Synthesis of 8-(S)-methoxy-11-desmethyl laulimalide: A novel laulimalide analogue

Article abstract of DOI:10.1016/j.tetlet.2004.12.056

A strategy is outlined which enables preparation of novel laulimalide analogues at C.8 and C.11. A representative analogue, 8-(S)-methoxy-11-desmethyl laulimalide, was synthesized via this route.

Full text of DOI:10.1016/j.tetlet.2004.12.056

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 923–926
Synthesis of 8-(S)-methoxy-11-desmethyl laulimalide: a novel
laulimalide analogue
Brian M. Gallagher, Jr.,* Hongjuan Zhao, Marc Pesant and Francis G. Fang
Eisai Research Institute, 100 Research Drive, Wilmington, MA 01887, USA and 4 Corporate Drive, Andover, MA 01810, USA
Received 30 November 2004; revised 8 December 2004; accepted 13 December 2004
Available online 29 December 2004
Abstract—A strategy is outlined which enables preparation of novel laulimalide analogues at C.8 and C.11. A representative ana-
logue, 8-(S)-methoxy-11-desmethyl laulimalide, was synthesized via this route.
Ó 2004 Elsevier Ltd. All rights reserved.
The marine natural product (À)-laulimalide (1, Fig. 1)
was first isolated in 1988 fromseveral sources of marine
sponge and shown to be highly cytotoxic in a number of
human cancer cell lines.1 Later it was reported that 1 in-
duces microtubule polymerization and stabilization sim-
ilar to paclitaxel, but retains activity in a P-glycoprotein
(PgP) over-expressing multidrug resistant cell line.2 It
was recently reported that laulimalide binds to a differ-
ent site of the tubulin polymer than most other microtu-
bule stabilizers and retains activity against cell lines
containing mutations in the b-tubulin gene.3 These re-
ports have generated an enormous amount of excite-
ment about the therapeutic potential of this natural
product and as a result, there has been a surge of syn-
thetic efforts toward 1 resulting in a number of total syn-
theses.4,5 Despite these synthetic efforts, there have been
few reports of biological evaluation of laulimalide ana-
logues to date.3,5,6
OH
20
O
O
15
O
27
R2
R2
OH
O
1
11
O
4
O
OH
OH
R1
8
HO
OH
D-Arabinose
OTBS
20
O
27
OHC
15
+
OMPM
O
HO
2
(R)-Glycidol
O
+
Br
14
R2
R2
AcO
AcO
11
O
OAc
2
R1
8
OH
O
D-Triacetylglucal
3
15
O
27
20
Figure 2. Strategy to access analogues at C.8 and C.11.
OH
O
O
11
1
O
4
We recently reported a total synthesis of laulimalide and
a series of analogues modified at C.2–C.3, C.15–C.17,
and C.20.5 In order to further probe the SAR of 1, we
wanted to explore changes in the C.8–C.11 region
(Fig. 2). Paterson et al. recently reported the molecular
modeling studies and syntheses of C.11 desmethyl
laulimalide analogues.6c Modeling predicted little per-
turbation to the conformations of the C.1–C.4 and
Laulimalide (1)
8
Figure 1. The marine natural product (À)-laulimalide with carbon
numbering.
Keywords: Laulimalide; Analogue.
*
Corresponding author. Tel.: +1 978 661 7264; fax: +1 978 657
7715; e-mail: brian_gallagher@eri.eisai.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.056

