Toward a synthesis of the antitumor macrolide peloruside A: A chiral pool approach for the C(1)-C(11) segment

Article abstract of DOI:10.1016/j.tetlet.2003.10.153

Dihydroxylation of the glucose derived α,β-unsaturated lactones 6 and 13 was found to be on the α-face of the pyranolactone ring exclusively. The resulting dihydroxylated compound from 13 has been used in a synthesis of the lactone 4, which corresponds to

Full text of DOI:10.1016/j.tetlet.2003.10.153

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 387–390
Toward a synthesis of the antitumor macrolide peloruside A:
a chiral pool approach for the C(1)–C(11) segment
Mukund K. Gurjar,* Yakambram Pedduri, C. V. Ramana, Vedavati G. Puranik
and Rajesh G. Gonnade
National Chemical Laboratory, Pune 411 008, India
Received 25 July 2003; revised 15 October 2003; accepted 24 October 2003
Abstract—Dihydroxylation of the glucose derived a,b-unsaturated lactones 6 and 13 was found to be on the a-face of the pyr-
anolactone ring exclusively. The resulting dihydroxylated compound from 13 has been used in a synthesis of the lactone 4, which
corresponds to C(1)–C(11) of peloruside A.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Peloruside A 1 is a recently discovered antimitotic mac-
rolide isolated from the New Zealand marine sponge
Mycale sp. Northcote and co-workers1 established its
structure as a polyoxygenated 16-membered macrolide
with an integrated pyranose ring and a branched unsat-
urated side chain, and its relative stereochemistry.
Peloruside A was found to be cytotoxic to P388 murine
leukemia cells as well as to other cancer cells and recent
studies demonstrated that peloruside functions by pro-
moting tubulin polymerization and by interfering with
microtubule dynamics like taxol and other microtubule
stabilizing agents.2 In the light of the inherent interest
generated by its promising biological activity, and with
the necessity of determining its absolute configuration,
peloruside A has been identified as an appropriate target
for totalsynthesis. During our work DeBrabander and
co-workers3 reported the first totalsynthesis of ( ))-
peloruside A and confirmed that natural peloruside has a
stereochemistry opposite to that shown in Scheme 1.
Meanwhile Paterson,4 Ghosh5 and their co-workers have
PO
HO
8
Me Me
Me Me
O
O
11
OP
O
11
PO
MeO
OMe
TBS
OP
OP
OH
OH
OSiR3 OP
OH
O
20
O
O
O
OMe O
+
8
5
1
15
1
24
OH
OP
17
HO
4
OH
Me
OH
OMe
O
OMe
3
2
1
O
O
O
OMe O
OH
O
OMe O
O
O
O
O
O
O
O
D-Glucose
O
O
O
O
7
6
5
Scheme 1. Retrosynthetic analysis of 1.
Keywords: Barbier reaction; Ring closing metathesis; Dihydroxylation; Barton–McCombie deoxygenation; Mitsunobu reaction; Dess–Martin peri-
odinane.
* Corresponding author. Tel.: +91-20-5882456; fax: +91-20-5893614; e-mail: gurjar@dalton.ncl.res.in
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.153

388
M. K. Gurjar et al. / Tetrahedron Letters 45 (2004) 387–390
OMe
OMe OH
OMe OH
O
OH
O
O
O
O
O
O
O
O
O
O
O
ref 6
a)
+
O
O
O
7
10
8
9
b)
O
O
O
O
OMe O
O
OMe O
d), e)
OMe O
c)
O
O
O
O
O
O
O
O
O
Molecular Structure of 12
12
6
11
Scheme 2. Reagents and conditions: (a) Zn, aq NH4Cl/THF (2:3), allyl bromide, 0 ꢁC, 0.5 h, 9/10 (9:1), 95%; (b) acryloyl chloride, EtNiPr2, CH2Cl2,
0 ꢁC, 0.5 h, 76%; (c) 5 mol% A, benzene, ›fl, 1 h, 72%; (d) (i) OsO4 (cat), 50% aq NMO, acetone/H2O (9:1), 10 h; (ii) PTSA (cat), 2,2-dimethoxy-
propane, acetone, rt, 0.5 h, 66%.
independently reported the synthesis of different frag-
ments corresponding to 1. Herein we describe our chiral
poolapproach for the synthesis of 4, an advanced in-
termediate corresponding to the C(1)–C(11) sector of 1.
