Synthesis of moenocinol and its analogs using BT-sulfone in Julia-Kocienski olefination

Article abstract of DOI:10.1016/j.tetlet.2006.12.119

Moenocinol (C₂₅H₄₂O), the acyclic terpenoid unsaturated lipid part of moenomycin antibiotics, was prepared by an expedient method, which comprised organometallic reaction, Julia-Kocienski olefination, and enolate carbon bond formation as the key steps. The starting materials, nerol and 3-butyn-1-ol, were elaborated to the benzothiazole sulfone 2 and aldehyde 3, and the subsequent Julia-Kocienski olefination occurred in a stereospecific manner to give the desired 6E-configuration of moenocinol. Moenocinol (1) was thus synthesized by 10 linear steps in 12% overall yield, and its analogs 23, 24, and 28 with different chain lengths and unsaturation degrees were also realized by the similar reaction sequences.

Full text of DOI:10.1016/j.tetlet.2006.12.119

Tetrahedron Letters 48 (2007) 1429–1433
Synthesis of moenocinol and its analogs using
BT-sulfone in Julia-Kocienski olefination
Hung-Jyun Huang and Wen-Bin Yang*
Genomics Research Center, Academia Sinica, No. 128, Academia Road Section 2, Nan-Kang, Taipei 11529, Taiwan
Received 17 November 2006; revised 13 December 2006; accepted 15 December 2006
Available online 23 December 2006
Abstract—Moenocinol (C25H42O), the acyclic terpenoid unsaturated lipid part of moenomycin antibiotics, was prepared by an
expedient method, which comprised organometallic reaction, Julia-Kocienski olefination, and enolate carbon bond formation as
the key steps. The starting materials, nerol and 3-butyn-1-ol, were elaborated to the benzothiazole sulfone 2 and aldehyde 3, and
the subsequent Julia-Kocienski olefination occurred in a stereospecific manner to give the desired 6E-configuration of moenocinol.
Moenocinol (1) was thus synthesized by 10 linear steps in 12% overall yield, and its analogs 23, 24, and 28 with different chain
lengths and unsaturation degrees were also realized by the similar reaction sequences.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The antibiotic moenomycin A (Scheme 1) belongs to one
of the most efficient inhibitors targeting transglycosylase
for the bacterial cell wall biosynthesis.1 The structure of
moenomycin consists of a pentasaccharide part linked to
the phosphoglycerate moiety that is modified with the
moenocinol (1). The moenocinol moiety is essential to
the antibacterial activity of moenomycin A; lack of moe-
nocinol or replacement of lipid chains with different
lengths or saturation degrees may change the potency
of such antibiotics.2
H2N
HO
O
CH3
CONH2
O
7
13
HO
O
O
HO
HO
HOOC
11
6
O
O
O
1
HO
P
O
O
1
moenocinol
O
O
OH
OH
NHAc
O
O
O
HO
O
HO
HO
NHAc
HO
HN
O
OH
Carbon-Carbon Bond
Formation via Enolate
Moenomycin A
O
7
6
HO
Julia-Kocienski
Olefination
Carbon-Carbon Bond Formation
via Organometallic Reaction
Scheme 1. Structure of moenocinol and its synthetic strategy.
Keywords: Moenocinol; Julia-Kocienski olefination; BT-sulfone; Molybdenum-catalyzed oxidation.
*
Corresponding author. Tel.: +886 2 27899930x339; fax: +886 2 27899931; e-mail: wbyang@gate.sinica.edu.tw
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.119

1430
H.-J. Huang, W.-B. Yang / Tetrahedron Letters 48 (2007) 1429–1433
Moenocinol 1 (C25H42O, 25:5), where 25 indicates the
carbon numbers and 5 indicates the degree of unsatura-
tion, has been synthesized using different strategies.2a,3
Herein, we demonstrate a new and straightforward syn-
thetic approach to obtain high yields of moenocinol and
its analogs. Based on the retrosynthetic analysis (Scheme
2), the strategic bonds at C6–C7, C8–C9, and C11–C12
could be formed, respectively, by using Julia-Kocienski
olefination, enolate alkylation, and organometallic reac-
tion. The Julia-Kocienski olefination would afford the
desired 6E-configuration in moenocinol.4 Benzothiazole
(BT) sulfone 2 could be derived from nerol. Aldehyde 3
could be prepared from methyl isobutyrate and iodide 4,
which was in turn built via substitution reaction of ger-
anyl bromide 5 with vinyl lithium. Nerol and geranyl
bromide are commercially available for this synthetic
application.
albeit in a lower yield. BT-sulfone 2 was stable on stand-
ing at room temperature for a prolonged period.
