A concise synthesis of mupirocin H using a cross-metathesis-based strategy

Article abstract of DOI:10.1002/ejoc.201402442

A highly efficient (10.1% overall yield) and convergent (longest linear sequence of 16 steps) synthesis of mupirocin H has been achieved, starting from commercially available (+)-(R)-Roche ester. The route relies on an efficient Grubbs cross-metathesis reaction to generate a key, late-stage E-olefin intermediate, and a cobalt-catalysed diastereoselective Reformatsky reaction to produce a β-hydroxy ester that serves as a late-stage intermediate.

Full text of DOI:10.1002/ejoc.201402442

FULL PAPER
DOI: 10.1002/ejoc.201402442
A Concise Synthesis of Mupirocin H Using a Cross-Metathesis-Based Strategy
Sandip Sengupta[a] and Taebo Sim*[a,b]
Keywords: Total synthesis / Natural products / Polyketides / Metathesis / Reformatsky reaction
A highly efficient (10.1% overall yield) and convergent
(longest linear sequence of 16 steps) synthesis of mupirocin
H has been achieved, starting from commercially available
(+)-(R)-Roche ester. The route relies on an efficient Grubbs
cross-metathesis reaction to generate a key, late-stage E-ole-
fin intermediate, and a cobalt-catalysed diastereoselective
Reformatsky reaction to produce a β-hydroxy ester that
serves as a late-stage intermediate.
coding gene in Pseudomonas fluorescens perturbs the nor-
mal mupirocin biosynthetic pathway, and gives rise to the
production of a new metabolite, mupirocin H (Figure 1).[4]
The structure of mupirocin H was determined by exten-
sive analysis of spectroscopic data, and confirmed by a re-
cent total synthesis.[5a] Its fascinating truncated pseu-
domonic acid structure and the important biological activi-
ties of members of the pseudomonic acid family have at-
tracted the attention of several synthetic groups. To date,
three total syntheses of mupirocin H have been reported.
The first, completed by Chakraborty and co-workers in
2011,[5a] used d-glucose as the source of the three ste-
reogenic hydroxymethine groups at C-3–C-5 of the target
compound, and Still–Barrish hydroboration and Julia–
Kocienski olefination as key processes. The synthesis, which
had an overall yield of 5%, started from a known d-gluc-
ose-derived intermediate, and required 26 steps, with a
longest linear sequence of 19 steps. The second total synthe-
sis of mupirocin H, described by Willis and co-workers[5b,5c]
in 2012, was based on a strategy involving conversion of a
six-membered lactone into a five-membered analogue. The
route, which started from a substance prepared by resolu-
tion of a bisulfite adduct,[5d] used a 16-step linear sequence
to produce the target in a 3% overall yield from a commer-
cially sourced starting material. Another synthesis of mupi-
rocin H by the She group,[5e] which appeared during the
preparation of this manuscript, used a Suzuki–Miyaura
coupling and a Mukaiyama aldol reaction as key steps, and
was accomplished in a total of 11 steps (longest linear se-
quence of 7 steps) and a 39% overall yield from known but
not commercially available starting materials.
Introduction
Mupirocin, a mixture of naturally occurring polyketides
isolated from Pseudomonas fluorescens (a soil isolate, NCIB
10586), is active against Gram-positive bacteria, including
methicillin-resistant Staphylococcus aureus (MRSA),[1] and
is clinically used for the treatment of bacterial skin infec-
tions. The mixture consists mainly of pseudomonic acids,
with its main constituents being pseudomonic acid A (90%)
along with pseudomonic acids B–D (Figure 1).[2] The 74 kb
mupirocin gene cluster that is responsible for the biosynthe-
sis of these substances has been sequenced, and many of its
open reading frames have been assigned putative func-
tions.[3] Mutagenesis of the HMG-CoA synthase (HCS) en-
Figure 1. Structure of pseudomonic acids and mupirocin H (1).
[a] Chemical Kinomics Research Center, Korea Institute of Science
and Technology,
As part of an ongoing program focussing on natural
products with unique biological activities, we have devel-
oped a concise and efficient asymmetric synthesis of mupir-
ocin H. Our route starts from commercially available (+)-
(R)-Roche ester (2), and follows the design shown in retro-
synthetic format in Scheme 1. The salient features of the
strategy include a Sharpless asymmetric epoxidation and a
base-catalysed enantioselective epoxide-opening protocol to
Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of
Korea
[b] KU-KIST Graduate School of Converging Science and
Technology,
145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea
E-mail: tbsim@kist.re.kr
www.kist.re.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402442.
Eur. J. Org. Chem. 2014, 5063–5070
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Sengupta, T. Sim
FULL PAPER
introduce the C-3–C-5 triol array in fragment B, and a form the β-hydroxy ester that serves as the precursor of the
Brown crotylboration process to prepare the blocked meth- γ-lactone moiety in the target compound. This route for the
ylpentenol fragment A. Coupling of these two fragments preparation of mupirocin H is much more efficient than
was accomplished using a Grubbs cross-metathesis reaction those reported previously.
