Synthesis of an advanced intermediate enroute to thiomarinol antibiotics

Article abstract of DOI:10.1016/j.tet.2017.03.089

A stereoselective synthesis of the C1-C14 fragment of thiomarinols is disclosed. The key steps include the stereoselective preparation of an allylic sulfide via a chloro sulfide by 1,2-asymmetric induction, ring-closing metathesis reaction, Kirmse-Doyle reaction for the preparation of a γ,δ-unsaturated ester, Nozaki-Hiyama-Kishi coupling and Julia-Kocienski olefination reaction. Substrate controlled asymmetric induction has been advantageously employed for the creation of stereogenic centers. Noyori transfer hydrogenation and asymmetric hydrogenation reactions have been utilized for the creation of carbinol stereocenters.

Full text of DOI:10.1016/j.tet.2017.03.089

Tetrahedron xxx (2017) 1e10
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Synthesis of an advanced intermediate enroute to thiomarinol
antibiotics
Sadagopan Raghavan*, Anil Ravi
Natural Products Chemistry Division, Indian Institute of Chemical Technology, Hyderabad, 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the C1-C14 fragment of thiomarinols is disclosed. The key steps include the
stereoselective preparation of an allylic sulfide via a chloro sulfide by 1,2-asymmetric induction, ring-
Received 17 January 2017
Received in revised form
11 March 2017
Accepted 31 March 2017
Available online xxx
closing metathesis reaction, Kirmse-Doyle reaction for the preparation of a
g,d-unsaturated ester,
Nozaki-Hiyama-Kishi coupling and Julia-Kocienski olefination reaction. Substrate controlled asymmetric
induction has been advantageously employed for the creation of stereogenic centers. Noyori transfer
hydrogenation and asymmetric hydrogenation reactions have been utilized for the creation of carbinol
stereocenters.
Keywords:
Thiomarinol
© 2017 Elsevier Ltd. All rights reserved.
Alpha-chloro sulfide
Kirmse-Doyle rearrangement
Julia-Kocienski reaction
NHK-Reaction
1. Introduction
application of an a-chloro sulfide for the stereoselective prepara-
tion of an allylic sulfide, ring-closing metathesis reaction and
Thiomarinols A, B, E and H (Fig. 1) rare natural products, isolated
from the marine bacterium Pseudoalteromonas sp. SANK73390,1e3
possess a pyrrothine moiety linked through an amide to mar-
inolic acids that are related to clinically potent antibiotic pseudo-
monic acid A.4,6 Thiomarinol H, possessing an anhydroornithine
moiety was isolated from Alteromonas sp.5 The thiomarinols display
potent activity against Gram-positive and Gram-negative bacteria
Kirmse-Doyle rearrangement as the crucial steps.
2. Results and discussion
The retrosynthesis is depicted in Scheme 1. Thiomarinol can be
obtained from the unsaturated acid 6 and alcohol 7. The acid 6 can
be obtained from the reaction of a suitable nucleophile derived
from the iodo alkene 9 with aldehyde 8. Aldehyde 8 can be derived
from aldehyde 10 by Julia-Kocienski olefination with sulfone 11.
Aldehyde 10 was envisaged to be obtained from the unsaturated
ester 12 which in turn can be traced to allyl sulfide 13. Sulfide 13
can readily be obtained from chloro diol 14.
including MRSA strain (MIC <0.01m
gmLꢀ1). Thiomarinols A, B, E and
H differ structurally from pseudomonic acid by the presence of a
C4-hydroxyl, a shorter C1-alkoxy chain and an E-alkene instead of
the C10-C11 epoxide and is more potent possessing wider spectrum
of activity.
Thiomarinols like pseudomonic acid A inhibit the bacterial
isoleucinyl tRNA synthetase enzyme responsible for loading the
amino acid isoleucine onto its associated tRNA required for ribo-
somal protein synthesis. The impressive bioactivity and intriguing
structure with five contiguous stereocenters (C4-C8) have attracted
considerable attention from synthetic and medicinal chemists.7
Herein, we describe a stereoselective route to the advanced inter-
mediate 6, constituting the C1-C14 subunit of thiomarinols by
The synthesis began with the chloro diol 14 (>95 ee), obtained
by hydrolytic kinetic resolution of epichlorohydrin,8 which on
treatment with thiophenol in the presence of DBU furnished the
diol sulfide 15. Selective mono protection of the primary hydroxyl
as its silyl ether 16 followed by allylation of the secondary hydroxyl
furnished compound 17. Reaction of 17 with N-chlorosuccinimide
yielded
a-chloro sulfide 18 which without isolation was treated
with vinylzinc bromide to afford allylic sulfide 19 (>95 dr).9 Ring-
closing metathesis using Grubbs' II generation catalyst10 20, fur-
nished sulfide 13, Scheme 2.
Syringe pump addition of ethyl diazoacetate to the solution of
sulfide 13 in the presence of catalytic rhodium acetate resulted
* Corresponding author.
E-mail address: sraghavan@iict.res.in (S. Raghavan).
http://dx.doi.org/10.1016/j.tet.2017.03.089
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
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S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
The enantiomeric excess was determined from its mandelate
ester derivative. Frater-Seebach alkylation16 of the dianion derived
from 25 with MeI afforded the ester 26 (95:5 dr). Protection of the
hydroxy group as its MOM-ether 27 followed by reduction of the
ester with LAH afforded alcohol 28. Treatment with N-phenyl-
tetrazole thiol 29 under Mitsunobu conditions17 cleanly afforded
sulfide 30 that was oxidized using mCPBA to furnish sulfone 11,
Scheme 4.
Treatment of sulfone18 11 with KHMDS followed by addition of
aldehyde 10 and stirring while gradually allowing it to attain rt
overnight furnished alkene 31 (E:Z ¼ 88:12). Deprotection of the
silyl ether using TBAF afforded alcohol 32. It is to be noted that
alcohol 32 has been employed as the key intermediate in the syn-
thesis of pseudomonic acid.19 Selective oxidation of the primary
alcohol using PhI(OAc)2 and TEMPO20 yielded aldehyde 8 which
was subjected to NHK coupling21 with iodo alkene 922 to furnish an
inseparable mixture of allylic alcohols 33 (dr 45:55). Oxidation of
the epimeric alcohols to the ketone 34 using Dess-Martin period-
inane23 followed by stereoselective reduction using Noyori's cata-
lyst24 afforded alcohol 36 (dr 92:8). Protection of the secondary
alcohol as the TBS ether 37 followed by selective removal of the
primary TBS ether afforded alcohol 38. Oxidation using PhI(OAc)2
and TEMPO in aq acetonitrile25 furnished the advanced interme-
diate 6, corresponding to the C1-C14 subunit of thiomarinol,
Scheme 5.
Fig. 1. Structures of thiomarinols and pseudomonic acid A.
sequentially in ylide formation and Kirmse-Doyle rearrangement11
to afford an inseparable epimeric mixture of esters 12. Catalytic
dihydroxylation employing the Upjohn process12 led to substrate-
controlled stereoselective introduction of the hydroxyl groups
with concomitant oxidation of the sulfide to furnish epimeric sul-
fones 21. Protection of the diol as the acetonide 22 followed by
reductive desulfonylation13 using Na-Hg yielded methyl ester 23
via transesterification. Partial reduction of the ester using DIBAL-H
yielded aldehyde 10, Scheme 3.
3. Conclusions
In conclusion, a stereoselective route to the advanced interme-
diate of thiomarinol antibiotics is described. The key steps include
the preparation of an allylic sulfide by reaction of vinylzinc bromide
with chloro sulfide, ring-closing metathesis reaction, Kirmse-Doyle
rearrangement, Julia-kocienski olefination and Nozaki-Hiyama-
Kishi coupling for the successful introduction of the C4-hydroxyl
group. Also Noyori transfer hydrogenation and asymmetric hy-
drogenation reactions have been used to introduce carbinol
The sulfone partner for Julia olefination was readily prepared
from ethyl acetoacetate 24. BINAP-Ru(II)-catalyzed Noyori asym-
metric hydrogenation14 furnished -hydroxy ester 25 (93:7 er).15
b
Scheme 1. Retrosynthetic Disconnection of Thiomarinol.
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S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
3
Scheme 2. Synthesis of allylic Sulfide 13.
Scheme 3. Synthesis of Aldehyde 10.
Scheme 4. Synthesis of Sulfone 11.
stereocenter stereoselectively. The utility of chloro sulfides in C-C
bond formation and introduction of stereogenic centers is elegantly
demonstrated.
use: THF from Na and benzophenone; CH2Cl2 and toluene from
CaH2; MeOH from Mg cake; CHCl3 from P2O5; acetone from KMnO4
and K2CO3. Commercial reagents were used without purification.
Column chromatography was carried out by using silica gel
(100e200 mesh). Analytical thin-layer chromatography (TLC) was
4. Experimental
run on silica gel 60 F254 precoated plates (250
mm thickness).
Optical rotations [
a
]
were measured on a polarimeter and are
Dry reactions were performed under an inert atmosphere using
argon or nitrogen. All glassware apparatus used for reactions were
thoroughly oven-dried. Anhydrous solvents were distilled prior to
given in units of 10ꢀ1Ddeg cm2
g
ꢀ1. Infrared spectra were recorded
neat or in KBr (as mentioned) and reported in wavenumbers
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S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
Scheme 5. Synthesis of advanced intermediate 6.
(cmꢀ1). Mass spectral data were obtained using MS (EI) ESI and
HRMS mass spectrometers. High-resolution mass spectra (HRMS;
ESIþ) were obtained using either a TOF or a double-focusing
spectrometer. 1H NMR spectra were recorded at 300, 400, or
500 MHz and 13C NMR spectra at 75, 100, or 125 MHz in CDCl3 with
the residual solvent signal as an internal standard unless
mentioned otherwise; chemical shifts are in ppm downfield from
tetramethylsilane, and coupling constants (J) are reported in hertz
(Hz). The following abbreviations are used to designate signal
multiplicity: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet, br ¼ broad.
