Synthetic studies toward the disorazoles: Synthesis of a masked northern half of disorazole D1 and a cyclopropane analog of the masked northern half of disorazole A1

Article abstract of DOI:10.1016/S0040-4020(03)00916-5

The synthesis of a masked northern half of the natural product disorazole D₁ and a cyclopropane analog of the masked northern half of disorazole A₁ is described. The synthesis involves in both cases as key steps a Z-selective Wittig olefination and a Sonogashira cross-coupling reaction.

Full text of DOI:10.1016/S0040-4020(03)00916-5

Tetrahedron 59 (2003) 6967–6977
Synthetic studies toward the disorazoles: synthesis of a masked
northern half of disorazole D1 and a cyclopropane analog of the
masked northern half of disorazole A1
Lars Ole Haustedt, Sreeletha B. Panicker, Mike Kleinert, Ingo V. Hartung, Ulrike Eggert,
*
Barbara Niess and H. M. R. Hoffmann
Department of Organic Chemistry, University of Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
Received 2 April 2003; accepted 10 June 2003
Dedicated to Professor K. C. Nicolaou with respect and admiration
Abstract—The synthesis of a masked northern half of the natural product disorazole D1 and a cyclopropane analog of the masked northern
half of disorazole A1 is described. The synthesis involves in both cases as key steps a Z-selective Wittig olefination and a Sonogashira
cross-coupling reaction.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
radicicols8 a cyclopropane was used as substitute for the
labile epoxide moiety, leading to more stable derivatives of
the natural products with comparable bioactivity profiles. In
this context, it is of interest to investigate if the natural
relatives of disorazole A1 without the C9–C10 epoxide are
bioactive as well.
The disorazoles comprise a family of 29 closely related
macrodiolides which were isolated in 1994 from the
myxobacterium Sorangium cellulosum by Hofle and
¨
co-workers (Fig. 1).1 Disorazole A1 initiates decay of
microtubules in subnanomolar concentration and arrests the
cell cycle in the G2/M phase.2 Disorazole A1 binds
irreversibly to the vinblastin binding site of tubulin.3 For
the cryptophycines,4 maytansine5 and rhizoxin,6 which are
epoxide bearing macrocycles, an irreversible binding to the
vinblastine binding site of tubulin by way of nucleophilic
epoxide opening was discussed. As the role of the epoxide
moiety of disorazole A1 is to date unknown there is a great
need for epoxide analogs which mimic either electronic and/
or steric behavior (e.g. hydrogen bond acceptor, confor-
mational clasp). In SAR studies on the epothilones7 and
Due to their extraordinary biological activity in combination
with a synthetically demanding array of double bonds and
oxygen functionality the disorazoles are a challenging target
for total synthesis. The ensemble of a polyketide chain with
a masked amino acid in form of an oxazole may be
biosynthesized by a PKS/NRPS assembly line.9 To
investigate some of these aspects we started a program
toward the synthesis of a masked northern half of disorazole
D1 as well as a cyclopropane analog of the masked northern
half of disorazole A1.
Figure 1. Disorazole A1 and disorazole D1.
Keywords: disorazoles; macrodiolides; cell cycle modulation; cyclopropane.
*
Corresponding author. Tel.: þ49-5117624611; fax: þ49-5117623011; e-mail: hoffmann@mbox.oci.uni-hannover.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00916-5

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2. Results and discussion
of disorazole A1 and D1.12 The so far unknown absolute
stereochemistry of the C9 and C10 stereocenters of the
northern half of disorazole D1 had to be determined by
synthesis.13
2.1. Retrosynthesis
Our retrosynthetic analysis of disorazole D1 is outlined in
Scheme 1. The C5–C6 and C11–C12 Z-double bonds were
thought to be sensitive toward isomerization. Thus, the C5–
C6 Z-olefin was protected in form of a triple bond. By way
of a syn-selective hydrogenation and macrodilactonization
the disorazole skeleton was planned to be assembled from
masked southern and northern halfs.10 The southern half of
disorazole D1 is identical to that of disorazole A1. Our
synthesis of the masked southern half of disorazole A1 was
published recently.11 The northern half was thought to be
accessible in a convergent and flexible manner by a
Z-selective Wittig olefination and a Sonogashira cross-
coupling reaction necessitating phosphonium salt A, vinyl
iodide B and the oxazole alkyne C as synthetic precursors.
Our retrosynthetic approach allows a straightforward
substitution of vinyl iodide B (e.g. with cyclopropane
bearing analog B0) to access derivatives of the northern half
2.2. Synthesis of C1–C11 fragments
The synthesis of the C7–C11 vinyl iodide B started from
tartaric acid diethyl ester using the Seebach protocol14
delivering the C2-symmetric diol 1 (Scheme 2). After
monoprotection and oxidation the E-configured vinyl iodide
3 was prepared by a Takai reaction.15
Oxazole aldehyde 4 was generated using a Hantzsch
protocol further modified by Panek.16 This 2,4-disubstituted
oxazole was converted into oxazole alkyne 5 under mild
conditions using the Ohira–Bestmann diazophosphono
ester.17 A Sonogashira cross-coupling was used for the
assembly of the protected C1–C11 enyne 6.18 Best yields
were achieved by addition of alkyne 5 after premixing the
catalyst, copper salt and vinyl iodide 3 in degassed DMF.
Scheme 1. Retrosynthetic analysis.
Scheme 2. Reaction conditions: (a) i: NaH, TBSCl, THF, rt, 85%; ii: SO3·py, DMSO, Et3N, CH2Cl2, 08C, 96%; (b) CrCl2, CHI3, THF, rt, 14 h, 72%, E/Z.10:1;
(c) EtOH, K2CO3, Ohira–Bestmann reagent, 08C!rt, 50%; (d) PdCl2(PPh3)2, CuI, DMF, 3, Et3N, rt, 86%; (e) i: TBAF, THF, 08C, 99%; ii: Dess–Martin
periodinane (2.0 equiv.), py (4.0 equiv.), CH2Cl2, 08C, 75%.

L. O. Haustedt et al. / Tetrahedron 59 (2003) 6967–6977
6969
The sensitive aldehyde 7 was generated after silyl
deprotection with TBAF and oxidation using buffered
Dess–Martin periodinane. Alternative oxidation methods
including PCC, Swern or TEMPO/BAIB oxidation
protocols led to significantly lower yields.19
propane diol in seven steps as reported in our synthesis of
the masked southern half of disorazole A1 (Scheme 4).11
The C17–C19 propenyl side chain was introduced without
diastereomeric control by nucleophilic addition of excess
trans-propenyl lithium formed in situ from trans-bromo-
propene and t-butyl lithium below 2908C, to the C16
aldehyde 14.11 The desired anti-diastereomer was separated
from the resulting diastereomeric mixture by chromato-
graphy and was further transformed in four steps to the
C12–C19 iodide 16 (88% overall yield). As an improve-
ment of our synthesis and for future SAR studies the C16
stereocenter remains to be installed in a stereocontrolled
fashion.
The synthesis of vinyl iodide B0 commenced with the
asymmetric Charette cyclopropanation20 of mono-PMB
protected cis-butene diol 8 (Scheme 3). Oxidation of the
primary alcohol followed by Takai reaction afforded the
E-vinyl iodide 11. Sonogashira cross-coupling21 of oxazole
alkyne 5 and vinyl iodide 11 under conditions as above
yielded protected C1–C11 cyclopropane enyne 12 in 48%
isolated yield. It is instructive that the more sensitive epoxy
analog of 11 afforded the Sonogashira product in at best
15% yield! Removal of the PMB group followed by
oxidation of the so formed alcohol using buffered Dess–
Martin periodinane provided the cyclopropane carbalde-
hyde 13.
In our initial retrosynthetic planning the propenyl side
chain was masked as an alkyne. The desired allylic
alcohol should be set free by aluminate reduction of the
propargylic alcohol 19.22 (Scheme 5) To this end,
aldehyde 17 was converted into alkynone 18 in quanti-
tative yield by Grignard addition and subsequent Dess–
Martin oxidation. For the construction of the C16
stereogenic center both chiral and achiral reducing agents
were tested (see Table 1).
2.3. Synthesis of the C12–C19 phosphonium iodide
The C12–C19 phosphonium iodide 16 was prepared from
the bisprotected triol 15, which was synthesized from 1,3-
Scheme 3. Reaction conditions: (a) i: Et2Zn, CH2Cl2, 08C, CH2I2, dioxaborolane 9, 4.5 h, 81%; ii: Dess–Martin periodinane (1.5 equiv.), NaHCO3
(4.0 equiv.), CH2Cl2, rt, 88%; (b) CrCl2, CHI3, THF, 08C, 4 h, 49%; (c) PdCl2(PPh3)2, CuI, DMF, 5, Et3N, 45 min, rt, 49%; (d) i: DDQ (2.5 equiv.), CH2Cl2/
H2O, rt; ii: Dess–Martin periodinane, NaHCO3 (3 equiv.), rt, 20 min, 71% (from 12).