to generate a key E-olefin intermediate, and a cobalt-cata-
lysed, diastereoselective Reformatsky reaction was used to
Results and Discussion
The sequence developed for the synthesis of fragment B,
which serves as an important intermediate in the route to
mupirocin H, began with conversion of commercially avail-
able (+)-(R)-Roche ester 2 into monoprotected diol 3 by
protection of the alcohol and reduction of the ester (77%
over two steps; Scheme 2).[6] Swern oxidation[7] of the pri-
mary alcohol in 3, followed by two-carbon Wittig elong-
ation[8] produced intermediate α,β-unsaturated ester 4 (E/Z
= 98:2; 84% over two steps). Chemoselective reduction of
4 using DIBAL-H (diisobutylaluminium hydride)[9] then
gave the corresponding allylic alcohol (i.e., 5)[9d,9e] (95%),
which underwent Sharpless asymmetric epoxidation[10]
using (–)-DIPT (diisopropyl tartrate), Ti(OiPr)4 (TIP), and
TBHP (tert-butyl hydroperoxide) in CH2Cl2 at –20 °C to
give an inseparable mixture of diastereomeric epoxy
alcohols 6 (87%, dr = 4:1; determined by 1H and 13C NMR
spectroscopy). Regioselective opening of the epoxide ring in
6 using NaOH in DMSO yielded triol 7 (78%),[11] and en-
abled separation of the minor undesired diastereomer. Se-
lective monoprotection of the primary alcohol group in en-
antiomerically and diastereomerically pure triol 7 was car-
ried out using TBDPSCl to generate diol 8 (90%), which
Scheme 1. TBS = tert-butyldimethylsilyl; TBDPS = tert-butyldi-
phenylsilyl.
Scheme 2. 2,2-DMP = 2,2-dimethoxypropane; PTSA = p-toluenesulfonic acid.
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A Concise Synthesis of Mupirocin H
was then transformed to acetonide 9 (96%). Finally, re- Table 1. Screening of the cross-metathesis reaction[a] between frag-
ments A and B using Grubbs’ 2nd generation catalyst.
moval of the benzyl protecting group in 9 by hydrogenolysis
(Pd/C in EtOAc) yielded primary alcohol 10 (92%). Ph3P/
I2 in diethyl ether was used to transform the primary
alcohol moiety in 10 into the corresponding iodide, which,
without purification, was subjected to a vinyl Grignard cou-
pling reaction[12] in presence of CuI to give fragment B
(75% over two steps).
Fragment A, with a simple 3-methylpent-1-en-4-ol struc-
ture, was constructed using a Brown crotylboration reaction
(Scheme 3). In this process, trans-2-butene was metallated
using a modification of the Schlosser procedure involving
treatment with potassium tert-butoxide and n-butyllithium
(THF at –45 °C). (E)-Crotylpotassium, generated in this
manner, was first treated with (–)-B-methoxydiisopinocam-
phenylborane (Ipc2BOMe) at –78 °C in Et2O, and then with
acetaldehyde. The resulting addition reaction produced en-
antiomerically pure threo-3-methyl-4-penten-2-ol, whose
secondary alcohol moiety was protected using TBSCl with
imidazole to generate fragment A (60% over two steps).[13]
Entry
Catalyst loading [mol-%]
Solvent
Yield[b] [%]
1
2
3
4
6
7
8
5
15
5
15
5
10
15
CH2Cl2
CH2Cl2
benzene
benzene
toluene
toluene
toluene
no reaction
71%
74%
82%
90%
90%
[a] All reactions were carried out under reflux for 24 h. [b] Isolated
yields.
wanted by-products (Table 2, entries 1 and 2). In addition,
a reaction with lithium diisopropyl amide and EtOAc,[16]
and a CrCl2/LiI-catalysed Reformatsky reaction[17] were
both sluggish, and a significant amount of unreacted alde-
hyde was recovered in both cases (Table 2, entries 3 and 4).
SmI2-mediated Reformatsky reaction[18] of the substrates at
–78 °C generated the desired β-hydroxy ester (i.e., 13) with
modest efficiency, but with an unsatisfactory level of dia-
stereoselectivity (Table 2, entry 5).
Table 2. Trial Reformatsky reactions and aldol reaction to form β-
hydroxy ester 13.
Scheme 3.
We next focussed on joining fragments A and B using a
Grubbs cross-metathesis (CM) process. Earlier studies of
CM[14] reactions have demonstrated that Grubbs’ 2nd gener-
ation catalyst would be appropriate for this reaction. An
examination of the process showed that CM between frag-
ments A and B with 5 mol-% catalyst did not take place in
CH2Cl2, even at reflux, but that reactions in both benzene
and toluene occurred efficiently to produce the desired E-
alkene 11 (Table 1). A higher yield of 11 was achieved when
toluene rather than benzene was used as solvent with a cat-
alyst loading of 5–10 mol-%, and the optimal reaction tem-
perature was determined to be 110 °C. Consequently, for
the most efficient CM reaction of fragments A and B to
form 11 (90%, 95:5 E/Z) a solution of the reactants and
Grubbs II catalyst was heated in refluxing toluene at 110 °C [a] Isolated yields over two steps. [b] Diastereomeric ratio was de-
1
termined by H NMR spectroscopic analysis of the crude reaction
for 24 h.
mixtures. LHMDS = lithium hexamethyldisilazide; DIPEA = diiso-
propylethylamine.
Owing to its volatility and homo-cross-metathesis issues,
fragment A was used in a sevenfold excess over fragment B.
Pure E-11, obtained using silica gel column chromatog-
As a result of these problems, we explored the cobalt-
raphy was then subjected to selective TBDPS-group re- trimethylphosphine-catalysed Reformatsky process[19] de-
moval using NH4F in MeOH to liberate the primary scribed by Orsini et al.[20] Treatment of a sub-stoichiometric
alcohol moiety in 12 (85%). DMP (Dess–Martin amount (5:1 molar ratio of the organic reagents to cobalt)
periodinane) oxidation of 12 formed the corresponding al- of in-situ-generated [Co{P(CH3)3}4] with the aldehyde de-
dehyde, which, without purification, was submitted to Re- rived from 12 and ethyl bromoacetate led to the production
formatsky reaction with ethyl α-bromoacetate. As data in of 13 in high yield (68% over two steps) and with high
Table 2 shows, reaction of the freshly prepared aldehyde diastereoselectivity (9:1; Table 2, entry 6). It should be
with ethyl α-bromoacetate using activated Zn and freshly noted that the use of chiral auxiliaries is not effective in
prepared Zn–Cu couple[15] resulted in the formation of un- promoting higher levels of diastereoselectivity in cobalt-cat-
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S. Sengupta, T. Sim
FULL PAPER
Scheme 4.
