Toward the total synthesis of disorazole A1: Asymmetric synthesis of the masked northern half

Article abstract of DOI:10.1055/s-2003-41033

The stereoselective synthesis of the masked northern half of the antimitotic natural product disorazole A₁ is described involving as key step a Z-selective Wittig olefination of a C1-C11 epoxy aldehyde with a C12-C19 phosphonium iodide.

Full text of DOI:10.1055/s-2003-41033

1844
PAPER
Toward the Total Synthesis of Disorazole A1: Asymmetric Synthesis of the
Masked Northern Half
S
ynthesi
n
s
of
a
N
orthe
g
rn Half of
D
o
A
V. Hartung, Ulrike Eggert, Lars Ole Haustedt, Barbara Niess, Peter M. Schäfer, H. Martin R. Hoffmann*
1
Department of Organic Chemistry, University of Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: hoffmann@mbox.oci.uni-hannover.de
Received 10 June 2003; revised 10 July 2003
Dedicated to Prof. Wolfgang Steglich on the occasion of his 70th birthday.
cle forming hydroxy acids consist of an unsaturated
Abstract: The stereoselective synthesis of the masked northern half
of the antimitotic natural product disorazole A1 is described invol-
ving as key step a Z-selective Wittig olefination of a C1–C11 epoxy
aldehyde with a C12–C19 phosphonium iodide.
polyketide chain with an amino acid terminus masked as
an oxazole. This ensemble may have its biosynthetic ori-
gin in the joint action of a polyketide synthase (PKS) and
a nonribosomal peptide synthetase (NRPS).3 In view of its
interesting biological profile and its challenging structural
features we have embarked on a program toward the total
synthesis of disorazole A1.
Key words: total synthesis, cell cycle modulation, polyketides, ox-
azoles, Wittig reactions
Our retrosynthetic disconnections of disorazole A1 are
outlined in Scheme 1. The C7 –C12 triene and C5–C8 di-
ene of disorazole A1 were expected to be prone to light or
heat-induced isomerization. Therefore, we decided to
mask these sensitive functionalities by installing triple
bonds in place of Z-olefins.4 Retrosynthetic cleavage of
the dilactone provides the masked southern half 1 and
northern half 2. Our stereoselective synthesis of the
The disorazoles are a family of 29 complex macrodiolides
isolated in 1994 from the fermentation broth of the gliding
bacterium Sorangium cellulosum.1 Disorazole A1, by far
the major component of the crude extraction residue,
causes beyond its antifungal activity, decay of microtu-
bules in subnanomolar concentration, initiates cell cycle
arrest in G2/M phase and competes in vitro with vinblas-
tin for the tubulin binding site.2 Structurally, the macrocy-
19
6
16
O
N
14
OH
9
10
O
O
lactonization/esterification
1
OH
O
O
N
1'
O
11'
16'
14'
O
lactonization/esterification
19'
10'
6'
OMe
Disorazole A1
MeO
OEt
1
O
1'
O
TBDMSO
OTIPS
N
N
12
3
SEMO
OTBDMS
14
16
O
19
O
8
6'
10
16'
14'
+
6
OMe
7'
O
Wittig olefination
10'
northern half
2
southern half
1
(Ref. 5)
OEt
1
O
OEt
1
N
TBDMSO
3
O
OPMB
OTIPS
O
12
O
8
8
10
10
N
+
IPh3P
14
16
I
19
+
3
6
O
O
O
Sonogashira
coupling
6
5
6
3
4
Scheme 1
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 13 08 2003.
Art Id.1437-210X,E;2003,0,12,1844,1850,ftx,en;T05003SS.pdf.
DOI: 10.1055/s-2003-41033
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of the Northern Half of Disorazole A1
1845
masked southern half 1 has been reported recently.5 The methane A12 produced the oxazole alkyne 5 in 30% yield,
masked northern half was thought to be assembled by a Z- whereas with the Gilbert–Seyferth reagent B none of the
selective Wittig olefination of epoxy aldehyde 3 with desired alkyne 5 was formed.13 Instead, oxazole alkyne 5
phosphonium iodide 4. A Sonogashira coupling between was formed in 50% yield under very mild conditions us-
oxazole alkyne 5 and E-configured vinyl iodide 6 was ini- ing the Ohira–Bestmann diazophosphono ester C.14
tially envisaged as a key step for the synthesis of the C1–
C11 fragment 3.
E-Configured vinyl iodide ent-615 was synthesized from
epoxy alcohol 1316 in three steps (Scheme 3). Our synthe-
The synthesis of the oxazole alkyne 5 commenced with tic plan required next the Sonogashira coupling of vinyl
the transformation of trans-cinnamamide (7)6 to the 2,4- iodide ent-6 with oxazole alkyne 5. Even after extensive
disubstituted oxazole ester 9 by reaction with -bromo- optimization efforts involving variations of catalyst, sol-
ethyl pyruvate (8)7 using Panek’s modification of the vent, base, temperature, concentration and order of addi-
Hantzsch protocol (Scheme 2).8 Oxidative cleavage of the tion, enyne 14 was isolated at best in discouraging 15%
double bond was initially achieved in two steps by Sharp- yield.
less dihydroxylation and subsequent glycol cleavage with
Pb(OAc)4 in 77% yield. By applying the Sharpless dihy-
OEt
1
O
droxylation protocol instead of trimethylamine oxide/
PMBO
PMBO
OsO4 oxidation,8 the necessary amount of toxic OsO4 was
reduced from 10 mol% to 1 mol%.9 Ozonolysis of 9 fol-
lowed by workup with Ph3P gave the oxazole aldehyde 11
in 45% yield.