As the dihydroxylation of lactone 6 having the correct
(S) stereochemistry at C(5) gave the undesired diaste-
reomer 12, we studied the same sequence of reactions
with the major isomer 9, anticipating a similar diaste-
reoselectivity from the a-face since inversion of the ste-
reochemistry at C(5) by means of Mitsunobu reaction
could be carried out at a later stage. Indeed the di-
hydroxylation of the a,b-unsaturated d-valerolactone 13
derived from 9 gave exclusively one diastereomer and
the resulting diol was characterized as its acetonide 14
(Scheme 3). NOE studies of 14 as well as single crystal
X-ray diffraction studies of the ethylgylcoside 1511 de-
rived from 14 following selective DIBAL-H reduction
and anomeric O-ethylation using NaH, EtI and clearly
established that the stereochemistry of the dihydroxyl-
ation was as expected.
Our projected program for the totalsynthesis of 1 en-
visaged a Mukaiyama aldol reaction between 2 and 3 as
the main key transformation for fabricating the total
carbon unit of peloruside A and subsequent macro-
lactonization. We noted the resemblance between the
stereochemistry of C(2) and C(3) to that of glucose di-
acetonide 7 and the feasibility of the selective methyla-
tion of C(3), and anticipated that dihydroxylation of the
unsaturated lactone 6 should dispose the other two
hydroxylgroups at C(7) and C(8) with the required
stereochemistry (Scheme 1).
The synthesis of 6 began with allylation of 86 under
Barbier conditions7 using allylbromide and Zn. The
(5R)- and (5S)-isomers 9 and 10 were obtained in a 95%
(9:1) yield. The minor isomer 10 was treated with acry-
loyl chloride to provide diene 11 (Scheme 2). Ring clos-
ing metathesis of 11 with the second generation GrubbsÕ
catalyst8 gave the a,b-unsaturated d-valerolactone 6.
Dihydroxylation9 of 6 gave only one isomer, which was
characterized as its acetonide 12.10 NOE experiments
with 12 clearly indicated that the dihydroxylation of 6
had resulted exclusively from the undesired a-face,5 this
being further confirmed by single crystal X-ray diffrac-
tion studies (Scheme 2).
Having an easy access to the key intermediate 15, we
addressed the inversion at C(5) and the chain extension
at C(9). As shown in Scheme 4, benzylation of the diol
15 gave the ethylpyranoside 16 in 90% yield. Following
a sequence of reactions (i) hydrolysis of the furanoside
acetonide, (ii) reduction of the resulting acetal with
LiAlH4, and (iii) selective acetonide protection, 16 was
converted to 17 in an overall yield of 61%. The Barton–
McCombie deoxygenation protocol12 was successfully
applied to the deoxygenation of the C(4)–OH in 17 and
the deoxygenated product 18 was obtained in good
yield. Deprotection of the isopropylidene system with
PPTS in methanoland protection of the resulting diolas
O
OMe OH
OMe O
O
O
O
O
a), b)
O
O
N
N
9
13
Mes
Cl
Cl
Mes
Ph
c)
Ru
OEt
O
PCy3
OH
OH
O
O
OMe O
OMe O
A
d) - f)
O
O
O
O
O
O
Molecular Structure of 15
15
14
Scheme 3. Reagents and conditions: (a) acryloyl chloride, EtNiPr2, CH2Cl2, 0 ꢁC, 0.5 h, 76%; (b) 5 mol% A, benzene, ›fl, 1 h, 72%; (c) (i) OsO4 (cat),
50% aq NMO, acetone/H2O (9:1); (ii) PTSA (cat), 2,2-dimethoxypropane, benzene, ›fl, 0.5 h, 66%; (d) DIBAL-H, toluene, )78 ꢁC; (e) NaH, DMF,
EtI, 0 ꢁC, 1 h; (f) PPTS (cat), MeOH, rt, 1 h, 71% (three steps).