Scheme 4. Reaction conditions: (a) i: trans-1-bromo-propene, t-BuLi, Et2O/THF 1:1, 2958C, 99% (anti/syn,1:1); ii: separation of diastereomers; (b) i:
TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 99%; ii: DDQ, CH2Cl2/H2O 10:1, 08C, 99%; iii: MsCl, Et3N, DMAP, THF, 08C, 99%; iv: NaI, NaHCO3, acetone, reflux,
91%.
Table 1.
Reducing conditions
Yield of 19 [%]
Anti/syna
LiBH4, CeCl3·7 H2O, MeOH/THF
94
1.0:1.5
5.3:1.0
1.7:1.0
2.0:1.0
(S)-Me-CBS (0.5 equiv.), BH3·DMS (1.0 equiv.), CH2Cl2, 2208C
(S)-Me-CBS (1.0 equiv.), catechol borane (2.0 equiv.), CH2Cl2, 2208C ! rt
Terashima reagent (2.1 equiv.), Et2O, 2788C
58b
66c
82
a
b
c
1
Based on H NMR integration.
35% Recovered starting material.
28% Recovered starting material.

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Scheme 5. Reaction conditions: (a) i: propynylmagnesium bromide, THF, 08C, 99% (anti/syn,1:1); ii: Dess–Martin periodinane, CH2Cl2, 08C !rt, 99%.
(b) see Table 1.
Although high levels of 1,2-reduction were achieved under
modified Luche reduction conditions23 (entry 1), only poor
diastereoselectivity slightly favouring the syn-diastereomer
was observed in this case. Competing 1,4-reduction caused
by the steric demand of the geminal dimethyl group
hampered the application of most other achiral reducing
agents (e. g. L-selectride gave the saturated ketone in
quantitative yield). CBS-reduction24 using borane dimethyl-
sulfide complex as stoichiometric reductant provided
predominantly the desired anti-diastereomer (entry 2),
whereas with catechol borane25 a significant decrease in
diastereoselectivity was observed (entry 3). The Terashima
reagent26 led to a 2:1 diastereomeric mixture in high yield
also favoring the desired anti-diastereomer (entry 4).
susceptible towards 1,4-reduction than the corresponding
alkynone 18. For example, reduction of 21 using the
aforementioned modified Luche conditions (LiBH4,
CeCl3·7H2O, MeOH) produced a complex mixture (58%
1,2-reduction accompanied by 24% 1,4-reduction) slightly
favouring the syn-diastereomer (anti/syn¼1.0:1.6). L-Selec-
tride, LiAlH4, LiHBEt3 or Zn(BH4)2/CeCl3·7H2O delivered
predominantly to exclusively the 1,4-reduction product.
Similarly, the saturated ketone was produced in 84% yield
under Terashima conditions. Employing the (S)-Me-CBS
reagent28 enone 21 (natural C14 configuration) was
converted with high diastereoselectivity into syn-diol 22
(Scheme 7). Stereoisomeric, enone 24 (non-natural C14
configuration) was converted under similar reaction con-
ditions into anti-diol 26. In the latter case the diastereo-
selectivity was significantly lower which might be due to a
matched-mismatched incident. Attempts to convert the
natural enone 21 into the natural anti-diol 23 were
unrewarding as in reductions of 21 with the (R)-Me-CBS
reagent the 1,4-reduction product was formed predomi-
nantly!
Surprisingly, the aluminate reduction of propargylic alcohol
19 with LiAlH4 or Red-Al failed following various
published procedures.27 We speculate that the aluminate is
chelated by the C14 oxygen and therefore does not attack
the C17/C18 triple bond.
As a further approach to C16 stereocontrol we modified our
synthetic strategy by employing enone 21 as substrate for
diastereoselective reductions. Enone 21 was readily avail-
able from aldehyde 14 by a three step sequence including
allylmagnesium bromide addition, oxidation and isomeriza-
tion to the a-enone (Scheme 6).
In conclusion, all four possible C12/C19 stereoisomers (22,
23, 25 and 26) were synthesized either by direct propenyl
lithium addition to a C16 aldehyde and subsequent
separation of diastereomers or by diastereoselective
reduction of a C12–C19 a-enone.
The isomerization was best achieved with a stoichiometric
amount of DBU, whereas triethylamine required elevated
temperature and prolonged reaction time and transition
metal catalysts failed to give satisfying yields and
E-selectivities. Unfortunately, enone 21 was even more
2.4. Fragment assembly via Z-selective Wittig olefination
The performance of the Z-selective Wittig reaction for
fragment assembly was critical for the success of our
synthetic plan. Therefore we prepared a less complex
Scheme 6. Reaction conditions: (a) i: allylmagnesium bromide, THF, 08C; ii: Dess–Martin periodinane, CH2Cl2, 08C!rt; (b) DBU (1.1 equiv.), CH2Cl2,
08C!rt, 75% (from 14), E/Z.40:1.
Scheme 7. Reaction conditions: (a) (S)-Me-CBS reagent (2.1 equiv.), BH3·DMS (5.0 equiv.), THF, 2308C, 3 h, 78% (þ17% 1,4-reduction); (b) (S)-Me-CBS
reagent (2.0 equiv.), BH3·DMS (5.0 equiv.), THF, 230!2208C, 6 h, 72% (þ18% 1,4-reduction).

L. O. Haustedt et al. / Tetrahedron 59 (2003) 6967–6977
6971
Scheme 8. Reaction conditions: (a) i: MsCl, DMAP, Et3N, THF, 08C, 93%; ii: NaI, acetone, NaHCO3, reflux, 3 h, 78%; (b) i: PPh3, i-Pr2NEt, 908C, 18 h; ii:
LiHMDS, THF/HMPA 10:1, 7, 2788C!rt, 1 h, 37% (from 28), Z/E 2.8:1.
phosphonium iodide for model reactions. Once generated,
iodide 28 might also be useful for the synthesis of analogs of
the northern halfs of disorazole A1 and D1 for SAR
investigations.
(Scheme 9). To our delight the Z-selectivity (Z/E 10:1)
was much higher than observed with the model system.
Under the same conditions the cyclopropane analog of the
northern half of disorazole A1 31 was generated in 40%
yield starting from iodide 16 (Z/E$5:1).
The preparation of the known alcohol 2729 involved as key
step a Brown asymmetric allylation.30 After silylation and
ozonolysis, the iodide 28 was again prepared from alcohol
27 via the corresponding mesylate (Scheme 8).
3. Conclusions
A masked northern half of disorazole D1 and a cyclopropane
analog of the masked northern half of disorazole A1 were
constructed by chemical synthesis. Both halfs were
assembled in a flexible and convergent manner using a
Sonogashira cross-coupling and a Z-selective Wittig
olefination. Our strategy is well suited for the synthesis of
various derivatives required for SAR studies of the
disorazoles.
Attempts at generating the phosphonium salt by reaction of
iodide 28 in a neat triphenylphosphine melt and following
chromatographic purification resulted in low yields. By
using Hu¨nig’s base as an additive and increasing the
pressure (sealed flask, 908C) the phosphonium salt was
formed smoothly. Conveniently, the phosphonium iodide
could be used after removal of the excess triphenyl-
phosphine with n-pentane without further purification steps.
Conditions for Z-selective Wittig olefinations of
unstabilized phosphonium salts with highly functionalized
aldehydes are strongly substrate dependent.31 After some
experimentation it was found that the combination of
LiHMDS and HMPA as co-solvent provided the C1–C16
fragment 29 in 37% yield starting from iodide 28
(Scheme 8).
4. Experimental
4.1. General
Infrared spectra were recorded on a Perkin–Elmer 1710
infrared spectrometer. 1H NMR and 13C NMR spectra were
recorded on Bruker AVS 400 and Bruker AVM 500
spectrometer in deuterated chloroform or acetone with
1
Analogously, iodide 16 was converted into the correspond-
ing phosphonium iodide. The ylide was again generated by
action of LiHMDS in THF/HMPA and after addition of
aldehyde 7 the masked northern half of disorazole D1 30
was isolated in 32% yield starting from iodide 16
tetramethylsilane as internal standard. H NMR chemical
shifts are reported in parts per million (ppm) downfield
from tetramethylsilane (0 ppm) as internal standard. The
following abbreviations are used to describe spin multi-
plicity: s¼singlet, br s¼broad singlet, d¼doublet, t¼triplet,
Scheme 9. Reaction conditions: (a) i: PPh3, i-Pr2NEt, 908C, 18 h; ii: LiHMDS, THF/HMPA 10:1, 2788C!rt, 32%, Z/E 10:1; (b) i: PPh3, i-Pr2NEt, 908C, 20 h;
ii: LiHMDS, HMPA/THF 10:1, 2788C!rt, 40%, Z/E$5:1.

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q¼quartet, m¼multiplet, dd¼doublet of doublets, etc.
