Studies directed toward the syntheses of amphidinolides: Formal total synthesis of (-)-amphidinolide P

Article abstract of DOI:10.1016/S0040-4039(01)00450-6

A formal total synthesis of (-)-amphidinolide P (1) has been achieved via an efficient convergent strategy for the stereoselective construction of the two advanced intermediates 2 and 3, used recently by Williams et al. in their synthesis of the same mole

Full text of DOI:10.1016/S0040-4039(01)00450-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3387–3390
Studies directed toward the syntheses of amphidinolides: formal
total synthesis of (−)-amphidinolide P
Tushar K. Chakraborty* and Sanjib Das
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 21 December 2000; revised 20 February 2001; accepted 15 March 2001
Abstract—A formal total synthesis of (−)-amphidinolide P (1) has been achieved via an efficient convergent strategy for the
stereoselective construction of the two advanced intermediates 2 and 3, used recently by Williams et al. in their synthesis of the
same molecule. © 2001 Elsevier Science Ltd. All rights reserved.
Amphidinolides represent a family of cytotoxic marine
natural products with diverse structural features and
pronounced biological activities that include very
potent anticancer activities displayed by many of these
molecules against various tumour cell lines and an
increase in rabbit skeletal muscle actomyosin ATPase
activity by one of them.1–3 Recently, Williams et al.
have achieved the total synthesis of (−)-amphidinolide
P (1),4 which turned out to be the enantiomer of the
natural product isolated by Kobayashi.5 In continua-
tion of our work on the synthesis of amphidinolides O
and P,6 we now report a formal total synthesis of
(−)-amphidinolide P (1) via the stereoselective construc-
tion of the two advanced intermediates 2 and 3 follow-
ing a concise strategy. A Stille coupling of 2 and 3 and
the conversion of the resulting acyclic precursor to the
final macrolide 1 in two steps have already been
reported.4
gyl alcohol 6 was alkylated with 2,3-dibromopropene
using ethylmagnesium bromide and a catalytic amount
of cuprous bromide,7 which was followed by acid-cata-
lyzed THP-deprotection to give the enyne 7 in 75%
yield. Hydride reduction of the acetylenic moiety of 7
using Red-Al gave a ‘1,4-diene’ intermediate with an
allylic alcohol moiety that was subjected to a Sharpless
asymmetric epoxidation reaction using natural diiso-
propyl -(+)-tartrate to furnish the chiral epoxy alcohol
L
8 (>98% ee)8 in 60% yield from 7.
Oxidation of 8 using SO3–py complex gave the C7–C11
aldehyde 4 in 70% yield. The two chiral centres in the
other component 5 were generated by an Evans aldol
reaction between the chiral oxazolidinone 9 and the
aldehyde 10,9 prepared from monoPMB-protected pro-
pane-1,3-diol by oxidation. The syn aldol adduct 11 was
transformed into the methyl ester intermediate 12 in
three steps in 70% overall yield: treatment with DDQ
under anhydrous conditions to convert the PMB-ether
to the PMP-acetal, oxidative removal of the chiral
auxiliary and conversion of the acid to an ester using
CH2N2. Next, the ester 12 was reacted with trimethylsi-
We planned the construction of the vinyl bromide 2
from two subunits, the C7–C11 aldehyde 4 and the
C1–C6 allylsilane component 5. The actual synthesis of
2 is outlined in Scheme 1. The THP-protected propar-
Bu3Sn
12
Me
17
Me
Br
O
O
H
H
H
H
PMP
O
OH Me
11
OTBS
O
7
H
Me
3
Me3Si
6
O
O
Br
O
1
H
H
O
CO2Me
H
1
O
H
OH
Me
7
Me
CHO
Me
4
5
2
1: (-)-amphidinolide P
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00450-6

