Studies towards the synthesis of epothilone A via organoboranes

Article abstract of DOI:10.1039/b508001k

Studies towards the synthesis of epothilone A via organoboranes have been described. A modified procedure for the large-scale preparation of B-γ,γ-dimethylallyldiisopinocampheylborane from prenyl alcohol has been developed. This reagent, upon reaction wit

Full text of DOI:10.1039/b508001k

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A R T I C L E
Studies towards the synthesis of epothilone A via organoboranes†
P. Veeraraghavan Ramachandran,* J. Subash Chandra, Bodhuri Prabhudas, Debarshi Pratihar
and M.Venkat Ram Reddy
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University,
West Lafayette, IN, USA 47907-2084. E-mail: chandran@purdue.edu; Fax: 1 (765) 494 0239;
Tel: 1 (765) 494 5303
Received 9th June 2005, Accepted 24th August 2005
First published as an Advance Article on the web 15th September 2005
Studies towards the synthesis of epothilone A via organoboranes have been described. A modified procedure for the
large-scale preparation of B-c,c-dimethylallyldiisopinocampheylborane from prenyl alcohol has been developed. This
reagent, upon reaction with various aldehydes, provides the corresponding a,a-dimethylhomoallylic alcohols in high
enantioselectivities. The application of this reagent for the synthesis of the C1–C6 subunit of epothilone has been
demonstrated. Alternatively, inter- and intramolecular asymmetric reduction protocols have also been utilized for the
synthesis of the C1–C6 subunit of epothilone A. The synthesis of the C7–C21 fragment of epothilone A involving
asymmetric alkoxyallyl- and crotylboration using a-pinene-derived reagents has also been described.
Introduction
Microtubules play an important role in normal cellular processes
and have become a key target for cancer chemotherapeutic drugs.
The success of Paclitaxel (TaxolTM) as an anti-cancer drug has led
to an invigorated quest for novel compounds with a mechanism
of action similar to that of Taxol, with greater efficacy towards
Taxol-resistant cells. One such compound is epothilone, which
not only binds to the microtubules in a paclitaxel-like manner,
but is much more active.1 Naturally occurring epothilone is a
mixture of epothilone A and B (Fig. 1). Epothilone A (1a) turned
out to be as active as Paclitaxel, whereas epothilone B is 50 times
more active.1,2a–c This simple structure and promising biological
properties led to extensive efforts towards the synthesis of
epothilone2 and its analogs.3
Fig. 1 Naturally occurring epothilones.
Fig. 2 Retrosynthetic analysis for epothilone A.
As part of our program on the development and applications
Results and discussion
of pinane-based versatile organoborane reagents4 for organic
synthesis,5 we undertook the synthesis of epothilones.6 Our
retrosynthetic analysis of 1a is shown in Fig. 2. We envisaged that
the required subunits C1–C6 (2) and C7–C21 (3) could be prepared
via a-pinene-derived asymmetric alkoxyallyl- and crotylboration
and dimethylallylboration protocols. We also envisioned that
the total synthesis of epothilone could be achieved via an
aldol coupling between the ethyl ketone 2 and the aldehyde 3,
followed by a macrolactonization under Yamaguchi conditions.
Several approaches towards the synthesis of these two subunits
are described in this manuscript. The C1–C6 subunit 2 was
realized via an asymmetric dimethylallylboration strategy. Wittig
olefination and alkoxyallyl- and crotylboration chemistry was
used for the synthesis of 3.
Synthesis of the C1–C6 subunit of epothilone
B-Chlorodiisopinocampheylborane is an excellent chiral reduc-
ing agent, which has been extensively used in the literature for
the asymmetric reduction of a wide variety of ketones.7 We
visualized the application of Ipc2BCl for the intermolecular
reduction of an acetylenic ketone8 en route to the synthesis of
the C1–C6 subunit of epothilone. We initiated the synthesis with
the reaction of propionaldehyde and dimethylallylzinc bromide
furnishing the homoallylic alcohol 10 (Scheme 1). Oxidation of
the alcohol, followed by ozonolysis, afforded the keto-aldehyde
11 in 70% combined yield. Treatment with ethynylmagnesium
bromide resulted in the chemoselective addition of the Grignard
to the aldehyde, which upon oxidation yielded the diketone 12 in
80% yield. With our prior knowledge that the rate of reduction of
tertiary ketones9 with Ipc2BCl is extremely slow, the diketone 12
was reacted with Ipc2BCl, and to our delight, reduction of the
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra. See http://dx.doi.org/10.1039/b508001k
3 8 1 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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or the cost of the starting materials. One such reagent is
B-c,c-dimethylallyldiisopinocampheylborane 20,15 which upon
reaction with aldehydes provides a,a-dimethylhomoallylic al-
cohols. Several natural products, such as artemesia alcohol,16
bryostatin,17 epothilone, pederin,18 and mycalamide19 contain an
a,a-dimethylhydroxy unit in them, and one could envisage the
use of 20 for the preparation of the a,a-dimethylalcohol moiety.
