Synthetic studies on a phenyl-laulimalide analogue

Article abstract of DOI:10.1016/j.tetlet.2006.09.104

An analogue of the paclitaxel-like antimicrotubule agent laulimalide with a phenyl in place of the dihydropyran has been synthesized. The fragments C₁-C₁₄ and C₁₅-C₂₈ were coupled via a stereoselective intermole

Full text of DOI:10.1016/j.tetlet.2006.09.104

Tetrahedron Letters 47 (2006) 8305–8308
Synthetic studies on a phenyl-laulimalide analogue
Christelle Faveau,a Martine Mondon,a Jean-Pierre Gesson,a,* Tobias Mahnke,b
Sandra Gebhardtb and Ulrich Koertb,*
aCNRS UMR 6514,Universite´ de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
bFachbereich Chemie, Philipps-Universita¨t Marburg, D-35032 Marburg, Germany
Received 17 July 2006; revised 18 September 2006; accepted 19 September 2006
Available online 9 October 2006
Abstract—An analogue of the paclitaxel-like antimicrotubule agent laulimalide with a phenyl in place of the dihydropyran has been
synthesized. The fragments C1–C14 and C15–C28 were coupled via a stereoselective intermolecular allylboration. Ring closure was
achieved using Yamaguchi’s protocol.
Ó 2006 Elsevier Ltd. All rights reserved.
The marine macrolide (ꢀ)-laulimalide 1 (Scheme 1)
exhibits a strong cytotoxicity against several human can-
cer cell lines.1 Its microtubule-stabilizing mode of action
is related to TaxolÒ (paclitaxel).2 Laulimalide is superior
in that it retains activity against cancer cells that are
resistant to Taxol.3 As a result of this biological profile,
a number of total syntheses of laulimalide4 and laulima-
lide analogues5,6 has been reported. Here, we present
our efforts towards laulimalide analogues, where the
dihydropyran is replaced by an aromatic moiety. As a
OMOM
OH
H
MOMO
O
H
O
HO
OH
15
22
18
R
12
O
COOH
H
H
H
H
O
O
2
H
Ph
8
O
O
H
3
B
H
O
OMOM
COOMe
1: R =
2 : R =
H
O
O
OTBDPS
4: C15-C28 fragment
5: C1-C14 fragment
Scheme 1. Retrosynthetic analysis.
Keywords: Synthesis; Natural product analogues; Laulimalide; Stereoselective synthesis; Allylboration.
*
Corresponding authors. Tel.: +49 6421 282 6970/5570; fax: +49 6421 282 5677 (U.K.); e-mail addresses: jean-pierre.gesson@univ-poitiers.fr;
koert@chemie.uni-marburg.de
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.104

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C. Faveau et al. / Tetrahedron Letters 47 (2006) 8305–8308
OH
OMOM
a
Cl
b, c
Cl
O
OH
6 (E/Z, 5:1)
7
8
OMOM
OMOM
HO
d, e
h
i
R2O
4
OR1
OTBDPS
9
R
1 = H, R2 = THP
10 R1 = TBDPS, R2 = H
11
f, g
Scheme 2. Reagents and conditions: (a) AD-mix a, tert-BuOH/H2O, MeSO2NH2, 20 °C, 80%; (b) NaOH, THF, 20 °C, 85%; (c) (i-Pr)2NEt,
MeOCH2Cl, 76%; (d) n-BuLi, HCCCH2OTHP, BF3–OEt2, THF, ꢀ78 °C, 83%; (e) Red-Al, THF, ꢀ20 °C 84%; (f) imidazole, TBDPSCl, DMF,
20 °C, 90%; (g) HCl/MeOH, 20 °C, 82%; (h) see (e), 55%; (i) MnO2, CH2Cl2, 40 °C, 95%.
prototype of these compounds we focused on phenyl-
a
b
laulimalide 2. Our synthetic strategy (Scheme 1) was
based on a final macrolactonization (3!2) and a stereo-
selective allylboration to connect C15–28 aldehyde 4 with
the C1–14 allyl boronate 5.