8
8
a
b
N
3
PMBO
10
10
I
HO
O
8
O
O
10
6
O
13
ent-6
14
Scheme 3 Reaction conditions: (a) 1. SO3·py, Et3N, CH2Cl2–
DMSO, 0 °C r.t., 95%; 2. Ph3P, CHI3, t-BuOK, THF, 75%; 3. Me-
Li, THF, –100 °C, 75%; (b) PdCl2(PPh3)2, CuI, Et3N, DMF, 5, r.t.,
15% (PMB = p-methoxybenzyl]
EtO
O
O
O
ref. 8
OEt
N
+
Ph
NH2
Br
O
Ph
O
7
8
9
To circumvent the low yielding alkynation Sonogashira
coupling sequence, we revised our synthetic strategy by
applying a Stille coupling and postponing the introduction
of the sensitive C9–C10 epoxide to a later stage of the syn-
thesis (Scheme 4).
c
a
EtO
EtO
EtO
O
O
O
N
N
OH
N
d
b
O
O
Ph
O
O
Bu3Sn
11
O
11
a
OH
10
b
OEt
15
OH
Br
Br
12
OTBDMS
7
11
9
f
9
16
17
e
c
EtO
O
P
MeO
O
O
P
OEt
1
O
OEt
1
H
H
TMS
MeO
MeO
MeO
O
N
O
d
N2
OTBDMS
N2
N2
N
11
N
Br
O
3
OH
A
B
C
O
8
5
O
10
7
5
9
6
19
18
Scheme 2 Reaction conditions: (a) K3[Fe(CN)6] (3 equiv), K2CO3
(3 equiv), OsO4 (0.01 equiv), (DHQD)2PHAL (0.01 equiv), t-BuOH,
H2O, r.t., 96%; (b) Pb(OAc)4, K2CO3, benzene, 0 °C, 80%; (c) NaIO4
(3 equiv), silica gel, RuCl3·xH2O (0.05 equiv), CH2Cl2, r.t., 68%; (d)
CBr4, Ph3P, CH2Cl2, 70%; (e) n-BuLi, THF, –78 °C, 30%; (f) A, t-
e
OEt
1
O
BuOK, THF, –78 °C, 30% or C, K2CO3, EtOH, 0 °C
1. CHI3, t-BuOK, CH2Cl2, r.t.; 2. n-BuLi, –100 °C, 41% (2 steps)
[(DHQD)2PHAL = hydroquinidine 1,4-phthalazinediyl diether]
r.t., 50% or
N
3
O
O
8
10
6
O
3
Gratifyingly, this one-step oxidative cleavage of 9 was
optimized to 68% yield by using NaIO4 on silica gel in the
presence of a catalytic amount of RuCl3.10 Homologation
to the oxazole alkyne 5 was first pursued under Corey–
Fuchs conditions11 via dibromo olefin 12. Unfortunately,
treatment of 12 with n-butyllithium produced the desired
alkyne 5 in only 30% yield. The direct conversion of alde-
hyde 11 into alkyne 5 was investigated using C1-transfer
reagents A–C. Commercially available TMS-diazo-
Scheme 4 Reaction conditions: (a) 1. LiBr, HOAc, MeCN; Et3N,
CuI (0.02 equiv), PdCl2(Ph3P)2 (0.01 equiv), HC CSiMe3, r.t., 79%;
2. DIBAH, THF, –78 0 °C, 85%; 3. TBAF, THF, 0 °C, 70%; (b) 1.
TBDMSCl, imidazole, DMF, r.t., 90%; 2. CuCN, n-BuLi, Bu3SnH,
THF, –78
–30 °C, 85%; (c) 12, TFP (0.15 equiv), Pd2dba3 (0.025
equiv), toluene, 100 °C, 86%; (d) TBAF (3.0 equiv), THF, 0 °C, 87%;
(e) 1. D-(–)-DET, Ti(i-PrO)4, t-BuOOH, MS 4Å, CH2Cl2, –18 °C,
84% (86% ee), 2. PhI(OAc)2 (1.1 equiv), TEMPO (0.1 equiv),
CH2Cl2, r.t., 81% [TFP = tris(2-furyl)phosphine, DET = diethyl tar-
trate, TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxyl]
Synthesis 2003, No. 12, 1844–1850 © Thieme Stuttgart · New York

1846
I. V. Hartung et al.
PAPER
Starting from ethyl propiolate, in situ formation of Z-vinyl The phosphonium iodide was conveniently used after re-
bromide and trapping under Sonogashira conditions with moval of excess triphenylphosphine with n-pentane with-
TMS-acetylene led to a TMS-protected enyne ester,17 out further purification steps. First, lithium salt-free
which was reduced and deprotected to give allylic alcohol conditions were employed for the Wittig reaction of phos-
16.
phonium iodide 4 and C1–C11 aldehyde 3.25 Using NaH-
MDS as base the masked northern half was isolated in
only 21% yield. For optimization studies epoxy aldehyde
22 and its enantiomer were used as model systems in com-
bination with phosphonium iodide 4 and its syn-diastereo-
mer (Scheme 6). In this case, the Wittig product was
formed using lithium salt free conditions in 45% yield (Z/
E = 9.5:1.0). By changing the base to LiHMDS with
HMPA as co-solvent26 Wittig product 23 was isolated in
61% yield (from syn-21).
After E-selective stannylation,18 diene 17 was coupled
with oxazole dibromoolefin 12 giving rise to bromotriene
18 of inconsequential geometry in excellent 86% yield.19
TBDMS-deprotection and dehydrobromination was
achieved in one-step using an excess of TBAF. The syn-
thesis of epoxy aldehyde 3 was completed by Sharpless
epoxidation (86% ee)20 and oxidation with PhI(OAc)2/
TEMPO.21
The C12–C19 phosphonium iodide 4 was prepared from
the bisprotected triol 20, which was synthesized from pro-
pane-1,3-diol in seven steps as reported in our synthesis of
the masked southern half of disorazole A1 (Scheme 5).5
TIPS-protection of the C16 hydroxy group,22 PMB-cleav-
age and transformation of the primary alcohol to the io-
dide 21 proceeded in 88% overall yield. Treatment of
iodide 21 with triphenylphosphine under standard condi-
tions (MeCN, reflux) afforded the phosphonium iodide 4
in less than 50% yield accompanied by significant decom-
position of starting material. Similar results were obtained
using solvent-free conditions (Ph3P, neat, 85 °C).23 In
contrast, by adding excess Hünig’s base24 the phosphoni-
um iodide was formed in 83% isolated yield.
