Concise synthesis of the C3-C14-fragment of the antitumor agent laulimalide. Application of Jacobsen's HKR reaction

Article abstract of DOI:10.1055/s-2001-15145

Bromide 3, which represents an appropriately functionalized C3-C14-fragment of the antitumor agent laulimalide (1) has been synthesized from (-)-citronellal (4) in an overall yield of ca. 17% (12 isolated intermediates). At a very early stage, the synthes

Full text of DOI:10.1055/s-2001-15145

LETTER
1105
Concise Synthesis of the C3-C14-Fragment of the Antitumor Agent
Laulimalide. Application of Jacobsen’s HKR Reaction
E. Kate Dorling, Elisabeth Öhler, Andreas Mantoulidis, Johann Mulzer*
Institut für Organische Chemie der Universität Wien, Währinger Strasse 38, A-1090 Wien, Austria
E-mail: johann.mulzer@univie.ac.at
Received 29 March 2001
lyl bromide 3, which corresponds to the C3-C14 section of
1 and is to be coupled with the C15 aldehyde derived from
2 by means of a Hiyama Nozaki reaction.9
Abstract: Bromide 3, which represents an appropriately function-
alized C3-C14-fragment of the antitumor agent laulimalide (1) has
been synthesized from (–)-citronellal (4) in an overall yield of ca.
17% (12 isolated intermediates). At a very early stage, the synthesis
makes use of Jacobsen' s HKR reaction to produce epoxide 8 in di-
astereomerically pure form.
Our plan (Scheme 1) was based on the similarity of 3 with
naturally occurring (–)-citronellal (4). In particular, the al-
dehyde function in 4 lent itself to some kind of diastere-
controlled CC connection which eventually should lead to
the formation of the dihydropyran ring. Among other op-
tions the conversion of the aldehyde into the epoxide10 ap-
peared attractive which could then be opened by acetylide
additions. The epoxide, in turn, should be generated in di-
astereopure form by Jacobsen's HKR (hydrolytic kinetic
resolution).11 As shown in Scheme 2, aldehyde 4 was con-
verted into a 1:1-mixture of the epoxide diastereomers 5
via Corey's sulfonium ylide addition.10
HKR of 5 with catalyst 613 led to the formation of diol 7
along with the desired epoxide 8, both diastereomerically
pure according to standard criteria. Diol 7 was quantita-
tively transformed into 8 by a dehydrative cyclization un-
der inversion of configuration at C9. In this way, aldehyde
4 was converted into epoxide 8 with an overall yield of
74%. The synthesis was continued by addition of ethyl
propiolate anion to C8; Lindlar hydrogenation afforded
the (Z)-enoate which was cyclized in situ to form lactone
9 in nearly quantitative yield. The differentiation of the
two double bonds turned out to be easy by epoxidizing the
electron rich olefin selectively with mCPBA, opening the
Key words: antitumor agents, epoxides, Jacobsen's HKR reaction,
Eschenmoser methylenation
Since the advent of paclitaxel (Taxol)1 a great deal of ef-
fort has been focused on potential successors with the
same mode of microtubule stabilizing antitumor action,
however with higher activity, in particular against multi-
drug resistant tumor cells, and better bioavailability.
Among recent advances have been epothilone B and de-
rivatives,2 discodermolide3 and eleutherobin.4 Quite re-
cently, it has been discovered that laulimalide (1), a
metabolite from various marine sponges,5 also shows mi-
crotubule stabilization in eukaryotic cells and is distin-
guished by an unusually high antitumor activity against
multidrug resistant cells lines.6 These findings have kin-
dled enormous interest in the total synthesis of the com-
pound, and, to date, only one total synthesis of 1 has been
published7 along with several approaches to major frag-
ments.8 In continuation of our earlier retrosynthetic analy-
sis, which has resulted in an efficient synthesis of the C27-
C15 fragment 2,8g we report now an efficient access to al-
OMOM
H
O
15
OH
19
O
27
20
17
OTBDPS
23
OH
O
17
H
Me
15
2
19
O
O
27
13
20
23
OH
H
Me
11
O
14
O
1
H
Me
Br
O
13
14
5
9
Me
11
3
13
Me
11
H
H
TBSO
5
9
3
Laulimalide (1)
O
9
H
3
(–)-citronellal (4)
Scheme 1
Synlett 2001, No. 7, 1105–1108 ISSN 0936-5214 © Thieme Stuttgart · New York

