Facile stereoselective synthesis of the C12-C24 fragment of macrolactin-A

Article abstract of DOI:10.1055/s-2007-966010

A simple and efficient stereoselective synthesis of the C12-C24 fragment of the natural product macrolactin-A was achieved from D-glucose as the starting material and with use of the Wittig and modified Julia olefination reactions as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-966010

PAPER
1343
Facile Stereoselective Synthesis of the C12–C24 Fragment of Macrolactin-A
S
tereosele
h
ctive
S
ynthe
i
sis of th
l
e
C12–
l
C24 F
u
ragment of Macrola
S
ctin-A . Yadav,* Manoj K. Gupta, I. Prathap
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 22 January 2007; revised 27 February 2007
ed in Scheme 1, which shows that the key fragment 4, ob-
Abstract: A simple and efficient stereoselective synthesis of the
C12–C24 fragment of the natural product macrolactin-A was
achieved from D-glucose as the starting material and with use of the
Wittig and modified Julia olefination reactions as key steps.
tained from D-glucose, provides the C13 and C15
stereocenters straightforwardly. Another fragment of the
molecule, the C19–C24 fragment 6, was prepared from
chiral epoxide 8a (Scheme 1).6 Coupling of the two frag-
ments 4 and 6 by modified Julia olefination completed the
synthesis of the C12–C24 fragment 3 of macrolactin-A
(Scheme 1).
Key words: D-glucose, Raney nickel, Wittig reaction, modified
Julia olefination
Macrolactin-A (1) (Figure 1), a 24-membered macrolide,
isolated from a taxonomically undefined deep-sea marine
bacterium,1 possesses strong cytotoxic activity in vitro on
B16-F10 murine melanoma cancer cells (IC50 = 3.5 mg/
mL) and powerful antiviral activity against HSV-I and
HSV-II and human HIV replication in T-lymphoblasts.1
Moreover, it was also found to be a neuronal-cell-protect-
ing substance against glutamate toxicity.1b,2 The absolute
and relative stereochemistry of macrolactin-A (1), estab-
lished by Smith,3a shows three sets of conjugated dienes
and four stereogenic centers in the molecule.
OH
OTBDMS
2
TMS
1
BnO
O
+
OTBDMS
O
3
OH
BnO
7
OTBDMS
1
N
S
O
O
S
O
O
+
23
13
O
CHO
HO
O
15
4
6
HO
1
Figure 1
O
OHC
O
O
Due to the unavailability of this sea-marine bacterium, no
macrolactin-A is readily available for further biological
studies. Because of its broad range of therapeutic potential
and unique structural complexity, macrolactin-A has at-
tracted the attention of many synthetic organic chemists.
Three total syntheses3 and many synthetic approaches4
+
BnO
O
5
7
8a
D-Glucose
have been reported in the literature so far. However, it is Scheme 1 Retrosynthetic analysis
still a challenge to synthesize this molecule from inexpen-
sive and readily available raw materials by short and fac-
Accordingly, the known aldehyde 5,5a was converted into
the corresponding primary alcohol 9 in 93% yield by so-
dium borohydride reduction in methanol (Scheme 2).
Then alcohol 9 was protected as benzyl ether 10 (95%
yield) by reaction with sodium hydride and benzyl bro-
mide in tetrahydrofuran (Scheme 2). Cleavage of the 1,2-
O-isopropylidene group of 10 by heating at 50 °C in 30%
aqueous acetic acid afforded lactol 11 in 92% yield
(Scheme 2).
ile routes. We describe here, as a part of our research
program aimed at developing enantioselective syntheses
of bioactive lactones,5 the synthesis of the C12–C24 frag-
ment 3 of macrolactin-A (Scheme 1), the lower fragment
in Bonini’s approach.4m Our synthetic strategy is illustrat-
SYNTHESIS 2007, No. 9, pp 1343–1348
x
x
.
x
x
.2
0
0
7
Advanced online publication: 05.04.2007
DOI: 10.1055/s-2007-966010; Art ID: Z02007SS
© Georg Thieme Verlag Stuttgart · New York

1344
J. S. Yadav et al.
PAPER
O
O
O
5
O
OHC
a
b
c
O
HO
O
BnO
D-Glucose
O
O
O
10
9
OH OH
O
O
e
OEt
BnO
BnO
d
OH
+
BnO
O
O
O
O
OH
12b (7%)
12a (E = 83%)
11
O
O
O
f
g
h
12a
BnO
OEt
OH
BnO
O
13
14
BnO
O
OTBDMS
O
O
i
H
BnO
O
O
4
3 : (E:Z = 9:1)
Scheme 2 Reagents and conditions: (a) Lit.5a; (b) NaBH4, MeOH, 0 °C to r.t., 2 h, 93%; (c) NaH, BnBr, THF, 0 °C to r.t., 4 h, 95%; (d) 30%
AcOH, 50 °C, 2 h, 92%; (e) Ph3PCHCO2Et (3 equiv), DMF, 60 °C, 6 h, 83% (E-12a only), 7% (12b); (f) Me2C(OMe)2, CSA, r.t., 12 h, 90%;
(g) LAH/AlCl3 (3:1), Et2O, –10 °C, 1 h, 92%; (h) DMP, CH2Cl2, 0 °C, 2 h; (i) 6, NaHMDS, THF, –78 °C, 30 min, 78%.
