CH2Cl2 (20
mL) were added successively pivaloyl chloride (0.26 mL, 2.13
mmol) and Et3N (0.45 mL, 3.28 mmol) at 0o C and the mixture was
stirred at 0o C for 4 h. The resulting reaction mixture was then
poured into ice-water (5 mL), warmed to rt and extracted with
CH2Cl2 (2 x 5 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude was purified by silica gel column
chromatography using Hexanes/EtOAc (9:1) to afford alcohol 29
20
clear oil. [α]D = - 12.4 (c 1.36, CHCl3); IR(Neat): 3405, 2961,
2869, 1612, 1513, 1461, 1354, 1300, 1245, 1174, 1067, 1034,
974, 819, 753 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.30-7.26 (m,
2H), 6.89-6.84 (m, 2H), 5.75 (dd, J = 15.5, 8.1 Hz, 1H), 5.64 (dd,
J = 15.5, 9.8 Hz, 1H), 4.50 (s, 2H), 4.06 (d, J = 5.7 Hz, 2H), 3.79
(s, 3H), 2.93 (dd, J = 6.7, 4.6 Hz, 1H), 2.53-2.43 (m, 1H), 1.81 (dq,
J = 13.4, 6.7 Hz,1H), 1.07 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.7 Hz,
3H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 158.9,
135.2, 131.0, 129.1, 128.7, 113.5, 88.7, 74.7, 63.7, 55.1, 39.5,
31.1, 19.8, 18.2, 18.1; ESI-HRMS: Calcd m/z for C17H26O3Na
(M+Na)+: 301.1780, found 301.1769.
20
as a colorless oil (0.606 g, 95%); [α]D = + 8.1 (c 1.71, CHCl3);
IR (neat): 3153, 2961, 1708, 1467, 1390, 1289, 1162, 1042, 973,
1
834, 772, 676 cm-1; H NMR (400 MHz, CDCl3): δ 4.29 (dd, J =
10.8, 5.2 Hz, 1H), 4.10 (dd, J = 10.8, 3.5 Hz, 1H), 3.60 (t, J = 4.1
Hz, 1H), 3.30 (d, J = 9.2 Hz, 1H), 1.94-1.83 (m, 2H), 1.82-1.71 (m,
1H), 1.21 (s, 9H), 0.94 (d, J = 6.9 Hz, 3H), 0.92-0.88 (m, 15H),
0.86 (d, J = 6.8 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H);13C NMR (100
MHz, CDCl3): δ 179.0, 80.2, 74.9, 66.8, 38.9, 36.7, 32.1, 27.2,
26.1, 19.3, 18.3, 17.5, 13.9, 8.3, -3.3, -4.0; ESI-HRMS: Calcd m/z.
for C21H44O4NaSi: 411.2907 (M+Na)+, found 411.2912.
((2S,3S)-3-((2S,3S)-3-((4-Methoxybenzyl)oxy)-4-
methylpentan-2-yl)oxiran-2-yl)methanol (18a)
Ethyl (4R,5S,E)-5-((4-methoxybenzyl)oxy)-4,6-dimethylhept-
2-enoate (19a)
To a solution of Ti(OiPr)4 (0.42 mL, 1.43 mmol) and 4Å molecular
sieves (0.79 g) in CH2Cl2 (30 mL), (+)-DIPT (0.30 mL, 1.43 mmol)
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10.1002/ejoc.201701748
European Journal of Organic Chemistry
FULL PAPER
was added at -20 °C. After 30 min at this temperature, a solution
of allyl alcohol 27a (2.0 g, 7.19 mmol) in dry CH2Cl2 (4 mL) was
added drop wise. The stirring was continued for additional 30 min
and TBHP (3.9 mL, 4M solution in toluene) was added at -20 °C.
The mixture was stirred for 10 h at this temperature and filtered.
The filtrate was diluted with water (8.6 mL), 20% aq NaOH
Solution (1.5 mL) was added and stirring was continued for 6 h.