alysed Reformatsky reactions.[21] Moreover, an attempt to
increase the diastereoselectivity by using an acetate aldol
reaction[22] following Crimmins’ procedure was not success-
ful (Table 2, entry 7). The assignment of the relative stereo-
reagents were used without further purification. All solvents were
purified by standard techniques. Reaction products were purified
by silica gel column chromatography using Kieselgel 60 Art. 9385
(230–400 mesh). The purity of all compounds was Ͼ95% and was
analysed using a Waters LCMS system (Waters 2998 Photodiode
Array Detector, Waters 3100 Mass Detector, Waters SFO System
Fluidics Organizer, Waters 2545 Binary Gradient Module, Waters
Reagent Manager, Waters 2767 Sample Manager) with a Sun-
FireTM C18 column (4.6ϫ50 mm, 5 μm particle size) [solvent gra-
dient: 60% (or 95%) A at 0 min, 1% A at 5 min. Solvent A: 0.035%
1
chemistry[20b] of 13 was aided by H NMR spectroscopic
data, but ultimately it was made based on the use of this
substance to complete the synthesis of mupirocin H.
In the final stage of the synthesis, key intermediate 13
was subjected to simultaneous removal of the acetonide and
TBS ether groups using HCl in MeOH (Scheme 4). This TFA in H2O; Solvent B: 0.035% TFA in MeOH; flow rate: 3.0 (or
2.5) mL/min]. 1H and 13C NMR spectra were obtained using a
process, carried out at 60 °C was accompanied by lactone-
1
Bruker 400 MHz NMR (400 MHz for H, and 100 MHz for 13C)
ring formation, and, as a result, produced mupirocin H (1)
in 60% yield. The analytical data (1H and 13C NMR spec-
spectrometer. Chemical shifts were calibrated to the CHCl3 (δ =
7.26 ppm) signal for 1H NMR spectra, and the CDCl3 (δ =
troscopy, IR spectroscopy, HRMS) and optical rotation of
77.0 ppm) signal for 13C NMR spectra. Infrared spectra were mea-
synthetic 1 are in full agreement with those reported for the
sured with an FTIR Nicolet iS10 spectrometer. Samples were re-
substance isolated from the natural source.[4,5]
corded neat or as KBr discs. High-resolution mass spectra (HRMS)
were recorded with a QTOF mass spectrometer. Optical rotations
were measured with a Rudolph Autopol III polarimeter at the
wavelength of sodium d-line (589 nm) at room temperature.
Conclusions
The route developed for the synthesis of mupirocin H is
short and highly efficient in terms of number of synthetic
Ethyl (E,4S)-5-(Benzyloxy)-4-methyl-2-pentenoate (4): DMSO
(3.54 mL, 49.8 mmol) was added to a cold (–78 °C) solution of
steps and overall yield (16 steps in its longest linear se- oxalyl chloride (3.56 mL, 41.5 mmol) in CH2Cl2 (50 mL). The mix-
ture was stirred for 10 min at –78 °C, then a solution of primary
alcohol 3 (5.0 g, 27.7 mmol) in CH2Cl2 (50 mL) was added drop-
wise. The solution was stirred for 15 min at the same temperature,
and then Et3N (23.2 mL, 166.2 mmol) was added dropwise. The
reaction mixture was stirred at that same temperature for 45 min,
then it was poured into saturated aqueous NH4Cl solution
(50 mL). The organic phase was separated and washed with satu-
rated aqueous NaHCO3 solution (20 mL). The aqueous phase was
washed with CH2Cl2 (3ϫ 50 mL), and the combined organic ex-
tracts were dried with MgSO4, and concentrated in vacuo. The
crude aldehyde was submitted to the C2 Wittig reaction without
any further purification.
quence, 17 steps overall, and 10.1% overall yield from com-
mercially available starting materials). Moreover, the sim-
plicity of the strategy should enable it to be used for the
large-scale production of mupirocin H. Finally, the conver-
gent strategy developed in this investigation, relying on a
Grubbs cross-metathesis process, should be applicable to
the synthesis of other members of the mupirocin family,
including mupirocin W, the thiomarinols, and the pseu-
domonic acids.
Experimental Section
A solution of the crude aldehyde in CH2Cl2 was treated with C2
Wittig ylide (13.1 g, 37.7 mmol), and the mixture was stirred for
6 h at room temperature. After TLC showed that the reaction was
complete, the organic phase was washed with H2O (30 mL), the
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3ϫ 30 mL). The combined organic extracts were washed
with brine, dried with MgSO4, and concentrated under reduced
General Remarks: All reactions were carried out under an inert
atmosphere of argon or nitrogen using standard syringe, septa, and
cannula techniques unless otherwise mentioned. Reactions were
monitored by TLC using precoated silica gel plates (E. Merck, 60
F254, 0.25 mm). TLC plates were visualized using a UV lamp, or
using ninhydrin or p-anisaldehyde stains. Commercially available
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A Concise Synthesis of Mupirocin H
pressure. The resulting crude product was purified by silica gel col-
umn chromatography (EtOAc/hexane, 1:10) to give compound 4
(5.7 g, 84% over two steps) as a yellow oil. Rf = 0.2 (EtOAc/hexane,
reflux for 12 h, then it was cooled to room temperature, and con-
centrated to a volume of 15 mL. The mixture was diluted with
CH2Cl2 (60 mL), and the layers were separated. The aqueous phase
was extracted with CH2Cl2 (3ϫ 50 mL), and the combined organic
extracts were washed with brine, dried with MgSO4, and filtered
through a pad of Celite. The filtrate was concentrated under re-
duced pressure, and the resulting crude product was purified by
1:9). [α]2D5 = –4.9 (c = 1.15, CHCl3). H NMR (400 MHz, CDCl3):
1
δ = 7.37–7.26 (m, 5 H), 6.94 (dd, J = 15.8, 7.0 Hz, 1 H), 5.88 (dd,
J = 15.8, 1.4 Hz, 1 H), 4.51 (s, 2 H), 4.18 (q, J = 7.1 Hz, 2 H),
3.44–3.36 (m, 2 H), 2.70–2.61 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H),
1.08 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = silica gel column chromatography (EtOAc/hexane, 1:1) to give com-
166.6, 151.0, 138.1, 128.3, 127.5, 127.4, 120.9, 73.8, 73.0, 60.1, 36.7,
15.9, 14.2 ppm. HRMS (ESI): calcd. for C15H20O3Na [M + Na]+
271.1310; found 271.1317.