(S)-(þ)-3-chloro-1,2-propanediol (22 g, 200 mmol) in anhydrous
CH3CN (100 mL) was added to the above reaction mixture at the
same temperature and allowed to warm to room temperature. After
6 h, CH3CN was evaporated under reduced pressure and the residue
was partitioned between EtOAc (100 mL) and H2O (100 mL). The
organic layer was separated and the aqueous layer was extracted
with EtOAc (2 ꢂ 200 mL). The combined organic layers were
washed with brine (300 mL), dried over anhydrous Na2SO4, filtered
and the solvent evaporated under reduced pressure to afford a
crude product. Purification by the flash column chromatography
using 30% EtOAc/hexane (v/v) as the eluent afforded diol 15 (31.6 g,
171.7 mmol) in 86% yield. TLC: Rf ¼ 0.2 (ethyl acetate:hexanes, 4:6);
20
[a
]
D: þ20.7ꢁ (c 1, MeOH); IR (neat): 3338, 2919, 1646, 1437, 1100,
4.1. Experimental procedures
1042 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.45e7.19 (m, 5H),
3.85e3.72 (m, 2H), 3.59 (dd, J ¼ 11.3, 6.0 Hz, 1H), 3.12 (dd, J ¼ 13.6,
4.1.1. (S)-3-Chloro-1,2-propanediol 14
To a solution of (S,S)-Jacobsen's catalyst (242 mg, 400
0.005 equiv) in CH2Cl2 (6 mL) was added AcOH (250 L) and the
3.8 Hz, 1H), 3.00 (dd, J ¼ 13.6, 8.3 Hz, 1H), 2.83e2.60 (bs, 1H),
mmol,
2.21e1.90 (bs, 1H); 13C NMR (75 MHz, CDCl3):
d 134.8, 130.1, 129.1,
m
126.8, 69.9, 65.1, 37.7; MS (ESI): 207 [MþNa]þ; HRMS (ESI): m/z
mixture stirred in air for 30 min. The crude catalyst residue ob-
tained after concentration was dissolved in ( )-epichlorohydrin
(6.25 mL, 80.0 mmol). The solution was cooled to 0 ꢁC and treated
Calcd. for C9H12O2SNa: 207.0450, found 207.0453.
with THF (2 mL) and H2O (760 m
L, 44.0 mmol). After 12 h at 4 ꢁC, the
4.1.3. (S)-1-((tert-Butyldiphenylsilyl)oxy)-3-(phenylthio)propan-2-
ol (16)
residual epoxide was removed in vacuo at 20 ꢁC. The residue was
diluted with hexanes:EtOAc (5:3, 100 mL) and H2O (30 mL) and the
resulting mixture was filtered to remove solid catalyst. The layers
were separated and the organic layer was washed with H2O
(2 ꢂ 30 mL). The combined aqueous layers were concentrated to
yield (S)-3-chloro-1,2-propanediol (ee >95%, 3.57 g, 32.3 mmol) in
43% yield. TLC: Rf ¼ 0.2 (ethyl acetate:hexanes, 4:6); 1H NMR
To a solution of diol 15 (29.4 g, 160 mmol) in DMF (200 mL) was
added imidazole (21.8 g, 320 mmol) followed by TBDPS-Cl (41 mL,
156.8 mmol) at 0 ꢁC and the stirring was continued for 4 h at room
temperature. The reaction was quenched by adding cold H2O
(120 mL) and diluted with dichloromethane (200 mL). The layers
were separated and the aqueous layer was extracted with
dichloromethane (2 ꢂ 100 mL). The combined organic layers were
washed with brine (100 mL), dried over anhydrous Na2SO4, filtered
and the solvent evaporated under reduced pressure to afford the
crude product. Purification by the flash column chromatography
using 4% EtOAc/hexane (v/v) as the eluent afforded compound 16
(300 MHz, CDCl3):
d 5.41e4.41 (bs, OH), 3.99e3.82 (m, 1H),
3.81e3.49 (m, 4H). MS (ESI): 133 [MþNa]þ.
4.1.2. (S)-3-(Phenylthio)propane-1,2-diol (15)
To a solution of PhSH (21.5 mL, 210 mmol) in anhydrous CH3CN
(300 mL) was added DBU (33.2 mL, 220 mmol) slowly via syringe at
0 ꢁC and the reaction mixture was stirred for 10 min. A solution of
(62.2 g, 147.4 mmol) in 92% yield. TLC: Rf ¼ 0.4 (ethyl acetate:-
20
hexanes, 1:9); [
a
]
D: þ37.7ꢁ (c 1, CHCl3); IR (neat): 3448, 2930,
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S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
5
2859, 1428, 1109 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
7.68e7.60 (m,
133.2, 132.2, 129.7, 128.6, 127.7, 126.6, 116.9, 116.4, 81.5, 72.0, 63.6,
4H), 7.48e7.31 (m, 8H), 7.30e7.14 (m, 3H), 3.88e3.77 (m, 1H),
3.76e3.69 (m, 2H), 3.15 (dd, J ¼ 13.6, 6.0 Hz, 1H), 3.03 (dd, J ¼ 13.6,
6.8 Hz, 1H), 2.65 (d, J ¼ 3.0 Hz, 1H), 1.06 (s, 9H); 13C NMR (75 MHz,
54.9, 26.9, 19.3; MS (ESI): 511 [MþNa]þ; HRMS (ESI): m/z Calcd. for
C30H36O2SSiNa: 511.2098, found 511.2113.
CDCl3):
d
135.5, 134.8, 132.9, 129.9, 129.5, 129.0, 127.8, 126.2, 70.2,
4.1.6. tert-Butyldiphenyl(((2S,3S)-3-(phenylthio)-3,6-dihydro-2H-
pyran-2-yl)methoxy)silane (13)
66.1, 37.2, 27.0, 19.3; MS (ESI): 461 [MþNaþO]þ; HRMS (ESI): m/z
Calcd. for C25H30O3SSiNa: 461.1577, found 461.1588. Note: The
sulfide was oxidised to the sulfoxide during analysis.
The solution of diene 19 (2.4 g, 5 mmol) in anhydrous toluene
(10 mL) was degassed by bubbling N2 for 15 min. Grubbs 2nd
generation catalyst (124 mg, 0.15 mmol, 3 mol%) was added and the
reaction mixture was refluxed for 8 h and then allowed to attain
ambient temperature. Toluene was removed under reduced pres-
sure. The crude reaction mixture was purified via flash column
chromatography on silica gel using 3% EtOAc/hexane (v/v) as the
4.1.4. (S)-(2-(Allyloxy)-3-(phenylthio)propoxy)(tert-butyl)
diphenylsilane (17)
To a suspension of NaH (60% Nujol, 6.8 g, 169 mmol) in anhy-
drous THF (280 mL) cooled to 0 ꢁC, maintained under N2 atmo-
sphere, was added a solution of compound 16 (54.8 g, 130 mmol) in
anhydrous THF (120 mL) dropwise. The reaction mixture was stir-
red at room temperature for 30 min, during which time a large
amount of opaque white solid had formed. The reaction mixture
was recooled to 0 ꢁC and allyl bromide (16.9 mL, 195 mmol) was
added dropwise and the stirring continued for 8 h at room tem-
perature. The reaction was quenched by adding ice pieces and the
mixture was diluted with EtOAc (100 mL). The layers were sepa-
rated and the organic layer was washed with H2O (50 mL), brine
(50 mL), dried over anhydrous Na2SO4 and filtered. The solvent was
removed under reduced pressure and the residue was purified by
flash column chromatography on silica gel using 2.5% EtOAc/hex-
ane (v/v) as the eluent to afford compound 17 as a colourless oil
eluent to afford sulfide 13 as a colourless oil (1.86 g, 4.04 mmol) in
20
81% yield. TLC: Rf ¼ 0.4 (ethyl acetate:hexanes,1:9); [
a
]
D: ꢀ117ꢁ (c
0.9, CHCl3); IR (neat): 2932, 2857, 1472, 1106 cmꢀ1
(300 MHz, CDCl3):
;
1H NMR
d
7.70e7.59 (m, 4H), 7.47e7.31 (m, 8H), 7.23e7.15
(m, 3H), 6.06e5.95 (m, 1H), 5.77e5.68 (m, 1H), 4.16e4.08 (m, 2H),
4.02e3.95 (m, 1H), 3.95e3.85 (m, 2H), 3.77e3.71 (m, 1H), 1.02 (s,
9H); 13C NMR (75 MHz, CDCl3):
d 135.6, 135.0, 133.1, 129.6, 128.5,
127.7, 127.5, 126.9, 126.1, 77.4, 66.1, 64.8, 45.4, 27.0, 19.3; MS (ESI):
499 [MþNaþO]þ; HRMS (ESI): m/z Calcd. for C28H32O3SSiNa:
499.1734, found 499.1732. Note: The sulfide was oxidised to the
sulfoxide during analysis.
4.1.7. (R)-Ethyl 2-((3R,6R)-6-(((tert-butyldiphenylsilyl)oxy)
(50 g, 108.2 mmol) in 83% yield. TLC: Rf ¼ 0.6 (ethyl acetate:hex-
methyl)-3,6-dihydro-2H-pyran-3-yl)-2-(phenylthio)acetate and
(S)-Ethyl 2-((3R,6R)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-3,6-
dihydro-2H-pyran-3-yl)-2-(phenylthio)acetate (12)
20
anes, 1:9); [
a]
D: þ2.7ꢁ (c 1, CHCl3); IR (neat): 2930, 2857, 1737,
1427, 1110 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.77e7.60 (m, 4H),
7.51e7.31 (m, 8H), 7.30e7.11 (m, 3H), 5.92e5.75 (m, 1H), 5.24e5.06
(m, 2H), 4.09e3.92 (m, 2H), 3.84e3.67 (m, 2H), 3.64e3.52 (m, 1H),
3.28 (dd, J ¼ 13.6, 5.3 Hz, 1H), 3.05 (dd, J ¼ 13.6, 6.8 Hz, 1H), 1.06 (s,
A magnetically stirred mixture of allylic sulfide 13 (4.2 g,
9 mmol), rhodium acetate (79.5 mg, 0.18 mmol, 2 mol%) in anhy-
drous toluene (15 mL) was heated at 90 ꢁC under nitrogen atmo-
sphere. Ethyl diazoacetate (1.9 mL, 18 mmol) in toluene (4 mL) was
added dropwise to the above mixture via a syringe pump during
3 h. The solution was refluxed for another 4 h and cooled to room
temperature. The catalyst was removed by partitioning between
toluene and aqueous 10% HCl solution (12 mL). The organic layer
was separated and washed with H2O (15 mL), brine (15 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to furnish the crude product. Purification of the crude
residue via flash column chromatography on silica gel using 3%
EtOAc/hexane (v/v) as the eluent afforded compound 12 (3.5 g,
6.4 mmol) in 71% yield. TLC: Rf ¼ 0.2 (ethyl acetate:hexanes, 1:9); IR
9H); 13C NMR (75 MHz, CDCl3):
d 136.8, 135.6, 134.8, 133.3, 133.2,
129.7, 129.0, 128.8, 127.7, 125.8, 117.0, 78.3, 71.4, 64.5, 35.4, 26.8,
19.2; MS (ESI): 501 [MþNaþO]þ; HRMS (ESI): m/z Calcd. for
C
28H34O3SSiNa: 501.1890, found 501.1884. Note: The sulfide was
oxidised to the sulfoxide during analysis.
