Grubbs' RCM in the total synthesis of the microtubule stabilizing drug laulimalide

Article abstract of DOI:10.1002/1615-4169(200208)344:6/7<573::AID-ADSC573>3.0.CO;2-C

Two independent syntheses of the microtubule stabilizing antitumor agent laulimalide are described, which mainly differ with respect to the macrocyclization step. The first synthesis employs a Still-Gennari olefination and the second one an Alexakis-type,

Full text of DOI:10.1002/1615-4169(200208)344:6/7<573::AID-ADSC573>3.0.CO;2-C

REVIEWS
Grubbs× RCM in the Total Synthesis of the Microtubule
Stabilizing Drug Laulimalide
Johann Mulzer,* Elisabeth ÷hler, Valentin S. Enev, Martin Hanbauer
Institut f¸r Organische Chemie der Universit‰t Wien, W‰hringer Strasse 38, 1090 Vienna, Austria
Fax: ( ‡ 43)-1-4277-52190, e-mail: johann.mulzer@univie.ac.at
Received: January 30, 2002; Accepted: March 12, 2002
Dedicated to Professor Lutz-F. Tietze on the occasion of his 60th birthday
Abstract: Two independent syntheses of the micro- 1 Introduction
tubule stabilizing antitumor agent laulimalide are 2 Still Gennari Macrocyclization Route
described, which mainly differ with respect to the 3 Allylsilane/Acetal Macrocyclization Route
macrocyclization step. The first synthesis employs a 4 Conclusion
Still Gennari olefination and the second one an
Alexakis-type, allylsilane/acetal addition to close the Keywords: allyl transfer; antitumor compounds; ma-
final ring. For the construction of the dihydropyran rine organisms; microtubule stabilization; ring-closing
subunits, RCM methodology and alternative strat- metathesis; Still Gennari macrocyclization, total syn-
egies are presented in comparison.
thesis
1 Introduction
highlight our two recent total syntheses of 1.[9d, e]
Specifically, we will focus on the two dihydropyran
Laulimalide (1), also known as fijianolide B, was fragments, which have been prepared by RCM and
isolated fromthe marine sponges Cacospongia mycofi- other methodology, so that a comparison can be made of
jiensis and Hyatella sp., respectively, by the groups of the alternative approaches.
Moore[1a] and Crews.[1b] Later Higa and his group
The total synthesis of 1 is complicated by the
isolated 1 fromthe Okinawan sponge Fasciospongia sensitivity of the compound towards dilute acid. Even
rimosa[2a] and determined the structure by X-ray anal- 0.01 N HCl[1a] (or camphorsulfonic acid in dichlorome-
ysis. Very recently, 1 (along with isolaulimalide, 2) has thane[9f]) causes rapid destruction of the epoxide by ring
also been isolated from Dactylospongia sp., a sponge closure to the tetrahydrofuran derivative isolaulimalide
[2b]
fromVanuatu islands.
Compound 1 exhibits antitu- (2) which shows a drastically reduced antitumor activity
mor activity against numerous tumor cell lines at the ng/ (Scheme 1). This fact makes the endgame of a total
mL level, and maintains a high toxicity even against the synthesis extremely challenging, in particular with
multi-drug-resistant cell line SKVLB-1. It has been respect to potential O-protective groups on the C20-
shown by Mooberry and coworkers[3] that 1 shows the hydroxy function. At any rate, O-protected deoxylauli-
same mechanism of action (i.e., microtubule stabiliza- malide 3 emerged as a logicalretrosynthetic precursor of
tion) as the extremely successful drug taxol (paclitax- 1, the imminent formation of 2 during protective group
el)[4] and its potential successors epothilone,[5] discoder- removal notwithstanding.
molide,[6] eleutherobin,[7] and FR182877.[8] A major
advantage of 1 may be seen in the fact that it inhibits
the P-glycoprotein which is responsible for multi-drug
resistance in tumor cells. This underscores the potential 2 Still Gennari Macrocyclization Route
that 1 has as a forthcoming anticancer drug.
So far, altogether five total syntheses of 1 have been For the formation of 3 two possible ring-closing
reported,[9] along with several approaches to major processes could be envisaged (Scheme 2): a Still
fragments thereof.[10] As in the total synthesis of the Gennari macrocyclization[12] of phosphonate aldehyde
epothilones, Grubbs ring-closing olefin metathesis 4, hopefully to generate an excess of the 2,3-Z-olefin, or
(RCM)[11] reactions have been used abundantly in alternatively a Yamaguchi-type macrolactonization[13]
many approaches to 1, in particular when preparing of seco-acid 5. The latter possibility was soon discarded,
the two dihydropyran rings.[9a, c,d, e,10b, c,f, g,i-l, n,o] Remark- as at the stage of the activated ester a rapid E/Z-
ably, an attempted RCM macrocyclization connecting equilibration ofthe 2,3-enoate had tobe expected. So we
C2-C3 has been unsuccessful so far.[9c] In this review we concentrated on precursor 4 (Scheme 3).