The crucial problem of elaborating tetrahydrofuran-2,3- desired product 12a was obtained in 83% yield
diol 11 by two-carbon homologation was achieved by use (Scheme 2). It was subsequently treated with 2,2-
of a Wittig reaction with [(ethoxycarbonyl)methyl- dimethoxypropane in the presence of a catalytic amount
ene]triphenylphosphorane (Scheme 2). It is well docu- of 10-camphorsulfonic acid to afford the corresponding
mented in the literature that some related Z-esters may acetonide 13 in 90% yield (Scheme 2).
undergo sequential lactonization/Michael ring closure,7
and therefore E selectivity of this olefination was of prime
Finally, the resulting acetonide-protected ester 13 was re-
duced in the presence of lithium aluminum hydride/alumi-
importance. In fact, the preliminary experiment was done
num trichloride in diethyl ether at –10 °C, and afforded
with lactol 11, in which the expected E-derivative 12a was
the primary alcohol 14 in 92% yield (Scheme 2). Alcohol
14 was further oxidized by Dess–Martin periodinane in
dichloromethane at 0 °C, furnishing the desired aldehyde
4 in 90% yield (Scheme 2). The key fragment 4 was treat-
accompanied by a variable amount of the bicyclic lactone
12b, while the Z-stereoisomer could not be detected in the
reaction mixture (Scheme 2). Good selectivity (8:1) was
achieved when the reaction was carried out in N,N-di-
ed with sulfone 6 (see Scheme 3 for its preparation) under
methylformamide at 60 °C. Under these conditions, the
modified Julia olefination conditions8 with sodium hex-
OTBDMS
OH
BnO
a
c
b
BnO
BnO
16
15
7
OTBDMS
OTBDMS
N
S
d (ii)
d (i)
S
HO
17
17a
OTBDMS
O
S
N
S
O
6
Scheme 3 Reagents and conditions: (a) n-BuLi, THF, BF3·OEt2, 8a, –78 °C, 2 h, 78%; (b) TBDMSCl, imidazole, DMF, 0 °C to r.t., 12 h,
92%; (c) H2, Pd/C, EtOAc, r.t., 12 h, 90%; (d) i. 2-mercaptobenzothiazole, Ph3P, DEAD, THF, 0 °C to r.t., 1 h, 95%; ii. MCPBA, CH2Cl2, r.t.,
3 h, 88%.
Synthesis 2007, No. 9, 1343–1348 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of the C12–C24 Fragment of Macrolactin-A
1345
13C NMR (75 MHz, CDCl3): d = 25.7, 26.8, 33.0, 64.8, 80.5, 81.6,
amethyldisilazide in tetrahydrofuran at –78 °C for 30 min-
utes; this afforded the C12–C24 fragment 3 of
106.3, 112.2.
macrolactin-A (E/Z, 9:1; 78% yield) (Scheme 2), whose ESI-MS: m/z = 197.1 [M+ + Na], 187.1, 175, 156.7, 149.1, 134.1,
116.2, 99.2, 69.2, 58.4.
spectral and analytical data agree with the reported struc-
ture.4m
HRMS (ESI): m/z calcd for C8H14O4Na: 197.0788; found:
197.0789.
The preparation of sulfone 6 is shown in Scheme 3. Ben-
zyl-protected propargyl alcohol 7 was metalated with n-
(3aR,5R,6aR)-5-[(Benzyloxy)methyl]-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxole (10)
butyllithium at –78 °C in tetrahydrofuran;9 addition of bo-
ron trifluoride–diethyl ether complex and (R)-propylene
oxide 8a followed,10 leading to homopropargyl alcohol 15
in 78% yield. Secondary alcohol 15 was then protected by
reaction with tert-butyldimethylsilyl chloride and imida-
zole in the presence of catalytic amount of 4-(N,N-di-
methylamino)pyridine in N,N-dimethylformamide; this
gave silyl ether 16, which was treated with palladium on
carbon (10%) under a hydrogen atmosphere in ethyl ace-
tate. This allowed simultaneous reduction of the triple
bond and deprotection of the benzyl ether to give the de-
sired saturated primary alcohol 17 in 90% yield
(Scheme 3). Finally, the required sulfone 6 was prepared
in 88% yield by treatment of primary alcohol 17 with 2-
mercaptobenzothiazole under Mitsunobu conditions,11
followed by oxidation with m-chloroperoxybenzoic acid
in dichloromethane (Scheme 3).
