LETTER
1093
Stereoselective Synthesis of C1–C18 Region of Palmerolide A from Tartaric
Acid
PalmerolideAfromTartaricAcid
Kavirayani
R. Prasad,* Amit B. Pawar
Abstract: A stereoselective synthesis of the C1–C18 region of marine natural product palmerolide A from chiral pool tartaric acid is
presented. The key synthetic sequence includes the elaboration of a
g-oxo-amide derived from tartaric acid and alkene formation involving Boord type fragmentation.
Key words: Palmerolide A, marine natural product, stereoselective
synthesis, tartaric acid
Natural products isolated from various sources continue
to play an important role in the advancement of drug discovery. Palmerolide A [(–)-1; Figure 1], a 20-membered
macrocyclic lactone, was isolated from the Antarctic tunicate Synoicum adareanum by Baker and co-workers.1 It
was found to be a potent inhibitor of vacuolar ATPase and
displayed selective cytotoxicity against human melanoma
cancer cells. Owing to the interesting biological activity
of palmerolide A, coupled with the international treaty
prohibiting the exploitation of resources of the Antarctic
region for commercial purposes, there has been a surge of
interest in its synthesis. Brabander’s group has disclosed
the first total synthesis of palmerolide A and revised the
stereochemistry of the natural product.2a Hitherto, three
total syntheses2a–d and a formal synthesis2e of palmerolide
A have been reported. Other groups have disclosed the
synthesis of some of the fragments towards the synthesis
palmerolide A.2e–k In light of recent reports concerning the
synthesis of palmerolide A, we report herein our contribution to this field.
Our strategy for the synthesis of (–)-1 is depicted in
Scheme 1. Synthesis of the macrolactone was envisaged
to take place by the convergence of three building blocks
2, 3 and 4. Formation of the crucial C19–C9 fragment was
expected to occur by metal-mediated addition of allylic
halide 3 to the aldehyde 2.Whereas aldehyde 2 can be easily accessed from commercially available Roche ester,
synthesis of the other fragments 3 and 4 (corresponding to
C9–C18 and C1–C8, respectively, of Palmerolide A) were
planned from tartaric acid. Elaboration of the g-hydroxy
amide 5,3 derived from D-tartaric acid, was identified as
the key building block for the synthesis of 3, whereas extension of the diol 6, obtained from L-tartaric acid, was envisaged for the synthesis of 4.
esterification
enamide
formation
H
N
H
N
19
O
OH
8
9
O
Figure 1
8
HO
allylation
of aldehyde
O
NH2
Palmerolide A
SYNLETT 2010, No. 7, pp 1093–1095xx. 201
Advanced online publication: 23.03.2010
DOI: 10.1055/s-0029-1219797; Art ID: D00710ST
© Georg Thieme Verlag Stuttgart · New York
OH
9
O
O
I/Br
18
HO
H
RCM
NH2
O
OPG O
OPG
1
9
Me
2
PG = suitable
protecting group
OPG
O
O
OH
HO
N
Me
OPG
8
4
3
O
MeO
O
OH
5
Scheme 1
HO
18
D-tartaric acid
1
1
O
O
O
O
O
O
6
L-tartaric acid
Retrosynthetic analysis for Palmerolide A
Accordingly, synthesis of the C1–C8 acid fragment 4
commenced with the mono-protected diol 7, derived from
L-tartaric acid (Scheme 2). Displacement of the triflate
obtained from 7 with 3-butenylmagnesium bromide followed by desilylation, generated the known alcohol 8 in
51% yield (3 steps).4 Ozonolysis of the alkene in 8, followed by Wittig–Horner olefination of the resulting aldehyde with triethyl phosphonoacetate furnished the a,bunsaturated ester 9 in 61% yield over two steps. Transformation of the primary hydroxy group in 9 into the corre-
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Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Fax +91(80)23600529; E-mail: prasad@orgchem.iisc.ernet.in
Received 7 January 2010
LETTER
K. R. Prasad, A. B. Pawar
sponding iodide 10, followed by zinc-mediated Boord
fragmentation,5 afforded the allylic alcohol 11 in 88%
yield. Protection of the hydroxy group in 11 as the MOM
ether, followed by ester hydrolysis with KOH, resulted in
the formation of fragment 4 {[a]D –80.9 (c 1.1, CHCl3);
Lit.2c [a]D +80.2 (c 1.5, CHCl3) for the enantiomer}, corresponding to C1–C8 of palmerolide A, in 83% yield.
