Synthesis of a sec-precursor and analogues of macrolactin A

Article abstract of DOI:10.1246/cl.2005.906

(Chemical Equation Presented) A highly convergent and efficient route to sec-precursor 26 of macrolactin A has been developed. In the synthesis, Wittig and Horner-Emmons reactions were utilized to construct the conjugated dienes and control the right conf

Full text of DOI:10.1246/cl.2005.906

906
Chemistry Letters Vol.34, No.7 (2005)
Synthesis of a sec-Precursor and Analogues of Macrolactin A
Xiangshu Xiao, Shukun Li, Xuebin Yan, Xuejun Liu, Rui Xu, and Donglu BaiÃ
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai 201203, P. R. China
(Received April 14, 2005; CL-050511)
A highly convergent and efficient route to sec-precursor 26
nate, followed by an ꢀ-alkylation of sulfone stabilized anion
from sulfone 6 with allyl bromide 21.
of macrolactin A has been developed. In the synthesis, Wittig
and Horner–Emmons reactions were utilized to construct the
conjugated dienes and control the right configurations of E,Z-
and E,E-dienes. The segment 2 and 3 were prepared from
the known compound 4 and 15 respectively. The coupling of
segments 2 and 3 proceeded in the presence of NaHMDS. The
analogues 7 and 32 were synthesized by the same strategy.
The synthesis of C1–C10 segment 2 (Scheme 2) started with
the known compound 4.4 Protection of the secondary alcohol in
4 as TBS ether furnished ester 8, which was then reduced with
DIBAL-H to allyl alcohol 9 in 91% yield in two steps. The
Swern oxidation of 9 gave aldehyde 10 which was converted into
the requisite dienoate 12 via the Horner–Emmons reaction with
phosphonate 116 as a mixture of isomers (Z,E:E,E = 5:1) in
72% overall yield in two steps. Selective hydrolysis of trityl
group in 12 with formic acid in ether7 followed by the Swern
oxidation and subsequent the Wittig reaction with formylmeth-
ylenetriphenylphosphorane furnished 2 in 60% overall yield in
three steps.
The preparation of C11–C24 phosphonium salt 3 (Scheme 3)
was accomplished by the Horner–Emmons reaction as well.
Conversion of triol 158 to monoprotected silyl compound 16 fol-
lowed by protection of the 1,3-anti diol furnished the acetonide
17 in 97% yield. Reductive removal of benzyl group in 17 by
Raney nickel followed by oxidation of the resulting alcohol 18
under Swern conditions provided the corresponding aldehyde
5 which was used directly to the next step without purification.
The Horner–Emmons reaction of 5 with triethylphosphonocrot-
onate using the Takacs modified procedure9 led to the conjugat-
ed dienoate 19 as a mixture of E,E- and Z,E-diene isomers in a
ratio of 5:1 in 62% yield in two steps. Selective reduction of the
ester group in 19 by DIBAL-H followed by bromination of the
resulting alcohol 20 at À78 ꢀC with Ph3P/NBS10 yielded allyl
bromide 21, which was unstable and decomposed on a silica gel
column. On the basis of our previous work,4 sulfone 6 and allyl
bromide 21 could be efficiently coupled by treatment with n-
BuLi, giving 22 in 93% yield as a mixture of two diastereomers.
The phenylsulfonyl group was then removed by 6% Na–Hg in
methanol, giving 23 as a single isomer in 66% yield. Fluoride
ion catalyzed hydrolysis of TBDPS group in 23 with TBAF,
and iodination of the corresponding alcohol 24 followed by
phosphonium salt formation of 25 delivered the requisite C11–
Macrolactin A (1) is the parent aglycone of a novel family
of polyene 24-membered macrolides isolated from a deep-sea
bacterium.1 It was showed to inhibit B16-F10 murine melanoma
cancer cells and mammalian HSV-I and HSV-II. More signifi-
cantly, it was found to inhibit the HIV replication in T-lympho-
blasts1 and to be a neuronal cell protecting substance against the
glutamate toxicity.2 The significant biological activities with the
unique structure prompted many synthetic organic chemists to
investigate its total synthesis.3,4 Three total syntheses by Smith,
Carreira, and Marino groups have been reported independently.5
Herein, we report our stereoselective synthesis of the sec-precur-
sor 26 of macrolactin A, which features the judicious use of
