Stereoselective preparation of C1-C10 and C11-O14 fragments of narbonolide: Exploiting the versatility of thiazolidinethione chiral auxiliary

Article abstract of DOI:10.1055/s-0028-1083321

An efficient stereoselective synthesis of the C1-C10 and C11-O14 fragments of narbonolide, have been accomplished by using a thiazolidinonethione as chiral auxiliary. The stereocenters at C2, C3, C4, C5, C8, and C9 in C1-C10 fragment and C12 and C13 in C1

Full text of DOI:10.1055/s-0028-1083321

PAPER
474
Stereoselective Preparation of C1–C10 and C11–O14 Fragments of
Narbonolide: Exploiting the Versatility of Thiazolidinethione Chiral
Auxiliary1
Stereoselective
P.
PC1–C10 and
r
C
11–O1
a
4 Fragment
s
s
of
N
ar
b
a
Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India
Fax +91(40)23045438; E-mail: parthasarathi@drreddys.com; E-mail: parthads@yahoo.com
Received 13 August 2008
complicating factors such as a low yield of the key mac-
rocyclization reaction, inability to differentiate the C3 and
C5 positions for chemoselective reactions and highly op-
timized protecting group strategies that decrease the syn-
Abstract: An efficient stereoselective synthesis of the C1–C10 and
C11–O14 fragments of narbonolide, have been accomplished by us-
ing a thiazolidinonethione as chiral auxiliary. The stereocenters at
C2, C3, C4, C5, C8, and C9 in C1–C10 fragment and C12 and C13
in C11–C14 fragment were generated via asymmetric acyl-thiazo- thetic efficiency.
lidinethione aldol reactions whereas the stereocenter at C6 was in-
stalled by means of Myers alkylation.
As part of our ongoing programme towards the total syn-
thesis of macrolides9 we became particularly interested in
the total synthesis of narbonolide (4). We envisaged that
the core structure of narbonolide (4) could be constructed
via ring-closing metathesis of the bis-alkene 5, which in
turn could be made via esterification of C1–C10 fragment
6 and C11–O14 fragment 7 (Scheme 1). In this paper, we
report the versatility of thiazolidinethione as a chiral aux-
iliary in the stereoselective preparation of C1–C1010 and
C11–O14 fragments of norbonolide.
Key words: acyl-thiazolidinethione, aldol reaction, Crimmins pro-
tocol, Myers alkylation, Tebbe reaction
The macrolide antibiotic erythromycin A (1) has served as
both a clinically useful agent for the treatment of Gram-
positive bacterial infections as well as a starting point for
the semisynthesis of derivatives with improved physio-
chemical and microbiological properties.2 Several of
these derivatives, including clarithromycin, azithromycin,
and roxithromycin, possess improved acid stability and
oral bioavailability and have enjoyed significant commer-
cial success. However, a serious problem, not adequately
addressed by these agents, is the growing prevalence of
erythromycin-resistant bacteria.3
Accordingly, our synthesis began with the condensation
of 3-propanoylthiazolidinethione11 8 with acrolein by uti-
lizing Crimmins’ protocol12 [Ti-mediated enolization us-
ing (–)-sparteine (1 equiv) and NMP (1 equiv)] to yield
the desired Evans syn-aldol product 9 in 80% with excel-
lent diastereoselectivity (20:1). Silylation of the aldol
product 9 with tert-butyldimethylsilyl triflate afforded 10
in good yield. The iodide 12 was obtained after the reduc-
tive removal of the chiral auxiliary from thione 10 with
lithium borohydride and subsequent iodination of the re-
sulting alcohol 11. The resulting iodide 12 was then sub-
jected to Myers alkylation13 conditions.
The discovery of the ketolides,4 erythromycin derivatives
incorporating a C3 ketone modification, revealed a class
of compounds with excellent activity against some mac-
rolide-resistant bacteria, especially the clinically impor-
tant
respiratory
tract
pathogen
Streptococcus
pneumoniae.5 The considerable promise shown by ke-
tolides have catalyzed a resurgence in macrolide antibiot-
ic research in the pharmaceutical industry.6 Ketolides like
telithromycin6a (2) from Aventis Pharma and
cethromycin6b,c (3) from Abbott Laboratories (Figure 1)
have been successfully launched into the market.
O
O
O
OMPM
OTBS
O
OH
Narbonolide (4) is a 14-membered polyketide macrolac-
tone biosynthesized by the pikromycin polyketide syn-
thase (PKS) system of Streptomyces venezuelae ATCC
15439.7 The macrolide 4 consists of seven stereocenters
including the sensitive chiral center at C2. Its significant
therapeutic potential, structural similarity to the macro-
cytes in telithromycin and cethromycin has resulted in to-
tal syntheses from the groups of Masamune8a and
Fecik.8b,c However, these syntheses have one or more
O
O
O
narbonolide (4)
5
OTBS
10
11
+
OTBS
O
OMPM
OTBS
14
1
SYNTHESIS 2009, No. 3, pp 0474–0482
x
x
.
x
x
.2
0
0
9
HO
7
Advanced online publication: 12.01.2009
DOI: 10.1055/s-0028-1083321; Art ID: P08708SS
© Georg Thieme Verlag Stuttgart · New York
6
Scheme 1 Retrosynthesis of narbonolide 4

PAPER
Stereoselective Preparation of C1–C10 and C11–O14 Fragments of Narbonolide
475
N
N
N
O
OH
HO
OH
O
OH Me
O
O
O
O
N
Me
N
O
O
O
O
O
OH Me
N
O
O
Me
MeO
O
O
O
OH
erythromycin A (1)
telithromycin (2)
N
O
O
H
N
O
O
OH Me
N
O
O
Me
O
O
O
cethromycin (3)
Figure 1
Treatment of the iodide 12 with (R,R)-N-propanoylpseu- ed C1–C10 fragment 6 with all the desired stereocenters
doephedrine (13) at 40 °C proceeded cleanly to furnish the (Scheme 3).
amide 14 in 77% yield. Removal of chiral auxiliary was
The synthesis of fragment 7 commenced with an Evans
syn-aldol reaction between thiazolidinethione 8 and pro-
panal to give aldol product 24. The resulting aldol 24 was
accomplished with lithium amidotrihydroborate14 to pro-
duce alcohol 15, which was further oxidized to aldehyde
16 by treatment with (diacetoxyiodo)benzene/2,2,6,6-tet-
silylated with tert-butyldimethylsilyl triflate, followed by
ramethyl-1-piperidinyloxyl (TEMPO) in excellent yield
the reductive removal of the chiral auxiliary with lithium
(Scheme 2).
borohydride to afford the alcohol 26.
The aldehyde 16 was condensed with 3-propanoylthiazo-
lidinethione 8 to give the non-Evans syn-aldol product 17
Oxidation of the alcohol 26 with (diacetoxyiodo)benzene/
2,2,6,6-tetramethyl-1-piperidinyloxyl produced aldehyde
27. At this stage terminal olefination of the aldehyde
proved to be problematic. Various attempts at the olefina-
tion of aldehyde 23 with methyltriphenylphosphonium
bromide with different bases (BuLi, NaHMDS) and di-
rect/indirect addition of substrates, as well as varying the
temperature (–78 °C to r.t.) were unsuccessful. However,
by Crimmins protocol [Ti-mediated enolization using
i-Pr2NEt (1 equiv) as a base].12 The reaction was readily
scalable, providing reproducible results in terms of both
yield and diastereoselectivity (20:1). Reductive removal
of thiazolidinethione of 17 with sodium borohydride pro-
duced diol 18. The 1,3-diol in 18 was then protected with
4-methoxybenzaldehyde dimethyl acetal affording the
terminal olefin of 27 was achieved by treatment with
corresponding acetal 19, which after reductive hydrolysis
with diisobutylaluminum hydride afforded primary alco-
hol 20 in good yield. The resulting alcohol was oxidized
to the corresponding aldehyde 21 and subjected to aldol
reaction with thiazolidinethione 8 to obtain non-Evans
syn-aldol adduct 2212 in 83% yield and excellent diaste-
reoselectivity (≥96%).The aldol product was silylated to
give 23, which on subsequent oxidative hydrolysis afford-
Tebbe’s reagent15 in 46% yield (Scheme 4).