On the other hand, 3-butyn-1-ol was treated with NaI
and Me3SiCl in acetonitrile to give 3-iodobut-3-en-1-
ol,9,10 which was converted to the TBDPS ether 11 in
72% overall yield (Scheme 4). Metalation of 11 by n-
BuLi (1.5 equiv) at À110 ꢁC gave the corresponding
vinyllithium, which reacted with geranyl bromide in
THF at À78 ꢁC, followed by removal of the TBDPS
group with 1 M TBAF to give alcohol 12 in 65% yield.11
Alcohol 12 was activated as the corresponding iodide 4
(PPh3, imidazole, I2, Garegg-Samuelsson reaction) for
the coupling reaction with the lithium enolate of methyl
isobutyrate. The coupling product was then reduced by
DIBAL-H (2.2 equiv) to afford alcohol 13 in 59% over-
all yield. Alcohol 13 was oxidized to aldehyde 3 (cat.
TPAP, NMO in CH2Cl2 at room temperature), which
underwent Julia-Kocienski olefination with BT-sulfone
2 to give 14 exclusively in the 6E form. The product
showed a large coupling constant (15.6 Hz) between
the olefinic protons on the newly formed C6@C7 double
bond. No 6Z isomer was observed in the 1H NMR spec-
trum of the reaction mixture. After removal of the
TBDPS group, moenocinol 112 was obtained in 12%
overall yield from 3-butyn-1-ol by 10 linear steps. The
spectral properties of this synthetic sample was in agree-
ment with the published data for moenocinol.3d,f,13
The benzothiazole (BT) 2 was prepared from nerol in
59% overall yield (Scheme 3). The OH group of nerol
was protected as the tert-butyldiphenylsilyl (TBDPS)
ether, giving 6, and epoxidation with m-CPBA afforded
a racemic mixture of ( )7,5 which was cleaved by peri-
odic acid to give aldehyde 8. When the TBDPS protect-
ing group in 6 was replaced by tert-butyldimethylsilyl
(TBDMS) group, the yield of the periodic acid cleavage
reaction dropped drastically due to the undesired acid-
catalyzed deprotection of the TBDMS group. Reduction
of compound 8 by NaBH4/EtOH, at 0 ꢁC gave 99% of
the alcohol 9. The Mitsunobu reaction6 with BT(SH),
PPh3, and DIAD (THF, 25 ꢁC, 4 h) gave 10 in 97% yield.
The molybdenum-catalyzed oxidation7 of sulfide 10 gave
BT-sulfone 2 in 77% yield.8 The double bond was not
affected under such mild oxidation conditions. The 1-
phenyltetrazole-2-sulfone analog of 2 was also prepared;
BT-sulfone 2 is a common precursor for the synthesis of
unsaturated analogs of moenocinol, for example, 23
(21:4) and 24 (26:5) as shown in Scheme 5. The lithium
enolate of methyl isobutyrate was reacted with geranyl
bromide or farnesyl bromide to give 15 (n = 1, 90%);
16 (n = 2, 93%), respectively. The reduction of esters
7
6
HO
moenocinol
1
O
S
7
N
S
9
OHC
+
6
10
O
TBDPSO
Aldehyde 3
BT-sulfone 2
O
8
+
I
MeO
11
12
6
Iodide 4
Isobutyrate
HO
Nerol
Br
+
Vinyl lithium
12
Geranyl bromide 5
Scheme 2. Retrosynthetic analysis of moenocinol 1.

H.-J. Huang, W.-B. Yang / Tetrahedron Letters 48 (2007) 1429–1433
-CPBA, CHCl3
1431
m
Ph2(t-Bu)SiCl
−30 oC to 0 oC
imidazole, DMF
99%
O
HO
93%
Nerol
TBDPSO
TBDPSO
6
( )-7
NaBH4
H5IO6, THF, Et2O
0 oC, 60 min, 86%
PPh3, DIAD, BT(SH)
THF, 25 oC, 4 h, 97%
OH
CHO
EtOH, 0 oC
99%
TBDPSO
TBDPSO
8
9
O
O
(NH4)6Mo7O24-4H2O (cat.)
S
N
S
N
S
excess 35% H2O2, EtOH
77%
S
TBDPSO
TBDPSO
2
10
Scheme 3. Synthesis of the common precursor 2, a BT-sulfone for Julia-Kocienski olefination.