Adv. Synth. Catal. 2002, 344, No. 6+7
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/02/3446+7-573 584 $ 17.50+.50/0
573

Johann Mulzer et al.
REVIEWS
Johann Mulzer was born in
1944 at Prien in Upper Bava-
ria. In 1974 he received his
PhD under the supervision of
Rolf Huisgen at the Ludwigs-
Maximilians University in
Munich, subsequently, he
joined the group of E. J. Cor-
Valentin Enev was born in
1957 in Sofia, Bulgaria and
received his PhD at the Bul-
garian Academy of Science.
From1986 1992 he was an
Assistant Professor at Bulgar-
ian Academy of Science. In
1992 he moved to the Univer-
sity of Z¸rich with a postdoc-
toral fellowship into the
group of Doz. Dr. S. Bienz,
ey at Harvard as a postdoc-
toral fellow. From1982 to
1996 he held professorships
at the University of D¸sseldorf, the Free University
of Berlin, and the Johann-Wolfgang-Goethe Uni-
versity in Frankfurt. Since 1996 he is a full professor
at the Institute of Organic Chemistry of the
University of Vienna. His main research interests
are focused on the total synthesis of structurally and
physiologically interesting natural products, among
others, morphine, tartrolone B, epothilones, cobyric
acid, and laulimalide.
and from1993 1997 he was a Senior Researcher at
Schering AG/Berlin. In 1998 he joined the Mulzer
group as a postdoctoral research fellow, and since
2002 he is a Vertragsassistent at the University of
Vienna.
Martin Hanbauer was born
1975 in Waidhofen/Ybbs;
Lower Austria and received
his diploma in 1998 under the
supervision of Prof. F. Ham-
merschmidt at the University
of Vienna. Since 1999 he is
working in the Mulzer group
on the total synthesis of lau-
limalide within the context of
his PhD thesis.
Elisabeth ÷hler was born in
Vienna and received her PhD
in organic chemistry at the
University of Vienna in 1968
for work on Reformatsky-
type reactions under the guid-
ance of Ulrich Schmidt. Af-
terwards she joined Erich
Zbiral to explore phospho-
rous chemistry. Since 1996
she is a senior research fellow
in the Mulzer group. Apart fromlaulimalide she has
greatly contributed to epothilone syntheses.
Furthermore, we planned to synthesize sulfone 6 and
aldehyde 7 frominexpensive chiral carbon pool com-
pounds, such as d-mannitol, S-malic acid, and d-glucose,
respectively. Intermediates 6 and 7 were to be assembled
fromthe smaller fragments 8, 9 and 10, 11, respectively,
and it was decided to prepare the dihydropyrans 8 and 11
The C16,17-E-olefinic bond of 4 was to be generated not only by the relatively obvious RCM,[15] but also by
fromfragments 6 and 7 by a Julia Kocienski olefina- other competing methodology. The C27-C17 sulfone 6
tion.[14] Concerning the protective group strategy in our was to be assembled via Horner Wadsworth Emmons
synthesis, we decided to use the same protective groups olefination of aldehyde 8 and ketophosphonate 9,
(i.e., MOM) for the C20- and the C15-alcohol and whereas aldehyde 7 should be prepared by addition of
orthogonal protective groups (TBS and PMB, respec- C13-metallated sulfone 11 to epoxide 10 and subsequent
tively) for the C3- and the C19-hydroxy functions. introduction of the C13 methylene group.
OH
O
OH
16 15
H
H
O
19
15
19
13
O
O
27
HO
O
0.01 N HCl
13
O
Me
11
O
OH
H
Me
11
O
H
H
H
Me
Me
O
O
3
3
isolaulimalide (2)
(much less active)
laulimalide (1)
Scheme 1. Acid-catalyzed rearrangement of laulimalide to isolaulimalide.
574
Adv. Synth. Catal. 2002, 344, 573 584

Grubbs× RCM in the Total Synthesis of the Microtubule Stabilizing Drug Laulimalide
REVIEWS
OPG1
H
15
19
13
O
Still-Gennari olefination
O
O
OPG2
Me
11
H
O
H
OPG1
O
Me
O
H
15
19
13
O
P
3
OCH2CF3
1
CF3CH2O
O
OPG2
Me
O
11
H
O
H
Me
4
3
Yamaguchi or Keck macrolactonization
3
OPG1
H
15
19
13
O
OH
OPG2
Me
11
CO2H
H
O
H
Me
3
5
Scheme 2. Macrocyclization strategies for laulimalide.