In summary, an efficient and enantioselective synthesis of
the C1–C10 and C11–O14 fragments of narbonolide have
been completed, demonstrating the versatility of thiazo-
lidinethione as chiral auxiliary. This successful approach
will be directly applicable to the synthesis of narbonolide;
progress toward this goal is currently underway in our lab-
oratory.
Synthesis 2009, No. 3, 474–482 © Thieme Stuttgart · New York

476
C. P. Narasimhulu, P. Das
PAPER
S
S
S
S
O
O
OH
O
O
OH
b
a
a
b
d
S
N
S
N
S
N
S
N
Bn
Bn
Bn
Bn
9
8
24
8
S
O
OTBS
OTBS
S
O
OTBS
OTBS
c
c
d
S
N
HO
S
N
HO
Bn
25
Bn
11
26
OTBS
10
O
OTBS
OTBS
O
OTBS
OTBS
e
Ph
e
N
I
OH Me
14
12
HO
27
7
OTBS
O
g
f
Scheme 4 Reagents and conditions: (a) TiCl4, (–)-sparteine, NMP,
EtCHO, –78 °C to 0 °C, 85%; (b) TBSOTf, 2,6-lutidine, 0 °C, 91%;
(c) LiBH4, Et2O, H2O, 0 °C, 70%; (d) TEMPO, PhI(OAc)2, CH2Cl2,
r.t., 90%; (e) Tebbe’s reagent, THF, 0 °C, 46%.
16
15
O
N
Ph
OH Me
Optical rotations were measured on a Jasco DIP-370 digital pola-
rimeter at 25 °C; concentrations (c) are quoted in g/100 mL. IR
spectra were recorded on a Schimadzu IR Prestige 21 FT-IR spec-
13
Scheme 2 Reagents and conditions: (a) TiCl4, (–)-sparteine, NMP,
acrolein, CH2Cl2, –78 °C to 0 °C, 80%; (b) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 °C, 85%; (c) LiBH4, Et2O, H2O, 0 °C, 76%; (d) Ph3P, I2,
imidazole, Et2O–MeCN (4:1), r.t., 79%; (e) 13, i-Pr2NH, BuLi, LiCl,
THF, 77%; (f) i-Pr2NH, BuLi, BH3·NH3, THF, 90%; (g) TEMPO,
PhI(OAc)2, CH2Cl2, r.t., 95%.
1
trophotometer. H NMR and 13C NMR spectra are determined in
CDCl3 were determined on Varian Mercury Plus 400 MHz and
Varian Gemini-2000 200 MHz spectrometers, respectively; 1H
NMR used TMS as an internal reference. Coupling constants were
corrected to the nearest value after decimal. ESI-MS spectra were
obtained on a Perkin Elmer API 3000 spectrometer. Column chro-
matography used silica gel, grade 60–120, 100–200 mesh. Reac-
tions were monitored by TLC (silica gel plates, 60 F254), visualized
with UV light or alkaline KMnO4 stain. Unless stated otherwise re-
S
O
OH
OTBS
OH
OTBS
a
b
S
N
16
HO
Bn
17
18
PMP
O
OMPM
OTBS
e
O
OTBS
c
d
HO
20
OTBS
19
OTBS
S
O
OH OMPM
g
O
OMPM
f
N
S
Bn
22
21
O
OTBS
OTBS
S
O
N
OTBS
OTBS
OMPM
OMPM
h
HO
S
Bn
6
23
Scheme 3 Reagents and conditions: (a) 8, TiCl4, i-Pr2NEt, CH2Cl2, 0 °C, 74%; (b) NaBH4, EtOH, r.t., 81%; (c) 4-MeOC6H4CH(OMe)2, CSA,
CH2Cl2, r.t., 92%; (d) DIBAL-H, CH2Cl2, 0 °C, 79%; (e) TEMPO, PhI(OAc)2, CH2Cl2, r.t., 95%; (f) 8, TiCl4, i-Pr2NEt, CH2Cl2, 0 °C, 83%; (g)
TBSOTf, i-Pr2NEt, CH2Cl2, 0 °C to r.t., 81%; (h) LiOH, 30% H2O2, THF–H2O, 0 °C, 65%.
Synthesis 2009, No. 3, 474–482 © Thieme Stuttgart · New York

PAPER
Stereoselective Preparation of C1–C10 and C11–O14 Fragments of Narbonolide
477
actions were performed under N2 atmosphere. All other reagents
were purchased from Aldrich at the highest commercial quality and
used without further purification.
(2R,3R)-3-(tert-Butyldimethylsilyloxy)-2-methylpent-4-en-1-ol
(11)
To a soln of thione 10 (10.2 g, 23.4 mmol) in Et2O (100 mL) at 0 °C
was added, H2O (0.94 mL, 58.6 mmol, 2.5 equiv) and LiBH4 (1.28
g, 58.6 mmol, 2.5 equiv) sequentially. The resulting mixture was
stirred at 0 °C for 1 h, by which time the yellow color of the reaction
had faded, whereupon the reaction was quenched by careful addi-
tion of sat. aq NH4Cl (100 mL) and extracted with Et2O (3 × 100
mL). The combined organic layers were dried (Na2SO4) and filtered
and the filtrate was concentrated under vacuum. The crude product
was purified by flash column chromatography (silica gel, EtOAc–
hexane, 5:95) to afford 11 as a colorless oil. Yield: 4.1 g (76%);
[a]D25 +16.4 (c 0.50, CHCl3).
(2S,3R)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-hydroxy-2-
methylpent-4-en-1-one (9)
To a soln of 8 (10.0 g, 37.7 mmol) in CH2Cl2 (100 mL) at 0 °C was
added TiCl4 (4.3 mL, 39.6 mmol). The resulting orange slurry was
stirred for 5 min and then (–)-sparteine (8.7 mL, 37.7 mmol) was
added; during the addition, the mixture became deep red in color
(characteristic of the enolate). The mixture was stirred at 0 °C for 20
min and then it was cooled to –78 °C. NMP (3.63 mL, 37.7 mmol)
was added. The mixture was stirred for a further 10 min at this tem-
perature then acrolein (3.0 mL, 45.2 mmol) was added dropwise;
the mixture was stirred at –78 °C for 1 h and then at 0 °C for 1 h.
Sat. aq NH4Cl (50 mL) was added, the layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were dried (Na2SO4) and filtered and the
filtrate was concentrated under vacuum. The crude product was pu-
rified by column chromatography (silica gel, EtOAc–hexane,
20:80) to afford 9 with excellent diastereoselectivity (20:1) as a
bright yellow oil. Yield: 9.7 g (80%); [a]D25 +184.7 (c 1.00, CHCl3).
IR (neat): 3369, 2956, 2858, 1028, 837, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.87 (ddd, J = 17.5, 10.5, 6.0 Hz,
1 H), 5.23 (dd, J = 17.5, 2.0 Hz, 1 H), 5.18 (dd, J = 10.5, 2.0 Hz, 1
H), 4.25 (dd, J = 6.0, 4.5 Hz, 1 H), 3.65 (dd, J = 11.0, 8.0 Hz, 1 H),
3.48 (m, 1 H), 2.72 (br s, 1 H), 1.99–1.95 (m, 1 H), 0.90 (s, 9 H),
0.81 (d, J = 7.0 Hz, 3 H), 0.08 (s, 3 H). 0.05 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 137.8, 115.8, 65.6, 40.9, 25.8,
18.1, 12.2, –4.5, –5.2.
