Highly stereoselective approach toward the synthesis of the macrolactone core of amphidinolide W

Article abstract of DOI:10.1016/j.tetlet.2008.11.088

The diastereoselective synthesis of the macrolactone core of amphidinolide W was successfully accomplished using Evans' asymmetric alkylation, Aldol reaction, Julia-Kocienski olefination, and Kita's macrocyclization protocol.

Full text of DOI:10.1016/j.tetlet.2008.11.088

Tetrahedron Letters 50 (2009) 755–758
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Tetrahedron Letters
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Highly stereoselective approach toward the synthesis of the macrolactone
core of amphidinolide W
*
Debendra K. Mohapatra , Bhaskar Chatterjee, Mukund K. Gurjar
Division of Organic Chemistry, National Chemical Laboratory, Pune, Maharashtra 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereoselective synthesis of the macrolactone core of amphidinolide W was successfully accom-
plished using Evans’ asymmetric alkylation, Aldol reaction, Julia-Kocienski olefination, and Kita’s macro-
cyclization protocol.
Received 6 October 2008
Revised 12 November 2008
Accepted 22 November 2008
Available online 27 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Amphidinolide W
Evans alkylation
Evans aldol
Julia–Kocienski olefination
Kita’s macrocyclization
Amphidinolides constitute a group of structurally unique natu-
rally occurring macrolides isolated from marine dinoflagellates of
the genus amphidinium, which are symbionts of okinawan marine
acoel flatworms Amphiscolops sp.1 Owing to their profound biolog-
ical activity (mainly antitumor properties) and scarce abundance,
this family of macrolides set a great challenge to synthetic organic
chemists.2 Amphidinolide W is a 12-membered macrolide isolated
by Kobayashi3 in 2002 and showed potent cytotoxicity against
murine lymphoma L1210 cells in vitro with an IC50 value of
provide exclusively trans-olefin and control the facile epimeriza-
tion at C-2 and expecting that this method will also be applied to
other related analogues.
Our initial target was the synthesis of the macrolactone core 3
containing four stereogenic centers and one D9,10 E-alkene which
can be prepared from the sulfone 4. The sulfone can be traced back
to the fragment 6 which could in turn be obtained by a diastereo-
selective Evans aldol reaction followed by simple protecting group
manipulations. At this point, we opt to take a simple aldehyde 5 for
the synthesis of 3 which not only would help us to study the ste-
reochemical course of reactions leading to the macrocycle but also
would act as a surrogate to the side chain aldehyde required for the
total synthesis of amphidinolide W (Scheme 1).
3.9 lg/mL. It is structurally unique, being the first and only mem-
ber in the family which lacks an exo-methylene unit.3 Recently, a
complete total synthesis of amphidinolide W was reported by
Ghosh et al.4 Their synthetic efforts were based on cross-metathe-
sis to install the C9–C10 olefin and a Yamaguchi macrolactoniza-
tion to make the lactone core. They also revised the originally
proposed structure of Amphidinolide W (1) to (2), a stereochemical
inversion at C6.4 However, in the course of its total synthesis, prob-
lems such as epimerization were faced due to the intrinsic lability
at the C2 center during base-catalyzed macrolactonization. Excited
by the interesting structural features in combination with its fasci-
nating biological activity, we wanted to develop a more potentially
useful synthetic protocol toward its total synthesis (Fig. 1).
The synthesis commenced with the known oxazolidinone 9,5
which on stereoselective methylation provided 10 with high dia-
stereoselectivity (17:1)6 (1H and 13C NMR). The stereochemical
outcome could be ascertained by hydrolyzing 10 to the corre-
sponding acid and comparing the data with the reported values.7
OH
10
OH
10
6
9
O
O
We initially focused our attention at devising a strategy toward
the macrolactone core of revised amphidinolide W (2) that would
1
2
6
9
TBSO
O
O
1
2
TBSO
Amphidinolide W
proposed (1)
Amphidinolide W
revised (2)
* Corresponding author. Address: Division of Organic Chemistry, Indian Institute
of Chemical Technology, Uppal Road, Hyderabad 500 007, India. Tel.: +91 20
25902586; fax: +91 20 25902629.