16
13
H
O
OMOM
H
O
MOMO
H
Me
11
19
17
SO2Ar
4
TBSO
O
OPMB
3
Me
6
7
16
BMPO
10
O
13
H
SO2Ph
14
H
H
H
17
21
19
OPMB
(EtO)2(O)P
OTES
O
O
27
Me
11
O
22
TBSO
O
9
3
Me
8
11
Scheme 3. Retrosynthetic considerations.
Our first approach[9d] to sulfone 11 was based on a 13. Elaboration into the dihydropyran 11 was accom-
Ghosez lactonization[16] of epoxide 13 which should be plished via reagent 21 which gave adduct 22 and, after
available frominexpensive tri- O-acetyl-d-glucal (14) two more work-up steps, lactone 23 in 88% overall yield
(Scheme 4). Thus, the synthesis started from the known (Scheme 5). Oxidation of the sulfide gave sulfone 12
a,b-unsaturated lactone 17, readily available from 14 in which was converted to the ethyl glycoside 24. The C3-
four steps.[17] After conversion to the OTBS-derivative, C4 unit was stereoselectively introduced (Scheme 3) by
axial addition of dimethylcopper lithium to conformer generating oxoniumion 25 from 24 which underwent
18 smoothly provided the desired 9,11-trans disubsti- axial addition[10a,20] of t-butyldimethylsilyl vinyl ether to
tuted lactone 19 as a single diastereomer.[18] The formaldehyde 26. Sodiumborohydride reduction and
formation of epoxide 13 required an inversion of TBS protection gave the C3-C13 fragment 11.
configuration at C9. Therefore, 19 was reduced to the
Alternatively, 24 was prepared via RCM of diene 28
1,5-diol, and the primary alcohol at C13 was selectively with Grubbs× catalyst 29[21] in 89% yield. Diene 28 was
transformed to the corresponding phenyl sulfide 20 by obtained fromepoxide 13 via sulfone 27 (Scheme 6).
treatment with tributylphosphine/diphenyl disulfide.[19] Additionally, intermediate 11 was prepared along
Mesylation of the C9-hydroxy group, desilylation, and another route also employing Grubbs RCM.[10f] Specif-
ring closure with sodiumhydroxide delivered epoxide
ically, known alcohol 30[22] was converted into aldehyde
Adv. Synth. Catal. 2002, 344, 573 584
575

Johann Mulzer et al.
REVIEWS
13
SPh
13
H
SO2Ph
13
Me
11
Ghosez
lactonization
Me
11
O
9
H
11
OAc
O
O
11
9
O
OAc OAc
Tri-O-acetyl-D-glucal (14)
13
12
PCC
O
O
O
or MCPBA, BF3. Et2O
1. DBU (cat)
2. 2N HCl
Zn / HOAc
O
13
O
9
13
O
9
13
14
11
11
11
72%
95%
84%
9
OAc
OH
OAc OAc
16
17
15
1. TBSCl
O
SPh
13
1. MsCl
2. Me2CuLi
2. TBAF
3. NaOH
1. LiBH4
O
9
13
2. PhSSPh/ Bu3P
OH
74%
O
11
Me
13
11
Me
O
9
81%
89%
OTBS
OTBS
OTBS
20
19
axial
18
Scheme 4. Synthesis of epoxide 13.
SPh
13
SPh
Me
11
PhSO2CH(Li)CH2C(OMe)3
(21), BF3. Et2O
OH
1. TFA, H2O
2. DBU
H
O
O
11
Me
OMe
9
9
13
MeO
MeO
SO2Ph
88% overall
23
22
SO2Ph
SO2Ph
1. DIBAH
montmorillonite
K-10
2. EtOH /PPTS
Me
11
MMPP
Me
11
H
H
O
O
EtO
O
95%
98%
9
9
24
12
SO2Ph
13
Me
11
1. NaBH4
2. TBSCl
CH2=CHOTBS
H
H
H
O
O
R
11
9
86% overall
O
26
25
Scheme 5. Synthesis of dihydropyran 11 by Ghosez lactonization.