O
OH
TBDMSO
i) Tf2O–DIPEA, CH2Cl2
–40°C, 10min
ii) H2C=CH(CH2)2MgBr, CuBr
THF, 45 min
O
iii) TBAF, THF, r.t., 1 h,
51% for three steps
O
7
In conclusion, the stereoselective synthesis of C1–C8 and
C9–C18 segments of the 20-membered macrolactone
plamerolide A has been accomplished from chiral pool
tartaric acid. The synthetic sequence is aptly applied for
orthogonally protected secondary alcohols with the installation of the triene unit required for the assembly of palmerolide A. Further examination of this approach for the
complete synthesis of palmerolide A is currently underway.
MeO
HO
8
N
O
O
MeO
3
O
OH
OEt
0 °C to r.t., 4 h
94%
OTBDMS
OMOM
OH
i) O3/O2, CH2Cl2–MeOH
Me2S, –78 to 0 °C, 3 h
O
11
HO
O
ii) NaH, EtO2CCH2P(O)OEt2
THF, –15 °C to r.t., 2.5 h
68% for two steps
OTBDMS
16
O
12
O
Synthesis of the C1–C8 fragment of palmerolide A
Synthesis of the C9–C18 fragment started with controlled
addition of 3-butenylmagnesium bromide to the bisWeinreb amide 13,6 which was derived from tartaric acid,
affording the keto-amide 147 in 92% yield (Scheme 3).
Reduction of the keto group in 14 with K-selectride produced the alcohol in 85% yield as a single diastereomer,8
which was protected as the corresponding silyl ether 15 in
82% yield. Reaction of the Weinreb amide in 15 with
NaBH4 furnished the corresponding primary alcohol 16 in
94% yield. Ozonolysis of the olefin in 16, followed by
Wittig–Horner olefination of the resulting aldehyde with
triethyl phosphonoacetate, yielded the a,b-unsaturated ester 17 in 68% yield. The primary alcohol in 17 was converted into the iodide which, on zinc-mediated Boord
fragmentation, produced the allylic alcohol 18 in 88%
yield. Protection of the secondary hydroxyl group in 18 as
the MOM ether, followed by reduction of the ester with
DIBAL-H, furnished the allylic alcohol 19 in 86% yield.
Oxidation of the allylic alcohol 19 with MnO2, followed
by Wittig–Horner homologation of the corresponding aldehyde with triethyl phosphonopriopionate, afforded the
triene ester 20 in 86% yield. Reduction of the ester in 20
with DIBAL-H produced the alcohol 21, corresponding to
the C9–C18 fragment of palmerolide A, in 88% yield.9
Synlett 2010, No. 7, 1093–1095
O
OEt
3
10
ii) KOH, dioxane–H2O
r.t., 36 h, 83%
NaBH4, MeOH
N
Me
O
O
15
Zn, EtOH
Δ, 88%
i) MOMCl, DIPEA
DMAP, CH2Cl2, 0 °C, 87%
Scheme 2
O
MeO
O
ii) TBDMSCl, Im, DMAP
DMF, 80 °C, 3 h, 82%
O
14
9
O
I
O
Ph3P, imidazole, I2
toluene, Δ, 4 h, 86%
OEt
O
i) K-Selectride, THF
–78 °C, 30 min, 85%
O
O
HO
THF, –15 °C, 20 min
92%
OMe
O
N
Me
O
MgBr
13
ii) NaH, EtO2CCH2P(O)OEt2
THF, –15 °C to r.t., 2.5 h
61% for two steps
O
Me
N
Me
i) O3/O2, CH2Cl2–MeOH
Me2S, –78 to 0 °C, 3 h
O
O
© Thieme Stuttgart · New York
i) Ph3P, imidazole, I2
toluene, Δ, 5 h, 93%
O
HO
OEt
O
OTBDMS
17
OH
O
i) MOMCl, DIPEA
CH2Cl2, 0 °C to Δ, 6 h, 92%
OEt
OTBDMS
ii) Zn, EtOH, Δ, 3.5 h
88%
ii) DIBAL-H, CH2Cl2,
−78 °C, 2 h, 86%
18
OMOM
i) MnO2, CH2Cl2, r.t., 24 h, 86%
OH
OTBDMS
ii) NaH, EtO2CCH(Me)P(O)OEt2
THF, –15 °C to r.t., 2.5 h, 91%
19
OMOM
OEt
DIBAL-H, CH2Cl2
O
OTBDMS
–78 °C, 2 h, 88%
20
OMOM
OH
OTBDMS
Scheme 3
21
Synthesis of the C9–C18 fragment of palmerolide A
Acknowledgment
The authors thank the Department of Science and Technology
(DST), New Delhi for funding of this project. K.R.P. is a Swarnajayanthi Fellow of DST. A.B.P. thanks CSIR for a research fellowship.