Coupling constants (J) are reported 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. Mass
spectra were performed on a Finnigan MAT 312 (70 eV) or
a VG Autospec (HR-MS) spectrometer. Microanalyses were
performed in the Department of Organic Chemistry of the
University of Hannover.
purified by column chromatography eluting with CH/MTBE
4:1 to yield 70.5 mg (50%) of a colourless solid. mp: 738C;
1H NMR (400 MHz, CDCl3, TMS): 8.18 (s, 1H, H-3); 4.37
(q, J¼7.1 Hz, 2H, H-10); 3.27 (s, 1H, H-6); 1.37 (t,
J¼7.1 Hz, 3H, H-20); 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 0(Cq, C-5); 70.4 (CH, C-6); 61.6 (CH2, C-10);
14.2 (CH3, C-2 ); IR (neat, cm21): 3199, 3163, 3125, 2994,
2908, 2126, 1716, 1575, 1533, 1476, 1449, 1367, 1312,
1299, 1211, 1154, 1114, 1022, 984, 946, 867, 830, 771, 748,
712, 611, 552; MS: m/z (%) 166 (Mþþ1; 12); 165 (Mþ; 84);
138 (22); 137 (100); 120 (56); 109 (18); 93 (12); 81 (11);
HRMS: calcd for C8H7NO3: 165.0426; found: 165.0427.
4.1.1. Vinyl iodide 3. To 2.73 g (17.04 mmol) SO3·py in
12.8 mL of CH2Cl2 were added 3 mL of DMSO and Et3N
(3 mL), followed by 1.17 g (4.26 mmol) of alcohol 1 in
5 mL of CH2Cl2 at 08C. After 4 h at 08C the reaction was
quenched with sat. NH4Cl solution. The mixture was
extracted with MTB ether. The combined organic layers
were dried (Na2SO4). The crude product was purified by
column chromatography (CH/MTBE 4:1) to furnish 1.12 g
(96%) of aldehyde 2 as a slightly yellow oil. Due to its
instability, aldehyde 2 was immediately used for the Takai
reaction. 1H NMR (400 MHz, CDCl3, TMS): 9.80 (d,
J¼1.6 Hz, 1H, H-8); 4.35 (dd, J¼7.3, 1.6 Hz, 1H, H-9); 4.17
(dt, J¼7.3, 4.4 Hz, 1H, H-10); 3.83 (d, J¼4.4 Hz, 2H,
H-11); 1.50 (s, 3H, C(CH3)2); 1.45 (s, 3H, C(CH3)2); 0.93 (s,
9H, TBS); 0.12 (s, 6H, TBS); 13C NMR (100 MHz, CDCl3,
TMS): 200.8 (Cq, C-8); 111.0 (CH, C-9); 109.0 (Cq,
C(CH3)2); 81.9 (CH, C-10); 62.9 (CH2, C-11); 26.8 (CH3,
C(CH3)2; 26.3 (CH3, C(CH3)2); 18.3 (CH3, TBS); 13.8 (Cq,
TBS); 25.5 (CH3, TBS).
4.1.3. Enyne 6. 25 mg of PdCl2(PPh3)2 (0.035 mmol) and
13.4 mg of CuI (0.070 mmol) were dissolved in degassed
DMF (3.4 mL), stirred for 15 min at rt and treated dropwise
with 278 mg (0.70 mmol) of vinyl iodide 3 in DMF
(3.5 mL). After addition of 3.4 mL Et3N it was stirred for
another 45 min. Finally 150 mg (0.91 mmol) of alkyne 5 in
DMF (3.5 mL) were added slowly and stirring was
continued for 7 h. The reaction was quenched with a
solution of sat. NH4Cl, extracted with MTB ether and the
organic layers were dried (Na2SO4). Purification by column
chromatography (CH/MTBE 20:1) furnished enyne 6 (85%)
1
as yellow oil. [a]2D0¼25.618 (c¼0.89, CHCl3); H NMR
(400 MHz, CDCl3, TMS): 8.15 (s, 1H, H-3); 6.43 (dd,
J¼15.9, 5.5 Hz, 1H, H-8); 5.97 (dd, J¼15.9, 1.5 Hz, 1H,
H-7); 4.43 (dt, J¼7.5, 1.5 Hz, 1H, H-9); 4.34 (q, J¼7.2 Hz,
2H, H-10); 3.72 (m, 1H, H-10); 3.71 (m, 2H, H-12) 1.36 (s,
3H, O2C(CH3)2); 1.35 (s, 3H, O2C(CH3)2); 1.32 (t,
J¼7.2 Hz, 3H, H-20); 0.86 (s, 9H, Si(CH3)2)C(CH3)3; 0.03
(s, 6H, Si(CH3)2)C(CH3)3; 13C NMR (100 MHz, CDCl3,
TMS): 160.4 (Cq, C-1), 147.0 (Cq, C-4); 145.7 (CH, C-8);
144.2 (CH, C-3); 134.5 (Cq, C-2); 109.8 (Cq, O2C(CH3)2);
108.7 (CH, C-7); 90.5 (Cq, C-6); 80.8 (CH, C-10); 78.4 (CH,
C-9); 76.8 (Cq, C-5); 62.7 (CH2, C-11); 61.3 (CH2, C-10);
26.9, 26.8 (CH3, O2C(CH3)2); 26.7 (CH3, O2C(CH3)2); 25.8
(CH3, TBS); 18.3 (Cq, TBS); 14.2 (CH3, C-20); 25.4 (CH3,
TBS), 25.5 (CH3, TBS); IR (neat, cm21): 3151, 2985, 2954,
2930, 2857, 2219, 2131, 1746, 1723, 1572, 1543, 1463,
1370, 1463, 1370, 1331, 1305, 1237, 1141, 1112, 1024, 980,
957, 925, 834, 775, 713, 670, 612, 568, 540; MS: m/z (%):
435 (Mþ; 20.0); 420 (26.2); 378 (17.5); 320 (100.0); 290
(43.5); 246 (25.3); 204 (72.6); 117 (17.1); HRMS: calcd for
C22H33N1O6Si: 435.2078; found: 435.2077.
To a suspension of 1.0 g (8.14 mmol) of CrCl2 in 32 mL of
THF a mixture of 802 mg (2.04 mmol) of CHI3 and 446 mg
(1.63 mmol) of aldeyhde 2 in 6.4 mL of THF was added
dropwise. After being stirred over night at rt the reaction
mixture was quenched with water. The mixture was
extracted with MTB ether and the combined organic layers
were dried (Na2SO4). The crude product was purified by
column chromatography (CH/MTBE 20:1) to yield 465 mg
(72%) of compound 3 as an orange oil. [a]2D0¼211.598
1
(c¼0.9, CHCl3); H NMR (400 MHz, CDCl3, TMS): 6.49
(dd, J¼14.5, 6.3 Hz, 1H, H-8); 6.49 (dd, J¼14.5, 0.8 Hz,
1H, H-7); 4.32 (dt, J¼6.4, 0.8 Hz, 1H, H-9); 3.8 (m, 2H,
H-11); 3.70 (m, 1H, H-10); 1.40 (s, 6H, C(CH3)2); 0.89 (s,
9H, TBS); 0.07 (s, 6H, TBS); 13C NMR (100 MHz, CDCl3,
TMS): 143.3 (CH, C-8); 109.5 (Cq, C(CH3)2); 80.6 (CH,
C-10); 80.3 (CH, C-9); 79.5 (CH, C-7); 62.6 (CH, C-11);
26.9 (CH3, C(CH3)2); 26.9 (CH3, C(CH3)2); 25.9 (CH3,
TBS); 25.8 (CH3, TBS); 25.8 (CH3, TBS); 18.3 (Cq, TBS);
25.3 (CH3, TBS); 25.3 (CH3, TBS); IR (neat, cm21): 2986,
2954, 2929, 2857, 1611, 1471, 1463, 1371, 1330, 1252,
1163, 1144, 1092, 1034, 1006, 944, 836, 812, 777, 673; MS:
m/z (%) 397 (Mþ21; 3); 383 (18); 297 (13); 283 (100); 253
(19); 224 (14); 215 (21); 195 (9); 185 (35); 156 (78); 141
(44); 126 (73).
4.1.4. Aldehyde 7. To a solution of 720 mg (1.52 mmol) of
silyl ether 6 in 4 mL of THF was added dropwise 1.82 mL
(1.824 mmol) of TBAF (1M in THF) at 08C. After 15 min
the reaction mixture was quenched with water, and the
mixture was extracted with MTB ether. Drying (Na2SO4)
and purification by column chromatography (CH/MTBE
2.5:1) afforded 483 mg (99%) of the alcohol as yellow oil.