1106
E. K. Dorling et al.
LETTER
14
14
14
ii
13
13
13
Me
11
Me
11
i
Me
11
4
+
N
O
N
HO
Co
tBu
O
tBu
9
9
O
9
O
OAc
tBu
tBu
HO
6
iii, iv, v
5
7
8
Scheme 2 Reagents and conditions: i, trimethylsulfonium iodide, KOH, CH3CN:H2O (1000:1), 60 °C, 2 h, 95%; ii, catalyst 6 (5 mol%), H2O
(0.5 mol equiv.), TBME, 22 °C, 48 h, 42% of 7, 41% of 8; iii, TBDPSCl, imidazole, DMF, 22 °C, 12 h, 94%; iv, MsCl, NEt3, CH2Cl2, 0 °C,
10 min; v, TBAF, THF, 0 °C, 5 min, then 20% NaOH-H2O, 22 °C, 10 min, 89% over two steps.
H
H
14
14
14
13
O
O
13
O
9
13
iv, v, vi
i, ii, iii
vii, viii, ix
Me
11
Me
11
Me
11
8
O
O
O
O
O
9
9
9
10
11
14
14
AcO
HO
13
O
13
xi, xii, xiii, xiv
x
xv, xvi
Me
11
Me
11
3
5
EtO
O
9
TBSO
9
3
12
13
Scheme 3 Reagents and conditions. i, ethyl propiolate, nBuLi, BF3-etherate, THF, -95 °C, 2 h, 91%; ii, Lindlar's catalyst, quinoline, H2,
EtOH, 22 °C, 6 h; iii, pTsOH (cat), benzene, reflux, 1 h, 97% over two steps; iv, mCPBA, NaHCO3, DCM, 0 °C, 20 min; v, HClO4, H2O, THF,
22 °C, 1 h; vi, NaIO4, MeOH, H2O, 22 °C, 3 h, 77% over three steps; vii, Me2N = CH2I, NEt3, DCM, 22 °C, 12 h; viii, MeI, Et2O, CHCl3,
22 °C, 12 h; ix, K2CO3, CHCl3, 22 °C, 6 h, 66% over three steps; x, DIBAL, DCM, -78 °C, 1 h, then ethanol, pTsOH, 22 °C, 1 h, 78%; xi,
Ac2O, DMAP, pyridine, 22 °C, 45 min, 93%; xii, vinyloxytrimethylsilane, LiClO4, EtOAc, DCM, 22 °C, 12 h; xiii, NaBH4, MeOH, 0 °C, 30
min, 85% over two steps; xiv, TBSCl, imidazole, DMF, 22 °C, 2 h, 73%; xv, K2CO3, MeOH, H2O, 22 °C, 3 h, 85%; xvi, CBr4, PPh3, acetonitrile,
22 °C, 1 h, 65%.
epoxide hydrolytically and cleaving the resulting diol Acknowledgement
with NaIO4. Without affecting the 6,7-double bond alde-
Financial support by the Austrian Research Foundation (FWF, pro-
ject P-13941-CHE) is gratefully acknowledged.
hyde 10 was generated which was used for an Eschen-
moser methylenation12 to introduce the exo-methylene
group at C13. In fact this operation could be performed in
References and Notes
one pot with an overall yield of ca. 70% to furnish olefin
11. The reaction with DIBAL converted the aldehyde into
the allylic alcohol and the lactone into the lactol which
was immediately transformed into an anomeric mixture of
the 5-ethyl acetals 12. After acetylation of the 14-alcohol
the compound was ready for the introduction of the C2-C3
appendage. Vinyloxytrimethylsilane was added with high
diastereoselectivity to the 5-oxonium ion generated from
12 and the resulting C3 aldehyde was reduced to the alco-
hol with sodium borohydride. TBS protection furnished
intermediate 13 which was selectively 14-O-deprotected
with potassium carbonate and the alcohol was converted
into the desired allylic bromide 3.