IR (neat): 3481, 2980, 2935, 1695, 1166 cm–1.
MS (ESI): m/z (%) = 231 (100) [M + H]+.
1H NMR (400 MHz, CDCl3): d = 7.36–7.26 (m, 5 H), 5.83 (ddd,
J = 17.5, 10.5, 5.0 Hz, 1 H), 5.32 (d, J = 17.5 Hz, 1 H), 5.33–5.22
(m, 1 H), 5.20 (d, J = 10.5 Hz, 1 H), 4.58 (m, 1 H), 4.46 (m, 1 H),
3.39 (dd, J = 12.4, 6.8 Hz, 1 H), 3.23 (dd, J = 13.5, 4.0 Hz, 1 H),
3.05 (dd, J = 13.5, 11.0 Hz, 1 H), 2.9 (d, J = 11.0 Hz, 1 H), 1.25 (d,
J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 201.3, 177.3, 137.4, 136.3, 129.4,
128.9, 127.2, 116.3, 116.0, 73.6, 72.6, 43.8, 36.7, 32.2, 11.0.
MS (ESI): m/z (%) = 322 (100) [M + H]+, 210 (80).
HRMS (ESI): m/z [M + Na]+ calcd for C16H19NaNO2S2: 344.0756;
HRMS (ESI): m/z [M + H]+ calcd for C12H27O2Si: 231.1780; found:
231.1780.
(2S,3R)-3-(tert-Butyldimethylsilyloxy)-1-iodo-2-methylpent-4-
ene (12)
To a soln of alcohol 11 (4.0 g, 17.4 mmol) in Et2O–MeCN (4:1, 80
mL) at r.t. was added Ph3P (9.12 g, 34.8 mmol) and then imidazole
(2.36 g, 34.8 mmol) sequentially and the mixture was stirred for 10
min; during this time the mixture became a clear soln. I2 (8.82 g,
34.8 mmol) was added and the mixture was stirred for 15 min,
washed with sat. aq Na2S2O3 (100 mL), and the aqueous layer was
extracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were dried (Na2SO4) and filtered and the filtrate was concentrated
under vacuum. The crude product was purified by flash column
chromatography (silica gel, EtOAc–hexane, 2:98) to afford 12 as a
colorless oil. Yield: 4.67 g (79%); [a]D25 +15.0 (c 1.00, CHCl3).
found: 344.0755.
(2S,3R)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-(tert-butyl-
dimethylsilyloxy)-2-methylpent-4-en-1-one (10)
To a soln of 9 (9.0 g, 28.0 mmol) in CH2Cl2 (150 mL) at 0 °C was
added 2,6-lutidine (4.9 mL, 42.0 mmol, 1.5 equiv) and TBSOTf (7.7
mL, 33.6 mmol, 1.2 equiv) sequentially and the mixture was stirred
at 0 °C for 1 h. The reaction was quenched with sat. aq NaHCO3
(100 mL), the layers were separated, and the aqueous layer was ex-
tracted with CH2Cl2 (2 × 100 mL). The combined organic layers
were washed with brine (100 mL), dried (Na2SO4), and filtered. The
filtrate was concentrated under vacuum to give a crude product that
was purified by column chromatography (silica gel, EtOAc–hex-
ane, 7:93) to afford 10 as a bright yellow oil. Yield: 10.3 g (85%);
[a]D25 +197.4 (c 1.00, CHCl3).
IR (neat): 2927, 2856, 1251, 1074, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.76 (ddd, J = 17.0, 10.5, 6.0 Hz,
1 H), 5.22 (dd, J = 17.0, 1.6 Hz, 1 H), 5.13 (dd, J = 10.5, 1.6 Hz, 1
H), 4.15–4.12 (m, 1 H), 3.33 (dd, J = 10.5, 6.0 Hz, 1 H), 3.01 (dd,
J = 10.0, 7.0 Hz, 1 H), 1.76–1.70 (m, 1 H), 1.00 (d, J = 7.0 Hz, 3 H),
0.89 (s, 9 H), 0.08 (s, 3 H), 0.03 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 139.2, 115.6, 76.0, 42.5, 25.8,
15.4, 12.6, –4.2, –4.8.
MS (ESI): m/z (%) = 341 (100) [M + H]+.
IR (neat): 2929, 2856, 1701, 1251, 837 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.26 (m, 5 H), 5.85 (ddd,
J = 17.5, 10.5, 6.0 Hz, 1 H), 5.16–5.09 (m, 3 H), 4.59 (m, 1 H), 4.32
(t, J = 6.5 Hz, 1 H), 3.32–3.27 (m, 2 H), 3.04 (dd, J = 13.0, 11.0 Hz,
1 H), 2.87 (d, J = 11.0 Hz, 1 H), 1.23 (d, J = 6.5 Hz, 3 H), 0.88 (s, 9
H), 0.03 (s, 3 H), 0.01 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 201.1, 176.2, 139.2, 136.6, 129.4,
128.8, 127.1, 115.7, 76.4, 69.4, 45.8, 36.5, 32.2, 25.7, 18.1, 12.5,
–4.3, –5.1.
(2S,4R,5R)-5-(tert-Butyldimethylsilyloxy)-N-[(1R,2R)-2-hy-
droxy-1-methyl-2-phenylethyl]-N,2,4-trimethylhept-6-en-
amide (14)
A stirrer bar and LiCl (6.53 g, 149.3 mmol, 12.7 equiv) were placed
in a 250-mL round-bottomed flask and flame dried for 10 min under
high vacuum, then allowed to cool to r.t. under N2 atmosphere. THF
(30 mL) was then added and cooled to –78 °C, whereupon i-Pr2NH
(7.14 mL, 50.7 mmol, 4.3 equiv) and 1.6 M BuLi in hexanes (29.4
mL, 46.8 mmol, 4 equiv) were added sequentially, and the resulting
mixture was stirred at this temperature for 5 min. The mixture was
then warmed to 0 °C for 10 min and then cooled to –78 °C. Pseu-
doephedrine amide 13 (5.45 g, 24.6 mmol, 2.1 equiv) in THF (30
mL) was added and the mixture was stirred at –78 °C for 1 h,
warmed to 0 °C for 15 min, then to r.t. for a further 10 min. The mix-
ture was cooled to 0 °C and iodide 12 (4.0 g, 11.8 mmol, 1 equiv) in
MS (ESI): m/z (%) = 436 (100) [M + H]+, 304 (80).
HRMS (ESI): m/z [M + H]+ calcd for C22H34NO2S2Si: 436.1803;
found: 436.1800.
Synthesis 2009, No. 3, 474–482 © Thieme Stuttgart · New York

478
C. P. Narasimhulu, P. Das
PAPER
THF (10 mL) was added. Then the mixture was slowly warmed to
40 °C and stirred overnight. Sat. aq NH4Cl (50 mL) was added to
quench the reaction, the layers were separated, and the aqueous lay-
er was extracted with EtOAc (3 × 75 mL). The combined organic
layers were dried (Na2SO4) and filtered and the filtrate was concen-
trated under vacuum. The crude product was purified by flash col-
umn chromatography (silica gel, EtOAc–hexane, 25:75) to afford
14 as a colorless viscous oil. Yield: 3.92 g (77%); [a]D –28.8 (c
1.00, CHCl3).