Me3Si
OTBDPS
OTBDPS
OH OH
12
13
TES
O
O
O
H
c
As outlined in Scheme 2, the synthesis of 4 relies on the
Sharpless asymmetric dihydroxylation reaction7 of the
1,3-enyne 6,8 to introduce the two stereocentres C19
and C20. Using AD-mix-a,9 (2R,3S)-diol 7 (ee 98%,
determined by Chiracel OD-H HPLC) was obtained.
Compound 7 contained traces of the (2S,3S) isomer de-
rived from traces of the Z-isomer in 6. These diastereo-
isomers were difficult to separate, however E-6 allylic
chloride was more reactive than Z-6, which allowed to
obtain (2R,3S)-7 diastereoisomer in a 16:1 ratio. Treat-
ment of the chlorodiol (2R,3S)-7 with sodium hydroxide
led after purification by flash chromatography to the
corresponding pure (S,S)-(ꢀ)-epoxy alcohol in an 85%
yield. MOM protection of the hydroxyl group furnished
epoxide 8 in 76% yield. Subsequent chain extension
(C15–C17) by the opening of epoxide 8 with the lithium
salt of THP propargylic ether10 in the presence of
BF3–Et2O11 furnished the di-protected triol in an 83%
yield. Reduction using Red-AlÒ12 led to E-alkene 9.
No reduction of the other triple bond was observed.
Alcohol 9 was subsequently protected as the TBDPS
ether and after removal of the THP ether with HCl in
methanol, compound 10 was obtained. The propargylic
alcohol in 10 was reduced with Red-AlÒ using the same
conditions as previously, to furnish the E-allylic alcohol
11. The MnO2-oxidation of 11 completed the synthesis
of C15–C28 fragment 4.13
N
O
O
OTBDPS
Ph
15
16
OTBDPS
OTBDPS
d
e
H
O
H
H
O
O
O
OH
18
17
Ph
H
O
O
B
B
O
O
O
O
H
Ph
19
N
O
f
5
Ph
14
Scheme 3. Reagents and conditions: (a) (i) NaH, TBDPSCl, THF,
0 °C, 96%, (ii) MsCl, NEt3, CH2Cl2, ꢀ5 °C, (iii) LiCl, acetone, 45 °C,
87% (two steps), (iv) Mg, TMSCl, THF, reflux, 87%; (b) 14, TiCl4,
CH2Cl2, ꢀ78 °C, 91%; (c) (i) DIBAH, toluene, ꢀ78 °C, 83%, (ii) LDA,
(R)-(+)-HYTRA, THF, ꢀ100 °C, 99%, (iii) TESCl, imidazole,
CH2Cl2, 20 °C, 98%, (iv) DIBAH, THF, ꢀ78 °C, 92%, (v) Dess–
Martin, 0 °C, 99%; (d) (i) LDA, (R)-(+)-HYTRA, THF, ꢀ100 °C, 4 h,
97%, de 88:12, (ii) TFA, H2O 20 °C, 50 min, 99%, (iii) NaOH, MeOH,
20 °C, 80 min, (iv) p-TsOH, CH2Cl2, 20 °C, 85 min, 93% (two steps);
(e) (i) MsCl, NEt3, CH2Cl2, 0 °C, 97%, (ii) DIBAH, toluene, ꢀ78 °C,
(iii) CSA, EtOH 20 °C, 91% (two steps), (iv) LiClO4, H2C@CH–OTBS,
EtOAc, 20 °C, 75%; (f) (i) Still–Gennari, ꢀ78 °C, Z:E = 10:1, 89%, (ii)
HF/pyridine, 20 °C, CH3CN, 97%, (iii) Ac2O, DMAP, NEt3, CH2Cl2,
0 °C, 97%, (iv) 19, Pd(dba)2, DMSO, 50 °C, 74%.