Figure 1. Proposed and revised structure of amphidinolide W.
E-mail address: mohapatra@iict.res.in (D.K. Mohapatra).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.088

756
D. K. Mohapatra et al. / Tetrahedron Letters 50 (2009) 755–758
OH
OTBDMS
OH
10
10
a
11
EtO2C
EtO2C
EtO2C
OBn
OBn
OBn
OBn
6
6
5
9
9
O
O
O
2
1
2
3
15
13
TBSO
TBSO
Ph
b
O
3
(R/S)
OMTPA
Amphidinolide W
revised (2)
N
N
N
OTBDMS
N
O
O
3
16 and 17
O
OTBS
H
2
O
c, d
S
HO
2
1
+
OBn
nOe correlations
between H1 and H2
H
O
HO
OBn
O
H
1
OBn
BnO
O
6
18
6
TBSO
5
4
protons in 18
O
O
O
O
Scheme 4. Reagents and conditions: (a) HF–Py, Py, THF, 0 °C–rt, 6 h, 73%; (b) R/S-
MTPA acid, DCC, DMAP, CH2Cl2, rt, 8 h, 73% for R-isomer and 76% for S-isomer; (c)
TBAF, THF, rt, 1 h, 90%; (d) 2,2-dimethoxy propane, acetone, p-TSA, rt, 4 h, 74%.
CHO
BnO
O
N
N
O
+
CH2Ph
CH2Ph
8
9
7
ondary hydroxyl as a TBS ether and removal of the oxazolidinone
using LiBH4 provided the alcohol 6. Oxidation of the primary
Scheme 1. Retrosynthetic analysis of amphidinolide W.
11
alcohol with PDC and a two-carbon Wittig homologation furnished
O
the a,b-unsaturated ester 13 (E:Z = 9:1). Chemoselective reduction
O
O
O
12
of the double bond using NiCl2/NaBH4 and subsequent LiAlH4
reduction of ester furnished the alcohol 14 in 89% yield (Scheme 3).
Before the Julia–Kocienski reaction, the absolute configurations
of the newly generated stereocenters of 6 were investigated. Re-
moval of silyl ether of 13 with HF–Py in Py/THF at room tempera-
ture13 produced the secondary alcohol 15 which was converted
into the respective MTPA esters14 R (16) and S (17) to evidence
our initially proposed stereochemistry of hydroxyl group as ‘R’ con-
figuration. Further establishment of the stereochemistry of the
adjacent methyl group was confirmed by converting 6 into its iso-
propylidene derivative 18 where NOESY correlations witnessed the
syn alignment of the two adjacent chiral centers (Scheme 4). For in-
stance the protons H1 and H2 showed significant NOE enhance-
ments in 18, hence establishing the stereochemistry of the
methyl center to be ‘R’ configuration.
a
O
N
O
N
CH2Ph
b
CH2Ph
10
9
CHO
c, d
BnO
BnO
8
11
Scheme 2. Reagents and conditions: (a) MeI, NaHMDS, ꢀ78 °C, 4 h, 85%; (b) (i) LAH,
Ether, 0 °C, 2 h, (ii) NaH, BnBr, THF, 0 °C–rt, 7 h, 86% over two steps; (c) BH3ꢁSMe2,
THF, 0 °C, 5 h, NaOH (10%), H2O2 (30%), 16 h, 88%; (d) Dess–Martin periodinane,
CH2Cl2, rt, 4 h, 94%.
Reductive removal of auxiliary,8 followed by sequential benzyla-
tion, hydroboration, and Dess Martin oxidation9 afforded the alde-
hyde 8 (Scheme 2) which was used for the next Evans’ aldol
reaction.
