Synthetic studies toward the microtubule-stabilizing agent laulimalide: Synthesis of the C1-C14 fragment

Article abstract of DOI:10.1016/S0040-4039(00)02116-X

The C₁-C₁₄ fragment of the paclitaxel-like antimicrotubule agent laulimalide has been synthesized in 15 steps from L-(-)-citronellal. The C₉ chiral center was established using an asymmetric allylation, the dihydropyran ring was prepared through ring-closing metathesis, and the exo-methylene was incorporated using Eschenmoser's salt.

Full text of DOI:10.1016/S0040-4039(00)02116-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 797–800
Synthetic studies toward the microtubule-stabilizing agent
laulimalide: synthesis of the C1–C14 fragment
Geoffry T. Nadolski and Bradley S. Davidson*
Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322-0300, USA
Received 16 November 2000; accepted 17 November 2000
Abstract—The C1–C14 fragment of the paclitaxel-like antimicrotubule agent laulimalide has been synthesized in 15 steps from
L
-(−)-citronellal. The C9 chiral center was established using an asymmetric allylation, the dihydropyran ring was prepared through
ring-closing metathesis, and the exo-methylene was incorporated using Eschenmoser’s salt. © 2001 Published by Elsevier Science
Ltd.
As part of a program aimed at the discovery of new
antimicrotubule agents, we recently identified the
marine macrolide laulimalide (1)1 as a new paclitaxel
(Taxol™)-like microtubule-stabilizing agent.2 Lauli-
malide is a potent inhibitor of cellular proliferation
with IC50 values in the low nanomolar range against
drug sensitive cell lines and it retains activity against a
P-glycoprotein overexpressing multidrug resistant
ovarian cancer cell line, suggesting that it is a poor
substrate for transport by P-glycoprotein. Laulimalide,
therefore, joins the marine metabolites discodermolide3
and eleutherobin4 and the microbial metabolites the
epothilones5 as a new class of microtubule-stabilizing
agent, with activities that may prove therapeutically
useful.
To date, three groups have published a total of seven
papers describing synthetic efforts targeting lauli-
malide.6,7 Among these, are five reports of syntheses of
the C1–C16 portion of the macrocyclic ring. In addition,
we recently completed a hetero Diels–Alder approach
to the preparation of the C20–C26 side chain of lauli-
malide8 and, in the adjoining paper, we describe a
synthesis of the C15–C28 segment of laulimalide.9 In this
letter, we describe our synthesis of the C1–C14 portion
of laulimalide.
Scheme 1. Retrosynthetic analysis.
Scheme 2. (a) PDC, MeOH, DMF, rt (80%); (b) O3, MeOH, −78°C; then NaBH4 (82%); (c) TBPSCl, DMAP, imidazole, DMF,
rt, 10 h (89%); (d) DIBAL, CH2Cl2, −78°C, 1.5 h (85%).
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02116-X

798
G. T. Nadolski, B. S. Da6idson / Tetrahedron Letters 42 (2001) 797–800
Our retrosynthetic strategy (Scheme 1) involves divid-
ing the molecule into two primary fragments; the C1–
C14 fragment (2) and the C15–C28 fragment (3).9
Fragments 2 and 3 are to be coupled using asymmetric
allylstannane or allylborane chemistry, either before or
after epoxidation. Because of the sensitivity of the
(Z)-a,b-unsaturated ester in 2 to basic conditions, we
have utilized a 2,4-dimethoxybenzyl (DMB) ester pro-
tecting group,10 envisioning simultaneous cleavage of
the C19 PMB ether (fragment 3) and the DMB ester
immediately prior to macrolactonization. We felt that
the dihydropyran ring in compound 2 could be pre-
pared either through an asymmetric hetero Diels–Alder
approach or through the use of an asymmetric allyla-
tion/ring-closing olefin metathesis sequence.
that developed by Paterson and Grieco in their synthe-
ses of swinholide.12,13 Specifically, 7 was reduced under
Luche conditions14 to give exclusively the equatorial
alcohol, which was acetylated to give 8. A Ferrier
rearrangement with CH2ꢀCHOTBS in the presence of
LiOCl4–EtOAc yielded 9, exclusively with the trans
disposition of dihydropyran ring substituents.
