Total synthesis of neomethymycin and novamethymycin

Article abstract of DOI:10.1016/j.tet.2010.04.039

Total synthesis of neomethymycin and novamethymycin has been achieved. These two macrolides contains 12-membered macrolactones as aglycones and belong to the methymycin family of antibiotics, which appears in the pikromycin biosynthetic pathway. The segme

Full text of DOI:10.1016/j.tet.2010.04.039

Tetrahedron 66 (2010) 4307e4317
Contents lists available at ScienceDirect
Tetrahedron
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Total synthesis of neomethymycin and novamethymycin
*
Hong-Se Oh, Han-Young Kang
Department of Chemistry, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Total synthesis of neomethymycin and novamethymycin has been achieved. These two macrolides
contains 12-membered macrolactones as aglycones and belong to the methymycin family of antibiotics,
which appears in the pikromycin biosynthetic pathway. The segments in the 12-membered macrolactone
that are responsible for causing structural difference in neomethymycin and novamethymycin were
Received 2 March 2010
Received in revised form 8 April 2010
Accepted 8 April 2010
Available online 14 April 2010
synthesized by starting with methyl
D
-(þ)-lactate and
D-glucose, for neomethynolide, and for novame-
thynolide, respectively. The key steps in synthesis of neomethynolide and novamethynolide, which are
aglycones for neomethymycin and novamethymycin, respectively, were asymmetric aldol reactions,
Yamaguchi esterification, and ring-closing metathesis using Grubbs’ second generation catalyst. Finally,
the coupling of agylcones with the corresponding trichloroacetimidates, followed by deprotection,
completed the total synthesis of these two macrolide antibiotics.
Keywords:
Neomethymycin
Novamethymycin
Pikromycin
Total synthesis
Macrolides
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
pattern during the post-PKS modification of 10-deoxymethynolide
(1a) and narbonolide (5a).
Macrolides belong to a large class of natural products that have
attracted considerable attention due to not only their biological
activities but also their structural diversity.1 Pikromycin was the
first macrolide antibiotic to be isolated and this has led to a new era
in natural product chemistry and has introduced new synthetic
challenges. In the course of biosynthetic pathway leading to pik-
romycin, Streptomyces venezuelae produces two major types of
macrolide antibiotics, that is, the methymycin and pikromycin
families, which contain the 12- and the 14-membered macro-
lactones as aglycones, respectively. The methymycin family of
macrolide antibiotics is biosynthetically produced from 10-deoxy-
methynolide (1a).2e4 The post-PKS (polyketide synthase) modifi-
cation of 10-deoxymethynolide (1a) converts it into a total of four
compounds, that is, YC-17 (1),5 methymycin (2),6 neomethymycin
(3),6 and novamethymycin (4)7 (Fig. 1). The aglycones of the
methymycin family of polyketides are 10-deoxymethyolide (1a),
methynolide (2a),8,9 neomethynolide (3a),10 and novamethynolide
(4a). Another family of macrolide antibiotics is also produced: the
pikromycin family. This family is made up of four macrolides, which
include narbomycin (5), pikromycin (6), neopikromycin (7),11 and
novapikromycin (8).11 Aglycones of the pikromycin family that have
14-membered lactones are narbonolide (5a),12 pikronolide (6a),13
neopikronolide (7a), and novapikronolide (8a), respectively. The
structures of these macrolides vary depending on the oxidation
For the synthesis of 10-deoxymethynolide (1a) and narbonolide
(5a) these lactones were retrosynthetically divided into segments.
Each segment was synthesized and assembled to achieve the total
synthesis.14 All the macrolactones shown in Figure 1 could, in
theory, be synthesized by switching their structurally different
segments (modules). This synthetic approach has been successfully
applied to the synthesis of methymycin (2). After methynolide (2a),
the aglycone of methymycin (2), was synthesized, glycosylation
with desosamine successfully afforded methymycin.15
Neomethymycin (3), belonging to one of the methymycin fam-
ilies of macrolide antibiotics, has been isolated and its structure
identified by Djerassi and Halpren.6 Although the synthesis of
neomethynolide (3a), the aglycone of neomethymycin (3), has been
reported by Yamaguchi, the chemical synthesis of neomethymycin
(3) has never been reported previously. Recently, Zang and Sher-
man reported the isolation of novamethymycin (4) from S. ven-
ezuelae, which has been known to produce methymycin (2) and
neomethymycin (3).7 This also shows the broad substrate flexibility
of the PikC cytochrome P450 hydroxylase, in accepting not only the
12- and 14-membered-ring macrolides but also those with addi-
tional hydroxyl groups.
Neomethymycin (3) and novamethymycin (4) are members of
the methymycin family of antibiotics and have never been chemi-
cally synthesized. Since our approach for synthesizing methymycin
(2) was successful, we decided to apply this approach to the syn-
thesis of neomethymycin (3) and novamethymycin (4). This would
not only prove the generality of our modular route but also provide
* Corresponding author. Tel.: þ82 43 261 2305; fax: þ82 43 267 2279; e-mail
address: hykang@chungbuk.ac.kr (H.-Y. Kang).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.039

4308
H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
Methymycin Family of Macrolide Antibiotics
R =
D-desosaminide
R=H
O
8
R1 = H,
R2 = H 10-Deoxymethynolide (1a)
YC-17 (1)
Methymycin (2)
Neomethymycin (3)
Novamethymycin (4)
R1
R1 = OH, R2 = H
R1 = H,
R1 = OH, R2 = OH Novamethynolide (4a)
Methynolide (2a)
O
10
3
R2 = OH Neomethynolide (3a)
R2
O
OR
NMe2
Pikromycin Family of Macrolide Antibiotics
R=H
O
OH
D-desosaminide
R =
O
R3 = H,
R3 = OH, R4 = H
R3 = H,
OR
R4 = H
Narbonolide (5a)
Pikronolide (6a)
Narbomycin (5)
Pikromycin (6)
Neopikromycin (7)
Novapikromycin (8)
R3
6
R4
R4 = OH Neopikronolide (7a)
O
3
R3 = OH, R4 = OH Novapikronolide (8a)
O
O
Figure 1. Methymycin and Pikromycin families of macrolide antibiotics.
an example of efficiency of modern synthetic methodology to
prepare these types of polyketide macrolides. Here, we report the
total synthesis of neomethymycin (3) and novamethymycin (4).
First, we focused on the synthesis of the segment 9a for neo-
methynolide (3a) as summarized in Scheme 1.
The synthesis was started with the commercially available methyl
D
-(þ)-lactate. Aldehyde 10 was prepared according to the reported
procedure.16 Then,aldehyde10 was subjected to the asymmetric aldol
reaction17 with 1118 to afford aldol adduct 12. After the newly formed
hydroxy group was protected with TES, LiBH4 reduction followed by
oxidation (ParikheDoering) yielded aldehyde 15. The Wittig reaction
followed by deprotection (HF, CH3CN) provided the required pro-
tected segment 9a for the synthesis of neomethynolide.
2. Results and discussion
According to the modular approaches we have previously de-
veloped for the synthesis of methymycin (2), neomethymycin (3),
and novamethymycin (4) can be divided into segments, as shown in
Figure 2.
R1
O
O
RCM
R2
N
N
O
R1
R1
HO
OH
HO
HO
O
O
+
+
R2
R2
O
O
O
O
OH
glycosylation
O
aldol
D-Desosamine
Yamaguchi
O
Neomethymycin (3) (R1 = H, R2 = OH)
Novamethymycin (4) (R1 = OH, R2 = OH)
Neomethynolide (3a) (R1 = H, R2 = OH)
Novamethynolide (4a) (R1 = OH, R2 = OH)
HO
OH
Figure 2. Retrosynthesis of neomethymycin (3) and novamethymycin (4).
Neomethymycin (3) and novamethymycin (4) could be synthe-
sized from the corresponding aglycones, neomethynolide (3a) and
novamethynolide (4a), respectively, via glycosylation. We expected
that optimum conditions for successful glycosylation must be
found for the synthesis of these two macrolides. Aglycones could be
prepared by the coupling of segments, as shown in Figure 2, and
eventually total synthesis could be started from the synthesis of the
corresponding segment 9. Specifically, segments 9a and 9b (as
suitably protected forms) are required for the synthesis of neo-
methymycin (3) and novamethymycin (4), respectively (Fig. 3).
The synthesis of segment 9b for novamethynolide (4a) is sum-
marized in Scheme 2.
We noted that glucosaccharinic acid lactone 17 would be a key
component in the preparation of the suitably protected segment
9b for the synthesis of novamethynolide (4a). The synthesis of
glucosaccharinic acid lactone 17 by original procedure was
hampered by low yield and long reaction time.19 Fortunately,
a recent report on the improvement of this procedure based on
the Amadori rearrangement encouraged us to adopt lactone 17 as
the starting material for segment 9b.20 Due to a handling prob-
lem, we had to purify after converting it to acetonide 18. Al-
though the yield was lower than that reported previously (18
from
was very competitive because it was efficient and an inexpensive
starting material ( -glucose) was used (one-pot with short re-
action time). We then synthesized segment 9b using the pro-
cedure summarized in Scheme 2. Protection of diol functionality
as an acetonide, iodination, and subsequent radical reduction
(Bu3SnH, AIBN, toluene) provided the compound 20 in good
yield. Reduction (LiBH4) was performed to provide diol 21; this
was followed by protection with the TBS group, to produce TBS-
protected diol 22. Selective deprotection with HF$pyridine
D-glucose, 8.3% yield), we still concluded that this procedure
HO
D
RO
RO
OH
OH
9a
9b
Figure 3. Fragments required for modular approaches.

H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
4309
Ph
Ph
O
O
O
OH
OPMB
Ph
O
OSiEt3
OPMB
ref (16)
(a)
(b)
O
O
H
N
N
N
OH
OPMB
O
O
O
O
O
O
11
Methyl D-(+)-lactate
10
12
13
(c)
OH OSiEt3
O
OSiEt3
(d)
(f)
OSiEt3
(e)
H
PMBO
OH
H
OPMB
14
OPMB
OPMB
16
9a
15
Scheme 1. (a) Compound 11, Bu2BOTf, Et3N, CH2Cl2, ꢀ78 ꢁC (75%); (b)Et3SiOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC (97%); (c) LiBH4$H2O, ether (73%); (d) SO3$pyridine, CH2Cl2, DMSO, Et3N
(75%); (e) H2C]PPh3, THF (80%); (f) HF, CH3CN, rt (98%).
O
O
HO
O
O
O
I
O
O
(c)
(g)
HOH2C
HO
17
O
(b)
(d)
(a)
D-glucose
O
O
O
O
O
O
OH
18
19
20
(e)
OTBS
OTBS
OTBS
OTBS
OTBS
OH
OH
HO
OH
(j)(k)(l)
(f)
(i)
(h)
O
AcO
OH
O
O
O
O
O
O
O
O
O
O
9b
25
24
23
22
21
Scheme 2. (a) Me2NH, EtOH, AcOH then Ca(OH)2, H2O (b) H2SO4, acetone (8.3%, two steps); (c) Ph3P, I2, imidazole, CH2Cl2 (73%); (d) Bu3SnH, AIBN, toluene (87%); (e) LiBH4, H2O,
ether, 0 ꢁC to rt (62%); (f) TBSOTf, 2,6-lutidine, CH2Cl2 (87%); (g) HF$pyridine,THF, pyridine, 0 ꢁC (81%); (h) DMP, CH2Cl2 (74%); (i) MePh3Br, n-BuLi, THF, ꢀ78 ꢁC to 0 ꢁC (83%); (j) TBAF,
THF (96%); (k) Ac2O, Et3N, DMAP (81%); (l) 80% AcOH, 80 ꢁC (69%).
generated a primary alcohol 23. Subsequent oxidation followed
by the Wittig olefination provided olefin 25. Finally, the removal
of the acetonide group under acidic conditions provided segment
9b in a properly protected form. After the required segments 9a
and 9b were obtained, we proceeded to synthesize the aglycones
for neomethynolide (3a) and novamethynolides (4a). The syn-
thesis of neomethynolide (a series) and novamethynolide (b se-
ries) is summarized in Scheme 3.
