Stereoselective synthesis of the C1-C12 fragment of the thuggacins

Article abstract of DOI:10.1016/j.tetasy.2009.08.015

A concise asymmetric synthesis of the C1-C12 fragment of the antibacterial natural product thuggacins has been achieved. The stereochemistry of this fragment was established efficiently via stereoselective reduction and Evans-aldol condensation. Hanztsch'

Full text of DOI:10.1016/j.tetasy.2009.08.015

Tetrahedron: Asymmetry 20 (2009) 2027–2032
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of the C1–C12 fragment of the thuggacins
a,b,
Shoubin Tang a, Zhengshuang Xu a,b, , Tao Ye
*
*
a Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China
b Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2009
Accepted 17 August 2009
Available online 14 September 2009
A concise asymmetric synthesis of the C1–C12 fragment of the antibacterial natural product thuggacins
has been achieved. The stereochemistry of this fragment was established efficiently via stereoselective
reduction and Evans-aldol condensation. Hanztsch’s method and a Horner–Wadsworth–Emmnons
reaction were employed for thiazole formation and the construction of the E-a,b-unsaturated double
bond.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
makes it hard for scale-up preparations, a study on a new synthetic
approach could be meaningful for further applications.
As part of our research program on the synthesis of bioactive
natural products,5 especially those with novel structural features,
we herein report a concise approach toward the synthesis of the
C1–C12 fragment of the thuggacins.
Nature has consistently provided mankind with structurally di-
verse and multi-bioactive pharmaceutical leads. The search for
new antibacterial drugs for the treatment of serious infections in
clinical practices is very important nowadays, as multi-drug resis-
tant bacteria pose a large threat to human health. Using a bioactiv-
ity-guided protocol for new natural chemical entities, the natural
products thuggacin A 1, B 2, and C 3 (Fig. 1)1 were isolated from
the myxobacterium Sorangium cellulosum by Jansen et al. The
thuggacins show strong antibiotic activity against various organ-
isms including mycobacterium tuberculosis. Thuggacin A has an
IC50 value of 8 ng/mL and thuggacin B and C have IC50 values of
around 20 ng/mL.1 Further study indicated their biological mecha-
nism of targeting the bacterial respiratory chain.2
All three thuggacins share the same structural features except
for the size of the macrolactone ring. The gross structures and their
stereochemistry were disclosed by two independent research
groups, Jansen et al.1 and Kirschning et al.3 in 2007. The feature
of the thuggacins comprises a 17–19 membered unsaturated mac-
rolactone ring with eight stereogenic centers, five alkenes, a thia-
zole ring, and an n-hexyl side chain at C2. The complicated
structures of the thuggacins and their excellent bioactivities have
made them attractive synthetic targets for drug development pur-
poses. In 2008, Kirschning et al. completed the first total synthesis
of thuggacin B.4 Their convergent synthesis involved 23 linear
steps (longest linear sequence) with 0.6% overall yield.
HO
OH
HO
OH OH
O
N
S
O
thuggacin A 1
thuggacin B 2
thuggacin C 3
HO
HO
OH
N
O
S
OH OH
O
HO
HO
OH
The cross-metathesis strategy was applied to construct the
C11–C12 double bond.4 Since this cross-metathesis strategy re-
quires the expensive second generation Grubbs catalyst, which
OH
O
O
OH
N
S
* Corresponding authors. Tel.: +852 34008722; fax: +852 22641912 (T. Ye).
E-mail addresses: xuzs@szpku.edu.cn (Z. Xu), bctaoye@inet.polyu.edu.hk (T. Ye).
Figure 1. Thuggacin A 1, B 2, and C 3.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.015

2028
S. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 2027–2032
17 to avoid epimerization. Thus the reaction of thioamide 7 with
2. Results and discussion
4 equiv of ethyl bromopyruvate at room temperature, followed
by treatment of the resulting thiozoline intermediate with trifluo-
roacetic anhydride and lutidine at ꢀ20 °C provided 17 in 68% yield.
After removal of the TMS group in 17, the palladium-catalyzed
hydrostannation/iodination of the alkyne 18 afforded the E-vinyl
iodide 19 in 87% yield (over two steps).18 Treatment of 19 with DI-
BAl-H at ꢀ78 °C gave the corresponding aldehyde 6 in 84% yield. A
straightforward Horner–Wardsworth–Emmnons olefination of 6
with ethyl 2-(diethoxyphosphinyl)-octanate 5 produced the de-
sired product 4 in 74% yield. The geometry of the E-acrylate was
ascertained by a sharp acrylic proton at 7.26 ppm, which was iden-
tical with the reported value.4
Our retrosynthetic analysis (Scheme 1) of thuggacins A–C is
based on a macrolactonization at the C1–C16 ester bond; a Sono-
gashira coupling reaction would be adopted to form the C12–13
bond linkage, thus the C1–C12 fragment 4 would serve as a key
intermediate for the total synthesis of the thuggacins. Fragment
4 can be prepared by a Horner–Wardsworth–Emmnons reaction
to form the C2–C3 E-double bond, which gives 5 and 6 as the key
intermediates. Aldehyde 6 can be derived from iodination of the
C11–C12 terminal alkyne, while the thiazole ring can be prepared
via Hantzsch condensation of thioamide 7 with bromopyruvate.