Scheme 6 Reaction conditions: (a) 1. syn-21, Ph3P (1.8 equiv),
DIPEA (7.0 equiv), sealed flask, 85 °C, 20 h; 2. removal of excess
Ph3P with n-pentane; 3. LiHMDS, THF, –78 °C, 15 min; 4. HMPA,
22, –78 °C r.t., 3 h, 61% (from syn-21)
By applying the optimized conditions to the Wittig olefi-
nation of oxazole epoxy aldehyde 3, the masked northern
half of disorazole was formed in 43% yield as a 5:1 Z/E
mixture (Scheme 5). The decrease in yield compared to
Wittig olefinations of model aldehyde 22 is most likely
due to the presence of the oxazole. The hydrogen atom of
2,4-disubstituted oxazoles is known to be sufficiently
acidic to be abstracted by common lithium bases.27 Nu-
cleophilic addition reactions of the so formed lithiated ox-
azole could possibly involve the C11 aldehyde,28 the C9–
C10 epoxide or even the C1 ester functionality leading to
diverse side products.
OH OTBDMS
TIPSO
OTBDMS
12
a
16
14
OPMB
I
19
20
21
b
OEt
O
1
TIPSO
OTBDMS
N
3
O
PPh3I
O
8
10
6
O
3
4
c
OEt
OEt
1
O
1
O
TBDMSO
12
OTIPS
N
TBDMSO
12
OTIPS
3
N
14
16
3
19
O
14
16
8
19
O
10
8
6
10
6
O
O
2
OEt
24
Scheme 5 Reaction conditions: (a) 1. TIPSOTf, 2,6-lutidine,
CH2Cl2, r.t., 99%; 2. DDQ, CH2Cl2/H2O 10:1, 0 °C, 99%; 3. MsCl,
Et3N, DMAP, THF, 0 °C, 99%; 4. NaI, NaHCO3, acetone, reflux,
91%; (b) Ph3P, DIPEA, sealed flask, 85 °C, 83%; (c) 1. 4, LiHMDS,
1
O
TBDMSO
OTIPS
N
12
3
14
16
19
O
8
10
THF, –78 °C
r.t.; 2. HMPA, 3, –78 °C
r.t., 43% (from 21)
6
[DIPEA = diisopropylamine; HMPA = hexamethylphosphoric tria-
mide; LiHMDS = lithium hexamethyldisilazide]
O
25
Figure 1 Structures of masked non-natural halves of disorazole A1
24 and 25
Synthesis 2003, No. 12, 1844–1850 © Thieme Stuttgart · New York

PAPER
Synthesis of the Northern Half of Disorazole A1
1847
1H NMR (400 MHz, CDCl3/TMS): = 8.18 (s, 1 H, H-3), 4.37 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 3.27 (s, 1 H, H-6), 1.37 (t, J = 7.1 Hz,
3 H, OCH2CH3).
13C NMR (100 MHz, CDCl3/TMS): = 160.3 (Cq, C-1), 145.9 (Cq,
C-4), 144.5 (CH, C-3), 134.3 (Cq, C-2), 81.2 (Cq, C-5), 70.4 (CH, C-
6), 61.6 (OCH2CH3), 14.2 (OCH2CH3).
We have applied our strategy for the synthesis of two
masked non-natural northern halves of disorazole A1 with
inverted configurations at C9/C10 (Figure 1, 24) and C16
(25), respectively. The modularity of our synthesis plan
thus proved to be applicable for future SAR studies.
With routes for both masked halves of disorazole A1 in
hand, our further synthetic efforts are focused on develop-
ing cyclization strategies targeting disorazole A1 and its
C2-symmetric homodimers disorazole B1 and disorazole
C1.
MS MAT: m/z (%) = 166 (12, [M+ + 1]), 165 (84, [M+]), 138 (22),
137 (100), 120 (56), 109 (18), 93 (12), 81 (11).
HRMS: m/z calcd for C8H7NO3: 165.0426; found: 165.0427.
tert-Butyldimethyl-(5-tributylstannanylpenta-2,4-dienyloxy)-
silane (17)
To a suspension of CuCN (104 mg, 1.16 mmol, 1.16 equiv) in THF
(7 mL) was added n-BuLi (1.6 M in hexane, 1.4 mL, 2.3 mmol, 2.3
equiv) dropwise at –78 °C. The mixture was allowed to reach
–30 °C to become homogeneous and was then cooled to –78 °C.
Tributyltin hydride (0.6 mL, 2.3 mmol, 2.3 equiv) was added drop-
wise. The yellow-orange solution was warmed to –30 °C and the
alkyne (196 mg, 1.0 mmol, 1.0 equiv) in THF (3 mL) was added
dropwise. After 1 h, the reaction was complete (TLC control). Sat.
aq NH4Cl solution (2.5 mL) and conc. aq NH3 solution (0.5 mL)
were added. The aqueous layer was extracted with MTBE, dried
(MgSO4) and the solvent removed. The crude product was purified
IR spectra were recorded on a Perkin-Elmer 1710 IR spectrometer.
1H NMR and 13C NMR spectra were recorded on Bruker AVS 400
and Bruker AVM 500 spectrometers in CDCl3 or acetone-d6 with
tetramethylsilane as internal standard. 1H NMR chemical shifts are
reported in parts per million (ppm) downfield from tetramethylsi-
lane (0 ppm) as internal standard. Coupling constants (J) are report-
ed in Hertz (Hz). 13C NMR spectra were fully decoupled with
chemical shifts reported relative to the solvent signal (CDCl3, 77.0
ppm). Signal assignments are based on DEPT and – if necessary –
on additional 1H-1H-COSY and HMQC experiments. The number-
ing of carbon and hydrogen signals refers to the numbering of the
natural product. Mass spectra were performed on a Finnigan MAT
312 (70 eV) or a VG Autospec (HR-MS) spectrometer. Microanal-
yses were performed in the Department of Organic Chemistry of the
University of Hannover. Petroleum ether (PE) used had bp 55–60
°C.
by chromatography on silica gel (PE–Et3N, 100:1
PE–MTBE–
Et3N, 95:5:1) to afford stannane 17 (416 mg, 85%).