To a well-stirred suspension of freshly activated NaH (60% w/v dis-
persion in mineral oil; 0.30 g, 12.64 mmol) in anhyd THF (15 mL),
a soln of 9 (1.1 g, 6.32 mmol) in anhyd THF (10 mL) was added
dropwise at 0 °C. After 30 min, BnBr (1.08 g, 6.32 mmol) was add-
ed and the mixture was warmed to r.t. and stirred for 3.5 h. The re-
action was quenched with crushed ice and the product was extracted
with Et2O (3 × 15 mL). The combined organic layer was washed
with H2O (15 mL), and brine (2 × 15 mL) and dried (Na2SO4). After
filtering of the mixture and removal of the volatiles under reduced
pressure, the crude product was purified by column chromatogra-
phy (EtOAc–hexane, 5:95).
Pale yellow liquid; yield: 1.58 g (95%); [a]D25 –8.9 (c 1.0, CHCl3).
IR (KBr): 3029, 2984, 2938, 2859, 1632, 1495, 1453, 1376, 1256,
1209, 1164, 1097, 1027, 940, 880, 849, 738, 698, 518 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.23 (m, 5 H), 5.76 (d, J =
3.7 Hz, 1 H), 4.69 (dt, J = 1.5, 3.7, 5.2 Hz, 1 H), 4.60 (d, J = 7.5 Hz,
2 H), 4.37–4.29 (m, 1 H), 3.67 (dd, J = 6.7, 9.8 Hz, 1 H), 3.56 (dd,
J = 6.7, 9.8 Hz, 1 H), 2.21–2.06 (m, 2 H), 1.43 (s, 3 H), 1.29 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 25.9, 26.9, 34.0, 72.5, 73.2, 79.5,
80.5, 106.6, 112.1, 127.5, 127.6, 128.2, 138.1.
ESI-MS: m/z = 287.1 [M+ + Na], 269.9, 224.1, 207, 189.1, 171,
116.2.
In conclusion, we have described here a concise synthesis
of the C12–24 fragment 3 of macrolactin-A from the
known aldehyde 5. The procedure involved Wittig and
modified Julia olefination reactions as key steps.
HRMS (ESI): m/z calcd for C15H20O4Na: 287.1250; found:
287.1259.
All solvents and reagents were purified by standard techniques.
Column chromatography was performed on silica gel (60–120
mesh). All solvents were dried and distilled prior to use. IR spectra
were recorded on a Perkin-Elmer infrared spectrophotometer as
KBr wafers, with the samples as thin films, neat or in CHCl3. 1H and
13C NMR spectra were recorded on a Varian Gemini 200, Bruker
Avance 300, or Varian Unity 400 instrument; TMS was used as in-
ternal standard. Mass spectra were obtained on an Agilent Technol-
ogies LC/MSD Trap SL spectrometer. The optical rotations were
recorded on a JASCO DIP-360 digital polarimeter at 25 °C.
(3R,5R)-5-[(Benzyloxy)methyl]tetrahydrofuran-2,3-diol (11)
A soln of 10 (1.2 g, 4.54 mmol) in 30% AcOH (2 mL) was heated
at 50 °C for 2 h. The mixture was cooled to r.t., diluted with EtOAc
(10 mL), and quenched with sat. NaHCO3 (15 mL); the layers were
separated and the aqueous layer was extracted with EtOAc (4 × 10
mL). The combined organic layer was washed with brine (2 × 10
mL), dried (Na2SO4), and concentrated; this gave a residue, which
was purified by column chromatography (EtOAc–hexane, 1:1).
Colorless liquid; yield: 0.94 g (92%).
[(3aR,5R,6aR)-2,2-Dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
yl]methanol (9)
Ethyl (E,4R,6R)-7-(Benzyloxy)-4,6-dihydroxyhept-2-enoate
(12a)
Aldehyde 5 (1.5 g, 8.72 mmol) was dissolved in anhyd MeOH (25
mL) and the resulting mixture was cooled to 0 °C. NaBH4 (0.36 g,
10.46 mmol) was added in portions and the mixture was stirred at
r.t. for 2 h. The reaction progress was monitored by TLC. After
completion of the reaction, the mixture was diluted with H2O, and
excess MeOH was removed in vacuo. The mixture was extracted
with EtOAc (3 × 15 mL). The combined organic layer was washed
with brine (2 × 15 mL) and dried (Na2SO4). The solvent was re-
moved under reduced pressure and the crude product was purified
by column chromatography (EtOAc–hexane, 3:7).