924
B. M. Gallagher, Jr. et al. / Tetrahedron Letters 46 (2005) 923–926
C.15–C.20 regions by removal of the C.11 stereocenter.
We wished to extend this concept by rigidifying the con-
formation of the C.5–C.9 dihydropyran. Examination of
the crystal structure of 1,1d indicates the 2,6-trans sub-
stituents of the lower dihydropyran ring adopt a pseu-
do-axial and pseudo-equatorial relationship for C.4
and C.10, respectively. It was hypothesized that a a-sub-
stituent at C.8 would reinforce the conformation of the
lower pyran and consequently the macrocycle. Thus a
C.8 (S)-methoxy C.11 desmethyl analogue was targeted.
ing fluoride removal of the TBS.9 The primary alcohol
of 5 was homologated to the alkynyl iodide 6 via dis-
placement of the corresponding triflate under carefully
controlled conditions.10 Alkynyl iodide 6 underwent effi-
cient coupling with aldehyde 1011 to produce the ynone
(7) after oxidation. The ynone 7 cleanly underwent a
double Stryker-type reduction12 to produce the corre-
sponding ketone, which was methylenated under typical
conditions. Selective removal of the dioxolane in the
presence of the TBDPS ether was accomplished using
80% aqueous HOAc to produce aldehyde 8. Corey–
Fuchs protocol of aldehyde 8 produced the terminal al-
kyne. Removal of the silyl ether and conversion to the
allylic bromide produced the C.2–C.14 fragment 9.
The requisite C.2–C.14 fragment was synthesized as out-
lined in Scheme 1. Triacetyl glucal underwent a carbon
Ferrier reaction with allyltrimethylsilane to produce
the allyl addition product with the 2,6 substituents
exclusively trans.7 The allyl addition product was con-
verted to the crystalline dioxolane intermediate (4) in
50% overall yield through a standard sequence of
dihydroxylation, diol cleavage,8 and protection of the
resultant aldehyde. Hydrolysis of the acetates, mono-
protection of the primary alcohol as a TBS ether, and
methylation of the secondary alcohol provided 5 follow-
The C.15–C.27 fragment was prepared as outlined in
Scheme 2. The known aldehyde 11,13 available in six
steps from D-arabinose, underwent Horner–Wads-
worth–Emmons reaction to produce the a,b-unsaturated
ester in a ꢀ4:1 mixture of E:Z stereoisomers. During the
course of this work, we found a convenient procedure
for improving the ratio to almost exclusively E by treat-
ing crude 12 with catalytic Bu3P in CH3CN at 60 °C
overnight.14 Removal of the acetonide and periodate
cleavage of the resultant diol produced the aldehyde
13. The aldehyde was efficiently coupled with the
known15 vinyl iodide 16 under NiCl2/CrCl2 mediated
conditions to give a ꢀ1:2 a:b-mixture of diastereomers.
O
AcO
AcO
O
O
a-d
e-h
AcO
AcO
O
Oxidation followed by reduction with L-SelectrideÒ
OAc
16
produced the desired stereoisomer,17 which was pro-
tected as the TBS ether 14. DIBAL-H reduction of the
methyl ester followed by Swern oxidation produced
the enal coupling partner 15.
4
OH
O
O
i-l
O
O
I
O
O
MeO
MeO
Indiummediated coupling of 9 and 15 produced a ꢀ1:1
5
6
mixture of diastereomeric alcohols at C.15 which were
O
OTBDPS
O
OTBDPS
m,n
o-q
O
O
a
b,c
O
O
O
O
OHC
MeO2C
CHO
OMPM
OMPM
O
MeO
MeO
11
12
7
8
OTBS
O
d-g
CHO
OMPM
MeO2C
MeO2C
Br
OMPM
r-t
OHC
OTBDPS
10
O
13
14
9
MeO
OTBS
I
O
O
h,i
OHC
Scheme 1. Reagents and conditions: (a) TFA, TMS allyl silane,
CH3CN, 0 °C; (b) K2OsO4, NMO, THF/H2O (2/1); (c) NaIO4,
CH2Cl2, aq NaHCO3; (d) p-TsOH, (CH2OH)2, PhH, reflux, –H2O
(50%); (e) K2CO3, MeOH; (f) TBSCl, imidazole, DMF, 10 °C; (g)
NaH, MeI, DMF; (h) TBAF, THF (75%); (i) Tf2O, 2,6-di-t-
butylpyridine, CH2Cl2, À50 °C; (j) TMSCCLi, HMPA, THF,
À78 °C (80%); (k) Cs2CO3, MeOH; (l) AgNO3, NIS, acetone (70%);
(m) 0.1% NiCl2/CrCl2, 10, THF; (n) TPAP, NMO, CH2Cl2 (80%);
(o) [(Ph3P)CuH]6 (0.6 M equiv), PhCH3, trace H2O (65%); (p)
Ph3PCH3Br, n-BuLi, THF, 0 °C (90%); (q) 80% aq HOAc, 60 °C
(50%); (r) CBr4, Ph3P, CH2Cl2, À78 °C; n-BuLi, THF, À78 °C; (s)
TBAF, THF; (t) Ph3P, NBS, CH2Cl2, 0 °C (70%).
OMPM
15
16
Scheme 2. Reagents and conditions: (a) (i) (MeO)2POCH2CO2Me,
NaH, THF, 0 °C, (ii) Bu3P (cat.), CH3CN, 60 °C (85%); (b) 1 M HCl/
THF (1/1); (c) NaIO4, THF/H2O (1/1), 0 °C (70%); (d) 0.1% NiCl2/
CrCl2, 16, DMSO (60%); (e) Dess–Martin periodane, CH2Cl2; (f)
L-SelectrideÒ, THF, À78 °C (50%); (g) TBSOTf, imidazole, DMF
(90%); (h) DIBAL, CH2Cl2, À78 °C (80%); (i) (COCl)2, DMSO,
Et3N, CH2Cl2, À78 °C (85%).