1. nBuLi, THF, −110 oC
1. NaI, TMSCl, CH3CN
H2O (cat.), 25 oC, 1 h
Geranyl bromide,
THF, −78 oC, 1 h
HO
OH
TBDPSO
11
I
2. TBDPSCl, imidazole
THF, 0 oC to 25 oC
72% for 2 steps
2. 1M TBAF, THF
25 oC, 3 h
65% for 2 steps
12
3-butyn-1-ol
1. LDA, methyl isobutyrate
PPh3, imidazole
I2, toluene, 97%
THF, −78 oC to 0 oC, 84%
I
HO
2. DIBAL-H, toluene, 1 h
−78 oC, 72%
13
4
O
O
TPAP (cat.), NMO
CH2Cl2, 25 oC, 88%
NaHMDS, THF
S
N
OHC
+
−78 oC, 2 h, 58%
S
OTBDPS
3
2
1M TBAF/THF
25 oC, 86%
OTBDPS
OH
14
Moenocinol 1 (C25H42O; 25:5)
Scheme 4. Stereoselective synthesis of moenocinol 1.
15 and 16 using 2.2 equiv of DIBAL-H gave alcohols 17
and 18, which were readily transformed into aldehydes
19 (82%) and 20 (80%) by NMO in the presence of a cat-
alytic amount of TPAP. Julia-Kocienski olefination of
19 and 20 with BT-sulfone 2 afforded 21 and 22 having
exclusively the 6E-configuration as shown by the large
coupling constant (15.6 Hz) in the 1H NMR spectra.
The TBDPS group was removed by 1 M TBAF to give
the moenocinol analogs 23 (C21H36O, 21:4)14 and 24
(C26H44O, 26:5)15 in 5 linear steps from geranyl
bromide and farnesyl bromide with 26% and 34% over-
all yields.
We also synthesized 28 (C22H38O, 22:4)16 bearing an
extra sp3 carbon (C9) by extension of geraniol (Scheme
6). Geraniol was oxidized to an aldehyde (SO3Æ
pyridine, DMSO), and reacted with Wittig reagent
(CH3P+Ph3BrÀ, NaHMDS) to give triene 25. The

1432
H.-J. Huang, W.-B. Yang / Tetrahedron Letters 48 (2007) 1429–1433
O
LDA, THF
O
DIBAL-H
Br
+
n
MeO
MeO
−78 oC to 0 oC
n
Et2O, toluene
−100 oC
Geranyl bromide (n=1)
Farnesyl bromide (n=2)
15 (n=1) 90%
16 (n=2) 93%
methyl isobutyrate
O
O
TPAP (cat.), NMO
CH2Cl2, 25 oC, 1 h
S
N
OHC
+
HO
n
n
S
OTBDPS
2
17 (n=1) 76%
18 (n=2) 76%
19 (n=1) 82%
20 (n=2) 80%
NaHMDS, THF
−78 oC, 2 h
1M TBAF, THF
25 oC, 4 h
n
n
OTBDPS
OH
21 (n=1) 55%
22 (n=2) 62%
23 (n=1) 84% (C21H36O; 21:4)
24 (n=2) 98% (C26H44O; 26:5)
Scheme 5. Synthesis of (21:4) and (26:5) moenocinol analogs 23 (C21H36O) and 24 (C26H44O).
1. SO -pyr., DMSO, Et N
3
3
o
9-BBN, 35% H O
CH Cl , −10 C, 97%
2
2
2
2
HO
+
-
o
2. CH P Ph Br , NaHMDS
3
3
3N NaOH, THF, 0 C, 75%
o
o
THF, 0 C to 25 C, 92%
25
Geraniol
PPh , imidazole, I
3
2
HO
I
o
toluene, 25 C, 85%
26
27
7
5 steps (24%)
6
OH
28 (C H O; 22:4)
22 38
Scheme 6. Synthesis of (22:4) moenocinol analog 28 (C22H38O) with sp3 carbon between isoprene units.
terminal double bond in 25 reacted selectively with 9-
BBN, and the subsequent oxidation with H2O2 in the
presence of 3 N NaOH gave alcohol 26. By the proce-
dures similar to that delineated in Scheme 4, alcohol
26 was activated as iodide 27 to culminate in the synthe-
sis of 28 with 14% overall yield in 9 linear steps from
geraniol. The C6@C7 double bond in 28 formed by the
Julia-Kocienski olefination also existed exclusively in
the E-configuration (J = 15.6 Hz).
with the lengthy procedures (>10 steps) and low yields
(<10%) in the previous syntheses of moenocinol,3 our
current synthetic method has the advantages of shorter
route (10 steps), higher yield (12%) and exclusive forma-
tion of the desired E-isomer. Further chemical modifica-
tions and linkage of the unsaturated lipids to
phosphoglycerate and sugars are under investigation in
order to establish the structure and activity relationship
of moenomycin antibiotics.