Having aldehyde 8 in hand, the Evans syn aldol reaction with
oxazolidinone 75a using Bu2BOTf at ꢀ78 °C afforded the desired
Evans’ syn-isomer 12 with good yield and high diastereoselectivity
(19:1).10 The relative stereochemistry of the newly generated ste-
reocenters was initially predicted through literature precedence10
and further confirmation of the absolute configuration was
achieved in the latter part of the synthesis. Protection of the sec-
The most crucial step was to perform the Julia–Kocienski reac-
tion to obtain the D9,10 E-alkene, exclusively. For that, Mitsunobu
substitution15 of the primary alcohol of 14 by 1-phenyl-1H-tetra-
zole-5-thiol followed by oxidation16 provided sulfone 4 in good
yield.17 For the Julia–Kocienski18,19 olefination, a variety of condi-
tions was exhaustively investigated. The best results were ob-
tained under conditions using KHMDS in DME at ꢀ60 °C with
aldehyde 5, prepared from
D
-mannitol,20 producing the desired
olefin 19 in 82% yield with exclusive E-selectivity.21 Confirmation
of E-selectivity was achieved from 1H NMR spectrum in which
the two olefinic protons at d 5.43 and 5.76 ppm displayed a vicinal
coupling constant of J = 15.3 Hz. The next step was the crucial mac-
rolactonization. For this purpose, the isopropylidine group was
selectively cleaved under mild Lewis acid conditions.22 Subsequent
Birch reduction with Li, liq. NH3 at ꢀ78 °C furnished triol 20 in
overall good yield. Bu2SnO-mediated selective protection of homo-
allylic primary hydroxyl as its benzyl ether 21 followed by oxida-
tion of the remaining primary hydroxyl to the seco acid was
achieved via a two step protocol. Oxidation with BAIB in the pres-
ence of TEMPO23 and subsequent oxidation of the intermediate
O
O
OH
O
O
b, c
a
OBn
O
N
O
N
CH2Ph
12
7
CH2Ph
OTBDMS
OTBDMS
d, e
EtO2C
OBn
OBn
HO
24
aldehyde with NaClO2 in presence of NaH2PO4 as buffer fur-
6
13
nished 22. The seco acid 22 was initially tested for Yamaguchi lact-
onization25 but unfortunately it furnished an inseparable mixture
of products 3 and 23 (1:1) in 55% combined yield, which was con-
firmed from its 1H and 13C NMR. Interestingly, when lactonization
was performed following Kita’s conditions,26,27 single desired iso-
mer of the macrolactone derivative 3 was obtained in 42% yield.
Rest of the mass was accountable for an intractable mixture of
products and 35% starting material which was recovered from
the reaction mixture. The compound was characterized by its
OTBDMS
f, g
OBn
HO
14
Scheme 3. Reagents and conditions: (a) Bu2BOTf, DIPEA, CH2Cl2, 0 °C; 8ꢁCH2Cl2,
ꢀ78 °C, 7 h, 75%; (b) TBDSOTf, 2,6-lutidine, CH2Cl2, 0 °C–rt, 0.5 h, 95%; (c) LiBH4,
EtOH/THF, 0 °C–rt, 6 h, 83%; (d) PDC, CH2Cl2, rt, 2 h, 81%; (e) Ph3P@CHCO2Et,
benzene, rt, 10 h, 79%; (f) NiCl2, NaBH4, MeOH, 0 °C, 0.5 h, 98%; (g) LAH, THF, 0 °C,
2 h, 89%.

D. K. Mohapatra et al. / Tetrahedron Letters 50 (2009) 755–758
757
mass, elemental analysis, and NMR studies.28 As per the minimum
energy diagram of 3 (Fig. 2) and 23 (Fig. 3), there should be a sig-
nificant NOE effect between Ha and Hb protons in 3. The stereo-
chemical identifications for the desired isomer were established
by NOESY experiment as shown in Figure 4, which showed consid-
erable NOE enhancement between Ha and Hb protons. This infor-
mation not only resolved the possible drawback faced in the
Yamaguchi’s lactonization (Scheme 5) but also can be utilized to
synthesize other related bioactive macrolactone compounds with
high selectivity.
In conclusion, we have developed a highly efficient route to the
macrolactone core of amphidinolide W. The synthesis features
highly stereo and regioselective incorporation of chiral centers uti-
lizing Evans’ asymmetric alkylation and aldol reactions together
with the execution of a highly stereoselective Julia–Kocienski olef-
ination for the construction of the D9,10 E-alkene. Selective oxida-
tion processes using BAIB in presence of TEMPO are well suited
in the synthesis. Of particular note is the final lactonization using
Kita’s protocol which selectively produced only the required iso-
mer thus overcoming the difficulty of epimerization encountered
in the Yamaguchi lactonization. Further insight into the total syn-
thesis of this natural product is in progress.