1H NMR (400 MHz, CDCl3/TMS): = 6.78 (ddd, J = 18.6, 10.5,
1.1 Hz, 1 H, H-8), 6.27 (d, J = 18.6 Hz, 1 H, H-7), 5.90–6.03 (m, 1
H, H-9), 5.42–5.50 (m, 1 H, H-10), 4.40 (dd, J = 6.6, 1.3 Hz, 2 H,
H-11), 1.46–1.54 (m, 6 H, 3 CH2, Bu), 1.26–1.36 (m, 6 H, 3 CH2,
Bu), 0.87–0.93 (m, 24 H, t-C4H9,TBDMS and 3 CH2CH3, Bu), 0.09
(s, 6 H, 2 CH3, TBDMS).
2-(2,2-Dibromovinyl)-oxazole-4-carboxylic Acid Ethyl Ester
(12)
To a solution of aldehyde 11 (869 mg, 5.14 mmol, 1.0 equiv) and
CBr4 (1.79 g, 5.4 mmol, 1.05 equiv) in CH2Cl2 (15 mL) was added
Ph3P (2.83 g, 10.8 mmol, 2.1 equiv) in four portions (5 min inter-
vals) at 0 °C. The mixture was stirred for 1 h at r.t. Then silica gel
was added followed by PE. The solvent was evaporated and the res-
idue filtered though a short column [PE/MTBE (methyl tert-butyl
ether)] to afford dibromoolefin 12 (1.08 g, 65%) as a colorless solid;
mp 68 °C.
13C NMR (100 MHz, CDCl3/TMS): = 141.55 (CH), 136.19 (CH),
132.16 (CH), 129.41 (CH), 59.72 (CH2, C-11), 29.13 (CH2, Bu),
27.30 (CH2, Bu), 25.99 (CH3, t-C4H9), 18.40 [Cq, t-C4H9), 13.69
(CH3, Bu), 9.58 (CH2, Bu), –5.07 (CH3, TBDMS).
MS-MAT (80 °C): m/z (%) = 488 (3, [M+]), 487 (4), 436 (15), 435
(27), 433 (70), 432 (47), 431 (100), 430 (93), 429 (92), 427 (91),
365 (50), 291 (22), 249 (83), 247 (87), 193 (89),191 (79).
HRMS: m/z calcd for C23H48OSiSn: 488.2496; found: 488.2494.
IR (neat): 3135, 2911, 1719, 1568, 1310, 1245, 1161, 1101, 1025,
988 cm–1.
1H NMR (400 MHz, CDCl3/TMS): = 8.25 (s, 1 H, H-3), 7.54 (s, 1
H, H-5), 4.39 (q, J = 7.3 Hz, 2 H, OCH2CH3), 1.37 (t, J = 7.3 Hz, 3
H, OCH2CH3).
13C NMR (100 MHz, CDCl3/TMS): = 160.8 (Cq, C-1), 158.4 (Cq,
C-4), 143.5 (CH, C-3), 134.6 (Cq, C-2), 123.4 (CH, C-5), 99.5 (Cq,
C-6), 61.5 (OCH2CH3), 14.3 (OCH2CH3).
2-[2-Bromo-7-(tert-butyldimethylsilyloxy)hepta-1,3,5-trienyl]-
oxazole-4-carboxylic Acid Ethyl Ester (18)
A solution of stannane 17 (292 mg, 0.6 mmol, 1.2 equiv), dibro-
moolefin 12 (163 mg, 0.5 mmol, 1.0 equiv) and TFP (17.4 mg,
0.075 mmol, 0.15 equiv) in toluene (2.5 mL) was degassed with ar-
gon for 30 min. Then Pd2dba3 (12.9 mg, 0.0125 mmol, 0.025 equiv)
was added and the mixture was heated to 100 °C. After 1 h, no start-
ing material was detectable by TLC. Sat. aq NaHCO3 solution was
added and the aqueous layer was extracted with MTBE. The com-
bined organic layers were dried (MgSO4), the solvent removed, and
the crude product purified by chromatography to afford 18 (190 mg,
86%) as a colorless solid; mp 93 °C.
1H NMR (400 MHz, CDCl3/TMS): = 8.28 (s, 1 H, H-3), 7.21 (dd,
J = 14.3, 11.9 Hz, 1 H, H-8), 6.98 (s, 1 H, H-5), 6.36 (d, J = 14.3 Hz,
1 H, H-7), 6.17–6.24 (m, 1 H, H-9), 5.81 (dt, J = 10.9, 6.3 Hz, 1 H,
H-10), 4.47 (dd, J = 6.3, 1.6 Hz, 2 H, H-11), 4.41 (q, J = 7.2 Hz, 2
H, OCH2CH3), 1.40 (t, J = 7.2 Hz, 3 H, OCH2CH3), 0.92 (s, 9 H, t-
C4H9, TBDMS), 0.11 (s, 6 H, 2 CH3, TBDMS).
MS-MAT (80 °C): m/z (%) = 325 (47, [M+ + 2]), 323 (26, [M+]),
297 (100), 295 (44), 280 (14), 215 (23), 211 (25).
HRMS: m/z calcd for C8H7Br2NO3: 322.8792; found: 322.8792.
2-Ethynyloxazole-4-carboxylic Acid Ethyl Ester (5)
To a solution of oxazole aldehyde 11 (150 mg, 0.89 mmol, 1.0
equiv) in EtOH (6 mL) was added sequentially K2CO3 (241 mg,
1.75 mmol, 2.0 equiv) and the Ohira–Bestmann reagent (256 mg,
1.33 mmol, 1.5 equiv) at 0 °C. After 16 h, the reaction mixture was
treated with 1 N HCl, and extracted with MTB ether. The combined
organic layers were dried (Na2SO4) and the solvent was evaporated.