O
OTBS
R1
OTBS
(b), (c)
R1
+
(a)
R1
R2O
O
O
O
OH
R2O
R2O
OTBS
OTBS
O
HO
OTBS
O
9a R1=H, R2=PMB
9bR1=OH, R2=Ac
28a / 28b
26
27a /27b
a Series R1=H, R2=PMB
b Series R1=OH, R2=Ac
(d), (e)
R1
O
O
O
O
R1
(h)
O
O
(f)
R2O
R2O
O
OTBS
OTBS
(for 30a)
O
PMBO
O
OH
(exclusively
31 formed)
29a / 29b
30a / 30b
(for 30b)
31
(g)
(for 30b)
+
O
(j)
(i)
O
O
O
(for 30a)
31(50%) + 3a
(46%) formed
HO
HO
HO
O
O
HO
AcO
O
OH
O
O
OH
OH
46%
Neomethynolide (3a)
Novamethynolide (4a)
32
Scheme 3. (a) 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, DMAP, benzene (97%(a)/76%(b)); (b) CSA, MeOH, (98%(a)/86%(b)); (c) DMP, CH2Cl2, (97%(a)/92%(b)); (d) vinylMgBr, THF
(82%(a)/85%(b)); (e) DMP, CH2Cl2, (95%(a)/92%(b)); (f) Grubbs’ second generation catalyst, CH2Cl2 (85%(a)/85%(b)); (g) HF, CH3CN (for 30a)(31(50%)þ3a(46%)); (h) TBAF, THF (for
30a)(exclusively 31 formed (85%)); (i) 48% HF/CH3CN/H2O¼1: 8.5: 0.5 (for 30b)(77%); (j) TBAF, THF (for 30b)(67%).

4310
H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
Carboxylic acid 2614 was esterified with 9a by means of Yama-
novamethymycin was started with glucose, utilizing the recently
reported procedure based on the Amadori rearrangement. The
synthesis of this segment was achieved efficiently in twelve steps.
Syntheses of these two segments were achieved efficiently and will
be useful for the syntheses of many related natural products. In
particular, the synthetic sequences developed for the segment re-
quired for novamethymycin 9b is unique and will be useful for the
synthesis of natural products.
guchi’s protocol21 to afford ester 27a, which was further subjected to
deprotection of TBS and oxidation to yield aldehyde 28a. The pre-
cursor for the critical ring-closing metathesis (RCM) reaction1,22 was
prepared by the addition of vinyl Grignard reagent followed by
DesseMartin oxidation. The key RCM reaction with the Grubbs’ sec-
ond generation catalyst, took place efficiently to afford the protected
form of neomethynolide 30a. Selective deprotection of the TBS group
with HF in CH3CN in the presence of the PMB-protected hydroxyl
group occurred with moderate efficiency producing the desired
protected neomethynolide 31 (50%) as well as neomethynolde (3a)
(46%). Employing TBAF, however, enabled us to deprotect selectively
and exclusive formation of the protected neomethymycin 31 was
achieved. A similar synthetic sequence was adopted for the synthesis
of the required protected novamethynolide, as shown in Scheme 3.
Starting with the Yamaguchi esterification of 26 with 9b, the key RCM
precursor 29b was prepared. The RCM reaction with the Grubbs’
second generation catalyst then provided lactone 30b. The protected
novamethynolide30bwasconvertedintonovamethynolide(4a)with
TBAF, which completed the first total synthesis of novamethynolide
(4a). Lactone 30b was also transformed into the protected novame-
thynolide 32, in which the hydroxyl group at the side chain was
protected by the acetyl group.23
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded on a Bruker DPX-
300 and Brucker Avance 500 NMR Spectrometer. The chemical
shifts are reported in parts per million on scale downfield from
TMS, and signal patterns are indicated as follows: s, singlet; d,
doublet; t, triplet; m, multiplet; br, broad peak. IR spectra were
recorded on JASCO FT/IR-300E. Optical rotations were measured by
JASCO DIP-1000 digital polarometer in solution in a 1-dm cell. High
resolution mass spectra were recorded on a Jeol JMS700 by using
FAB method. All reagent and solvents were reagent grade and used
without further purification unless specified otherwise. Technical
grade ethyl acetate, hexane, and pentane used for column chro-
matography were distilled prior to use. Tetrahydrofuran (THF) and
diethyl ether, when used as solvents for reactions, were freshly
distilled from sodiumebenzophenone ketyl. Dimethylformamide
The final stages of the total syntheses are illustrated in Scheme 4.
Glycosylation of the PMB-protected neomethynolide 31 with tri-
chloroacetimidate 3324 was performed in the presence of a Lewis acid
(BF3$OEt2)toproducecompound 34.25 Deprotectionof thePMBgroup
O
O
O
O
O
(a)
(c)
(b)
O
PMBO
AcO
PMBO
HO
O
O
O
HO
OH
OH
O
O
O
O
O
NMe2
AcO
NMe2
HO
Neomethymycin (3)
34
31
O
O
N
HO
HO
AcO
O
O
O
O
O
O
O
NH
HO
NMe2
Cl3C
32
Novamethymycin (4)
33
ꢁ
Scheme 4. (a) Compound 33, BF3$OEt, CH2Cl2, 4 A MS, ꢀ20 C (46%); (b) (1) DDQ, CH2Cl2/H2O¼10:1 (79%); (2) Et3N, H2O, MeOH (80%); (c) (1) 33, BF3$OEt, CH2Cl2, 4 A MS, ꢀ20 ꢁC
ꢀ
ꢀ
(52%); (2) Et3N, H2O, MeOH (75%).
and deacetylation provided the desired neomethymycin (3).26 The
total synthesis of novamethymycin (4) was also achieved under sim-
ilarconditions. Glycosylation of the Ac-protected novamethynolide 32
with trichloroacetimidate 33, followed by deacetylation provided
novamethymycin (4). The spectroscopic properties of the synthesized
neomethymycin (3) and novamethymycin (4) were identical to those
of an authentic sample or reported in the literatures.6,7
(DMF) was stored over 4-A molecular sieves, and triethylamine was
distilled before use. Flash chromatography was carried out on
ꢀ
Woelm 32e64 mm silica packed in glass columns.
4.1.1. (S)-4-Benzyl-3-[(2S,3S,4R)-3-hydroxy-4-(4-methoxy-
benzyloxy)-2-methylpentanoyl]-1,3-oxazolidin-2-one (12). To a so-
lution of (4S)-3-propionyl-4-benzyl-2-oxazolidinone (1.40 g,
5.96 mmol) in CH2Cl2 (20 mL) was added dibutylboron triflate
(7.94 mL of a 1.0 M solution in CH2Cl2, 7.94 mmol) and triethyl-
amine (1.40 mL, 9.93 mmol) dropwise at 0 ꢁC. The solution was
cooled down to ꢀ78 ꢁC. To this solution was added a solution of
(2R)-2-(4-methoxybenzyloxy)propanal 10 (1.30 g, 6.62 mmol) in
CH2Cl2 (5 mL) at ꢀ78 ꢁC. The resulting solution was stirred for 1 h at
ꢀ78 ꢁC. The solution was then warmed to 0 ꢁC and stirred for 1 h
additionally. The reaction was terminated by adding a pH 7 aqueous
phosphate buffer solution (0.2 M-sodium hydrogen phosphate:
0.1 M citric acid¼82:18, 20 mL) and methanol (20 mL). To this
cloudy solution was added a solution of methanol and 30% hy-
drogen peroxide (2:1, 20 mL) and the resulting solution was stirred
for 2 h at 0 ꢁC. After the solution was concentrated, it was extracted
3. Conclusion
The first total synthesis of two members of methymycin families
of macrolide antibiotics, neomethymycin and novamethymycin was
achieved. These two macrolides were retrosynthetically divided
into two parts: sugar and aglycone. The corresponding aglycones
were also divided into two parts, with one part of each of the two
macrolides different from each other, and the other identical, which
has already prepared previously during the synthesis of methy-
mycin. Segment 9a for neomethymycin was synthesized using
methyl
D
-(þ)-lactate as a starting material, which is commercially
available, in eight steps. The synthesis of the segment 9b for

H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
4311
with CH2Cl2 (3ꢂ20 mL). The organic layer was washed with satu-
rated aqueous sodium bicarbonate (20 mL) and saturated aqueous
NaCl (20 mL), dried (MgSO4), and concentrated. Purification of the
residue by flash chromatography (hexane/EtOAc¼4:1) provided the
(10 mL) was added a solution of pyridineeSO3 complex (1.13 g,
7.07 mmol) in DMSO (10 mL) under room temperature with stir-
ring. After 1 h, the reaction mixture was terminated by addition of
aqueous saturated NaCl (20 mL). The mixture was extracted with
CH2Cl2 (3ꢂ20 mL) and the organic solution was dried (MgSO4) and
concentrated. Purification of the residue by flash chromatography
(hexane/EtOAc¼5:1) afforded the desired aldehyde 15 (554 mg,
desired aldol product 12 (1.90 g, 75%) as a colorless oil: [
a]
27.8 þ32.5
D
(c 1.85, CHCl3); IR (film): 3515, 2933, 1779, 1695, 1611, 1513, 1455,
1386, 1248, 1106, 1028, 824 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 7.11
(m, 5H), 6.97 (d, J¼6.5 Hz, 2H), 6.68 (d, J¼8.7 Hz, 2H), 4.39 (d,
J¼11.1 Hz, 1H), 4.28 (m, 1H), 4.13 (d, J¼11.1 Hz, 1H), 3.91 (m, 1H),
3.81 (dd, J¼2.8, 9.0 Hz, 1H), 3.71 (m, 1H), 3.59 (m, 1H), 3.55 (s, 3H),
3.28 (dddd, J¼6.0, 6.0, 6.0, 12.1 Hz, 1H), 3.07 (s, 1H), 2.96 (dd, J¼3.2,
13.4 Hz, 1H), 2.54 (dd, J¼9.2, 13.4 Hz, 1H), 1.14 (d, J¼6.0 Hz, 3H), 1.06
75%) as a colorless liquid: 1H NMR (300 MHz, CDCl3):
d 9.45 (s, 1H),
7.00 (d, J¼8.4 Hz, 2H), 6.64 (d, J¼8.2 Hz, 2H), 4.30 (d, J¼11.2 Hz, 1H),
4.11 (d, J¼11.2 Hz, 1H), 3.85 (dd, J¼3.8, 6.7 Hz, 1H), 3.55 (s, 3H), 3.19
(dddd, J¼6.2, 6.2, 6.2, 12.4 Hz, 1H), 2.48 (m, 1H), 1.01 (d, J¼6.1 Hz,
3H), 0.82 (d, J¼7.0 Hz, 3H), 0.71 (t, J¼8.0 Hz, 9H), 0.36 (q, J¼7.9 Hz,
(d, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
176.9, 158.8, 152.6,
6H); 13C NMR (75 MHz, CDCl3):
d 204.2, 159.1, 130.2, 129.3, 113.6,
134.9, 130.1, 129.1, 129.0, 128.6, 127.0, 113.4, 75.2, 74.3, 70.0,
65.6, 54.9, 54.5, 39.2, 37.4, 15.8, 12.0; HRMS: m/z calcd for
C24H29NO6[MþNa]þ: 450.1893; found, 450.1889.
75.6, 74.6, 70.4, 55.0, 49.8, 16.0, 7.9, 6.8, 5.1.