The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 x 10 mL). The combined organic layers
were washed with water (2 x 10 mL), dried over anhydrous
Na2SO4, and evaporated. The crude was purified by silica gel
column chromatography using Hexanes/EtOAc (8:2) to give
epoxy alcohol 18a as a clear oil (1.79 g, 85%, diastereoselectivity
97:3): [α]D20 = - 15.2 (c 1.37, CHCl3); IR(neat): 3422, 2927, 1612,
1513, 1461, 1383, 1300, 1245, 1175, 1062, 1034, 967, 922, 890,
818, 755 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.32-7.27 (m, 2H),
6.90-6.86 (m, 2H), 4.53 (q, J = 10.6 Hz, 2H), 3.88 (dd, J = 12.3,
2.7 Hz, 1H), 3.80 (s, 3H), 3.59 (dd, J = 12.3, 4.4 Hz, 1H), 3.10 (dd,
J = 7.2, 2.3 Hz, 1H), 3.05 (dd, J = 7.1, 4.1 Hz, 1H), 2.91 (dt, J =
2.5, 4.7 Hz, 1H), 2.03 (dq, J = 13.7, 6.8 Hz, 1H), 1.84-1.76 (m,
1H), 1.01 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 3.9 Hz, 3H), 0.97 (d, J
= 3.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 159.1, 131.0, 129.2,
113.7, 88.1, 74.8, 62.1, 57.1, 56.2, 55.2, 37.8, 31.4, 19.9, 18.7,
14.1; ESI-HRMS: Calcd for C17H26O4Na (M+Na)+: 317.1729,
found 317.1712.
1.6 Hz, 1H), 3.55-3.50 (m, 1H), 3.43 (bs, 1H), 3.22 (dd, J = 7.0,
3.9 Hz, 1H), 2.03-1.94 (m, 2H), 1.85-1.80 (m, 1H), 1.13 (d, J = 7.0
Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.87
(d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 159.3, 129.8,
129.4, 113.8, 90.9, 80.5, 75.2, 64.9, 55.2, 38.9, 35.6, 31.7, 20.6,
16.9, 16.3, 15.5; ESI-HRMS: Calcd m/z, for C18H30O4Na:
333.2042 (M+Na)+, found 333.2045.
(2R,3R,4R,5S)-1-((tert-butyldimethylsilyl)oxy)-5-((4-
methoxybenzyl)oxy)-2,4,6-trimethylheptan ol (31)
To a cold stirred solution of alcohol 28a (1.0 g, 3.22 mmol),
imidazole (0.658 g, 9.67 mmol) and TBSCl (0.729 g, 4.83 mmol)
in dry CH2Cl2 (25 mL) were added. After 2 h, the reaction was
quenched with sat. NH4Cl (8 x 1 mL), and the mixture was
extracted with CH2Cl2 (2 x 4 mL), dried with (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified by column chromatography over silica gel using
petroleum ether/EtOAc (9.5:0.5) to afford TBS ether 31 as a
colourless oil (1.23 g, 90%); Rf = 0.5 (SiO2, 10% EtOAc/hexane);
[α]D20 = + 14.3 (c 0.30, CHCl3); IR (neat): 3498, 2930, 2857, 1613,
1513, 1463, 1362, 1247, 1072, 1036, 988, 833, 774, 754, 667 cm-
. 1H NMR (500 MHz, CDCl3): δ 7.29-7.25 (m, 2H), 6.88-6.84 (m,
2H), 4.61 (d, J = 10.8 Hz, 1H), 4.51 (d, J = 10.9 Hz, 1H), 4.05 (d,
J = 3.9 Hz, 1H), 3.80 (s, 3H), 3.71-3.63 (m, 2H), 3.50-3.46 (m,
1H), 3.38 (dd, J = 6.4, 3.9 Hz, 1H), 2.08-2.00 (m, 1H), 1.99-1.90
(m, 1H), 1.01 (t, J = 6.5 Hz, 6H), 0.95 (d, J = 6.7 Hz, 3H), 0.93 (d,
J = 7.0 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 6H).13C NMR (125 MHz,
CDCl3): δ 158.9, 131.0, 129.0, 113.6, 87.3, 79.4, 73.7, 66.0, 55.2,
39.1, 36.7, 30.8, 25.8, 21.1, 18.1, 17.2, 15.3, 15.0, -5.5; ESI-
HRMS: Calcd m/z, for C24H44O4SiNa: 447.2907 (M+Na)+, found
447.2895.