[a]2D0¼20.858 (c¼0.89, CHCl3); 1H NMR:(400 MHz,
CDCl3, TMS): 8.17 (s, 1H, H-3); 6.38 (dd, J¼15.9,
6.0 Hz, 1H, H-8); 5.98 (dd, J¼15.9, 1.4 Hz, 1H, H-7);
4.45 (dt, J¼6.0, 1.4 Hz, 1H, H-9); 4.35 (q, J¼7.0 Hz, 2H,
H-10); 3.80 (m, 2H, H-11); 3.64 (m, 1H, H-10); 2.09 (bs, 1H,
OH); 1.42, (s, 3H, O2C(CH3)2); 1.41 (s, 3H, O2C(CH3)2);
1.34 (t, J¼7.2 Hz, 3H, H-20); 13C NMR (100 MHz, CDCl3,
TMS): 160.5 (Cq, C-1); 146.9 (Cq, C-4); 144.8 (CH, C-8);
144.3 (CH, C-3); 134.5 (Cq, C-2); 110.0 (Cq, O2C(CH3)2);
4.1.2. Oxazole alkyne 5. 150 mg (0.89 mmol) of oxazole
aldehyde 4 was dissolved in 6 mL of EtOH and treated
subsequently with 241 mg (1.75 mmol) of K2CO3 and
256 mg (1.33 mmol) of the Ohira–Bestmann reagent at 08C.
Having been stirred over night, the reaction was treated with
1N HCl. The mixture was extracted with MTB ether, the
organic layers were dried (Na2SO4). The crude product was

L. O. Haustedt et al. / Tetrahedron 59 (2003) 6967–6977
6973
109.7 (CH, C-7); 90.1 (Cq, C-6); 80.8 (CH, C-9); 77.2 (Cq,
C-5); 76.8 (CH, C10); 61.4 (CH2, C-11); 60.7 (CH2, C-10);
26.9 (CH03, O2C(CH3)2); 26.9 (CH3, O2C(CH3)2); 14.2
(CH3, C-2 ); IR (neat, cm21): 3435, 3153, 2984, 2932, 2877,
2662, 2218, 2091, 1724, 1636, 1573, 1543, 1507, 1455,
1371, 1333, 1305, 1236, 1163, 1147, 1110, 1051, 1021, 981,
957, 926, 899, 856, 830, 770, 713, 669; MS: m/z (%) 321
(Mþ, 2.1); 324 (2.4); 307 (36.7); 276 (36.5); 264 (40.3); 232
(35.3); 192 (100); 187 (35.7); 158 (43.1); HRMS: calcd for
C16H20N1O6 (Mþ þ1): 321.1212; found 322.1290.
4.37 (m, 2H, PMB), 3.80 (dd, J¼10.4, 5.5 Hz, 1H, H-11a),
3.79 (s, 3H, OMe), 3.39 (dd, J¼10.4, 8.4 Hz, 1H, H-11b),
2.07–2.01 (m, 1H, H-9), 1.90–1.80 (m, 1H, H-10), 1.33–
1.21 (m, 2H, Cp–CH2); 13C NMR (100 MHz, CDCl3):
200.51 (CH, C-8), 159.26 (Cq, PMB), 130.01 (CH, PMB),
129.33 (Cq, PMB), 113.79 (CH, PMB), 72.64 (CH2, PMB),
67.54 (CH2, C-11), 55.21 (OMe), 26.80 (CH, C-9), 23.59
(CH, C-10), 12.33 (CH2, Cp–CH2); IR (neat, cm21): 2837,
2359, 1698, 1612, 1585, 1511, 1375, 1301, 1244, 1173,
1078, 1031; MS: m/z (%) 220 (Mþ; 6.22), 164 (4.12), 137
(51.68), 121 (100.0), 109 (7.91), 91 (8.71), 77 (26.12), 66
(3.16); HRMS: calcd for C13H16O3: 220.1099; found:
220.1098.
163 mg (0.507 mmol) of this alcohol was dissolved in
CH2Cl2 (5 mL) at 08C. After addition of 165 mL
(2.03 mmol) of pyridine and 421 mg (1.014 mmol) of
Dess–Martin periodinane the reaction mixture was stirred
for 6 h at 08C. Finally the mixture was diluted with MTB
ether, treated with sat. NH4Cl solution, and extracted with
MTB ether. The combined organic layers were dried
(Na2SO4), the crude product was purified by column
chromatography (CH/MTBE 1:1) to yield 75% of aldeyhde
7 as colorless oil. 1H NMR (400 MHz, CDCl3, TMS): 9.76
(s, 1H, H-11); 8.18 (s, 1H, H-3); 6.41 (dd, J¼15.9, 5.7 Hz,
1H, H-8); 6.29 (dd, J¼15.9, 1.5 Hz, 1H, H-7); 4.59 (dt,
J¼7.3, 1.6 Hz, 1H, H-9); 4.35 (q, J¼7.2 Hz, 2H, H-10); 4.09
(dd, J¼7.3, 1.6 Hz, 1H, H-10); 1.49 (s, 3H, O2C(CH3)2);
4.1.6. Vinyl iodide 11. 1.96 g of CrCl2 (15.9 mmol) was
suspended in dry THF (11 mL) and cooled to 08C. To this
slurry was added a solution of 433 mg of aldehyde 10
(2.27 mmol) and 1.87 g of CHI3 (4.77 mmol) in 15 mL of
THF. The resulting mixture was stirred at 08C for 4 h,
diluted with water and extracted with MTB ether. The
combined organic extracts were washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was
purified by silica gel column chromatography affording
383 mg (49%) of the E-vinyl iodide. [a]2D0¼þ 18.48
(c¼1.19, CHCl3); 1H NMR (400 MHz, CDCl3, TMS):
7.25–7.24 (m, 2H, PMB), 6.91–6.81 (m, 2H, PMB), 6.21
(dd, J¼14.3, 8.5 Hz, 1H, H-8), 6.04 (d, J¼14.6 Hz, 1H,
H-7), 4.50–4.38 (m, 2H, PMB), 3.81 (s, 3H, OMe), 3.56
(dd, J¼10.2, 6.0 Hz, 1H, H-11a), 3.24 (dd, J¼10.1, 8.4 Hz,
1H, H-11b), 1.69–1.61 (m, 1H, H-10), 1.44–1.34 (m, 1H,
H-9), 1.01–0.95 (m, 1H, Cp–Ha), 0.49–0.45 (m, 1H, Cp–
Hb); 13C NMR (100 MHz, CDCl3): 159.21 (Cq, PMB),
144.90 (CH, C-8), 130.34 (Cq, PMB), 129.34 (CH, PMB),
113.91 (CH, PMB), 73.38 (CH, C-7), 72.48 (CH2, PMB),
69.41 (CH2, C-11), 55.28 (OMe), 21.83 (CH, C-10), 18.25
(CH, C-9), 10.51 (CH2, Cp–CH2); IR (neat, cm21): 2854,
2360, 1611, 1510, 1462, 1301, 1244, 1172, 1078, 1033, 943,
817; MS: m/z (%) 344 (Mþ; 5.88), 313 (5.15), 273 (1.38),
217 (32.68), 199 (9.04), 175 (28.20), 147 (7.50), 121 (100),
91 (9.75), 77 (25.55); HRMS: calcd for C14H17O2:
344.0273; found: 344.0274.
1.44 (s, 3H, O2C(CH3)2); 1.37 (t, J¼7.2 Hz, 3H, H-20); 13
C
NMR (100 MHz, CDCl3, TMS): 199.7 (CH, C-11); 160.4
(Cq, C-1); 146.8 (Cq, C-4); 144.3 (CH, C-3); 143.5 (CH,
C-8); 134.5 (Cq, C-2); 112.1 (Cq, O2C(CH3)2); 110.1 (CH,
C-7); 89.7 (CH, C-10); 84.1 (CH, C-9); 77.6 (Cq, C-6); 76.5
(Cq, C-5); 61.5 (CH2, C-10); 26.6 (CH3, O2C(CH3)2); 26.1
(CH3, O2C(CH3)2); 14.2 (CH3, C-20).
4.1.5. Aldehyde 10. To a solution of diethyl zinc (9.3 mL,
9.3 mmol, 1M in heptane) in 17 mL of CH2Cl2 at 08C was
added 4.33 g of CH2I2 (18.4 mmol) dropwise and stirred for
10 min. To this mixture was added rapidly a preformed
solution of the dioxaborolane complex20 (4.8 mmol) and
mono-PMB protected cis-1,4-butenediol (4.2 mmol) in
30 mL of CH2Cl2. The reaction mixture was allowed to
stir under an argon atmosphere for 4.5 h and was quenched
with sat. NH4Cl solution. The two layers were separated and
the aqueous layer was washed several times with CH2Cl2.
The organic extracts were pooled, washed with brine and
dried (Na2SO4). After removal of the solvent the residue
was purified by silica gel column chromatography (1:1
CH/MTBE) to afford 755 mg (81%) of cyclopropane
alcohol as colorless oil.