4.1.5. (2R,3S,4R)-2-(4-Methoxybenzyloxy)-4-methyl-3-(triethylsilyl-
oxy)hex-5-ene (16). To a solution of MePh3PBr (1.74 g, 4.86 mmol)
in THF (10 mL) was added n-BuLi (3.38 mL, 1.6 M in hexanes,
5.40 mmol) at 0 ꢁC. The solution was cooled to ꢀ78 ꢁC, after which
aldehyde 15 (496 mg, 1.35 mmol) was added. After 30 min, the
temperature of the solution was raised to room temperature, and
stirred for additional 1 h. After reaction was completed, saturated
NH4Cl (20 mL) was added. The organic layer was separated and the
aqueous layer was extracted with ether (3ꢂ10 mL). The organic
solutions were combined, dried (MgSO4), and concentrated. Puri-
fication of the residue by flash chromatography (hexane/
4.1.2. (S)-4-Benzyl-3-[(2S,3S,4R)-4-(4-methoxybenzyloxy)-2-methyl-
3-(triethylsilyloxy)pentanoyl]-1,3-oxazolidin-2-one (13). To a stirred
solution of aldol product 12 (1.90 g, 4.45 mmol), 2,6-lutidine
(1.03 mL, 8.90 mmol) in CH2Cl2 (20 ml) was added triethylsilyl tri-
fluoromethanesulfonate (TESOTf)(1.50 mL, 6.68 mmol) at 0 ꢁC. The
reaction mixture was stirred for 2 h at 0 ꢁC. After reaction was
completed, aqueous saturated NaCl (20 mL) was added. The organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (3ꢂ20 mL). The organic solutions were combined, dried
(MgSO4), and concentrated. Purification of the residue by flash
chromatography (hexane/EtOAc¼5:1) afforded the TES-protected
EtOAc¼15:1) afforded the alkene 16 (394 mg, 80%) as a colorless oil:
25.9
[a
]
ꢀ8.4 (c 1.62, CHCl3); IR (film): 2955, 2875, 1613, 1513, 1460,
D
product 13 (2.36 g, 97%) as a colorless oil: [
a
]
27.8 þ37.6 (c 1.41, CHCl3);
1382, 1301, 1248, 1155, 1108, 1039 cmꢀ1; 1H NMR (300 MHz, CDCl3):
D
IR (film): 2955, 2876, 1781, 1696, 1612, 1513, 1456, 1385, 1351, 1248,
d
7.20 (d, J¼8.1 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H), 5.68 (ddd, J¼8.0, 10.3,
1111,1038, 971, 824, 743 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
7.09 (m,
17.3 Hz,1H), 4.94 (m, 2H), 4.37 (dd, J¼11.4, 32.0 Hz, 2H), 3.76 (s, 3H),
3.54 (dd, J¼4.1, 6.5 Hz, 1H), 3.43 (dddd, J¼4.1, 8.3, 8.3, 8.3 Hz, 1H),
2.28 (m, 1H), 1.09 (d, J¼6.2 Hz, 3H), 0.96 (d, J¼6.8 Hz, 3H), 0.90 (t,
J¼8.1 Hz, 9H), 0.57 (q, J¼7.6 Hz, 6H); 13C NMR (75 MHz, CDCl3):
5H), 6.96 (d, J¼7.5 Hz, 2H), 6.64 (d, J¼8.6 Hz, 2H), 4.33 (d, J¼11.3 Hz,
1H), 4.13 (d, J¼11.3 Hz, 1H), 4.09 (m, 1H), 3.97 (m, 1H), 3.74 (m, 2H),
3.53 (s, 3H), 3.28 (t, J¼8.7 Hz, 1H), 3.17 (m, 1H), 2.97 (dd, J¼2.5,
13.3 Hz, 1H), 2.48 (dd, J¼9.5, 13.1 Hz, 1H), 1.06 (m, 6H), 0.83 (t,
J¼7.8 Hz, 9H), 0.52 (q, J¼7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d
158.9, 141.9, 131.0, 129.2, 114.1, 113.6, 78.6, 76.0, 70.2, 55.2, 41.5,
15.9, 14.0, 7.0, 5.3.
d
175.6,158.7,152.7,128.6,130.6,129.6,129.2,128.7,128.6,113.3, 78.3,
76.4, 70.1, 65.3, 54.9, 54.8, 41.4, 37.5, 15.6, 14.9, 6.9, 5.2; HRMS: m/z
calcd for C30H43NO6Si[MþNa]þ: 564.2757; found, 564.2760.
4.1.6. (2R,3S,4R)-2-(4-Methoxybenzyloxy)-4-methylhex-5-en-3-ol
(9a). To a solution of alkene 16 (394 mg, 1.08 mmol) and CH3CN
(10 mL) at room temperature, was added a solution of [HF/H2O/
CH3CN(v/v/v)¼1:0.5:8.5] (5 mL). After the mixture was stirred for
3 h, it was neutralized with saturated NaHCO3 (5 mL) and extracted
with ether (3ꢂ10 mL). The combined organic solution was washed
with saturated NaCl (10 mL) and dried (MgSO4), and concentrated.
Purification by flash chromatography (hexane/EtOAc¼7:1) afforded
4.1.3. (2R,3S,4R)-4-(4-Methoxybenzyloxy)-2-methyl-3-(triethylsily-
loxy)pentan-1-ol (14). To a solution of TES-protected product 13
(1.63 g, 3.00 mmol) in ether (30 mL) was added distilled water
(81 mL, 4.5 mmol) at room temperature. After the solution was
cooled to 0 ꢁC, lithium borohydride (3.0 mL of a 2.0 M solution in
THF, 6.00 mmol) was added slowly with stirring. After 10 min, the
temperature of the solution was raised to room temperature, and
stirred for additional 2 h. The reaction was terminated with addi-
tion of an aqueous NaOH solution (1.0 M, 20 mL) and extracted with
ether (3ꢂ30 mL). After the organic layer was washed with satu-
rated NaCl (30 mL), the ethereal solution was dried (MgSO4) and
concentrated. Purification by flash chromatography (hexane/
the desired alcohol 9a (264 mg, 98%) as a colorless oil: [
a
]
27.4 ꢀ12.5
D
(c 1.50, CHCl3); IR (film): 3464, 2974, 1613, 1513, 1459, 1379, 1301,
1248, 1174, 1036, 986, 915 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.16
(d, J¼8.4 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H), 5.57 (ddd, J¼8.3, 10.3,
17.3 Hz,1H), 4.94 (m, 2H), 4.36 (dd, J¼11.2, 28.1 Hz, 2H), 3.70 (s, 3H),
3.45 (m, 2H), 2.20 (m, 2H), 1.08 (d, J¼6.1 Hz, 3H), 1.00 (d, J¼6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3):
d 159.1, 140.4, 130.5, 129.2, 114.9,
EtOAc¼2:1) provided the desired alcohol 14 (798 mg, 73%) as
113.7, 75.6, 75.5, 70.1, 55.1, 40.2, 16.3, 12.8; HRMS: m/z calcd for
C15H22O3[MþNa]þ: 273.1467; found, 273.1469.
27.3
a colorless oil: [
a
]
ꢀ11.2 (c 1.18, CHCl3); IR (film): 3417, 2955,
D
2876, 1613, 1513, 1461, 1302, 1248, 1037, 803, 740 cmꢀ1
;
1H NMR
(300 MHz, CDCl3):
d
7.02 (d, J¼8.6 Hz, 2H), 6.63 (d, J¼8.6 Hz, 2H),
4.1.7. 2-C-Methyl-
D
-ribono-1,4-lactone (17)17. To
a solution of
3.54 (dd, J¼11.3, 37.9 Hz, 2H), 3.55 (s, 3H), 3.54 (m, 1H), 3.28 (m,
3H), 2.26 (br t, J¼4.9 Hz, 1H), 1.75 (m, 1H), 0.99 (d, J¼6.2 Hz, 3H),
0.74 (t, J¼8.1 Hz, 9H), 0.41 (q, J¼7.5 Hz, 6H); 13C NMR (75 MHz,
D-Glucose (15 g, 83 mmol) in ethanol (25 mL) and glacial acetic acid
(4.8 mL) was added dimethylamine (40% solution in water, 16 mL,
141 mmol) at room temperature. The solution was stirred for 1.5 h
at 80 ꢁC. The resulting dark orange solution was concentrated. The
dark oil was dissolved in water (200 mL), and to this was added
calcium oxide (26.2 g, 467 mmol) at room temperature. The mix-
ture was stirred for 24 h at 70 ꢁC. The mixture was cooled to room
temperature, and to this was added oxalic acid dehydrate (31.5 g,
250 mmol). After 10 min, filtration through a pad of Celite with
MeOH (2ꢂ100 mL) and the solution was passed through Amberlite
CDCl3):
d 158.9, 130.6, 129.2, 113.5, 76.5, 76.0, 70.4, 65.5, 55.0, 38.6,
16.0, 11.9, 6.9, 5.1; HRMS: m/z calcd for C20H36O4Si[MþNa]þ:
369.2461; found, 369.2457.
4.1.4. (2S,3S,4R)-4-(4-Methoxybenzyloxy)-2-methyl-3-(triethylsilyl-
oxy)pentanal (15). To
2.02 mmol) and triethylamine (844
a
solution of the alcohol 14 (743 mg,
L, 6.06 mmol) in CH2Cl2
m

4312
H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
IR 120 ion exchange resin. After the solution was concentrated, the
concentrate was then dissolved in water (200 mL). The solution was
stirred for 15 min at 40 ꢁC. The water was removed under vacuum
afforded the desired crude product 17 (10 g).
J¼8.6 Hz, 1H), 3.30 (d, J¼10.4 Hz, 1H), 1.38 (s, 3H), 1.32 (s, 6H), 1.28
(d, J¼6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 107.2, 86.4, 81.9, 66.3,
64.7, 28.3, 26.3, 23.8, 20.8; HRMS: m/z calcd for C9H18O4[MþNa]þ:
213.1103; found, 213.1107.
4.1.8. 2,3-O-Isopropylidene-2-C-methyl-
D
-ribono-1,4-lactone (18)17
.
4.1.12. (4S,5R)-5-[(R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(tert-
butyldimethylsilyloxy)methyl]-2,2,4-trimethyl-1,3-dioxolane (22). To
a stirred solution of diol 21 (482 mg, 2.53 mmol), 2,6-lutidine (943
Toamixture ofcrude product 17 (10 g, 61.7 mmol)inacetone(100 mL)
at room temperature was added concentrated sulfuric acid (1.26 mL,
12.34 mmol). After the mixture was stirred for 30 h at room temper-
ature, the reaction mixture was added to aqueous ammonia (1 mL).
The resulting mixture was filtered and concentrated. Purification by
flash chromatography (pentane/ether¼1:5) afforded the desired lac-
tone 18 (1.4 g, 8.3%, two steps) as a colorless oil: 1H NMR (300 MHz,
m
L, 8.10 mmol) in CH2Cl2 (10 ml) was added tert-butyldimethylsilyl
trifluoromethanesulfonate (TBDMSOTf)(943
m
L, 8.10 mmol) at 0 ꢁC.
The reaction mixture was stirred for 2 h at 0 ꢁC. After reaction was
completed, aqueous saturated NaCl (20 mL) and aqueous saturated
NH4Cl solution (10 mL) were added. The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3ꢂ15 mL).
The organic solutions were combined, dried (MgSO4), and con-
centrated. Purification of the residue by flash chromatography
CDCl3):
3.37 (s, 3H), 1.60 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz,
CDCl3): 177.1, 112.7, 83.6, 82.8, 82.4, 61.8, 26.7, 26.5, 19.6.
d
4.51 (s, 2H), 3.92 (d, J¼12.3 Hz, 1H), 3.77 (d, J¼13.7 Hz, 1H),
d
(hexane/EtOAc¼7:1) afforded the TBS-protected product 22
24.6
4.1.9. 5-Iodo-2,3-O-isopropylidene-2-C-methyl-
D
-ribolactone
(19).
(920 mg, 87%) as a colorless oil: [
a]
ꢀ26.4 (c 1.31, CHCl3); IR
D
To a solution of alcohol 18 (1.52 g, 7.50 mmol) in CH2Cl2 (30 mL)
at room temperature were added PPh3 (2.95 g, 11.3 mmol), im-
idazole (1.53 g, 22.5 mmol) and I2 (2.66 g, 10.5 mmol). The mix-
ture was stirred for 2 h at room temperature. After the reaction
was completed, the solution was filtered through a pad of silica
gel. The silica gel pad was washed with CH2Cl2 (3ꢂ20 mL). After
the combined filtrate was concentrated, purification by flash
(film): 2931, 2858, 1463, 1369, 1255, 1214, 1103, 993, 962, 930, 909,
838, 775, 665 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
4.11 (q, J¼6.1 Hz,
1H), 3.58 (m, 3H), 1.39 (s, 3H), 1.31 (d, J¼10.2 Hz, 6H), 1.24 (d,
J¼6.1 Hz, 3H), 0.87 (d, J¼4.6 Hz, 18H), 0.05 (m, 12H); 13C NMR
(75 MHz, CDCl3): d 106.8, 86.7, 82.1, 66.9, 65.9, 28.0, 26.6, 26.0, 25.9,
23.0, 21.8, 18.3, 18.0, ꢀ3.5, ꢀ4.6, ꢀ5.4, ꢀ5.4; HRMS: m/z calcd for
C21H46O4Si2[MþH]þ: 419.3013; found, 419.3009.
chromatography (hexane/EtOAc¼3:1) afforded the desired iodo-
25.2
lactone 19 (1.70 g, 73%) as a colorless oil: [
a
]
ꢀ46.6 (c 1.47,
4.1.13. (4S,5R)-5-[(R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-hydroxy-
D
CHCl3); IR (film): 2989, 1789, 1453, 1378, 1346, 1217, 1167, 1099,
methyl-2,2,4-trimethyl-1,3-dioxolane
(23). The
TBS-protected
1009, 930, 862 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
4.53 (dd,
product 22 (910 mg, 2.17 mmol) was dissolved in THF (15 mL). To
this solution was added HF$pyridine/pyridine(v/v)¼1:1 (4 mL). The
resulting solution was stirred at 0 ꢁC for 16 h. After the reaction was
completed, aqueous saturated NaHCO3 (20 mL) was added and the
mixture was extracted with ether (3ꢂ15 mL). The organic layer was
separated, dried (MgSO4), and concentrated. Purification by flash
chromatography (hexane/EtOAc¼4:1) offered the desired alcohol
J¼5.6, 8.6 Hz, 1H), 4.32 (d, J¼0.6 Hz, 1H), 3.31 (dd, J¼5.2, 10.8 Hz,
1H), 3.13 (dd, J¼8.6, 10.8 Hz, 1H), 1.54 (s, 3H), 1.31 (d, J¼2.3 Hz,
6H); 13C NMR (75 MHz, CDCl3):
d 175.0, 113.1, 83.3, 81.7, 81.1, 26.6,
20.7, 2.8; HRMS: m/z calcd for C9H13IO4[MþH]þ: 312.9937; found,
312.9939.