(2R,3R,4R,5S)-5-((4-Methoxybenzyl)oxy)-2,4,6-
trimethylheptane-1,3-diol (28a)
To a suspension of CuI (0.641 g, 3.36 mmol) in 30 mL of THF at
-20 °C was added methyl magnesium bromide in THF (22.44 mL,
33.67 mmol, 1.5 M solution in THF, 3.0 eq.). The resulting yellow-
lemon precipitate was cooled to -25 °C and stirring continued for
30 min. Then a solution of epoxide 18a (3.3 g, 11.22 mmol) in
THF (14 mL) was added dropwise. The mixture was stirred for 1
h at -25 °C and then warmed to 0 °C and further stirred
continuously for 14 h. The reaction was quenched at 0 °C by the
careful addition of saturated aqueous NH4Cl + NH4OH (1:1 ratio,
30 mL) until the precipitate turned grey and gas evolution was no
longer in observed. The solids were removed by filtration, rinsed
with ethyl acetate, and the combined filtrates were treated with
additional aqueous NH4Cl + NH4OH (1:1 ratio, 12 mL) until the
aqueous washes were no longer blue in color. The aqueous
phase was then separated, the organic phase was extracted with
EtOAc(4 x 10 mL), dried over anhydrous Na2SO4 and the solvents
were evaporated. The crude mixture (1,2 and 1,3-diol) was
analysed with LCMS to show the presence of 1,3 and 1,2-diols in
91.5:8.5 ratio. The crude mixture (dissolved in THF:H2O (3:1
ratio, 40 mL) was treated with NaIO4 to oxidatively cleave the 1,2-
diol product leaving the 1,3-diol intact. After the filtration, the
reaction mixture was quenched with aqueous solution of NaHCO3
and extracted with ethyl acetate. Evaporation of the solvent
followed by silica gel column chromatography using petroleum
ether/EtOAc (7:3) afforded diol 28a as a colorless viscous oil (3.02
g, 87%); [α]D20 = + 29.89 (c 0.91, CHCl3); IR (neat): 3386, 2961,
2931, 2874, 1612, 1513, 1462, 1382, 1300, 1246, 1175, 1029,
971, 817, 754 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.30-7.23 (m,
2H), 6.91-6.86 (m, 2H), 4.64 (bs, 1H), 4.58 (q, J = 10.5 Hz, 2H),
3.91 (dd, J = 10.8, 1.6 Hz, 1H), 3.80 (s, 3H), 3.57 (dd, J = 10.8,
(2R,3R,4R,5S)-3-Hydroxy-5-((4-methoxybenzyl)oxy)-2,4,6-
trimethylheptyl pivalate (32)
To a cooled solution of diol 28a (1.0 g, 3.22 mmol) in CH2Cl2 (25
mL) were added successively pivaloyl chloride (0.47 mL, 3.87
mmol) and Et3N (0.67 mL, 4.83 mmol) at 0 oC and the mixture was
o
stirred at 0 C for 4 h. The resulting reaction mixture was then
poured into ice-water (5 mL), warmed to rt and extracted with
CH2Cl2 (2 x 5 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude was purified by silica gel column
chromatography using Hexanes/EtOAc (9:1) to afford alcohol 32
as a colorless oil (1.2 g, 95%); [α]D20 = +38.54 (c 1.30, CHCl3); IR
(neat): 3480, 2965, 1721, 1621, 1514, 1465, 1368, 1289, 1246,
1
1161, 1034, 982, 820, 754 cm-1; H NMR (400 MHz, CDCl3): δ
7.29-7.24 (m, 2H), 6.90-6.84 (m, 2H), 4.58 (s, 2H), 4.30 (dd, J =
11.0, 5.1 Hz, 1H), 4.04 (bs, 1H), 3.91 (dd, J = 10.9, 7.9 Hz, 1H),
3.80 (s, 3H), 3.47 (dt, J = 8.5, 1.7 Hz, 1H), 3.20 (dd, J = 7.3, 3.5
Hz, 1H), 2.14-2.04 (m, 1H), 2.00-1.93 (m, 1H), 1.93-1.86 (m, 1H),
1.19 (s, 9H), 1.05 (dd, J = 8.8, 6.9 Hz, 6H), 0.94 (d, J = 6.8 Hz,
3H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 178.7,
159.3, 130.1, 129.4, 113.8, 90.6, 77.9, 74.9, 65.5, 55.2, 38.8,
38.7, 34.6, 31.6, 27.2, 20.7, 16.7, 16.0, 15.9; ESI-HRMS: Calcd
m/z. for C23H38O5Na: 417.2617 (M+Na)+, found 417.2615.