4.1.5. (((2S,3S)-2-(Allyloxy)-3-(phenylthio)pent-4-en-1-yl)oxy)(tert
butyl)diphenylsilane (19)
To a solution of vinylmagnesium bromide (1 M in THF, 30 mL,
30 mmol) cooled to ꢀ10 ꢁC was added ZnBr2 (1.5 M in THF, 20 mL,
30 mmol) dropwise and the mixture was stirring for 1 h at room
temperature. While transmetalation was in progress, the chloro
sulfide intermediate 18 was prepared by addition of N-chlor-
osuccinimide (2.9 g, 22 mmol) to a solution of the sulphide 17
(9.3 g, 20 mmol) in anhydrous benzene (200 mL) at ambient tem-
perature and stirred for a period of 15 min. The resulting chloro
sulfide solution in benzene (200 mL) was added to the vinylzinc
bromide reagent and stirring continued at ambient temperature for
7 h. The reaction was quenched by the addition of aqueous satu-
rated ammonium chloride solution (100 mL). The layers were
separated and the aqueous layer was extracted with EtOAc
(3 ꢂ 100 mL). The combined organic layers were washed with brine
(150 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure to furnish the crude product. Purification of
the crude residue via flash column chromatography on silica gel
using 2.5% EtOAc/hexane (v/v) as the eluent afforded diene 19
;
(neat): 2931, 2859, 1728, 1108 cmꢀ1 1H NMR (500 MHz, CDCl3):
d
7.74e7.64 (m, 2H), 7.47e7.38 (m, 8H), 7.27e7.24 (m, 3H),
6.27e6.22 (m, 1H), 5.93e5.89 (m, 1H), 4.24e4.18 (m, 1H), 4.11e4.08
(m, 2H), 3.78e3.71 (m, 4H), 3.66e3.60 (m, 1H), 2.56e2.49 (m, 1H),
1.16e1.12 (m, 3H), 1.08e1.05 (s, 9H); MS (ESI): 569 [MþNa]þ. Note:-
The spectrum is of the product along with inseparable impurities
formed during the reaction.
4.1.8. (R)-Ethyl- 2-((3S,4R,5R,6S)-6-(((tert-butyldiphenylsilyl)oxy)
methyl)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)-2-
(phenylsulfonyl)acetate and (S)-Ethyl 2-((3S,4R,5R,6S)-6-(((tert-
butyldiphenylsilyl)oxy)methyl)-4,5-dihydroxytetrahydro-2H-pyran-
3-yl)-2-(phenylsulfonyl)acetate (21)
To a solution of dihydropyran 12 (6.6 g, 12 mmol) in acetone:-
water (9:1, 48 mL), N-methylmorpholine N-oxide (4.2 g, 36 mmol)
and osmium tetroxide (0.04 M in Toluene, 6 mL, 0.24 mmol) were
added and the mixture stirred at ambient temperature overnight.
The reaction was quenched with aq saturated sodium sulphite
(50 mL) and extracted with EtOAc (3 ꢂ 60 mL). The combined
organic layers ware washed with H2O (50 mL), brine (50 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to furnish the crude product. Purification of the crude
(6.4 g, 13.1 mmol) in 65% yield. TLC: Rf ¼ 0.6 (ethyl acetate:hexanes,
20
1:9); [
a]
D: þ15.8ꢁ (c 1.4, CHCl3); IR (neat): 2931, 2858, 1732, 1428,
1109 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.73e7.63 (m, 4H),
7.47e7.33 (m, 8H), 7.28e7.16 (m, 3H), 5.93e5.81 (m, 2H), 5.25e5.10
(m, 2H), 5.02e4.95 (m, 2H), 4.11 (dd, J ¼ 12.4, 4.8 Hz, 1H), 4.06e3.93
(m, 3H), 3.79 (dd, J ¼ 10.5, 4.8 Hz, 1H), 3.66e3.61 (m, 1H), 1.05 (s,
9H); 13C NMR (75 MHz, CDCl3):
d 136.3, 135.6, 135.6, 134.9, 133.3,
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S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
residue via flash column chromatography on silica gel using 30%
EtOAc/hexane (v/v) as the eluent afforded diol 21 (5.8 g, 9.5 mmol)
in 79% yield. TLC: Rf ¼ 0.2 (ethyl acetate:hexanes, 4:6); IR (neat):
IR (neat): 2958, 2931, 1738, 1087, 800 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): 7.75e7.64 (m, 4H), 7.46e7.32 (m, 6H), 4.13e4.08 (m, 1H),
d
4.04e3.97 (m, 1H), 3.91e3.84 (dd, J ¼ 11.3, 2.3 Hz, 1H), 3.82e3.64
3447, 2924, 2854, 1612, 1515 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
(m, 6H), 3.43e3.35 (m, 1H), 2.66e2.40 (m, 3H), 1.42 (s, 3H), 1.33 (s,
d
7.92e7.84 (m, 2H), 7.74e7.62 (m, 5H), 7.60e7.49 (m, 2H),
3H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 172.5, 135.7, 135.7,
7.48e7.35 (m, 6H), 4.69e4.64 (m, 0.5H), 4.48e4.35 (m, 1H),
4.33e4.24 (m, 0.5H), 4.17e3.86 (m, 4H), 3.85e3.74 (m, 2.5H),
3.67e3.56 (m, 1H), 3.40e3.32 (m, 0.5H), 2.82e2.71 (m, 1H),
1.10e1.05 (m, 9H), 0.94 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
133.6, 133.6, 129.6, 127.6, 127.5, 108.9, 79.0, 75.3, 69.9, 65.9, 64.5,
51.7, 34.8, 33.9, 28.2, 26.9, 26.4, 19.3; MS (ESI): 521 [MþNa]þ; HRMS
(ESI): m/z Calcd. for C28H38O6NaSi: 521.2330, found 521.2345.
d
165.6, 165.5*, 137.6, 137.5*, 135.6, 135.6*, 135.5, 134.4*, 134.3, 132.8,
4.1.11. 2-((3aR,4S,7S,7aR)-4-(((tert-Butyldiphenylsilyl)oxy)methyl)-
2,2dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-yl)
acetaldehyde (10)
132.7*, 132.5, 130.0, 129.9*, 129.3, 129.0*, 127.9, 127.8, 75.6, 75.0*,
70.2, 68.9*, 68.1, 68.0*, 67.2, 66.2*, 65.4, 64.8*, 63.3, 62.4*, 62.3,
62.2*, 40.4, 40.0*, 26.9, 26.8*, 19.2, 19.1*, 13.7, 13.5*; MS (ESI): 635
[MþNa]þ; HRMS (ESI): m/z Calcd. for C32H40O8SSiNa: 635.2105,
found 635.2108. Note:- The 13C signals for one of the epimeric
alcohol is denoted by an asterisk mark.
To a solution of ester 23 (1.75 g, 3.5 mmol) in anhydrous CH2Cl2
(25 mL) cooled to ꢀ78 ꢁC, maintained under nitrogen atmosphere
was added DIBAL-H (1.2 M in Toluene, 2.9 mL, 3.5 mmol) dropwise
during 15 min and the mixture stirred further for a period of
15 min. The reaction mixture was quenched using an aqueous
saturated solution of sodium potassium tartrate (5 mL) and
extracted with CH2Cl2 (3 ꢂ 50 mL). The combined organic layers
were washed with brine (100 mL), dried over anhydrous Na2SO4
and filtered. Evaporation of the solvent under reduced pressure
afforded the crude product which was purified by the flash column
chromatography using 10% EtOAc/hexane (v/v) as the eluent to
4.1.9. (R)-Ethyl 2-((3aR,4S,7S,7aR)-4-(((tert-butyldiphenylsilyl)oxy)
methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-
yl)-2-(phenylsulfonyl)acetate and (S)-Ethyl 2-((3aR,4S,7S,7aR)-4-
(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-
3aH-[1,3]dioxolo[4,5-c]pyran-7-yl)-2-(phenylsulfonyl)acetate (22)
To a stirred suspension of diol 21 (4.9 g, 8 mmol) and anhydrous
Na2SO4 (1.3 g, 9 mmol) in EtOAc (16 mL) was added 2,2-
dimethoxypropane (16 mL) and a few crystals of p-toluene-
sulfonic acid monohydrate. After 4 h of stirring at room tempera-
ture, the solution was diluted with EtOAc (20 mL) and anhydrous
Na2SO4 was removed via filtration. The resulting solution was
washed with aq saturated NaHCO3 (25 mL), brine (25 mL), dried
over anhydrous Na2SO4, filtered, and the solvent evaporated under
reduced pressure to afford the crude product. Purification by the
flash column chromatography using 10% EtOAc/hexane (v/v) as the
eluent afforded compound 22 (4.4 g, 6.7 mmol) in 84% yield. TLC:
Rf ¼ 0.5 (ethyl acetate:hexanes, 2:8); IR (neat): 2930, 1737, 1145,
afford aldehyde 10 (1.5 g, 3.21 mmol) in 92% yield. TLC: Rf ¼ 0.4
20
(ethyl acetate:hexanes, 3:7); [
a]
D: ꢀ14.2ꢁ (c 1, CHCl3); IR (neat):
2930, 2859, 1729, 1109, 1060 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
d
9.82 (s, 1H), 7.74e7.65 (m, 4H), 7.46e7.32 (m, 6H), 4.09e3.97 (m,
2H), 3.89 (dd, J ¼ 11.3, 2.3 Hz, 1H), 3.83e3.69 (m, 2H), 3.64 (dd,
J ¼ 12.1,1.5 Hz,1H), 3.43e3.35 (m,1H), 2.78 (dd, J ¼ 16.6, 6.8 Hz,1H),
2.68e2.50 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H), 1.06 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 200.2, 135.6, 133.4, 129.5, 127.5, 108.9, 78.8, 75.3,
69.7, 65.9, 64.3, 44.5, 31.4, 28.1, 26.8, 26.3, 19.2; MS (ESI): 491
[MþNa]þ; HRMS (ESI): m/z Calcd. for C27H36O5SiNa: 491.2224,
found: 491.2226.