Following Brown’s initial report of the synthesis of artemesia
alcohol,15 only Schinzer has described the application of 20
for the synthesis of epothilones.20 Brown’s original preparation
of 20 involved the hydroboration of relatively expensive 1,1-
dimethylallene 21 with diisopinocampheylborane, thus making
it impractical for large-scale applications (Scheme 3). The wide
range of potential applications as well as the highly expensive
starting materials involved in the preparation of 20 persuaded us
to develop an inexpensive method for the large-scale synthesis
of this reagent.
Scheme 1 Chemoselective reduction of the acetylenic ketone. Reagents
and conditions: (a) Zn, 80%; (b) DMP, 87%; (c) O3, Me2S, 80%; (d)
HCe¨´ıCMgBr, 69%; (e) DMP, 80%; (f) Ipc2BCl, 76% yield, 96% ee; (g)
Cy2BH, Cl2BH, BH3·Me2S, etc.
acetylenic ketone occurred highly regioselectively (rather than
reduction of the ethyl ketone), to give the propargylic alcohol 13
in 76% yield and 96% ee. At this stage, our efforts towards the
hydroboration of alkyne did not materialize, and resulted in the
formation of a complex mixture of products (Scheme 1). Having
failed to achieve the hydroboration of the propargylic alcohol,
we diverted our attention towards the intramolecular reduction
of b-hydroxyketones for the synthesis of 2.
Hydroxyketones10 and keto-acids11 undergo intramolecular
reduction with Ipc2BH (or Ipc2BCl) yielding the corresponding
diols or hydroxyacids respectively in very high ee. We planned
the synthesis of the C1–C6 subunit via this intramolecular re-
duction protocol. Monosilylation of 1,3-propanediol, followed
by Dess–Martin periodinane (DMP)12 oxidation provided 3-
silyloxypropionaldehyde 15 (Scheme 2). Allylation with the
prenylzinc reagent furnished the homoallylic alcohol 16 in 71%
yield. Oxidation and deprotection of the silyl ether afforded
the b-hydroxyketone 17. Intramolecular reduction of the b-
hydroxyketone with Ipc2BH provided the diol 18 in 75% yield
and in very high ee (98%). Sequential protection of the primary
alcohol as the PMB ether and the secondary alcohol as the TBS
ether yielded 19. Ozonolytic cleavage of the olefin afforded the
aldehyde, which upon reaction with ethylmagnesium bromide,
followed by DMP oxidation yielded 2, the C1–C6 subunit of
epothilone A (Scheme 2) in 77% yield.
Scheme 3 Literature synthesis of 20.
The traditional preparation of B-allyldialkylboranes involves
the reaction of the corresponding allyl Grignard reagent with B-
halodialkylborane or B-methoxydialkylborane. We envisioned
the use of dimethylallyl Grignard, which can be readily prepared
from the commercially available and relatively inexpensive
prenyl alcohol. The reaction of prenyl alcohol with PBr3
produced the corresponding bromide. However, the reaction
of the dimethylallyl bromide with magnesium turnings was
not satisfactory and resulted in the predominant formation
of homocoupling products. The subsequent addition of (+)-
Ipc2BOMe to the reaction mixture resulted in very low yields
of the allylborane 20 (∼10% on the basis of 11B NMR
spectroscopy). Consequently, the bromide was replaced with
chloride on the basis that the chloride might reduce the risk of
homocoupling. Accordingly, the dimethylallyl chloride 22 was
prepared by the reaction of prenyl alcohol with thionyl chloride.