pound 7 (4.2 g, 78%) as a viscous liquid. Rf = 0.2 (EtOAc/hexane,
1:1). [α]2D7 = –7.1 (c = 1.62, CHCl ). IR (KBr): ν = 3405, 1652,
˜
3
1
1073 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38–7.24 (m, 5 H),
4.52 (s, 2 H), 3.82–3.72 (m, 2 H), 3.70–3.63 (m, 2 H), 3.63–3.53 (m,
2 H), 2.65 (br. s, 3 H), 2.13–2.04 (m, 1 H), 0.98 (d, J = 7.0 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.4, 128.5, 127.8,
127.7, 76.5, 73.5 73.1, 72.2, 63.6, 34.9, 14.2 ppm. HRMS (ESI):
calcd. for C13H20O4Na [M + Na]+ 263.1260; found 263.1260.
(E,4S)-5-(Benzyloxy)-4-methyl-2-penten-1-ol (5): DIBAL-H (20%
solution in toluene; 64.5 mL, 90 mmol) was added slowly over
15 min to a cooled (0 °C) solution of 4 (11 g, 44.35 mmol) in anhy-
drous CH2Cl2 (120 mL). The reaction mixture was stirred for 1 h
at 0 °C, then it was quenched with methanol (3 mL) and saturated
aqueous sodium potassium tartarate solution (50 mL). The mixture
was passed through a small pad of Celite. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3ϫ
50 mL). The combined organic extracts were dried with MgSO4,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (EtOAc/hexane, 1:4) to give
allylic alcohol 5 (8.67 g, 95%) as a colourless liquid. Rf = 0.4
(2S,3R,4R)-5-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)-4-methyl-
pentane-2,3-diol (8): Imidazole (1.70 g, 25.0 mmol) and TBDPS-Cl
(5.50 g, 19.9 mmol) were added to a stirred solution of triol 7
(4.0 g, 16.66 mmol) in dry CH2Cl2 (50 mL) at 0 °C, and the reac-
tion mixture was stirred at room temperature for 30 min. After the
reaction was complete, the reaction mixture was diluted with
CH2Cl2 (20 mL) and washed with water (10 mL) and brine
(10 mL), dried with anhydrous MgSO4, and filtered through a pad
of Celite. The filtrate was concentrated under reduced pressure, and
the resulting crude product was purified by silica gel column
chromatography (EtOAc/hexane, 3:7) to give compound 8 (7.56 g,
(EtOAc/hexane, 3:7). [α]2D6 = –3.5 (c = 1.10, CHCl ). IR (Neat): ν
˜
3
=
3444, 2925, 2856, 1637, 1094, 756, 698 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.26 (m, 5 H), 5.71–5.64 (m, 2 H),
4.51 (s, 2 H), 4.10–4.09 (m, 2 H), 3.41–3.29 (m, 2 H), 2.57–2.47 (m,
1 H), 1.03 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 138.3, 134.9, 128.8, 128.2, 127.5, 127.4, 74.9, 72.8, 63.4, 36.7,
16.8 ppm. HRMS (ESI): calcd. for C13H18O2Na [M + Na]+
229.1204; found 229.1203.
95%) as a colourless liquid. Rf = 0.2 (EtOAc/hexane, 3:7). [α]2D7
=
+0.7 (c = 0.66, CHCl ). IR (KBr): ν = 3484, 2959, 2930, 2857,
˜
3
1471, 1427, 1112, 1028, 823 cm–1. H NMR (400 MHz, CDCl3): δ
1
= 7.68–7.66 (m, 4 H), 7.46–7.36 (m, 6 H), 7.35–7.26 (m, 5 H), 4.49
(s, 2 H), 3.85 (d, J = 5.5 Hz, 2 H), 3.73–3.67 (m, 1 H), 3.63–3.57
(m, 3 H), 3.19 (d, J = 5.6 Hz, 1 H), 3.10 (d, J = 4.9 Hz, 1 H), 2.12–
2.03 (m, 1 H), 1.07 (s, 9 H), 1.01 (d, J = 7.1 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 137.6, 135.5, 132.9, 132.8, 129.8,
128.4, 127.7, 127.6, 76.1, 73.4, 72.6, 72.1, 65.7, 34.5, 26.8, 19.1,
14.6 ppm. HRMS (ESI): calcd. for C29H38O4SiNa [M + Na]+
501.2437; found 501.2436.
(2R,3R)-3-[(1R)-2-(Benzyloxy)-1-methylethyl]oxiran-2-ylmethanol
(6): Ti(OiPr)4 (2.44 mL, 8.25 mmol) and TBHP (5 m in toluene;
16.5 mL, 82.52 mmol) were sequentially added to a solution of
(–)-DIPT (1.72 mL, 8.25 mmol) in dry CH2Cl2 (100 mL) at –30 °C
containing molecular sieves (4 Å; 3.5 g). The reaction mixture was
stirred for 30 min, then a solution of alcohol 5 (8.5 g, 41.26 mmol)
in CH2Cl2 (30 mL) was added. The mixture was then stirred for an
additional 12 h at –30 °C. The reaction mixture was quenched with
water (45 mL) and NaOH solution (30% aq.) saturated with NaCl
(20 mL), and the resulting mixture was stirred vigorously for an
additional 30 min at room temperature. The mixture was then vac-
uum filtered through a pad of Celite, and the filter cake was washed
with CH2Cl2 (100 mL). The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2 (3ϫ 100 mL). The com-
bined organic extracts were washed with brine, dried with MgSO4,
and concentrated under reduced pressure. The resulting crude
product was purified by silica gel column chromatography (EtOAc/
hexane, 3:7) to give compound 6 (7.96 g, 87%) as a viscous liquid.