Compound 11 (0.8 g, 3.57 mmol) was added slowly to a suspension
of Ph3P=CHCO2Et (3.72 g, 10.71 mmol) in DMF (15 mL). The re-
sulting mixture was heated at 60 °C for 6 h. After completion of the
reaction as indicated by TLC, the mixture was cooled to r.t., diluted
with Et2O (15 mL) and H2O (15 mL), and stirred for 5 min. The lay-
ers were separated and the aqueous layer was extracted with Et2O
(3 × 15 mL). The combined organic layer was dried (Na2SO4) and
concentrated. The residue was purified by column chromatography
(EtOAc–hexane, 2:8); this gave 12a as a colorless liquid.
Colorless liquid; yield: 1.70 g (93%); [a]D25 –32.6 (c 1.0, CHCl3).
Yield: 0.87 g (83%); [a]D25 +12.9 (c 1.0, CHCl3).
IR (KBr): 3431, 2985, 2941, 1635, 1441, 1379, 1213, 1162, 1026,
879, 849, 520 cm–1.
IR (KBr): 3414, 2923, 2853, 1779, 1714, 1656, 1458, 1368, 1303,
1274, 1175, 1117, 984, 725, 698, 542 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.23 (m, 5 H), 6.91 (dd, J =
4.1, 15.6 Hz, 1 H), 6.08 (dd, J = 1.8, 15.6 Hz, 1 H), 4.59–4.52 (m, 1
H), 4.52 (s, 2 H), 4.17 (q, J = 7.1 Hz, 2 H), 4.11–4.02 (m, 1 H), 3.44
(dd, J = 3.5, 9.2 Hz, 1 H), 3.52 (dd, J = 7.5, 9.2 Hz, 1 H), 3.22 (br s,
1H NMR (300 MHz, CDCl3): d = 5.76 (d, J = 3.7 Hz, 1 H), 4.70
(ddd, J = 1.5, 5.2, 6.7 Hz, 1 H), 4.30–4.23 (m, 1 H), 3.75 (dd, J =
7.5, 11.3 Hz, 1 H), 3.53 (dd, J = 3.7, 11.3 Hz, 1 H), 2.34 (br s, 1 H,
OH), 2.21–2.11 (m, 1 H), 1.98 (dd, J = 2.2, 14.3 Hz, 1 H), 1.52 (s,
3 H), 1.29 (s, 3 H).
Synthesis 2007, No. 9, 1343–1348 © Thieme Stuttgart · New York

1346
J. S. Yadav et al.
PAPER
1 H, OH), 2.78 (br s, 1 H, OH), 1.84–1.75 (m, 1 H), 1.62–1.54 (m,
1 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 37.9, 60.3, 67.9, 68.5, 84.1,
120.4, 127.7, 128.3, 128.4, 137.6, 149.8, 166.5.
ESI-MS: m/z = 317.1 [M+ + Na], 293, 279, 271.1, 249, 231.2, 217,
185.1, 172.1, 156.2, 116.1.
ferred into an Erlenmeyer flask containing sat. aq NaHCO3 (20 mL).
The separated organic layer was washed with brine (2 × 5 mL) and
H2O (5 mL), dried (Na2SO4), filtered, and the solvent was removed
in vacuo. Crude 4 was utilized in the next step without further puri-
fication.
Yellow oil; yield: 38 mg (95%).
HRMS (ESI): m/z calcd for C16H22O5Na: 317.1354; found:
317.1364.
(R)-6-(Benzyloxy)hex-4-yn-2-ol (15)
A 1.6 M soln of n-BuLi in hexane(7.7 mL, 12.32 mmol) was added
slowly to a suspension of 7 (1.5 g, 10.27 mmol) in anhyd THF (20
mL) at –78 °C. After the mixture had stirred for 1 h at the same tem-
perature, BF3·OEt2 (1.94 g, 12.3 mmol) followed by 2-methylox-
irane (8a; 1.19 g, 20.5 mmol) were added. The resulting mixture
was stirred at the same temperature for 1 h. After completion of the
reaction (by TLC) (ca. 1 h), the mixture was quenched with sat. aq
NH4Cl (3 mL) followed by sat. aq NaHCO3 (3 mL). After a few
minutes, the layers were separated and the aqueous layer was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layer was
dried (Na2SO4) and concentrated; this afforded a residue, which was
purified by column chromatography (EtOAc–hexane, 2:8).