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10.1002/ejoc.201701748
European Journal of Organic Chemistry
FULL PAPER
(2R,3R,4S,5S)-5-((4-Methoxybenzyl)oxy)-2,4,6-trimethyl-1-
(0.494 g, 85% yield) as a clear oil and the other minor epimer
which was not separated earlier was separable at this stage.
(pivaloyloxy)heptan-3-yl
(2R,3R,4R,5R)-3,5-bis((tert-
butyldimethylsilyl)oxy)-2,4-dimethylheptanoate (33)
Major isomer was utilized further. Rf = 0.5 (SiO2, 20%
A stirred solution of alcohol 32 (500 mg, 1.26 mmol) and acid 13
(583 mg, 1.39 mmol) in anhydrous toluene (15 mL) was treated
with Et3N (0.53 mL, 3.80 mmol), DMAP (0.775 g, 6.34 mmol) and
2,4,6-trichlorobenzoyl chloride (0.39 mL, 2.53 mmol) at 0 oC. The
resulting white suspension was stirred at rt for 6 h. The reaction
was quenched with saturated aqueous NaHCO3 (7.5 mL) at 0 oC
and diluted with water (5 mL). The reaction mixture was extracted
with ethyl acetate (3 x 6 mL) and the combined organic extracts
were washed with water (5 mL) and brine (5 mL). The organic
layer was dried over anhydrous sodium sulphate and filtered. The
filtrate was concentrated under reduced pressure to give the
crude product which was purified by silica gel column
chromatography (hexanes/EtOAc) to afford inseparable
diastereomeric mixture of ester 33 (0.715 g, 71%) as a colorless
oil. (The diastereomer was observed due to epimerization at C7
in 33 under basic conditions (TEA, DMAP) which was confirmed
by the 1H NMR of the crude product. The diastereomeric ratio was
EtOAc/hexane); [α]D20 = +20.1 (c 1.12, CHCl3); IR (neat) 3503,
2945, 1721, 1515, 1463, 1377, 1248, 1047, 946, 831, 757, 670
cm-1; 1H NMR (500 MHz, CDCl3): δ 7.27-7.23 (m, 2H), 6.89-6.85
(m, 2H), 5.02 (dd, J = 7.8, 3.3 Hz, 1H), 4.55 (q, J = 10.8 Hz, 2H),
4.12 (dd, J = 9.3, 3.0 Hz, 1H), 3.88 (m, 1H), 3.80 (s, 3H), 3.54-
3.43 (m, 2H), 3.28 (dd, J = 7.3, 3.5 Hz, 1H), 2.73 (qd, J = 7.2, 3.0,
7.0 Hz, 1H), 2.23-2.16 (m, 1H), 2.11-2.05 (m, 1H), 1.94-1.85 (m,
2H), 1.37-1.30 (m, 2H), 1.21 (d, J = 7.1 Hz, 3H), 1.03 (dd, J = 6.7,
4.5 Hz, 6H), 0.99 (d, J = 7.1 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H),
0.92-0.88 (m, 21H), 0.73 (d, J = 7.1 Hz, 3H), 0.08 (d, J = 4.4 Hz,
6H), 0.05 (d, J = 2.9 Hz, 6H); 13C NMR (125 MHz, CDCl3): δ 174.6,
159.0, 131.0, 128.6, 113.6, 84.8, 78.6, 74.0, 73.7, 73.2, 64.4,
55.2, 45.7, 42.7, 37.7, 37.5, 30.6, 25.9, 25.8, 23.3, 21.6, 18.1,
18.0, 16.5, 15.3, 14.7, 10.6, 9.4, 9.1, -4.3, -4.5, -4.6; ESI-HRMS:
Calcd m/z, For C39H74O7NaSi2 (M+Na)+: 733.4871, found
733.4869.