4.1.7. Cyclopropane enyne 12. 14.3 mg of CuI
(0.075 mmol) and 529.8 mg of Pd(PPh3)2Cl2 (0.75 mmol)
were taken up in 3.5 mL of degassed DMF and stirred for
20 min at rt. 258 mg of vinyl iodide 11 (0.75 mmol) in
3.5 mL of DMF and Et3N (3.5 mL) were added and the
resulting mixture was stirred at rt under an atmosphere of
argon for 3–4 h before adding alkyne 5 (1.13 mmol) in
3.5 mL of DMF (slow addition). The reaction mixture was
stirred over night, quenched with sat. NH4Cl solution and
extracted with MTB ether. The organic extracts were
pooled, washed with brine and dried (Na2SO4). The residue
was purified by column chromatography (CH/MTBE 2:1) to
obtain 141 mg (49%) of the product as viscous oil.
[a]2D0¼þ30.08 (c¼1.03, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): 8.18 (s, 1H, H-3), 7.27–7.25 (m, 2H,
PMB), 7.91–6.89 (m, 2H, PMB), 6.15 (dd, J¼15.7, 9.8 Hz,
1H, H-8), 5.77 (d, J¼15.7 Hz, 1H, H-7), 4.49–4.40 (m, 2H,
PMB), 4.37 (q, J¼7.1 Hz, 2H, H-10), 3.70 (s, 3H, OCH3),
3.60 (dd, J¼10.2, 6.0 Hz, 1H, H-11a), 3.24 (dd, J¼10.2,
8.0 Hz, 1H, H-11b), 1.77–1.74 (m, 1H, H-9), 1.59–1.53 (m,
1H, H-10), 1.38 (t, J¼7.1 Hz, 3H, H-20), 1.17–1.12 (m, 1H,
To 1.02 g of cyclopropane alcohol (4.6 mmol) in 15 mL of
CH2Cl2 were added 2.82 g of Dess–Martin periodinane
(6.95 mmol) and 1.55 g of NaHCO3 (18.4 mmol) and the
mixture was stirred at rt for 4 h. The reaction mixture was
diluted with CH2Cl2. After addition of sat. NaHCO3
solution, and Na2S2O3 (30 mL, 10% solution), the resulting
mixture was stirred for 1 h at rt. The aqueous phase was
extracted with MTB ether and the combined organic
extracts were washed with brine, dried (Na2SO4) and
concentrated. The residue was purified by silica gel column
chromatography (CH/MTBE 2:1) to afford 890 mg (88%) of
aldehyde 10. [a]D20¼222.78 (c¼1.17, CHCl3); 1H NMR
(400 MHz, CDCl3, TMS): 9.41 (d, J¼4.6 Hz, 1H, H-8),
7.28–7.20 (m, 2H, PMB), 6.90–6.85 (m, 2H, PMB), 4.41–

6974
L. O. Haustedt et al. / Tetrahedron 59 (2003) 6967–6977
Cp–Ha), 0.62–0.58 (m, 1H, Cp–Hb); 13C NMR (100 MHz,
CDCl3): 160.91 (Cq, C-1), 159.57 (Cq, PMB), 150.75 (CH,
C-8), 147.85 (Cq, C-4), 144.21 (CH, C-3), 134.71 (Cq, C-2),
130.40 (Cq, PMB), 129.67 (CH, PMB), 114.71 (CH, PMB),
106.82 (CH, C-7), 92.44 (Cq, C-6), 75.50 (Cq, C-5), 72.80
(CH2, PMB), 69.44 (CH2, C-11), 61.64 (CH2, C-10), 55.58
(OCH3), 20.81 (CH, C-10), 20.44 (CH, C-9), 14.5 (CH3,
C-20), 13.20 (CH2, Cp–CH2); IR (neat, cm21): 2211, 1741,
1721, 1612, 1573, 1541, 1511, 1368, 1333, 1297, 1172,
1143, 1111, 1079, 1024, 977, 950, 925, 818; MS: m/z (%)
381 (Mþ; 4.37); 279 (80.09); 261 (4.38); 239 (2.61); 218
(4.08); 198 (5.90); 167 (72.46); 149 (100); 121 (91.65); 97
(11.90); 84 (11.94); 71 (51.47); HRMS: calcd for
C22H23NO5: 381.1576; found: 381.1575.
MTB ether, dried (Na2SO4) and purified by flash chroma-
tography yielding 16.0 mg (82%) of propargylic alcohol 19
as a colorless oil (2:1 diastereomeric mixture); H NMR
1
(500 MHz, CDCl3, TMS): 7.26–7.36 (m, 5H, OCH2Ph);
4.46–4.52 (m, 2H; OCH2Ph); 4.45 (m, 1H, H-16); 3.81 (dd,
J¼7.0, 3.3 Hz, 1H, H-14); 3.46–3.62 (m, 2H; H-12); 2.22
(br s, 1H; OH); 2.04 (dtddddd, J¼14.4, 7.7, 3.2 Hz, 1H,
H-13a); 1.85 (d, J¼2.2 Hz, 3H, H-19); 1.73 (mdddd, 1H,
H-13b); 1.06 (s, 3H, Me); 0.89 (s, 3H, Me); 0.88 (s, 9H,
TBS); 0.10 (s, 3H, TBS); 0.06 (s, 3H, TBS); 13C NMR
(125 MHz, CDCl3, TMS): 138.34 (Cq, Bn); 128.32 (CH,
Bn); 127.59 (CH, Bn); 127.53 (CH, Bn); 81.35 (Cq, C-17/
C-18); 78.55 (Cq, C-17/C-18); 76.85 (CH, C-14); 72.86
(CH2, OCH2Ph); 68.54 (CH, C-16); 67.62 (CH2, C-12);
42.10 (Cq, C-15); 33.32 (CH2, C-13); 25.99 (CH3, TBS);
21.40 (CH3, Me); 18.38 (CH3, Me0); 18.18 (Cq, TBS); 13.55
(CH3, C-19); 24.23 (CH3, TBS); 24.27 (CH3, TBS); IR
(neat, cm21): 3451, 3030, 2955, 2918, 2883, 2855, 2116,
1674, 1496, 1471, 1386, 1360, 1253, 1205, 1088, 1027,
1003, 938, 880, 834, 773, 733, 696, 666, 609; MS: m/z
(%) 333 (Mþ2tBu; 2.60), 321 (1.97), 280 (2.28), 279
(8.58), 241 (2.87), 240 (4.53), 239 (23.24), 225 (4.05),
187 (4.21), 173 (23.62), 133 (12.45), 131 (32.14), 92
(9.03), 91 (100.00), 75 (14.68), 73 (13.80); HRMS:
calcd for C19H29O3Si1 (Mþ2tBu): 333.1886; found:
333.1886.
4.1.8. Aldehyde 13. To a stirred solution of 64.8 mg of
Sonogashira product 12 (0.17 mmol) in 2 mL of a CH2Cl2/
water mixture (9:1) was added 38.4 mg of DDQ
(0.425 mmol) at rt. The reaction mixture was stirred for
30 min (TLC showed absence of starting material),
quenched with sat. NaHCO3 solution and extracted with
CH2Cl2. After removal of the solvent the residue was used
without further purification for the next step. The crude
product was dissolved in CH2Cl2 (5 mL), 106 mg of Dess–
Martin periodinane (0.25 mmol) and 43 mg of NaHCO3
(0.51 mmol) were added to the solution which was stirred
for about 20–30 min. Extraction and purification (MTBE/
CH 3:1) afforded 31 mg of aldehyde 13 as brownish yellow
liquid (71% over two steps). [a]2D0¼286.88 (c¼0.22,
CHCl3); 1H NMR (400 MHz, CDCl3, TMS): 9.57 (d,
J¼3.8 Hz, 1H, H-11), 8.19 (s, 1H, H-3), 6.37 (dd, J¼15.8,
9.6 Hz 1H, H-8), 5.87 (d, J¼15.8 Hz, 1H, H-7), 4.38 (q,
J¼7.1 Hz, 2H, H-10), 2.34 (m, 1H, H-10), 2.32–2.24 (m,
1H, H-9), 1.64–1.61 (m, 1H, Cp–Ha), 1.56–1.53 (m, 1H,
Cp–Hb), 1.38 (t, J¼7.1 Hz, 3H, H-20); 13C NMR (100 MHz,
CDCl3, TMS): 199.03 (CH, C-11), 160.56 (Cq, C-1), 147.19
(Cq, C-4), 145.94 (CH, C-8), 144.17 (CH, C-3), 134.42
(Cq, C-2), 108.94 (CH, C-7), 90.89 (Cq, C-6), 76.22 (Cq,
C-5), 61.43 (CH2, C-10), 30.74 (CH, C-10), 27.15 (CH,
C-9), 15.87 (CH2, Cp–CH2), 14.25 (CH3, C-20); IR
(neat, cm21): 2924, 2854, 2214, 1721, 1542, 1370, 1296,
1240, 1145, 1110, 1018, 957, 832, 769, 713; MS: m/z
(%) 259 (Mþ; 10.0), 258 (Mþ21;37.1), 230 (37.7), 202
(23.4), 185 (29.2), 157 (47.3), 128 (100.0), 90 (51.4), 77
(54.2); HRMS: calcd for C14H13NO4: 259.0845; found:
259.0820.