Temperature played a crucial role in the formation of the
Grignard. When the temperature was too high, homocoupling
dominated, and when the temperature was kept below 0 ◦C,
the formation of the Grignard reagent was arrested. Grignard
formation was finally achieved by carefully keeping the reaction
temperature in the range 0–5 ◦C. Upon successful formation
of the Grignard, the reaction mixture was transferred to a
solution of (+)-Ipc2BOMe in ether at 0 ◦C to furnish the
required dimethylallylborane 20 in essentially quantitative yield
(Scheme 4).6a The methoxymagnesium chloride salt was filtered
using a Kramer’s filter under nitrogen, and the solvent was
evaporated under vacuum to provide 90% yield of 20 (11B
NMR peak at d 79). Similarly, starting from (−)-Ipc2BOMe,
the antipode of the reagent 20 was prepared. The reagent was
tested for its large-scale applicability by carrying out the reaction
on a 0.5 mole scale – highly reproducible results were obtained.
Scheme 2 Intramolecular reduction of the b-hydroxy ketone. Reagents
and conditions: (a) TBSCl, imidazole, 89%; (b) DMP, 81%; (c) Zn,
71%; (d) DMP, 83%; (e) HCl, 80%; (f) (+)-Ipc2BH, NaOH, H2O2, 75%
yield, 98% ee; (g) MeOC6H4CH2OC(NH)CCl3, CSA, 80%; (h) TBSCl,
imidazole, 86%; (i) O3, Me2S, 78%; (j) EtMgBr, 76%; (k) DMP, 77%.
Even though we were able to synthesize the subunit with high
stereoselectivity, we were not satisfied with the overall yield and
number of steps required for the synthesis. With the intent of
overcoming these shortcomings, we concentrated our efforts
on the development of an asymmetric dimethylallylboration
protocol.
Improved procedure for the synthesis of B-c,c-dimethylallyl-
diisopinocampheylborane6a. “Allyl”boration is one of the most
important carbon–carbon bond forming reactions in organic
synthesis.13 Over the past two decades, we have developed
several highly functionalized “allyl”boranes based on terpenes.4
While some of these reagents have been well utilized by
the synthetic organic community for the total synthesis of
a variety of complex natural products,14 others have been
sparsely used, probably due to the difficulty in their preparation
Scheme 4 Modified procedure for the synthesis of 20.
We then examined 20 for the allylboration of various aldehy-
des. The reaction with aliphatic aldehydes such as propionalde-
hyde 23a, isobutyraldehyde 23b, pivalaldehyde 23c (Table 1,
entries 1–3), took place smoothly and the product homoallylic
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4
3 8 1 3

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Table 1 Dimethylallylboration of aldehydes
Entry
Aldehyde
R
Homoallylic alcohol
Yield (%)
ee/de (%)
1
2
3
4
5
6
7.
23a
23b
23c
23d
23e
23f
23g
CH3CH2-
(CH3)2CH-
(CH3)3C-
C6H5-
C6H5CH CH-
PMBOCH2CH2-
24a
24b
24c
24d
24e
24f
24g
81
85
88
92
90
82
90
97
95
95
95
87
95
92
=
8
23h
24h
93
95
alcohols 24a–c were obtained in very good yields (81–88%) and
in excellent ee (95–97%). The ee was determined by making
the p-nitrobenzoate esters of the homoallylic alcohols, and
analyzing them by HPLC. Similarly, benzaldehyde 23d and
cinnamaldehyde 23e (entries 4 and 5) provided alcohols 24d
and 24e in excellent yield and ee. The reaction with a-chiral
(23g) and b-chiral aldehydes (entries 7 and 8) took place in a
reagent-controlled manner, and the homoallylic alcohols 24g
and 24h were obtained in 92% and 95% de, respectively.
The modified synthesis of dimethylallylborane was then
utilized in the synthesis of the C1–C6 subunit 2 of epothilone.
Dimethylallylboration of aldehyde 23f using 20 at −100 ◦C
furnished the homoallylic alcohol 24f in 82% yield and 95%
ee. The completion of the synthesis of the C1–C6 subunit was
achieved without any difficulty by a silyl protection, ozonol-
ysis, alkylation, and oxidation sequence as described earlier
(Scheme 2).
ester using BH3·Me2S, and iodination with I2/PPh3 furnished the
iodide 30. Nucleophilic substitution of the iodide with higher-
order allyl cuprate,21 generated by the reaction of allyl Grignard
with Li2CuCl4 or CuI, provided the olefin 31 in 22–50% yield.