found to be 9:1 by LCMS analysis (this was also in consistence
(2R,3R,4R,5R)-(3S,4S,5S,6S)-3-((4-Methoxybenzyl)oxy)-2,4,6-
20
with 1H NMR data). Rf = 0.5 (SiO2, 10% EtOAc/hexane); [α]D
=
trimethyl-7-oxononan-5-yl
3,5-bis((tert-
+32.0, (c 1.05, CHCl3); IR (Neat): 2958, 2930, 2857, 1729, 1613,
1514, 1362, 1250, 1156, 1066, 1005, 938, 833, 754, 666 cm-1; 1H
NMR (400 MHz, CDCl3): δ 7.29-7.23 (m, 2H), 6.87-6.84 (m, 2H),
5.10 (t, J = 5.2 Hz, 1H), 4.58 (d, J = 10.7, Hz, 1H), 4.48 (d, J =
10.7, Hz, 1H), 4.19 (dd, J = 10.9, 3.9, Hz, 1H), 4.14 (dd, J = 9.7,
2.9 Hz, 1H), 3.88-3.85 (m, 1H), 3.85-3.81 (m, 1H), 3.80 (s, 3H),
3.17 (dd, J = 6.5, 4.4, Hz, 1H), 2.68 (qd, J = 7.1, 2.8,7.2 Hz, 1H),
2.43-2.33 (m, 1H), 2.27-2.17 (m, 1H), 1.93-1.83 (m, 2H), 1.41-
1.28 (m, 2H), 1.26-1.19 (m, 12H), 1.01 (dd, J = 7.2, 4.7 Hz, 6H),
0.97 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.91-0.88 (m,
21H), 0.71 (d, J = 7.2 Hz, 3H), 0.10 (s, 3H), 0.07 (s, 3H), 0.06-
0.03, (m, 6H); 13C NMR (100 MHz, CDCl3): δ 178.3, 175.2, 158.9,
131.1, 128.8, 113.6, 84.8, 77.3, 73.7, 73.2, 72.8, 65.7, 55.2, 43.2,
42.7, 38.7, 37.6, 34.7, 30.3, 27.1, 26.1, 25.9, 25.1, 21.1, 18.4,
18.1, 17.5, 15.6, 13.7, 12.0, 11.7, 9.6, -3.7, -4.3, -4.4, -4.5; ESI-
HRMS: Calcd m/z, For C44H83O8Si2 (M+H)+: 795.5626, found
795.5624.
butyldimethylsilyl)oxy)-2,4-dimethylheptanoate (35)
To a solution of IBX (0.315 g, 1.12 mmol) in DMSO (1.0 mL) was
added compound 34 (400 mg, 0.56 mmol) dissolved in CH2Cl2 (2
mL). The reaction mixture was stirred at rt. for 2 h and quenched
by the addition of aqueous saturated Na2S2O3 solution. The
aqueous layer was extracted with CH2Cl2 and the organic layer
washed with aqueous saturated NaHCO3 (9 x 1 mL) solution,
water (4 x 1 mL), brine (8 x 1 mL) and dried over Na2SO4. The
solvent was evaporated under reduced pressure to afford the
crude product which was used directly for further step.
To the solution of above crude aldehyde in THF (10 mL)
at 0 oC was added EtMgBr (1.68 mL, 1.68 mmol, 1 M in THF) drop
wise. The solution was then allowed to warm up to rt over 1 h. The
reaction was quenched with saturated aq NH4Cl (10 x 1mL) and
extracted with EtOAc (6 x 3 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure to
give a crude material which was passed through a small pad of
silica gel to afford the mixture of secondary alcohols as a colorless
oil. The mixture was directly utilized for oxidation reaction with
IBX.