31, which was elaborated into diene 32 via Brown handicapped by the tricky transketalizations required to
allylation[23] (de 92%) and transketalization with acro- formthe dienes 28 and 32, respectively.
lein diethyl acetal. The anomeric mixture of acetals 32
Next (Scheme 7) sulfone 11 was converted into a 1:1
was treated as before to form 34, which was converted mixture of the C13-epimeric sulfones 35 by deprotona-
into intermediate 11 in three steps. On comparing the tion and subsequent treatment with glycidyl ether 10.[24]
three alternative routes to key intermediate 11, the After formation of the 15-OMOM ether 36 the C13-
Ghosez lactonization pathway appears the best one with methylene moiety was introduced via a Julia methyle-
respect to overall yield and ease of preparation. The nation[25] to give 37. Deprotection of the 16-PMB ether
RCM routes (which have been used in modified forms followed by Swern oxidation completed the synthesis of
also by Ghosh[9a,10b] and Davidson[10j]) performwell with
aldehyde 7,[9d] which is also a key fragment in the Ghosh
respect to the yield, however, in our synthesis, they are synthesis.[9a, c]
576
Adv. Synth. Catal. 2002, 344, 573 584

Grubbs× RCM in the Total Synthesis of the Microtubule Stabilizing Drug Laulimalide
REVIEWS
SO2Ph
13
SO2Ph
PCy3
Cl
Cl
1. vinylMgBr, CuI
2. CH2=CH-CH(OEt)2
PPTS
Ru CHPh
PCy3
(5 mol %)
Me
11
Me
11
(29)
MMPP
96 %
H
H
EtO
O
24
13
9
9
O
82 %
89 %
27
28
OPMB
Me
11
OPMB
Me
1. TsCl, pyridine
2. NaCN, DMSO, 80 °C
3. DIBAL, THF
1. (–)-Ipc2Ballyl, Et2O, –100 °C
2. CH2=CHCH(OEt)2, PPTS
OPMB
Me
29
H
EtO
O
DCM, reflux
9
O
75 %
94 %
HO
64 %
H
30
32
31
OPMB
Me
11
OPMB
1. TBSO-CH=CH2,
1. DDQ
2. PPh3, imidazole, I2
3. Li-CH2SO2Ph
montmorilionite K-10
2. NaBH4, MeOH
Me
11
3. TBSCl, imidazole, DMF
H
H
H
3
11
EtO
O
O
TBSO
9
9
81 %
75 %
33
34
Scheme 6. Synthesis of dihydropyran 11 by RCM.
13
H
SO2Ph
15
13
H
1. n-BuLi /BF3.Et2O
2. 10
SO2Ph
15
BMPO
BMPO
MOMCl
94 %
OH
H
Me
11
MOMO
H
Me
11
11
86 %
TBSO
O
TBSO
O
9
3
9
3
35
36
13
H
1. DDQ
15
1. n-BuLi, THF –78 °C
BMPO
2. Swern oxidation
2. CH2I2, i-PrMgCl
MOMO
H
Me
11
7
75 %
82 %
TBSO
O
Julia methylenation
9
3
37
Scheme 7. Synthesis of the C3-C16 fragment.
We next turned to the synthesis of dihydropyran
In a more sophisticated approach,[10i] two-directional
aldehyde 8. Altogether three approaches were tested, synthesis[27] was applied by starting frommannitol-
two of which were based on RCM. In the first one derived acetonide 46, which was converted into bis-
(Scheme 8),[10g] we used non-RCM chemistry by starting epoxide 47[28] under two-fold inversion of configuration.
fromglycidyl ether 10, which was opened at the least Further transformation as described above gave tet-
hindered side with the anion of ethyl propiolate to give raene 48 which was subjected to Grubbs RCM. No
alcohol 38. Stereoselective cuprate addition and cycli- medium ring-sized cycloolefins were formed across the
zation with acetic acid led to lactone 39, which was central acetonide ring which served as a barrier to cross-
reduced with DIBAL to give lactol 40. Reduction of the over metathesis.[29] In this way the bis-dihydropyran 49
hemiacetal with triethylsilane furnished dihydropyran was obtained which was converted into 8 via hydrolysis
41 which was deprotected and oxidized to aldehyde 8. of the central acetonide and glycol cleavage. This
The first RCM route[10g] (Scheme 9) started with glycidyl approach had the advantage of generating the highly
ether 42 which was opened with isopropenylmagnesium volatile and sensitive aldehyde 8 in high purity under
bromide under copper(I) catalysis. Allylation of the neutral conditions, which were not so easily achieved
resulting alcohol furnished diene 43, which gave dihy- when preparing 8 fromthe corresponding alcohol. In the
dropyran 44 under modified[26] Grubbs RCM conditions. meantime, a series of close analogues (50 57) of dienes
Deprotection and oxidation furnished aldehyde 8.