Attempts towards obtaining a higher yield for the substitution
proved futile even after an extensive study of reagents and
conditions. Hydroboration-oxidation of the olefin 31 to the
primary alcohol, followed by iodination provided the required
iodide 25 (Scheme 5).
Scheme 5 Preparation of the C7–C12 segment 33. Reagents and
conditions: (a) TBSCl, imidazole, DMF, 0 ◦C, 90%; (b) BH3·Me2S, NEt3,
MeOH, THF, 25 ◦C, 78%; (c) I2, PPh3, imidazole, CH2Cl2, 8 h, 87%; (d)
allylMgBr, Li2CuCl4, THF, −78 ◦C, 30–50%; (e) BH3·Me2S, 3 h, NaOH,
H2O2, 3 h, 40%; (f) I2, PPh3, imidazole, CH2Cl2, 8 h, 80%.
Synthesis of the C7–C21 subunit of epothilone
We envisaged the synthesis of the C7–C21 subunit (3) by the
convergence of the three subunits C7–C12 (25), C13–C16 (26), and
C17–C21 (5) using a sequential Wittig coupling protocol. Our
initial plan was to couple thiazolyl chloride 5 with 26 to yield
27, followed by a second Wittig coupling with the primary iodide
25 (path A, Fig. 3). Alternatively, a Wittig coupling between 25
and 26 would provide 28, which after another Wittig coupling
with thiazolyl chloride should also provide the required C7–C21
subunit of epothilone (path B, Fig. 3). Our results are discussed
below.
The synthesis of C13–C16 segment proved to be challeng-
ing. The synthesis was initiated with the alkoxyallylboration22
of acetaldehyde with B-c-methoxyethoxymethoxyallyldiiso-
pinocampheylborane to furnish the homoallylic alcohol 33
(Scheme 6). The corresponding alkoxyallylborane reagent was
prepared by the reaction of lithiated allyl methoxyethoxymethyl
ether 32 with B-methoxydiisopinocampheylborane. Attempts
towards the oxidation of the homoallylic alcohol under Jones
(CrO3) or Swern [Me2SO, (COCl)2] conditions, to our dismay,
led to isomerization yielding the a,b-unsaturated ketone 34.
Oxidation of the homoallylic alcohol 33 was finally achieved
with Dess–Martin periodinane to yield the ketone 35 in 76%
yield. Hydroboration of 35 proved futile and we could not
The C7–C12 segment (iodide 25) was prepared as shown in
Scheme 5. Silyl protection of the commercially available (R)-3-
hydroxy-2-methylpropionate (Roche ester, 29), reduction of the
Fig. 3 Retrosynthetic analysis for the C7–C21 subunit.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4
3 8 1 4

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Scheme 6 Preparation of the C13–C16 segment 38. Reagents and
conditions: (a) s-BuLi, THF, 0.5 h, (+)-Ipc2BOMe, 1 h, BF3·Et2O, 5 min,
CH3CHO, −78 ◦C, 3 h, (ii) NaOH, H2O2, 3 h, 75% yield, 95% ee;
(b) CrO3, CH2Cl2; (c) Me2SO, (COCl)2, NEt3; (d) DMP, CH2Cl2, 25 ◦C,
76%; (e) BH3·THF, Cy2BH, 9-BBN, Cl2BH, CatBH/RhCl(PPh3)3 etc.
(f) Cy2BH, NaOH, H2O2, 76%; (g) (i) Br2, Na2CO3, MeOH, 0 ◦C; or
(ii) Br2, HMPT, NaHCO3, H2O, CH2Cl2, 25 ◦C; or (iii) (Bu3Sn)2O,
Br2, CH2Cl2, 25 ◦C; or (iv) NaOCl, CH3COOH, 25 ◦C; or (v) KBrO3,
NaHSO3, CH3CN, H2O; or (vi) (NH4)2Ce(NO3)6, KBrO3, CH3CN,
80 ◦C etc. (h) TBSCl, imidazole, DMF, 25 ◦C, 87%; (i) DMP, CH2Cl2,
25 ◦C, 80%.
realize the formation of the hydroxyketone 36, irrespective of
the borane reagents used, such as BH3, Cy2BH, 9-BBN, Cl2BH,
catecholborane etc. (Scheme 6).