4.1.10. Enone 21. 3.68 mL of allylmagnesium bromide
solution (1.0 M in Et2O; 3.68 mmol) was added at 08C to a
solution of 1.0 g of aldehyde 14 (2.63 mmol) in 5.3 mL of
dry THF (0.5 M). After 2 h at 08C the mixture was
hydrolyzed with saturated NH4Cl solution, extracted with
MTB ether, dried (Na2SO4) with and evaporate. The residue
was dissolved in dry CH2Cl2 and transferred to an ice-cold
suspension of 1.45 g of Dess–Martin periodinane
(3.42 mmol) in 6.6 mL of dry CH2Cl2 (0.4 M). After
being stirred for 3 h at rt the mixture was hydrolyzed with
2N NaOH, extracted with MTB ether, dried and evaporated.
The residue was dissolved in 5.3 mL of dry CH2Cl2 (0.5 M)
and 0.43 mL DBU (2.89 mmol) was added at 08C. The
reaction mixture was warmed to rt, stirred for additional
20 h, hydrolyzed with saturated NH4Cl solution, extracted
with MTB ether, dried (Na2SO4) and evaporated to dryness.
Purification by flash chromatography yielded 832 mg (75%)
of enone 21 as colorless oil. [a]2D0¼23.38 (c¼1.08, CHCl3);
1H NMR (400 MHz, CDCl3, TMS): 7.22–7.25 (m, 2H,
PMB); 6.85–6.88 (m, 2H, PMB); 6.89 (dq, J¼15.1, 6.9 Hz,
1H, H-18); 6.53 (dq, J¼15.1, 1.6 Hz, 1H, H-17); 4.39 (m,
2H, OCH2Ar); 4.03 (dd, J¼7.8, 3.0 Hz, 1H, H-14); 3.80 (s,
3H, OMePMB); 3.45 (m, 2H, H-12); 1.85 (dd, J¼7.0, 1.6 Hz,
3H, H-19); 1.74 (dtddddd, J¼14.1, 7.8, 3.1 Hz, 1H, H-13a);
1.58 (mddt, J¼14.1, 7.8, 6.0 Hz, 1H, H-13b); 1.10 (s, 3H,
Me); 1.07 (s, 3H, Me0); 0.87 (s, 9H, TBS); 0.05 (s, 3H,
TBS); 0.02 (s, 3H, TBS); 13C NMR (100 MHz, CDCl3,
TMS): 203.07 (Cq, C-16); 159.07 (Cq, PMB); 142.37 (CH,
C-18); 130.61 (Cq, PMB); 129.12 (CH, PMB); 127.22 (CH,
C-17); 113.69 (CH, PMB); 73.66 (CH, C-14); 72.32 (CH2,
OCH2Ar); 67.18 (CH2, C-12); 55.24 (CH3, OMePMB); 51.84
(Cq, C-15); 34.21 (CH2, C-13); 26.00 (CH3, TBS); 21.78
(CH3, Me); 19.85 (CH3, Me0); 18.29 (Cq, TBS); 18.17 (CH3,
C-19); 24.02 (CH3, TBS); 24.09 (CH3, TBS); IR (neat,
cm21): 2954, 2939, 2855, 1688, 1624, 1586, 1513, 1464,
1442, 1387, 1360, 1301, 1246, 1173, 1093, 1037, 1005, 967,
4.1.9. Propargylic alcohol 19. Preparation of the
Terashima-Reagent: In a flame-dried flask fitted with a
reflux condenser 104 mg of LiAlH4 (2.74 mmol) were
suspended in 3.0 mL of dry Et2O under a positive pressure
of nitrogen. Within 30 min a solution of 490 mg of (2)-N-
methylephedrine (2.74 mmol) in 8.0 mL of dry Et2O was
added dropwise and the resulting mixture was heated to
reflux for 1 h. Subsequently, 0.69 mL of N-ethylaniline
(5.48 mmol) were added dropwise and the mixture was
again heated to reflux for 1 h.
20 mg of alkynone 18 (0.05 mmol) was solved in 0.2 mL of
dry Et2O (0.25 M). At 2788C 0.43 mL of the Terashima
reagent (0.25 M in Et2O; 0.108 mmol) was added dropwise.
After 2 h at 2788C the reaction mixture was hydrolyzed
with saturated NaHCO3 solution (1 h, rt), extracted with

L. O. Haustedt et al. / Tetrahedron 59 (2003) 6967–6977
6975
924, 834, 773, 732, 673; MS: m/z (%) 421 (Mþ, 0.53), 419
(0.73), 386 (0.55), 364 (1.76), 362 (4.91), 309 (22.97), 287
(5.79), 284 (8.19), 283 (9.30), 227 (7.14), 173 (12.80), 152
(12.16), 147 (7.57), 137 (10.19), 122 (30.89), 121 (100);
HRMS: calcd for C24H40O4Si: 420.2696; found: 420.2697;
Elementary Analysis: calcd for C24H40O4Si: C 68.53; H
9.58; found: C 67.62; H 9.46.
0.91 (s, 3H, C(CH3)2); 0.88 (s, 9H, Si(CH3)2)C(CH3)3); 0.87
(s, 3H, C(CH3)2); 0.08, 0.06 (2 s, 6H, Si(CH3)2)C(CH3)3);
13C NMR:(100 MHz, CDCl3, TMS): 138.72 (Cq, Ph);
128.36 (CH, Ph); 127.51 (CH, Ph); 127.50 (CH, Ph);
77.43 (CH2, CH2Ph); 73.26 (CH2, C-16); 73.79 (CH, C-14);
68.22 (CH2, C-12); 39.97 (Cq, C-15); 37.48 (CH3, CH3SO3);
32.95 (CH2, C-13); 26.13, 26.10 (CH3, C(CH3)2); 21.50,
21.38 (CH3, Si(CH3)2)C(CH3)3); 18.40 (Cq, Si(CH3)2)-
C(CH3)3); 3.80, 24.22 (CH3, Si(CH3)2)C(CH3)3; IR (neat,
cm21): 3360, 2959, 2857, 2390, 2348, 2283, 1720, 1547,
1503, 1567, 1354, 1259, 1202, 1174, 1120, 1075, 1048, 977,
846, 778, 736, 702; (Mþ, 9); 307 (6); 281 (11); 277 (19); 267
(28); 261 (18); 220 (6); 201 (18); 188 (28); 172 (21); 170
(68); 154 (21); 107 (28); ESI-MS: submitted.
4.1.11. syn-Alcohol 22. To a solution of 48.5 mg of enone
21 (0.115 mmol) in 0.58 mL of dry THF (0.2 M) were added
at 2308C simultaneously and dropwise 242 mL (S)-Me-
CBS reagent (1.0 M in toluene; 0.242 mmol) and 288 mL
BH3·DMS solution (2.0 M in THF; 0.576 mmol). After 3 h
at 2308C to 2208C the mixture was hydrolyzed with
ethanol and dist. H2O, extracted with MTB ether, dried
(Na2SO4) and evaporated. Flash chromatography yielded
37.8 mg (78%) of the 1,2-reduction products (22/
23¼10.8:1.0) and 8.4 mg of the saturated ketone (17%).
Spetroscopic data for syn-alcohol 22: [a]2D0¼þ2.68 (c¼0.98,
CHCl3); 1H NMR (400 MHz, CDCl3, TMS): 7.23–7.26 (m,
2H, PMB); 6.86–6.89 (m, 2H, PMB); 5.64 (dqd, J¼15.3,
6.2, 0.7 Hz, 1H, H-18); 5.53 (ddq, J¼15.3, 7.0, 1.4 Hz, 1H,
H-17); 4.40–4.48 (m, 2H, OCH2Ar); 3.95 (d, J¼6.9 Hz, 1H,
H-16); 3.80 (s, 3H, OMePMB); 3.70 (dd, J¼5.6, 3.4 Hz, 1H,
H-14); 3.45–3.57 (m, 2H, H-12); 2.77 (br. s, 1H, OH);
2.04–2.14 (mdddd, 1H, H-13a); 1.71 (dd, J¼6.5, 0.7 Hz, 3H,
H-19); 1.56–1.65 (m, 1H, H-13b); 0.88 (s, 9H, TBS); 0.87
(s, 3H, Me); 0.73 (s, 3H, Me0); 0.03 (s, 3H, TBS); 0.00 (s,
3H, TBS); 13C NMR (100 MHz, CDCl3, TMS): 159.27 (Cq,
PMB); 130.75 (CH, C-18); 130.24 (Cq, PMB); 129.40 (CH,
PMB); 127.70 (CH, C-17); 113.85 (CH, PMB); 77.72 (CH,
C-16); 76.02 (CH, C-14); 72.71 (CH2, OCH2Ar); 68.09
(CH2, C-12); 55.27 (CH3, OMePMB); 42.61 (Cq, C-15);
33.71 (CH2, C-13); 26.06 (CH3, TBS); 19.38 (CH3, Me);
18.70 (CH3, Me0); 18.26 (Cq, TBS); 17.83 (CH3, C-19);
23.69 (CH3, TBS); 24.36 (CH3, TBS); IR (neat, cm21):
3439, 2955, 2930, 2883, 2855, 1670, 1612, 1586, 1513,
1463, 1361, 1302, 1247, 1173, 1071, 1036, 1005, 969, 938,
925, 875, 833, 772, 733, 667, 638; MS: m/z (%) 423 (Mþ,
1.35), 365 (1.39), 355 (1.53), 351 (1.42), 347 (1.70), 311
(2.20), 309 (14.01), 270 (3.67), 269 (11.36), 220 (11.47),
187 (5.27), 178 (4.08), 173 (11.15), 149 (3.88), 147 (3.71),
137 (11.75), 131 (16.29), 122 (32.61), 121 (100), 83 (10.60),
75 (24.00), 73 (16.76); ESI-MS (MþNaþ): calcd for
C24H42O4SiNa: 445.2750; found: 445.2758; Elementary
Analysis: calcd for C24H42O4Si: C 68.20H 10.02; found: C
68.02; H 10.06.