Ethyl (E)-3-{(4R,6R)-6-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-
dioxan-4-yl}acrylate (13)
Me2C(OMe)2 (10 mL) and CSA (cat.) were added to 12a (0.50 g,
1.70 mmol) at r.t. After 12 h the solvent was removed in vacuo, and
the crude residue was diluted with Et2O (15 mL). Sat. aq NaHCO3
(10 mL) was added, and the organic layer was washed with brine
(2 × 5 mL) and H2O (5 mL) and then dried (Na2SO4). The filtrate
was concentrated under reduced pressure and the residue was puri-
fied by chromatography (silica gel, hexane–EtOAc, 9:1).
Pale yellow oil; yield: 0.51 g (90%); [a]D25 +24.8 (c 1.15, CHCl3).
Colorless liquid; yield: 1.63 g (78%); [a]D25 –7.4 (c 1.0, CHCl3).
IR (KBr): 3063, 2986, 2931, 2860, 1721, 1661, 1498, 1454, 1374,
1303, 1270, 1224, 1167, 1119, 1038, 982, 908, 849, 740, 700, 610,
513 cm–1.
IR (KBr): 3116, 3031, 2970, 2926, 2857, 1633, 1494, 1452, 1353,
1262, 1209, 1068, 1025, 938, 830, 714, 698, 605 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.32–7.25 (m, 5 H), 6.87 (dd, J =
3.9, 15.6 Hz, 1 H), 5.96 (dd, J = 1.5, 15.6 Hz, 1 H), 4.54 (s, 2 H),
4.50–4.41 (m, 1 H), 4.17 (q, J = 7.0 Hz, 2 H), 4.09–3.97 (m, 1 H),
3.49–3.36 (m, 2 H), 1.91–1.66 (m, 2 H), 1.39 (s, 3 H), 1.36 (s, 3 H),
1.28 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 24.5, 25.3, 33.3, 60.2, 65.6,
65.8, 72.3, 73.2, 100.5, 120.0, 127.5, 128.2, 138.0, 147.0, 166.2.
1H NMR (200 MHz, CDCl3): d = 7.32–7.22 (m, 5 H), 4.55 (s, 2 H),
4.12 (t, J = 2.3 Hz, 2 H), 3.89 (q, J = 6.2 Hz, 1 H), 3.41–3.24 (m, 2
H), 2.02 (s, 1 H, OH), 1.25 (d, J = 6.2 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 22.2, 28.9, 57.3, 65.9, 71.1, 77.8,
85.5, 127.5, 127.8, 128.1, 137.1.
ESI-MS: m/z = 227.1 [M+ + Na], 187.1, 169.1, 153, 143, 128.1,
117.1, 103, 91.2.
ESI-MS: m/z = 357.1 [M+ + Na].
HRMS (ESI): m/z calcd for C13H16O2Na: 227.1057; found:
227.1047.
HRMS (ESI): m/z calcd for C19H26O5Na: 357.1691; found:
357.1677.
{[(R)-5-(Benzyloxy)-1-methylpent-3-yn-1-yl]oxy}(tert-bu-
tyl)dimethylsilane (16)
(E)-3-{(4R,6R)-6-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxan-
4-yl}prop-2-en-1-ol (14)
TBDMSCl (1.47 g, 9.80 mmol) was added dropwise to a stirred soln
of 15 (1.0 g, 4.90 mmol) in anhyd DMF (20 mL) and imidazole
(1.33 g, 19.6 mmol) at 0 °C. The mixture was stirred at r.t. for 12 h,
and then quenched with H2O (20 mL) and diluted with Et2O (20
mL). After a few minutes, the layers were separated and the aqueous
layer was extracted with Et2O (3 × 15 mL). The combined organic
layer was washed with brine (2 × 20 mL) and dried (Na2SO4). The
solvent was concentrated under reduced pressure and the residue
was purified by column chromatography (EtOAc–hexane, 1:9).
A suspension of LAH (34 mg, 0.90 mmol) and AlCl3 (40 mg, 0.30
mmol) in anhyd Et2O (3 mL) was stirred for 30 min at –10 °C; then
13 (0.2 g, 0.59 mmol) was added slowly at the same temperature.
After 30 min, the mixture was warmed to r.t. and 20% aq NaOH (1
mL) was added slowly to quench the mixture. After a few minutes,
the layers were separated; the aqueous layer was extracted with
Et2O (3 × 15 mL) and the combined organic layers were dried
(Na2SO4) and concentrated to afford a residue, which was purified
by column chromatography (EtOAc–hexane, 3:7).
Colorless liquid, yield: 1.43 g (92%); [a]D25 +0.59 (c 2.0 CHCl3).
Colorless liquid; yield: 0.16 g (92%); [a]D25 +40.8 (c 1.6, CHCl3).