B. M. Gallagher, Jr. et al. / Tetrahedron Letters 46 (2005) 923–926
925
to access additional analogues modified in the C.8 and
C.11 regions of laulimalide to further probe the SAR.
Efforts in this area will be reported in due course.
OTBS
TBSO
O
OMPM
a,b
9
15
+
References and notes
O
1. (a) Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988,
53, 3642–3644; (b) Corley, D. G.; Herb, R.; Moore, R. E.;
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17
MeO
OTBS
TBSO
O
O
O
f,g
c-e
O
18
MeO
OTBS
O
h,i
TBSO
O
O
O
19
MeO
4. (a) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122,
11027–11028; (b) Ghosh, A. K.; Wang, Y. Tetrahedron
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Crimmins, M. T.; Stanton, M. G.; Allwein, S. P. J. Am.
Chem. Soc. 2002, 124, 5958–5959; (j) Williams, D. R.; Mi,
L.; Mullins, R. J.; Stites, R. E. Tetrahedron Lett. 2002, 43,
4841–4844; (k) Nelson, S. G.; Cheung, W. S.; Kassick, A.
J.; Hilfiker, M. A. J. Am. Chem. Soc. 2002, 124, 13654–
13655; See also: Mulzer, J.; Enev, V. S. EP 1295886, 2003;
Ashley, G.; Metcalf, B. WO 02064589, 2002; Ghosh, A. K.
WO 03076445, 2003, Ref. 6b. For recent reviews, see:
Crimmins, M. T. Curr. Opin. Drug Disc. Dev. 2002, 5,
944–959, and; Mulzer, J.; Ohler, E. Chem. Rev. 2003, 103,
3753–3786.
OH
O
O
O
OH
O
O
20
MeO
Scheme 3. Reagents and conditions: (a) indium, THF/H2O (3/1), HCl
(cat.) (65%); (b) TBSOTf, DMAP, pyridine (80%); (c) (i) n-BuLi, THF,
À78 °C, (ii) CO2 (gas); (d) DDQ, CH2Cl2/H2O (2/1) (70%); (e) 2,4,6-
trichlorobenzoyl chloride, DMAP, toluene (45%); (f) H2, Lindlar cat.,
quinoline, hexane/CH2Cl2 (3/1) (80%); (g) HPLC; (h) H2SiF6, CH3CN;
(i) (+)-DIPT, Ti(OiPr)4, t-BuOOH, CH2Cl2, À15 °C (50%).
protected as the TBS ethers (Scheme 3). Carboxylation
of the alkyne of 17 and removal of the MPM group
allowed for macrolactonization under Yamaguchi-type
conditions4b to produce 18. Lindlar reduction and chiral
HPLC (ChiralpakÒ AD) separation of the C.15 diaste-
reomers produced the Z enoate 19. Deprotection and
Sharpless epoxidation produced the 8-(S)-methoxy-11-
desmethyl laulimalide (20).18
5. Gallagher, B. M., Jr.; Fang, F. G.; Johannes, C. W.;
Pesant, M.; Tremblay, M. R.; Zhao, H.; Akasaka, K.; Li,
X.; Liu, J.; Littlefield, B. A. Biorg. Med. Chem. Lett. 2004,
14, 575–579.
6. (a) Wender, P. A.; Hegde, S. G.; Hubbard, R. D.; Zhang,
L.; Mooberry, S. L. Org. Lett. 2003, 5, 3507–3509; (b)
Ahmed, A.; Hoegenauer, E. K.; Enev, V. S.; Hanbauer,
M.; Kaehlig, H.; Ohler, E.; Mulzer, J. J. Org. Chem. 2003,
68, 3026–3042; (c) Paterson, I.; Bergmann, H.; Menche,
D.; Berkessel, A. Org. Lett. 2004, 6, 1293–1295; (d)
Mooberry, S. L.; Randall-Hlubek, D. A.; Leal, R. M.;
Hegde, S. G.; Hubbard, R. D.; Zhang, L.; Wender, P. A.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8803–8808.
7. Danishefsky, S.; Kerwin, J. F., Jr. J. Org. Chem. 1982, 47,
3803–3805.
The route outlined above contains sufficient flexibility to
provide additional analogues at C.8 and C.11 to further
probe the structure–activity relationships of laulimalide
analogues. For example, cuprate additions to the ynone
7 (Scheme 1) should provide access to various substitu-
ents at C.11 such as gem di-methyl analogues.19
In summary, the total synthesis of a novel analogue, 8-
(S)-methoxy-11desmethyl laulimalide, has been accom-
plished. The key C.2–C.14 fragment is readily prepared
fromtriacetyl glucal. The strategy provides the flexibility
8. Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J.
L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C.
S. J. Org. Chem. 1991, 56, 4056–4058.