M. K. Gurjar et al. / Tetrahedron Letters 45 (2004) 387–390
389
OEt
OEt
OEt
OEt
OBn
OBn
OBn
OMe O
OH
OMe O
OH
OH
OBn
OBn
a)
g)
b)
f)
c)
e)
OMe O
O
OMe O
O
OBn
O
O
O
O
O
O
O
O
18
d)
16
15
17
OPiv
OPiv
OPiv
OEt
OBn
OBn
OBn
OBn
OBn
OMe OH
OMe OBz
OMe OH
OMe O
OBn
OBn
OBn
BnO
BnO
BnO
BnO
BnO
OBn
OBn
OBn
OBn
22
h)
OH
21
20
19
CO2Me
CO2Me
O
O
O
HO
TBS
OMe O
TBS
OMe
TBS
OMe O
TBS
OMe O
OBn
OBn
OBn
OBn
OBn
OBn
O
i)
j)
k)
O
OH
BnO
BnO
HO
OBn
OBn
OBn
OH
23
4
24
25
Scheme 4. Reagents and conditions: (a) NaH, DMF, BnBr, 0 ꢁC, 1 h, 90%; (b) (i) TFA/H2O (4:1); 0 ꢁC, 1 h; (ii) LiAlH4, THF, rt, 3 h; (iii) PTSA (cat),
2,2-dimethoxypropane, CH2Cl2, rt, 0.5 h, 61%; (c) (i) NaH, THF, CS2, MeI, 0 ꢁC, 1.5 h; (ii) Bu3SnH, AIBN (cat), toluene, ›fl, 1 h, 55%; (d) (i) PPTS
(cat), MeOH, rt, 8 h; (ii) NaH, DMF, BnBr, 0 ꢁC, 1 h, 90%; (e) (i) H2SO4 (cat), AcOH/H2O (4:1), ›fl, 0.5 h; (ii) LiAlH4, THF, rt, 1 h; (iii) pivalolyl
chloride, pyridine, 0 ꢁC, 0.5 h, 62%; (f) DIAD, TPP, PhCO2H, THF, 0 ꢁC, 0.5 h, 79%; (g) (i) DIBAL-H, toluene, 0 ꢁC, 1 h; (ii) pivalolyl chloride,
pyridine, 0 ꢁC, 0.5 h, 81%; (h) (i) TBSOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 1 h; (ii) DIBAL-H, toluene, )78 ꢁC, 2 h, 92%; (i) (i) Dess–Martin periodinane,
CH2Cl2, rt, 3 h; (ii) (Me)2CH–CO2Me, LDA, THF, )78 ꢁC, 0.5 h, 69%; (j) Dess–Martin periodinane, CH2Cl2, 1.5 h, 79%; (k) 10% Pd–C/H2, MeOH,
AcOH (cat), 1 atm, rt, 82%.
the benzylether using NaH and benzylbromide gave the
fully protected pyranoside 19. Removalof the glycosidic
ethylprotection of 19, reduction of the cyclic acetal with
LiAlH4, and selective protection of the 1ꢁ-OH with
pivaloyl chloride in pyridine at 0 ꢁC gave the pivaloyl
ester 2013 in 62% overall yield.
Acknowledgement
P.Y. thanks the CSIR (New Delhi) for financial assis-
tance in the form of a research fellowship.
Inversion of the C(5) center in 20, as envisioned at the
planning stage was accomplished under Mitsunobu
References and Notes
conditions14
using diisopropylazodicarboaxtyel
1. West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org.
Chem. 2000, 65, 445–449.