A solution of 100 mg (0.232 mmol) of the above mesylate in
2.3 mL of acetone, 104 mg (0.696 mmol) sodium iodide and
97.4 mg (1.16 mmol) NaHCO3 were refluxed for 2 h. A
second charge of 0.696 mmol of NaI and 1.16 mmol
NaHCO3 was added followed by reflux for 1 h. After
addition of sat. NH4Cl-solution extraction and purification
(CH/MTBE 40:1) afforded 84 mg (0.181 mmol) of a
1
colourless oil. [a]2D0¼219.328 (c¼1.0, CHCl3); H NMR:
(400 MHz, CDCl3, TMS): 7.34 (m, 5H, PhCH2); 4.43–4.50
(m, 2H, PhCH2); 3.59 (dd, J¼7.2, 3.0 Hz, 1H, H-14); 3.31
(dt, J¼9.4, 5.0 Hz, 1H, H-12a); 3.25 (d, J¼8.8 Hz, 1H, H-
16a); 3.14 (d, J¼8.8 Hz, 1H, H-16b); 3.11 (dt, J¼9.4,
7.4 Hz, 1H, H-12b); 2.15 (m, 1H, H-13a); 1.97 (m, 1H, H-
13b); 0.90 (s, 3H, C(CH3)2); 0.89 (s, 3H, C(CH3)2); 0.87 (s,
9H, Si(CH3)2C(CH3)3); 0.09 (s, 3H, Si(CH3)2C(CH3)3);
0.06 (s, 3H, Si(CH3)2C(CH3)3); 13C NMR (100 MHz,
CDCl3, TMS): 138.7 (Cq, PhCH2); 128.3 (CH, PhCH2);
127.4 (CH, PhCH2); 127.3 (CH, PhCH2); 77.1 (CH2, C-16);
73.2 (CH2, PhCH2); 39.9 (Cq, C-15); 38.0 (CH2, C-13); 26.1
(CH3, Si(CH3)2C(CH3)3); 21.7 (CH3, C(CH3)2); 21.3 (CH3,
C(CH3)2); 18.5 (Cq, Si(CH3)2C(CH3)3); 4.7 (CH2, C-12);
23.5 (CH3, Si(CH3)2C(CH3)3; 24.2 (CH3, Si(CH3)2-
C(CH3)3; MS: m/z (%) 462 (Mþ, 1.8); 405 (35.3);
371 (1.8); 349 (17.3); 313 (30.8); 299 (41.6); 270 (4.0);
244 (9.3); 187 (25.5); 159 (7.9); 126 (36.6); 91
(100); HRMS: calcd for C20H35IO2Si: 462.1451; found:
462.1449.
4.1.13. Benzyl ether 29. 68 mg (0.150 mmol) of iodide 28,
69 mg (0.266 mmol) of PPh3 and 181 mL (1.036 mmol)
i-PrNEt2 were heated in a sealed flask at 908C for 18 h.
i-Pr2NEt was carefully removed with dry n-pentane in
vacuo and the residue was resuspended in dry n-pentane.
After 1 min the n-pentane was removed by pipette (repeated
twice). After removal of the remaining solvent in vacuo the
residue was dissolved in 3 mL of THF and 158 mL
(0.158 mmol) of LiHMDS were added at 2788C. After
stirring for 15 min a solution of 0.15 mL of HMPA and
0.15 mL of THF was added dropwise at 2788C followed by
the dropwise addition of a solution of 48 mg (0.150 mmol)
of aldehyde 7 in 1 mL of THF. Stirring for 15 min at 2788C
and 1 h at rt was followed by addition of saturated NaHCO3-
solution. The solution was extracted with MTB ether and the
combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by flash
column chromatography (CH/MTBE 20:1) to furnish 35 mg
4.1.12. Iodide 28. To a solution of 273 mg (0.78 mmol) of
alcohol 27 in THF was added 206 mL (1.55 mmol) of
triethylamine followed by 9 mg (0.078 mmol) DMAP und
81 mL (1.09 mmol) of mesyl chloride at 08C. After being
stirred for 3 h at 08C the reaction mixture was quenched by
addition of sat. NH4Cl-solution and extracted with MTB
ether. The combined organic extracts were dried over
Na2SO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatography (CH/MTBE 20:1) to
furnish 310 mg (93%) of a colourless oil. [a]2D0¼212.838
1
(c¼1.1, CHCl3); H NMR:(400 MHz, CDCl3, TMS): 7.32
(m, 5H, PhCH2); 4.42–4.49 (m, 2H; PhCH2); 4.41 (m, 1H,
H-12a); 4.25 (m, 1H, H-12b); 3.73 (m, 1H, H-14); 3.24 (d,
J¼8.8 Hz, 1H, H-16a); 3.16 (d, J¼8.8 Hz, 1H, H-16b); 2.93
(s, 3H, CH3SO3); 2.04 (m, 1H, H13a); 1.81 (m, 1H, H-13b);
1
(37%) of a yellow oil. [a]2D0¼12.088 (c¼2.4, CHCl3); H
NMR: (400 MHz, CDCl3, TMS): 8.20 (s, 1H, H-3); 7.32 (m,

6976
L. O. Haustedt et al. / Tetrahedron 59 (2003) 6967–6977
5H, Ph); 6.87 (m, 1H, H-12); 6.34 (dd, J¼16.0, 5.9 Hz, 1H,
H-8); 6.03 (dd, J¼16.0, 1.3 Hz, 1H, H-7); 5.71 (dd, J¼11.4,
9.2 Hz, 1H, H-11); 4.51 (m, 2H, PhCH2); 4.41 (q, J¼7.2 Hz,
2H, H-10); 4.40 (m, 1H, H-9); 4.15 (m, 1H, H-10); 3.71 (m,
1H, H-14); 3.24 (d, J¼8.7 Hz, 1H, H-16a); 3.17 (d,
J¼8.7 Hz, 1H, H-16b); 2.31 (m, 2H, H-13); 1.45 (s, 3H,
C(CH3)2); 1.44 (s, 3H, C(CH3)2); 0.90 (s, 9H, TBS); 0.87 (s,
6H, C17/18); 0.02 (s, 6H, TBS); 13C NMR:(100 MHz,
CDCl3, TMS): 160.5 (Cq, C-1); 146.9 (Cq, C-4); 144.3 (CH,
C-3); 144.2 (CH, C-8); 138.8 (Cq, PhCH2); 135.4 (CH,
C12); 134.5 (Cq, C-2); 128.2 (CH, PhCH2); 127.2 (CH,
PhCH2); 127.3 (CH, PhCH2); 124.8 (CH, C-11); 109.8 (CH,
C-7); 109.8 (Cq, O2C(CH3)2); 90.2 (Cq, C-6); 80.8 (CH,
C-10); 77.2 (CH2, C-16); 77.1 (CH, C-9); 76.9 (Cq, C-5);
75.9 (CH, C-14); 73.1 (CH2, PhCH2); 61.5 (CH2, C-10); 40.4
(Cq, C-15); 31.9 (CH2, C-13); 27.2 (CH3, O2C(CH3)2); 26.7
(CH3, O2C(CH3)2); 26.0 (CH3, TBS); 22.7 (CH3, C(CH3)2);
21.5 (CH3, C(CH3)2); 18.1 (Cq, TBS); 14.2 (CH3, C-20);
23.3 (CH3, TBS); 24.6 (CH3, TBS); IR (neat, cm21): 2925,
2854, 2219, 2116, 1746, 1724, 1572, 1543, 1462, 1370,
1304, 1236, 1142, 1110, 1087, 1051, 1025, 980, 955,
934, 878, 833, 811, 773, 743, 713, 697, 666. ESI-MS
(MþNaþ): calcd for C36H51N1Na1O7Si1: 660.3332; found:
660.3319.