IR (KBr): 3031, 2930, 2893, 2856, 1638, 1461, 1357, 1253, 1128,
1085, 997, 939, 892, 833, 775, 737, 697, 664, 605 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.21 (m, 5 H), 4.54 (s, 2 H),
4.10 (t, J = 2.2 Hz, 2 H), 3.98–3.87 (m, 1 H), 2.42–2.21 (m, 2 H),
1.22 (d, J = 6.0 Hz, 3 H), 0.89–0.84 (m, 9 H), 0.07 (s, 3 H), 0.06 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = –4.78, –4.70, 18.0, 23.3, 25.7, 25.9,
29.7, 57.6, 67.6, 71.3, 84.4, 127.6, 127.9, 128.3, 137.6.
ESI-MS: m/z = 341.2 [M+ + Na], 318.9, 289.1, 275.2, 245.1, 187.1,
169.1, 159.1, 143.1, 129.1, 117.1, 93.1, 75.2.
IR (KBr): 3410, 3030, 2924, 2856, 1627, 1451, 1375, 1221, 1093,
1010, 973, 771, 743, 698, 609 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.22 (m, 5 H), 5.79 (dt, J =
3.7, 9.0, 14.3 Hz, 1 H), 5.70 (dd, J = 5.1, 14.3 Hz, 1 H), 4.53 (d, J =
5.2 Hz, 2 H), 4.35–4.28 (m, 1 H), 4.11 (d, J = 5.2 Hz, 2 H), 4.05–
3.99 (m, 1 H), 3.46 (dd, J = 6.0, 10.5 Hz, 1 H), 3.40 (dd, J = 4.5, 9.8
Hz, 1 H), 1.77–1.66 (m, 2 H), 1.37 (s, 3 H), 1.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 24.8, 25.4, 34.0, 62.8, 66.0, 66.8,
72.5, 73.3, 100.4, 127.6, 128.2, 130.4, 131.4, 138.1.
ESI-MS: m/z = 315.1 [M+ + Na], 275, 259.9, 242.2, 235, 226, 217,
204, 188.1.
HRMS (ESI): m/z calcd for C19H30O2NaSi: 341.1914; found:
341.1912.
(E)-3-{(4R,6R)-6-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxan-
4-yl}acrylaldehyde (4)
A soln of 14 (40 mg, 0.14 mmol) in anhyd CH2Cl2 (1.5 mL) was
added by cannula to a soln of DMP (87 mg, 0.21 mmol) in anhyd
CH2Cl2 (1.5 mL) at r.t. After 2 h, the pale pink mixture was trans-
(R)-5-(tert-Butyldimethylsiloxy)hexan-1-ol (17)
A soln of 16 (1.20 g, 3.77 mmol) in EtOAc (15 mL) was mixed with
Pd/C (10 mol%) and stirred for 12 h under H2 atmosphere (55 psi).
The catalyst was removed by filtration and the solvent was evapo-
Synthesis 2007, No. 9, 1343–1348 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of the C12–C24 Fragment of Macrolactin-A
1347
rated; this gave a residue, which was purified by column chroma-
tography (EtOAc–hexane, 3:7).
IR (KBr): 2928, 2856, 1661, 1458, 1374, 1252, 1223, 1171, 1131,
1097, 1025, 901, 834, 773, 738, 698 cm–1.
Colorless liquid, yield: 0.78 g (90%); [a]D25 –13.2 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.38–7.24 (m, 5 H), 6.11 (dd, J =
10.1, 15.1 Hz, 1 H), 5.99 (dd, J = 10.5, 14.7 Hz, 1 H), 5.69–5.48 (m,
2 H), 4.59, 4.49 (d, J = 12.4 Hz, 2 H), 4.32 (tdd, J = ca. 7.0 Hz each,
1 H), 4.12–3.99 (m, 1 H), 3.76–3.70 (m, 1 H), 3.49–3.33 (m, 2 H),
2.17–2.02 (m, 2 H), 1.71 (t, J = 7.5 Hz, 2 H), 1.47–1.36 (m, 10 H),
1.10 (d, J = 5.2 Hz, 3 H), 0.87 (s, 9 H), 0.02 (s, 6 H).
IR (KBr): 3351, 2932, 2859, 1466, 1372, 1253, 1137, 1104, 1058,
1007, 834, 774, 710, 661 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.83–3.74 (m, 1 H), 3.61 (t, J =
6.0 Hz, 2 H), 1.58–1.46 (m, 2 H), 1.44–1.33 (m, 4 H), 1.22 (d, J =
6.0 Hz, 3 H), 0.88–0.84 (m, 9 H), 0.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = –4.74, –4.43, 18.0, 21.8, 23.7, 25.8,
32.7, 39.3, 62.7, 68.5.