(1) For a review, see: Nicolaou, K.C.; Dai, W.-M.; Guy, Angew.
Chem Int. Ed. Engl. 1994, 33, 15-44.
(2) For a review, see: Nicolaou, K.C.; Roschangar, F.;
Vourloumis, D., Angew. Chem. Int. Ed. Engl. 1998, 37, 2014-
2045.
(3) Gunasekara, S.P.; Gunasekara, M.; Longley, R.E. J. Org.
Chem. 1990, 55, 4912-4915.
(4) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza,
A. M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997,
119, 8744-8745.
Synlett 2001, No. 7, 1105–1108 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Concise Synthesis of the C3-C14-Fragment of the Antitumor Agent Laulimalide
1107
(5) Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53
3642-3644. Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P.
J.; Paul, V. J. J. Org. Chem. 1988, 53 3644-3646. Jefford, C.
W.; Bernardinelli, G.; Tanaka, J.-I.; Higa, T. Tetrahedron
Lett. 1996, 37, 159-162.
(6) Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plubrukarn, A.;
Davidson, B. S. Cancer Res. 1999, 59, 653-660.
(7) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122 11027-
11028. Tetrahedron Lett. 2001, 42, 3399-3402.
Conversion of 7 into 8:
TBDPSCl (0.20 mL, 0.77 mmol) and imidazole (56 mg, 0.92
mmol) were added to a solution of diol 7 (143 mg, 0.77 mmol)
in DMF (1.5 mL) and the resulting solution allowed to stir
overnight. The reaction was quenched by addition of water
and ethyl acetate and the layers partitioned. The aqueous
phase was extracted three times with ethyl acetate and the
combined organic extracts washed twice with water, once
with brine, dried (MgSO4) and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography, eluting with hexane ethyl acetate (10:1), to
yield (2S,4S)-1-{[tert-butyl(diphenyl)silyl]oxy}-4,8-
dimethylnon-7-en-2-ol (308 mg, 94%) as a clear, colorless oil.
H (400 MHz, CDCl3) 1.09 (9 H, s), 1.10 (1 H, m), 1.29-1.42
(3 H, m), 1.55 (1 H, m), 1.59 (3 H, s), 1.68 (3 H, s), 1.93 (1 H,
m), 2.00 (1 H, m), 2.51 (1 H, d, J 3.3), 3.47 (1 H, dd, J 4.7
10.0), 3.66 (1 H, dd, J 3.2, 10.2), 3.82 (1 H, m), 5.09 (1 H, tt,
J 1.3, 7.1), 7.43 (6 H, m) and 7.69 (4 H, m). C (100 MHz,
CDCl3) 14.2, 17.6, 19.2, 20.1, 25.3, 25.7, 26.9, 29.3, 36.8,
40.1, 68.2, 70.2, 124.8, 127.7, 127.8, 129.8 (2 signals), 131.1,
133.2 (2 signals) and 135.5 (2 signals). max (Si pellet, liquid
film, cm-1) 702, 1113, 1261, 1428, 1462, 1472, 2858, 2929,
3071 and 3583 b. HRMS (EI, 90 C, 70 eV) found 367.2101.
C23H31O2Si requires 367.2093. m/z (EI, 90 C) 367 (M+ - Bu,
(8) a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron
Lett. 1997, 38 2427-2430. b) Ghosh, A. K.; Wang, Y.
Tetrahedron Lett. 2000, 41 2319-2322. c) Ghosh, A. K.;
Wang, Y. Tetrahedron Lett. 2000, 41 2319-2322. d) Shimizu,
A.; Nishiyama, S. Tetrahedron Lett. 1997, 38 6011-6014.
e) Shimizu, A.; Nishiyama, S. Synlett 1998 1209-1210.
f) Mulzer, J.; Hanbauer, M. Tetrahedron Lett. 2000, 41, 33-36.
g) Mulzer, J.; Dorling, E. K.; Öhler, E. Tetrahedron Lett.
2000, 41 6323-6326. h) Paterson, I.; De Savi, C.; Tudge, M.
Org. Lett. 2001, 3, 213-215. i) Messenger, T.; Davidson, B. S.