28, 32, and 43 have been subjected to RCM by other
Adv. Synth. Catal. 2002, 344, 573 584
577

Johann Mulzer et al.
REVIEWS
1. Me2CuLi, THF
2. AcOH, benzene
H
H
CO2Et,
n-BuLi, BF3.Et2O
HO
O
O
OPMB
OPMB
10
91 %
95 %
EtO2C
Me
39
38
Et3SiH,
BF3.Et2O
H
1. DDQ
2. SO3.pyridine
H
DIBAL, DCM
90 %
O
HO
O
OPMB
OPMB
8
80 %
Me
41
Me
40
Scheme 8. Synthesis of aldehyde 8 via acetylide addition.
H
1. HCO2H, then OH
2. NEt3, SO3 pyridine,
DMSO
H
O
O
27
1. CH2=C(Me)MgBr/CuI
OTr
OTr
OTr
2. allyl bromide, KOBu-t
23
29
99 %
23
O
8
92 %
99 %
Me
43
Me
44
42
OH HO
O
O
1. BzCl
2. MsCl
3. NaOH
1. CH2=C(Me)MgBr/CuI
2. allyl bromide, KOBu-t
HO
OH
O
O
O
D-mannitol
(45)
O
Me
95 %
Me
98%
Me
Me
47
46
Me
O
O
Me
1. TFA, DCM
O
O
29
83 %
2. Pb(OAc)4, Na2CO3
8
81 %
O
O
Me
Me
O
O
Me
Me
Me
Me
48
49
Scheme 9. Synthesis of aldehyde 8 by RCM.
O
authors to prepare the C5-C9- and C27-C23-dihydro-
pyrans of 1 (Scheme 10). Aldehyde 51 and acrylate 55
exhibit a relatively low RCM yield, whereas the yields of
the other examples are close to ours.
O
O
O
OPMB
H
OTHP
Me
Me
Me
52[9f]
The synthesis[9d] of b-oxophosphonate 9 (Scheme 11)
started fromthe known butyrolactone 58,[30] easily
obtained fromnatural S-malic acid. Reaction of 58
with the lithiumsalt of diethyl methanephosphonate
and subsequent addition of one equivalent of lithium
diisopropylamide[31] provided enolate 59 which was
silylated to give 9 after hydrolytic work-up.
51[10k]
50[10c]
O
O
O
O
O
OTBS
OTr
N
O
Bn
Me
Me
Me
53[10n,o]
43[10l]
54[10n]
OBn
OBn
TBSO
Me
Me
Me
OPMB
OLi
O
O
O
EtO
O
MeO
OLi
TESCl
83%
1. LiCH2P(O)(OEt)2
2. LDA
EtO
EtO
O
9
P
OPMB
O
O
56[9c]
55[9a,c,10b]
57[10j]
58
59
Scheme 10. Literature substrates for RCM preparation of
laulimalide dihydropyran subunits.
Scheme 11. Synthesis of phosphonate 9.
578
Adv. Synth. Catal. 2002, 344, 573 584

Grubbs× RCM in the Total Synthesis of the Microtubule Stabilizing Drug Laulimalide
REVIEWS
O
OH
20
H
H
O
19
17 OTES
1. LiCl, NEt3
2. + 8
27
NaBH4, CeCl3
96%
17
OTES
O
23
27
23
9
OPMB
OPMB
86%
Me
60
Me
61
20(S) : 20(R) = 7.8 : 1
OMOM
20
OMOM
1. MOMCl
2. TBAF
H
O
PT-SH, PPh3, DEAD, THF
90%
H
17
SPT
17
O
OH
27
20
23
OPMB
93%
OPMB
Me
Me
62
63
OMOM
19
H
OMOM
20
(NH4)2Mo7O24 x 4 H2O
30% H2O2, EtOH
15
OMOM
O
17
O
13
O
H
1. KHMDS
2. + 7
O
S
27
PT
23
OPMB
Me
11
OPMB
63%
H
H
74%
Me
TBSO
O
Me
3
64
65
Ph
(E) : (Z) = 11.4 : 1
N
= PT
N
N
N
Scheme 12. Synthesis of fragment 65.