ESI-MS: m/z = 511.3 [M+ + Na], 461.8, 431.1, 391.1, 363.3, 338.1,
299.2, 220.9, 191.1, 149.1, 85.2, 59.3.
HRMS (ESI): m/z calcd for C29H48O4NaSi: 511.3224; found:
511.3219.
ESI-MS: m/z = 255.2 [M+ + Na], 245.1, 231, 217, 192.2, 173.1,
149.1, 143, 121.1, 101.1, 91.2, 84.3.
HRMS (ESI): m/z calcd for C12H28O2NaSi: 255.1750; found:
255.1756.
Acknowledgements
MKG and IP thank CSIR, New Delhi for research fellowships.
(R)-2-{[5-(tert-Butyldimethylsiloxy)hexyl]sulfonyl}benzothiaz-
ole (6)
DEAD (0.75 g, 4.31 mmol) was added dropwise to a stirred soln of
17 (0.50 g, 2.15 mmol), 2-mercaptobenzothiazole (0.72 g, 4.31
mmol), and Ph3P (1.13 g, 4.31 mmol) in anhyd THF (50 mL) at 0
°C. The mixture was stirred at r.t. for 1 h, and then diluted with H2O
(50 mL) and extracted with EtOAc (3 × 40 mL). The combined or-
ganic layer was washed with brine (2 × 40 mL) and dried (Na2SO4).
The solvent was concentrated under reduced pressure and the resi-
due was purified by column chromatography (EtOAc–hexane,
5:95); this gave pure sulfide 17a; yield: 0.75 g (95%).
References
(1) (a) Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem.
Soc. 1989, 111, 7519. (b) Rychnovsky, S. D.; Skalitzky, D.
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(2) (a) Kim, H.-H.; Kim, W.-G.; Ryoo, I.-J.; Kim, C.-J.; Suk, J.-
E.; Han, K.-H.; Hwang, S.-Y.; Yoo, I.-D. J. Microbiol.
Biotechnol. 1997, 7, 429. (b) Jaruchoktaweechai, C.;
Suwanborirus, K.; Tanasupawatt, S.; Kittakoop, P.;
Menasveta, P. J. Nat. Prod. 2000, 63, 984. (c) Nagao, T.;
Adachi, K.; Sakai, M.; Nishijima, M.; Sano, H. J. Antibiot.
2001, 54, 333.
(3) (a) Smith, A. B. III; Ott, G. R. J. Am. Chem. Soc. 1996, 118,
13095. (b) Kim, Y.; Singer, R. A.; Carreira, E. M. Angew.
Chem. Int. Ed. 1998, 37, 1261. (c) Marino, J. P.; McClure,
M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am.
Chem. Soc. 2002, 124, 1664.
MCPBA (0.64 g, 4.07 mmol) in anhyd CH2Cl2 (10 mL) was added
to 17a (0.75 g, 2.04 mmol) at 0 °C. The mixture was stirred for 3 h
and then quenched with sat. NH4Cl (3 mL) and extracted with
CH2Cl2 (3 × 40 mL). The combined organic layer was washed with
brine (2 × 40 mL) and dried (Na2SO4). The solvent was concentrat-
ed under reduced pressure and the residue was purified by column
chromatography (EtOAc–hexane, 1:9); this gave pure 6.
Colorless liquid; yield: 0.74 g (88%); [a]D25 –9.2 (c 1.0, CHCl3).
(4) For partial syntheses, see: (a) Benvegnu, T.; Schio, L.; Le
Floch, Y.; Gree, R. Synlett 1994, 505. (b) Donaldson, W.
A.; Bell, P. T.; Wang, Z.; Bennett, D. W. Tetrahedron Lett.
1994, 35, 5829. (c) Boyce, R. J.; Pattenden, G. Tetrahedron
Lett. 1996, 37, 3501. (d) Benvegnu, T.; Toupet, L.; Gree, R.
Tetrahedron 1996, 52, 11811. (e) Prahlad, V.; Donaldson,
W. A. Tetrahedron Lett. 1996, 37, 9169. (f) Gonzalez, A.;
Aiguade, J.; Urp, F.; Villarasa, J. Tetrahedron Lett. 1996, 37,
8949. (g) Tanimori, S.; Morita, Y.; Tsubota, M.; Nakayama,
M. Synth. Commun. 1996, 26, 559. (h) Bärmann, H.;
Prahlad, V.; Tao, C.; Yun, Y. K.; Wang, Z.; Donaldson, W.
A. Tetrahedron 2000, 56, 2283. (i) Li, S.; Xu, R.; Bai, D.
Tetrahedron Lett. 2000, 41, 3463. (j) Hoffmann, H. M. R.;
Vakalopoulos, A. Org. Lett. 2001, 3, 177. (k) Li, S.;
Donaldson, W. A. Synthesis 2003, 2064. (l) Fukuda, A.;
Kobayashi, Y.; Kimachi, T.; Takemoto, Y. Tetrahedron
2003, 59, 9305. (m) Bonini, C.; Chiummiento, L.; Pullez,
M.; Solladié, G.; Colobert, F. J. Org. Chem. 2004, 69, 5015.