A second approach utilized a strategy analogous to the
one we used for the preparation of compound 2.9 Using
Keck’s asymmetric allylation conditions,15 aldehyde 6
was treated with allyltributyltin in the presence of the
chiral Lewis acid formed from (S)-BINOL and
Ti(OiPr)4, giving homoallylic alcohol 10 in 80% yield
and 71% de. An MPA ester analysis16 of the alcohol
confirmed that the new chiral center had the desired
S-chirality. The use of chiral allyl borane B-allyldi-
isopinocampheylborane (Ipc2BAll)17 resulted in a com-
parable yield, but provided an improved diastereomeric
excess (92%). The reaction of 10 with methoxyallene in
To prepare for the dihydropyran ring synthesis, -(−)-
L
citronellal was converted to aldehyde 6 in four steps
(see Scheme 2). Oxidation of the aldehyde with PDC in
MeOH gave ester 4, which was treated with ozone
followed by NaBH4, yielding a primary alcohol that
was protected as its TBPS ether 5. Finally, conversion
of the ester back to an aldehyde yielded compound 6,
bearing an aldehyde in the position that is to become
C9 of laulimalide.
18
the presence of Pd(OAc)2 provided allylic acetal 11,
which was poised for a ring closing olefin metathesis
reaction.18,19 Indeed, treatment of 11 with Grubbs’ cat-
alyst in CH2Cl2 cleanly yielded compound 12, which
could then be converted to 9 using the same conditions
as were used for the conversion of 8 to 9, presumably
via the identical oxonium ion intermediate.
Our initial approach to the dihydropyran ring (Scheme
3) involved the use of Keck’s asymmetric hetero Diels–
Alder conditions.11 Reaction of 6 with a Danishefsky-
type diene yielded dihydropyranone 7 in 53% yield, but
with a disappointing 67% de. Compound 7 was then
converted to aldehyde 9 using methodology similar to
From aldehyde 9, three tasks remained: (1) preparation
of the (Z)-a,b-unsaturated ester; (2) incorporation of
the exo-methylene at C13; and (3) installation of the
H
H
H
H
H
O
O
O
d
b, c
TBPSO
TBPSO
TBPSO
CHO
a
7
O
8
9
OAc
O
6
d
e or f
H
H
OH
OMe
O
OMe
g
h
TBPSO
TBPSO
TBPSO
10
11
12
Scheme 3. (a)
, (S)-BINOL, Ti(OiPr)4; then TFA (53%); (b) NaBH4, CeCl3–7H2O, MeOH (97%); (c) Ac2O,
iPrNEt2, DMAP, CH2Cl2 (96%); (d) CH2ꢀCHOTBS, 3.0 M LiClO4–EtOAc (86% from 8; 78% from 12); (e) allyltributyltin,
(S)-BINOL, Ti(OiPr)4 (80%); (f) Ipc2BAll, THF, −78°C, 1 h; NaOH, H2O2, 3 h (80%); (g) methoxyallene, Pd(OAc)2, CH3CN,
reflux, 20 h (83%); (h) 0.1 M Cl2(PCy3)2RuꢀCHPh, CH2Cl2, rt, 36 h (85%).
CO2R
CO2R
H
H
H
H
a or b
O
c, d
OHC
O
e
TBPSO
9
14 R = Me
16 R = DMB
17
O
CO2DMB
CO2DMB
(CF3CH2O)2P
13 R = Me
15 R =
CO2R
H
H
O
H
H
OHC
O
h
f
RO
2
18
19 R = H
20 R = Ac
g
MeO
OMe
Scheme 4. (a) 13, KHMDS, 18-crown-6, THF, −78°C (83%); (b) 15, KHMDS, 18-crown-6, THF, −78°C (80%); (c) HF–py., THF
(91%); (d) (COCl)2, DMSO, −78°C; Et3N, −78°C to rt (90%); (e) Me2N+ꢀCH2Cl−, CH2Cl2, then Et3N (84%); (f) NaBH4,
i
CeCl3–7H2O, EtOH (90%); (g) Ac2O, DMAP, Pr2NEt, CH2Cl2 (90%); (h) Bu3SnAlEt2, Pd(PPh3)4 (60%).