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1094
References and Notes
(1) (a) Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.;
Baker, B. J. J. Am. Chem. Soc. 2006, 128, 5630. (b) Lebar,
M. D.; Baker, B. J. Tetrahedron Lett. 2007, 48, 8009.
(2) (a) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K.
J. Am. Chem. Soc. 2007, 129, 6386. (b) Nicolaou, K. C.;
Guduru, R.; Sun, Y. P.; Banerji, B.; Chen, D. Y. K. Angew.
Chem. Int. Ed. 2007, 46, 5896. (c) Penner, M.; Rauniyar,
V.; Kaspar, L. T.; Hall, D. G. J. Am. Chem. Soc. 2009, 131,
14216. (d) Nicolaou, K. C.; Leung, Y. C. G.; Dethe, D. H.;
Guduru, R.; Sun, Y. P.; Lim, C. S.; Chen, D. Y. K. J. Am.
Chem. Soc. 2008, 130, 10019. Formal synthesis: (e) Jägel,
J.; Maier, M. E. Synthesis 2009, 2881. (f) Jones, D. M.;
Dudley, G. B. Synlett 2010, 223. (g) Lebar, M. D.; Baker, B.
J. Tetrahedron 2010, 66, 1557. (h) Kaliappan, K. P.;
Gowrisankar, P. Synlett 2007, 1537. (i) Cantagrel, G.;
Meyer, C.; Cossy, J. Synlett 2007, 2983. (j) Chandrasekhar,
S.; Vijeender, K.; Chandrasekhar, G.; Reddy, C. R.
Tetrahedron: Asymmetry 2007, 18, 2473. (k) Jägel, J.;
Schmauder, A.; Binanzer, M.; Maier, M. E. Tetrahedron
2007, 63, 13006.
(3) (a) For a general approach to the synthesis of g-keto amides
from tartaric acid, see: Prasad, K. R.; Chandrakumar, A.
Tetrahedron 2007, 63, 1798. For recent application of gketo amides derived from tartaric acid in natural product
synthesis, see: (b) Prasad, K. R.; Gandi, V. R. Synlett 2009,
2593. (c) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008,
73, 2. (d) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008,
73, 2916. (e) Prasad, K. R.; Swain, B. Tetrahedron:
Asymmetry 2008, 19, 1134. (f) Prasad, K. R.; Gandi, V.
Tetrahedron: Asymmetry 2008, 19, 2616. (g) Prasad, K. R.;
Chandrakumar, A. J. Org. Chem. 2007, 72, 6312.
(h) Prasad, K. R.; Dhaware, M. Synthesis 2007, 3697.
(i) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71,
3643. (j) Prasad, K. R.; Anbarasan, P. Tetrahedron Lett.
2006, 47, 1433. (k) Prasad, K. R.; Anbarasan, P.