Thioamide 7 could be obtained from aldehyde 8 via a classical
Evans asymmetric aldol reaction.6 Aldehyde 8 is a known interme-
diate that can be prepared via different methods.7–9
3. Conclusion
The synthesis of fragment 4 started with ketone 9, (Scheme 2)
which was readily prepared according to reported methods.10
Firstly, (1S)-alpine-9-BBN (93% ee, from Aldrich) mediated Midland
reduction11,12 converted ketone 9 into alcohol 10 in 72% yield with
82% ee (as determined by the Mosher ester method, its absolute
stereochemistry was also confirmed by conversion of 10 into a
known compound13). Silyl-protection of the secondary hydroxyl
group, followed by oxidative removal of the PMB ether, produced
the primary alcohol 11 (83% yield over two steps). Alcohol 11
was then oxidized to aldehyde 8 with Dess–Martin periodinane.14
Aldehyde 8 was reacted with the boron enolate of (R)-4-benzyl-3-
propionyloxazolidin-2-one 12, in an Evans asymmetric aldol reac-
tion resulting in a 77% yield of 13 in >92% de (by 1H NMR). The
resulting secondary alcohol was protected as a tert-butyldimethyl-
silyl (TBS) ether 14, and the chiral auxiliary moiety was then re-
moved under basic conditions to give acid 14 in 74% yield. It is
noteworthy that the base-sensitive TMS-protecting group of 14
was stable under the conditions employed for the cleavage of the
Evans chiral auxiliary. With the key intermediate 15 in hand, we
were ready for the construction of the thiazole moiety via thioam-
ide 7 as shown in Scheme 1. Thus, acid 15 was first converted into
thioamide 7, in two steps and 62% yield, by amide formation and
the Lawesson reagent.15,16 A modified Hantzsch’s thiazole synthe-
sis procedure17 was employed for the preparation of chiral thiazole
In conclusion, we have completed the synthesis of the C1–C12
fragment of thuggacins in 13 linear steps with 4.8% overall yield.
The synthesis started with commercially available precursors and
no expensive catalysts were applied. Further studies toward the to-
tal synthesis thuggacins will be reported in due course.
4. Experimental
4.1. General
All non-aqueous reactions were run under an inert atmosphere
(nitrogen or argon) with rigid exclusion of moisture from reagents
and all reaction vessels were oven-dried. Solvents were distilled
prior to use: THF from Na/benzophenone, dichloromethane, DMF,
triethylamine, and diisopropylethylamine from CaH2. NMR spectra
were recorded on Bruker Avance DPX 300 MHz or AV 500 MHz
spectrometers. Chemical shifts are reported in parts per million
(ppm), relative to either a tetramethylsilane internal standard or
the signals due to the solvent. Data are reported as follows: chem-
ical shift, integration, multiplicity (s = singlet, d = doublet, t = trip-
let, q = quartet, and br = broad), and coupling constants. High-
resolution ESI mass spectra were obtained using a JMS SX-102A
11
HO
HO
14
16
TBSO
TBSO
I
OH
OH OH
O
1
N
4
7
N
S
OH
O
O
S
HWE Olefination
4
Thuggacin A (1)
Iodolation
I
TBSO
TBSO
TMS
OTBS
O
O
P
O
TBSO
+
O
(EtO)2
NH2
N
TMS
CHO
S
TBSO
S
Evan's aldol
Hantzsch's thiazole formation
8
7
6
5
Scheme 1. Retrosynthetic analysis.

S. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 2027–2032
2029
O
OH
OTBS
O
OTBS
c
a
b
PMBO
PMBO
HO
TMS
TMS
TMS
TMS
9
10
11
8
TBS
TBS
O
O
OTBS
O
O
OH
OTBS
Y
O
OTBS
O
f
e
d
O
N
N
X
O
TMS
TMS
TMS
Bn
Bn
15 X = OH, Y = O
16 X = NH2, Y = O
g
13
14
h
7
X = NH2, Y = S
TBS
TBS
TBS
O
OTBS
S
O
OTBS
O
OTBS
S
S
l
i
k
EtOOC
EtOOC
OHC
N
N
I
N
I
R
17 R = TMS
18 R = H
19
6
j
O
O
O
C6H13
S
EtOOC
TBS
EtOOC
m
N
O
OTBS
PO(OEt)2
N
I
Bn
5
12
4
Scheme 2. Reagents and conditions: (a) (1S)-alpine-9BBN, THF, 72%; (b) (i) TBSCl, Imi. DMF, rt; (ii) DDQ, 0 °C, DCM, 83% (two-steps); (c) DMP, DCM, 0 °C, 90%; (d) 12, Bu2BOTf,
TEA, ꢀ78 °C, 77%; (e) TBSOTf, 2,6-lutidine, ꢀ20 °C, 96%; (f) LiOH/H2O2, THF, 0 °C, 74%; (g) ClCO2Et, TEA, THF, 0 °C, then ꢀ15 °C NH3/MeOH, 86%; (h) DCM, Lawesson’s reagent,
rt, 72%; (i) ethyl bromopyruvate, THF, then ꢀ20 °C, TFAA, 2,6-lutidine, 68%; (j) K2CO3, EtOH, 95%; (k) Pd(PPh3)2Cl2, Bu3SnH, 0 °C, then ꢀ78 °C, I2, 92%; (l) DIBAL-H, ꢀ78 °C 84%;
(m) 22, NaHMDS, ꢀ30 °C, 74%.
mass spectrometer. Specific optical rotations were recorded on a
Perkin-Elmman 343 polarimeter. TLC was carried out using pre-
coated sheets (Qingdao Silica Gel 60-F250, 0.2 mm) and com-
pounds were visualized at 254 nm, and/or stained in p-anisole, nin-
hydrin, or phosphomolybdic acid solution followed by heating.
Flash column chromatography was performed using the indicated
solvents (with Rf 1.5–3.0 for the desired component) on Qingdao
Silica Gel 60 (230–400 mesh ASTM).
ethyl acetate in n-hexane) to provide 9 (2.43 g, 62%) as a colorless
oil. 1H NMR (300 MHz, CDCl3): d 7.16 (2H, d, J = 8.1 Hz), 6.78 (2H,
d, J = 8.1 Hz), 4.37 (2H, s), 3.70 (2H, t, J = 7.8 Hz), 3.69 (3H, s), 2.73
(2H, t, J = 7.8 Hz), 0.1 (9H, s) ppm. 13C NMR (75 MHz, CDCl3):
d 185.4, 159.3, 130.1, 129.3, 113.8, 101.9, 98.2, 72.9, 64.5, 55.2,
45.5, ꢀ0.8 ppm. HR-ESIMS for C16H23O3Si (M+H) (m/z): calcd
291.1416, observed 291.1394.