MeO
O
O
1. PLE
2. (COCl)2
Cl
1
1
O
O
P
P
2
CF3CH2O
CF3CH2O
95%
CF3CH2O
CF3CH2O
67
66
OMOM
19
OMOM
19
H
O
H
1. HOAc
15
OMOM
15
OMOM
13
13
O
1. DDQ
2. Dess–Martin
2. 67, DMAP
periodinane
O
O
Me
11
O
Me
11
O
(E)-65
H
H
H
H
CF3CH2O
CF3CH2O
CF3CH2O
CF3CH2O
79%
2
2
Me
Me
O
O
95%
3
P
P
3
O
O
O
OTBS
68
69
OMOM
19
OH
H
H
15
OMOM
13
15
O
19
13
Me2BBr
O
KHMDS
(Z)-70
O
2
Me
11
O
O
OH
H
Me
11
O
85%
85%
H
H
H
Me
2
Me
O
O
3
3
71
70
(E) : (Z) = 1.8 : 1
Scheme 13. Still Gennari macrocyclization in the synthesis of deoxylaulimalide 71.
Olefination[32] of 9 with aldehyde 8 afforded enone 60 sulfone 64, which was connected with aldehyde 7 by a
stereoselectively in 87% yield (Scheme 12). Luche one-pot Julia Kocienski olefination[14] to give an 11.4:1
reduction[33] at 95 8C produced a 7.8:1 C20-epimeric E,Z-mixture of olefins, from which (E)-65 was isolated
mixture in favor of the desired (20S)-epimer 61. After by chromatography. For the completion of the synthesis
separation by HPLC, the (20R)-epimer was recycled by (Scheme 13) bis(2,2,2-trifluoroethyl)phosphonoacetyl
Parikh Doering oxidation.[34]
chloride 67 was prepared from commercially available
Alcohol 62 was obtained from 61 by MOM-protection methyl ester 66 by PLE-catalyzed ester hydrolysis and
and desilylation and treated with 1-phenyl-1H-tetra- subsequent treatment with oxalyl chloride. The C19
zole-5-thiol under Mitsunobu conditions[35] to give hydroxy group in (E)-65 was deprotected and acylated
sulfide 63. Oxidation[36] of 63 furnished the crystalline with 67 to formketophosphonate 68. 3-O-Desilylation
Adv. Synth. Catal. 2002, 344, 573 584
579

Johann Mulzer et al.
REVIEWS
was achieved smoothly with acetic acid (attempted diastereotopic differentiation of the two oxygens occurs
desilylation with tetra-n-butylammonium fluoride re- during activation with Lewis acids, e.g., EtAlCl2.[40c,41]
sulted in decomposition of the phosphonate moiety) and Altogether, four diastereomeric complexes (77 80) can
the resulting alcohol was converted into aldehyde 69 by be formed, among which 77 is energetically favored,
Dess Martin oxidation.[37] Macrocyclization under because AlR×3 has only one syn-interaction with a
Still Gennari conditions (KHMDS, 18-crown-6, THF, vicinal substituent. In contrast, 78 80 all have two such
50 min, 78 8C) led to a 1.8:1 E,Z-mixture of the olefins vicinal interactions. Thus, the allylsilane selectively
70, which could be separated by chromatography. (Z)-70 reacts with 77 to generate 81 under inversion of
was O-deprotected with dimethylboron bromide[38] to configuration at C15.[40c]
generate 16,17-deoxy-laulimalide 71.
The synthesis of the allylsilane 75 was started from
commercially available (R) ethyl hydrogen 3-methyl-
glutarate 82 (Scheme 16), which was elaborated into the
diene 84 via homoallylic alcohol 83. The transketaliza-
tion fromacrolein diethyl acetal was facilitated by the
stability of the amide; subjecting ester 83 to the same
3 Allylsilane/Acetal Macrocyclization
Route
To avoid the formation of 2,3-E,Z-mixtures, an alter- conditions led to the formation of the d-lactone.
native approach to 71 was envisaged. Instead of forming Grubbs RCM worked perfectly to convert 84 into
the macrocyclic ring by olefination, it appeared more dihydropyran 85, and the introduction of the C3-C4
appropriate to use an allylic transfer reaction[39] for side-chain was performed as before to generate alde-
closing the C14-C15-bond (Scheme 14).
hyde 86. Three additionalstepswere required toprepare
For instance, the cyclization of seco-precursor 72 ketone 87. Under kinetically controlled deprotonation
should occur under very mild conditions, so that a (Z)- (KHMDS, 1.5 equiv.), and subsequent treatment with
enoate in the C2-C3-position could easily survive. For PhNTf2 enol triflate 88 was obtained as a single
obtaining stereocontrol over center C15 it was advisable regioisomer, which was following Kuwajima×s proto-
to convert aldehyde 72 into the chiral acetal[40] 73 which col[42] treated with TMSCH2MgBr (6 equiv.) in the
would be opened by the allylsilane in a stereodefined presence of Pd(PPh3)4 (30 mol %) to give, after 1 h, an
manner. Retrosynthetically, 73 was to be generated by inseparable 1:1 mixture of allylsilane 89 and its D12,13
-
combining fragments 74 and 75 via Still Gennari isomers. Quite obviously, the large amount of the
olefination. catalyst and the long reaction time have led to isomer-
Acetals of type 76 contain a non-stereogenic chiro- ization. The similarity of the described protocol and the
topic acetal center, so that no stereounambiguity can Stille coupling[43] prompted us to perform the reaction in
arise in the formation of center C15 (Scheme 15). The the presence of 5 equiv. LiCl and 5 mol % Pd(PPh3)4.