(n) Li, S.; Xiao, X.; Yan, X.; Liu, X.; Xu, R.; Bai, D.
Tetrahedron 2005, 61, 11291. For a total synthesis of an
analogue of macrolactin-A, see: (o) Kobayashi, Y.; Fukuda,
A.; Kimachi, T.; Ju-ichi, M.; Takemoto, Y. Tetrahedron
Lett. 2004, 45, 677. (p) Kobayashi, Y.; Fukuda, A.;
Kimachi, T.; Ju-ichi, M.; Takemoto, Y. Tetrahedron 2005,
61, 2607.
IR (KBr): 2928, 2859, 1470, 1325, 1252, 1145, 1086, 1024, 849,
764, 728, 628, 594, 521 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.39 (d, J = 6.0 Hz, 1 H), 8.18 (d,
J = 7.5 Hz, 1 H), 7.84–7.77 (m, 2 H), 3.93 (q, J = 6.0 Hz, 1 H), 3.67
(dd, J = 7.5, 15.8 Hz, 2 H), 2.12–2.02 (m, 2 H), 1.78–1.58 (m, 4 H),
1.27 (d, J = 6.0 Hz, 3 H), 1.04 (s, 9 H), 0.17 (d, J = 7.5 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = –4.86, –4.45, 17.9, 22.3, 22.6, 24.3,
25.7, 38.7, 54.6, 67.8, 122.2, 125.3, 127.5, 127.9, 139.7, 152.6,
165.8.
ESI-MS: m/z = 436.1 [M+ + Na], 413.9 [M+H]+, 337.9, 282.1, 228,
181.1, 153.1.
HRMS (ESI): m/z calcd for C19H32NO3SiS2: 414.1589; found:
414.1592.
(+)-({(1R,5E,7E)-8-[(4R,6R)-6-(Benzyloxymethyl)-2,2-dimeth-
yl-1,3-dioxan-4-yl]-1-methylocta-5,7-dienyl}oxy)(tert-bu-
tyl)dimethylsilane (3)
A suspension of sulfone 6 (0.11 g, 0.26 mmol) and aldehyde 4 (38
mg, 0.13 mmol) in anhyd THF (5 mL) at –78 °C was treated with
2.0 M NaHMDS in THF (0.4 mL, 0.20 mmol), and the mixture was
stirred at r.t. for 30 min. After completion of the reaction, the mix-
ture was quenched with sat. aq NH4Cl (5 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layer was washed with
brine (2 × 10 mL) and dried (Na2SO4). Volatiles were removed un-
der reduced pressure and the crude product was purified by column
chromatography (EtOAc–hexane, 1:9).
(5) (a) Yadav, J. S.; Prathap, I.; Tadi, B. P. Tetrahedron Lett.
2006, 47, 3773. (b) Yadav, J. S.; Rao, K. V.; Reddy, M. S.;
Prasad, A. R. Tetrahedron Lett. 2006, 47, 4393. (c) Yadav,
J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005,
46, 2133.
Pale yellow liquid; yield: 49 mg (78%); [a]D25 +22.8 (c 0.4, CHCl3)
[Lit.4m [a]D25 +25 (c 0.3, CHCl3)].
Synthesis 2007, No. 9, 1343–1348 © Thieme Stuttgart · New York

1348
J. S. Yadav et al.
PAPER
(6) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 1307.
(7) Prakash, K. R.; Rao, S. P. Tetrahedron 1993, 49, 1505.
(8) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563; and references cited therein. (b) Harris, J. M.;
O’Doherty, G. A. Tetrahedron 2001, 57, 5161.
OH
O
O
(i)
+
HO
8
8a
8b
Scheme 4 Reagents and conditions: (i) [Co(OAc){(R,R)-sa-
len}] (0.003 equiv), H2O (0.55 equiv), 0 °C, 12 h, 47% (8a),
48% (8b).
(c) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley,
A. Synlett 1998, 26.
(11) Mitsunobu, O. Synthesis 1981, 1; and references cited
(9) Yamagushi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(10) Propylene oxide 8a was obtained by a literature procedure6
and is easily isolated from the more polar diol 8b by
distillation (Scheme 4). Compound 8a: [a]D25 +11.5 (neat)
[Lit.6 for S-isomer of 8a: [a]D25 –11.7 (neat)].
therein.
Synthesis 2007, No. 9, 1343–1348 © Thieme Stuttgart · New York