The crude product was purified by chromatography (cylohexane–
MTBE, 4:1) to afford oxazole alkyne 5 (70.5 mg, 50%) as a color-
less solid; mp 73 °C.
13C NMR (100 MHz, CDCl3/TMS): = 160.97 (Cq), 159.87 (Cq),
143.43 (CH), 136.19 (CH), 134.76 (Cq), 133.96 (CH), 132.08 (CH),
129.48 (Cq), 127.21 (CH), 116.81 (CH), 61.29 (CH2), 59.92 (CH2),
25.88 (CH3), 18.28 (Cq), 14.23 (CH3), –5.18 (CH3).
IR (neat): 3199, 2994, 2126, 1716, 1575, 1367, 1211, 1022, 946,
830 cm–1.
Synthesis 2003, No. 12, 1844–1850 © Thieme Stuttgart · New York

1848
I. V. Hartung et al.
PAPER
MS-MAT (130 °C): m/z (%) = 443 (36), 441 (17, [M+]), 387 (11),
386 (89), 384 (41), 362 (33), 306 (22), 264 (20), 236 (35), 230
(100), 202 (90), 129 (33).
2-[4-(3-Formyloxiranyl)but-3-en-1-ynyl]oxazole-4-carboxylic
Acid Ethyl Ester (3)
A solution of the above prepared epoxy alcohol (131.6 mg, 0.5
mmol, 1.0 equiv), BAIB [bis(acetoxy)iodobenzene, 177 mg, 0.55
mmol, 1.1 equiv] und TEMPO (8 mg, 0.05 mmol, 0.1 equiv) in
CH2Cl2 (1 mL) was stirred for 2.5 h at r.t. Silica gel was added and
the solvent removed. The crude product was purified by chromato-
graphy (EtOAc–PE, 1:2) to afford aldehyde 3 (106 mg, 81%) as a
colorless solid; mp 97 °C; [ ]D20 –118.2 (c = 0.45, CHCl3).
1H NMR (400 MHz, CDCl3/TMS): = 9.44 (d, J = 5.2 Hz, 1 H, H-
11), 8.22 (s, 1 H, H-3), 6.36 (dd, J = 15.9, 7.0 Hz, 1 H, H-8), 6.24
(dd, J = 15.9, 0.6 Hz, 1 H, H-7), 4.40 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 3.86 (ddd, J = 7.0, 4.5, 0.6 Hz, 1 H, H-9), 3.64 (dd,
J = 5.3, 4.6 Hz, 1 H, H-10), 1.39 (t, J = 7.2 Hz, 3 H, OCH2CH3).
HRMS: m/z calcd for C19H28BrNO4Si: 441.0971; found: 441.0973.
2-(7-Hydroxy-hepta-3,5-dien-1-ynyl)oxazole-4-carboxylic Acid
Ethyl Ester (19)
To a solution of protected bromotriene 18 (442 mg, 1.0 mmol, 1.0
equiv) in THF (10 mL) was added TBAF (1.0 M in THF, 3.0 mL,
3.0 mmol, 3.0 equiv) dropwise at 0 °C. After 30 min, H2O was add-
ed and the aqueous layer was extracted with MTBE. The combined
organic layers were dried (MgSO4) and the solvent was evaporated.
The crude product was purified by chromatography to afford allylic
alcohol 19 (216 mg, 87%) as colorless needles; mp 91 °C.
1H NMR (400 MHz, CDCl3/TMS): = 8.20 (s, 1 H, H-3), 7.17
(ddd, J = 15.6, 11.7, 1.4 Hz, 1 H, H-8), 6.15–6.23 (m, 1 H, H-9),
5.82–5.89 (m, 1 H, H-10), 5.81 (d, J = 15.6 Hz, 1 H, H-7), 4.40 (q,
J = 7.2 Hz, 2 H, OCH2CH3), 4.39–4.42 (m, 2 H, H-11), 1.66 (br, 1
H, OH), 1.39 (t, J = 7.2 Hz, 3 H, OCH2CH3).
13C NMR (100 MHz, CDCl3/TMS): = 196.75 (CH, C-11), 160.39
(Cq, C-1), 146.57 (Cq, C-4), 144.52 (CH, C-3), 139.01 (CH, C-7/C-
8), 134.70 (Cq, C-2), 114.30 (CH, C-7/C-8), 88.82 (Cq, C-5/C-6),
78.98 (Cq, C-5/C-6), 61.56 (OCH2CH3), 59.49 (CH, C-9/C-10),
57.34 (CH, C-9/C-10), 14.25 (OCH2CH3).
13C NMR (100 MHz, CDCl3/TMS): = 160.58 (Cq), 147.21 (Cq),
144.30 (CH), 140.96 (CH), 135.88 (CH), 134.51 (Cq), 128.46 (CH),
109.57 (CH), 92.17 (Cq), 78.69 (Cq), 61.53 (CH2), 58.88 (CH2),
14.25 (CH3).
MS-MAT (100 °C): m/z (%) = 262 (24), 261 (100, [M+]), 233 (32),
232 (69), 216 (32), 204 (53), 187 (51), 159 (30), 149 (40), 105 (64).
HRMS: m/z calcd for C13H11NO5: 261.0637; found: 261.0637.
MS-MAT (120 °C): m/z (%) = 248 (20), 247 (53, [M+]), 219 (29),
218 (80), 202 (37), 192 (19), 179 (13), 173 (77), 172 (100), 145
(39), 116 (510), 105 (43).