4.2. 1-Trimethylsilyl-5-(4-methoxybenzyloxy)-1-pentyn-3-one 9
4.3. (3S)-1-Trimethylsilyl-5-(4-methoxybenzyloxy)-
1-pentyn-3-ol 10
At ꢀ78 °C, to a solution of trimethylsilyl acetylene (2.5 mL,
17.4 mmol) and HMPA (5 mL, 26.0 mmol) in THF (45 mL) was added
n-butyl lithium (10 mL, 21.0 mmol, 2.1 M in hexane) dropwise. The
mixture was stirred for 30 min, then 3-(4-methoxybenzyloxy)-pro-
pionaldehyde (2.66 g, 13.6 mmol) in THF (10 mL) was added via a
cannula. The solution was stirred at ꢀ78 °C for 1 h and allowed to
warm to ꢀ40 °C within 1.5 h. Saturated aqueous ammonium chlo-
ride (40 mL) was added to quench the reaction and the mixture
was extracted with ether (50 mL ꢁ 2). The combined organic layers
were sequentially washed with saturated ammonium chloride
(30 mL), water (30 mL), and brine (30 mL), and dried over anhydrous
sodium sulfate. The solvent was evaporated in vacuo. The crude
product was dissolved in CH2Cl2 (40 mL) and pre-activated MnO2
powder (8.90 g, 69.5 mmol) was added to the solution in one por-
tion. The reaction mixture was then stirred at room temperature
overnight before it was filtered through a pad of Celite. The filtrate
was dried over anhydrous magnesium sulfate and evaporated to
afford a crude oil, which was purified by flash chromatography (5%
To a solution of 9 (1.90 g, 6.5 mmol) in THF (25 mL) under an ar-
gon atmosphere was added (S)-alpine-9-BBN (17 mL, 8.5 mmol,
0.5 M, 93% ee from Aldrich). The reaction mixture was stirred at
40 °C for 16 h before it was evaporated to dryness in vacuo. The
crude residue was re-dissolved in ether (30 mL) and cooled to
0 °C. After ethanolamine (2 mL, 33.1 mmol) was added, the reac-
tion mixture was stirred at 0 °C for 1 h, then it was filtered through
a pad of Celite; the filter cake was further washed with ether
(50 mL). The combined filtrate was dried over anhydrous magne-
sium sulfate and concentrated in vacuo to afford a crude oil, which
was purified by flash chromatography (8% ethyl acetate in n-hex-
ane) to provide 10 (1.40 g, 72%, 82% ee13) as a colorless oil.
½
a 2D0
ꢂ
¼ ꢀ13:7 (c 2.4, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.18
(2H, d, J = 8.0 Hz), 6.78 (2H, d, J = 8.0 Hz), 4.50 (1H, m), 4.41–4.36
(2H, m), 3.75 (1H, m), 3.73 (3H, s), 3.58 (1H, m), 2.98 (1H, br s),
2.00–1.98 (1H, m), 1.87–1.84 (1H, m), 0.09 (9H, s) ppm. 13C NMR
(125 MHz, CDCl3): d 159.2, 129.9, 129.4, 113.7, 106.5, 89.0, 72.8,

2030
S. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 2027–2032
67.1, 61.2, 55.1, 36.8, ꢀ0.1 ppm. HR-ESIMS for C16H25O3Si (M+H)
(m/z): calcd 293.1494, observed 293.1504.
sequentially washed with saturated sodium bicarbonate (30 mL)
and brine (30 mL), and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the crude product
was purified by flash chromatography (15% ethyl acetate in n-hex-
ane) to furnish the product 13 (1.13 g, 77%) as a colorless oil.
4.4. (3S)-1-Trimethylsily-3-(tert-butyldimethylsilanyl-oxy)-1-
pentyne-5-ol 11
½
a 2D0
ꢂ
¼ ꢀ44:3 (c 1.5, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.26–
7.23 (2H, m), 7.20–7.18 (1H, m), 7.14–7.11 (2H, m), 4.64–4.62 (1H,
m), 4.59 (1H, dd, J = 7.8, 3.4 Hz), 4.23–4.20 (1H, m), 4.12 (1H, t,
J = 9.0 Hz), 4.08 (1H, dd, J = 9.0, 2.8 Hz), 3.76–3.74 (1H, m), 3.18
(1H, dd, J = 13.0, 3.2 Hz), 2.70 (1H, dd, J = 13.0, 9.5 Hz), 1.80 (1H,
ddd, J = 14.0, 10.0, 3.5 Hz), 1.68 (1H, ddd, J = 14.0, 8.0, 1.9 Hz), 1.18
(3H, d, J = 7.0 Hz), 0.87 (9H, s), 0.09, (9H, s), 0.08 (3H, s), 0.06 (3H,
s) ppm; 13C NMR (125 MHz, CDCl3): 176.5, 153.1, 135.3, 129.5,
129.0, 127.4, 106.9, 89.5, 68.5, 66.2, 61.2, 55.3, 42.5, 41.6, 37.8,
25.9, 18.2, 11.3, ꢀ0.18, ꢀ4.5, ꢀ5.0 ppm. HR-ESIMS for C27H44NO5Si2
(M+H) (m/z): calcd 518.2758, observed 518.2775.
To a solution of 10 (1.1 g, 3.8 mmol) in DMF (20 mL) were added
tert-butyldimethylsilyl chloride (0.68 g, 4.5 mmol) and imidazole
(0.61 g, 9.0 mmol) at room temperature. The reaction mixture was
then stirred for 16 h before it was quenched by saturated sodium
bicarbonate (20 mL) and extracted with ethyl acetate (50 mL ꢁ 3).