G. T. Nadolski, B. S. Da6idson / Tetrahedron Letters 42 (2001) 797–800
799
allyltin necessary for coupling fragments 2 and 3.
Although application of Still’s fluorinated phospho-
nate ester (13)20 provided a good yield of cis-methyl
ester 14, for reasons described earlier, we were inter-
ested in preparing 2,4-dimethoxybenzyl ester analog
16 (Scheme 4), requiring 2,4-dimethoxybenzyl phos-
phonate ester 15 as a reagent. After extensive experi-
mentation, we developed an inexpensive, three-step
route from methylphosphonic dichloride that allows
the preparation of large amounts of 15.21 Treatment
of 9 with 15 in the presence of KHMDS and 18-
crown-6 yielded compound 16 as the exclusive
product in 83% yield. HF–pyridine cleanly removed
the TBPS group, exposing the primary alcohol, which
was oxidized to give aldehyde 17. Treatment of eno-
lizable aldehyde 17 with Eschenmoser’s salt in CH2Cl2
for 2 days followed by addition of Et3N yielded
unsaturated aldehyde 18, which was reduced to give
alcohol 19. Because of the tendency of the unsatu-
rated ester to isomerize, our original plan of convert-
2. Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plu-
brukarn, A.; Davidson, B. S. Cancer Res. 1999, 59,
653.
3. (a) ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C.
M.; Longley, R. E.; Gunasekera, S. P.; Rosenkranz, H.
S.; Day, B. W. Biochemistry 1996, 35, 243; (b) Kowal-
ski, R. J.; Giannakakou, P.; Gunasekera, S.; Longley,
R. E.; Day, B. W.; Hamel, E. Mol. Pharmacol. 1997,
52, 613.
4. (a) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.;
Casazza, A. M.; Carboni, J.; Fairchild, C. R. J. Am.
Chem. Soc. 1997, 119, 8744; (b) Long, B. H.; Carboni,
J. M.; Wasserman, A. J.; Cornell, L. A.; Casazza, A.
M.; Jensen, P. R.; Lindel, T.; Fenical, W.; Fairchild, C.
R. Cancer Res. 1998, 58, 1111.
5. (a) Kowalski, R. J.; Giannakakou, P.; Hamel, E. J.
Biol. Chem. 1997, 272, 2534; (b) Nicolaou, K. C.; He,
Y.; Vourloumis, D.; Vallberg, H.; Yang, Z. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2014; (c) Harris, C. R.;
Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434.
6. (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetra-
hedron Lett. 1997, 38, 2427; (b) Shimizu, A.;
Nishiyama, S. Tetrahedron Lett. 1997, 38, 6011; (c)
Shimizu, A.; Nishiyama, S. Synlett 1999, 1209; (d)
Mulzer, J.; Hanbauer, M. Tetrahedron Lett. 2000, 41,
33; (e) Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000,
41, 2319; (f) Ghosh, A. K.; Wang, Y. Tetrahedron Lett.
2000, 41, 4705.
ing the alcohol to
a
bromide followed by
displacement with tributylstannyllithium was aborted,
substituting the more mild method reported by Trost
and coworkers.22 To this end, 19 was acetylated to
give 20.23 In a single attempt, 20 was exposed to
Bu3SnAlEt2 and Pd(PPh3)4, providing allyl stannane
in approximately 60% yield, along with a small
amount of the hydrodestannylation product.
7. While this manuscript was in preparation, a route simi-
lar to ours for the preparation of 10 was published:
Dorling, E. K.; Ohler, E.; Mulzer, J. Tetrahedron Lett.
2000, 41, 6323.