(2R,3R,4R,5R)-(2R,3R,4S,5S)-1-Hydroxy-5-((4-
methoxybenzyl)oxy)-2,4,6-trimethylheptan-3-yl 3,5-bis((tert-
butyldimethylsilyl)oxy)-2,4-dimethylheptanoate (34)
A solution of pivolate 33 (0.65 g, 0.818 mmol) (diastereomeric
To the solution of IBX (0.398 g, 1.42 mmol) in DMSO
(1.0 mL) was added above crude mixture of alcohols in CH2Cl2 (2
mL). The reaction mixture was stirred at rt. for 2 h and quenched
by the addition of aq saturated Na2S2O3 solution. The aq layer
was extracted with CH2Cl2 and the organic layer washed with
saturated NaHCO3 solution (10 x 1mL), water (5 x 1 mL), brine (9
x 1 mL) and dried over Na2SO4. The solvent was evaporated
under reduced pressure to afford the crude product which was
purified by silica gel column chromatography (hexane/EtOAc) to
yield ketone 35 (0.251 g, 77% yield) as a clear oil. Rf = 0.5 (SiO2,
20% EtOAc/hexane); [α]D20 = +44.3 (c 1.45, CHCl3); IR(neat):
2952, 2932, 2857, 1732, 1613, 1514, 1464, 1382, 1301, 1251,
1186, 1065, 1032, 941, 833, 755, 665 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.32-7.27 (m, 2H), 6.91-6.86 (m, 2H), 5.35 (dd, J = 7.4,
4.1 Hz, 1H), 4.58 (q, J = 10.9 Hz, 2H), 4.12 (dd, J = 9.8, 2.9, Hz,
o
mixture) in CH2Cl2 (25 mL) was cooled to -78 C and DIBAL-H
(1.0 mL, 1.80 mmol 1.7 M in toluene, 2.2 equiv) was added drop
wise. After 5 min, the reaction was diluted with CH2Cl2 (5 mL) at
0 °C, and the mixture was allowed to warm to room temperature
and then quenched with saturated aqueous Na+/K+-tartrate
solution (10 mL). The resulting mixture was vigorously stirred until
formation of clear separation of both organic and aqueous phase
was observed. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (6 x 3 mL); The combined organic
extracts were washed with saturated aqueous NaCl solution (5
mL), dried over anhydrous Na2SO4, and the solvents were
evaporated. The crude was purified by silica gel column
chromatography using (hexanes/EtOAc) to yield alcohol 34
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10.1002/ejoc.201701748
European Journal of Organic Chemistry
FULL PAPER
1H), 3.90-3.84 (m, 1H), 3.81 (s, 3H), 3.22 (dd, J = 7.2, 4.0 Hz,
1H), 3.11-3.02 (m, 1H), 2.59 (qd, J = 7.1, 3.0, 7.0 Hz, 1H), 2.50-
2.39 (m, 1H), 2.36-2.34 (m, 1H), 2.20-2.11 (m, 1H), 1.93-1.81 (m,
2H), 1.40-1.29 (m, 2H), 1.16 (d, J = 7.1 Hz, 3H), 1.04 (dd, J =
10.2, 7.2 Hz, 6H), 0.98-0.93 (m, 6H), 0.91 (d, J = 3.7 Hz, 3H), 0.91
(s, 9H), 0.89 (s, 9H), 0.69 (d, J = 7.1 Hz, 3H), 0.08 (s, 3H), 0.07
(s, 3H), 0.04 (d, J = 1.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
212.4, 173.0, 158.9, 131.0, 128.6, 113.7, 85.2, 77.6, 77.2, 73.7,
73.1, 55.2, 48.7, 45.8, 42.7, 37.0, 34.3, 30.7, 25.9, 25.7, 23.2,
20.9, 18.0, 17.9, 16.8, 14.7, 13.7, 10.8, 8.8, 8.7, 7.5, -4.3, -4.4, -
4.5, -4.6; ESI-HRMS: Calcd m/z, For C41H76O7NaSi2 (M+Na)+:
759.5027, found 759.5023.
3.69 (d, J = 8.5 Hz, 1H), 3.31 (s, 3H), 3.18 (dd, J = 6.8, 4.1 Hz,
1H), 3.10 (m, 1H), 2.70-2.62 (m, 2H), 2.25-2.11 (m, 4H), 1.87-1.79
(m, 1H), 1.17 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 1.01-
0.98 (m, 6H), 0.98-0.93 (m, 9H), 0.91 (d, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, C6D6): δ 214.2, 212.0, 174.1, 159.7, 131.4, 129.4,
114.1, 85.9, 77.9, 76.6, 74.4, 54.7, 48.8, 48.7, 43.9, 37.1, 36.0,
34.6, 31.2, 21.3, 17.2, 15.8, 15.0, 14.5, 14.0, 7.7, 7.6; ESI-HRMS:
Calcd m/z, For C29H46O7 Na (M+Na)+: 529.3141, found 529.3131.