Scheme 7 Coupling of 5, 25 and 38. Reagents and conditions:
(a) (i) PBu3; (ii) NaHMDS, 74%; (b) AcOH, 83%; (c) DMP, 85%;
(d) (i) 25, PPh3; (ii) NaHMDS.
Selective oxidation of secondary alcohols in the presence
of a primary alcohol is a well-studied field of chemistry,23
and we attempted to use this reaction in our synthesis. Hy-
droboration of the homoallylic alcohol 33 was achieved by
treatment with 2.5 eq. of dicyclohexylborane, and the 1,4-
diol 37 was obtained in 76% yield and >98% regioselectivity.
However, selective oxidation of the secondary alcohol in 37
did not work under a variety of conditions. Oxidizing agents
such as Br2/Na2CO3, Br2/HMPT, Br2/(Bu3Sn)2O, NaOCl,
KBrO3/NaHSO3, CAN/KBrO3 etc. did not provide the re-
quired hydroxyketone. As a final resort, a two-step indirect
formation of the C13–C16 subunit 38 was achieved by selective
protection of the primary alcohol as the silyl ether, followed by
oxidation of the secondary alcohol to the corresponding ketone
38 in 70% combined yield (Scheme 6).
Having achieved the synthesis of the segments C7–C12 (25,
Scheme 5), C13–C16 (38, Scheme 6), and C17–C21 (524), we
proceeded further towards the coupling of these pieces by path
A, Fig. 3. Formation of the Wittig salt was realized by refluxing
5 with tri-n-butylphosphine (the Schlosser modification of
the Armstrong protocol).25 Treatment of the Wittig salt with
NaHMDS, followed by the addition of the ketone 38 furnished
the olefin 39. Protolytic cleavage of the silyl ether, followed by
DMP oxidation provided the aldehyde 27. Wittig coupling of the
aldehyde 27 with the C7–C12 subunit (iodide, 25) under standard
highly basic conditions led to extensive b-elimination of the
alkoxy (MEM) group to furnish the conjugated trienyl thiazole
42 as the major coupling product (Scheme 7).
Scheme 8 Wittig olefination of c-lactol 55 with iodide 33. Reagents
and conditions: (a) (i) Cy2BH, NaOH, H2O2, 76%; (ii) TPAP, NMO,
85%; (b) (i) 25, PPh3; (ii) NaHMDS; (c) TBSCl, imidazole, 25 ◦C , 89%;
(d) Cy2BH, NaOH, H2O2, 25 ◦C, 3 h, 78%; (e) DMP, 25 ◦C, 0.3 h, 97%.
With the intent of increasing the yield for the Wittig coupling,
we used the alternative Wittig olefination protocol shown in path
B, Fig. 3. Partial oxidation of the primary alcohol in the diol
37 yielded the c-lactol, 43. Treatment of this hemiacetal with
the Wittig ylide generated from the primary iodide 25 resulted
in very low yields of the olefinic alcohol 44 (Scheme 8). Having
failed to optimize the yields in the Wittig olefination of the c-
lactol, we resorted to a protected aldehyde for the coupling.
Thus, the homoallylic alcohol 33 was protected as the silyl ether
45. Hydroboration of the olefin 45 with dicyclohexylborane fur-
nished the primary alcohol in >98% regioselectivity. Oxidation
of the primary alcohol to the aldehyde 46, followed by a Wittig
coupling with the ylide obtained from the primary iodide 25,
yielded the olefin 47 in <5% yield (Scheme 8).