The combined organic layers were washed with water (50 mL) and
brine (50 mL), evaporated in vacuo to afford a crude oil. The crude
product, without further purification, was dissolved in CH2Cl2
(50 mL), after which DDQ (890 mg, 3.9 mmol) was added to the
above solution at 0 °C. One hour later, the reaction was diluted with
CH2Cl2 (100 mL) and washed with saturated aqueous sodium
thiosulfate solution (50 mL ꢁ 2), followed with water (50 mL) and
brine (50 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated in vacuo. The residue was purified by
flash chromatography (15% ethyl acetate in n-hexane) to give com-
4.7. (R)-4-Benzyl-3-[(S)-3-(R)-5-bis-(tert-butyl-dimethyl-
silanyloxy)-(R)-2-methyl-7-trimethylsilyl-hept-6-ynoyl]-
oxazolidin-2-one 14
pound 11 (0.91 g, 83%) as a yellow syrup. ½a D20
¼ ꢀ9:8 (c 1.4, CHCl3);
ꢂ
To a solution of 13 (1.10 g, 2.2 mmol) in CH2Cl2 (15 mL) were
sequentially added 2,6-lutidine (0.5 mL, 4.4 mmol) and TBSOTf
(1.0 mL, 4.2 mmol) dropwise at ꢀ20 °C. The reaction was allowed
to warm to 0 °C within 4 h, and then quenched by the addition of
phosphate buffer (pH 7.0, 25 mL). The mixture was extracted with
ethyl acetate (50 mL ꢁ 3). The combined organic phase was
washed with brine (50 mL), and dried over anhydrous sodium sul-
fate. The solvent was removed in vacuo, after which the residue
was purified by flash chromatography (5% ethyl acetate in n-hex-
ane) to produce the title compound 14 (1.32 g, 96%) as a colorless
1H NMR (500 MHz, CDCl3): d 4.61 (1H, t, J = 5.6 Hz), 3.93–3.89 (1H,
m), 3.81–3.75 (1H, m), 2.33 (1H, br s), 1.95–1.89 (2H, m), 0.90 (9H,
s), 0.16 (3H, s), 0.15 (9H, s), 0.13 (3H, s) ppm. 13C NMR (125 MHz,
CDCl3): d 106.8, 90.0, 62.8, 60.3, 40.2, 25.9, 18.3, ꢀ0.13, ꢀ4.35,
ꢀ4.95 ppm. HR-ESIMS for C14H31O2Si2 (M+H) (m/z): calcd 287.1862,
observed 287.1869.
4.5. (3S)-5-Trimethylsily-3-(tert-butyldimethylsilanyl-oxy)-4-
pentynaldehyde 8
oil. ½a 2D0
ꢂ
¼ ꢀ38:4 (c 2.1, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.32–
7.30 (2H, m), 7.27–7.25 (1H, m), 7.21–7.19 (2H, m), 4.61–4.58 (1H,
m), 4.44 (1H, dd, J = 8.5, 4.8 Hz), 4.09–4.01 (3H, m), 3.98–3.96 (1H,
m), 3.28 (1H, dd, J = 13.5, 2.8 Hz), 2.78 (1H, dd, J = 13.5, 4.5 Hz),
2.04–1.95 (2H, m), 1.21 (3H, d, J = 7.0 Hz), 0.90 (9H, s), 0.87 (9H,
s), 0.19 (3H, s), 0.17 (3H, s), 0.16 (9H, s), 0.08 (3H, s), 0.01 (3H, s)
ppm. 13C NMR (125 MHz, CDCl3): d 175.0, 153.1, 135.6, 129.6,
129.1, 127.5, 107.8, 89.5, 70.5, 66.0, 60.2, 55.9, 44.7, 43.2, 37.8,
26.1, 26.0, 18.4, 18.2, 11.8, ꢀ0.1, ꢀ3.5, ꢀ4.05, ꢀ4.17, ꢀ4.72 ppm.
HR-ESIMS for C33H58NO5Si3 (M+H) (m/z): calcd 632.3622, observed
632.3596.
To a solution of 11 (0.91 g, 3.2 mmol) in CH2Cl2 (20 mL) was
added Dess–Martin periodate (5.30 g, 126.0 mmol) at 0 °C. The reac-
tion mixture was stirred at 0 °C for 3 h before it was diluted with
ether (80 mL) and filtered through a pad of Celite. The filtrate was
washed with saturated sodium bicarbonate (30 mL), water
(30 mL), and brine (30 mL), and dried over anhydrous sodium sul-
fate. The solvent was removed in vacuo and the residue was purified
by flash chromatography (5% ethyl acetate in n-hexane) to furnish
compound 8 (0.80 g, 90%) as a yellow syrup. ½a D20
¼ ꢀ13:2 (c 2.1,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3): d 9.79 (1H, t, J = 2.1 Hz), 4.84
(1H, dd, J = 7.2, 4.8 Hz), 2.75 (1H, ddd, J = 16.2, 7.2, 2.1 Hz), 2.63
(1H, ddd, J = 16.2, 4.8, 2.1 Hz), 0.87(9H, s), 0.146(12H, s, overlapped),
0.11(3H, s) ppm. 13C NMR(75 MHz, CDCl3): d 200.2, 105.6, 90.6, 58.8,
51.4, 25.8, 18.2, ꢀ0.24, ꢀ4.42, ꢀ5.00 ppm. HR-ESIMS for C14H29O2Si2
(M+H) (m/z): calcd 285.1706, observed 285.1694.