Tetrahedron: Asymmetry 2006, 17, 850. (l) Prasad, K. R.;
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K. R.; Anbarasan, P. Synlett 2006, 2087.
(4) Mukai, C.; Sonobe, H.; Kim, J. S.; Hanaoka, M. J. Org.
Chem. 2000, 65, 6654.
(5) (a) Swallen, L. C.; Boord, C. E. J. Am. Chem. Soc. 1930, 52,
651. For application of this strategy in the synthesis of allylic
alcohols, see: (b) Schneider, C.; Kazmaier, U. Synthesis
1998, 1314. (c) Ramarao, A. V.; Reddy, E. R.; Joshi, B. V.;
Yadav, J. S. Tetrahedron Lett. 1987, 28, 6497.
(6) (a) Nugiel, D. A.; Jakobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F. III.; Meyer, D. T.; Jadhav, P. K.; De
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(7) Formation of a minor amount (5%) of diketone resulting
from the addition of Grignard reagent to both amide groups
was observed
(8) Formation of the other diasteromer was not observed within
detectable limits by 1H NMR
(9) All new compounds exhibited satisfactory spectroscopic
data. Compound 9: [a]D –23 (c 0.5, CHCl3); IR (neat): 3483,
2985, 1718, 1653, 1399 cm–1; 1H NMR (300 MHz, CDCl3):
Palmerolide A from Tartaric Acid
1095
d = 6.89 (dt, J = 15.2, 6.6 Hz, 1 H), 5.78 (dt, J = 15.6, 6.6 Hz,
1 H), 4.12 (q, J = 6.9 Hz, 2 H), 3.90–3.60 (m, 3 H), 3.54 (dd,
J = 11.6, 4.6 Hz, 1 H), 2.37–2.28 (br s, 1 H), 2.27–2.12 (m,
2 H), 1.64–1.44 (m, 4 H), 1.35 (s, 3 H), 1.34 (s, 3 H), 1.23 (t,
J = 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 166.6,
148.4, 121.7, 108.6, 81.3, 76.5, 61.8, 60.1, 32.3, 31.9, 27.3,
26.9, 24.4, 14.2; HRMS: m/z calcd for C14H24O5Na:
295.1521; found: 295.1519. Compound 11: [a]D +4.0 (c 1.0,
CHCl3); IR (neat): 3441, 2982, 1721, 1652, 1369 cm–1; 1H
NMR (400 MHz, CDCl3): d = 6.95 (dt, J = 15.6, 6.8 Hz,
1 H), 5.95–5.75 (m, 2 H), 5.23 (d, J = 17.2 Hz, 1 H), 5.12 (d,
J = 10.4 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.11 (q, J = 6.0
Hz, 1 H), 2.24 (q, J = 6.0 Hz, 2 H), 1.75–1.62 (br s, 1 H),
1.60–1.43 (m, 4 H), 1.29 (t, J = 7.1 Hz, 3 H); 13C NMR (75
MHz, CDCl3): d = 166.7, 148.8, 140.9, 121.6, 114.9, 72.9,
60.2, 36.2, 31.9, 23.7, 14.2; HRMS: m/z calcd for
C11H18O3Na: 221.1154; found: 221.1153. Compound 15:
[a]D +9.4 (c 2.0, CHCl3); IR (neat): 3079, 2932, 1674, 1382,
1256 cm–1; 1H NMR (300 MHz, CDCl3): d = 5.75 (ddt,
J = 16.5, 10.2, 6.3 Hz, 1 H), 5.03–4.83 (m, 2 H), 4.68–4.62
(m, 1 H), 4.54–4.48 (m, 1 H), 3.84–3.70 (m, 1 H), 3.67 (s,