4.1.10. 5-Deoxy-2,3-O-isopropylidene-2-C-methyl-
D
-ribolactone
23 (535 mg, 81%) as a colorless oil: [
a
]
25.2 ꢀ26.5 (c 0.87, CHCl3); IR
D
(20). To a solution of iodolactone 19 (1.62 g, 5.19 mmol) in toluene
(30 mL) at room temperature were added AIBN (85 mg, 0.52 mmol)
and Bu3SnH (3.00 mL, 10.4 mmol). The solution was stirred for 16 h
at 120 ꢁC. After the reaction was completed, the solution was cooled
at room temperature. The solution was then concentrated to give
a yellow oil. Purification of this residue by flash chromatography
(film): 3493, 2932, 2858, 1735, 1463, 1371, 1255, 1215, 1106, 1062,
988, 959, 932 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
4.16 (q, J¼6.3 Hz,
1H), 3.60 (m, 2H), 3.43 (dd, J¼10.2, 17.0 Hz, 1H), 2.88 (t, J¼6.9 Hz,
1H),1.41 (s, 3H), 1.36 (d, J¼6.9 Hz, 6H),1.29 (d, J¼6.4 Hz, 3H), 0.89 (s,
9H), 0.11 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 106.6, 85.7, 82.2, 67.3,
65.2, 28.2, 26.5, 25.8, 23.1, 21.5, 18.0, ꢀ4.1, ꢀ4.6; HRMS: m/z calcd
(hexane/EtOAc¼5:1) afforded desired the lactone 20 (843 mg, 87%)
for C15H32O4Si[MþH]þ: 305.2148; found, 305.22151.
26.2
as a white solid: mp: 87e89 ꢁC; [
a
]
ꢀ68.0 (c 1.28, CHCl3); IR
D
(film): 2997, 2941, 1772, 1453, 1377, 1292, 1213, 1107, 1062, 1031,
989, 955 cmꢀ1; 1H NMR (300 MHz, CDCl3):
4.55 (q, J¼7.1 Hz, 1H),
4.11 (s, 1H), 1.53 (s, 3H), 1.33 (m, 9H); 13C NMR (75 MHz, CDCl3):
4.1.14. (4R,5R)-5-[(R)-1-(tert-Butyldimethylsilyloxy)ethyl]-2,2,4-tri-
methyl-1,3-dioxolane-4-carbaldehyde (24). To a solution of the al-
cohol 23 (300 mg, 0.99 mmol) obtained as described in the
previous procedure in CH2Cl2 (10 mL) was added the DesseMartin
periodinane (840 mg, 1.98 mmol) at room temperature. The
resulting solution was stirred for 2 h and was diluted with CH2Cl2
(10 mL). After the reaction was completed, aqueous saturated
NaHCO3 (20 mL) and aqueous saturated Na2S2O3 (10 mL) were
added. The resulting mixture was stirred and the organic layer was
extracted and washed with saturated aqueous NaHCO3 (10 mL),
water (10 mL), dried (MgSO4), and concentrated. Purification of the
residue by flash chromatography (hexane/EtOAc¼10:1) afforded
the desired aldehyde 24 (220 mg, 74%) as a colorless oil: 1H NMR
d
d
176.2,112.5, 84.5, 81.6, 78.2, 26.7, 26.3, 20.6, 18.9; HRMS: m/z calcd
for C9H14O4[MþH]þ: 187.0970; found, 187.0971.
4.1.11. 5-Deoxy-2,3-O-isopropylidene-2-C-methyl-ribitol
(21). To
a solution of lactone 20 (780 mg, 4.19 mmol) in ether (30 mL) was
added distilled water (226 L, 12.6 mmol) at room temperature.
m
After the solution was cooled to 0 ꢁC, lithium borohydride (8.4 mL
of a 2.0 M solution in THF, 16.8 mmol) was added slowly with
stirring. After 10 min, the temperature of the solution was raised to
room temperature, and stirred for additional 2 h. The reaction was
terminated by addition of an aqueous NaOH solution (1.0 M, 20 mL)
and extracted with ether (3ꢂ30 mL). After the organic layer was
washed with aqueous saturated NaCl (30 mL), the ethereal solution
was dried (MgSO4), and concentrated. Purification by flash chro-
matography (hexane/EtOAc¼1:1) provided the desired diol 21
(300 MHz, CDCl3):
d
9.55 (s, 1H), 4.08 (dddd, J¼5.0, 6.5, 6.5, 6.5 Hz,
1H), 3.80 (d, J¼5.0 Hz,1H), 1.51 (s, 3H), 1.40 (d, J¼4.5 Hz, 6H), 1.19 (d,
J¼6.5 Hz, 3H), 0.84 (s, 9H), 0.03 (d, J¼1.5 Hz, 6H); 13C NMR (75 MHz,
CDCl3): d 199.5,109.3, 89.1, 84.7, 66.8, 27.8, 26.4, 25.7, 21.0, 20.7,18.0,
ꢀ4.6, ꢀ4.7.
(496 mg, 62%) as a white solid: mp 67e70 ꢁC; [
a
]
D
25.6 ꢀ30.8 (c 0.93,
CHCl3); IR (film): 3259, 2983, 2932, 2872, 1444, 1367, 1249, 1216,
4.1.15. (4S,5R)-5-[(R)-1-(tert-Butyldimethylsilyloxy)ethyl]- 2,2,4-tri-
1187, 1100, 1064, 986, 913 cmꢀ1; 1H NMR (300 MHz, CDCl3,):
(s, 1H), 4.10 (s, 1H), 3.94 (m, 1H), 3.70 (d, J¼10.5 Hz, 1H), 3.53 (d,
d
4.23
methyl-4-vinyl-1,3-dioxolane (25). To
a solution of MePh3PBr
(1.30 g, 3.65 mmol) in THF (10 mL) was added n-BuLi (2.28 mL,

H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
4313
1.6 M in hexanes, 3.65 mmol) at 0 ꢁC. The solution was cooled to
ꢀ78 ꢁC, after which aldehyde 24 (220 mg, 0.73 mmol) was added.
After 30 min, the temperature of the solution was raised to room
temperature, and stirred for additional 1 h. After reaction was
completed, aqueous saturated NH4Cl (20 mL) was added. The or-
ganic layer was separated and the aqueous layer was extracted with
ether (3ꢂ15 mL). The organic solutions were combined, dried
(MgSO4), and concentrated. Purification of the residue by flash
4.1.17. (2R,3S,4R)-2-(4-Methoxybenzyloxy)-4-methylhex-5-en-3-yl
(2R,3S,4S,6R)-3,7-bis(tert-butyldimethylsilyloxy)-2,4,6-trime-
thylheptanoate (27a). To a solution of carboxylic acid 26 (583 mg,
1.33 mmol) in THF (10 mL) at room temperature were added trie-
thylamine (278
mL, 2.00 mmol) and 2,4,6-trichlorobenzoyl chloride
(270 L, 1.73 mmol). The mixture was stirred for 3 h at room tem-
m
perature, and the solids were filtered off and washed with hexane
(10 mL). The combined solution was concentrated. The residue was
dissolved in benzene (10 mL), and to this solution, a solution of al-
cohol 9a (500 mg, 2.00 mmol) and DMAP (227 mg, 1.86 mmol) in
benzene (3 mL) was added. After being stirred for 15 h, the reaction
mixture was diluted with ether (20 mL), and washed with saturated
NaHCO3 (10 mL) and saturated NaCl (10 mL), dried (MgSO4), and
concentrated. Purification of the residue by flash chromatography
(hexane/EtOAc¼10:1) afforded the desired ester 27a (860 mg, 97%) as
chromatography (hexane/EtOAc¼15:1) afforded the desired alkene
25.3
25 (182 mg, 83%) as a colorless oil: [
a
]
ꢀ20.2 (c 1.71, CHCl3); IR
D
(film): 2928, 2857, 1642, 1471, 1368, 1256, 1213, 1108, 1065, 1005,
986, 945 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
5.91 (dd, J¼10.7,
17.3 Hz, 1H), 5.31 (dd, J¼1.6, 17.3 Hz, 1H), 5.09 (dd, J¼1.5, 10.7 Hz,
1H), 3.78 (m, 1H), 3.53 (d, J¼8.6 Hz, 1H), 1.39 (d, J¼5.5 Hz, 6H), 1.33
(s, 3H), 1.21 (d, J¼6.0 Hz, 3H), 0.83 (s, 9H), 0.02 (d, J¼7.4 Hz, 6H); 13C
NMR (75 MHz, CDCl3):
d
139.5, 114.2, 107.2, 87.5, 82.6, 68.3, 27.8,
a colorless oil: [
a
]
29.1 þ9.0 (c 1.46, CHCl3); IR (film): 2954, 2857, 1735,
D
26.5, 26.4, 26.0, 22.3, 18.0, ꢀ3.2, ꢀ4.5; HRMS: m/z calcd for
1613, 1514, 1462, 1377, 1251, 1170, 1059, 837 cmꢀ1; 1H NMR (300 MHz,
C16H32O3Si[MþH]þ: 301.2199; found, 301.2204.
CDCl3):
d
7.21(d, J¼8.7 Hz,2H),6.83(d, J¼8.7 Hz,2H),5.66(ddd, J¼8.3,
10.3,17.3 Hz,1H), 5.01 (m, 3H), 4.40 (q, J¼11.3 Hz, 2H), 3.89 (dd, J¼5.1,
8.1 Hz,1H), 3.77 (s, 3H), 3.57 (m,1H), 3.46 (dd, J¼4.6, 9.7 Hz,1H), 3.21
(dd, J¼7.2, 9.7 Hz,1H), 2.59(q, J¼7.1 Hz,1H), 2.48(q, J¼7.4 Hz,1H),1.64
(m, 2H),1.38 (m,1H),1.12 (d, J¼6.4 Hz, 6H), 0.98 (d, J¼6.7 Hz, 3H), 0.87
(m, 24H), 0.03 (d, J¼4.5 Hz, 6H), 0.00 (s, 6H); 13C NMR (75 MHz,
4.1.16. (2R,3R,4S)-3,4-Dihydroxy-4-methylhex-5-en-2-yl acetate (9b).
To a stirred solution of alkene 25 (182 mg, 0.61 mmol) in dry THF
(10 mL) at room temperature was added 1.0 M tetrabutyla-
mmonium fluoride (TBAF) (1.22 mL, 1.22 mmol). After 2.5 h, the
reaction mixture was concentrated. Purification of the residue by
CDCl3): d 175.6, 159.6, 139.9, 130.6, 129.3, 115.2, 113.6, 76.0, 75.8, 73.8,
flash chromatography (hexane/EtOAc¼4:1) afforded alcohol
70.0, 67.8, 55.2, 42.6, 39.0, 36.9, 35.4, 33.5, 26.0, 25.9, 18.3, 18.3, 18.3,
16.9, 16.1, 14.8, 14.7, ꢀ4.0, ꢀ4.1, ꢀ5.4; HRMS: m/z calcd for
C37H69O6Si2[MþH]þ: 665.4633; found, 665.4630.