4.8. (2R,3S,5S)-3,5-Di-(tert-butyldimethylsilyloxy)-2-methyl-7-
trimethylsilyl-6-heptynoic-acid 15
To a solution of 14 (1.25 g, 2.0 mmol) in THF (25 mL) were
sequentially added H2O2 (0.36 g, 3.2 mmol, 30% solution) and LiOH
(12 mL, 12.0 mmol, 1.0 M in water) at 0 °C. The reaction mixture
was stirred at 0 °C for 0.5 h, then allowed to warm to room temper-
ature, and stirred for 16 h. The reaction was quenched by saturated
aqueous sodium thiosulfate solution (30 mL). THF was removed
under reduced pressure and the aqueous layer was extracted with
ether (50 mL ꢁ 3). The combined organic layers were washed with
brine (50 mL), dried over anhydrous sodium sulfate, and concen-
trated under reduced pressure. The residue was purified by flash
chromatography (8% ethyl acetate in n-hexane) to give 15 as a color-
4.6. (R)-4-Benzyl-3-[(S)-(5-tert-butyldimethylsilanyloxy)-(S)-3-
hydroxy-(R)-2-methyl-7-trimethylsilyl-hept-6-ynoyl]-
oxazolidin-2-one 13
At ꢀ20 °C, to a solution of (R)-4-benzyl-3-propionyl-oxazolidin-
2-one 12 (0.65 g, 2.8 mmol) in CH2Cl2 (25 mL) was added n-Bu2BOTf
(0.8 mL, 3.6 mmol) dropwise, followed by triethylamine (0.3 mL,
3.9 mmol). The mixture was allowed to warm to 0 °C within 1 h
and stirred at 0 °C for 15 min. The mixture was then cooled to
ꢀ78 °C, and aldehyde 8 (0.8 g, 2.8 mmol) in CH2Cl2 (8 mL) was
added. After being stirred at ꢀ78 °C for 3 h, the reaction was warmed
to 0 °C and quenched by the addition of phosphate buffer (pH 7.0,
15 mL) and a pre-mixed solution of methanol—hydrogen peroxide
(30% solution) (2:1, 8 mL). The mixture was further stirred at 0 °C
for 1 h. Volatiles were removed in vacuo, the aqueous layer was
extracted with ether (50 mL ꢁ 3). The combined organic phase was
less oil (0.68 g, 74%). ½a D20
ꢂ
¼ ꢀ28:8 (c 1.2, CHCl3); 1H NMR (500 MHz,
CDCl3): d 4.35 (1H, dd, J = 8.4, 4.8 Hz), 4.22–4.20 (1H, m), 2.63–2.61
(1H, m), 1.85–1.80 (1H, m), 1.77–1.73 (1H, m), 1.06 (3H, d,
J = 7.0 Hz), 0.82 (9H, s), 0.81 (9H, s), 0.10 (3H, s), 0.09 (9H, s), 0.08
(3H, s), 0.04 (3H, s), 0.01 (3H, s) ppm. 13C NMR (125 MHz, CDCl3): d
181.3, 107.0, 89.8, 70.1, 60.3, 44.7, 43.5, 26.0, 25.9, 18.3, 18.1, 10.0,
ꢀ0.17, ꢀ3.78, ꢀ4.12, ꢀ4.43, ꢀ4.70 ppm. HR-ESIMS for C23H49O4Si3
(M+H) (m/z): calcd 473.2938, observed 473.2915.

S. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 2027–2032
2031
4.9. (2R,3S,5S)-3,5-Di-(tert-butyldimethylsilyloxy)-2-methyl-7-
trimethylsilyl-6-heptynamide 16
8.5, 2.8 Hz), 1.67 (1H, ddd, J = 14.0, 6.5, 2.0 Hz), 1.41 (3H, d,
J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz), 0.89 (9H, s), 0.86 (9H, s), 0.15
(3H, s), 0.14 (3H, s), 0.13 (9H, s), 0.06 (3H, s), ꢀ0.13 (3H, s) ppm.
13C NMR (125 MHz, CDCl3): d 174.1, 161.9, 146.5, 127.2, 107.4,
90.0, 72.4, 61.2, 60.4, 44.2, 43.5, 26.1, 26.0, 18.4, 18.2, 14.5, ꢀ0.12,
ꢀ3.66, ꢀ4.14, ꢀ4.35 ppm. HR-ESIMS for C28H54NO4Si3S (M+H)
(m/z): calcd 584.3081, observed 584.3088.
To a 0 °C solution of acid 15 (0.53 g, 1.1 mmol) in THF (15 mL)
were added ethyl chloroformate (0.14 mL, 1.5 mmol) and triethyl-
amine (0.22 mL, 1.6 mmol). The reaction mixture was stirred at
0 °C for 0.5 h, then cooled to ꢀ15 °C before methanolic solution
of ammonia (2.5 mL, 10 mmol, 4.0 M) was added. Then the reaction
mixture was stirred at ꢀ15 °C for another 1.5 h and diluted with
ethyl acetate (100 mL). The organic phase was washed with water
(100 mL ꢁ 3) and brine (50 mL), and dried over anhydrous sodium
sulfate. The solvent was removed in vacuo and the residue was
purified by flash chromatography (5% ethyl acetate in n-hexane)
to furnish the desired compound 16 (0.46 g, 86%) as a yellow oil.
4.12. 2-[(10R,20S,40S)-20,40-Di(tert-butyldimethyl-silyloxy)-10-
methyl-50-hexynyl]-4-thiazole carboxylic acid, ethyl ester 18
To a solution of 17 (0.12 g, 0.2 mmol) in absolute ethanol (10 mL)
was added K2CO3 (0.30 g, 2.17 mmol), the mixture was stirred
at room temperature for 2 h before it was poured into a satu-
rated aqueous ammonia chloride solution (20 mL) and extracted
with ethyl acetate (25 mL ꢁ 3). The combined organic layers were
washed with water (30 mL) and brine (30 mL), dried over anhydrous
sodium sulfate, and concentrated in vacuo. The residue was purified
by flash chromatography (3% ethyl acetate in n-hexane) to give com-
½
a 2D0
ꢂ
¼ ꢀ34:5 (c 3.3, CHCl3); 1H NMR (500 MHz, CDCl3): d 6.47
(1H, br s), 6.30 (1H, br s), 4.31 (1H, dd, J = 8.8, 4.5 Hz), 3.89–3.86
(1H, m), 2.45–2.40 (1H, m), 1.74–1.65 (2H, m), 0.92 (3H, d,
J = 7.0 Hz), 0.75 (9H, s), 0.72 (9H, s), 0.02 (3H, s), ꢀ0.02 (9H, s),
ꢀ0.03 (3H, s), ꢀ0.04 (3H, s) ppm, ꢀ0.08 (3H, s). 13C NMR
(125 MHz, CDCl3): d 176.2, 107.4, 90.0, 71.2, 59.9, 45.4, 42.2,
26.0, 18.2, 18.0, 12.5, ꢀ0.20, ꢀ3.34, ꢀ4.11, ꢀ4.47, ꢀ4.54 ppm.