3388
T. K. Chakraborty, S. Das / Tetrahedron Letters 42 (2001) 3387–3390
1. EtMgBr, THF,
then CuBr (cat.), followed
by
1. Red-Al, Et2O
2. (+)-DIPT, Ti(OiPr)4,
TBHP, 4Ao MS, CH2Cl2
Br
SO3-py, DMSO, Et3N,
CH2Cl2
Br
Br
O
Br
H
4
H
OTHP
2. TsOH (cat.), MeOH
75%
60%
HO
OH
OH
70%
6
7
8
1. DDQ, 4Ao MS, CH2Cl2
2. LiOH, H2O2, THF-H2O
3. CH2N2, Et2O
PMP
O
Bu2BOTf, Et3N, CH2Cl2
O
O
O
O
then
PMBO
O
CHO
N
O
MeO2C
10
PMBO
N
O
Me
Bn
70%
92%
Me
12
Bn
11
9
Br
O
H
1. TBSOTf, 2,6-lutidine, CH2Cl2
2. NaCNBH3, TMSCl, CH3CN
H
4, BF3.Et2O,
CH2Cl2
PMP
1. Me3SiCH2MgCl, CeCl3, THF
2. Silica gel, CH2Cl2
7
OH
O
O
5
85%
40%
60%
Me
13
Br
Br
O
H
O
H
H
H
OTBS
OH
OTBS
OPMB
+
OPMB
Me
OH
Me
O
14
15
(3:2)
1. SO3-py, DMSO, Et3N,
CH2Cl2
Br
Br
1. TESOTf, 2,6-lutidine,
CH2Cl2
2. DDQ, CHCl3-H2O
2. NaClO2, 2-methyl-2-butene,
NaH2PO4, t-BuOH
3. CH2N2, Et2O
1. CSA (cat.), CH2Cl2-MeOH
2. (COCl)2, DMSO, Et3N,
CH2Cl2
O
H
H
H
OTBS
OTES
H
OTBS
OTES
14
2
85%
90%
60%
CO2Me
OH
Me
Me
16
17
1. SO3-py, DMSO, Et3N,
CH2Cl2
Br
2. NaClO2, 2-methyl-2-butene,
NaH2PO4, t-BuOH
3. CH2N2, Et2O
O
1. DDQ, CHCl3-H2O
2. (COCl)2, DMSO, Et3N, CH2Cl2
H
H
OTBS
15
2
OPMB
92%
60%
CO2Me
Me
18
Scheme 1. Stereoselective synthesis of 2.
lylmethylmagnesium chloride in the presence of anhy-
drous cerium(III) chloride.10,11 The resulting b-hydroxy-
silane underwent Peterson-type elimination in the pres-
ence of silica gel to furnish the allylsilane 5 in 60%
yield.
C7 centre was assigned based on the known diastereo-
facial selectivity found in the nucleophilic additions to
chiral epoxy aldehydes.14 Silylation of 13 was followed
by acetal deprotection. Most of the acid-catalyzed
deprotection procedures resulted in the decomposition
of the starting material. Finally, a silyl-promoted acetal
ring opening was successfully carried out using sodium
cyanoborohydride in the presence of TMSCl.15 Two
PMB-ethers 14 and 15 were formed in ꢀ3:2 ratio in
85% total yield. Although the acetal opening failed to
give any selectivity, both 14 and 15 were useful and
The Sakurai reaction12,13 between 4 and 5 provided the
required adduct 13 in 40% yield, the major product
being an acid-catalyzed rearranged product from 5. The
only isomer that could be detected was the expected
product 13. The stereochemistry of the newly generated