Tetrahedron Lett. 2001, 42, 787-800. j) Nadolski, G. T.;
Davidson, B. S Tetrahedron Lett. 2001, 42, 801-803.
(9) For reviews, see: Cintas, P. Synthesis 1992, 248-257.
Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1-36.
(10) Borredon, E.; Delmas, M.; Gaset, A. Tetrahedron Lett. 1982,
23 5283-5286.
(11) Jacobsen, E. N.; Hinterding, K. J. Org. Chem. 1999, 64, 2164-
2165. Jacobsen, E. N.; Tokunaga, M.; Larrow, J. F.; Kakiuchi,
F. Science 1997, 277, 936-938. Jacobsen, E. N.; Furrow, M.
E.; Schaus, S. E. J. Org. Chem. 1998, 63, 6776-6777.
(12) Paquette, L.; Dyck, B. P. J. Am. Chem. Soc. 1998, 120, 5953-
5960.
(13) Procedure for Jacobsen’s HKR, preparation of 8. The
Jacobsen (salen)Co(III)(OAc) catalyst 6 (150 mg, 1 mol%)
was added to a solution of the epimeric epoxides 5 (3.80 g,
22.6 mmol) in dry TBME (4 mL, resulting in a 5 M solution).
The solution was cooled to 0 °C and water (203 L, 11.3
mmol) was added. The resulting mixture was stirred at 22 °C
for 36 h. The reaction mixture was diluted with DCM and
filtered though a short pad of celite, washing with DCM. The
organic solution was concentrated under reduced pressure and
the crude product purified by flash column chromatography,
eluting with hexane-ethylacetate (50:1 then 1:2), to yield 1.57
g (42%) of 7 and 1.72 g (41%) of 8 as colorless oils.
(2R)-2-[(2S)-2,6-dimethylhept-5-enyl]oxirane (8):
17%), 241 (42), 199 (100), 181 (41), 123 (71) and 77 (70).
20
[ ]D
0.82 (1.82, CHCl3).
TEA (0.14 mL, 1.00 mmol) and MsCl (54 L, 0.68 mmol)
were added to a solution of (2S,4S)-1-{[tert-butyl(diphenyl)-
silyl]oxy}-4,8-dimethylnon-7-en-2-ol (258 mg, 0.61 mmol) in
DCM (4 mL) at 0 C and the solution stirred for 15 min. After
this time, the reaction was quenched by addition of an
ammonium chloride solution and the layers partitioned. The
aqueous phase was extracted three times with DCM, the
combined organic extracts washed with brine, dried (MgSO4)
and concentrated under reduced pressure. The crude product
was redissolved in THF (4 mL) and TBAF (0.7 mL, 1.0 M in
THF, 0.7 mmol) was added. The solution was stirred for 10
min, then a 20% aqueous solution of NaOH (7 mL) was added
and the mixture stirred for 20 min. After this time, the mixture
was diluted with ether and the layers partitioned. The organic
phase was washed with water then brine, dried (MgSO4) and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography, eluting with
hexane toluene (1:20), to yield 8 (91 mg, 89%) as a clear,
colorless oil.
H (400 MHz, CDCl3) 0.98 (3 H, d, J 6.6), 1.21-1.44 (3 H, m),
1.54-1.60 (1 H, m), 1.61 (3 H, s), 1.69 (3 H, d, J 1.3), 1.67-1.74
(1 H, m), 2.01 (2 H, m), 2.46 (1 H, dd, J 2.8, 5.1), 2.78 (1 H,
td, J 0.5, 4.6), 2.94 (1 H, dtt, J 5.2, 2.6, 3.9) and 5.11 (1 H,
tsept, J 1.2, 6.8). C (100 MHz, CDCl3) 17.6, 19.5, 25.4, 25.7,
30.6, 37.3, 39.8, 47.5, 51.1, 124.5 and 131.3. max (Si pellet,
liquid film, cm-1) 702, 822, 1114, 1428, 2857 and 2930.
HRMS (EI, 40 C, 70 eV) found 168.1509. C11H20O requires
168.1514. m/z (EI, 40 C) 168 (M+, 0.8%), 150 (13), 135 (36),
123 (11), 109 (35), 95 (91), 81 (77), 69 (100) and 55 (78).