IR (neat): 3365, 2956, 2927, 1620, 835, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 5.78 (ddd,
J = 17.0, 10.5, 6.5 Hz, 1 H), 5.40 (s, 1 H), 5.09 (dd, J = 17.0, 1.6 Hz,
1 H), 5.07 (dd, J = 10.5, 1.6 Hz, 1 H), 4.61 (m, 1 H), 4.11 (br s, 1
H), 3.94 (dd, J = 5.5, 4.5 Hz, 1 H), 2.84 (s, 3 H), 2.78–2.73 (m, 1 H),
1.84–1.78 (m, 1 H), 1.53–1.42 (m, 2 H), 1.15 (d, J = 7.0 Hz, 3 H),
1.08 (d, J = 6.5 Hz, 3 H), 0.89 (s, 9 H), 0.76 (d, J = 7.0 Hz, 3 H),
0.04 (s, 3 H), 0.007 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 179.0, 142.6, 139.9, 128.2, 127.4,
126.1, 114.7, 78.1, 76.3, 59.5, 37.6, 36.8, 34.2, 25.8, 18.2, 18.0, –
4.2, –4.9.
was quenched by the addition sat. aq Na2S2O3–sat. aq NaHCO3 (5:1,
50 mL). The layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were dried (Na2SO4) and filtered and the filtrate was concentrated
under vacuum. The crude product was purified by flash column
chromatography (silica gel, EtOAc–hexane, 2:98) to afford 16 as a
colorless oil. Yield: 940 mg (95%); [a]D25 +24.2 (c 0.50, CHCl3).
25
IR (neat): 2958, 2929, 1732, 1251, 837, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.52 (d, J = 3.0 Hz, 1 H), 5.76
(ddd, J = 17.0, 10.5, 6.0 Hz, 1 H), 5.13 (dd, J = 17.0, 2.0 Hz, 1 H),
5.08 (dd, J = 10.5, 2.0 Hz, 1 H), 3.96–3.93 (m, 1 H), 2.45–2.41 (m,
1 H), 1.93–1.86 (m, 1 H), 1.62–1.57 (m, 2 H), 1.07 (d, J = 7.0 Hz, 3
H), 0.87 (s, 9 H), 0.86 (d, J = 7.0 Hz, 3 H), 0.01 (s, 3 H), –0.01 (s, 3
H).
13C NMR (50 MHz, CDCl3): d = 205.4, 139.0, 115.2, 77.3, 44.1,
37.1, 33.6, 25.8, 18.2, 15.3, 14.4, –4.3, –4.9.
MS (ESI): m/z (%) = 271 (100) [M + H]+, 155 (40).
HRMS (ESI): m/z [M + Na]+ calcd for C15H30NaO2Si: 293.1915;
found: 293.1913.
MS (ESI): m/z (%) = 434 (100) [M + H]+, 302 (20).
HRMS (ESI): m/z [M + H]+ calcd for C25H44NO3Si: 434.3099;
(2R,3S,4S,6R,7R)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-7-
(tert-butyldimethylsilyloxy)-3-hydroxy-2,4,6-trimethylnon-8-
en-1-one (17)
found: 434.3090.
To a soln of 8 (900 mg, 3.4 mmol) in CH2Cl2 (10 mL) at 0 °C was
added TiCl4 (0.4 mL, 3.5 mmol). The resulting orange slurry was
stirred for 5 min, i-Pr2NEt (0.6 mL, 3.5 mmol) was added (deep red)
and the mixture was stirred at 0 °C for 20 min. To this mixture, al-
dehyde 16 (916 mg, 3.4 mmol) in CH2Cl2 (2 mL) was added and the
mixture was stirred at 0 °C for 1 h. The reaction was quenched by
addition of sat. aq NH4Cl (10 mL). The layers were separated and
the aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The
combined organic layers were dried (Na2SO4) and filtered and the
filtrate was concentrated under vacuum. The crude product was pu-
rified by flash column chromatography (silica gel, EtOAc–hexane,
(2S,4R,5R)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethylhept-6-
en-1-ol (15)
To a soln of i-Pr2NH (4.39 mL, 31.2 mmol) in THF (20 mL) at –78
°C was added 1.6 M BuLi in hexanes (18.2 mL, 29.1 mmol) and the
soln was stirred for 5 min at –78 °C. The resulting soln was then
warmed to 0 °C for 10 min and then to r.t. for 5 min and it was then
cooled to 0 °C. Solid NH3·BH3 complex (0.96 g, 31.1 mmol) was
then added; during the addition vigorous evolution of gas ensued.
The mixture was stirred at 0 °C for 10 min and then it was warmed
to r.t. and stirred for an additional 10 min. The mixture was cooled
to 0 °C then the amide 14 (3.0 g, 6.9 mmol) in THF (20 mL) was
added and the mixture was warmed to r.t. and stirred overnight. The
soln was quenched with 10% aq HCl (50 mL) at 0 °C and stirred at
this temperature for 30 min and then the layers were separated and
the aqueous layer was extracted with Et2O (3 × 75 mL). The com-
bined organic layers were washed successively with 10% aq HCl
(50 mL) and 5 M aq NaOH (50 mL), then dried (Na2SO4) and fil-
tered and he filtrate was concentrated under vacuum. The crude
product was purified by flash column chromatography (silica gel,
EtOAc–hexane, 10:90) to afford 15 as a colorless oil. Yield: 1.69 g
(90%); [a]D25 +16.4 (c 0.50, CHCl3).
25
4:96) to afford 17 as a bright yellow oil. Yield: 1.35 g (74%); [a]D
+107.0 (c 0.50, CHCl3).
IR (neat): 2956, 2927, 1678, 1255, 1163, 837, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.26 (m, 5 H), 5.84 (ddd,
J = 17.0, 10.5, 6.5 Hz, 1 H), 5.38–5.33 (m, 1 H), 5.13 (dd, J = 17.0,
2.0 Hz, 1 H), 5.07 (dd, J = 10.5, 2.0 Hz, 1 H), 4.90–4.88 (m, 1 H),
4.00–3.98 (m, 1 H), 3.71 (dd, J = 9.0, 2.0 Hz, 1 H), 3.35 (dd,
J = 11.5, 7.0 Hz, 1 H), 3.25 (dd, J = 13.0, 4.0 Hz, 1 H), 3.02 (dd,
J = 13.0, 10.5 Hz, 1 H), 2.87 (d, J = 11.5 Hz, 1 H), 1.98–1.91 (m, 2
H), 1.80–1.73 (m, 2 H), 1.17 (d, J = 7.5 Hz, 3 H), 0.90 (d, J = 8.0
Hz, 3 H), 0.89 (s, 9 H), 0.87 (d, J = 7.0 Hz, 3 H), 0.05 (s, 3 H), 0.007
(s, 3 H).
IR (neat): 3334, 2956, 2927, 1251, 1028, 837, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.78 (ddd, J = 17.0, 10.5, 6.5 Hz,
1 H), 5.12 (dd, J = 17.0, 1.5 Hz, 1 H), 5.08 (dd, J = 10.5, 1.5 Hz, 1
H), 3.96–3.93 (m, 1 H), 3.53 (dd, J = 10.5, 4.5 Hz, 1 H), 3.39 (dd,
J = 10.5, 6.5 Hz, 1 H), 1.75–1.73 (m, 1 H), 1.72–1.60 (m, 2 H),
1.53–1.48 (m, 2 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.89 (s, 9 H), 0.87 (d,
J = 7.0 Hz, 3 H), 0.04 (s, 3 H), 0.01 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 201.2, 179.0, 140.2, 136.5, 129.4,
128.9, 127.2, 114.5, 77.6, 75.4, 69.0, 40.7, 37.4, 37.3, 36.9, 34.1,
31.7, 25.9, 18.2, 16.5, 16.4, 10.1, –4.2, –4.8.
MS (ESI): m/z (%) = 536 (100) [M + H]+, 520 (60), 404 (60).
HRMS (ESI): m/z [M + H]+ calcd for C28H46NO3S2Si: 536.2675;
13C NMR (50 MHz, CDCl3): d = 139.7, 114.8, 77.5, 67.8, 37.0,
35.9, 33.1, 25.9, 18.2, 17.9, 15.7, –4.3, –4.9.
found: 536.2688.