25.5
(110 mg, 96%) as a colorless oil: [
a]
ꢀ29.0 (c 1.61, CHCl3); IR
D
(film): 3416, 2982, 1373, 1208, 1059, 929, 874 cmꢀ1
(500 MHz, CDCl3):
;
1H NMR
d
6.01 (dd, J¼11.0, 17.5 Hz, 1H), 5.32 (dd, J¼2.0,
17.5 Hz, 1H), 5.14 (dd, J¼1.5, 11.0 Hz, 1H), 3.76 (m, 1H), 3.55 (d,
4.1.18. (2R,3S,4R)-2-(4-Methoxybenzyloxy)-4-methylhex-5-en-3-yl
(2R,3S,4S,6R)-3-(tert-butyldimethylsilyloxy)-2,4,6-trimethyl-7-oxo-
heptanoate (28a). Ester 27a (860 mg, 1.29 mmol) was dissolved in
MeOH (15 mL). To this solution was added DL-10-camphorsulfonic
acid (60 mg, 0.26 mmol). The resulting solution was stirred at 0 ꢁC
for 2 h. The reaction was terminated by addition of triethylamine
J¼8.5 Hz, 1H), 1.91 (s, 3H), 1.43 (d, J¼1.5 Hz, 6H), 1.37 (s, 3H), 1.27 (d,
J¼6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 139.9, 114.2, 107.9, 87.3,
82.6, 66.7, 28.0, 26.6, 26.0, 21.6.
To a solution of the alcohol (110 mg, 0.59 mmol) prepared as
described in the previous procedure in CH2Cl2 (10 mL) were added
DMAP (36 mg, 0.30 mmol), triethylamine (246
m
L, 1.77 mmol) and
(93 mL, 0.67 mmol). After the solution was concentrated, purifica-
acetic anhydride (167
m
L, 1.77 mmol at 0 ꢁC ). The resulting solution
tion by flash chromatography (hexane/EtOAc¼5:1) gave the desired
was stirred for 10 min at 0 ꢁC before it was warmed to room tem-
perature. After additional stirring for 1 h at room temperature and
then to this was added a saturated aqueous NaHCO3 solution
(15 mL). The organic layer was separated, and the aqueous layer
was extracted with ether (3ꢂ15 mL). The organic solutions were
combined, dried (MgSO4), and concentrated. Purification of the
primary alcohol (700 mg, 98%) as a colorless oil: [
a
]
30.1 þ21.6 (c
D
1.20, CHCl3); IR (film): 3453, 2955, 1732, 1613, 1514, 1461, 1378,
1302, 1251, 1174, 1040 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.15 (d,
J¼8.7 Hz, 2H), 6.78 (d, J¼8.7 Hz, 2H), 5.60 (ddd, J¼8.2, 10.3, 17.2 Hz,
1H), 4.98 (m, 3H), 4.34 (q, J¼11.4 Hz, 2H), 3.74 (dd, J¼2.2, 7.9 Hz,
1H), 3.71 (s, 3H), 3.54 (ddddd, J¼3.7, 6.3, 6.3, 6.3, 12.6 Hz, 1H), 3.25
(m, 1H), 2.62 (q, J¼7.1 Hz, 1H), 2.39 (q, J¼6.9 Hz, 1H), 2.10 (br s, 1H),
1.63 (m, 1H), 1.43 (m, 2H), 1.18 (d, J¼7.0 Hz, 3H), 1.07 (d, J¼6.3 Hz,
3H), 0.93 (d, J¼6.7 Hz, 3H), 0.83 (m, 15H), 0.00 (d, J¼1.4 Hz, 6H); 13C
residue by flash chromatography (hexane/EtOAc¼7:1) afforded the
25.7
desired acetylated product (110 mg, 81%) as a colorless oil: [a]
D
ꢀ16.9 (c 1.98, CHCl3); IR (film): 2983, 2936, 2870, 1739, 1643, 1456,
1371, 1240, 1131, 1094, 1060, 929 cmꢀ1; 1H NMR (500 MHz, CDCl3):
NMR (75 MHz, CDCl3): d 175.7,159.0,139.5,130.4, 129.3,115.4,113.6,
d
5.69 (dd, J¼11.0, 17.5 Hz,1H), 5.22 (dd, J¼1.5, 17.5 Hz, 1H), 5.07 (dd,
77.0, 76.0, 73.8, 70.0, 66.4, 55.1, 44.0, 39.3, 35.4, 34.1, 32.8, 26.0, 18.3,
18.3, 17.5, 16.4, 15.4, 14.2, ꢀ3.9, ꢀ4.0; HRMS: m/z calcd for
C31H54O6Si[MþH]þ: 573.3587; found, 573.3590.
J¼1.5, 10.5 Hz, 1H), 4.76 (dddd, J¼6.0, 6.0, 6.0, 9.0 Hz, 1H), 3.76 (d,
J¼8.5 Hz, 1H), 1.96 (s, 3H), 1.41 (s, 3H), 1.36 (d, J¼7.0 Hz, 6H), 1.25 (d,
J¼6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d
169.4, 138.7, 114.6,
The alcohol (700 mg, 1.27 mmol) obtained as described in the
previous procedure was dissolved in CH2Cl2 (20 mL). To this solu-
tion was added DesseMartin periodinane (DMP) (1.10 g,
2.54 mmol). The resulting solution was stirred for 1 h at room
temperature. After the reaction was completed, saturated NaHCO3
(10 mL) was added. The mixture was extracted with CH2Cl2
(3ꢂ20 mL). The organic layer was separated, dried (MgSO4), and
concentrated. Purification by flash chromatography (hexane/
EtOAc¼7:1) offered the desired aldehyde 28a (680 mg, 97%) as
108.2, 85.1, 82.3, 69.6, 28.0, 26.6, 25.4, 20.9, 17.9; HRMS: m/z calcd
for C12H20O4Si[MþH]þ: 229.1440; found, 229.1443.
The acetylated product (110 mg, 0.48 mmol) obtained as de-
scribed in the previous procedure was dissolved in 80% acetic acid
(10 mL). The solution was stirred at 80 ꢁC for 4 h. After the reaction
was completed, the solution was cooled at room temperature. The
solution was then concentrated. Purification of the residue by flash
chromatography (hexane/EtOAc¼2:1) offered the desired diol 9b
(62 mg, 69%) as a colorless oil: [
a
]
26.0 þ16.7 (c 1.25, CHCl3); IR
a colorless liquid: 1H NMR (300 MHz, CDCl3):
d
9.51 (d, J¼2.5 Hz,
D
(film): 3449, 2982, 1723, 1373, 1252, 1044, 923 cmꢀ1
;
1H NMR
1H), 7.22 (d, J¼8.5 Hz, 2H), 6.85 (d, J¼8.5 Hz, 2H), 5.67 (ddd, J¼8.1,
10.2, 17.8 Hz, 1H), 5.04 (m, 3H), 4.41 (q, J¼11.3 Hz, 2H), 3.86 (dd,
J¼2.6, 7.6 Hz, 1H), 3.79 (s, 3H), 3.60 (m, 1H), 2.65 (q, J¼7.2 Hz, 1H),
2.49 (q, J¼7.0 Hz, 1H), 2.34 (m, 1H), 1.83 (ddd, J¼4.1, 8.9, 13.7 Hz,
1H),1.65 (m,1H), 1.17 (d, J¼7.1 Hz, 3H),1.14 (d, J¼6.3 Hz, 3H),1.05 (d,
J¼6.9 Hz, 3H), 0.99 (d, J¼6.7 Hz, 3H), 0.90 (m, 12H), 0.03 (s, 6H); 13C
(500 MHz, CDCl3):
d
5.83 (dd, J¼10.5, 17.0 Hz, 1H), 5.22 (dd, J¼1.5,
17.5 Hz, 1H), 5.04 (dd, J¼1.0, 11.0 Hz, 1H), 4.88 (dddd, J¼4.5, 6.5, 6.5,
6.5 Hz,1H), 3.46 (d, J¼4.5 Hz,1H), 2.50 (br s, 2H),1.92 (s, 3H),1.25 (s,
3H), 1.18 (d, J¼6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 170.6,
140.5, 113.1, 77.7, 74.5, 71.3, 26.4, 21.4, 15.4; HRMS: m/z calcd for
C9H16O4[MþH]þ: 189.1127; found, 189.1129.
NMR (75 MHz, CDCl3):
d 205.2, 175.2, 159.0, 139.7, 130.5, 129.3,

4314
H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
115.4, 113.6, 76.4, 76.0, 73.8, 70.0, 55.2, 44.1, 43.5, 39.1, 36.3, 32.5,
26.0, 18.3, 16.9, 15.3, 14.5, 14.5, ꢀ3.9, ꢀ4,0.
30a (330 mg, 0.60 mmol) and CH3CN (5 mL) at room temperature,
was added a solution of [HF/H2O/CH3CN(v/v/v)¼1:0.5:8.5 (10 mL).
After the mixture was stirred for 17 h, it was neutralized with
saturated NaHCO3 (10 mL) and extracted with ether (3ꢂ20 mL). The
combined organic solution was washed with aqueous saturated
NaCl (10 mL) and dried (MgSO4), and concentrated. Purification by
flash chromatography (hexane/EtOAc¼2:1) afforded the desired
4.1.19. (2R,3S,4R)-2-(4-Methoxybenzyloxy)-4-methylhex-5-en-3-yl
(2R,3S,4S,6R)-3-(tert-butyldimethylsilyloxy)-2,4,6-trimethyl-7-ox-
onon-8-enoate (29a). To a stirred solution of the aldehyde 28a
(680 mg, 1.24 mmol) and THF (10 mL) was added vinylmagnesium
bromide (1 M in THF, 1.49 mL, 1.49 mmol) at 0 ꢁC. After 1 h, the
reaction mixture was diluted by adding Et2O (10 mL), and then to
this was added a saturated aqueous NH4Cl solution (10 mL). The
organic layer was separated, and the aqueous layer was extracted
with ether (3ꢂ20 mL). The organic solutions were combined, dried
(MgSO4), and concentrated. Purification of the residue by flash
chromatography (hexane/EtOAc¼7:1) afforded a mixture of vinyl
alcohols (590 mg, 82%) as a colorless oil.
alcohol 31 (130 mg, 50%) as a colorless oil and neomethynolide (3a)
25.5
(86 mg, 46%) as a white solid: 31: [
a
]
27.9 (c 1.40, CHCl3); IR
D
(film): 3478, 2969, 1731, 1688, 1626, 1513, 1460, 1376, 1251, 1162,
1031, 993 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
7.26 (d, J¼8.3 Hz, 2H),
6.89 (d, J¼8.3 Hz, 2H), 6.74 (dd, J¼5.4, 15.7 Hz, 1H), 6.39 (dd, J¼1.2,
15.7 Hz,1H), 4.95 (dd, J¼2.3, 9.3 Hz,1H), 4.62 (d, J¼11.1 Hz,1H), 4.36
(d, J¼11.1 Hz, 1H), 3.81 (s, 3H), 3.60 (m, 2H), 3.05 (m, 1H), 2.55 (m,
2H), 1.59 (m, 2H), 1.31 (m, 3H), 1.30 (d, J¼6.9 Hz, 3H), 1.21 (d,
J¼7.0 Hz, 3H), 1.17 (d, J¼6.0 Hz, 3H), 1.01 (d, J¼6.7 Hz, 6H); 13C NMR
The mixture of vinyl alcohols (590 mg, 1.02 mmol) obtained as
described in the previous procedure was dissolved in CH2Cl2
(20 mL). To this solution was added DesseMartin periodinane
(DMP) (867 mg, 2.04 mmol). The resulting solution was stirred for
1 h at room temperature. After the reaction was completed, satu-
rated NaHCO3 (20 mL) was added. The mixture was extracted with
CH2Cl2 (3ꢂ20 mL). The organic layer was separated, dried (MgSO4),
and concentrated. Purification by flash chromatography (hexane/
EtOAc¼7:1) offered the desired vinyl ketone 29a (560 mg, 95%) as
(75 MHz, CDCl3): d 204.7, 174.2, 159.4, 147.7, 129.9, 125.7, 113.9, 77.9,
77.2, 74.4, 72.1, 70.4, 55.3, 45.2, 43.1, 35.4, 33.3, 33.0, 17.7, 17.5, 16.3,
16.2, 9.7; HRMS: m/z calcd for C25H36O6[MþNa]þ: 455.2410; found,
455.2406: 3a mp 101e104 ꢁC; [ 22.1 73.8 (c 1.52, CHCl3); IR (film):
a]
D
3439, 2970, 1728, 1684, 1627, 1458, 1377, 1155, 996, 740 cmꢀ1
;
1H
6.75 (dd, J¼5.4, 15.7 Hz, 1H), 6.53 (dd,
NMR (500 MHz, CDCl3,):
d
J¼1.3,15.7 Hz,1H), 4.83 (dd, J¼2.3, 9.0 Hz,1H), 3.89 (dddd, J¼6.1, 6.1,
6.1, 12.4 Hz, 1H), 3.56 (d, J¼10.4 Hz, 1H), 3.07 (m, 1H), 2.62 (dddd,
J¼6.9, 6.9, 6.9, 10.4 Hz, 1H), 2.52 (m, 1H), 1.63 (t, J¼12.8 Hz, 1H), 1.51
(br s, 2H),1.35e1.22 (m, 2H), 1.30 (d, J¼6.9 Hz, 3H),1.22 (d, J¼6.7 Hz,
3H), 1.21 (d, J¼5.9 Hz, 3H), 1.17 (d, J¼6.9 Hz, 3H), 1.01 (d, J¼6.2 Hz,
a colorless liquid: [
a
]
27.6 þ21.6 (c 1.04, CHCl3); IR (film): 2931, 2861,
D
1732, 1698, 1612, 1524, 1461, 1378, 1294, 1250, 1173, 1056 cmꢀ1; 1H
NMR (500 MHz, CDCl3):
d
7.22 (d, J¼8.5 Hz, 2H), 6.85 (d, J¼8.5 Hz,
2H), 6.43 (dd, J¼11.0, 17.5 Hz, 1H), 6.26 (dd, J¼1.0, 17.5 Hz, 1H), 5.74
(dd, J¼1.5, 10.5 Hz, 1H), 5.68 (ddd, J¼8.0, 10.5, 17.5 Hz, 1H), 5.02 (m,
3H), 4.42 (q, J¼11.5 Hz, 2H), 3.89 (dd, J¼3.0, 7.0 Hz, 1H), 3.79 (s, 3H),
3.60 (dd, J¼4.0, 6.0 Hz, 1H), 2.86 (m, 1H), 2.63 (q, J¼7.0 Hz, 1H), 2.50
(dddd, J¼7.0, 7.0, 7.0, 14.5 Hz, 1H), 1.86 (ddd, J¼4.0, 8.5, 13.5 Hz, 1H),
1.54 (m, 1H), 1.16 (t, J¼7.0 Hz, 6H), 1.08 (d, J¼7.0 Hz, 3H), 1.00 (d,
J¼7.0 Hz, 3H), 0.91 (d, J¼7.0 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); 13C
3H); 13C NMR (125 MHz, CDCl3):
d 204.7, 174.3, 147.4, 125.9, 78.0,
75.4, 66.4, 45.2, 43.2, 35.5, 33.3, 33.1, 21.0, 17.7, 17.5, 16.2, 9.8; HRMS:
m/z calcd for C17H28O5: 312.1937; found, 312.1936.