The synthesis of allyl boronate 5 is summarized in
Scheme 3. The stereogenic centre C11 was built up via
a stereocontrolled Sakurai reaction.14 Starting point
was the mono-protection of diol 12 with TBDPSCl.
Conversion of the alcohol into an allyl chloride followed
by treatment with TMSMgCl afforded the allylsilane
13.15 The reaction of 13 and 1416 with TiCl4 gave 15
in a 91% yield and 98% ds. After conversion of the
oxazolidinone into an aldehyde, the reaction with lithi-
ated (R)-(+)-2-acetoxy-1,1,2-triphenylethanol ((R)-(+)-
HYTRA)17 introduced the C9 stereocentre (ds 89:11).
A subsequent TES protection followed by a DIBAH
reduction/Dess–Martin oxidation afforded aldehyde
16. A second (R)-(+)-HYTRA addition (ds 88:12) and

C. Faveau et al. / Tetrahedron Letters 47 (2006) 8305–8308
8307
an acid-mediated lactonization led to the b-hydroxy
lactone 17.
Due to the Z/E isomerization under Yamaguchi condi-
tions, a Mitsunobu macrolactonization strategy would
be advantageous. This requires the synthesis of the C19
epimer of aldehyde 4, which is under current investiga-
tion. In conclusion, the intermolecular allylboration
proved to be an efficient synthetic route to the molecular
framework of laulimalide analogues.
Mesylation/elimination of 17 introduced the C6,7 double
bond. Subsequent DIBAH-reduction led to the lactol
and the corresponding ethyl acetal. The installation of
the C5 stereocentre was achieved using Mulzer’s enol
ether method.4f Compound 18 was the only stereoiso-
mer obtained. The trans configuration of the dihydro-
pyran was proven by NOESY-NMR experiments. A
Still–Gennari-reaction of 18 led to the corresponding
Z a,b-unsaturated ester. After deprotection of the
TBDPS ether, the resulting alcohol was converted into
the corresponding allylic acetate. A Pd(0) mediated reac-
tion of the allylic acetate with the chiral diborane
reagent 1918 in DMSO,19 furnished the desired allyl
boronate 520 (74% based on recovered starting material).
Acknowledgement
This work was supported by CERC3, the CNRS and the
DFG.
References and notes
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Sc(OTf)3 mediated21 intermolecular allylboration
(Scheme 4). The use of 10 equiv of Sc(OTf)3 in CH2Cl2
gave the homoallylic alcohol 20 with a 7:1 stereoselectiv-
ity. The diastereoselectivity of the allylboration was
determined after esterification with (R)-(ꢀ)-methoxy-
phenylacetic acid. In preparation of the following mac-
rolactonization, 20 was converted into hydroxy acid 3.
Macrolactonization under Yamaguchi conditions22 fur-
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isomerization is in accordance with earlier observa-
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after MOM-ether cleavage and chromatography. The
first attempts to introduce the epoxide according to
Mulzer5a led to an inseparable mixture of phenyl-lauli-
malide 2 and its isolaulimalide isomer.
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OMOM
¨
Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. 2001, 40,
HO
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OTBDPS
a
+
4
5
CO2Me
H
H
O
20
b
3
OH
5. (a) Ahmed, A.; Hoegenauer, K.; Enev, V. S.; Hanbauer,
HO
¨
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O
c
O
H
H
O
21
Scheme 4. Reagents and conditions: (a) Sc(OTf)3, CH2Cl2, ꢀ78 °C,
92%; (b) (i) MOMCl, i-Pr2NEt, CH2Cl2, 20 °C, 92%, (ii) DIBAH,
toluene, ꢀ78 °C, 92%, (iii) MnO2, CH2Cl2, 40 °C, 88%, (iv) NaClO2,
NaH2PO4, (CH3)2C@CHCH3, tBuOH, H2O, 20 °C, 89%, (v) TBAF,
THF, 20 °C, 79%; (c) (i) Yamaguchi, 20 °C, 42%, (ii) Me2BBr, CH2Cl2,
ꢀ78 °C, 71%.