({(4S,5R)-5-[(R)-1-(Benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}methoxy)(tert-butyl)diphenylsilane (9): 2,2-Dimeth-
oxypropane (3.8 mL, 30 mmol) and PTSA (catalytic amount) were
successively added to a stirred solution of compound 8 (5.0 g,
10.46 mmol) in CH2Cl2 (30 mL) at room temperature. The reaction
mixture was stirred for 30 min at room temperature, then it was
quenched with saturated aqueous NaHCO3 (10 mL). The mixture
was diluted with CH2Cl2 (30 mL). The aqueous layer was extracted
with CH2Cl2 (3ϫ 30 mL), and the combined organic extracts were
dried with MgSO4, and filtered through a pad of Celite. The filtrate
was concentrated under reduced pressure, and the resulting crude
product was purified by silica gel column chromatography (EtOAc/
hexane, 1:20) to give compound 9 (5.2 g, 96%) as a colourless li-
quid. Rf = 0.6 (EtOAc/hexane, 1:9). [α]2D4 = +9.3 (c = 0.72, CHCl3).
Rf = 0.3 (EtOAc/hexane, 3:7). [α]2D5 = +20.5 (c = 0.83, CHCl3). IR
1
(Neat): ν = 3442, 1638, 1455, 1365, 1092, 741, 699 cm–1. H NMR
˜
(400 MHz, CDCl3, data for major diastereomer): δ = 7.36–7.27 (m,
5 H), 4.53 (d, J = 1.5 Hz, 2 H), 3.92–3.86 (m, 1 H), 3.60 (dd, J =
12.4, 3.8 Hz, 1 H), 3.52–3.41 (m, 2 H), 3.00 (m, 1 H), 2.96 (dd, J
= 6.9, 2.4 Hz, 1 H), 1.85–1.68 (m, 2 H), 1.01 (d, J = 7.0 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3, data for major diastereomer):
δ = 138.4, 128.4, 128.3, 127.5, 127.4, 73.1, 72.5, 61.8, 57.7, 56.9,
35.7, 13.3 ppm. HRMS (ESI): calcd. for C13H18O3Na [M + Na]+
245.1154; found 245.1157.
IR (KBr): ν = 2931, 2857, 1495, 1428, 1274, 1112, 1071, 824 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.71–7.66 (m, 4 H), 7.44–7.35
(m, 6 H), 7.34–7.23 (m, 5 H), 4.50 (q, J = 12.0 Hz, 2 H), 4.19 (q,
J = 5.4 Hz, 1 H), 3.98 (dd, J = 10.0, 5.3 Hz, 1 H), 3.80 (dd, J =
10.8, 6.1 Hz, 1 H), 3.63 (dd, J = 9.2, 3.4 Hz, 1 H), 3.60 (dd, J =
10.8, 5.3 Hz, 1 H), 3.46 (dd, J = 9.0, 6.9 Hz, 1 H), 2.15–2.03 (m, 1
H), 1.32 (d, J = 6.3 Hz, 6 H), 1.08 (s, 9 H), 1.06 (d, J = 6.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.1, 135.7, 135.6,
133.6, 133.5, 129.6, 128.2, 127.7, 127.4, 127.3, 107.6, 79.3, 78.3,
73.2, 73.1, 63.4, 33.1, 28.2, 26.9, 25.7, 19.2, 14.9 ppm. HRMS
(2S,3R,4R)-5-(Benzyloxy)-4-methylpentane-1,2,3-triol (7): NaOH
(0.5 n; 10 mL) was added to a solution of epoxy alcohol 6 (5 g,
22.5 mmol) in 1,4-dioxane (30 mL). The mixture was stirred under
Eur. J. Org. Chem. 2014, 5063–5070
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5067

S. Sengupta, T. Sim
FULL PAPER
(ESI): calcd. for C32H42O4SiNa [M + Na]+ 541.2750; found
541.2756.
(100 mL) at –78 °C. The reaction mixture was stirred for 5 min,
and then a cooled (–78 °C) solution of nBuLi (2.5 m in hexane;
25 mL, 63 mmol) in THF (30 mL) was added slowly by cannula.
The reaction mixture was warmed to –55 °C, stirred for 45 min
and then recooled to –78 °C. A cooled (–40 °C) solution of (–)-
Ipc2BOMe (23 g, 72 mmol) in THF (50 mL) was then slowly added
by cannula, and the mixture was stirred for 1 h at –78 °C. BF3·Et2O
(1.23 mL, 10 mmol) was then added dropwise, and then a cooled
(–78 °C) solution of acetaldehyde (10 g, 50 mmol) in THF (25 mL)
was added dropwise by cannula. The reaction mixture was stirred
at –78 °C for 4 h, and then NaOH solution (3 m aq.; 30 mL,
85 mmol) and H2O2 (30% solution; 30 mL, 85 mmol) were added
slowly at –78 °C. The reaction mixture was warmed to room tem-
perature and then heated at reflux for 4 h. The layers were then
separated, and the aqueous layer was extracted with diethyl ether
(3 ϫ 70 mL). The combined organic extracts were washed with
brine (30 mL), dried with MgSO4, filtered, and concentrated in
vacuo. The resulting crude volatile allylic alcohol was directly pro-
tected as its TBS ether.