(2R,3R,4S)-(2R,3S,4S,5S,6S)-2-Ethyl-2-hydroxy-6-isopropyl-
3,5-dimethyltetrahydro-2H-pyran-4-yl
3-hydroxy-2,4-
dimethyl-5-oxoheptanoate (1) (Dolabriferol)
DDQ (9.69 mg, 0.042 mmol) was added to the PMB ether 37 (12
mg, 0.023 mmol), in CH2Cl2 (2 mL) and PH =7 buffer (0.2 mL) at 0
oC. The mixture was stirred for 1 h, then diluted with PH =7 buffer
solution (2 mL) and CH2Cl2 (2 mL). The organic phase was
separated, the aqueous phase was extracted with CH2Cl2 (2 × 2
mL) and the combined organic extracts was dried over Na2SO4,
then concentrated under reduced pressure to give the crude
material which was further purified by column chromatography
over silica gel (hexanes/EtOAc) (8:2) to afford the (-)-dolabriferol
1 as a white solid (4.5 mg, 50 %). Rf = 0.4 (SiO2, 20%
EtOAc/hexanes); m.p 115-118, [α]D25 = −28.3 (c 0.3, CHCl3) (Lit.2
[α]D25 = −29.4 (c 0.7, CHCl3); IR (neat): 3433, 2962, 2923, 2854,
1718, 1460, 1378, 1275, 1240, 1165, 1127, 1090, 978, 912, 840,
756 cm-1; 1H NMR (500 MHz, CDCl3): δ 5.25 (t, J = 2.6 Hz, 1H),
3.79-3.73 (m, 1H), 3.65 (bs, 1H), 3.61 (dd, J = 10.6, 2.1 Hz, 1H),
3.46 (bs, 1H), 2.79 (dq, 7.1, 7.1 Hz, 1H), 2.74 (dq, 7.1, 4.8 Hz,
1H), 2.57 (dq, J = 14.4, 7.3 Hz, 1H), 2.46 (dq, J = 14.4, 7.3 Hz,
1H), 1.91 (dq, J = 7.2, 2.8 Hz, 1H), 1.81 (dqq, J = 2.0, 6.8, 6.8 Hz,
1H), 1.79-1.73 (m, 1H), 1.68-1.59 (m, 2H), 1.33 (d, J = 7.1 Hz,
3H), 1.15 (d, J = 7.0 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H), 1.01 (d, J =
6.8, Hz, 3H), 1.00 (d, J = 7.2, Hz, 3H) 0.91 (t, J = 7.4 Hz, 3H), 0.83
(d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 215.1, 173.7, 98.5, 76.8, 75.6, 72.5, 49.4, 43.6, 39.4,
36.4, 35.9, 32.4, 27.9, 20.2, 15.5, 14.3, 13.9, 12.9, 12.7, 7.4, 7.2;
ESI-HRMS Calcd m/z, for C21H38O6Na (M+Na)+: 409.2566,
Found: 409.2564.
(2R,3R,4R,5R)-(3S,4S,5S,6S)-3-((4-Methoxybenzyl)oxy)-2,4,6-
trimethyl-7-oxononan-5-yl
dimethylheptanoate (36)
3,5-dihydroxy-2,4-
To a cooled (0 oC) solution of compound 35 (200 mg, 0.27 mmol)
in THF (9 mL) in a Teflon tube was added HF-Pyridine (0.2 mL).