HR-ESIMS for C23H50NO3Si3 (M+H) (m/z): calcd 472.3098, observed
472.3101.
pound 18 (0.098 g, 95%) as a yellow oil. ½a D20
¼ ꢀ21:4 (c 1.05, CHCl3);
ꢂ
1H NMR (500 MHz, CDCl3): d 8.05 (1H, s), 4.42–4.38 (3H, m), 4.24–
4.22 (1H, m), 3.40 (1H, dd, J = 7.0, 3.5 Hz), 2.40 (1H, d, J = 2.0 Hz),
1.93 (1H, ddd, J = 14.5, 8.5, 2.8 Hz), 1.70 (1H, ddd, J = 14.5, 6.5,
2.0 Hz), 1.42 (3H, d, J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz) 0.89 (9H, s),
0.86 (9H, s), 0.15 (3H, s), 0.13 (3H, s), 0.06 (3H, s), ꢀ0.12
(3H, s) ppm. 13C NMR (125 MHz, CDCl3): d 173.9, 161.8, 146.5,
127.2, 85.4, 73.4, 72.4, 61.2, 59.8, 44.3, 43.7, 26.1, 26.0, 18.3, 18.2,
14.7, 14.5, ꢀ3.79, ꢀ4.18, ꢀ4.19, ꢀ4.45 ppm. HR-ESIMS for
C25H46NO4Si2S (M+H) (m/z): calcd 512.2686, observed 512.2688.
4.10. (2R,3S,5S)-3,5-Di-(tert-butyldimethylsilyloxy)-2-methyl-
7-trimethylsilyl-6-heptyne-thioamide 7
To a solution of 16 (0.40 g, 0.85 mmol) in CH2Cl2 (10 mL) was
added Lawesson’s reagent (0.69 g, 1.7 mmol) at room temperature.
The reaction mixture was stirred for 16 h before it was concentrated
in vacuo. The residue was dissolved in ether (100 mL) and washed
with saturated solution of sodium bicarbonate (50 mL) and brine
(50 mL). The organic phase was dried over anhydrous sodium sulfate
and concentrated under reduced pressure, the residue was purified
by flash chromatography (5% ethyl acetate in n-hexane) and gave 7
4.13. 2-[(10R,20S,40S)-20,40-Di-(tert-butyldimethyl-silyloxy)-60-
iodo-10-methyl-(E)-50–hexenyl]-4-thiazole carboxylic acid, ethyl
ester 19
To a solution of 18 (0.094 g, 0.2 mmol) in THF (7 mL) was added
Pd(PPh3)2Cl2 (5 mg, 3% mmol catalyst) under an argon atmosphere.
The solution was cooled to 0 °C, and tri-n-butylstannane (0.14 mL,
0.5 mmol) was added via a cannula. The reaction mixture was then
stirred at 0 °C for 2 h, and the solvent was removed under reduced
pressure. The residue was dissolved in CH2Cl2 (5 mL) and titrated
with a solution of iodine in CH2Cl2 (0.02 g/mL) at ꢀ78 °C until a
purple-brown color persisted. The reaction was then added to a
saturated aqueous sodium thiosulfate solution (30 mL) and ex-
tracted with ethyl acetate (30 mL ꢁ 3). The combined organic lay-
ers were washed with saturated aqueous sodium thiosulfate
solution (30 mL), water (30 mL), and brine (30 mL), dried over
anhydrous sodium sulfate, and concentrated in vacuo. The residue
was further purified by flash chromatography (3% ethyl acetate in
n-hexane) to give compound 19 (0.10 g, 92%) as a yellow oil.
(0.29 g, 72%) as a yellow liquid. ½a D20
ꢂ
¼ ꢀ26:8 (c 0.85, CHCl3); 1H
NMR (500 MHz, CDCl3): d 7.91 (1H, br s), 7.80 (1H, br s), 4.35 (1H,
dd, J = 8.5, 4.8 Hz), 4.05–4.01 (1H, m), 2.84–2.79 (1H, m), 1.82–1.78
(1H, m), 1.73–1.68 (1H, m), 1.21 (3H, d, J = 7.5 Hz), 0.85
(9H, s), 0.83 (9H, s), 0.02 (3H, s), 0.01 (9H, s), ꢀ0.01 (3H, s), ꢀ0.02
(3H, s), ꢀ0.03 (3H, s) ppm. 13C NMR (125 MHz, CDCl3): 212.1,
107.4, 90.2, 72.8, 60.0, 51.2, 42.1, 26.0, 25.9, 18.2, 18.0, 15.7, ꢀ0.20,
ꢀ3.56, ꢀ4.27, ꢀ4.31, ꢀ4.54 ppm. HR-ESIMS for C23H50NO2Si3S
(M+H) (m/z): calcd 488.2870, observed 488.2880.