[ ]D20+33.8 (0.94, CHCl3).
(2-{(2R,6R)-6-[(2S)-4-(Bromomethyl)-2-methylpent-4-
enyl]-5,6-dihydro-2H-pyran-2-yl}ethoxy)(tert-butyl)-
dimethylsilane (3)
Triphenylphosphine (640 mg, 2.40 mmol) and carbon
tetrabromide (800 mg, 2.40 mmol) were added to a solution of
2-{(2S)-3-[(2R,6R)-6-(2-[(tert)-butyl{dimethyl}silyloxy]-
ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}prop-2-
en-1-ol (650 mg, 1.80 mmol) in acetonitrile (20 mL) at 22 °C
and the solution stirred for 10 min. After this time, the reaction
was quenched by addition of NaHCO3 solution and diluted
with ether. The layers were partitioned and the aqueous phase
was extracted three times with ether. The combined organic
extracts were washed with brine, dried (MgSO4) and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography, eluting with
hexane ethyl acetate (20:1), to yield the title compound and
excess triphenylphosphine as a mixture that could only be
separated by HPLC. 490 mg (65%) of 3 was obtained as a
clear, colorless oil.
(2S,4S)-4,8-dimethylnon-7-en-1,2-diol (7):
H (400 MHz, CDCl3) 0.94 (3 H, d, J 6.6), 1.09-1.19 (1 H, m),
1.37-1.45 (3 H, m), 1.58 (1 H, m), 1.60 (3 H, s), 1.68 (3 H, s),
1.89-2.08 (2 H, m), 2.45-2.70 (2 H, bm), 3.39 (1 H, dd, J 8.1,
10.6), 3.64 (1 H, bd, J 10.9), 3.80 (1 H, bq, J 6.6) and 5.09 (1
H, tsept, J 7.1, 1.4). C (100 MHz, CDCl3) 17.6, 20.2, 25.3,
25.7, 29.2, 36.7, 40.5, 66.9, 70.5, 124.6 and 131.3. max (Si
pellet, liquid film, cm-1) 1066, 1377, 1458, 2924 and 3367 b.
HRMS (EI, 60 C, 70 eV) found 186.162. C11H22O2 requires
186.1620. m/z (EI, 60 C) 186 (M+, 11%), 169 (7), 155 (13),
137 (17), 123 (7), 109 (32), 95 (44), 86 (94), 84 (100) and 69
(82). [ ]D20 -10.3 (1.38, CHCl3).
H (250 MHz, CDCl3) 0.08 (6 H, s), 0.91 (9 H, s), 0.92 (3 H,
m), 1.19 (1 H, ddd, J 3.3, 9.9, 13.6), 1.54-1.75 (2 H, m), 1.78-
2.25 (6 H, m), 3.65-3.84 (3 H, m), 3.95 (1 H, d, J 10.1), 4.00
Synlett 2001, No. 7, 1105–1108 ISSN 0936-5214 © Thieme Stuttgart · New York

1108
E. K. Dorling et al.
LETTER
(1 H, d, J 10.1), 4.34 (1 H, m), 4.98 (1 H, d, J 0.7), 5.22 (1 H,
s), 5.70 (1 H., m) and 5.81 (1 H, ddt, J 5.4, 9.9, 1.9).
C (62.5 MHz, CDCl3) -5.3, 18.3, 19.3, 26.0, 26.6, 31.5, 36.6,
36.8, 41.7, 42.5, 59.9, 64.7, 69.5, 116.6, 124.0, 130.0 and
144.0. max (Si pellet, liquid film, cm-1) 836, 1095, 1256, 1391,
1437, 1462, 2857 and 2928. m/z (EI, 40 °C) 359 (M+- Bu,
0.3%), 337 (2), 205 (7), 187 (46), 155 (27), 125 (59), 107 (56),
20
81 (100). [ ]D
36.1 (1.38, CHCl3).
Article Identifier:
1437-2096,E;2001,0,07,1105,1108,ftx,en;G06401ST.pdf
Synlett 2001, No. 7, 1105–1108 ISSN 0936-5214 © Thieme Stuttgart · New York