The reaction mixture was stirred 1 h at 0 oC and 6 h at rt. Reaction
mixture was quenched with saturated NaHCO3 solution (6 mL)
and the aqueous layer was extracted with EtOAc (5 x 3 mL) and
washed with brine (1 x 5 mL) and dried over Na2SO4. The solvent
was evaporated under reduced pressure to afford the crude
product which was purified by column chromatography
(hexanes/EtOAc) to yield diol 36 (104 mg, 76% yield) as a clear
20
oil Rf = 0.5 (SiO2, 40% EtOAc/hexane); [α]D = +34.3 (c 0.9,
CHCl3); IR(neat): 3456, 2956, 2925, 1717, 1607, 1516, 1458,
1378, 1252, 1172, 1073, 1025, 801, 755, 671 cm-1; 1H NMR (400
MHz, CDCl3): δ 7.31-7.24 (m, 2H), 6.92-6.85 (m, 2H), 5.28 (dd, J
= 6.8, 4.4 Hz, 1H), 4.55 (dd, J = 13.4, 10.8 Hz, 2H), 3.81 (s, 3H),
3.64 (td, J = 7.8, 2.9 Hz, 1H), 3.50 (dd, J = 8.3, 3.9 Hz, 1H), 3.18-
3.08 (m, 2H), 2.83 (qd, J = 7.1, 3.1 Hz, 1H), 2.45-2.32 (m, 1H),
2.32-2.21 (m, 1H), 2.19-2.09 (m, 1H), 1.92-1.81 (m, 1H), 1.72-
1.65 (m, 1H), 1.64-1.58 (m, 1H), 1.42 (dt, J = 7.4, 7.1 Hz, 1H),
1.28 (d, J = 7.1 Hz, 3H), 1.06 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9
Hz, 3H) 0.98-0.90 (m, 12H), 0.87 (d, J = 6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3): δ 213.2, 175.1, 159.1, 130.8, 129.0, 113.7,
85.9, 79.0, 77.7, 76.6, 74.2, 55.2, 47.8, 42.7, 41.6, 36.9, 35.0,
31.0, 27.1, 20.8, 17.3, 15.4, 15.3, 14.3, 14.1, 9.4, 7.5; ESI-HRMS:
Calcd m/z For C29H48O7: 531.3298, found 531.3296.
Acknowledgements
(2R,3R,4S)-(3S,4S,5S,6S)-3-((4-Methoxybenzyl)oxy)-2,4,6-
trimethyl-7-oxononan-5-yl
oxoheptanoate (37)
3-hydroxy-2,4-dimethyl-5-
GN acknowledges UGC, New Delhi for financial assistance. BS
acknowledge CSIR, New Delhi for financial assistance and PS
acknowledge DST and CSIR, New Delhi for funding the project
under budget head GAP-584.
Dess-Martin periodinane (30 mg, 0.070 mmol, 1.8 equiv.) was
added to a stirred solution of the diol 36 (20 mg, 0.039 mmol) and
NaHCO3 (39 mg, 0.47 mmol, 12 equiv.) in CH2Cl2 (4 mL). After
stirring for 1 h, the mixture was diluted with pentane, filtered
through a thin SiO2 plug and concentrated under reduced
pressure to give a crude material which was purified by column
Conflict of Interest
chromatography over silica gel (hexanes/EtOAc) to afford 37
The authors declare no conflict of interest.
20
(12.5 mg, 63 %). Rf = 0.5 (SiO2, 20% EtOAc/hexane); [α]D
=
+34.2 (c 0.33, CHCl3), (Lit.6b [α]D = +30.0 (c 0.25, CHCl3); IR(neat):
Keywords: polyketide • aldol • natural products • Yamaguchi
3499, 2970, 1712, 1610, 1514, 1458, 1374, 1244, 1173, 1073,
1
esterification• Sharpless epoxidation
973, 819, 753, 666 cm-1. H NMR (400 MHz, C6D6): δ 7.37-7.31
(m, 2H), 6.86-6.81 (m, 2H), 5.45 (dd, J = 7.4, 4.4 Hz, 1H), 4.62 (d,
J = 10.8 Hz, 1H), 4.51 (d, J = 10.7 Hz, 1H), 3.81-3.75 (m, 1H),
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European Journal of Organic Chemistry
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Total Synthesis
Naresh Gantasala, Suresh Borra, Srihari
Pabbaraja *
Page No. – Page No.
Title: Stereoselective total synthesis
of non-contiguous polyketide natural
product (-)-dolabriferol
The stereoselective total synthesis of dolabriferol is accomplished in 17 steps
following a divergent cum convergent approach. The effect of protecting groups on
alcohol substrate played a pivotal role for Yamaguchi esterification reaction
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