(2S,3S,4S,6R,7R)-7-(tert-Butyldimethylsilyloxy)-2,4,6-trimeth-
ylnon-8-ene-1,3-diol (18)
MS (ESI): m/z (%) = 273 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H32NaO2Si: 295.2071;
To a soln of thione 17 (1.2 g, 2.2 mmol) in EtOH (20 mL) was added
NaBH4 (340 mg, 9.0 mmol) and the mixture was stirred for 15 min;
by this time yellow color of the reaction had faded. The reaction was
then quenched by the addition of sat. aq NH4Cl (25 mL) and then it
was diluted with CH2Cl2 (50 mL), the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The com-
bined organic layers were dried (Na2SO4) and filtered and the fil-
trate was concentrated in vacuo. The crude product was purified by
found: 295.2069.
(2S,4R,5R)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethylhept-6-
enal (16)
To a soln of 15 (1.0 g, 3.6 mmol) in CH2Cl2 (20 mL) was added
PhI(OAc)2 (1.42 g, 4.4 mmol) followed by the addition of TEMPO
(57 mg, 0.4 mmol) and the mixture was stirred for 2 h. The reaction
Synthesis 2009, No. 3, 474–482 © Thieme Stuttgart · New York

PAPER
Stereoselective Preparation of C1–C10 and C11–O14 Fragments of Narbonolide
479
flash column chromatography (silica gel, EtOAc–hexane, 25:75) to
afford diol 18 as a colorless oil. Yield: 600 mg (81%); [a]D25 +8.4
(c 0.50, CHCl3).
2.04 (m, 1 H), 1.93–1.90 (m, 1 H), 1.73–1.66 (m, 3 H), 0.95 (d,
J = 5.5 Hz, 3 H), 0.94 (d, J = 5.0 Hz, 3 H), 0.88 (d, J = 6.5 Hz, 3 H),
0.87 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3 H).
IR (neat): 3485, 2958, 2929, 1415, 1334, 835, 775 cm–1.
13C NMR (50 MHz, CDCl3): d = 159.0, 139.9, 131.1, 129.1, 114.7,
113.7, 83.7, 76.4, 72.7, 67.4, 55.2, 37.2, 36.8, 36.4, 33.0, 25.9, 18.2,
16.8, 16.3, 11.5, –4.2, –4.9.
MS (ESI): m/z (%) = 451 (100) [M + H]+, 319 (20).
HRMS (ESI): m/z [M + Na]+ calcd for C26H46NaO4Si: 473.3068;
1H NMR (400 MHz, CDCl3): d = 5.80 (ddd, J = 17.0, 10.5, 6.5 Hz,
1 H), 5.14–5.02 (m, 2 H), 3.99–3.98 (m, 1 H), 3.73–3.42 (m, 3 H),
2.55 (br s, 1 H), 2.15 (br s, 1 H), 1.82–1.67 (m, 4 H), 0.92 (d, J = 7.0
Hz, 3 H), 0.87 (s, 9 H), 0.86 (d, J = 6.0 Hz, 3 H), 0.81 (d, J = 7.0 Hz,
3 H), 0.02 (s, 3 H), 0.001 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 139.3, 115.0, 114.5, 79.9, 77.7,
68.1, 37.8, 36.8, 36.0, 35.0, 25.9, 17.2, 17.0, 8.8, –4.2, –4.8.
found: 473.3063.
(2R,3S,4S,6R,7R)-7-(tert-Butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-2,4,6-trimethylnon-8-enal (21)
MS (ESI): m/z (%) = 331 (100) [M + H]+, 199 (60).
To a soln of 20 (500 mg, 1.1 mmol) in CH2Cl2 (10 mL) was added
PhI(OAc)2 (429 mg, 1.3 mmol) followed by the addition of TEMPO
(10 mg, 0.05 equiv). The mixture was stirred for 2 h and then the re-
action was quenched by the addition of sat. aq Na2S2O3–sat. aq
NaHCO3 (5:1, 20 mL). The layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined organ-
ic layers were dried (Na2SO4) and filtered and the filtrate was con-
centrated under vacuum. The crude product was purified by flash
column chromatography (silica gel, EtOAc–hexane, 3:97) to afford
HRMS (ESI): m/z [M + Na]+ calcd for C18H38NaO3Si: 353.2489;
found: 353.2488.
(3R,4R,6S)-3-(tert-Butyldimethylsilyloxy)-6-[(4S,5S)-2-(4-meth-
oxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-methylhept-1-ene (19)
To a soln of diol 18 (500 mg, 1.5 mmol) in CH2Cl2 (10 mL) was
added 4-MeOC6H4CH(OMe)2 (0.5 mL, 3.0 mmol) and CSA (18
mg, 0.07 mmol). The mixture was stirred overnight and then
washed with 10% aq NaHCO3 (20 mL). The layers were separated
and the aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The
combined organic layers were dried (Na2SO4) and filtered and the
filtrate was concentrated under vacuum. The crude product was pu-
rified by flash column chromatography (silica gel, EtOAc–hexane,
25
21 as a colorless oil. Yield: 470 mg (95%); [a]D –0.66 (c 1.00,
CHCl3).
IR (neat): 2956, 2929, 1726, 1514, 1249 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.70 (d, J = 1.0 Hz, 1 H), 7.20 (d,
J = 9.0 Hz, 2 H), 6.85 (d, J = 9.0 Hz, 2 H), 5.77 (ddd, J = 17.0, 10.0,
6.5 Hz, 1 H), 5.13–5.05 (m, 2 H), 4.42 (d, J = 11.0 Hz, 1 H), 4.40
(d, J = 11.0 Hz, 1 H), 3.95–3.92 (m, 1 H), 3.80 (s, 3 H), 3.68 (dd,
J = 6.0, 3.0 Hz, 1 H), 2.56–2.53 (m, 1 H), 2.08–2.05 (m, 1 H), 1.71–
1.58 (m, 3 H), 1.17 (d, J = 7.0 Hz, 3 H), 0.95 (d, J = 7.0 Hz, 3 H),
0.87 (d, J = 7.0 Hz, 3 H), 0.80 (s, 9 H), 0.01 (s, 3 H), –0.003 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 204.8, 159.1, 139.7, 130.6, 129.1,
114.9, 113.7, 81.1, 77.4, 72.4, 55.2, 48.5, 37.2, 36.2, 33.6, 25.9,
18.2, 16.8, 16.3, 8.7, –4.2, –4.9.
25
17:83) to afford 19 as a colorless oil. Yield: 624 mg (92%); [a]D
–7.2 (c 1.00, CHCl3).
IR (neat): 2956, 1517, 1247, 829, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40 (d, J = 9.0 Hz, 2 H), 6.86 (d,
J = 9.0 Hz, 2 H), 5.79 (ddd, J = 17.0, 10.5, 6.0 Hz, 1 H), 5.39 (s, 1
H), 5.07 (dd, J = 17.0, 2.0 Hz, 1 H), 5.02 (dd, J = 10.5, 2.0 Hz, 1 H),
4.02–3.93 (m, 3 H), 3.80 (s, 3 H), 3.41 (dd, J = 9.5, 2.0 Hz, 1 H),
1.97–1.83 (m, 2 H), 1.77–1.68 (m, 2 H), 1.67–1.62 (m, 1 H), 1.15
(d, J = 7.0 Hz, 3 H), 0.85 (d, J = 6.5 Hz, 3 H), 0.83 (s, 9 H), 0.83 (d,
J = 6.5 Hz, 3 H), –0.03 (s, 3 H), –0.038 (s, 3 H).
MS (ESI): m/z (%) = 471 (100) [M + Na]+.
13C NMR (50 MHz, CDCl3): d = 159.7, 140.5, 131.8, 127.4, 114.2,
113.4, 101.7, 85.1, 74.1, 55.3, 37.1, 37.0, 32.3, 30.2, 25.8, 18.1,
16.2, 15.0, 11.0, –4.2, –4.9.
HRMS (ESI): m/z [M + Na]+ calcd for C26H44NaO4Si: 471.2915;
found: 471.2907.