T. K. Chakraborty, S. Das / Tetrahedron Letters 42 (2001) 3387–3390
3389
1. (+)-DET, Ti(OiPr)4,
TBHP, 4Ao MS, CH2Cl2
1. NaH, BnBr, TBAI (cat.),
THF
Me
2. Me2CuLi, Et2O
2. Red-Al, Et2O
OH
OH
BnO
BnO
HO
OH
60%
OH
72%
20
21
19
1. TBDPSCl, Et3N, DMAP (cat.), CH2Cl2
2. PMBOC(=NH)CCl3, TfOH (cat.),
CH2Cl2-cyclohexane
1. Piv-Cl, CH2Cl2-pyridine
2. Pd-C, H2, MeOH
Me
Me
3. MeLi, Et2O
OPiv
OH
HO
TBDPSO
50%
92%
OH
OPMB
Me
22
23
1. (COCl)2, DMSO, Et3N, CH2Cl2
2. MeMgI, Et2O
3. Step 1
1. TBAF, THF
Me
4. Ph3P=CH2, Et2O
2. (COCl)2, DMSO, Et3N, CH2Cl2
OHC
PMBO
TBDPSO
PMBO
24
65%
Me
Me
85%
25
Bu3Sn
Me
1. CHI3, CrCl3-LAH, THF
2. n-BuLi, n-Bu3SnCl, Et2O
DDQ, CHCl3-H2O
PMBO
Me
3
72%
26
Scheme 2. Stereoselective synthesis of 3.
could be converted easily to the desired b-ketoester 2 by
routine functional group manipulations. In the case of
14, TES-protection of the secondary hydroxyl group was
followed by deprotection of the C1-hydroxyl group.
A two-step oxidation protocol was followed to oxidize
the primary hydroxyl group of 16 to a carboxylic acid
that was esterified with CH2N2 to give 17. Selective
removal of the TES-group was followed by Swern
oxidation of the resulting C3-hydroxyl group to furnish
2. On the other hand, the primary hydroxyl group of 15
was first transformed into the ester 18 and was subse-
quently subjected to PMB-deprotection and Swern oxi-
dation to reach the target 2.
yield of 65% from 23. Desilylation of 24 was followed by
Swern oxidation to furnish the aldehyde 25 in 85% yield.
The aldehyde 25 was reacted with CHI3 in the presence
of anhydrous CrCl2, generated in situ from CrCl3 and
LAH, following the Takai protocol18 to introduce an
E-vinyl iodide moiety that was next subjected to an
iodine–tin exchange to give the E-vinyl stannane 26 in
72% yield. Finally, deprotection of the PMB-ether fur-
nished the desired intermediate 3. The spectroscopic data
and specific rotations of 2 and 3 prepared by us were
identical with the reported values.4
In conclusion, the convergent synthetic protocol reported
herein for the stereoselective construction of the two
advanced intermediates 2 and 3 that were used by
Williams et al. in their synthesis of (−)-amphidinolide P
(1) demonstrates a formal total synthesis of the molecule.
The starting material for the synthesis of 3 was 2-butyne-
1,4-diol (19, Scheme 2). A slight modification of a
reported procedure16 was followed to prepare the allylic
alcohol 20 from 19, in 60% yield, by monobenzylation
and Red-Al reduction. Sharpless asymmetric epoxida-
tion of 20 using natural diethyl
L
-(+)-tartrate and
Acknowledgements
Ti(OiPr)4 in stoichiometric amounts (>98% ee)17 was
followed by epoxide ring opening using dimethylcopper
lithium to give the 1,3-diol 21 in 72% overall yield in two
steps. The minor 1,2-diol was removed from the crude
product by oxidative cleavage using NaIO4. Selective
protection of the primary hydroxyl group of 21 as a
pivalate was followed by the Bn-deprotection to give the
1,2-diol 22 in 92% yield. Routine functional group
manipulations transformed 22 into 23 (50% yield in three
steps), which was subsequently converted to the olefin 24
in four steps of which the first three were to prepare a
methylketo intermediate that was subjected to a Wittig
olefination reaction in the fourth step giving an overall
The authors wish to thank Drs. A. C. Kunwar and M.
Vairamani for NMR and mass spectroscopic assistance,
respectively; UGC, New Delhi for a research fellowship
(S.D.) and CSIR, New Delhi for a Young Scientist
Award Research Grant (T.K.C.).
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