Figure 2. Minimum energy diagram of 3.
Acknowledgments
BC thanks UGC, New Delhi, India, for the financial assistance in
the form of fellowship. We are thankful to Dr. Ganesh Pandey,
HOD, for his constant support and encouragement.
Figure 3. Minimum energy diagram of 23.
OBn
Supplementary data
Hb
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.088.
O
TBSO
Me
Ha
3
NOE interactions
between Ha and Hb protons
References and notes
Figure 4.
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Ph
N
OH
O
O
N
N
OTBDMS
S
a, b
c
N
OBn
OBn
TBSO
14
OBn
4
OTBS
OTBS
OH
d, e
Me
g, h
O
20: R= H
21: R= Bn
f
HO
O
19
OTBS
O
OR
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OH
Lett. 1993, 34, 7081–7084; (b) Literature ½a D25
ꢂ
+10.1 (CHCl3), Observed ½a D25
ꢂ
+9.5
i
O
Me
(CHCl3).
Yamaguchi
lactonization
22
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13. Nicolaou, K. C.; Ray, M.; Finlay, V.; Ninkovic, S.; Sarabia, F. Tetrahedron 1998, 54,
7127–7166.
O
TBSO
X
HO
Y
Kita's
macrocyclization
protocol
OBn
3: X = Me, Y = H
23: X = H, Y = Me
j
3:23 = 1:1
OBn
H
O
H
O
TBSO
CH3
14. (a) Mosher, H. S.; Dale, J. A. J. Am. Chem. Soc. 1973, 95, 512–519; (b) Kakisawa,
H.; Ohtani, I.; Kusumi, T.; Kashman, Y. J. Am. Chem. Soc. 1991, 113, 4092–4096.
15. Mitsunobu, O. Synthesis 1981, 1–28.
3
Scheme 5. Reagents and conditions: (a) PTSH, DIAD, Ph3P, THF, 0 °C, 89%; (b)
(NH4)6Mo7O24ꢁ4H2O, H2O2, EtOH, 0 °C–rt, 92%; (c) KHMDS, DME, 5, ꢀ60 °C, 2 h, 82%;
(d) Zn(NO3)2ꢁ6H2O, CH3CN, 50 °C, 74%; (e) Li, liq. NH3, ꢀ78 °C, 78%; (f) Bu2SnO, BnBr,
TBAI, toluene, reflux, 84%; (g) PhI(OAc)2, TEMPO, CH2Cl2, rt, 92%; (h) NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (3:1), 87%; (i) 2,4,6-trichlorobenzoyl
chloride, DIPEA, THF, rt; DMAP, benzene, 80 °C, 55% combined yield; (j) EtOCCH,
[{Ru(p-cymene)Cl2}2], toluene, 0 °C–rt, 30 min; CSA, toluene, rt–50 °C, 2 h, 42%.
16. Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963, 28, 1140–1142.
17. ½ ꢂ +1.53 (c 1.2, CHCl3); IR (CHCl3): 2929, 1596, 1497, 1344, 1152, 1045, 836,
a 2D5
761; 1H NMR (200 MHz, CDCl3): d 0.02 (s, 6H), 0.82–0.86 (m, 12H), 0.92 (d, 3H,
J = 6.9 Hz), 1.03 (m, 1H), 1.25–1.48 (m, 6H), 1.63–1.76 (m, 2H), 1.95 (m, 1H),
3.19–3.32 (m, 2H), 3.49 (m, 1H), 3.68 (t, 2H, J = 7.8 Hz), 4.48 (s, 2H), 7.30 (m,
5H), 7.59–7.71 (m, 5H); 13C NMR (50 MHz, CDCl3): d ꢀ4.4, ꢀ4.1, 13.9, 17.2,
18.1, 20.4, 25.9, 29.9, 30.7, 31.3, 33.7, 37.2, 56.2, 72.99, 75.5, 75.8, 125.0, 127.4,

758
D. K. Mohapatra et al. / Tetrahedron Letters 50 (2009) 755–758
127.5, 128.3, 129.7, 131.3, 133.1, 138.7, 153.5; ESI-MS m/z 623.3904 (M+Na)+.