SiMe3
Me
OMOM
O
H
14
O
O
15
O
O
H
H
Me
72
3
OMOM
O
H
15
O
Me
O
O
SiMe3
O
Me
Me
H
Me
H
O
14
73
OMOM
O
Me
H
Me
O
O
H
H
O
73
O
O
O
SiMe3
+
3
H
Me
O
P
Me
OCH2CF3
CF3CH2O
75
74
Scheme 14. Allylsilane cyclization strategies for the synthesis of protected deoxylaulimalide 3.
580
Adv. Synth. Catal. 2002, 344, 573 584

Grubbs× RCM in the Total Synthesis of the Microtubule Stabilizing Drug Laulimalide
REVIEWS
Me
AlR'3
Me
Me
Me
R'3Al
R
15
R'3Al
O
R
Me
O
+
O
+
O
R
Me
Me
O
Me
R
O
O
O
AlR'3
77
76
78
79
Me
allylsilane
+
O
R
Me
O
AlR'3
80
Me
H
Nu
R
O
S
Me
O
AlR'3
81
Scheme 15. Stereochemical course of acetal/allylsilane addition.
1. BH3.Me2S
2. Dess-Martin
1. Me2NH
Me
H
O
NMe2
2. CH2=CH-CH(OEt)2
13
O
Me
H
HO
p-TsOH
OEt
Me
9
OEt
3. (–)-IPC2B-allyl
O
EtO
O
O
90%
85%
OH
82
83
O
84
Me
H
1. NaBH4
2. TESCl
3. MeLi
NMe2
CH2=CHOTBS,
LiClO4
Me
Me
H
NMe2
O
Me
H
29
O
O
H
H
EtO
O
TESO
O
O
92%
80%
3
89%
86
85
87
Me
1. K2CO3, MeOH
Me
Me3SiCH2MgBr
LiCl, Pd(PPh3)4
KHDMS /
PhNTf2
2. Dess–Martin oxidn.
H
H
TESO
O
H
H
75
TESO
O
OTf
SiMe3
3
3
96%
85%
79%
88
89
Scheme 16. Synthesis of aldehyde 75.
O
Me
CN
1. DDQ
2. TsCl
3. NaCN
Me
11
Me
11
MeLi
86%
H
H
H
H
TBSO
O
TBSO
O
34
3
3
75%
90
91
Scheme 17. Simplified synthesis of methyl ketone 91.
Under these conditions, 88 reacted with TMSCH2MgBr the desired (20S)-alcohol which was protected with MOM
(2 equiv.) to give, after 10 min, allylsilane 89 in 96% chloride to give 95. Removal of the THP group and
yield. Removal of the TES group (K2CO3-MeOH) reduction of the propargylic alcohol furnished the corre-
followed by Dess Martin oxidation afforded aldehyde sponding allyl alcohol (E)-selectively which was oxidized
75 which was thus available from 82 in 14 steps and 31% to aldehyde 96 with Dess Martin periodinane.
overall yield. An alternative approach to ketone 87 in Acetalization of aldehyde 96 with (R,R)-(‡)-2,4-
formof the 3-OTBS-derivative 91 utilizes our pre- pentanediol, removal of the TBDPS group, and acyla-
vious[10f] intermediate 34 ( Scheme 17).
tion of the corresponding alcohol with phosphonoacetyl
For the synthesis of the C27-C15 component 74 chloride 67 provided C15-C27 fragment 74. Quite
(Scheme 18), our previous[10g] intermediate 38 was con- recently, we developed a more efficient synthesis of
verted into protected triol92, fromwhichthephosphonate
aldehyde 96 by starting fromlactone 97 (Scheme 19); in
93 was prepared via deprotection, oxidation, and chain particular, the Luche reduction of enone 99 proceeded
elongation. Horner Wadsworth Emmons olefination with complete stereoselectivity.
with aldehyde 8 furnished enone 94 (E)-selectively. Luche
Starting the next set of operations, phosphonate 74
reduction of the ketone led to the exclusive formation of was deprotonated (KHMDS, THF) and treated with
Adv. Synth. Catal. 2002, 344, 573 584
581

Johann Mulzer et al.