(2R)-2-{(4R,5S)-5-[(tert-Butyldiphenylsilyloxy)methyl]-2-methyl-
1,3-dioxolan-4-yl}propan-1-ol (10): Palladium on activated carbon
(10 wt.-%; 200 mg) was added to a solution of benzyl ether 9 (5.0 g,
9.65 mmol) in ethyl acetate (20 mL) under a nitrogen atmosphere.
The reaction mixture was flushed with nitrogen, and then stirred
under a hydrogen atmosphere for 6 h until the consumption of the
starting material was complete. The reaction mixture was diluted
with diethyl ether (60 mL), and filtered through a pad of Celite.
The filtrate was concentrated under reduced pressure, and the re-
sulting crude product was purified by silica gel column chromatog-
raphy (EtOAc/hexane, 1:5) to give compound 10 (3.80 g, 92%) as
a colourless oil. Rf = 0.3 (EtOAc/hexane, 1:4). [α]2D5 = –40.9 (c =
1.75, CHCl ). IR (KBr): ν = 3448, 2931, 2857, 1472, 1427, 1112,
˜
3
1070, 824 cm–1. H NMR (400 MHz, CDCl3): δ = 7.69–7.66 (m, 4
1
H), 7.46–7.36 (m, 6 H), 4.25–4.21 (m, 1 H), 3.97 (dd, J = 10.2,
5.3 Hz, 1 H), 3.79 (dd, J = 10.8, 7.0 Hz, 1 H), 3.67–3.57 (m, 2 H),
3.55 (dd, J = 10.8, 4.5 Hz, 1 H), 2.84 (dd, J = 9.0, 2.6 Hz, 1 H),
2.23–2.10 (m, 1 H), 1.34 (s, 6 H), 1.06 (s, 9 H), 0.91 (d, J = 6.6 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.6, 135.5, 133.2,
133.1, 129.7, 127.7, 108.2, 82.9, 78.3, 68.1, 63.1, 34.2, 28.1, 26.8,
25.7, 19.1, 14.1 ppm. HRMS (ESI): calcd. for C25H36O4SiNa [M +
Na]+ 451.2281; found 451.2271.
Imidazole (3.57 g, 52.5 mmol) was added to a solution of the crude
volatile allylic alcohol in CH2Cl2 (100 mL) at 0 °C. The reaction
mixture was stirred for 10 min, and then TBSCl (6.3 g, 42 mmol)
was added slowly. The mixture was stirred for 6 h at room tempera-
ture until the reaction was complete, and then it was quenched by
the addition of saturated NH4Cl solution (20 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (3ϫ
30 mL). The combined organic extracts were washed with brine,
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. The resulting crude product was purified by silica gel column
chromatography (EtOAc/hexane, 1:30) to give fragment A (6.4 g,
60% over two steps) as a colourless liquid. Rf = 0.8 (EtOAc/hexane,
tert-Butyl({(4S,5R)-2,2-dimethyl-5-[(R)-pent-4-en-2-yl]-1,3-dioxol-
an-4-yl}methoxy)diphenylsilane (Fragment B): Triphenylphosphine
(1.46 g, 5.59 mmol), imidazole (475 mg, 6.99 mmol), and then io-
dine (1.89 g, 7.46 mmol) were added successively to a solution of
alcohol 10 (2.0 g, 4.66 mmol) in diethyl ether (20 mL) at 0 °C. The
reaction mixture was stirred for 6 h at 0 °C, then it was quenched
with saturated aqueous sodium thiosulfate solution (10 mL), and
diluted with Et2O (30 mL). The aqueous layer was extracted with
Et2O (3ϫ 30 mL). The combined extracts were dried with MgSO4,
filtered, and concentrated under reduced pressure. to give the crude
iodo compound as a colourless liquid. This was used for the next
Grignard reaction without any further purification.
1:19). [α]2D6 = +8.2 (c = 2.31, CHCl ). IR (KBr): ν = 2944, 2929,
˜
3
2886, 2858, 1472, 1421, 1255, 1103, 1039, 912 cm–1
.
1H NMR
(400 MHz, CDCl3): δ = 5.85–5.74 (m, 1 H), 5.01–4.96 (m, 2 H),
3.74–3.69 (m, 1 H), 2.21–2.12 (m, 1 H), 1.05 (d, J = 6.1 Hz, 3 H),
0.99 (d, J = 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 141.1, 114.2, 71.7, 45.5, 25.9, 20.6,
18.1, 15.5, –4.3, –4.8 ppm.
Vinyl Grignard (1 m in THF; 14 mL) was slowly added to a suspen-
sion of CuI (895 mg, 4.66 mmol) in diethyl ether (20 mL) at 0 °C.
The resulting mixture was stirred for 30 min, and then a solution
of the crude iodo compound in Et2O (20 mL) was added slowly at
0 °C. The reaction mixture was stirred for 5 h at the same tempera-
ture, and then it was quenched with saturated NH4Cl solution
(10 mL). The reaction mixture was diluted with EtOAc (30 mL),
and the aqueous layer was extracted with EtOAc (3ϫ 30 mL). The
combined organic extracts were washed with brine, dried with
MgSO4, filtered, and concentrated under reduced pressure. The re-
sulting crude product was purified by silica gel column chromatog-
raphy (EtOAc/hexane, 1:25) to give fragment B (1.53 g, 75% over
two steps) as a colourless liquid. Rf = 0.8 (EtOAc/hexane, 1:9).