20.4 (CH3, C(CH3)2); 20.2 (CH3, C(CH3)2); 18.4 (CH3,
TIPS); 18.3 (CH3, TIPS); 18.2 (Cq, TBS); 17.7 (CH3, C-19);
14.2 (CH3, C-20); 12.8 (CH, TIPS); 22.9 (CH3, TBS); 24.2
(CH3, TBS); IR (neat, cm21): 2928, 2863, 2219, 1748, 1724,
1572, 1543, 1462, 1370, 1305, 1236, 1164, 1141, 1110,
1079, 1047, 975, 955, 930, 880, 833, 809, 772, 734, 713,
676; ESI-MS (MþNaþ): calcd for C41H69NO7Si2Na1:
766.4510; found: 766.4517.
4.1.15. Cyclopropane analog of the masked northern half
of disorazole A1 31. 40 mg of iodide 16 (0.070 mmol),
34 mg of PPh3 (0.127 mmol) and 86 mL of i-Pr2NEt
(0.49 mmol) were heated in a sealed flask to 858C for
20 h. i-Pr2NEt was carefully removed with dry n-pentane in
vacuo and the residue was resuspended in dry n-pentane.
After 1 min the n-pentane was removed by pipette (repeated
twice). The residue was dissolved in 1.4 mL of dry THF
(0.05 M) and cooled to 2788C. 74 mL of LiHMDS solution
(1.0 M in THF, 0.074 mmol) were added to this solution.
After 15 min at 2788C, 0.14 mL of HMPA (in 0.3 mL of
dry THF) and 21 mg of aldehyde 12 (0.081 mmol) in
0.3 mL of dry THF were subsequently added. The mixture
was gradually warmed to rt and stirred for 3 h. The mixture
was hydrolyzed with saturated NaHCO3 solution, extracted
with MTB ether, dried (Na2SO4), filtered through Celite
and evaporated to dryness. After flash chromatography
18.9 mg of 31 (40%) were isolated as a slightly yellow oil
(Z/E.5:1); 1H NMR: (400 MHz, CDCl3, TMS): 8.19 (s, 1H,
H-3); 6.22 (dd, J¼15.8, 9.9 Hz, 1H, H-8); 5.75 (d,
J¼15.8 Hz, 1H, H-7); 5.55 (dt, J¼10.2, 7.0 Hz, 1H, H-
12); 5.48–5.50 (m, 2H, H-17 þ H-18); 5.08 (t, J¼9.8–
10.5 Hz, 1H, H-11); 4.40 (q, J¼7.1 Hz, 2H, OEt); 4.07 (d,
J¼8.3 Hz, 1H, H-16); 3.57 (dd, J¼6.5, 3.8 Hz, 1H, H-14);
2.35–2.45 (m, 1H, H-13a); 2.22–2.33 (m, 1H, H-13b);
1.98–2.07 (m, 1H, H-9/H-10); 1.82–1.90 (m, 1H, H-9/H-
10); 1.70 (d, J¼4.4 Hz, 3H, H-19); 1.06 (br. s, 21H, TIPS);
0.93 (s, 3H, Me); 0.90 (s, 9H, TBS); 0.87 (s, 3H, Me0);
0.73–0.82 (m, 2H, Cp–CH2); 0.04 (s, 3H, TBS); 0.03 (s,
3H, TBS); 13C NMR:(100 MHz, CDCl3, TMS): 160.64 (Cq,
C-1); 151.02 (CH, C-8); 147.58 (Cq, C-4); 143.89 (CH, C-
3); 134.42 (Cq. C-2); 132.08 (CH, C-17/C-18/C-11/C-12);
131.14 (CH, C-17/C-18/C-11/C-12); 127.60 (CH, C-17/C-
18/C-11/ C-12); 127.37 (CH, C-17/C-18/C-11/C-12);
106.38 (CH, C-7); 92.11 (Cq, C-5/C-6); 79.16 (CH, C-16);
76.91 (CH, C-14); 75.19 (Cq, C-5/C-6); 61.35 (CH2, OEt);
44.76 (Cq, C-15); 31.60 (CH2, C-13); 26.18 (CH3, TBS);
22.92 (CH, C-9/C-10); 20.18 (CH3, Me); 19.85 (CH3, Me0);
19.83 (CH, C-9/C-10); 18.39 (Cq, TBS); 18.37 (CH3, TIPS);
18.25 (CH3, TIPS); 17.70 (CH3, C-19); 16.67 (CH2, Cp–
CH2); 14.24 (CH3, OEt); 12.86 (CH, TIPS); 23.07 (CH3,
TBS); 24.08 (CH3, TBS); IR (neat, cm21): 2930, 2864,
2215, 1748, 1724, 1624, 1573, 1543, 1463, 1369, 1314,
1251, 1142, 1113, 1080, 1049, 976, 948, 882, 834, 773, 715,
679; ESI-MS (MþNaþ): calcd for C39H65NO5Si2Na1:
706.4299; found: 706.4311.
4.1.14. Masked northern half of disorazole D1 30. 40 mg
(0.071 mmol) of iodide 16, 34 mg (0.129 mmol) of PPh3
and 87 mL (0.499 mmol) of i-PrNEt2 were heated in a sealed
flask at 908C for 18 h. i-Pr2NEt was carefully removed with
dry n-pentane in vacuo and the residue was resuspended in
dry n-pentane. After 1 min the n-pentane was removed by
pipette (repeated twice). After removal of the remaining
solvent in vacuo the residue was dissolved in 1.4 mL of THF
and 79 mL (0.079 mmol) of LiHMDS were added at 2788C.
After stirring for 15 min a solution of 0.10 mL of HMPA
and 0.10 mL of THF was added dropwise at 2788C
followed by the dropwise addition of a solution of 30 mg
(0.093 mmol) of aldehyde 7 in 1 mL of THF. Stirring for
15 min at 2788C and 1 h at rt was followed by addition of
saturated NaHCO3-solution. The solution was extracted
with MTB ether and the combined organic phases were
dried (Na2SO4) and concentrated in vacuo. The residue was
purified by flash column chromatography (CH/MTBE 20:1)
to furnish 17 mg (32%) of a yellow oil. [a]2D0¼220.338
1
(c¼1.5, CHCl3); H NMR: (400 MHz, CDCl3, TMS): 8.21
(s, 1H, H-3); 6.35 (dd, J¼15.9, 5.9 Hz, 1H, H-8); 6.05 (dd,
J¼15.9, 1.26 Hz, 1H, H-7); 5.85 (dt, J¼9.0, 2.0 Hz, 1H,
H-12); 5.48 (m, 2H, H-17/H-18); 5.39 (dt, J¼9.0, 1.5 Hz,
1H, H-11); 4.42 (m, 1H, H-9); 4.35 (q, J¼7.2 Hz, 2H, H-10);
4.16 (m, 1H, H-10); 4.00 (m, 1H, H-16); 3.53 (dtm, J¼4.4,
2.0 Hz, 1H, H-14); 2.28 (m, 2H, H-13); 1.71 (d, J¼4.5 Hz,
3H, H-19); 1.47 (s, 3H, O2C(CH3)2); 1.43 (s, 3H,
O2C(CH3)2); 1.40 (t, J¼7.2 Hz, 3H, H-20); 1.03 (s, 21H,
TIPS); 0.90 (s, 9H, TBS); 0.86 (s, 3H, C(CH3)2); 0.85 (s,
3H, C(CH3)2); 0.04 (s, 3H, TBS); 0.03 (s, 3H, TBS); 13C
NMR (100 MHz, CDCl3, TMS): 160.5 (Cq, C-1); 146.9 (Cq,
C-4); 144.2 (CH, C-3); 144.07 (CH, C-12); 135.6 (CH, C-8);
134.6 (Cq, C-2); 132.1 (CH, C-18); 127.8 (CH, C-17); 124.8
(CH, C-11); 109.7 (CH, C-7);109.6 (Cq, C(CH3)2); 90.2 (Cq,
C-6); 80.8 (Cq, C-5); 90.2 (CH, C-9); 79.3 (CH, C-16); 76.9
(CH, C-10); 76.5 (CH, C-14); 61.5 (CH2, C-10); 44.7 (Cq,
C-15); 31.8 (CH2, C-13); 29.7 (CH3, C-20); 26.8 (CH3,
O2C(CH3)2); 26.7 (CH3, O2C(CH3)2); 26.7 (CH3, TBS);
Acknowledgements
We are grateful to the Alexander von Humboldt Foundation
(S.B.P), the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft for support.

L. O. Haustedt et al. / Tetrahedron 59 (2003) 6967–6977
6977
951–953. (c) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem.
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