REVIEWS
1. DDQ, DCM-H2O
2. SO3-pyridine
3. NaClO2
1. TPDPSCl
2. DIBAL
3. DHP, p-TsOH
O
P
O
19
OTBDPS
MeO
MeO
4. CH2N2
OTHP
OTHP
BMPO
5. (MeO)2P(O)CH2Li
15
38
OTBDPS
93
OMOM
87%
70%
92
1. NaBH4, CeCl3, MeOH
2. MOMCl, DIEA, Bu4NI
H
O
1.NEt3, THF, LiCl
OTHP
O
2. +
8
H
O
OTHP
OTBDPS
OTBDPS
60%
92%
Me
Me
94
95
1. (R,R)-2, 4-pentanediol,
montmorillonite K10
2. TBAF
1. HCl, MeOH
2. Red-Al
3. Dess-Martin oxidn.
OMOM
3. 67, DMAP
H
O
O
74
OTBDPS
77%
81%
Me
96
Scheme 18. Synthesis of acetal 74.
5. (MeO)2P(O)CH2Li
O
2. LDA
H
1. NEt3, THF, LiCl
2. +
O
P
O
OTES
OTBDPS
O
3. TESCl
8
MeO
MeO
OTBDPS
O
OTES
OTBDPS
92%
O
Me
84%
98
99
97
1. NaBH4, CeCl3, MeOH
2. MOMCl, DIEA, Bu4NI
3. p-TsOH
OMOM
1. (MeO)2P(O)CHNaC(O)NMe(OMe),
2. DIBAL
H
4. SO3-pyridine
O
O
96
OTBDPS
78%
Me
82%
100
Scheme 19. Alternative synthesis of aldehyde 96.
OH
Me
OMOM
19
Me
O
EtAlCl2, CH2Cl2,
H
Dess-Martin
oxidn.
O
KHMDS, then75
82%
–50 °C
73
15
H
74
O
Me
11
O
3
86%
H
Me
95%
O
101
O
Me
Me
OMOM
19
1. TFA, MeOH
2. Me2BBr, ether
(+)-DIPT, tBuOOH,
Ti(Oi-Pr)4
O
H
O
15
H
71
1
O
Me
11
O
3
H
76%
80%
Me
O
102
Scheme 20. Synthesis of deoxylaulimalide 71 by allyl transfer cyclization. Completion of the synthesis by SAE.
aldehyde 75 to give pure Z-enoate 73 in 82% yield induce the 2,3-Z-E-isomerization which has been so
(Scheme 20).
painfully experienced in previous syntheses. After
The cyclization of 73 was performed in 4 ¥ 10-4 M oxidation of 101 to ketone 102, both protective groups
CH2Cl2 solution with 2 equiv. of EtAlCl2 and provided were removed in succession to generate 16,17-deoxy-
macrolide 101 as a single isomer in 86% yield. As laulimalide 71, which was identical (TLC and spectral
expected, these conditions were so mild that they did not data) with the compound obtained previously. The
582
Adv. Synth. Catal. 2002, 344, 573 584

Grubbs× RCM in the Total Synthesis of the Microtubule Stabilizing Drug Laulimalide
REVIEWS
epoxidation of 71[9d] was performed via SAE [(‡)-DIPT,
t-BuOOH, Ti(Oi-Pr)4 , CH2Cl2, 20 8C][44] which gave 1
as the only product.
Kim, J. Org. Chem. 2001, 66, 8973 8882; d) J. Mulzer, E.
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Tudge, Org. Lett. 2001, 3, 3149 3153.
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Y. Wang, Tetrahedron Lett. 2000, 41, 4705 4708; d) A.
Shimizu, S. Nishiyama, Tetrahedron Lett. 1997, 38, 6011
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[11] Reviews: A. F¸rstner, Angew. Chem. Int. Ed. 2000, 39,
3012 3043; R. H. Grubbs, S. Chang, Tetrahedron 1998,
54, 4413 4450; T. M. Trinka, R. H. Grubbs, Acc. Chem.
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[12] W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405
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4 Conclusion
In conclusion, we have presented two total syntheses of
16,17-deoxy-laulimalide (71), which was epoxidized to 1
by regio- and stereoselective SAE. RCM played a
central role for preparing the two dihydropyran sub-
units, although alternative methods were shown to
provide acceptable results as well.
Acknowledgements
Financial support bythe FWF (project 13941-CHE) is greatfully
acknowledged.
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