8308
C. Faveau et al. / Tetrahedron Letters 47 (2006) 8305–8308
6. (a) Paterson, I.; Menche, D.; Hakansson, A. E.; Longstaff,
1722 (s), 1643 (w), 1438 (m), 1372 (m), 1324 (m), 1216 (m),
1168 (s), 1017 m, 699 (m); H NMR (CDCl3, 300 MHz)
1
A.; Wong, D.; Barasoain, I.; Bury, R. M.; Diaz, J. F.
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d = 0.75 (d, J = 6.0 Hz, 3H, CH3–C-20), 0.83–1.05 (m, 3H,
10-H2, 6000-H2), 0.93 (s, 3H, 10000-H3), 1.08 (s, 3H, 8000-H3),
1.22 (s, 3H, 9000-H3), 1.47–1.61 (m, 3H, 10-H2, 5000-H2), 1.67
(s, 2H, 10000-H2), 1.83–2.00 (m, 5H, 5-H2, 20-H, 30-H2), 2.34
(pd, J = 3.6 Hz, 1H, 4000-H), 2.86–3.04 (m, 2H, 400-H2), 3.70
(s, 3H, O–CH3), 3.71–3.78 (m, 1H, 6-H), 4.23–4.25 (m,
1H, 2-H), 4.54 (s, 2H, 2000-H), 4.61 (s, 1H, 50-H2), 4.66 (s,
1H, 50-H2), 5.67–5.70 (m, 1H, 3-H), 5.81–5.83 (m, 1H, 4-
H), 5.86 (pd, J = 11.6 Hz, 1H, 200-H), 6.39 (dt,
J = 11.6 Hz, 7.0 Hz, 1H, 300-H), 7.29–7.43 (m, 5H, Ph);
13C NMR (CDCl3, 75 MHz) d = 11.2 (C-10000), 19.3 (CH3–
C-20), 21.1 (C-8000), 22.8 (C-9000), 24.2 (C-6000), 26.4 (C-20),
31.1 (C-5), 31.8 (C-5000), 33.5 (C-400), 42.2 (C-30), 46.0 (C-
10), 48.5 (C-10000), 49.0 (C-7000), 51.0 (O–CH3), 52.9 (C-4000),
65.1 (C-6), 71.8 (C-2), 90.9 (C-1000), 93.5 (C-2000), 93.7 (C-
3000), 111.0 (C-50), 120.3 (C-200), 124.9 (C-4), 126.1, 127.4,
128.3, 142.7 Ph, 128.9 (C-3), 144.5 (C-40), 147.4 (C-300),
166.8 (C-100); 11B NMR (160 MHz, CDCl3) d = 10.6;
HRMS (ESI) calcd for C33H45BNaO5 [M+Na]+:
555.3258, found: 555.3263.
7. Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547.
8. Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B.
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12. Crousse, B.; Alami, M.; Linstrumelle, G. Synlett 1997,
992–994.
13. Compound 4: Rf = 0,16 (nhexane/MTBE = 5:1); IR
(cmꢀ1): 3070 w, 2932 m, 2890 m, 2858 m, 1693 s, 1427 m,
21. Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am.
Chem. Soc. 2003, 125, 10160–10161.