(DIAD)/PPh3 and benzoic acid to give the diester 21 in
79% yield. For convenience in comparison of spectral
data, 21 was treated with DIBAL-H and the 1ꢁ-OH of
the resulting diol was protected selectively as its pivaloyl
ester 22.15 Spectraldata of 20 and 22 clearly confirmed
the inversion at C(5). The TBS ether 23 obtained from
22 (following a sequence of 2ꢁ-OH protection as its TBS
ether and depivaloylation using DIBAL-H) was sub-
jected to oxidation using Dess–Martin16 periodinane.
The resulting aldehyde was treated with the lithium
enolate of methyl 2-methylpropionate and oxidation of
the condensed product 24 with the Dess–Martin peri-
odinane gave 25 in good yield. As anticipated, hydro-
genation of 25 with 10% Pd–C gave the ketolactone 4.
The spectraldata of 417 are in agreement with the as-
signed structure.
€
€
2. (a) Hood, K. A.; Backstrom, B. T.; West, L. M.;
Northcote, P. T.; Berridge, M. V.; Miller, J. H. Anti-
Cancer Drug Des. 2001, 16, 155–166; (b) Hood, K. A.;
West, L. M.; Rouw, B.; Northcote, P. T.; Berridge, M. V.;
Wakefield, S. J.; Miller, J. H. Cancer Res. 2002, 62, 3356–
3360.
3. Liao, X.; Wu, Y.; DeBrabander, J. F. Angew. Chem., Int.
Ed. 2003, 42, 1648–1652.
€
4. Paterson, I.; Francesco, E. D.; Kuhn, T. Org. Lett. 2003,
5, 599–602.
5. Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44,
3967–3969.
6. Zehani, S.; Llauro, M. F.; Gelbard, G. Bull. Soc. Chim. Fr.
1989, 104–113.
7. (a) Petrier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910–
912; (b) Luche, J.-L.; Einhorn, C. J. Organomet. Chem.
1987, 322, 177–183; (c) Gurjar, M. K.; Reddy, D. P. S.
Tetrahedron Lett. 2002, 43, 295–298.
In conclusion, a compound corresponding to the C(1)–
C(11) fragment of peloruside A has been synthesized
€
8. Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.;
Nolan, S. P. J. Org. Chem. 2000, 65, 2204–2207.
9. During their synthesis of the C(1)–C(9) fragment of ())-
peloruside A, Ghosh et al. noticed a similar undesired
a-face selective dihydroxylation of the corresponding
using a chiron approach from
D
-glucose.18 Efforts are
underway to complete a synthesis of ())-peloruside A, a
totalsynthesis of the naturalproduct (+)-peol ruside A,
as well as to apply the resulting strategy to generate
structural analogues of (+)-peloruside A with useful
in vivo activity.
unsaturated lactone. See Ref. 5.
25
D
10. Spectraldata of 12: ½aŠ )65.33 (c 0.96, CHCl3); mp 121–
124 ꢁC; 1H NMR (500 MHz, CDCl3) d 1.32, 1.36 (2s, 6H),

390
M. K. Gurjar et al. / Tetrahedron Letters 45 (2004) 387–390
1.48, 1.50 (2s, 6H), 1.87 (ddd, 1H, J ¼ 14:8, 11.5, 3.6 Hz),
(s), 138.0 (s), 138.3 (s), 138.6 (s), 178.1 (s). Anal. Calcd
for C43H54O8: C, 73.90; H, 7.79. Found: C, 73.95; H,
7.75.