(2R,3S,4S,5S,6S,8R,9R)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-
yl]-9-(tert-butyldimethylsilyloxy)-3-hydroxy-5-(4-methoxyben-
zyloxy)-2,4,6,8-tetramethylundec-10-en-1-one (22)
MS (ESI): m/z (%) = 449 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C26H45O4Si: 449.3102; found:
449.3087.
To a soln of 8 (265 mg, 1.0 mmol) in CH2Cl2 (5 mL) at 0 °C was
added TiCl4 (0.11 mL, 1.0 mmol). The resulting orange slurry was
stirred for 5 min, i-Pr2NEt (0.14 mL, 1.0 mmol) was added (deep
red) and the mixture was stirred for 20 min. Aldehyde 21 (450 mg,
1.00 mmol) in CH2Cl2 (2 mL) was added and the mixture was
stirred at 0 °C for 1 h. The reaction was quenched by the addition of
sat. aq NH4Cl (10 mL), the layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 25 mL). The combined organ-
ic layers were dried (Na2SO4) and filtered and the filtrate was con-
centrated under vacuum. The crude product was purified by flash
column chromatography (silica gel, EtOAc–hexane, 7:93) to afford
aldol 22 as a bright yellow oil. Yield: 591 mg (83%); [a]D25 –85.4
(c 0.50, CHCl3).
(2S,3S,4S,6R,7R)-7-(tert-Butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-2,4,6-trimethylnon-8-en-1-ol (20)
To a soln of 19 (550 mg, 1.2 mmol) in CH2Cl2 (10 mL) at 0 °C, was
added 20% soln of DIBAL-H in toluene (2.2 mL, 3.1 mmol) and the
mixture was stirred for 30 min. The mixture was gradually warmed
to r.t. and stirred for 3 h and then it was cooled to 0 °C and quenched
by dropwise addition of EtOH (1 mL) and followed by sat. aq po-
tassium sodium tartrate (20 mL). The soln was warmed to r.t. and
stirred until 2 clear layers were observed. The layers were separated
and the aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The
combined organic layers were dried (Na2SO4) and filtered and the
filtrate was concentrated under vacuum. The crude product was pu-
rified by flash column chromatography (silica gel, EtOAc–hexane,
12:88) to afford 20 as a colorless oil. Yield: 436 mg (79%); [a]D
+22.2 (c 0.50, CHCl3).
IR (neat): 3419, 2956, 2929, 1514, 1247 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 8.5 Hz, 2 H), 6.86 (d,
J = 8.5 Hz, 2 H), 5.79 (ddd, J = 17.0, 10.5, 6.5 Hz, 1 H), 5.10 (dd,
J = 17.0, 1.2 Hz, 1 H), 5.06 (dd, J = 10.5, 1.2 Hz, 1 H), 4.57 (d,
J = 11.0 Hz, 1 H), 4.39 (d, J = 10.5 Hz, 1 H), 3.96–3.93 (m, 1 H),
3.80 (s, 3 H), 3.54 (br s, 2 H), 3.33 (dd, J = 6.5, 3.0 Hz, 1 H), 2.08–
IR (neat): 3512, 2954, 2929, 1691, 1514, 1249 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.27 (m, 5 H), 7.24 (d,
J = 9.0 Hz, 2 H), 6.85 (d, J = 9.0 Hz, 2 H), 5.82 (ddd, J = 17.0, 10.5,
6.5 Hz, 1 H), 5.24–5.15 (m, 1 H), 5.10–5.03 (m, 2 H), 4.61 (d,
J = 11.0 Hz, 1 H), 4.52 (t, J = 7.0 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1
H), 3.96–3.91 (m, 2 H), 3.78 (s, 3 H), 3.31–3.26 (m, 2 H), 3.21–3.18
(m, 2 H), 3.03 (dd, J = 13.0, 10.5 Hz, 1 H), 2.88 (d, J = 11.0 Hz, 1
H), 2.16–2.14 (m, 1 H), 1.72–1.59 (m, 4 H), 1.32 (d, J = 6.5 Hz, 3
25
Synthesis 2009, No. 3, 474–482 © Thieme Stuttgart · New York

480
C. P. Narasimhulu, P. Das
PAPER
H), 0.98 (d, J = 6.5 Hz, 3 H), 0.93 (d, J = 7.0 Hz, 3 H), 0.89 (s, 9 H),
0.88 (d, J = 6.5 Hz, 3 H), 0.02 (s, 3 H), 0.005 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 200.7, 177.7, 159.1, 140.2, 136.3,
130.5, 129.4, 129.0, 128.9, 127.2, 114.7, 113.7, 86.1, 77.6, 76.4,
72.3, 68.6, 55.2, 42.1, 37.0, 36.8, 36.8, 36.6, 32.8, 32.1, 25.9, 18.2,
16.2, 16.1, 13.4, 8.6, –4.1, –4.8.
13C NMR (50 MHz, CDCl3): d = 179.2, 159.0, 140.1, 131.1, 129.0,
114.7, 113.6, 83.6, 76.4, 74.9, 73.1, 55.2, 43.0, 39.5, 37.5, 36.2,
33.6, 26.1, 25.9, 23.8, 20.8, 18.3, 16.9, 16.8, 11.2, 10.9, –4.0, –4.1,
–4.2, –4.8.
MS (ESI): m/z (%) = 659 (100) [M + Na]+, 637 (95) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C35H65O6Si2: 637.0687;
MS (ESI): m/z (%) = 714 (20) [M + H]+, 560 (100).
found: 637.0661.
HRMS (ESI): m/z [M + Na]+ calcd for C39H59NaO5SiS2: 736.3526;
found: 736.3502.
(2S,3R)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-hydroxy-2-
methylpentan-1-one (24)
To a soln of 8 (5 g, 18.8 mmol) in CH2Cl2 (75 mL) at 0 °C was added
TiCl4 (2.17 mL, 19.8 mmol). The resultant orange slurry was stirred
for 5 min, (–)-sparteine (4.33 mL, 18.8 mmol) was added forming
the characteristic enolate color (deep red). The mixture was stirred
at 0 °C for 20 min, then cooled to –78 °C and NMP (1.81 mL, 18.8
mmol) was added. The mixture was stirred for 10 min and then
freshly distilled propanal (1.51 mL, 20.6 mmol) was added drop-
wise. The mixture was stirred at –78 °C for 1 h and then at 0 °C for
1 h. The reaction was quenched by the addition of sat. aq NH4Cl (75
mL). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 75 mL). The combined organic layers were dried
(Na2SO4) and filtered. The filtrate was concentrated under vacuum.
The crude product was purified by flash column chromatography
(silica gel, EtOAc–hexane, 10:90) to afford 24 as a bright yellow
oil. Yield: 5.18 g (85%); [a]D25 +78.0 (c 1.00, CHCl3).
(2R,3S,4R,5S,6S,8R,9R)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-
yl)-3,9-bis(tert-butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-
2,4,6,8-tetramethylundec-10-en-1-one (23)
To a soln of 22 (300 mg, 0.4 mmol) in CH2Cl2 (5 mL) at 0 °C was
added i-Pr2NEt (0.18 mL, 1.0 mmol) followed by the dropwise ad-
dition of TBSOTf (0.12 mL, 0.5 mmol). The mixture was stirred at
this temperature for 30 min, brought to up r.t. and then stirred over-
night. The mixture was cooled and quenched by the addition sat. aq
NaHCO3 (10 mL). It was then diluted with CH2Cl2 (10 mL), the lay-
ers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4) and filtered and the filtrate was concentrated under vacu-
um. The crude product was purified by flash column chromatogra-
phy (silica gel, EtOAc–hexane, 4:96) to afford 23 as a bright yellow
oil. Yield: 281 mg (81%); [a]D25 –66.8 (c 0.35, CHCl3).
IR (neat): 3402, 2962, 1693, 1165 cm–1.