In order to overcome the low yields in the Wittig coupling in
our synthesis, we used the relatively non-labile benzyl ether as the
protecting group. Thus, the protection of the homoallylic alcohol
33 as its benzyl ether, followed by hydroboration and oxidation
using DMP yielded aldehyde 7 (Scheme 9). Although one of the
chiral centers derived from alkoxyallylboration will be converted
Scheme 9 Preparation of the C7–C21 subunit. Reagents and conditions:
(a) NaH, BnBr, THF, 0–25 ◦C , 78%; (b) BH3·Me2S, 0 ◦C, 4 h,
NaOH, H2O2, 25 ◦C, 3 h, 82%; (c) DMP, CH2Cl2, 25 ◦C, 0.3 h, 97%;
(d) (i) 25, PPh3, benzene, 80 ◦C, 12 h; (ii) NaHMDS, HMPA, THF,
−78 ◦C, (iii) 7, 25 ◦C, 58%; (e) Li, NH3(l), THF, −78 ◦C, 3.5 h,
MeOH–NH4Cl, 25 ◦C, 15 h, 85%; (f) DMP, CH2Cl2, 25 ◦C, 8 h, 95%;
(g) (i) 5, PBu3, 3 h, 70 ◦C; (ii) NaHMDS, THF, 0 ◦C, 0.8 h; (iii) 28, 0 ◦C,
6 h, 98%; (h) AcOH–H2O–THF (3 : 1 : 1), 25 ◦C, 18 h, 80%; (i) DMP,
CH2Cl2, 25 ◦C, 3 h, 98%.
to the ketone at a later stage of the synthesis, the protocol
does not necessitate any additional steps to create this chiral
center. Wittig coupling of aldehyde 7 with the primary iodide 25
provided the olefin 48 in 58% yield (∼9 : 1 Z : E). Debenzylation,
under Birch reduction conditions, furnished the alcohol, which
upon DMP oxidation provided the ketone 28 in 95% yield.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4
3 8 1 5

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A modified Wittig coupling between thiazolyl chloride 5 and
the ketone 28 yielded 49. Silyl deprotection and DMP oxidation
furnished the required C7–C21 subunit 3 of epothilone in 98%
yield.
providing homoallylic alcohols in high diastereo- and enan-
tioselectivities. We have further demonstrated the application
of this reagent for the synthesis of the C1–C6 subunit of the
potent anti-cancer agent epothilone B. With an economical
procedure, we believe that this reagent will find further ap-
plications in organic synthesis. We have also achieved the
synthesis of the C7–C21 subunit of epothilone A using a Wittig
reaction and pinane-based alkoxyallyl- and crotylboration as
key steps. The present study provides subunits that should be
amenable to conversion into epothilone, since similar subunits
have been successfully utilized previously for the synthesis of
epothilone.2k
Even though the synthesis of the C7–C21 subunit of epothilone
was achieved, the unreliable yields during the allyl substi-
tution of the primary iodide 30 compelled us to modify
the synthetic scheme. We designed a protocol utilizing a-
pinene-based crotylboration.26 This procedure is advantageous
because it replaces the relatively expensive Roche ester 29.
We began our synthesis with the Z-crotylboration of tert-
butyldimethylsiloxyacetaldehyde 50 to furnish the homoallylic
alcohol 51. Silyl protection, followed by oxidative cleavage of
the olefin furnished the aldehyde 52. Wittig coupling of 52
with 3-benzyloxypropyl iodide,27 under standard conditions, led
to the stereoselective formation of Z-olefin 53. Pd-catalyzed
hydrogenation resulted in the simultaneous debenzylation and
reduction of the double bond yielding the primary alcohol,
which upon iodination provided 6. Formation of the Wittig
ylide of 6, followed by treatment with the aldehyde 7, furnished
the coupled olefin 54. It is noteworthy that the Z-olefin was
formed selectively and in high yield (85%) from the substrate,
which is prone to b-elimination, as was the case in the earlier
protocols. Birch reduction afforded the debenzylated secondary
alcohol, which underwent oxidation, yielding the ketone 4.
Wittig coupling of the ketone 4 with thiazolyl chloride 5 using
the Schlosser modification of the Armstrong protocol provided
55 in 83% yield. Selective deprotection of the two silyl groups
using dilute HCl, followed by Pb(OAc)4 cleavage provided the
required C7–C21 subunit 3 (Scheme 10).