1109 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.94e7.84 (m, 2H),
7.74e7.63 (m, 5H), 7.60e7.50 (m, 2H), 7.46e7.31 (m, 6H), 4.71e4.65
(m, 0.5H), 4.35e4.29 (m,1H), 4.25e4.05 (m, 2H), 4.01e3.80 (m, 4H),
3.76e3.66 (m, 1H), 3.65e3.57 (m, 0.5H), 3.53e3.37 (m, 1H),
2.97e2.79 (m, 1H), 1.63e1.43 (m, 6H), 1.00e0.97 (m, 12H); 13C NMR
4.1.12. tert-Butyl(((3aR,4S,7S,7aR)-7-((4R,5S,E)-5-
(methoxymethoxy)-4-methylhex-2-en-1-yl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)methoxy)
diphenylsilane (31)
(75 MHz, CDCl3):
d
165.6, 165.2*, 137.7, 137.7*, 135.7, 135.6*, 134.3,
The solution of sulfone 11 (1.3 g, 3.84 mmol) in anhydrous THF
(40 mL) cooled to ꢀ78 ꢁC was treated dropwise with potassium
bis(trimethylsilyl)amide (0.5 M in Toluene, 9.2 mL, 4.6 mmol) under
argon. The resulting yellow solution was stirred at ꢀ78 ꢁC for 0.5 h.
The solution of aldehyde 10 (1.5 g, 3.2 mmol) in anhydrous THF
(20 mL) was slowly introduced via syringe. The reaction mixture
was stirred at ꢀ78 ꢁC for 1.5 h and then allowed to warm to ambient
temperature and stirred overnight. The cloudy white reaction
mixture was quenched with water (100 mL). The layers were
separated and the aqueous layer was extracted with EtOAc
(2 ꢂ 100 mL). The combined organic layers were washed with brine
(100 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by flash column
chromatography using 10% EtOAc/hexane (v/v) as the eluent to
134.3*, 133.4, 133.4*, 133.4, 129.6, 129.6*, 129.3, 129.1*, 127.6, 127.6,
127.6*, 109.2, 108.9*, 79.2, 78.7*, 72.9, 72.8*, 70.6, 70.5*, 69.7, 69.6*,
64.5, 64.2*, 63.6, 62.3, 62.2*, 37.0, 36.9*, 28.0, 26.9, 26.8*, 26.5, 26.4*,
19.3, 19.3*, 13.7, 13.6*; MS (ESI): 675 [MþNa]þ; HRMS (ESI): m/z
Calcd. for C35H44O8SSiNa: 675.2418, found 675.2421. Note:- The 13
C
signals for one of the epimeric alcohol is denoted by an asterisk
mark.
4.1.10. Methyl 2-((3aR,4S,7S,7aR)-4-(((tert-butyldiphenylsilyl)oxy)
methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-yl)
acetate (23)
Sodium amalgam (6%, 3.06 g, 13.7 mmol) was added in four
equal portions during 15 min to a stirred, ice-cooled mixture of the
sulfone 22 (2.5 g, 4.57 mmol), anhydrous disodium orthophosphate
(1.94 g, 13.7 mmol) in anhydrous methanol (40 mL). The resulting
mixture was stirred further for a period of 1 h with continued
cooling and then allowed to warm to ambient temperature and
stirred for 2 h. Methanol was evaporated and crude residue was
partitioned between ether (50 mL) and water (50 mL). The ether
layer was separated and washed with water (25 mL), brine (25 mL),
dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure to afford the crude product. Purification by the
flash column chromatography using 10% EtOAc/hexane (v/v) as the
afford compound 31 (E:Z ¼ 88:12) as a colorless oil (1.4 g, 2.4 mmol)
20
in 75% yield. TLC: Rf ¼ 0.5 (ethyl acetate:hexanes, 2:8); [
a]
D: ꢀ3.5ꢁ (c 0.7, CHCl3); IR (neat): 2960, 2929, 1735, 1384, 1035,
800 cmꢀ1 1H NMR (500 MHz, CDCl3):
; d 7.74e7.67 (m, 4H),
7.44e7.34 (m, 6H), 5.51e5.38 (m, 2H), 4.68 (d, J ¼ 6.9 Hz, 1H), 4.61
(d, J ¼ 6.9 Hz, 1H), 4.19e4.08 (m, 1H), 4.01 (dd, J ¼ 8.9, 5.0 Hz, 1H),
3.88 (dd, J ¼ 11.3, 2.1 Hz, 1H), 3.76 (dd, J ¼ 11.3, 5.3 Hz, 1H),
3.72e3.68 (m, 2H), 3.63e3.56 (m, 1H), 3.39e3.33 (m, 4H),
2.37e2.15 (m, 3H), 2.01e1.94 (m, 1H), 1.42 (s, 3H), 1.33 (s, 3H), 1.10
(d, J ¼ 6.4 Hz, 3H), 1.07 (s, 9H), 1.01 (d, J ¼ 7.0 Hz, 3H); 13C NMR
eluent afforded ester 23 (1.81 g, 3.64 mmol) in 80% yield. TLC:
Rf ¼ 0.3 (ethyl acetate:hexanes, 2:8); [
(125 MHz, CDCl3): d 135.7, 135.7, 135.1, 133.7, 133.7, 129.5, 127.8,
20
a
]
D: ꢀ9.8ꢁ (c 2.84, CHCl3);
127.5, 127.5, 108.5, 95.1, 78.9, 76.6, 75.5, 69.8, 65.7, 64.5, 55.3, 42.2,
Please cite this article in press as: Raghavan S, Ravi A, Synthesis of an advanced intermediate enroute to thiomarinol antibiotics, Tetrahedron
(2017), http://dx.doi.org/10.1016/j.tet.2017.03.089

S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
7
36.8, 33.7, 28.3, 26.8, 26.4, 19.3, 17.0, 15.8; MS (ESI): 605 [MþNa]þ;
saturated NH4Cl solution (60 mL) and extracted with EtOAc
(3 ꢂ 60 mL). The combined extracts were washed with H2O
(80 mL), brine (80 mL), dried over anhydrous Na2SO4 and concen-
trated in vacuo. The residue was purified by flash column chro-
matography on silica gel using 30% EtOAc/hexane (v/v) as the
eluent to provide allylic alcohol 33(dr 45:55) as an epimeric
mixture (0.36 g, 0.69 mmol) in 81% yield. TLC: Rf ¼ 0.4 (ethyl ace-
tate:hexanes, 4:6); IR (neat): 3416, 2927, 2832, 1731, 1384, 1059,
HRMS (ESI): m/z Calcd. for
C34H50O6NaSi: 605.3269, found:
605.3283.
4.1.13. ((3aR,4S,7S,7aR)-7-((4R,5S,E)-5-(methoxymethoxy)-4-
methylhex-2-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo
[4,5-c]pyran-4-yl)methanol (32)
To a solution of compound 31 (1.0 g, 1.72 mmol) in THF (8 mL)
was added TBAF (1 M in THF, 1.72 mL, 1.72 mmol). The reaction was
stirred at room temperature for 3 h and then quenched with
saturated NH4Cl solution (10 mL). The layers were separated and
the aqueous layer was extracted with EtOAc (2 ꢂ 20 mL). The
combined organic layers were washed with water (20 mL), brine
(20 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by flash column
chromatography using 30% EtOAc/hexane (v/v) as the eluent to
770 cmꢀ1 1H NMR (500 MHz, CDCl3):
; d 5.67e5.59 (m, 1H),
5.51e5.35 (m, 2H), 4.67 (d, J ¼ 6.9 Hz, 1H), 4.60 (d, J ¼ 6.9 Hz, 1H),
4.26 (d, J ¼ 5.8 Hz, 2H), 4.14e4.10 (m, 1.5H), 4.05e3.98 (m, 1H),
3.96e3.92 (m, 0.5H), 3.74e3.63 (m, 2H), 3.62e3.55 (m, 1H), 3.42
(dd, J ¼ 8.9, 5.2 Hz, 0.5H), 3.38e3.32 (m, 3.5H), 2.64e2.55 (bs,
0.5OH), 2.48e2.43 (bs, 0.5OH), 2.34e2.25 (m, 1H), 2.21e2.12 (m,
2H), 2.00e1.94 (m, 1H), 1.63 (s, 3H), 1.50 (s, 3H), 1.32 (s, 3H), 1.09 (d,
J ¼ 6.3 Hz, 3H), 1.01 (d, J ¼ 6.9 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 6H); 13
C
afford compound 32 as a colorless oil (0.52 g, 1.51 mmol) in 88%
NMR (75 MHz, CDCl3): d 135.3, 135.2*, 134.9*, 134.2, 128.1, 127.6*,
20
yield. TLC: Rf ¼ 0.3 (ethyl acetate:hexanes, 3:7); [
a]
D: ꢀ6.5ꢁ (c 1,
127.5, 108.7, 108.5*, 95.1, 78.6, 78.5*, 77.4, 76.5, 75.4, 75.3*, 70.8,
70.6*, 66.2, 65.9*, 60.1, 60.0*, 55.4, 42.2, 36.7, 33.8, 33.7*, 28.2, 26.3,
26.0, 18.3, 17.0, 15.8, 13.0*, 12.9, ꢀ5.1, ꢀ5.2; MS (ESI): 551 [MþNa]þ;
HRMS (ESI): m/z Calcd. for C28H52O7SiNa: 551.3375, found 551.3381.