4.11. 2-[(10R,20S,40S)-20,40-Di(tert-butyldimethyl-silyloxy)-10-
methyl-60-trimethylsilyl-50-hexynyl]-4-thiazolecarboxy-lic acid,
ethyl ester 17
To a solution of 7 (0.15 g, 0.3 mmol) in THF (15 mL) was added
ethyl bromopyruvate (0.19 mL, 1.5 mmol), and the reaction mixture
was stirred at room temperature for 1 h. Then the reaction mixture
was cooled to ꢀ20 °C, a pre-mixed solution of trifluoroacetic anhy-
dride (0.11 mL, 0.8 mmol) and 2,6-lutidine (0.18 mL, 1.5 mmol) in
THF (5 mL) was added dropwise via a cannula over 30 min. The reac-
tion mixture was stirred at ꢀ20 °C for 1.5 h and warmedto 0 °C with-
in 1 h. Phosphate buffer (pH 7.0, 15 mL) was used to quench the
reaction. Volatiles were removed in vacuo, and the aqueous phase
was extracted with ethyl acetate (20 mL ꢁ 3). The combined organic
layers were washed with water (30 mL) and brine (30 mL), and dried
over anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by flash chromatog-
raphy (1% ethyl acetate in n-hexane) to produce the desired
½
a 2D0
ꢂ
¼ ꢀ27:2 (c 1.4, CHCl3); 1H NMR (500 MHz, CDCl3): d 8.05
(1H, s), 6.48 (1H, dd, J = 14.5, 7.5 Hz), 6.25 (1H, d, J = 14.5 Hz),
4.40 (2H, q, J = 7.0 Hz), 4.15–4.10 (2H, m), 3.34 (1H, dd, J = 7.0,
3.5 Hz), 1.76 (1H, ddd, J = 14.0, 8.5, 4.5 Hz), 1.41 (3H, d,
J = 7.0 Hz), 1.39 (3H, t, J = 7.0 Hz), 1.32–1.29 (1H, m), 0.87 (9H, s),
0.86 (9H, s), 0.06 (3H, s), 0.05 (3H, s), 0.02 (3H, s), 0.01 (3H, s)
ppm; 13C NMR (125 MHz, CDCl3): d 173.8, 161.8, 149.3, 146.6,
127.2, 77.3, 73.2, 72.6, 61.3, 44.6, 42.9, 26.1, 26.0, 18.3, 18.2,
14.8, 14.5, ꢀ3.7, ꢀ4.1, ꢀ4.2, ꢀ4.4 ppm. HR-ESIMS for C25H47INO4-
Si2S (M+H) (m/z): calcd 640.1809, observed 640.1832.
4.14. 2-[(10R,20S,40S)-20,40-Di-(tert-butyldimethyl-silyloxy)-60-
iodo-10-methyl-(E)-50–hexenyl]-4-formylthiazole 6
compound 17 (0.12 g, 68%) as a yellow oil. ½a D20
ꢂ
¼ ꢀ18:4 (c 1.05,
To a solution of 19 (0.09 g, 0.14 mmol) in THF (10 mL) at ꢀ78 °C,
DIBAL-H (0.18 mL, 0.3 mmol, 1.7 M in hexane) was added under an
argon atmosphere. The reaction mixture was stirred for 2 h, and
CHCl3); 1H NMR (500 MHz, CDCl3): d 8.06 (1H, s), 4.42–4.37 (3H,
m), 4.26–4.22 (1H, m), 3.41–3.39 (1H, m), 1.92 (1H, ddd, J = 14.0,

2032
S. Tang et al. / Tetrahedron: Asymmetry 20 (2009) 2027–2032
quenched by careful addition of methanol (3 mL) before it was
poured into aqueous sodium potassium tartate (10 mL, 1 M). Vola-
tiles were removed in vacuo, and the aqueous phase was extracted
with ethyl acetate (30 mL ꢁ 3). The combined organic layers were
washed with water (30 mL) and brine (30 mL), dried over anhy-
drous sodium sulfate, and concentrated in vacuo. The residue
was purified by flash chromatography (3% ethyl acetate in n-hex-
ane) to produce compound 6 (0.07 g, 84%) as a colorless oil.
for R&D of Sciences and Technologies (SZKJ-2007011, SY2008063
00179A), Nanshan Branch of Shenzhen Science & Technology (NAN-
KEYUAN2007019), and Natural Science Foundation of GuangDong
Province (8451805704000656).
References
1. Steinmetz, H.; Irschik, H.; Kunze, B.; Reichenbach, H.; Hofle, G.; Jansen, R. Chem.
Eur. J. 2007, 13, 5822–5832.
2. Irschik, H.; Reichenbach, H.; Hofle, G.; Jansen, R. J. Antibiot. 2007, 60,
733–738.
3. Bock, M.; Miller, R.; Buntin, K.; Kirschning, A. Angew. Chem., Int. Ed. 2008, 47,
2308–2311.
4. Bock, M.; Dehn, R.; Kirschning, A. Angew. Chem., Int. Ed. 2008, 47, 9134–9137.
5. (a) Li, S.; Liang, S.; Tan, W. F.; Xu, Z. S.; Ye, T. Tetrahedron 2009, 65, 2695–2702;
(b) Ren, Q.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z. S.; Ye, T. Synlett 2008, 2379–2383;
(c) Li, S.; Liang, S.; Xu, Z. S.; Ye, T. Synlett 2008, 569–574; (d) Chen, Z.; Ye, T. New
J. Chem. 2006, 30, 518–520; (e) Pang, H. W.; Xu, Z. S.; Chen, Z. Y.; Ye, T. Lett. Org.
Chem. 2005, 2, 699–702; (f) Pang, H. W.; Xu, Z. S.; Ye, T. Lett. Org. Chem. 2005, 2,
703–706; (g) Xu, Z. S.; Ye, T. Tetrahedron: Asymmetry 2005, 16, 1905–1912; (h)
Chen, H. L.; Xu, Z. S.; Ye, T. Tetrahedron 2005, 11132–11140; (i) Chen, Z. Y.; Ye,
T. Synlett 2005, 2781–2785; (j) Xu, Z. S.; Chen, Z. Y.; Ye, T. Tetrahedron:
Asymmetry 2004, 15, 355–363; (k) Peng, Y. G.; Pang, H. W.; Ye, T. Org. Lett. 2004,
6, 3781–3784; (l) Chen, Z. Y.; Deng, J. G.; Ye, T. ARKIVOC 2003, Part VII, 268–285;
(m) Xu, Z. S.; Peng, Y. G.; Ye, T. Org. Lett. 2003, 5, 2821–2824.