IR (neat): 2954, 2927, 1691, 1249 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.25 (m, 5 H), 5.37–5.32 (m,
1 H), 4.54–4.48 (m, 1 H), 3.86–3.82 (m 1 H), 3.42–3.37 (m, 1 H),
3.22 (dd, J = 13.0, 4.0 Hz, 1 H), 3.04 (dd, J = 13.0, 11.0 Hz, 1 H),
2.89 (d, J = 11.0 Hz, 1 H), 2.62 (br s, 1 H), 1.60–1.49 (m, 1 H),
1.48–1.41 (m, 1 H), 1.24 (d, J = 7.0 Hz, 3 H), 0.95 (t, J = 7.5 Hz, 3
H).
13C NMR (50 MHz, CDCl3): d = 201.3, 178.4, 136.3, 129.4, 128.9,
127.3, 73.7, 68.8, 42.8, 36.7, 32.0, 27.2, 10.3, 10.2.
MS (ESI): m/z (%) = 324 (85) [M + H]+, 209 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C16H21NNaO2S2: 346.0909;
1H NMR (400 MHz, CDCl3): d = 7.33–7.26 (m, 5 H), 7.24 (d,
J = 8.0 Hz, 2 H), 6.82 (d, J = 8.0 Hz, 2 H), 5.88 (ddd, J = 17.0, 10.5,
6.5 Hz, 1 H), 5.18–5.06 (m, 3 H), 4.55–4.53 (m, 1 H), 4.50 (d,
J = 11.0 Hz, 1 H), 4.42 (d, J = 11.0 Hz, 1 H), 4.01 (dd, J = 6.5, 3.5
Hz, 1 H), 3.96–3.94 (m, 1 H), 3.77 (s, 3 H), 3.31–3.29 (m, 1 H),
3.23–3.20 (m, 2 H), 3.01 (dd, J = 13.0, 11.0 Hz, 1 H), 2.80 (d,
J = 11.0 Hz, 1 H), 2.09–2.08 (m, 1 H), 1.77–1.69 (m, 2 H), 1.58–
1.54 (m, 2 H), 1.27 (d, J = 6.5 Hz, 3 H), 0.99 (d, J = 7.0 Hz, 3 H),
0.95 (d, J = 7.0 Hz, 3 H), 0.93 (s, 9 H), 0.89 (s, 9 H), 0.88 (d, J = 6.0
Hz, 3 H), 0.10 (s, 3 H), 0.08 (s, 3 H), 0.04 (s, 3 H), 0.01 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 200.5, 177.3, 158.8, 140.3, 136.6,
131.6, 129.4, 128.8, 128.7, 127.1, 114.8, 113.5, 83.5, 78.1, 75.7,
73.2, 69.3, 55.2, 43.3, 40.6, 37.3, 36.4, 35.1, 33.2, 32.0, 26.3, 26.0,
18.5, 18.3, 17.4, 17.1, 15.0, 11.1, –3.3, –3.8, –4.1, –4.7.
found: 346.0911.
(2S,3R)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-(tert-butyl-
dimethylsilyloxy)-2-methylpentan-1-one (25)
MS (ESI): m/z (%) = 828 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C45H73NNaO5S2Si2:
To a soln of 24 (5.1 g, 15.8 mmol) in CH2Cl2 (75 mL) at 0 °C was
added 2,6-lutidine (2.75 mL, 23.7 mmol) and TBSOTf (4.35 mL,
18.9 mmol) sequentially. The mixture was stirred for 1 h and then
the reaction was quenched by the addition of sat. aq NaHCO3 (50
mL). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were dried
(Na2SO4) and filtered and the filtrate was concentrated under vacu-
um. The crude product was purified by flash column chromatogra-
phy (silica gel, EtOAc–hexane, 5:95) to afford 25 as a bright yellow
oil. Yield: 6.27 g (91%); [a]D25 +23.4 (c 1.00, CHCl3).
850.4359; found: 850.4366.
(2R,3S,4R,5S,6S,8R,9R)-3,9-Bis(tert-butyldimethylsilyloxy)-5-
(4-methoxybenzyloxy)-2,4,6,8-tetramethylundec-10-enoic Acid
(6)
To a soln of thione 23 (220 mg, 0.265 mmol) in a mixture of THF
and H2O (4:1, 5 mL) at 0 °C was added 30% aq H2O2 (0.3 mL, 2.7
mmol) followed by the addition of LiOH (33.5 mg, 0.8 mmol). The
mixture was stirred for 1 h and then directly loaded on to a column
(silica gel, EtOAc–hexane, 10:90) and eluted to afford 6. Yield: 109
mg (65%); [a]D25 +1.6 (c 1.00, CHCl3).
IR (neat): 1691, 1253, 1163, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.27 (m, 5 H), 5.22–5.16 (m,
1 H), 4.61–4.55 (m, 1 H), 3.99–3.95 (m, 1 H), 3.34–3.26 (m, 2 H),
3.04 (dd, J = 13.0, 11.0 Hz, 1 H), 2.88 (d, J = 11.0 Hz, 1 H), 1.61–
1.47 (m, 2 H), 1.22 (d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H), 0.87 (t, J = 3.0
Hz, 3 H), 0.05 (s, 3 H), 0.02 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 200.9, 176.9, 136.7, 129.5, 128.9,
127.2, 74.9, 69.5, 43.7, 36.5, 31.9, 28.0, 25.8, 18.0, 12.0, 9.4, –4.1,
–4.7.
IR (neat): 2954, 2929, 1707, 1514, 1249, 835, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 8.5 Hz, 2 H), 6.79 (d,
J = 8.5 Hz, 2 H), 5.74 (ddd, J = 17.0, 10.5, 6.5 Hz, 1 H), 5.05 (dd,
J = 17.0, 2.0 Hz, 1 H), 5.00 (dd, J = 10.5, 1.2 Hz, 1 H), 4.47 (d,
J = 11.0 Hz, 1 H), 4.36 (d, J = 11.0 Hz, 1 H), 4.02–3.99 (m, 1 H),
3.90–3.88 (m, 1 H), 3.73 (s, 3 H), 3.14 (dd, J = 5.5, 3.5 Hz, 1 H),
2.67 (dd, J = 7.0, 3.5 Hz, 1 H), 2.02–1.98 (m, 1 H), 1.83–1.80 (m, 1
H), 1.68–1.61 (m, 4 H), 1.13 (d, J = 7.0 Hz, 3 H), 0.97 (d, J = 6.5
Hz, 3 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.90 (s, 3 H), 0.905 (s, 9 H), 0.88
(s, 9 H), 0.02 (s, 6 H), 0.001 (s, 6 H).
MS (ESI): m/z (%) = 438 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H36NO2S2Si: 438.7438;
found: 438.7392.
Synthesis 2009, No. 3, 474–482 © Thieme Stuttgart · New York

PAPER
Stereoselective Preparation of C1–C10 and C11–O14 Fragments of Narbonolide
481
(2R,3R)-3-(tert-Butyldimethylsilyloxy)-2-methylpentan-1-ol
(26)
References
(1) DRL Publication No. 670.
To a soln of thione 25 (6.0 g, 13.7 mmol) in Et2O (50 mL) at 0 °C
was added, H2O (0.62 mL, 34.3 mmol, 2.5 equiv) and LiBH4 (720
mg, 58.6 mmol, 2.5 equiv) sequentially; the resulting mixture was
stirred at 0 °C for 1 h. At this time yellow color of the reaction had
faded, whereupon the reaction was quenched by careful addition of
sat. aq NH4Cl (50 mL) and extracted with Et2O (3 × 100 mL). The
organic layer was dried (Na2SO4) and filtered and the filtrate was
concentrated under vacuum. The crude product was purified by
flash column chromatography (silica gel, EtOAc–hexane, 15:85) to
afford 26 as a colorless oil. Yield: 2.23 g (70%); [a]D25 +1.4 (c 1.00,
CHCl3).