Note:- The 13C signals for one of the epimeric alcohol is denoted by
an asterisk mark.
CHCl3); IR (neat): 3416, 2927, 1731, 1342, 1059, 770 cmꢀ1 1H NMR
;
(500 MHz, CDCl3):
d
5.52e5.38 (m, 2H), 4.67 (d, J ¼ 6.8 Hz, 1H), 4.60
(d, J ¼ 6.8 Hz, 1H), 4.17e4.11 (m, 1H), 3.87 (dd, J ¼ 9.2, 5.0 Hz, 1H),
3.84e3.77 (m, 1H), 3.74 (dd, J ¼ 11.5, 2.9 Hz, 1H), 3.71e3.65 (m, 1H),
3.62e3.52 (m, 2H), 3.39e3.31 (m, 4H), 2.35e2.12 (m, 3H),
2.07e1.94 (m, 2H), 1.49 (s, 3H), 1.34 (s, 3H), 1.09 (d, J ¼ 6.2 Hz, 3H),
1.01 (d, J ¼ 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d
135.2, 127.5,
4.1.16. (E)-4-((tert-Butyldimethylsilyl)oxy)-1-((3aR,4R,7S,7aR)-7-
((4R,5S,E)-5-(methoxymethoxy)-4-methylhex-2-en-1-yl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-2-
108.7, 95.1, 78.4, 76.5, 75.2, 70.0, 66.0, 63.2, 55.3, 42.2, 36.6, 33.8,
28.2, 26.2, 17.0, 15.8; MS (ESI): 367 [MþNa]þ; HRMS (ESI): m/z
Calcd. for C18H32O6Na: 367.2091, found: 367.2093.
methylbut-2-en-1-one (34)
To a stirred solution of alcohol 33 (0.264 g, 0.5 mmol) in anhy-
drous dichloromethane (4 mL) was added solid NaHCO3 (0.17 g,
2 mmol) followed by the DesseMartin periodinane (0.28 g,
0.65 mmol). After stirring for 30 min, the reaction mixture was
filtered through a pad of Celite. To the organic layer, aqueous
saturated Na2S2O3 solution (6 mL) and aqueous saturated NaHCO3
solution (5 mL) were added and the biphasic mixture was stirred
until both the layers had cleared. The aqueous layer was extracted
with CH2Cl2 (2 ꢂ 10 mL), the combined organic layers were washed
with brine (8 mL) and dried over anhydrous Na2SO4. The solution
was filtered and concentrated under reduced pressure to provide
ketone 34 as a clear colorless oil (0.22 g, 0.42 mmol) in 84% yield
which was taken ahead to the next step without any further puri-
fication. TLC: Rf ¼ 0.3 (ethyl acetate:hexanes, 3:7); IR (neat): 3447,
2924, 2874, 1654, 1515, 1301, 852 cmꢀ1; 1H NMR (400 MHz, CDCl3):
4.1.14. (3aR,4R,7S,7aR)-7-((4R,5S,E)-5-(Methoxymethoxy)-4-
methylhex-2-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo
[4,5-c]pyran-4-carbaldehyde (8)
To a solution of alcohol 32 (0.76 g, 2.2 mmol) in anhydrous
CH2Cl2 (11 mL) cooled to 0 ꢁC was added BAIB (0.85 g, 2.64 mmol),
TEMPO (40 mg, 0.22 mmol) under nitrogen atmosphere and stirred
at 0 ꢁC until complete consumption of starting material occurred
(ca. 4 h). The reaction mixture was passed through a short pad of
Celite, the volatiles were removed under reduced pressure to afford
the crude aldehyde which was purified by flash column chroma-
tography using 25% EtOAc/hexane (v/v) as the eluent to afford
aldehyde 8 (0.55 g, 1.6 mmol) in 73% yield. TLC: Rf ¼ 0.2 (ethyl
20
acetate:hexanes, 3:7); [
a
]
D: ꢀ12.5ꢁ (c 1, CHCl3); IR (neat): 2960,
ꢀ1
;
1H NMR (500 MHz, CDCl3):
2938, 1735, 1325, 1065, 835 cm
d
9.73 (s, 1H), 5.53e5.37 (m, 2H), 4.67 (d, J ¼ 6.9 Hz, 1H), 4.60 (d,
d
6.84 (tq, J ¼ 5.1, 1.0 Hz, 1H), 5.53e5.30 (m, 2H), 4.67 (d, J ¼ 6.8 Hz,
J ¼ 6.9 Hz, 1H), 4.20e4.11 (m, 2H), 3.94 (d, J ¼ 7.6 Hz, 1H), 3.80 (dd,
J ¼ 11.6, 3.2 Hz, 1H), 3.66 (dd, J ¼ 11.6, 3.2 Hz, 1H), 3.62e3.55 (m,
1H), 3.36 (s, 3H), 2.34e2.25 (m, 1H), 2.24e2.12 (m, 2H), 2.05e1.96
(m, 1H), 1.56 (s, 3H), 1.38 (s, 3H), 1.09 (d, J ¼ 6.4 Hz, 3H), 1.00 (d,
1H), 4.60 (d, J ¼ 6.8 Hz, 1H), 4.53 (d, J ¼ 7.3 Hz, 1H), 4.45 (dd, J ¼ 5.1,
1.0 Hz, 2H), 4.36 (dd, J ¼ 7.0, 5.1 Hz, 1H), 4.20e4.17 (m, 1H), 3.79 (dd,
J ¼ 11.5, 3.3 Hz, 1H), 3.62e3.51 (m, 2H), 3.36 (s, 3H), 2.34e1.95 (m,
4H), 1.76 (s, 3H), 1.56 (s, 3H), 1.36 (s, 3H), 1.08 (d, J ¼ 6.2 Hz, 3H), 1.00
(d, J ¼ 6.8 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 6H); MS (ESI): 549 [MþNa]þ;
J ¼ 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 200.4, 135.5, 127.1,
109.4, 95.0, 77.3, 76.5, 75.2, 70.8, 66.3, 55.3, 42.1, 36.5, 33.3, 28.2,
HRMS (ESI): m/z Calcd. for C28H50O7SiNa: 549.3218, found
26.1, 17.1, 15.8; MS (ESI): 365 [MþNa]þ; HRMS (ESI): m/z Calcd. for
549.3234.
C
18H30O6Na: 365.1935, found 365.1937.
4.1.17. (R,E)-4-((tert-Butyldimethylsilyl)oxy)-1-((3aR,4S,7S,7aR)-7-
((4R,5S,E)-5-(methoxymethoxy)-4-methylhex-2-en-1-yl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-2-
4.1.15. (R,E)-4-((tert-Butyldimethylsilyl)oxy)-1-((3aR,4S,7S,7aR)-7-
((4R,5S,E)-5-(methoxymethoxy)-4-methylhex-2-en-1-yl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-2-
methylbut-2-en-1-ol and (S,E)-4-((tert-Butyldimethylsilyl)oxy)-1-
((3aR,4S,7S,7aR)-7-((4R,5S,E)-5-(methoxymethoxy)-4-methylhex-
2-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-
yl)-2-methylbut-2-en-1-ol (33)
To a stirred suspension of NiCl2 (7.3 mg, 0.05 mmol) and CrCl2
(0.84 g, 6.8 mmol) in degassed DMSO (25 mL) under an argon at-
mosphere was added a solution of the aldehyde 8 (0.29 g,
0.85 mmol) and iodo alkene 9 (2.12 g, 6.8 mmol) in degassed DMSO
(8 mL). The mixture was stirred for 19 h, diluted with an aq
methylbut-2-en-1-ol (36)
To a solution of ketone 34 (100 mg, 0.19 mmol) in mixture of
CH2Cl2 and H2O (1:1, 10 mL) at 25 ꢁC were added HCO2Na (0.13 g,
1.9 mmol), n-Bu4NBr (18 mg, 0.06 mmol) and cat. RuCl(p-cymene)
[(S,S)-Ts-DPEN] (2.5 mg, 0.004 mmol) and the biphasic mixture was
stirred vigorously at 25 ꢁC for 24 h. The mixture was then diluted
with H2O (8 mL), extracted with CH2Cl2 (3 ꢂ 10 mL) and the
combined organic layers were washed with brine (15 mL) and dried
over anhydrous Na2SO4. The solution was filtered and concentrated
under reduced pressure to provide alcohol 36 (dr 92:8) as a clear
Please cite this article in press as: Raghavan S, Ravi A, Synthesis of an advanced intermediate enroute to thiomarinol antibiotics, Tetrahedron
(2017), http://dx.doi.org/10.1016/j.tet.2017.03.089

8
S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
colorless oil (93 mg, 0.176 mmol) in 93% yield which was used
1H), 5.47e5.36 (m, 2H), 4.67 (d, J ¼ 6.9 Hz, 1H), 4.61 (d, J ¼ 6.9 Hz,
1H), 4.26e4.16 (m, 3H), 4.12e4.06 (m, 2H), 3.67 (dd, J ¼ 11.4, 2.9 Hz,
1H), 3.61e3.56 (m, 2H), 3.41 (dd, J ¼ 8.2, 3.1 Hz, 1H), 3.36 (s, 3H),
2.36e2.26 (m, 1H), 2.21e2.13 (m, 2H), 1.94e1.87 (m, 1H), 1.70 (s,
3H), 1.45 (s, 3H), 1.29 (s, 3H), 1.09 (d, J ¼ 6.3 Hz, 3H), 1.00 (d,
J ¼ 6.9 Hz, 3H), 0.91 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR
without any further purification. TLC: Rf ¼ 0.4 (ethyl acetate:hex-
20
anes, 4:6); [
a
]
D: þ0.7ꢁ (c 0.9, CHCl3); IR (neat): 3448, 2931, 2854,
1728, 1427, 1384, 1108 cm-1; 1H NMR (500 MHz, CDCl3):
d 5.64 (t,
J ¼ 5.8 Hz, 1H), 5.61e5.35 (m, 2H), 4.67 (d, J ¼ 6.9 Hz, 1H), 4.60 (d,
J ¼ 6.9 Hz, 1H), 4.26 (d, J ¼ 5.8 Hz, 2H), 4.14e4.10 (m, 2H), 4.02 (dd,
J ¼ 8.7, 5.2 Hz, 1H), 3.73e3.63 (m, 2H), 3.62e3.56 (m, 1H), 3.42 (dd,
J ¼ 8.9, 5.2 Hz, 1H), 3.36 (s, 3H), 2.59 (d, J ¼ 3.2 Hz, 1OH), 2.34e2.25
(m, 1H), 2.21e2.11 (m, 2H), 2.20e1.93 (m, 1H), 1.65 (s, 3H), 1.50 (s,
3H), 1.32 (s, 3H), 1.09 (d, J ¼ 6.3 Hz, 3H), 1.01 (d, J ¼ 6.9 Hz, 3H), 0.90
(125 MHz, CDCl3):
d 139.0, 135.2, 127.7, 124.4, 108.1, 95.2, 79.4, 77.0,
76.7, 75.5, 69.0, 65.3, 58.5, 55.3, 42.3, 36.8, 33.2, 28.3, 26.5, 25.9,
18.3, 17.0, 15.8, 13.8, ꢀ4.8; MS (ESI): 551 [MþNa]þ; HRMS (ESI): m/z
Calcd. for C28H52O7SiNa: 551.3375, found 551.3384.