Method 2. To a stirred solution of lactone 30a (17 mg, 0.031 mmol)
in dry THF (2 mL) at room temperature was added 1.0 M TBAF (60 mL,
0.062 mmol) via a syringe. After 3 h, the reaction mixture was con-
centrated. Purification by flash chromatography (hexane/EtOAc¼3:1)
afforded alcohol 31 (11 mg, 85%) as a colorless oil.
NMR (125 MHz, CDCl3):
d 203.8, 175.4, 159.0, 139.9, 135.0, 130.6,
129.3, 128.0, 115.2, 113.6, 76.0, 76.0, 73.9, 70.1, 55.2, 42.9, 41.4, 39.1,
37.1, 35.0, 26.0, 18.3, 17.7, 16.5, 16.1, 15.1, 14.7, -4.1, -4.1; HRMS: m/z
calcd for C33H54O6Si[MþH]þ:597.3587; found, 597.3585.
4.1.22. (2R,3R,4S)-2-Acetoxy-4-hydroxy-4-methylhex-5-en-3-yl
(2R,3S,4S,6R)-3,7-bis(tert-butyldimethylsilyloxy)-2,4,6-trime-
thylheptanoate (27b). To a solution of carboxylic acid 26 (144 mg,
0.33 mmol) in THF (5 mL) at room temperature were added trie-
4.1.20. (E)-(3R,4S,5S,7R,11R,12S)-4-(tert-Butyldimethylsilyloxy)-12-
[(R)-1-(4-methoxybenzyloxy)ethyl]-3,5,7,11-tetramethylox-
acyclododec-9-ene-2,8-dione (30a). A flame-dried round-bottomed
flask was charged with a solution of vinyl ketone 29a (560 mg,
0.97 mmol) in CH2Cl2 (30 mL). Grubbs catalyst (second generation)
(82 mg, 0.097 mmol) was subsequently added as a solid, producing
a light brown solution, which was stirred for 18 h at room tem-
perature. The mixture was then concentrated to give a dark brown
oil. Purification of this residue by flash chromatography (hexane/
EtOAc¼5:1) afforded the lactone 30a (450 mg, 85%) as a colorless
thylamine (69
mL, 0.50 mmol) and 2,4,6-trichlorobenzoyl chloride
(67 L, 0.43 mmol). The mixture was stirred for 3 h at room temper-
m
ature, and the solids were filtered off and washed with hexane
(10 mL). The combined solution was concentrated under reduced
pressure. The residue was dissolved in benzene (5 mL), and to this
solution a solution of alcohol 9b (62 mg, 0.33 mmol) and DMAP
(20 mg, 0.17 mmol) in benzene (2 mL) was added. After being stirred
for 15 h, the reaction mixture was diluted with ether (10 mL), and
washed with saturated NaHCO3 (10 mL) and saturated NaCl (10 mL),
dried (MgSO4), and concentrated. Purification of the residue by flash
chromatography (hexane/EtOAc¼7:1) afforded the desired ester 27b
oil: [a
]
25.5 þ45.1 (c 1.85, CHCl3); IR (film): 2933, 2864, 1732, 1692,
D
1629, 1514, 1462, 1375, 1324, 1253, 1162, 1090, 1056, 985 cmꢀ1
;
1H
NMR (300 MHz, CDCl3):
d
7.26 (d, J¼8.5 Hz, 2H), 6.89 (d, J¼8.5 Hz,
(151 mg, 76%) as a colorless oil: [
a
]
25.0 þ12.8 (c 0.96, CHCl3); IR (film):
D
2H), 6.74 (dd, J¼5.5, 15.7 Hz, 1H), 6.40 (d, J¼15.7 Hz, 1H), 4.92 (dd,
J¼2.1, 9.3 Hz, 1H), 4.61 (d, J¼11.0 Hz, 1H), 4.35 (d, J¼11.0 Hz, 1H),
3.80 (s, 3H), 3.59 (m, 1H), 3.05 (m, 1H), 2.63 (dddd, J¼7.0, 7.0, 7.0,
10.0 Hz, 1H), 2.48 (m, 1H), 1.62 (m, 1H), 1.31 (m, 1H), 1.20 (d,
J¼7.0 Hz, 6H), 1.16 (d, J¼6.0 Hz, 3H), 1.00 (d, J¼6.8 Hz, 3H), 0.93 (d,
J¼6.3 Hz, 3H), 0.90 (s, 9H), 0.06 (d, J¼4.2 Hz, 6H); 13C NMR (75 MHz,
3516, 2955,1740,1462,1371,1255,1156,1078, 928, 839, 809 cmꢀ1; 1H
NMR (500 MHz,CDCl3):
d
5.92(dd, J¼11.0,17.0 Hz,1H), 5.38(dd, J¼1.0,
17.5 Hz,1H),5.16(m,2H),5.05(d, J¼3.5 Hz,1H),3.95(dd,J¼3.5,6.5 Hz,
1H), 3.45 (dd, J¼5.0,10.0 Hz,1H), 3.26 (dd, J¼7.0, 9.5 Hz,1H), 2.71 (m,
1H), 2.09(s,1H),1.95 (s, 3H),1.67 (m, 2H),1.43 (ddd, J¼5.0, 7.5,14.0 Hz,
1H), 1.24 (m, 9H), 0.94 (d, J¼7.0 Hz, 3H), 0.89 (m, 21H), 0.06 (d,
CDCl3):
d
204.9, 174.8, 159.3, 147.4, 129.9, 125.9, 113.8, 79.0, 74.2,
J¼7.0 Hz, 6H), 0.02 (s, 6H); 13C NMR (125 MHz, CDCl3):
d 175.3, 170.3,
72.2, 70.3, 55.2, 45.0, 44.0, 35.2, 34.1, 33.6, 26.2, 18.5, 18.5, 17.7, 16.9,
16.3, 9.7, ꢀ3.2, ꢀ3.4; HRMS: m/z calcd for C31H50O6Si[MþNa]þ:
569.3274; found, 569.3272.
140.1, 113.9, 77.1, 75.4, 74.0, 69.7, 67.8, 42.2, 37.0, 35.7, 33.6, 26.7, 25.9,
25.9, 21.2,18.3,18.1,16.7,15.3,14.8, ꢀ4.1, ꢀ4.2, ꢀ5.4; HRMS: m/z calcd
for C31H62O7Si2[MþH]þ: 603.4112; found, 603.4114.
4.1.21. (E)-(3R,4S,5S,7R,11R,12S)-4-Hydroxy-12-[(R)-1-(4-methoxy-
benzyloxy)ethyl]-3,5,7,11-tetramethyloxacyclododec-9-ene-2,8-dione
(31) and neomethynolide (3a). Method 1. To a solution of lactone
4.1.23. (2R,3R,4S)-2-Acetoxy-4-hydroxy-4-methylhex-5-en-3-yl
(2R,3S,4S,6R)-3-(tert-butyldimethylsilyloxy)-2,4,6-trimethyl-7-ox-
oheptanoate (28b). Ester 27b (143 mg, 0.24 mmol) was dissolved in

H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
4315
MeOH (5 mL). To this solution was added DL-10-camphorsulfonic
acid (11 mg, 0.05 mmol). The resulting solution was stirred at 0 ꢁC
for 2 h. The reaction was terminated by addition of Et3N (35 mL,
2.98 (m, 2H), 2.04 (ddd, J¼2.0, 11.0, 13.5 Hz, 1H), 1.94 (s, 3H), 1.66 (s,
1H), 1.31 (d, J¼6.5 Hz, 3H), 1.24 (d, J¼7.5 Hz, 3H), 1.13 (d, J¼7.0 Hz,
3H),1.13 (s, 3H), 0.94 (d, J¼7.0 Hz, 3H), 0.91 (s, 9H), 0.08 (d, J¼2.0 Hz,
0.24 mmol). After the solution was concentrated, purification by
flash chromatography (hexane/EtOAc¼2:1) gave the desired pri-
6H); 13C NMR (125 MHz, CDCl3):
d 205.2, 176.0, 170.2, 139.8, 135.5,
129.2, 113.8, 77.6, 77.1, 73.5, 70.2, 43.7, 40.6, 36.5, 33.6, 26.9, 26.1,
21.2, 19.1, 18.5, 18.3, 16.1, 14.9, ꢀ3.6, ꢀ3.7; HRMS: m/z calcd for
C27H48O7Si[MþH]þ: 535.3067; found, 535.3071.
mary alcohol (100 mg, 86%) as a colorless oil: [
a
]
25.9 þ19.1 (c 1.56,
D
CHCl3); IR (film): 3430, 2955,1739, 1461,1372,1254,1164,1055, 927,
837 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
5.94 (dd, J¼10.0, 17.0 Hz,
1H), 5.38 (dd, J¼1.0, 17.5 Hz, 1H), 5.18 (dd, J¼1.5, 11.0 Hz, 1H), 5.14
(dddd, J¼3.5, 6.5, 6.5, 6.5 Hz, 1H), 5.06 (d, J¼3.5 Hz, 1H), 3.89 (dd,
J¼2.5, 7.5 Hz, 1H), 3.50 (dd, J¼4.5, 11.0 Hz, 1H), 3.40 (dd, J¼5.0,
11.0 Hz, 1H), 2.81 (q, J¼7.0 Hz,1H), 1.96 (s, 3H), 1.70 (m, 3H), 1.59 (m,
1H),1.26 (s, 3H),1.24 (d, J¼6.5 Hz, 3H),1.23 (d, J¼7.0 Hz, 3H), 0.96 (d,
J¼7.5 Hz, 3H), 0.94 (d, J¼6.5 Hz, 3H), 0.91 (s, 9H), 0.08 (d, J¼2.0 Hz,
4.1.25. (E)-(3R,4S,5S,7R,11S,12R)-4-(tert-Butyldimethylsilyloxy)-12-
[(R)-1-acetoxyethyl]-3,5,7,11-tetramethyloxacyclododec-9-ene-2,8-
dione (30b). A flame-dried round-bottomed flask was charged with
a solution of vinyl ketone 29b (65 mg, 0.13 mmol) in CH2Cl2
(15 mL). Grubbs catalyst (second generation) (22 mg, 0.026 mmol)
was subsequently added as a solid, producing a light brown solu-
tion, which was stirred for 18 h at room temperature. The mixture
was then concentrated to give a dark brown oil. Purification of this
residue by flash chromatography (hexane/EtOAc¼3:1) afforded the
6H); 13C NMR (125 MHz, CDCl3):
d 175.9, 170.3, 139.9, 114.0, 77.6,
76.3, 73.8, 69.8, 66.8, 43.1, 36.1, 34.3, 32.6, 26.6, 26.0, 21.2, 18.4, 18.2,
17.5, 15.5, 15.3, ꢀ3.9, ꢀ4.0; HRMS: m/z calcd for C25H48O7Si[MþH]þ:
489.3248; found, 489.3246.