(2) Macrolide Antibiotics: Chemistry, Biology and Practice,
2nd ed.; Omura, S., Ed.; Academic: San Diego, 2002.
(3) Leclercq, R. Clin. Infect. Dis. 2002, 34, 482.
(4) (a) Agouridas, C.; Denis, A.; Auger, J.-M.; Benedetti, Y.;
Bonnefoy, A.; Bretin, F.; Chantot, J.-F.; Dussarat, A.;
Fromentin, C.; D’Ambrieres, S. G.; Lachaud, S.; Laurin, P.;
Le Martret, O.; Loyau, V.; Tessot, N. J. Med. Chem. 1998,
41, 4080. (b) Zhanel, G. G.; Walters, M.; Noreddin, A.;
Vercaigne, L. M.; Wierzbowski, A.; Embil, J. M.; Gin, A. S.;
Douthwaite, S.; Hoban, D. J. Drugs 2002, 62, 12.
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Nemoto, P. A.; Chu, D. T. W.; Plattner, J. J.; Zhang, X.;
Zhong, P.; Cao, Z.; Nilius, A. M.; Shortridge, V. D.; Flamm,
R.; Mitten, M.; Meulbroek, J.; Ewing, P.; Alder, J.; Or, Y. S.
J. Med. Chem. 2001, 44, 4137.
IR (neat): 3348, 2958, 2929, 1253 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.71–3.66 (m, 2 H), 3.51 (dd,
J = 11.0, 5.5 Hz, 1 H), 2.53 (br s, 1 H), 1.97–1.94 (m, 1 H), 1.54–
1.47 (m, 2 H), 0.90 (s, 9 H), 0.89 (t, J = 4.0 Hz, 3 H), 0.81 (d, J = 7.5
Hz, 3 H), 0.09 (s, 3 H), 0.07 (s, 3 H).
(6) (a) Denis, A.; Agouridas, C.; Auger, J.-M.; Benedetti, Y.;
Bonnefoy, A.; Bretin, F.; Chantot, J.-F.; Dussarat, A.;
Fromentin, C.; D’Ambrieres, S. G.; Lachaud, S.; Laurin, P.;
Le Martret, O.; Loyau, V.; Tessot, N.; Pejac, J.-M.; Perron,
S. Bioorg. Med. Chem. Lett. 1999, 9, 3075. (b) Plata, D. J.;
Leanna, M. R.; Rasmussen, M.; McLaughlin, M. A.;
Condon, S. L.; Kerdesky, F. A. J.; King, S. A.; Peterson, M.
J.; Stoner, E. J.; Wittenberger, S. J. ChemInform 2005, 36,
10. (c) Henninger, T. C.; Xu, X.; Abbanat, D.; Baum, E. Z.;
Foleno, B. D.; Hilliard, J. J.; Bush, K.; Hlasta, D. J.;
Macielag, M. J. Bioorg. Med. Chem. Lett. 2004, 14, 4495.
(7) (a) Hori, T.; Maezawa, I.; Nagahama, N.; Suzuki, M. Chem.
Commun. 1971, 304. (b) Maezawa, I.; Hori, T.; Kinumaki,
A.; Suzuki, M. J. Antibiot. 1973, 26, 771. (c) Xue, Y.;
Zhao, L.; Liu, H.-W.; Sherman, D. H. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 12111. (d) Xue, Y.; Sherman, D. H. Met.
Eng. 2001, 3, 15.
13C NMR (50 MHz, CDCl3): d = 76.4, 66.1, 39.2, 25.8, 25.1, 18.0,
11.8, 10.7, –4.4, –4.5.
MS (ESI): m/z (%) = 233 (100) [M + H]+.
(2S,3R)-3-(tert-Butyldimethylsilyloxy)-2-methylpentanal (27)16
To a soln of 26 (300 mg, 1.3 mmol) in CH2Cl2 (5 mL) was added
PhI(OAc)2 (499 mg, 1.5 mmol) followed by the addition of TEMPO
(10 mg, 0.05 equiv). The mixture was stirred for 2 h and then the re-
action was quenched by the addition of sat. aq Na2S2O3–sat. aq
NaHCO3 (5:1, 10 mL). The layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined organ-
ic layers were dried (Na2SO4) and filtered and the filtrate was con-
centrated under vacuum. The crude product was purified by flash
column chromatography (silica gel, EtOAc–hexane, 4:96) to afford
25
27 as a colorless oil. Yield: 265 mg (90%); [a]D +54.2 (c 0.7,
CHCl3).
(8) (a) Kaiho, T.; Masamune, S.; Toyoda, T. J. Org. Chem.
1982, 47, 1612. (b) Venkatraman, L.; Aldrich, C. C.;
Sherman, D. H.; Fecik, R. A. J. Org. Chem. 2005, 70, 7267.
(c) Venkatraman, L.; Salomon, C. E.; Sherman, D. H.; Fecik,
R. A. J. Org. Chem. 2006, 71, 9853.
(9) (a) Sai Baba, V.; Das, P.; Mukkanti, K.; Iqbal, J.
Tetrahedron Lett. 2006, 47, 6083. (b) Sai Baba, V.; Das, P.;
Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2006, 47, 7927.
(c) Saibaba, V.; Sampath, A.; Mukkanti, K.; Iqbal, J.; Das, P.
Synthesis 2007, 2797. (d) Das, P.; Saibaba, V.; Kirankumar,
C.; Mahendar, V. Synthesis 2008, 445.
(3R,4R)-4-(tert-Butyldimethylsilyloxy)-3-methylhex-1-ene (7)
To a soln of aldehyde 27 (200 mg, 0.9 mmol) in THF (5 mL) at 0 °C
was added 0.5 M Tebbe’s reagent (1.7 mL, 1.0 mmol) dropwise.
The resulting dark-brown mixture was allowed to warm to r.t. for 10
min, diluted with Et2O (10 mL), and aq 0.1 M NaOH (5 drops) was
added. Some bubbling was observed at this point, Na2SO4 added,
and the slurry was filtered through a short pad of silica gel. The fil-
trate was concentrated under vacuum and purified by flash column
chromatography (silica gel, EtOAc–hexane, 2:98) to afford 7 as a
colorless oil. Yield: 90 mg (46%); [a]D25 +24.4 (c 0.50, CHCl3).
IR (neat): 2956, 2927, 1462, 1251, 771 cm–1.
(10) Narsimhulu, C. P.; Iqbal, J.; Mukkanti, K.; Das, P.
Tetrahedron Lett. 2008, 49, 3185.
1H NMR (400 MHz, CDCl3): d = 5.81 (ddd, J = 18.0, 10.5, 7.5 Hz,
1 H), 4.98 (dd, J = 10.5, 1.6 Hz, 1 H), 4.95–4.93 (m, 1 H), 3.47–3.42
(m, 1 H), 2.31–2.26 (m, 1 H), 1.46–1.37 (m, 2 H), 0.94 (d, J = 7.0
Hz, 3 H), 0.87 (s, 9 H), 0.86 (t, J = 2.0 Hz, 3 H), 0.02 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 141.8, 113.6, 76.4, 42.3, 26.5,
25.9, 15.0, 9.5, –4.3, –4.4.
(11) (a) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita,
E. J. Chem. Soc., Chem. Commun. 1985, 1418. (b) Nagao,
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(b) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary,
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McKinstry, L. J. Am. Chem. Soc. 1996, 118, 2428.
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6496.
MS (ESI): m/z (%) = 229 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H29OSi: 229.4535; found:
229.4482.
Acknowledgment
We thank Dr. Reddy’s Laboratories Ltd. for financial support and
encouragement. Help from the analytical department in recording
spectral data is appreciated.
Synthesis 2009, No. 3, 474–482 © Thieme Stuttgart · New York

482
C. P. Narasimhulu, P. Das
PAPER
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Synthesis 2009, No. 3, 474–482 © Thieme Stuttgart · New York