(s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 135.2, 134.2, 128.2,
127.6, 108.7, 95.1, 78.6, 77.4, 76.5, 75.4, 70.9, 66.2, 60.0, 55.4, 42.2,
36.7, 33.8, 28.2, 26.3, 26.0, 18.3, 17.0, 15.8, 12.9, ꢀ5.1, ꢀ5.2; MS (ESI):
551 [MþNa]þ; HRMS (ESI): m/z Calcd. for C28H52O7SiNa: 551.3375,
found 551.3382.
4.1.20. (R,E)-4-((tert-Butyldimethylsilyl)oxy)-4-((3aR,4R,7S,7aR)-7-
((4R,5S,E)-5-(methoxymethoxy)-4-methylhex-2-en-1-yl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-3-
methylbut-2-enoic acid (6)
4.1.18. (R,E)-5-((3aR,4R,7S,7aR)-7-((4R,5S,E)-5-
(Methoxymethoxy)-4-methylhex-2-en-1-yl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-
2,2,3,3,6,10,10,11,11-nonamethyl-4,9-dioxa-3,10-disiladodec-6-ene
(37)
To a stirred solution of alcohol 38 (10 mg, 0.019 mmol) in a
mixture of CH3CN:H2O (1:1, 3 mL) were added BAIB (177.5 mg,
0.57 mmol) and TEMPO (5.6 mg, 0.04 mmol) at 0 ꢁC. The reaction
mixture was warmed to room temperature and stirred further for a
period of 2 h. The reaction mixture was passed through a short pad
of silica gel and the volatiles were removed under reduced pressure
to afford the crude residue. The residue was dissolved in CH2Cl2 and
the pH adjusted to 9 using saturated NaHCO3 solution. The layers
were separated and the aqueous layer was adjusted to pH ¼ 3e4
using aqueous 1N HCl. The acid was extracted with CH2Cl2
(3 ꢂ 5 mL), the combined extracts were washed with brine (6 mL),
dried over anhydrous Na2SO4, filtered and concentrated under
To a stirred solution of allylic alcohol 36 (44 mg, 0.083 mmol) in
CH2Cl2 (2 mL) cooled to ꢀ20 ꢁC were added 2,6 lutidine (22
mL,
0.19 mmol) followed by TBSOTf (20 mL, 0.09 mmol) and the reaction
mixture was stirred at the same temperature for 3 h. The reaction
mixture was then quenched with aqueous saturated NH4Cl solution
(1 mL) and the biphasic mixture was extracted with CH2Cl2
(2 ꢂ 2 mL). The combined organic layers were washed with brine
(4 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure to afford the crude product. Purification by
the flash column chromatography using 20% EtOAc/hexane (v/v) as
the eluent afforded compound 37 with dr 45:55 (43 mg,
reduced pressure to afford acid 6 (9 mg, 0.017 mmol) in 92% yield.
20
TLC: Rf ¼ 0.2 (ethyl acetate:hexanes, 6:4); [
a
]
D: þ29ꢁ (c 0.7,
CHCl3); IR (neat): 3447, 2927, 2857, 1691, 1617, 1315, 1059,
770 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
6.05 (q, J ¼ 1.2 Hz, 1H),
0.067 mmol) in 81% yield. TLC: Rf ¼ 0.6 (ethyl acetate:hexanes, 4:6);
5.48e5.35 (m, 2H), 4.68 (d, J ¼ 6.9 Hz, 1H), 4.61 (d, J ¼ 6.9 Hz, 1H),
4.28e4.24 (m, 1H), 4.17 (dd, J ¼ 8.3, 5.1 Hz, 1H), 4.09 (dd, J ¼ 4.8,
2.0 Hz, 1H), 3.69 (dd, J ¼ 11.5, 2.7 Hz, 1H), 3.64e3.55 (m, 2H), 3.46
(dd, J ¼ 8.4, 2.4 Hz, 1H), 3.36 (s, 3H), 2.38e2.27 (m, 2H), 2.21e2.12
(m, 4H), 1.95e1.89 (m, 1H), 1.43 (s, 3H), 1.29 (s, 3H), 1.09 (d,
J ¼ 6.3 Hz, 3H), 1.00 (d, J ¼ 6.9 Hz, 3H), 0.93 (s, 9H), 0.07 (s, 3H), 0.03
(s, 3H); MS (ESI): 565 [MþNa]þ; HRMS (ESI): m/z Calcd. for
20
[
a]
D: þ1.1ꢁ (c 1, CHCl3); IR (neat): 2930, 2858, 1732, 1412, 1357,
1100 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
5.56 (tq, J ¼ 6.1, 1.2 Hz,1H),
5.46e5.35 (m, 2H), 4.67 (d, J ¼ 6.9 Hz, 1H), 4.60 (d, J ¼ 6.9 Hz, 1H),
4.23 (d, J ¼ 5.9 Hz, 2H), 4.15e4.08 (m, 2H), 4.05e4.02 (m, 1H), 3.63
(dd, J ¼ 11.4, 3.1 Hz,1H), 3.60e3.56 (m,1H), 3.54 (dd, J ¼ 11.4, 3.1 Hz,
1H), 3.46 (dd, J ¼ 7.6, 3.5 Hz, 1H), 3.36 (s, 3H), 2.34e2.24 (m, 1H),
2.20e2.07 (m, 2H), 1.93e1.85 (m, 1H), 1.62 (s, 3H), 1.45 (s, 3H), 1.31
(s, 3H), 1.08 (d, J ¼ 6.3 Hz, 3H), 0.99 (d, J ¼ 6.9 Hz, 3H), 0.90 (s, 9H),
0.89 (s, 9H), 0.06 (s, 9H), 0.02 (S, 3 h); 13C NMR (125 MHz, CDCl3):
C28H50O8SiNa: 565.3167, found 565.3186.
d
135.2, 135.0, 127.8, 127.2, 108.1, 95.1, 80.1, 77.7, 76.6, 75.6, 69.8,
4.1.21. (S)-Ethyl 3-hydroxybutanoate (25)
65.4, 60.0, 55.3, 42.2, 37.1, 33.3, 28.3, 26.5, 25.9, 18.3, 16.9, 15.7,
13.1, ꢀ4.7, ꢀ4.9, ꢀ5.15, ꢀ5.2; MS (ESI): 665 [MþNa]þ; HRMS (ESI):
m/z Calcd. for C34H66O7Si2Na: 665.4239, found 665.4261.
A 100-mL, parr hydrogenation vessel was charged with Ethyl
acetoacetate (6.5 g, 50 mmol) and degassed Ethanol (70 mL). To this
mixture was added the in situ prepared [(S)-2,20 Bis(diphenyl-
phosphino)-1,1'-binaphthyl]ruthenium(II) complex (0.1 mol%,
43 mg, 0.05 mmol) in degassed Ethanol (5 mL) under an argon. The
hydrogenation vessel was attached to a hydrogen source and hy-
drogenation was carried out at 50 psig H2 and 80 ꢁC for 8 h. After
the reaction mixture was allowed to cool to room temperature, the
stop valve was opened, excess hydrogen was carefully bled off, and
the apparatus was disassembled. The resulting orange solution was
poured into a 250 mL, round-bottomed flask, and the hydrogena-
tion vessel was rinsed with dichloromethane (3 ꢂ 30 mL). The
solvent was removed by a rotary evaporator, and the residue was
distilled to give hydroxy ester 25 with er 93:7 (6.3 g, 47.5 mmol) in
95% yield (bp 72 ꢁC,12 mm Hg). TLC: Rf ¼ 0.3 (ethyl acetate: hexane,
4.1.19. (R,E)-4-((tert-Butyldimethylsilyl)oxy)-4-((3aR,4R,7S,7aR)-7-
((4R,5S,E)-5-(methoxymethoxy)-4-methylhex-2-en-1-yl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-3-
methylbut-2-en-1-ol (38)
A solution of 37 (20 mg, 0.03 mmol) in anhydrous THF (1.5 mL)
cooled to 0 ꢁC was treated with a solution of HF-pyridine (ca ~70%
HF, 0.2 mL). The reaction was stirred at the same temperature for a
period of 3 h, at which time the reaction was diluted dropwise with
aqueous saturated NaHCO3 solution (1 mL) and warmed to room
temperature with stirring. The reaction mixture was extracted with
CH2Cl2 (3 ꢂ 2 mL). The combined organic layers were washed with
brine (3 mL), dried over anhydrous Na2SO4, filtered and concen-
trated under reduced pressure to afford the crude product. Purifi-
cation by the flash column chromatography using 30% EtOAc/
hexane (v/v) as the eluent afforded compound 38 (12 mg,
30:70); [
a
]
25D ¼ þ38ꢁ (c ¼ 1.0, CHCl3); IR (neat) nmax: 3449, 2979,
ꢀ1
2938, 1732, 1377, 1188 cm
;
1H NMR (500 MHz, CDCl3):
d
4.18e4.10 (m, 3H), 2.94e2.68 (bs, OH), 2.43 (dd, J ¼ 16.8, 4.0 Hz,
1H), 2.37 (dd, J ¼ 16.8, 8.9 Hz, 1H), 1.27 (t, J ¼ 6.9 Hz, 3H), 1.20 (d,
0.023 mmol) in 77% yield. TLC: Rf ¼ 0.3 (ethyl acetate:hexanes, 4:6);
J ¼ 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 172.6, 64.1, 60.5, 42.8,
20
[
a]
D: þ17ꢁ (c 2.3, CHCl3); IR (neat): 3416, 2927, 2857, 1731,1487,
22.3, 14.0; MS (ESI): 133 [MþH]þ; HRMS (ESI): m/z Calcd. for
1335, 1059, 770 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
5.83e5.69 (m,
C6H13O3: 133.0859, found 133.0860.