1
1152 m, 1106 s, 1030 s, 974 m, 741 m, 704 s, 508 m; H
NMR (CDCl3, 300 MHz) d = 1.09 (s, 9H, SiC(CH3)3),
2.42–2.65 (m, 2H, 4-H2), 3.23 (s, 3H, O–CH3), 4.06–4.11
(m, 1H, 5-H), 4.20–4.24 (m, 1H, 6-H), 5.94 (dd,
J = 15.6 Hz, 8.1 Hz, 1H, 2-H), 6.22 (dd, J = 16.1 Hz,
6.8 Hz, 1H, 7-H), 6.59 (d, J = 16.1 Hz, 1H, 8-H), 6.63–
6.74 (m, 1H, 3-H), 7.18–7.39 (m, 11H, TBDPS-Ph, Ph),
7.55–7.61 (m, 4H, TBDPS-Ph), 9.27 (d, J = 8.1 Hz, 1H, 1-
H); 13C NMR (CDCl3 75 MHz) d = 19.4 (SiC(CH3)3),
27.0 (SiC(CH3)3), 36.1 (C-4), 55.6 (O–CH3), 74.2 (C-5),
78.9 (C-6), 94.6 (O–CH2–O), 125.5 (C-7), 126.5, 127.7,
127.8, 128.6, 129.9, 130.0, 133.3, 133.4, 135.9 Ph, TBDPS-
Ph, 134.4 (C-8), 136.0 (C-2), 155.7 (C-3), 193.8 (C-1);
HRMS (ESI) calcd for C32H38NaO4Si [M+Na]+:
537.2437, found: 537.2426.
22. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yama-
guchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
23. Compound 21: Rf = 0.34 (nhexane/MTBE = 1:2); 1H
NMR: (600 MHz, CDCl3) d = 0.74 (ddd, J = 14.2 Hz,
10.9 Hz, 3.1 Hz, 1H, 10-H2), 0.87 (d, J = 6.4 Hz, 3H,
CH3–C-11), 1.60–1.72 (m, 2H, 8-H2, 11-H), 1.81–2.03 (m,
5H, 10-H2, 12-H2, 14-H2, OH–C-15, OH–C-20), 2.07–2.13
(m, 1H, 12-H2), 2.16–2.23 (m, 2H, 4-H2, 14-H2), 2.32–2.49
(m, 3H, 8-H2, 18-H2), 3.38–3.42 (m, 1H, 4-H2), 4.00–4.10
(m, 1H, 9-H), 4.12–4.15 (m, 1H, 5-H), 4.17–4.22 (m, 1H,
15-H), 4.32–4.36 (m, 1H, 20-H), 4.88, 4.92 (je s, 2H, 23-
H2), 5.13–5.18 (m, 1H, 19-H), 5.60–5.72 (m, 3H, 6-H, 16-
H, 17-H), 5.75–5.77 (m, 1H, 7-H), 5.90 (d, J = 11.6 Hz,
1H, 2-H), 6.19 (dd, J = 16.0 Hz, 6.4 Hz, 1H, 21-H), 6.52–
6.57 (m, 1H, 3-H), 6.70 (d, J = 16.0 Hz, 1H, 22-H), 7.25–
7.31 (m, 5H, Ph); 13C NMR: (125 MHz, CDCl3) d = 18.3,
19.8 (CH3–C-11), 25.8 (C-11), 29.1 (C-8), 33.8 (C-18), 38.0
(C-10), 42.5 (C-14), 45.9 (C-12), 67.5 (C-9), 68.5 (C-15),
69.1 (C-5), 74.4 (C-20), 74.9 (C-19), 114.5 (C-23), 120.2 (C-
2), 123.7 (C-7), 124.9 (C-17), 126.6, 128.0, 129.0, 129.2,
135.8 Ph, 127.5 (C-21), 128.0 (C-6), 132.8 (C-22), 136.6 (C-
16), 144.6 (C-13), 149.3 (C-3), 165.5 (C-1); IR (cmꢀ1): 3435
(br), 3029 (m), 2924 (s), 1717 (s), 1641 (m), 1433 (w), 1410
(w), 1327 (w), 1216 (m), 1167 (s), 1076 (m), 969 (m), 894
(w), 818 (w), 751 (w), 694 (w); [a]D ꢀ108.1 (c 1.27, CHCl3);
HR-MS (ESI) calcd for C30H38NaO5 [M+Na]+: 501.2611,
found: 501.2616.
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20
20. Compound 5: Rf = 0.14 (nhexane/MTBE = 10:1); ½aꢁD
+38.8 (c 0.98 in CHCl3); IR (cmꢀ1): 2950 (m), 2927 (m),