3-(tert-Butyldimethylsilyloxy)-4,4-dimethyl-5-triisopropylsilyl-
oxyoct-6-en-1-ol
To a solution of alcohol 20 (150 mg, 0.35 mmol, 1.0 equiv) in
CH2Cl2 (0.7 mL) was added DMAP (cat.), 2,6-lutidine (124 L,
1.06 mmol, 3.0 equiv) and TIPSOTf (124 L, 0.46 mmol, 1.3 equiv)
at 0 °C. After 16 h at r.t., H2O was added and the aqueous layer was
extracted with MTBE. The combined organic layers were dried
(Na2SO4) and the solvent was evaporated. Purification of the crude
product by chromatography afforded the TIPS ether (201 mg, 99%)
as a colorless oil. To a solution of this PMB ether (1235 mg, 2.13
mmol, 1.0 equiv) in CH2Cl2 (25 ml) was added H2O (2.5 mL) and
DDQ (629.5 mg, 2.77 mmol, 1.3 equiv) at 0 °C. After 1 h at r.t., cy-
clohexa-1,4-diene (3 mL) and sat. aq NaHCO3 solution were added
and the aqueous layer was extracted with MTBE. The combined or-
ganic layer was dried (Na2SO4) and the solvent was evaporated.
Purification of the crude product by chromatography afforded the
free primary alcohol (977 mg, 99%) as a colorless oil; [ ]D20 –11.5
(c = 1.01, CHCl3).
HRMS: m/z calcd for C13H13NO4: 247.0845; found: 247.0845.
2-[4-(3-Hydroxymethyloxiranyl)but-3-en-1-ynyl]oxazole-4-car-
boxylic Acid Ethyl Ester
To a solution of 4Å molecular sieves (206 mg), Ti(i-PrO)4 (35 L,
0.028 mmol, 0.14 equiv) and D-(–)-diethyl tartrate (24 mg, 0.028
mmol, 0.14 equiv) in CH2Cl2 (4 mL) was added t-BuOOH (5.5 M
in decane, 0.31 mL, 1.74 mmol, 2.1 equiv) at –20 °C. The solution
was stirred for 15 min and then the allylic alcohol 19 (206 mg, 0.83
mmol, 1.0 equiv) in CH2Cl2 (4 mL) was added. The resulting mix-
ture was stored for 3 d in a refrigerator (–18 °C) and then suction-
filtered through Celite. To the filtrate was added FeSO4/tartaric acid
solution and the mixture was stirred for 1 h at r.t. The aqueous layer
was extracted with CH2Cl2, the combined organic layers were dried
(MgSO4) and the solvent was evaporated. Purification of the crude
product by chromatography afforded the epoxide (184 mg, 84%) as
a colorless solid; mp 89 °C; [ ]D20 +72.2 (c = 0.63, CHCl3).
IR (neat): 3327, 2938, 1672, 1386, 1082, 1049, 1004, 834, 773 cm–1.
1H NMR (400 MHz, CDCl3/TMS): = 5.40–5.55 (m, 2 H, H-18, H-
17), 4.03 (d, J = 8.2 Hz, 1 H, H-16), 3.71–3.77 (m, 1 H, H-12a),
3.59–3.68 (m, 1 H, H-12b), 3.56 (dd, J = 7.9, 2.7 Hz, 1 H, H-14),
1.78–1.86 (mdddd, 1 H, H-13a), 1.68 (d, J = 5.0 Hz, 3 H, H-19),
1.60–1.66 (m, 1 H, H-13b), 1.04 [m, 21 H, CH(CH3)2, TIPS], 0.95
(s, 3 H, CH3), 0.91 (s, 9 H, t-C4H9, TBDMS), 0.88 (s, 3 H, CH3 ),
0.07 (s, 3 H, CH3, TBDMS), 0.06 (s, 3 H, CH3, TBDMS).
13C NMR (100 MHz, CDCl3/TMS): = 131.97 (CH, C-18), 127.66
(CH, C-17), 79.12 (CH, C-16), 74.35 (CH, C-14), 60.86 (CH2, C-
12), 44.28 (Cq, C-15), 35.69 (CH2, C-13), 26.17 (CH3, TBDMS),
20.32 (CH3,), 19.68 (CH3 ), 18.34 (CH3, TIPS), 18.22 (CH3, TIPS),
18.09 [C(CH3)3, TBDMS], 17.66 (CH3, C-19), 12.83 (CH, TIPS),
–3.66 (CH3, TBDMS), –3.72 (CH3, TBDMS).
IR (neat): 3382, 1720, 1544, 1305, 1239, 1153, 1108, 1020, 948
cm–1.
1H NMR (400 MHz, CDCl3/TMS): = 8.21 (s, 1 H, H-3), 6.40 (dd,
J = 16.0, 6.8 Hz, 1 H, H-8), 6.06 (dd, J = 16.1, 1.0 Hz, 1 H, H-7),
4.40 (q, J = 7.2 Hz, 2 H, OCH2CH3), 3.85 (dd, J = 12.4, 4.4 Hz, 1
H, H-11a), 3.74 (dd, J = 12.4, 6.2 Hz, 1 H, H-11b), 3.63 (ddd,
J = 6.8, 4.4, 1.0 Hz, 1 H, H-9), 3.42 (dt, J = 6.2, 4.4 Hz, 1 H, H-10),
1.53 (br, 1 H, OH), 1.39 (t, J = 7.2 Hz, 3 H, OCH2CH3).
13C NMR (100 MHz, CDCl3/TMS): = 160.50 (Cq, C-1), 146.88
(Cq, C-4), 144.46 (CH), 142.13 (CH), 134.47 (Cq, C-2), 112.29
(CH), 90.01 (Cq), 77.72 (Cq), 61.57 (OCH2CH3), 60.06 (CH2, C-11),
59.91 (CH, C-9/C-10), 55.91 (CH, C-9/C-10), 14.24 (OCH2CH3).
MS (80 °C): m/z (%) = 417 (1), 416 (2), 415 (5, [M+]), 414 (0.6),
399 (2), 359 (2), 345 (1), 326 (2), 320 (4), 319 (14), 315 (9), 305 (4),
284 (6), 283 (18), 263 (7), 245 (5), 243 (5), 242 (14), 241 (34), 229
(29), 228 (39), 227 (89), 213 (12), 203 (20), 199 (9), 190 (16), 189
(40), 187 (31), 186 (32), 185 (53), 173 (41), 171 (57), 157 (32), 153
(33), 131 (100), 119 (36), 115 (32), 103 (27), 89 (32), 75 (47), 73
(54).