tert-Butyl({(4S,5R)-5-[(2R,6R,7S,E)-7-(tert-butyldimethylsilyloxy)-
6-methyloct-4-en-2-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methoxy)di-
phenylsilane (11): A solution of fragment B (300 mg, 0.7 mmol) in
anhydrous toluene (2 mL) was added to a solution of fragment A
(1 g, 4.67 mmol) in anhydrous toluene (0.5 mL) under N2. Grubbs
II catalyst (60 mg, 10 mol-%) was added, and the mixture was
heated for 24 h at 110 °C, and then concentrated under reduced
pressure. The resulting crude product was purified by silica gel col-
umn chromatography (EtOAc/hexane, 1:25) to give compound 11
(393 mg, 90 %) as a colourless liquid. Rf = 0.8 (EtOAc/hexane,
1:19). [α]2D6 = –10.8 (c = 0.52, CHCl ). IR (KBr): ν = 3071, 2958,
˜
3
2931, 2857, 1429, 1462, 1378, 1249, 1112, 1040, 836 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.70–7.67 (m, 4 H), 7.46–7.36 (m, 6 H),
5.45–5.22 (m, 2 H), 4.24–4.14 (m, 1 H), 3.87–3.74 (m, 2 H), 3.74–
3.66 (m, 1 H), 3.59–3.54 (m, 1 H), 2.41–2.30 (m, 1 H), 2.21–2.08
(m, 1 H), 1.99–1.80 (m, 2 H), 1.34 (d, J = 7.1 Hz, 6 H), 1.06 (s, 9
H), 1.03 (dd, J = 7.5, 6.2 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3 H), 0.95
(d, J = 6.5 Hz, 3 H), 0.90 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 135.6, 134.8, 133.5, 133.3, 129.6, 127.6, 107.4, 83.4,
81.6, 78.2, 71.9, 63.3, 44.3, 31.9, 28.2, 26.8, 25.9, 25.8, 20.4, 19.9,
19.2, 18.1, –4.8, –4.4 ppm. HRMS (ESI): calcd. for C37H60O4Si2Na
[M + Na]+ 647.3928; found 647.3930.
[α]2D5 = –13.1 (c = 0.75, CHCl ). IR (KBr): ν = 2983, 2959, 2931,
˜
3
2857, 1428, 1379, 1275, 1112, 1072, 914 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.69–7.64 (m, 4 H), 7.46–7.35 (m, 6 H), 5.83–5.70 (m,
1 H), 5.07–4.97 (m, 2 H), 4.24–4.15 (m, 1 H), 3.85–3.75 (m, 2 H),
3.55 (dd, J = 10.8, 5.0 Hz, 1 H), 2.47–2.41 (m, 1 H), 1.99–1.84 (m,
2 H), 1.33 (d, J = 9.0 Hz, 6 H), 1.05 (s, 9 H), 0.89 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.1, 135.6, 135.5,
133.4, 133.2, 129.6, 127.6, 116.5, 107.4, 81.5, 78.2, 63.3, 38.1, 31.5,
27.1, 26.8, 25.7, 19.1, 16.2 ppm. HRMS (ESI): calcd. for C27H38O3-
SiNa [M + Na]+ 461.2488; found 461.2500.
tert-Butyldimethyl[(2S,3R)-3-methylpent-4-en-2-yloxy]silane (Frag-
ment A): trans-2-Butene (12 mL, 120 mmol) was added by cannula
to a solution of tBuOK (1.0 m in THF; 60 mL, 60 mmol) in THF
{(4S,5R)-5-[(2R,6R,7S,E)-7-(tert-Butyldimethylsilyloxy)-6-methyl-
oct-4-en-2-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol (12): NH4F
5068
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5063–5070

A Concise Synthesis of Mupirocin H
(145 mg, 3.85 mmol) was added to a stirred solution of 11 (300 mg,
0.5 mmol) in anhydrous MeOH (2 mL) at 25 °C. The reaction mix-
ture was stirred for 12 h at room temperature, then saturated
NH4Cl solution (4 mL) was added, and the mixture was concen-
trated under reduced pressure. The concentrated reaction mixture
was diluted with EtOAc (10 mL). The layers were separated, and
the aqueous layer was extracted with EtOAc (3ϫ 10 mL). The com-
bined organic extracts were washed with brine, dried with MgSO4,
filtered, and concentrated under reduced pressure. The resulting
crude product was purified by silica gel column chromatography
(EtOAc/hexane, 1:5) to give compound 12 (164 mg, 85 %) as a
colourless oil. Rf = 0.3 (EtOAc/hexane, 1:4). [α]2D4 = –21.2 (c = 1.3,
(100 MHz, CDCl3): δ = 173.6, 134.8, 127.2, 107.4, 82.0, 78.9, 71.9,
66.8, 60.7, 44.2, 38.1, 36.9, 31.8, 27.7, 25.9, 25.4, 20.4, 18.1, 16.6,
14.1, –4.4, –4.8 ppm. HRMS (ESI): calcd. for C25H48O6SiNa [M +
Na]+ 495.3118; found 495.3120.
(4S,5S)-5-[(1R,2R,6R,7S,E)-1,7-Dihydroxy-2,6-dimethyloct-4-enyl]-
4-hydroxydihydrofuran-2(3H)-one (mupirocin H, 1): Concd. HCl
(0.1 mL) was added to ester compound 13 (20 mg, 0.04 mmol) in
methanol (2 mL) . The reaction mixture was stirred at 65 °C for
8 h, then it was cooled to room temperature, and treated with
CH2Cl2 (10 mL) and half-saturated aqueous NaCl solution
(10 mL). The layers were separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3ϫ 10 mL). The combined organic extracts
were dried with MgSO4, filtered, and concentrated under reduced
pressure. The resulting crude product was purified by silica gel col-
umn chromatography (MeOH/CH2Cl2, 1:8) to give mupirocin H
(1; 6.5 mg, 60%) as a colourless oil. Rf = 0.3 (SiO2, MeOH/chloro-
form, 1:9). [α]2D4 = +28.3 (c = 0.18, CHCl3) (ref.[4] [α]2D4 = +30.5 (c
CHCl ). IR (KBr): ν = 3441, 2958, 2929, 2856, 1668, 1462, 1378,
˜
3
1251, 1064, 1034, 971 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.48–
5.29 (m, 2 H), 4.18–4.08 (m, 1 H), 3.83 (q, J = 5.5 Hz, 1 H), 3.71–
3.66 (m, 1 H), 3.62–3.56 (m, 2 H), 2.42–2.32 (m, 1 H), 2.19–2.07
(m, 1 H), 2.05–1.98 (m, 1 H), 1.98–1.86 (m, 1 H), 1.47 (m, 3 H),
1.36 (s, 3 H), 1.04 (d, J = 6.1 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H),
0.88 (m, 12 H), 0.02 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 135.2, 126.5, 108.1, 80.9, 77.7, 71.9, 61.5, 44.3, 36.9, 31.8, 28.5,
25.8, 20.6, 18.1, 16.0, 15.7, –4.4, –4.8 ppm. HRMS (ESI): calcd. for
C21H42O4SiNa [M + Na]+ 409.2750; found 409.2748.