2.01 (dt, 1H, J ¼ 14:8, 1.8 Hz), 3.40 (s, 3H), 3.75 (d, 1H,
J ¼ 3:8 Hz), 4.22 (dd, 1H, J ¼ 7:5, 3.8 Hz), 4.58 (d, 1H,
J ¼ 6:7 Hz), 4.60 (d, 1H, J ¼ 3:9 Hz), 4.66 (br ddd, 1H,
J ¼ 6:7, 3.6, 1.9 Hz), 4.90 (ddd, 1H, J ¼ 11:5, 7.5, 1.8 Hz),
5.95 (d, 1H, J ¼ 3:9 Hz); 13C NMR (125 MHz, CDCl3) d
24.1 (q), 25.8 (q), 26.2 (q), 26.7 (q), 29.9 (t), 57.5 (q), 71.6
(d). 72.8 (d), 74.2 (d), 80.8 (d), 81.0 (d), 83.9 (d), 105.1 (d),
110.6 (s), 111.9 (s), 167.1 (s). Anal. Calcd for C16H24O8: C,
14. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Hughes, D. L.
Org. Prep. Proced. Int. 1996, 28, 157–164.
D
15. Spectraldata of 22: ½aŠ )12.64 (c 1.22, CHCl3); 1H NMR
25
(300 MHz CDCl3) d 1.20 (s, 9H), 1.47–1.74 (m, 4H), 3.39
(s, 3H), 3.52–3.63 (m, 3H), 3.67–3.78 (m, 2H), 3.91–4.02
(m, 2H), 4.12 (dd, 1H, J ¼ 11:8, 6.3 Hz), 4.32 (dd, 1H,
J ¼ 11:8, 3.8 Hz), 4.47 (s, 2H), 4.54 (d, 1H, J ¼ 11:4 Hz),
4.55 (d, 1H, J ¼ 11:8 Hz), 4.59 (d, 1H, J ¼ 11:4 Hz), 4.64
(d, 1H, J ¼ 11:8 Hz), 4.66 (d, 1H, J ¼ 11:4 Hz), 4.70
(d, 1H, J ¼ 11:8 Hz), 7.25–7.40 (m, 20H); 13C NMR
(125 MHz, CDCl3) d 27.0 (q), 37.3 (t), 38.6 (s), 38.9 (t),
58.1 (q), 63.5 (t), 67.1 (d), 69.9 (t), 72.3 (t), 72.8 (t), 72.9 (t),
73.3 (t), 76.0 (d), 78.4 (d), 79.3 (d), 80.9 (d), 127.4–128.2
(severalarom. ds), 138.0 (s), 138.2 (s), 138.3 (s), 138.4 (s),
178.1 (s). Anal. Calcd. for C43H54O8: C, 73.90; H, 7.79.
Found: C, 73.49; H, 7.66.
55.81; H, 7.02. Found: C, 55.73; H, 7.21.
D
11. Spectraldata of 15: ½aŠ +34.08 (c 1.4, CHCl3); mp 142–
25
145 ꢁC; 1H NMR (500 MHz, CDCl3) d 1.28 (t, 3H,
J ¼ 7:1 Hz), 1.31, 1.48 (2s, 6H), 1.65 (t, 1H, J ¼ 13:3 Hz),
2.19 (br dt, 1H, J ¼ 13:3, 2.8 Hz), 2.47 (br s, 1H, OH), 2.51
(br s, 1H, OH), 3.40 (dt, 1H, J ¼ 7:7, 2.8 Hz), 3.44 (s, 3H),
3.57 (dq, 1H, J ¼ 9:3, 7.2 Hz), 3.78 (d, 1H, J ¼ 2:9 Hz),
3.92 (dq, 1H, J ¼ 9:3, 7.2 Hz), 4.02 (dd, 1H, J ¼ 8:9,
2.9 Hz), 4.17 (ddd, 1H, J ¼ 11:6, 8.9, 2.8 Hz), 4.22–4.24 (m,
1H), 4.53 (d, 1H, J ¼ 3:7 Hz), 4.63 (d, 1H, J ¼ 7:7 Hz),
5.85 (d, 1H, J ¼ 3:7 Hz); 13C NMR (50 MHz, CDCl3) d
14.7 (q), 25.7 (q), 26.2 (q), 34.6 (t), 57.6 (q), 64.4 (t), 66.0
(d), 66.8 (d), 71.0 (d), 81.3 (d), 82.9 (d), 99.8 (d), 104.4 (d),
110.9 (s). Anal. Calcd for C15H26O8: C, 53.88; H, 7.84.