MS-MAT (130 °C): m/z (%) = 264 (42), 263 (100, [M+]), 247 (13),
235 (14), 234 (62), 233 (84), 232 (84), 220 (89), 218 (84), 195 (56),
188 (85), 174 (83), 121 (73).
HRMS: m/z calcd for C13H13NO5: 263.0794; found: 263.0790.
HRMS: m/z calcd for C22H47O3Si2: 415.3064; found: 415.3061.
Synthesis 2003, No. 12, 1844–1850 © Thieme Stuttgart · New York

PAPER
Synthesis of the Northern Half of Disorazole A1
1849
Methanesulfonic Acid 3-(tert-Butyl-dimethylsilyloxy)-4,4-dime-
thyl-5-triisopropylsilyloxyoct-6-enyl Ester
(39), 229 (29), 228 (43), 227 (100), 203 (45), 185 (68), 153 (40),
115 (42).
To a solution of the above primary alcohol (583 mg, 1.27 mmol, 1.0
equiv) in THF (5 mL) was added DMAP (cat.), Et3N (0.35 mL, 2.54
mmol, 2.0 equiv) and MsCl (0.14 mL, 1.78 mmol, 1.4 equiv) at
0 °C. After 2 h at 0 °C, sat. aq NH4Cl solution was added and the
aqueous layer was extracted with MTBE. The combined organic
layers were dried (Na2SO4) and the solvent was evaporated. Purifi-
cation of the crude product by chromatography afforded the corre-
sponding mesylate (682.4 mg, 99%) as a colorless oil; [ ]D20 –15.3
(c = 1.11, CHCl3).
HRMS: m/z calcd for C22H46IO2Si2: 525.2081; found: 525.2078.
Anal. Calcd for C25H53IO2Si2: C, 52.79; H; 9.39. Found: C, 52.47;
H, 9.20.
2-(4-{3-[4-(tert-Butyldimethylsilyloxy)-5,5-dimethyl-6-triiso-
propylsilyloxynona-1,7-dienyl]oxiranyl}but-3-en-1-ynyl)ox-
azole-4-carboxylic Acid Ethyl Ester (2)
Iodide 21 (40 mg, 0.070 mmol, 1.0 equiv), Ph3P (34 mg, 0.127
mmol, 1.8 equiv) and i-Pr2NEt (86 L, 0.49 mmol, 7.0 equiv) were
heated in a sealed flask to 85 °C for 20 h. i-Pr2NEt was carefully re-
moved with anhyd n-pentane in vacuo (3 ×) and the residue was re-
suspended in anhyd n-pentane. After 1 min, the n-pentane was
removed by pipette (repeated twice). The residue was dissolved in
anhyd THF (1.4 mL), cooled to –78 °C and a 1 M solution of
LiHMDS in THF (74 L, 0.074 mmol, 1.05 equiv) was added drop-
wise. After 15 min at –78 °C, HMPA (0.14 ml) and aldehyde 3 (19.3
mg, 0.074 mmol, 1.05 equiv) in anhyd THF (0.3 mL) were subse-
quently added. The mixture was gradually warmed to r.t. and stirred
for 3 h. The mixture was hydrolyzed with sat. aq NaHCO3 solution,
extracted with MTBE, dried (Na2SO4), filtered through Celite, and
evaporated to dryness. After chromatography, the Wittig product
was isolated (20.8 mg, 43%) as a slightly yellow oil (Z/E >5:1).
IR (neat): 2939, 1690, 1358, 1176, 1082, 1005, 971, 881, 834, 773
cm–1.
1H NMR (400 MHz, CDCl3/TMS): = 5.53 (dq, J = 15.4, 5.9 Hz, 1
H, H-18), 5.46 (ddq, J = 15.5, 8.5, 1.3 Hz, 1 H, H-17), 4.37 (ddd,
J = 9.6, 8.2, 4.8 Hz, 1 H, H-12a), 4.21 (dt, J = 9.5, 7.7 Hz, 1 H, H-
12b), 4.01 (d, J = 8.5 Hz, 1 H, H-16), 3.60 (dd, J = 8.0, 2.6 Hz, 1 H,
H-14), 3.00 (s, 3 H, CH3, mesylate), 2.01–2.10 (mdtd, 1 H, H-13a),
1.74–1.84 (mdtd, 1 H, H-13b), 1.71 (dd, J = 5.8, 0.8 Hz, 3 H, H-19),
1.06 [br s, 21 H, CH(CH3)2, TIPS], 0.92 (br s, 12 H, CH3, TBDMS),
0.90 (s, 3 H, CH3 ), 0.09 (2 × 3 H, CH3, TBDMS).
13C NMR (100 MHz, CDCl3/TMS): = 131.47 (CH, C-18), 128.17
(CH, C-17), 79.25 (CH, C-16), 73.42 (CH, C-14), 68.08 (CH2, C-
12), 44.17 (Cq, C-15), 37.39 (CH3, mesylate), 32.76 (CH2, C-13),
26.12 (CH3, TBDMS), 20.39 (CH3), 19.84 (CH3 ), 18.44 [C(CH3)3,
TBDMS], 18.37 (CH3, TIPS), 18.25 (CH3, TIPS), 17,73 (CH3, C-
19), 12.81 (CH, TIPS), –3.63 (CH3, TBDMS), –3.71 (CH3,
TBDMS).
IR (neat): 2928, 2863, 1745, 1465, 1306, 1251, 1143, 1081, 1051,
835, 809, 773 cm–1.