= 1.3, CHCl ). IR (KBr): ν = 3407, 2960, 2922, 2853, 1742, 1668,
˜
3
1457, 1376, 1259, 1195, 1070 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 5.60 (ddd, J = 14.9, 8.4, 6.0 Hz, 1 H), 5.38 (dd, J = 15.4, 8.6 Hz,
1 H), 4.59 (m, 1 H), 4.41 (dd, J = 5.6, 3.4 Hz, 1 H), 3.58 (dd, J =
6.6, 6.2 Hz, 1 H), 3.51 (m, 1 H), 2.93 (dd, J = 18.1, 7.5 Hz, 1 H),
2.51 (dd, J = 18.1, 4.4 Hz, 1 H), 2.34–2.18 (m, 2 H), 2.10–1.99 (m,
1 H), 1.93–1.84 (m, 1 H), 1.18 (d, J = 6.3 Hz, 3 H), 1.03 (d, J =
7.0 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 175.3, 135.0, 129.5, 87.2, 75.7, 71.5, 68.8, 45.3, 38.2,
35.4, 34.8, 20.7, 16.8, 16.0 ppm. HRMS (ESI): calcd. for
C14H24O5Na [M + Na]+ 295.1521; found 295.1535.
(S)-Ethyl 3-((4S,5S)-5-{(2R,6R,7S,E)-7-[(tert-Butyldimethylsilyl)-
oxy]-6-methyloct-4-en-2-yl}-2,2-dimethyl-1,3-dioxolan-4-yl)-3-
hydroxypropanoate (13): Dess–Martin periodinane (65 mg,
0.15 mmol) was added to a stirred solution of primary alcohol 12
(43 mg, 0.11 mmol) in anhydrous CH2Cl2 (2 mL) at 0 °C. The reac-
tion mixture was warmed to room temperature and stirred for
30 min. The reaction mixture was then filtered through a small pad
of Celite, and the filtrate was washed with saturated NaHCO3 and
brine. The separated aqueous layer was extracted with CH2Cl2 (3ϫ
10 mL). The combined organic extracts were dried with MgSO4,
filtered, and concentrated under reduced pressure. The crude alde-
hyde was used in the next step without any further purification.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for all compounds.
Acknowledgments
This research was supported by the Korea Institute of Science and
Technology and the National Research Foundation of Korea (grant
number NRF-2011-0028676 from the creative/challenging research
program, and grant number NRF-220-2011-1-C00042 from the
global research network research program.
Trimethylphoshine (1 m solution in THF; 0.04 mL) was added to a
mixture of activated magnesium turnings (20 mg) and anhydrous
COCl2 (2.5 mg, 0.02 mmol) in THF (0.2 mL) at room temperature.
The reaction mixture was stirred for 3 h at room temperature, and
the yellow-brown colour of the low-oxidation-state cobalt complex
developed. The reaction mixture was then cooled to 0 °C and then
treated slowly with a THF solution (1 mL) containing ethyl bromo-
acetate (0.05 mL, 0.5 mmol) and the freshly prepared aldehyde
from 12. The addition rate was modulated so as to preserve the
original brown colour and reduce to a minimum the time of devel-
opment of the blue colour (CoII complex). Completion of the reac-
tion was indicated by the persistence of the brown colour for a few
minutes (low-oxidation-state cobalt complex). After TLC showed
that the reaction was complete, the mixture was diluted with EtOAc
(5 mL) and poured into crushed ice. The layers were separated, and
the aqueous layer was extracted with ethyl acetate (3ϫ 10 mL).
The combined organic extracts were dried with MgSO4, filtered,
and concentrated under reduced pressure. The resulting crude
product was purified by silica gel column chromatography (EtOAc/
hexane, 1:10) to give compound 13 (35 mg, 68% over two steps) as
a pale yellow oil. Rf = 0.5 (EtOAc/hexane, 1:4). [α]2D4 = –10.3 (c =
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1634, 1457, 1373, 1255, 836 cm–1. H NMR (400 MHz, CDCl3): δ
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3.97–3.90 (m, 1 H), 3.89–3.83 (m, 1 H), 3.73–3.67 (m, 1 H), 2.78
(dd, J = 16.9, 2.4 Hz, 1 H), 2.51 (dd, J = 17.1, 8.9 Hz, 1 H), 2.35
(m, 1 H), 2.18–2.09 (m, 1 H), 2.05–1.91 (m, 2 H), 1.39 (s, 3 H),
1.32 (s, 3 H), 1.29–1.25 (m, 6 H), 1.03 (d, J = 6.1 Hz, 3 H), 0.95
(d, J = 6.7 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H) ppm. 13C NMR
Eur. J. Org. Chem. 2014, 5063–5070
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5069

S. Sengupta, T. Sim
FULL PAPER
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Received: April 18, 2014
Published Online: July 11, 2014
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Eur. J. Org. Chem. 2014, 5063–5070