lactone 30b (51 mg, 85%) as a colorless oil: [
a
]
30.7 þ62.1 (c 1.65,
D
The alcohol (87 mg, 0.18 mmol) obtained as described in the
previous procedure was dissolved in CH2Cl2 (10 mL). To this solu-
tion was added DesseMartin periodinane (DMP) (151 mg,
0.36 mmol). The resulting solution was stirred for 1 h at room
temperature. After the reaction was completed, saturated NaHCO3
(10 mL) was added. The mixture was extracted with CH2Cl2
(3ꢂ10 mL). The organic layer was separated, dried (MgSO4), and
concentrated. Purification by flash chromatography (hexane/
EtOAc¼7:1) offered the desired aldehyde 28b (80 mg, 92%) as
CHCl3); IR (film): 3483, 2930, 2856, 1741, 1694, 1630, 1461, 1371,
;
1318, 1251, 1137, 1089, 1061, 979, 894 cmꢀ1 1H NMR (500 MHz,
CDCl3):
d
6.59 (d, J¼16.0 Hz, 1H), 6.31 (d, J¼16.0 Hz, 1H), 5.28 (m,
1H), 4.90 (d, J¼5.0 Hz, 1H), 3.63 (d, J¼10.0 Hz, 1H), 3.02 (s, 1H), 2.70
(dddd, J¼7.0, 7.0, 7.0, 10.0 Hz, 1H), 2.53 (ddddd, J¼4.5, 7.0, 7.0, 7.0,
11.5 Hz, 1H), 2.06 (s, 3H), 1.72 (s, 1H), 1.64 (t, J¼13.5 Hz, 1H), 1.40 (s,
3H), 1.24 (d, J¼7.0 Hz, 3H), 1.23 (d, J¼6.5 Hz, 3H), 1.19 (d, J¼7.0 Hz,
3H), 0.93 (d, J¼6.5 Hz, 3H), 0.90 (s, 9H), 0.07 (d, J¼3.5 Hz, 6H); 13C
NMR (125 MHz, CDCl3): d 204.0, 174.6, 170.7, 148.8, 125.8, 79.1, 74.5,
a colorless liquid: 1H NMR (500 MHz, CDCl3):
d
9.54 (d, J¼2.3 Hz,
69.2, 45.3, 44.4, 38.8, 33.6, 26.4, 21.5, 20.4, 18.7, 18.7, 17.9, 17.3, 17.0,
ꢀ2.9, ꢀ3.2; HRMS: m/z calcd for C25H44O7Si[MþNa]þ: 507.2754;
found, 507.2759.
1H), 5.92 (dd, J¼10.8, 17.2 Hz, 1H), 5.39 (dd, J¼1.3, 17.2 Hz, 1H), 5.16
(dd, J¼1.3, 10.8 Hz, 1H), 5.13 (dddd, J¼3.2, 6.6, 6.6, 6.6 Hz, 1H), 5.03
(d, J¼3.2 Hz, 1H), 3.86 (dd, J¼2.1, 8.4 Hz, 1H), 2.84 (m, 2H), 2.44 (m,
1H),1.93 (s, 3H),1.89 (ddd, J¼3.2,10.1,13.7 Hz,1H),1.53 (m,1H),1.25
(d, J¼6.6 Hz, 3H), 1.23 (d, J¼7.2 Hz, 3H), 1.21 (s, 3H), 1.11 (d, J¼7.2 Hz,
3H), 0.94 (d, J¼6.9 Hz, 3H), 0.89 (s, 9H), 0.07 (d, J¼1.1 Hz, 6H); 13C
4.1.26. Novamethynolide (4a). To a stirred solution of lactone 30b
(20 mg, 0.041 mmol) in dry THF (3 mL) at room temperature was
added 1.0 M TBAF (160 mL, 0.16 mmol) via a syringe. After 5 h, the
NMR (125 MHz, CDCl3):
d
205.7, 175.4, 170.2, 139.9, 113.9, 77.5, 76.6,
reaction mixture was concentrated. Purification by flash chroma-
tography (hexane/EtOAc¼1:1) afforded novamethynolide (4a)
73.7, 69.9, 44.1, 43.7, 36.4, 32.2, 26.7, 26.1, 21.1, 18.4, 17.6, 15.7, 15.1,
15.0, ꢀ3.8, ꢀ3.9.
(9.0 mg, 67%) as a white solid: mp 143e146 ꢁC; [
a
]
26.2 þ39.5 (c 0.74,
D
CHCl3); IR (film): 3441, 2924, 1735, 1688, 1633, 1459, 1377, 1271,
4.1.24. (2R,3R,4S)-2-Acetoxy-4-hydroxy-4-methylhex-5-en-3-yl
(2R,3S,4S,6R)-3-(tert-butyldimethylsilyloxy)-2,4,6-trimethyl-7-ox-
onon-8-enoate (29b). To a stirred solution of the aldehyde 28b
(80 mg, 0.16 mmol) and THF (10 ml) was added vinylmagnesium
1133, 991 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
6.64 (d, J¼16.0 Hz,
1H), 6.31 (d, J¼16.0 Hz, 1H), 4.70 (d, J¼9.4 Hz, 1H), 4.14 (m, 1H), 4.02
(s, 3H), 3.58 (d, J¼8.9 Hz, 1H), 3.14 (s, 1H), 2.58 (m, 2H), 1.61 (m, 2H),
1.52 (s, 3H), 1.32 (m, 1H), 1.30 (d, J¼6.9 Hz, 3H), 1.25 (m, 1H), 1.21 (d,
J¼6.9 Hz, 3H), 1.20 (d, J¼6.0 Hz, 3H), 1.00 (d, J¼6.6 Hz, 3H); 13C NMR
bromide (1 M in THF, 250 m
L, 0.25 mmol) at 0 ꢁC. After 1 h, the re-
action mixture was diluted by adding Et2O (10 mL), and then to this
was added a saturated aqueous NH4Cl solution (10 mL). The organic
layer was separated, and the aqueous layer was extracted with
ether (3ꢂ10 mL). The organic solutions were combined, dried
(MgSO4), and concentrated. Purification of the residue by flash
chromatography (hexane/EtOAc¼7:1) afforded a mixture of vinyl
alcohols (71 mg, 85%) as a colorless oil.
(125 MHz, CDCl3): d 203.9, 173.7, 148.3, 125.2, 77.7, 75.5, 74.3, 67.8,
45.3, 43.2, 33.3, 33.0, 21.0, 17.6, 17.4, 16.2; HRMS: m/z calcd for
C17H28O6[MþNa]þ: 351.1784; found, 351.1781.
4.1.27. (E)-(3R,4S,5S,7R,11S,12R)-12-[(R)-1-Acetoxyethyl]-4-hydroxy-
3,5,7,11-tetramethyloxacyclododec-9-ene-2,8-dione (32). To a solu-
tion of lactone 30b (40 mg, 0.083 mmol) and CH3CN (2 mL) at room
temperature, was added a solution of [HF/H2O/CH3CN(v/v/v)¼
1:0.5:8.5] (5 mL). After the mixture was stirred for 17 h, it was
neutralized with saturated NaHCO3 (10 mL) and extracted with
ether (3ꢂ10 mL). The combined organic solution was washed with
aqueous saturated NaCl (10 mL) and dried (MgSO4), and concen-
trated. Purification by flash chromatography (hexane/EtOAc¼1:1)
The mixture of vinyl alcohols (71 mg, 0.14 mmol) obtained as
described in the previous procedure was dissolved in CH2Cl2
(10 mL). To this solution was added DesseMartin periodinane
(DMP) (117 mg, 0.28 mmol). The resulting solution was stirred for
1 h at room temperature. After the reaction was completed, aque-
ous saturated NaHCO3 (10 mL) was added. The mixture was
extracted with CH2Cl2 (3ꢂ10 mL). The organic layer was separated,
dried (MgSO4), and concentrated. Purification by flash chroma-
tography (hexane/EtOAc¼7:1) offered the desired vinyl ketone 29b
afforded the desired compound 32 (24 mg, 77%) as a white solid:
27.7
mp 87e90 ꢁC; [
a
]
72.4 (c 1.08, CHCl3); IR (film): 3407, 2968,
1H NMR
6.59 (d, J¼16.0 Hz, 1H), 6.32 (d, J¼16.0 Hz, 1H),
D
2924, 1727, 1633, 1464, 1375, 1244, 1133, 1072, 983 cmꢀ1
(500 MHz, CDCl3):
;
(65 mg, 92%) as a colorless liquid: [
a
]
25.5 þ29.0 (c 1.16, CHCl3); IR
d
D
(film): 3493, 2932, 2857, 1737, 1673, 1612, 1461, 1409, 1371, 1247,
5.29 (dddd, J¼6.5, 6.5, 6.5, 12.0 Hz, 1H), 4.93 (d, J¼5.0 Hz, 1H), 3.58
(d, J¼10.0 Hz, 1H), 3.03 (s, 1H), 2.66 (dddd, J¼7.0, 7.0, 7.0, 10.5 Hz,
1H), 2.57 (m, 1H), 2.07 (s, 3H), 1.74 (s, 2H), 1.63 (t, J¼13.0 Hz, 1H),
1.42 (s, 3H), 1.33 (m, 2H), 1.33 (d, J¼7.0 Hz, 3H), 1.25 (d, J¼6.5 Hz,
3H), 1.20 (d, J¼7.0 Hz, 3H), 1.00 (d, J¼6.5 Hz, 3H); 13C NMR
1161, 1093, 1050, 926 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d 6.39 (dd,
J¼10.0, 17.5 Hz, 1H), 6.28 (dd, J¼1.0, 17.5 Hz, 1H), 5.95 (dd, J¼11.0,
17.5 Hz, 1H), 5.38 (dd, J¼1.0, 10.5 Hz, 1H), 5.44 (dd, J¼1.5, 17.5 Hz,
1H), 5.18 (dd, J¼1.5, 11.0 Hz, 1H), 5.15 (dddd, J¼3.0, 6.5, 6.5, 6.5 Hz,
1H), 5.02 (d, J¼3.0 Hz, 1H), 3.82 (dd, J¼1.0, 9.0 Hz, 1H), 3.74 (s, 1H),
(125 MHz, CDCl3): d 203.6, 173.8, 170.5, 148.6, 125.4, 77.8, 74.4, 74.3,

4316
H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
69.0, 45.2, 43.3, 33.5, 32.9, 21.3, 20.1, 17.6, 17.4,16.9,16.2; HRMS: m/z
calcd for C19H30O7[MþNa]þ: 393.1889; found, 393.1891.
(d, J¼6.2 Hz, 3H),1.20 (d, J¼6.2 Hz, 3H),1.19 (d, J¼7.1 Hz, 3H), 1.16 (d,
J¼6.8 Hz, 3H), 1.02 (d, J¼6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d
205.2, 174.8, 147.0, 126.2, 105.0, 85.6, 75.4, 70.3, 69.5, 66.5, 65.9,
4.1.28. Protected neomethymycin 34. To
a
solution of tri-
45.1, 43.9, 40.2, 35.4, 34.1, 33.4, 29.7, 28.4, 22.7, 21.1, 21.0, 17.6, 17.4,
15.9, 14.1, 9.8; HRMS: m/z calcd for C25H43NO7[MþH]þ: 470.3118;
found, 470.3120.
chloroacetimidate 33 (50 mg, 0.14 mmol) and PMB-protected-
neomethynolide 31 (30 mg, 0.069 mmol) in CH2Cl2 (5 mL) was
added molecular sieves (300 mg). The resulting solution was
stirred at room temperature. After 30 min the mixture was cooled
4.1.30. Novamethymycin (4). To a solution of trichloroacetimidate
33 (22 mg, 0.060 mmol) and the protected novamethynolide 32
(13 mg, 0.030 mmol) in CH2Cl2 (4 mL) was added molecular sieves
(200 mg). The resulting solution was stirred for 30 min at room
temperature. The mixture was cooled ꢀ20 ꢁC and then BF3$OEt2
to ꢀ20 ꢁC and then BF3$OEt2 (12
mL, 0.083 mmol) was added. The
resulting mixture was stirred for 3 h at ꢀ20 ꢁC before it was
warmed to room temperature. After additional stirring for 12 h at
room temperature NaHCO3 (10 mg) was added to the mixture.