In summary, we have reported a new synthesis of the
C1–C14 fragment of the microtubule-stabilizing agent
laulimalide. In order to facilitate deprotection of the
(Z)-a,b-unsaturated ester prior to macrolactonization,
we have incorporated a 2,4-dimethoxybenzyl ester,
which required the preparation of the new phospho-
nate ester 15. We have described both hetero Diels–
Alder and RCM approaches for the preparation of
the dihydropyran ring and have generated the requi-
site allyl stannane in the presence of the base-sensitive
(Z)-double bond. Further work toward the synthesis
of laulimalide is underway.
8. Plubrukarn, A. Ph.D. Dissertation; University of
Hawaii: Hawaii, 1999.
9. Messenger, D. T.; Davidson, B. S. Tetrahedron Lett.
2001, 42, 797.
10. Kim, C. U.; Misco, P. F. Tetrahedron Lett. 1985, 26,
2027.
11. Keck, G. E.; Li, X. Y.; Krishnamurthy, D. J. Org.
Chem. 1995, 60, 5998.
12. Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron
1995, 51, 9413.
13. Grieco, P. A.; Speake, J. D. Tetrahedron Lett. 1998, 39,
1275.
Acknowledgements
14. Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981,
103, 5454.
15. (a) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993,
34, 7827; (b) Keck, G. E.; Tarbet, K. H.; Geraci, L. S.
J. Am. Chem. Soc. 1993, 115, 8467.
16. Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal,
P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.;
Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org.
Chem. 1986, 51, 2370.
We thank the NIH (CA81388) and Utah State Uni-
versity, through a New Faculty Research Grant, for
support of this research. MS data was provided by
the Washington University Mass Spectrometry
Resource with support from the NIH National Center
for Research Resources (P41RR0954).
17. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56,
401.
18. Rutjes, F. P. J. T.; Kooistra, T. M.; Schoemaker, H. E.
Synlett 1998, 192.
References
19. Recent reviews: (a) Grubbs, R. H.; Chang, S. Tetra-
hedron 1998, 54, 4413; (b) Furstner, A. Top. Catal.
1997, 4, 285; (c) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2036.
20. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24,
4405.
1. (a) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P.
J.; Paul, V. J. J. Org. Chem. 1988, 53, 3644; (b)
Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988,
53, 3642; (c) Jefford, C. W.; Bernardinelli, G.; Tanaka,
J.; Higa, T. Tetrahedron Lett. 1996, 37, 159.

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G. T. Nadolski, B. S. Da6idson / Tetrahedron Letters 42 (2001) 797–800
21. For the preparation of 15 see below:
5.88 (dt, 11.5, 1.7; 1H), 5.80 (m; 1H), 5.66 (dq, 10.3, 2.3;
1H), 5.13 (d, 12.2; 1H), 5.09 (d, 12.2; 1H), 5.04 (s; 1H),
4.90 (s; 1H), 4.47 (s; 2H), 4.24 (m; 1H), 3.83 (s; 6H), 3.75
(m; 1H), 3.01 (dddd, 15.9, 9.5, 7.1, 1.7; 1H), 2.87 (dddd,
15.9, 7.1, 4.3, 1.9; 1H), 2.08 (s; 3H), 2.07 (m; 1H), 1.91
(m; 4H), 1.57 (ddd, 13.8, 9.7, 3.5; 1H), 1.08 (ddd, 13.8,
9.0, 3.2; 1H), 0.82 (d, 6.3; 3H); 13C NMR (CDCl3) l
170.6, 166.4, 161.3, 159.0, 146.8, 142.4, 131.3, 129.1,
124.7, 121.0, 117.0, 113.7, 140.1, 98.6, 72.2, 66.8, 65.1,
61.1, 55.5, 55.4, 42.6, 41.9, 33.5, 31.3, 27.0, 20.9, 19.3;
LRFAB m/z (relative intensity) 479 (M++Li; 25), 335 (9),
151 (100); HRFAB calcd for C27H36O7 (M++Li)
479.2621, found 479.2613.
22. Trost, B. M.; Herndon, J. W. J. Am. Chem. Soc. 1984,
106, 6835.
1
23. Compound 20 data: H NMR (CDCl3) l (mult., J in Hz)
7.22 (d, 8.9; 1H), 6.44 (m; 2H), 6.34 (dt, 11.5, 7.1; 1H),
.
.