½
a 2D0
ꢂ
¼ ꢀ14:3 (c 1.1, CHCl3); 1H NMR (500 MHz, CDCl3): d 10.0
(1H, s), 8.07 (1H, s), 6.47 (1H, dd, J = 14.5, 7.5 Hz), 6.25 (1H, d,
J = 14.5 Hz), 4.19–4.13 (2H, m), 3.34 (1H, ddd, J = 7.0, 3.5 Hz),
1.76 (1H, ddd, J = 14.0, 8.5, 4.5 Hz), 1.43 (3H, d, J = 7.0 Hz), 1.37
(1H, ddd, J = 14.0, 8.5, 3.5 Hz), 0.87 (9H, s), 0.86 (9H, s), 0.07 (3H,
s), 0.06 (3H, s), 0.04 (3H, s), ꢀ0.09 (3H, s) ppm; 13C NMR
(125 MHz, CDCl3): 185.2, 174.5, 154.4, 149.2, 127.0, 77.3, 73.3,
72.7, 44.6, 42.6, 26.1, 26.0, 18.3, 18.2, 14.5, 1.15, ꢀ3.58, ꢀ4.16,
ꢀ4.31 ppm. HR-ESIMS for C23H43INO3Si2S (M+H) (m/z): calcd
596.1546, observed 596.1534.
4.15. Ester 4
6. Evans, D. A.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129.
7. Reddy, Y. K.; Falck, J. R. Org. Lett. 2002, 4, 969–971.
8. Paquette, L. A.; Duan, M.; Konetzki, I.; Kempmann, C. J. Am. Chem. Soc. 2002,
124, 4257–4270.
9. Smith, A. B.; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935–3948.
10. Marshall, J. A.; Eidam, P.; Eidam, H. S. J. Org. Chem. 2006, 71, 4840–4844.
11. Midland, M. M.; Macdowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc.
1980, 102, 867–869.
To a solution of ethyl 2-(diethoxyphosphinyl)-octanoate 5
(0.05 g, 0.2 mmol) in THF (5 mL) at ꢀ30 °C, NaHMDS (0.24 mL,
0.12 mmol, 0.5 M in THF) was added dropwise. After being stirred
for 20 min, a solution of 6 (0.035 g, 0.06 mmol) in THF (3 mL) was
added via a cannula. The reaction mixture was then stirred at
ꢀ30 °C for 30 min and allowed to warm to 0 °C within 1 h, before it
was poured into a saturated aqueous ammonium chloride solution
(20 mL) and extracted with ethyl acetate (30 mL ꢁ 3). The combined
organic layers were washed with brine (30 mL), dried over anhy-
drous sodium sulfate, and concentrated in vacuo. The residue was
purified by flash chromatography (5% ethyl acetate in n-hexane) to
produce compound 4 (E isomer, 0.34 g, 74%) as a colorless oil.
12. Midland, M. M.; Tramontano, A. J. Org. Chem. 1978, 43, 1470–1471.
13. Esterification of alcohol 10 with (S)-MTPA chloride was carried out according
to Mosher’s method (Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973,
38, 2173–2176). 1H NMR spectrum showed a clear split of the MTPA’s methoxy
signal of two isomers (dR = 3.86, dS = 3.79, IntS:IntR = 10:1), as well as the TMS
methyl signal of two isomers (dS = 0.15, dR = 0.06, IntS:IntR = 10:1), thus ee%
value was determined as around 82%. The (3S)-configuration of alcohol 10 was
confirmed by removal of the TMS group and a subsequent hydrogenation to
produce the known (3R)-1,3-pentanediol and the specific rotation data for this
½
a 2D0
ꢂ
¼ ꢀ36:3 (c 1.2, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.51 (1H,
product were ½a 2D0
¼ ꢀ17:4 (c 1.88, EtOH), which were comparable to those
ꢂ
s), 7.26 (1H, s), 6.48 (1H, dd, J = 15.5, 7.5 Hz), 6.24 (1H, d,
J = 15.5 Hz), 4.25 (2H, q, J = 7.0 Hz), 4.15–4.12 (2H, m), 3.30 (1H,
dd, J = 7.0, 3.5 Hz), 2.93–2.90 (2H, m), 1.77 (1H, ddd, J = 14.0, 8.5,
4.5 Hz), 1.40 (3H, d, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 1.33–1.24
(9H, m), 0.88 (9H, s), 0.87 (9H, s), 0.06 (3H, s), 0.05 (3H, s), 0.03
(3H, s), ꢀ0.09 (3H, s) ppm; 13C NMR (125 MHz, CDCl3): d 172.3,
169.0, 151.6, 149.4, 133.9, 130.2, 121.5, 77.3, 73.3, 73.0, 60.8, 44.6,
42.7, 32.0, 29.8, 29.4, 28.0, 26.1, 26.0, 22.8, 18.3, 18.2, 14.7, 14.5,
14.2, ꢀ3.6, ꢀ4.2, ꢀ4.3, ꢀ4.4 ppm. HR-ESIMS for C33H61INO4Si2S
(M+H) (m/z): calcd 750.2904, observed 750.2880.
reported in the literature. The reported specific rotation data for (3R)-1,3-
pentanediol were ½ ꢂ ¼ ꢀ22:5 (c 1.06, EtOH) (Bertelsen, S.; Diner, P.;
a 2D0
Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536–1537); and
the specific rotation data for (3S)-1,3-pentanediol were reported as
½ ꢂ ¼ þ16:6 (c 1.04, EtOH) (Yang, D.; Zhang, Y. H.; Zhang, D. W. J. Org.
a 2D0
Chem. 2004, 69, 7577–7581).
OH
OH
TBAF
PMBO
HO
TMS
H2, Pd/C
10
14. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
15. Allali, H.; Tabti, B.; Alexandre, C.; Huet, F. Tetrahedron: Asymmetry 2004, 15,
1331–1333.
Acknowledgments
16. Rega, M.; Candal, P.; Jimenez, C.; Rodriguez, J. Eur. J. Org. Chem. 2007, 6, 934–
942.
17. (a) Bredenkamp, M. W.; Holzapfel, C. W.; Van Zyl, W. J. Synth. Commun. 1990,
20, 2235–2238; (b) Dondoni, A.; Merino, P.. In Comprehensive Heterocyclic
Chemistry II; Pergamon, 1996; Vol. 3. pp 432–434.
We acknowledge financial support from the Shenzhen Bureau of
Science, Technology, and Information (Shenzhen Key Laboratory
Advancement Scheme and Basic Research Scheme, 08systs-01).
Z.S.X. would like to thank the support from Shenzhen foundation
18. Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857–1867.