3 H), 3.14 (s, 3 H), 2.24–1.96 (m, 2 H), 1.72–1.55 (m, 1 H),
1.52–1.40 (m, 1 H), 1.38 (s, 3 H), 1.36 (s, 3 H), 0.80 (s, 9 H),
0.01 (s, 6 H); 13C NMR (100 MHz, CDCl3): d = 170.4, 138.4,
114.6, 111.0, 80.0, 72.3, 71.5, 61.8, 32.2, 31.9, 29.8, 27.0,
26.2, 25.8, 18.1, –4.5, –4.6; HRMS: m/z calcd for
C19H37NO6SiNa: 410.2339; found: 410.2350. Compound
17: [a]D –6.0 (c 1.0, CHCl3); IR (neat): 3469, 2950, 1723,
1657, 1464, 1370 cm–1; 1H NMR (300 MHz, CDCl3): d =
6.86 (dt, J = 15.3, 6.6 Hz, 1 H), 5.73 (d, J = 15.9 Hz, 1 H),
4.08 (q, J = 7.2 Hz, 2 H), 4.00–3.87 (m, 1 H), 3.82–3.53 (m,
4 H), 2.38 (br s, 1 H), 2.37–2.04 (m, 2 H), 1.79–1.62 (m,
1 H), 1.58–1.40 (m, 1 H), 1.30 (s, 3 H), 1.29 (s, 3 H), 1.18 (t,
J = 7.2 Hz, 3 H), 0.80 (s, 9 H), 0.10 (s, 6 H); 13C NMR (75
MHz, CDCl3): d = 166.5, 148.3, 121.6, 108.8, 79.8, 77.1,
71.4, 62.8, 60.1, 31.1, 28.5, 27.0, 25.8, 18.1, 14.2, –4.2, –4.7;
HRMS: m/z calcd for C20H38O6SiNa: 425.2335; found:
425.2333. Compound 19: [a]D +15.1 (c 1.8, CHCl3); IR
(neat): 3445, 2925, 2854, 1464, 1256 cm–1; 1H NMR (300
MHz, CDCl3): d = 5.85–5.55 (m, 2 H), 5.32–5.20 (m, 2 H),
4.64 (d, J = 6.6 Hz, 1 H), 4.58 (d, J = 6.6 Hz, 1 H), 4.07 (br
d, J = 4.5 Hz, 1 H), 4.02–3.93 (m, 1 H), 3.78–3.63 (m, 1 H),
3.36 (s, 3 H), 2.28–1.92 (m, 2 H), 1.73–1.55 (m, 2 H), 1.53–
1.33 (m, 1 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H); 13C
NMR (75 MHz, CDCl3): d = 134.7, 133.1, 129.0, 118.0,
96.6, 79.9, 73.1, 63.8, 55.5, 32.0, 28.2, 25.9, 18.1, –4.2, –4.6;
HRMS: m/z calcd for C17H34O4SiNa: 353.2124; found:
353.2122. Compound 21: [a]D +21.0 (c 0.8, CHCl3); IR
(neat): 3401, 2953, 1678, 1255, 1036 cm–1; 1H NMR (400
MHz, CDCl3): d = 6.26 (dd, J = 15.0, 10.9 Hz, 1 H), 6.01 (d,
J = 10.8 Hz, 1 H), 5.80 (ddd, J = 17.2, 10.5, 6.6 Hz, 1 H),
5.69 (dt, J = 15.0, 6.8 Hz, 1 H), 5.32–5.23 (m, 2 H), 4.68 (d,
J = 6.6 Hz, 1 H), 4.60 (d, J = 6.6 Hz, 1 H), 4.05 (br s, 2 H),
4.04–3.96 (m, 1 H), 3.73 (dt, J = 8.2, 4.0 Hz, 1 H), 3.37 (s,
3 H), 2.30–2.06 (m, 2 H), 1.78 (s, 3 H), 1.70–1.62 (m, 1 H),
1.54–1.40 (m, 1 H), 0.9 (s, 9 H), 0.1 (s, 6 H); 13C NMR (100
MHz, CDCl3): d = 134.8, 134.7, 134.6, 126.0, 125.2, 118.0,
94.6, 79.8, 73.6, 68.7, 55.5, 32.1, 28.9, 25.9, 18.2, 14.1, –4.2,
–4.6; HRMS: m/z calcd for C20H38O4SiNa: 393.2437; found:
393.2423.
Synlett 2010, No. 7, 1093–1095
© Thieme Stuttgart · New York
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LETTER