Please cite this article in press as: Raghavan S, Ravi A, Synthesis of an advanced intermediate enroute to thiomarinol antibiotics, Tetrahedron
(2017), http://dx.doi.org/10.1016/j.tet.2017.03.089

S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
9
4.1.22. (2S,3S)-Ethyl 3-hydroxy-2-methylbutanoate (26)
3.76e3.60 (m, 2H), 3.56 (dd, J ¼ 10.9, 5.8 Hz, 1H), 3.40 (s, 3H),
2.87e2.40 (bs, OH), 1.81e1.67 (m, 1H), 1.21 (d, J ¼ 6.2 Hz, 3H), 0.95
n-BuLi (2.5 M in hexane, 37.8 mL, 94.5 mmol) was added
dropwise to a solution of diisopropylamine (13.9 mL, 99 mmol) in
anhydrous THF (100 mL) cooled to ꢀ78 ꢁC. The resulting yellow
solution was stirred at this temperature for 1 h before a solution of
ethyl (S)-3-hydroxybutyrate 25 (5.9 g, 45 mmol) in anhydrous THF
(32 mL) and anhydrous HMPA (15 mL) was slowly added via can-
nula. The mixture was allowed to warm to ꢀ40 ꢁC and stirred for
20 min before it was recooled to ꢀ78 ꢁC and iodomethane (3.5 mL,
56.3 mmol) was introduced and stirred for 1 h. The mixture was
warmed to 0 ꢁC and stirred further for a period of 2 h before the
reaction was quenched with aq saturated NH4Cl solution (12 mL).
1N HCl (10 mL) was then added to adjust the pH to 7. The layers
were separated and the aq layer was extracted with Et2O
(3 ꢂ 50 mL). The combined organic layers were dried over anhy-
drous Na2SO4, evaporated and the residue was purified by flash
column chromatography using 30% EtOAc/hexane (v/v) as the
eluent to afford compound 26 (dr 95:5) as a colourless oil (5.4 g,
(d, J ¼ 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 94.9, 77.2, 65.8, 55.5,
41.0, 17.7, 13.6; MS (ESI): 171 [MþNa]þ; HRMS (ESI): m/z Calcd. for
C7H16O3Na: 171.0992, found 171.0990.
4.1.25. 5-(((2S,3S)-3-(Methoxymethoxy)-2-methylbutyl)thio)-1-
phenyl-1H-tetrazole (30)
To a solution of the mixture of alcohol 28 (3.4 g, 23 mmol) and
triphenylphosphine (7.8 g, 29.9 mmol) in anhydrous toluene
(38 mL) cooled to 0 ꢁC was added 1-phenyltetrazole-5-thiol 29
(5.3 g, 29.9 mmol) followed by dropwise addition of DEAD (4.7 mL,
29.9 mmol). The reaction mixture was stirred gradually allowing it
to warm to room temperature over a period of 20 min. The reaction
mixture was quenched by adding aqueous saturated NaHCO3 so-
lution (22 mL). The layers were separated and the aqueous layer
was extracted with dichloromethane (3 ꢂ 15 mL). The combined
organic layers were washed with brine (40 mL), dried over anhy-
drous Na2SO4, filtered and concentrated under reduced pressure to
furnish the crude product. Purification of the crude residue via flash
column chromatography using 8% EtOAc/hexane (v/v) as the eluent
37 mmol) in 82% yield. TLC: Rf ¼ 0.3 (ethyl acetate:hexane, 35:65);
20
[
a]
D: þ21.8ꢁ (c 1, CHCl3), IR (neat): 3449, 2979, 2938, 1732, 1377,
1188 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
4.17 (q, J ¼ 7.2 Hz, 2H),
3.91e3.83 (m, 1H), 2.74e2.68 (bs, OH), 2.43 (quintet, J ¼ 7.2 Hz, 1H),
afforded compound 30 as a colourless oil (5.4 g, 17.5 mmol) in 76%
20
1.27 (t, J ¼ 7.2 Hz, 3H), 1.22 (d, J ¼ 6.4 Hz, 3H), 1.18 (d, J ¼ 7.2 Hz, 3H);
yield. TLC: Rf ¼ 0.5 (ethyl acetate:hexane, 20:80); [
a
]
D: þ28.2ꢁ (c
13C NMR (75 MHz, CDCl3):
d
175.8, 69.2, 60.5, 46.8, 20.5, 14.1, 13.8;
0.55, CHCl3); IR (neat): 3065, 2971, 2930,1499, 1385,1037 cm ꢀ1; 1H
MS (ESI): 147 [MþH]þ; HRMS (ESI): m/z Calcd. for C7H15O3:
NMR (500 MHz, CDCl3):
d
7.65e7.44 (m, 5H), 4.67 (d, J ¼ 6.9 Hz, 1H),
147.1016, found 147.1015.
4.56 (d, J ¼ 6.9 Hz, 1H), 3.72e3.60 (m, 2H), 3.40e3.20 (m, 4H),
2.17e2.00 (m,1H),1.22 (d, J ¼ 6.9 Hz, 3H),1.07 (d, J ¼ 6.9 Hz, 3H); 13
C
4.1.23. (2S,3S)-Ethyl 3-(methoxymethoxy)-2-methylbutanoate (27)
To a stirred solution of compound 26 (5.1 g, 35 mmol) and TBAI
(564 mg, 1.75 mmol) in anhydrous dichloromethane (70 mL) cooled
to 0 ꢁC was added dropwise N,N-diisopropylethylamine (9.2 mL,
52.5 mmol). The reaction mixture was stirred at 0 ꢁC for 10 min and
then MOM-Cl (3.2 mL, 42 mmol) was added and the mixture was
stirred gradually allowing it to attain room temperature and stirred
further for 4 h. The reaction mixture was diluted with CH2Cl2
(50 mL), washed with water (70 mL), dried over anhydrous Na2SO4
and filtered. The solvent was evaporated under reduced pressure to
furnish the crude product which was purified by flash column
chromatography using 10% EtOAc/hexane (v/v) as the eluent to give
NMR (75 MHz, CDCl3): d 154.6, 133.7, 130.0, 129.7, 123.8, 95.2, 75.8,
55.5, 38.6, 36.6, 16.9, 15.2; MS (ESI): 309 [MþH]þ; HRMS (ESI): m/z
Calcd. for C14H21O2N4S: 309.1380, found 309.1379.
4.1.26. 5-(((2S,3S)-3-(Methoxymethoxy)-2-methylbutyl)sulfonyl)-
1-phenyl-1H-tetrazole (11)
To a solution of sulfide 30 (4.9 g, 16 mmol) in anhydrous CH2Cl2
(32 mL) cooled to ꢀ30 ꢁC was added mCPBA (6.0 g, 35.2 mmol). The
reaction mixture was stirred for 3 h at the same temperature and
then quenched by the addition of saturated sodium sulfite (10 mL).
The layers were separated and the aqueous layer was extracted with
dichloromethane (3 ꢂ 20 mL). The combined organic layers were
washed with NaHCO3 (30 mL), brine (40 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure to furnish
the crude product. Purification of the crude residue via flash column
chromatography using 30% EtOAc/hexane (v/v) as the eluent affor-
compound 27 as a colourless oil (5.7 g, 30 mmol) in 85% yield. TLC:
20
Rf ¼ 0.4 (ethyl acetate:hexane, 20:80); [
a
]
D: þ21.9ꢁ (c 1.0, CHCl3);
ꢀ1
IR (neat): 2981, 2938, 1735, 1379, 1190, 1037 cm
;
1H NMR
(300 MHz, CDCl3):
d
4.65e4.52 (m, 2H), 4.11 (q, J ¼ 7.6 Hz, 2H),
3.93e3.82 (m, 1H), 3.31 (s, 3H), 2.62e2.59 (m, 1H),1.27 (t, J ¼ 7.6 Hz,
ded compound 11 as a colourless oil (4.7 g, 13.8 mmol) in 86% yield.
3H), 1.16 (d, J ¼ 6.0 Hz, 3H), 1.10 (d, J ¼ 6.8 Hz, 3H); 13C NMR
TLC: Rf ¼ 0.3 (ethyl acetate:hexane, 30:70); [
a
]
D: þ19.8ꢁ (c 0.75,
20
(75 MHz, CDCl3):
d
174.8, 95.4, 74.9, 60.3, 55.4, 45.9, 17.1, 14.2, 12.7;
CHCl3); IR (neat): 3072, 2930, 1702, 1343, 1151, 1037 cm ꢀ1; 1H NMR
MS (ESI): 213 [MþNa]þ; HRMS (ESI): m/z Calcd. for C9H18O4Na:
(500 MHz, CDCl3): d 7.68e7.62 (m, 2H), 7.61e7.52 (m, 3H), 4.65 (d,
213.1097, found 213.1098.
J ¼ 6.9 Hz, 1H), 4.52 (d, J ¼ 6.9 Hz, 1H), 4.02 (dd, J ¼ 14.7, 3.2 Hz, 1H),
3.66e3.57 (m, 1H), 3.52 (dd, J ¼ 14.7, 9.2 Hz, 1H), 3.33 (s, 3H),
4.1.24. (2R,3S)-3-(Methoxymethoxy)-2-methylbutan-1-ol (28)
To a suspension of LAH (2.3 g, 59.4 mmol) in anhydrous THF
(50 mL) cooled to 0 ꢁC was added a solution of 27 (5.1 g, 27 mmol)
in anhydrous THF (20 mL) dropwise during 10 min. The reaction
mixture was stirred for an additional 15 min at 0 ꢁC and then
allowed to warm to room temperature. After 3 h, the reaction
mixture was diluted with ether (100 mL) and quenched with ice
pieces. The resulting reaction mixture was filtered through a Celite
pad. The filtrate was dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure to yield the crude product.