After filtration through a pad of Celite with CH2Cl2 (3ꢂ5 mL), the
solution was concentrated. Purification of the residue by flash
chromatography (EtOAc/MeOH¼10:1) afforded the protected 34
(6 mL, 0.045 mmol) was added. The resulting mixture was stirred
for 3 h at ꢀ20 ꢁC before it was warmed to room temperature. After
additional stirring for 12 h at room temperature NaHCO3 (10 mg)
was added to the mixture. After filtration through a pad of Celite
with CH2Cl2 (3ꢂ5 mL), the solution was concentrated. Purification
of the residue by flash chromatography (EtOAc/MeOH¼10:1)
afforded the diacetyleprotected novamethymycin (8.8 mg, 52%)
(20 mg, 46%) as a colorless oil: [
a
]
26.1 þ50.7 (c 0.94, CHCl3); IR
D
(film): 2933, 1734, 1686, 1624, 1513, 1455, 1375, 1242, 1156, 1103,
1056, 987 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
7.25 (d, J¼8.6 Hz,
2H), 6.89 (d, J¼8.6 Hz, 2H), 6.71 (dd, J¼5.5, 15.7 Hz, 1H), 6.39 (dd,
J¼1.0, 15.7 Hz, 1H), 4.90 (dd, J¼2.3, 9.3 Hz, 1H), 4.77 (dd, J¼7.6,
10.6 Hz, 1H), 4.61 (d, J¼11.1 Hz, 1H), 4.35 (d, J¼11.1 Hz, 1H), 4.29 (d,
J¼7.6 Hz, 1H), 3.81 (s, 3H), 3.59 (m, 1H), 3.53 (d, J¼10.5 Hz, 1H),
3.46 (m, 1H), 3.04 (m, 1H), 2.69 (m, 2H), 2.52 (m, 1H), 2.26 (s, 6H),
2.08 (s, 3H), 1.81 (m, 3H), 1.73 (m, 2H), 1.54 (t, J¼12.7 Hz, 1H), 1.37
(m, 4H), 1.28 (d, J¼6.9 Hz, 3H), 1.23 (d, J¼6.1 Hz, 3H), 1.17 (d,
J¼7.0 Hz, 3H), 1.15 (d, J¼6.1 Hz, 3H), 0.99 (d, J¼6.8 Hz, 6H); 13C
as a colorless oil: [
a
]
25.3 þ67.4 (c 0.53, CHCl3); IR (film): 3353,
D
2925, 2852, 1739, 1630, 1459, 1378, 1243, 1127, 1056, 835 cmꢀ1; 1H
NMR (500 MHz, CDCl3):
d
6.58 (d, J¼16.0 Hz, 1H), 6.31 (d,
J¼16.0 Hz, 1H), 5.27 (m, 1H), 4.89 (d, J¼5.3 Hz, 1H), 4.79 (m, 1H),
4.31 (d, J¼7.5 Hz, 1H), 4.12 (q, J¼7.1 Hz, 1H), 3.56 (d, J¼10.5 Hz, 1H),
3.48 (m, 1H), 3.35 (m, 1H), 2.75 (dd, J¼6.8, 10.4 Hz, 1H), 2.56 (m,
2H), 2.29 (s, 6H), 2.09 (s, 3H), 2.08 (s, 3H), 2.05 (m, 1H), 1.68 (m,
2H), 1.57 (m, 2H), 1.42 (s, 3H), 1.36 (m, 2H), 1.31 (d, J¼6.9 Hz, 3H),
1.25 (d, J¼5.9 Hz, 3H), 1.24 (d, J¼8.1 Hz, 3H), 1.18 (d, J¼7.0 Hz, 3H),
NMR (125 MHz, CDCl3):
d 205.1, 174.4, 169.9, 159.4, 147.2, 129.9,
129.5, 126.1, 113.9, 102.9, 85.5, 74.5, 72.2, 71.6, 70.4, 69.1, 63.5, 52.3,
45.1, 43.7, 40.6, 35.3, 33.6, 33.4, 30.3, 21.3, 20.9, 17.6, 17.4, 16.3, 15.7,
9.7; HRMS: m/z calcd for C35H53NO9[MþH]þ: 632.3799; found,
632.3796.
0.98 (d, J¼6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 203.8, 173.9,
169.8, 169.6, 148.2, 125.9, 102.9, 85.0, 74.4, 74.3, 70.5, 69.7, 69.0,
63.5, 63.1, 45.1, 43.9, 40.6, 33.9, 33.3, 30.5, 30.3, 21.4, 21.1, 20.9.
20.2, 17.3, 16.9, 15.7; HRMS: m/z calcd for C29H47NO10[MþH]þ:
570.3278; found, 570.3285.
4.1.29. Neomethymycin (3). To a solution of product 34 (15 mg,
0.024 mmol) in CH2Cl2/H2O [10:1(v/v), 3 mL] was added dichlor-
odicynoquinone (DDQ) (16 mg, 0.072 mmol) at 0 ꢁC. The solution
was stirred for 2 h. After the reaction was completed, the solution
was filtered through a pad of Celite. The Celite pad was washed
with CH2Cl2 (3ꢂ10 mL). After the combined filtrate was concen-
trated, purification by flash chromatography (EtOAc/MeOH¼10:1)
provided the desired alcohol product (9.7 mg, 79%) as a colorless
To a stirred solution of diacetyleprotected novamethymycin
(5.1 mg, 0.0090 mmol) prepared as described in the previous pro-
cedure in MeOH (1 mL) at room temperature was added H2O
(100 mL) and triethylamine (100 mL). After stirred for 5 h, the re-
action mixture was concentrated. Purification of the residue by
flash chromatography (EtOAc/MeOH¼10:1) afforded novamethy-
mycin (4) (3.3 mg, 75%) as a colorless oil: [
a
]
21.8 þ97.3 (c 0.13,
D
oil: [
a
]
D
25.7 þ59.4 (c 0.54, CHCl3); IR (film): 3388, 2924, 2853, 2333,
CHCl3); IR (film): 3402, 2925, 1736, 1693, 1633, 1460, 1377, 1271,
1730, 1686, 1626, 1462, 1378, 1246, 1162, 1062 cmꢀ1
;
1H NMR
1159, 1111, 1051, 989 cmꢀ1 1H NMR (500 MHz, CDCl3):
; d 6.64 (d,
(500 MHz, CDCl3):
d
6.74 (dd, J¼5.6, 15.7 Hz, 1H), 6.43 (dd, J¼1.3,
J¼16.0 Hz, 1H), 6.32 (d, J¼16.0 Hz, 1H), 4.68 (d, J¼9.3 Hz, 1H), 4.23
(d, J¼7.3 Hz, 1H), 4.13 (m, 1H), 3.61 (d, J¼10.7 Hz, 1H), 3.49 (m, 1H),
3.23 (dd, J¼7.4, 10.2 Hz, 1H), 2.86 (dddd, J¼7.0, 7.0, 7.0, 10.7 Hz, 1H),
2.58 (m, 1H), 2.52 (m,1H), 2.29 (s, 6H),1.68 (m, 2H),1.52 (s, 3H),1.46
(m, 1H), 1.41 (d, J¼7.0 Hz, 3H), 1.23 (d, J¼6.2 Hz, 3H), 1.20 (d,
J¼6.2 Hz, 3H), 1.17 (d, J¼7.0 Hz, 3H), 1.02 (d, J¼6.7 Hz, 3H); 13C NMR
15.7 Hz, 1H), 4.78 (m, 2H), 4.30 (d, J¼7.6 Hz, 1H), 3.88 (m, 1H), 3.53
(d, J¼10.5 Hz, 1H), 3.47 (ddd, J¼1.8, 6.2, 11.0 Hz, 1H), 3.05 (m, 1H),
2.70 (m, 2H), 2.52 (m, 1H), 2.26 (s, 6H), 2.08 (s, 3H), 1.73 (m, 2H),
1.56 (t, J¼14.2 Hz, 1H), 1.43 (m, 2H), 1.34 (m, 2H), 1.29 (d, J¼7.0 Hz,
3H), 1.23 (d, J¼6.1 Hz, 3H), 1.20 (d, J¼6.1 Hz, 3H), 1.19 (d, J¼7.0 Hz,
3H), 1.16 (d, J¼6.9 Hz, 3H), 1.00 (d, J¼6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d 203.9, 174.1, 147.9, 125.6, 105.0, 85.3, 75.5, 74.2,
(125 MHz, CDCl3):
75.4, 71.6, 69.1, 66.5, 63.5, 45.1, 43.7, 40.6, 35.4, 33.6, 33.5, 30.3, 29.7,
21.4, 21.0, 21.0, 17.6, 17.3, 15.7, 9.8.
d
205.2, 174.5, 169.9, 146.8, 126.3, 102.9, 85.4,
70.3, 69.5, 67.9, 65.9, 45.2, 44.0, 40.2, 33.8, 33.6, 39.7, 21.1, 21.1, 20.3,
17.6, 17.4, 15.8; HRMS: m/z calcd for C25H43NO8[MþH]þ: 486.3067;
found, 486.3070.
To a stirred solution of the alcohol product (7.0 mg, 0.014 mmol)
(preparedas describedin the previous procedure) in MeOH(2 mL) at
Acknowledgements
room temperature was added H2O (200
(200 L). After 3 h, the reaction mixture was concentrated. Purifi-
cation of the residue by flash chromatography (EtOAc/MeOH¼10:1)
mL) and triethylamine
m
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD) (KRF-2007-
521-C00152). The authors are grateful to Prof. Yeo Joon Yoon (Ewha
Womans University) for supplying the cell culture from which an
authentic sample of neomethymycin was isolated.
18.3
afforded neomethymycin (3) (5.3 mg, 80%) as a colorless oil: [
124.6 (c 0.35, CHCl3); IR (film): 3385, 2925, 2858, 1732, 1685, 1625,
1460, 1377, 1255, 1158, 1109, 1050, 994 cmꢀ1 1H NMR (500 MHz,
CDCl3):
a]
D
;
d
6.76 (dd, J¼5.5, 15.7 Hz, 1H), 6.44 (dd, J¼1.2, 15.7 Hz, 1H),
4.79 (dd, J¼2.2, 9.0 Hz, 1H), 4.24 (d, J¼7.3 Hz, 1H), 3.89 (dddd, J¼6.1,
6.1, 6.1, 8.8 Hz,1H), 3.77 (d, J¼2.5 Hz,1H), 3.59 (d, J¼10.5 Hz,1H), 3.48
(m, 1H), 3.23 (dd, J¼7.4, 10.2 Hz, 1H), 3.05 (m, 1H), 2.88 (dddd, J¼7.1,
7.1, 7.1, 10.6 Hz, 1H), 2.54 (m, 2H), 2.36 (s, 1H), 2.29 (s, 6H), 1.86 (m,
2H),1.69 (m, 4H),1.46 (m, 2H),1.41 (d, J¼7.0 Hz, 3H),1.28 (m, 2H),1.23
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.04.039.

H.-S. Oh, H.-Y. Kang / Tetrahedron 66 (2010) 4307e4317
15. Oh, H.-S.; Xuan, R.; Kang, H.-Y. Org. Biomol. Chem. 2009, 7, 4458.
4317
References and notes
16. Imuta, S.; Tanimoto, H.; Momose, M. K.; Chida, N. Tetrahedron 2006, 62, 6926.
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Bartroli, J. Pure Appl. Chem. 1981, 53, 1109; (c) Kürti, L.; Czakó, B. Strategic
Applications of Named Reactions in Organic Synthesis; Elsevier Academic:
Amsterdam, 2005; p 162 and references therein.
1. For recent reviews on the application to the total synthesis of macrocyclic
natural products, see: (a) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed.
2006, 45, 6086; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490; (c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
2. Isolation of 10-deoxymethynolide from Streptomyces venezuelae ATCC 15439:
Kinumaki, A.; Suzuki, M. J. Chem. Soc., Chem. Commun. 1972, 744.
3. Total synthesis of 10-deoxymethynolide: (a) Pilli, R. A.; de Andrade, C. K.; Souto,
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7 Hz) ppm. For 32, these signals appear at 6.59 (d, J¼16.0 Hz) and 6.32 (d, J¼16.
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