1H-1H-COSY (400 MHz, CDCl3/TMS): = 8.22 (s, 1 H, H-3), 6.35
(dd, J = 16.0, 6.8 Hz, 1 H; H-8), 6.06 (d, J = 16.0 Hz, 1 H, H-7),
5.87–5.94 (m, 1 H, H-12), 5.42–5.57 (m, 2 H, H-17 + H-18); 5.21
(tdd, J = 9.5–10.5 Hz, 1 H, H-11), 4.41 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.05 (d, J = 7.8 Hz, 1 H, H-16), 3.88 (dd, J = 8.7, 4.2
Hz, 1 H, H-10), 3.67 (dd, J = 6.5, 4.3 Hz, 1 H, H-9), 3.59 (dd,
J = 6.6, 3.7 Hz, 1 H, H-14), 2.35–2.49 (m, 2 H, H-13), 1.71 (d,
J = 4.5 Hz, 3 H, H-19), 1.40 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.06 (br
s, 21 H, TIPS), 0.91 (s, 3 H, CH3), 0.90 (s, 9 H, t-C4H9, TBDMS),
0.89 (s, 3 H, CH3 ), 0.05 (s, 3 H, CH3, TBDMS), 0.01 (s, 3 H, CH3,
TBDMS).
MS (100 °C): m/z (%) = 536 (1, [M+]), 535 (2), 496 (2), 495 (3), 494
(5), 493 (13), 479 (2), 449 (3), 437 (4), 397 (9), 383 (9), 361 (12),
353 (9), 341 (137), 311 (10), 309 (20), 301 (18), 287 (24), 283 (23),
280 (20), 279 (57), 267 (46), 246 (53), 228 (54), 227 (56), 209
(100), 185 (80), 171 (72), 153 (81), 115 (53), 73 (87).
HRMS: m/z calcd for C26H56O5Si2S: 536.3387; found: 536.3392.
6-(tert-Butyldimethylsilyloxy)-8-iodo-5,5-dimethyl-4-triisopro-
pylsilyloxyoct-2-ene (21)
To a solution of the above mesylate (450 mg, 0.84 mmol, 1.0 equiv)
in acetone (9 mL) was added solid NaHCO3 (422 mg, 5.03 mmol,
6.0 equiv) and NaI (503 mg, 3.35 mmol, 4.0 equiv) at r.t. After 6 h
at reflux, H2O was added and the aqueous layer was extracted with
MTBE. The combined organic layers were dried (Na2SO4) and the
solvent was evaporated. Purification of the crude product by chro-
matography afforded iodide 21 (434.1 mg, 91%) as a colorless oil;
[ ]D20 –32.3 (c = 0.93, CHCl3).
13C NMR (100 MHz, CDCl3/TMS): = 160.48 (Cq, C-1), 146.94
(Cq, C-4), 144.29 (CH, C-3), 142.76 (CH, C-8), 138.15 (CH, C-12),
134.56 (Cq, C-2), 131.82 (CH, C-17/C-18), 127.87 (CH, C-17/C-
18), 122.44 (CH, C-11), 111.81 (CH, C-7), 90.07 (Cq, C-5/C-6),
79.27 (CH, C-14/C-16), 77.61 (Cq, C-5/C-6), 76.53 (CH, C-14/C-
16), 61.48 (OCH2CH3), 57.45 (CH, C-9), 55.59 (CH, C-10), 44.69
(Cq, C-15), 31.64 (CH2, C-13), 26.14 (CH3, TBDMS), 20.30 (CH3),
19.97 (CH3 ), 18.39 [C(CH3)3, TBDMS], 18.36 (CH3, TIPS), 18.23
(CH3, TIPS), 17.74 (CH3, C-19), 14.23 (OCH2CH3), 12.80 (CH,
TIPS), –3.00 (CH3, TBDMS), –4.00 (CH3, TBDMS).
IR (neat): 2960, 1669, 1471, 1462, 1255, 1083, 1046, 833, 772 cm–1.
1H NMR (400 MHz, CDCl3/TMS): = 5.53 (dq, J = 15.4, 5.8 Hz, 1
H, H-18), 5.43–5.49 (ddq, 1 H, H-17), 3.99 (d, J = 8.4 Hz, 1 H, H-
16), 3.47 (dd, J = 8.0, 2.3 Hz, 1 H, H-14), 3.36 (mddd, 1 H, H-12a),
3.11 (dt, J = 9.4, 8.3 Hz, 1 H, H-12b), 2.12 (dtd, J = 14.6, 8.5, 2.4
Hz, 1 H, H-13a), 1.93 (dtd, J = 15.2, 7.4–8.0, 4.6 Hz, 1 H, H-13b),
1.72 (d, J = 5.8 Hz, 3 H, H-19), 1.07 [br s, 21 H, CH(CH3)2, TIPS],
0.93 (br s, 12 H, CH3 and t-C4H9, TBDMS), 0.90 (s, 3 H, CH3 ), 0.13
(s, 3 H, CH3, TBDMS), 0.11 (s, 3 H, CH3, TBDMS).
13C NMR (100 MHz, CDCl3/TMS): = 131.51 (CH, C-18), 128.18
(CH, C-17), 79.36 (CH, C-16), 77.55 (CH, C-14), 44.26 (Cq, C-15),
37.33 (CH2, C-13), 26.24 (CH3, TBDMS), 20.50 (CH3), 20.18
(CH3 ), 18.58 (Cq, TBDMS), 18.38 (CH3, TIPS), 18.26 (CH3, TIPS),
17.72 (CH3, C-19), 12.83 (CH, TIPS), 5.05 (CH2, C-12), –3.19
(CH3, TBDMS), –3.74 (CH3, TBDMS).
ESI-MS: m/z calcd for C38H63NNaO6Si2: 708.4092; found:
708.4059.
Acknowledgment
We are grateful to the Innovation Campaign of the University of
Hannover, the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft for support.
References
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(29), 415 (43), 375 (10), 374 (25), 373 (36), 317 (14), 315 (29), 311
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Synthesis 2003, No. 12, 1844–1850 © Thieme Stuttgart · New York

1850
I. V. Hartung et al.
PAPER
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