Purification of the crude residue via flash column chromatography
using 15% EtOAc/hexane (v/v) as the eluent afforded compound 28
2.42e2.30 (m,1H), 1.18 (d, J ¼ 6.8 Hz, 3H),1.17 (d, J ¼ 6.4 Hz, 3H); 13
C
NMR (75 MHz, CDCl3):
d 154.0, 133.0, 131.3, 129.5, 125.1, 95.0, 75.7,
58.2, 55.6, 33.8, 17.1, 16.4; MS (ESI): 341 [MþH]þ; HRMS (ESI): m/z
Calcd. for C14H21O4N4S: 7341.1278, found 341.1277.
4.1.27. (S)-Mandelate ester of rac 25
To a solution of racemic alcohol (33 mg, 0.25 mmol), obtained by
treatment of ethyl acetoacetate with NaBH4, in DCM (1.0 mL) was
added (S)-(ꢀ)-
a-methoxy phenylacetic acid (45.5 mg, 0.275 mmol),
DMAP (5 mg, 15 mol%) and DCC (62.3 mg, 0.275 mmol) at 0 ꢁC. The
reaction mixture was stirred for 2 h at rt and the solvent was
evaporated in vacuo. The crude product was triturated with cold
ether (2 mL) to afford the mandelate ester of the alcohol in 90%
yield as mixture of diastereomer. TLC: Rf 0.3 (9:1 hexanes:ethyl
as a colourless oil (3.76 g, 25.4 mmol) in 94% yield. TLC: Rf ¼ 0.2
20
(ethyl acetate:hexane, 15:85); [
a]
D: þ17.3ꢁ (c 1.3, CHCl3); IR
ꢀ1
(neat): 3430, 2971, 2932, 2888, 1454, 1380, 1037 cm
;
1H NMR
acetate). 1H NMR (300 MHz, CDCl3):
d
7.45e7.40 (m, 4H), 7.39e7.30
(300 MHz, CDCl3):
d
4.74 (d, J ¼ 6.8 Hz, 1H), 4.61 (d, J ¼ 6.8 Hz, 1H),
(m, 6H), 5.40e5.26 (m, 2H), 4.74e4.71 (2s, 2H), 4.13e4.04 (m, 2H),
Please cite this article in press as: Raghavan S, Ravi A, Synthesis of an advanced intermediate enroute to thiomarinol antibiotics, Tetrahedron
(2017), http://dx.doi.org/10.1016/j.tet.2017.03.089

10
S. Raghavan, A. Ravi / Tetrahedron xxx (2017) 1e10
3.96e3.77 (m, 2H), 3.42e3.39 (2s, 6H), 2.69e2.36 (m, 4H),1.32e1.16
(m, 9H), 1.09 (t, J ¼ 6.8 Hz, 3H).
References
1. Shiozawa H, Kagasaki T, Kinoshita T, et al. J Antibiot. 1993;46:1834.
2. Shiozawa H, Kagasaki T, Torikata A, et al. J Antibiot. 1995;48:907.
3. Shiozawa H, Shimada A, Takahashi S. J Antibiot. 1997;50:449.
4. (a) Chain EB, Mellows G. J Chem Soc Perkin Trans. 1977;1:294;
(b) Class YJ, DeShong P. Chem Rev. 1995;95:1843 (and references cited therein);
(c) Innis LV, Plancher JM, Marko IE. Org Lett. 2006;8:6111.
5. Thomas CM, Hothersall J, Willis CL, Simpson TJ. Nat Rev Micobiol. 2010;8:281.
6. Stierle DB, Stierle AA. Experientia. 1992;48:1165.
4.1.28. (S)-Mandelate ester of 25
The ester was prepared as detailed above. TLC: Rf 0.3 (9:1 hex-
anes:ethyl acetate); 1H NMR (300 MHz, CDCl3):
d 7.45e7.39 (m, 2H),
ꢀ
7.39e7.31 (m, 3H), 5.40e5.27 (m, 1H), 4.72 (s, 1H), 3.98e3.76 (m,
2H), 3.40 (s, 3 H), 2.55 (dd, J ¼ 15.9, 8.3 Hz, 1H), 2.41 (dd, J ¼ 15.9,
5.3 Hz, 1H), 1.32 (d, J ¼ 6.8 Hz, 3H), 1.09 (t, J ¼ 6.8 Hz, 3H).
7. (a) Gao X, Hall DG. J Am Chem Soc. 2005;127:1628;
(b) Marion O, Gao X, Marcus S, Hall DG. Bioorg Med Chem. 2009;17:1006;
(c) Al-Zoubi RM, Hall DG. Mol Divers. 2014;18:701.
4.1.29. (E)-tert-Butyl((3-iodobut-2-en-1-yl)oxy)dimethylsilane
(9)
8. (a) Tokunaga M, Larrow JF, Kakiuchi F, Jacobsen EN. Science. 1997;277:936;
(b) Furrow ME, Schaus SE, Jacobsen EN. J Org Chem. 1998;63:6776.
9. Raghavan S, Vinoth Kumar V, Raju Chowhan L. The structure was assigned to
compound 19 based on precedent. Synlett. 2010:1807.
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Grubbs RH. J Am Chem Soc. 2000;122:58;
To a solution of Cp2ZrCl2 (321 mg, 1.1 mmol) in anhydrous THF
(4 mL) cooled to 0 ꢁC was added DIBAL-H (0.91 mL,1.1 mmol) under
nitrogen atmosphere. The resultant suspension was stirred for
30 min at 0 ꢁC, followed by addition of a solution of (but-2-yn-1-
yloxy)(tert-butyl)dimethylsilane (184 mg, 1.0 mmol) in anhydrous
THF (1.0 mL). The mixture was warmed to room temperature and
stirred until a homogeneous solution resulted (ca. 1 h) and then
cooled to ꢀ78 ꢁC, followed by addition of the solution of I2 (330 mg,
1.3 mmol) in THF (3 mL). After 30 min at ꢀ78 ꢁC, the reaction
mixture was quenched with aq HCl (1N, 2 mL). The layers were
separated and the aq layer extracted with ether (20 mL). The
combined organic layers were washed successively with aq satu-
rated Na2S2O3 (10 mL), NaHCO3 (10 mL), brine (20 mL), dried over
NaSO4, filtered and the solvent evaporated under reduced pressure
to afford the crude product. Purification by the flash column
chromatography using 4% EtOAc/hexane (v/v) as the eluent affor-
ded compound 9 (274 mg, 0.88 mmol) in 88% yield. TLC: Rf ¼ 0.4
(b) Raghavan S, Anil R. Org Biomol Chem. 2016;14:10222.
11. (a) Kirmse W, Kapps M. Chem Ber. 1968;101:994;
(b) Doyle MP, Griffin JH, Chinn MS, van Leusen D. J Org Chem. 1984;49:1917;
(c) Raghavan S, Ravi Kumar C, Ganapathy Subramanian S. J Org Chem. 2016;81:
4252.
12. VanRheenen V, Kelly RC, Cha DY. Tetrahedron Lett. 1976;17:1973.
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14. Noyori R, Okhuma T, Kitamura M, et al. J Am Chem Soc. 1987;109:5856.
15. The enantiomer ratio was determined by converting the alcohol to mandelate
ester using (S)-mandelic acid.
16. (a) Frater G. Helv Chim Acta. 1979;62:2828;
(b) Seebach D, Wasmuth D. Helv Chim Acta. 1980;63:197.
17. Mitsunobu O, Yamada Y. Bull Chem Soc Jpn. 1967;40:2380;
(b) Mitsunobu O. Synthesis. 1981:1.
18. (a) Bellingham R, Jarowicki K, Kocienski P, Martin V. Synthesis. 1996:285;
(b) For a review, see: Blakemore PR J Chem Soc, Perkin Trans. 2002;1:2563.
19. Sridhar Y, Srihari P. Org Biomol Chem. 2014;12:2950.
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6974.
(ethyl acetate:hexanes, 1:9); 1H NMR (500 MHz, CDCl3):
d 6.29 (tq,
21. (a) Jin H, Uenishi J, Christ WJ, Kishi Y. J Am Chem Soc. 1986;108:5644;
(b) Kishi Y. Pure Appl Chem. 1992;64:343;
J ¼ 6.5, 1.5 Hz, 1H), 4.12 (d, J ¼ 6.4 Hz, 2H), 2.41 (s, 3H), 0.89 (s, 9H),
0.07 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 140.6, 95.9, 60.6, 28.1, 25.9,
(c) Takai K, Tagashira M, Kuroda T, Oshima K, Utimoto K, Nozaki H. J Am Chem
Soc. 1986;108:6048.
18.3, ꢀ5.2. MS (ESI): 313 [MþH]þ.
22. For the preparation of iodo alkene see: Huang, Z.; Negishi, E. Org. Lett. 2006, 8,
3675. It is noteworthy that the reaction of alkenyl lithium, derived from iodo
alkene 99 by treatment with t-BuLi, with aldehyde 88 resulted in the formation
of a dihydyropyran by elimination of the acetonide by abstraction of C5 H. For a
related precedent see: Williams, D. R.; Moore, J. L.; Yamada, M. J. Org. Chem.
1986; 51: 3918.
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Acknowledgment
R. Anil is thankful to Council of Scientific and Industrial Research
(CSIR)-New Delhi for fellowship. S. R is grateful to the Department
of Science and Technology, New Delhi for funding the project (SR/
S1/OC-5/2011) and CSIR, New Delhi for funding under the XII five
year plan programme entitled ORIGIN (CSC-108).
Please cite this article in press as: Raghavan S, Ravi A, Synthesis of an advanced intermediate enroute to thiomarinol antibiotics, Tetrahedron
(2017), http://dx.doi.org/10.1016/j.tet.2017.03.089