Found: C, 53.73; H, 8.19.
16. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,
4155–4156; (b) Dess, D. B.; Martin, J. C. J. Am. Chem.
Soc. 1991, 113, 7277–7287.
D
17. Spectraldata of 4: ½aŠ )7.15 (c 0.3, CHCl3); 1H NMR
25
(500 MHz CDCl3) d 0.10, 0.12 (2s, 6H), 0.88 (s, 9H), 1.32,
1.33 (2s, 6H), 1.68 (ddd, 1H, J ¼ 14:7, 5.0, 2.2 Hz), 1.88 (t,
2H, J ¼ 6:3 Hz), 2.22 (ddd, 1H, J ¼ 15:0, 11.3, 4.2 Hz),
3.37–3.40 (m, 1H), 3.42 (s, 3H), 3.64–3.67 (m, 2H), 3.73
(dd, 1H, J ¼ 13:3, 6.3 Hz), 4.11–4.19 (m, 1H), 4.38 (td,
1H, J ¼ 11:2, 2.5 Hz), 4.59 (d, 1H, J ¼ 2:5 Hz); 13C NMR
(125 MHz, CDCl3) d )4.7 (q), )4.6 (q), 17.9 (s), 19.2 (q),
21.9 (q), 25.7 (q), 36.1 (t), 44.7 (s), 57.9 (q), 63.9 (t), 67.9
(d), 68.9 (d), 72.5 (d), 78.8 (d), 85.9 (d), 177.7 (s), 211.5 (s).
Anal. Calcd for C20H38O8Si: C, 55.27; H, 8.81. Found: C,
54.89; H, 8.96.
12. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585.
D
25
1
13. Spectraldata of 20: ½aŠ )9.67 (c 0.65, CHCl3); H NMR
(500 MHz, CDCl3) d 1.21 (s, 9H), 1.48 (dd, 1H, J ¼ 6:3,
2.8 Hz), 1.58 (br dt, 1H, J ¼ 14:2, 4.0 Hz), 1.64 (ddd, 1H,
J ¼ 14:2, 4.0, 2.8 Hz), 1.83 (dt, 1H, J ¼ 14:7, 8.8 Hz), 3.39
(s, 3H), 3.56 (dd, 1H, J ¼ 9:9, 6.3 Hz), 3.63 (br dt, 1H,
J ¼ 9:1, 3.8 Hz), 3.65–3.71 (m, 2H), 3.76 (dt, 1H, J ¼ 6:3,
3.8 Hz), 3.84 (dt, 1H, J ¼ 8:3, 3.8 Hz), 3.90–3.94 (m, 1H),
4.18 (dd, 1H, J ¼ 11:9, 6.3 Hz), 4.38 (dd, 1H, J ¼ 11:9,
3.8 Hz), 4.53 (s, 2H), 4.57 (d, 1H, J ¼ 11:6 Hz), 4.63 (d,
1H, J ¼ 11:6 Hz), 4.64 (d, 1H, J ¼ 12:0 Hz), 4.70 (br d,
2H, J ¼ 11:6 Hz), 4.73 (d, 1H, J ¼ 12:0 Hz), 7.17–7.38 (m,
20H); 13C NMR (125 MHz, CDCl3) d 27.2 (q), 38.5 (t),
38.6 (t), 38.7 (s), 59.0 (q), 63.5 (t), 66.9 (d), 70.3 (t),
72.3 (t), 72.6 (t), 72.9 (t), 73.3 (t), 77.8 (d), 78.7 (d),
78.9 (d), 79.2 (d), 127.4–128.4 (severalarom. ds), 137.7
18. The crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as deposition
Nos. CCDC-219593 (15) and CCDC-219594 (12). Copies
of the data can be obtained, free of charge, on applica-
tion to the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44(1223)336033; e-mail: deposit@ccdc. cam.
ac.uk].