the Wittig and Horner–Emmons reactions to elaborate all three
stereofined 1,3-diene units in the target molecule. Furthermore,
the same strategy was used to synthesize the macrolide ana-
logues of macrolactin A, 7 and 32.
Our strategy for the asymmetric synthesis of 1 is based
on the Wittig coupling of the advanced segments 2 and 3
(Scheme 1). Macrolactonization of sec-precursor 26 was specu-
lated to provide the targeted 24-membered ring. Retrosynthetic
analysis revealed that the Wittig and Horner–Emmons reactions
could be feasible to construct the C1–C10 polyene segment 2
from building blocks 4. C11–C24 Segment 3 was further divided
into subunits 5 and 6. They could be linked with each other by
the Horner–Emmons reaction of 5 and triethylphosphonocroto-
OH
OH
TrO
CO2Et
Me
4
Z:E = 5:1
OTBS
O
P
O
O
OTBS
OR1
(
)
O 2
CH2CO2Et
HO
HO
R
Tr O
R2
11
d
2
O
CO2Et
CO2Et
+
4 R1 = H, R2 = CO2Et
12 R = CH2OTr
13 R = CH2OH
a
e
macrolactin A (1)
P+Ph3I
OPMB
8 R1 = TBS, R2 = CO2Et
b
c
f
OTBDPS
O
9 R1 = TBS, R2 = CH2OH
10 R1 = TBS, R2 = CHO
14 R = CHO
OH
O
g
O
2 R = CH=CH-CHO
O
3
O
Scheme 2. (a) TBSOTf, Et3N, CH2Cl2, 0 ꢀC, 40 min, 95%. (b)
DIBAL-H, CH2Cl2, À78 ꢀC, 1 h, 96.5%. (c) (COCl)2, DMSO,
Et3N, CH2Cl2, À78 ꢀC–0 ꢀC. (d) 11, NaH, and then 10, THF,
60% in two steps. (e) HCOOH, Et2O, 75%. (f) (COCl)2, DMSO,
Et3N, CH2Cl2, À78 ꢀC–0 ꢀC. (g) Ph3P=CHCHO, CHCl3, 80%
in two steps.
O
O
5
OPMB
PhSO2
7
6
Scheme 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
907
OH
OTBS
O
O
OH OH
b
e
OBn
TBDPSO
R
RO
O
O
17 R = CH2OBn
18 R = CH2OH
e
O
15 R = H
16 R = TBDPS
OEt
OR
c
c
a
PMBO (CH2)13
R
d
5 R = CHO
27 R = OH
28 R = I,
a
b
7
R1
OPMB
R2
+
30 R = PMB
31 R = H
2-E-isomer
E:Z = 5:1
h
d
O
O
29 R = +PPh3I
O
O
32
TBDPSO
R
Scheme 5. (a) Ph3P, imidazole, I2, benzene, rt, 90%. (b) Ph3P,
CH3CN, reflux, 48 h, 95%. (c) NaHMDS, 2, THF, À78 ꢀC, 75%.
(d) DDQ, CH2Cl2/H2O (17:1), rt, 70%. (e) i) LiOH, THF/
MeOH/H2O, rt; ii) 2,4,6-trichlorobenzoyl chloride, i-Pr2NEt,
toluene, DMAP, 90 ꢀC; iii) TBAF/AcOH (1:1), THF, rt, 70%
in three steps.
22 R1 = OTBDPS, R2 = SO2Ph
23 R1 = OTBDPS, R2 = H
19 R = CO2Et
20 R = CH2OH
21 R = CH2Br
i
j
f
g
24 R1 = OH, R2 = H
k
l
25 R1 = I, R2 = H
3 R1
=
+PPh3 I , R2 = H
Scheme 3. (a) TBDPSCl, imidazole, CH2Cl2, 84%. (b) Me2C-
(OMe)2, CSA, 97%. (c) Raney Ni, EtOH, 98%. (d) (COCl)2,
DMSO, Et3N, CH2Cl2, À78 ꢀC–0 ꢀC. (e) triethylphosphono-
Now we have succeeded in the removal of PMB protecting
group, and the yield of the resulting hydroxy ester needs to be
improved. The total synthesis of macrolactin A is underway.
ꢀ
crotonate, LiOH, 4 A MS, THF, reflux, 10 h, 62% in two steps.
(f) DIBAL-H, CH2Cl2, À78 ꢀC, 1 h, 92%. (g) NBS, PPh3,
CH2Cl2, À78 ꢀC, 30 min, 95%. (h) 6, n-BuLi, and then 21,
THF, À78 ꢀC; 93%. (i) 6% Na–Hg, Na2HPO4, MeOH, 0 ꢀC,
66%. (j) TBAF, THF, 89%. (k) Ph3P, imidazole, I2, benzene,
0 ꢀC, 92%. (l) Ph3P, CH3CN, reflux, 48 h, 97%.
This work was supported by a grant from the National
Natural Science Foundation of China and a grant from the State
Key Laboratory of Bio-organic and Natural Products Chemistry.
References
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2
+
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C24 segment 3.
With the advanced segments 2 and 3 in hand, the coupling of
two segments via Wittig reaction in the presence of NaHDMS
smoothly provided the fully protected sec-precursor 26 in 79%
yield (Scheme 4). The Z:E ratio of the newly formed double
bond is 98:2. In order to test the deprotection of PMB group
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6
7
8
9
In summary, a synthesis of a sec-precursor of macrolactin A
was achieved through a highly convergent and efficient route. In
the synthesis, the Wittig reaction and the Horner–Emmons reac-
tion were utilized to construct the three characteristic E,Z- and
E,E-dienes. An ꢀ-alkylation of sulfone stabilized anion with
allyl bromide was used for the synthesis of C11–C24 segment.
The macrolide analogues of macrolactin A were also synthesized
using this strategy.
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Published on the web (Advance View) July 5, 2005; DOI 10.1246/cl.2005.906