926
B. M. Gallagher, Jr. et al. / Tetrahedron Letters 46 (2005) 923–926
13. Motoyoshi, H.; Ishigami, K.; Kitahara, T. Tetrahedron
9. Intermediate 4 could be deacetoxylated to the laulimalide
dihydropyran under standard conditions (Pd2dba3, Bu3P,
Hco2H–NEt3), albeit as a ꢀ2:1 mixture favoring the
desired isomer.
2001, 57, 3899–3908.
14. We have found this reaction may also be run in DMF or
THF and at rt, but CH3CN at 60 °C provided the shortest
reaction times.
15. (a) Messenger, B. T.; Davidson, B. S. Tetrahedron Lett.
2001, 42, 401–403; (b) ref. 4k.
O
O
Pd2dba3, Bu3P
AcO
AcO
16. Shimizu, A.; Nishiyama, S. Synlett 1998, 1209–1210.
17. The stereochemistry of the newly formed center was
confirmed by analysis of the R- and S-MosherÕs esters.
See: (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973,
95, 512–519; (b) Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
18. Preliminary biological evaluation of this analogue indi-
cates it retains sub-micromolar growth inhibition potency
in the MDA-MB-435 human breast cancer cell line. For
assay conditions, see Ref. 5. Investigations of this
analogue for activity against multidrug resistant cell lines
will be reported in due course.
O
HCO2H-NEt3
dioxane, reflux
4
O
O
O
O
AcO
AcO
O
O
2 : 1
10. Shen, Q.; Sloss, D. G.; Berkowitz, D. B. Synth. Commun.
1994, 24, 1519–1530.
11. Choi, W.-B.; Wilson, L. J.; Yeola, S.; Liotta, D. C.;
Schinazi, R. F. J. Am. Chem. Soc. 1991, 113, 9377–9379.
12. To the best of our knowledge, a double Stryker-type
reduction of an ynone to the saturated ketone appears to
be unprecedented.
19. A gem di-methyl strategy was undertaken in the crypto-
phycins to stabilize the macrolactone and faciliate process
scale-up by eliminiating a sterocenter, but was also found
to increase potency. See: Eggen, M.; Georg, G. I. Med.
Res. Rev. 2002, 22, 85–101.