In conclusion, we have devised an efficient and high-
yielding method for the synthesis of moenocinol 1 and
its analogs 23, 24, and 28. A BT-sulfone 2 served as
the common precursor for Julia-Kocienski olefination
to build the desired E-configuration at the C6@C7 dou-
ble bonds of these unsaturated lipids. In comparison
Acknowledgments
We thank Academia Sinica for financial support and
Professor Jim-Min Fang (Department of Chemistry,
National Taiwan University) for helpful discussion.

H.-J. Huang, W.-B. Yang / Tetrahedron Letters 48 (2007) 1429–1433
1433
973; 1H NMR (600 MHz, CDCl3) d 0.94 (s, 6H, CH3 · 2),
1.37–1.34 (m, 2H), 1.58 (s, 3H), 1.59 (s, 3H), 1.66 (s, 3H),
1.72 (s, 3H), 1.88–1.86 (m, 2H), 2.01–1.99 (m, 2H), 2.13–
2.05 (m, 6H), 2.67 (d, J = 7.2 Hz, 2H, 12-H), 4.09 (d,
J = 7.2 Hz, 2H, exo-C@CH2), 4.66 (d, J = 4.2 Hz, 2H, 1-
H), 5.08 (t, J = 6.6 Hz, 1H, 17-H), 5.15 (t, J = 7.2 Hz, 1H,
13-H), 5.23 (dt, J = 15.6, 6.6 Hz, 1H, 6-H), 5.34 (d,
J = 15.6 Hz, 1H, 7-H), 5.42 (t, J = 7.2 Hz, 1H, 2-H); 13C
NMR (150 MHz, CDCl3) d 150.1, 140.7, 139.8, 136.4,
131.4, 125.2, 124.4, 124.3, 121.9, 108.3, 59.1, 41.4, 39.8,
35.5, 35.0, 32.2, 31.4, 31.3, 27.3, 26.7, 25.7, 23.5, 17.7, 15.9;
HRMS (ESI) m/z 359.3372 (M+H)+; calcd for C25H42OH:
359.3314.
References and notes
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Org. Chem. 1980, 45, 2685–2697; (e) Kocienski, P. J. J.
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Ho, D. K. H.; Nap, W. M. Org. Biomol. Chem. 2005, 3,
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P. J.; Morley, A. Synlett 1998, 26–28.
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¨
D.; Fehlhaber, H.-W.; Markus, A.; van Heijenoort, Y.;
van Heijenoort, J. Tetrahedron 1995, 51, 8471–8482.
14. Data for compound 23: IR (neat) cmÀ1 = 3339, 2960, 2925,
2864, 2360, 1445, 1377, 971; 1H NMR (400 MHz, CDCl3)
d 0.92 (s, 6H, CH3 · 2), 1.11 (br, 1H, OH), 1.55 (s, 3H,
CH3), 1.58 (s, 3H, CH3), 1.66 (s, 3H, CH3), 1.72 (s, 3H,
CH3), 1.91 (d, J = 7.6 Hz, 2H, 9-H), 1.97–2.14 (m, 8H),
4.08 (d, J = 7.2 Hz, 2H, 1-H), 5.05–5.12 (m, 2H, 10-H and
14-H), 5.23 (dt, J = 15.6, 6.4 Hz, 1H, 6-H), 5.38–5.44 (m,
2H, 2-H and 7-H); 13C NMR (100 MHz, CDCl3) d 141.1,
139.8, 136.2, 131.2, 124.7, 124.5, 124.4, 121.4, 59.1, 41.0,
40.0, 36.6, 32.3, 31.4, 29.4, 27.0, 26.7, 25.7, 23.5, 17.7, 16.1;
HRMS (ESI) m/z 327.2691 (M+Na)+; calcd for
C21H36ONa: 327.2664.
5. Muto, S. E.; Nishimura, Y.; Mori, K. Eur. J. Org. Chem.
1999, 2159–2165.