22. Takeuchi, T.; Kuramochi, K.; Kobayashi, S.; Sugawara, F. Org. Lett. 2006, 8,
Anal. Calcd for C31H48N4O4SSi: C, 61.96; H, 8.05; N, 9.32. Found: C, 61.82; H,
7.97; N, 9.16.
18. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26–28.
19. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
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H.; Simko, B.; Blaber, L. C. J. Med. Chem. 1983, 26, 1561–1569.
5307–5310.
23. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974–6977.
24. Sasaki, M.; Inoue, M.; Tachibana, K. J. Org. Chem. 1994, 59, 715–717.
25. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
21.
½
a 2D5
ꢂ
+17.9 (c 2.2, CHCl3); IR (CHCl3): 2929, 1591, 1455, 1379,1252, 1061,
26. Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. J. Chem. Soc., Perkin Trans. 1
1993, 2999–3005.
836, 773, 697; 1H NMR (400 MHz, CDCl3): d 0.00 (s, 3H), 0.01 (s, 3H), 0.79
(d, 3H, J = 6.7 Hz), 0.86 (s, 9H), 0.92 (d, 3H, J = 6.8 Hz), 1.00 (m, 1H), 1.16 (m,
1H), 1.37 (s, 3H), 1.41 (s, 3H), 1.43–1.52 (m, 4H), 1.71 (m, 1H), 1.93–2.01 (m,
2H), 2.08 (m, 1H), 3.23 (dd, 1H, J = 6.6, 9.0 Hz), 3.30 (dd, 1H, J = 6.2, 9.0 Hz),
3.48 (m, 1H), 3.53 (t, 1H, J = 8.0 Hz), 4.04 (dd, 1H, J = 6.1, 8.0 Hz), 4.45 (m,
1H), 4.49 (s, 2H), 5.41 (dd, 1H, J = 8.0, 15.3 Hz), 5.76 (dt, 1H, J = 6.8, 15.3 Hz),
7.32-7.37 (m, 5H); 13C NMR (100 MHz, CDCl3): d ꢀ4.5, ꢀ4.2, 14.1, 17.2, 18.1,
25.9, 26.7, 29.9, 30.3, 30.7, 31.8, 33.7, 37.1, 69.5, 72.97, 75.8, 75.9, 77.4,
108.97, 127.0, 127.4, 127.5, 128.3, 136.3, 138.8; ESI-MS m/z 527.4708
(M+Na)+. Anal. Calcd for C30H52O4Si: C, 71.38; H, 10.38. Found: C, 71.14; H,
10.22.
27. Trost, B. M.; Chilsom, J. D. Org. Lett. 2002, 4, 3743–3745.
28. ½ ꢂ +29.0 (c 0.6, CHCl3); IR (CHCl3): 2929, 1722, 1598, 1384, 1255, 1115, 1026,
a 2D5
772, 618; 1H NMR (500 MHz, CDCl3): d 0.01 (s, 6H), 0.85 (d, 3H, J = 6.7 Hz), 0.87
(s, 9H), 1.18 (d, 3H, J = 6.9 Hz), 1.36–1.42 (m, 2H), 1.49–1.57 (m, 5H), 1.75 (m,
1H), 2.14 (m, 1H), 2.26 (m, 1H), 3.28 (m, 1H), 3.57 (dd, 1H, J = 4.4, 10.8 Hz), 3.61
(dd, 1H, J = 6.7, 10.8 Hz), 4.58 (ABq, 2H, J = 12.4 Hz), 5.44–5.53 (m, 2H), 5.91
(ddd, 1H, J = 6.2, 9.4, 15.5 Hz), 7.28–7.35 (m, 5H); 13C NMR (125 MHz, CDCl3): d
ꢀ4.9, ꢀ4.4, 17.5, 17.8, 18.2, 25.95, 28.4, 30.2, 30.4, 33.3, 34.1, 41.7, 70.7, 72.4,
73.2, 74.0, 127.5, 127.56, 127.6, 128.4, 138.2, 138.3, 175.4; ESI-MS m/z 483.243
(M+Na)+. Anal. Calcd for C27H44O4Si: C, 70.39; H, 9.63. Found: C, 70.34; H, 9.55.