15. Data for compound 24: IR (neat) cmÀ1 = 3358, 2959, 2925,
2855, 2360, 1446, 1379, 972; 1H NMR (400 MHz, CDCl3)
d 0.92 (s, 6H, CH3 · 2), 1.07 (br, 1H, OH), 1.56 (s, 3H,
CH3), 1.58 (s, 6H, CH3 · 2), 1.66 (s, 3H, CH3), 1.72 (s, 3H,
CH3), 1.90–2.11 (m, 14H), 4.09 (m, 2H), 5.06–5.13 (m,
3H), 5.23 (dt, J = 15.6, 8.4 Hz, 1H, 7-H), 5.40 (d,
J = 15.6 Hz, 1H, 6-H), 5.42 (t, J = 6.0 Hz, 1H, 2-H); 13C
NMR (100 MHz, CDCl3) d 141.2, 139.9, 136.3, 134.9,
131.3, 124.7, 124.4, 124.3, 124.2, 121.3, 59.1, 41.0, 40.0,
39.8, 36.6, 32.3, 31.4, 29.4, 27.0, 26.8, 26.6, 25.7, 23.5, 17.7,
16.2, 16.0; HRMS (ESI) m/z 395.3245 (M+Na)+; calcd for
C26H44ONa: 395.3290.
6. Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski,
E. J. J. J. Am. Chem. Soc. 1988, 110, 6487–6491.
7. (a) Vaz, B.; Alvarez, R.; Bruckner, R.; Lera, A. R. Org.
Lett. 2005, 7, 545–548; (b) Jasper, C.; Wittenberg, R.;
Quitschalle, M.; Jakupovic, J.; Kirschning, A. Org. Lett.
2005, 7, 479–482; (c) Schultz, H. S.; Freyermuth, H. B.;
Buc, S. R. J. Org. Chem. 1963, 28, 1140–1142.
8. Data for compound 2: IR (neat) cmÀ1 = 2930, 2856, 1715,
1326, 1148, 701; 1H NMR (400 MHz, CDCl3) d 0.98 (s, 9H,
t-Bu), 1.64 (s, 3H, 3-CH3), 1.86–1.91 (m, 2H), 1.97–2.00 (m,
2H), 3.32 (m, 2H), 4.11 (d, J = 6.0 Hz, 2H, O–CH2), 5.45 (t,
J = 6.0 Hz, 1H, 2-H), 7.33–8.15 (m, 14H); 13C NMR
(100 MHz, CDCl3) d 165.7, 152.6, 136.7, 135.5, 135.4,
135.0, 133.7, 129.6, 128.0, 127.6, 126.8, 125.4, 122.3, 60.2,
53.9, 30.0, 26.7, 22.7, 20.2, 19.0; HRMS (ESI) m/z
(M+Na)+ 572.1712; calcd for C30H35NO3S2SiNa: 572.1725.
9. Sugiyama, H.; Yokokawa, F.; Shioiri, T. Tetrahedron
2003, 59, 6579–6593.
16. Data for compound 28: IR (neat) cmÀ1 = 3341, 2959, 2924,
2856, 2361, 1446, 1377, 972; 1H NMR (400 MHz, CDCl3)
d 0.93 (s, 6H, CH3 · 2), 1.25–1.20 (m, 2H), 1.36 (br s, 1H,
OH), 1.56 (s, 3H), 1.58 (s, 3H), 1.66 (s, 3H), 1.71 (s, 3H),
1.88–1.82 (m, 2H), 1.96–1.92 (m, 2H), 2.13–2.01 (m, 6H),
4.09 (dd, J = 7.2, 0.8 Hz, 2H), 5.09–5.06 (m, 2H), 5.23 (dt,
J = 15.6, 6.0 Hz, 1H), 5.36 (d, J = 15.6 Hz, 1H), 5.42 (t,
J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 140.9,
139.8, 134.6, 313.3, 125.1, 125.0, 124.4 (2 · C), 59.1, 43.2,
39.7, 35.7, 32.3, 31.4, 27.3 (2 · C), 26.8, 25.7, 23.4, 23.3,
17.7, 15.9; HRMS (ESI) m/z 319.2980 (M+H)+; calcd for
C22H38OH: 319.3001.
10. Barriault, L.; Deon, D. H. Org. Lett. 2001, 3, 1925–1927.
11. Uenishi, J.; Matsui, K.; Wada, A. Tetrahedron Lett. 2003,
44, 3093–3096.
12. Data for compound
1
(moenocinol): IR (neat)
cmÀ1 = 3318, 2901, 2924, 2855, 2361, 1446, 1377, 999,