Experimental
( )-4,4-Dimethylhex-5-en-3-ol, C8H16O, 10
A solution of dimethylallylbromide 9 (10.0 g, 67.1 mmol)
was added to a suspension of zinc (8.8 g, 134.2 mmol) and
propionaldehyde (9.8 mL, 134.2 mmol) in 100.0 mL THF. A
saturated solution of NH4Cl was added dropwise to the reaction
mixture and stirred for 3 h at 25 ◦C. After the completion
of reaction as indicated by TLC, the reaction mixture was
filtered under suction and the residue was worked up with
ether and 10% HCl. The combined organic layers were dried
(MgSO4), concentrated under vacuum, and purified by column
chromatography (silica gel, pentane–ether, 4 : 1) to obtain 6.9 g
(80%) of the homoallylic alcohol 10. dH(300 MHz; CDCl3;
Me4Si) 5.80 (1 H, dd, J 10.8 and 17.4), 4.98–5.06 (2 H, m), 3.13
(1 H, dd, J 1.9 and 10.4), 1.49–1.62 (1 H, m), 1.11–1.28 (1 H,
m), 0.99 (3 H, s), 0.98 (3 H, s), 0.97 (3 H, t, J 7.3); dC(75.5 MHz;
CDCl3; Me4Si) 145.6, 113.1, 80.0, 41.7, 24.3, 23.1, 22.2,
11.6.
4,4-Dimethylhex-5-en-3-one, C8H14O, keto-10
Alcohol 10 (6.0 g, 46.9 mmol) was added to a suspension
of Dess–Martin periodinane (29.8 g, 70.4 mmol) in 70.0 mL
CH2Cl2 and stirred for 2 h at 25 ◦C. After the completion of
reaction, the reaction mixture was filtered and washed with
pentane. The combined organic layers were concentrated under
vacuum and purified by column chromatography (silica gel,
pentane–ether, 5 : 1) to obtain 5.1 g (87%) of the ketone keto-10.
dH(300 MHz; CDCl3; Me4Si) 5.91 (1 H, dd, J 10.5 and 17.6),
5.09–5.14 (2 H, m), 2.47 (2 H, q, J 7.3), 1.20 (6 H, s), 0.99 (3 H,
t, J 7.3); dC(75.5 MHz; CDCl3; Me4Si) 213.8, 142.8, 114.0, 50.7,
30.6, 23.6, 8.3.
2,2-Dimethyl-3-oxopentanal, C7H12O2, 11
A solution of the olefinic ketone keto-10 (5.0 g, 39.7 mmol) in
CH2Cl2–CH3OH (1 : 1) was cooled to −78 ◦C and ozone gas
was bubbled through the solution until the formation of the
ozonide was complete, as indicated by the deep blue color of
the solution. The resulting ozonide was quenched with Me2S
(14.6 mL, 200.0 mmol) and stirred at 25 ◦C for 4 h. The reaction
mixture was concentrated under vacuum to obtain 4.0 g (80%)
yield of the crude product. The resultant crude keto-aldehyde
11 was used for the next step without further purification.
dH(300 MHz; CDCl3; Me4Si) 9.62 (1 H, s), 2.47 (2 H, q, J 7.3),
1.38 (6 H, s), 0.98 (3 H, t, J 7.3); dC(75.5 MHz; CDCl3; Me4Si)
209.9, 201.2, 60.2, 32.3, 19.3, 7.6.
Scheme 10 Revised procedure for the preparation of the C7–C21
subunit. Reagents and conditions: (a) (i) n-BuLi, cis-2-butene, KOtBu,
THF, −45 ◦C, 0.3 h; (+)-Ipc2BOMe, −78 ◦C, 1 h; BF3·Et2O, 5 min; 67,
−78 ◦C, 3 h; (ii) NaOH, H2O2, 25 ◦C, 3 h, 82%; (b) TBSCl, imidazole,
DMF, 25 ◦C, 9 h, 89%; (c) (i) OsO4, NMO, acetone–water (3 : 1), 25 ◦C,
4 h; (ii) NaIO4, acetone–water (3 : 1), 25 ◦C, 2.5 h, 90%; (d) (i) 71,
PPh3, p-xylene, 150 ◦C, 12 h; (ii) NaHMDS, 0 ◦C, THF, 70, 3 h, 77%;
(e) H2, Pd/C, EtOAc, 8 h, 60%; (f) I2, PPh3, imidazole, CH2Cl2, 8 h,
78%; (g) (i) 6, PPh3, p-xylene, 150 ◦C, 3 h; (ii) NaHMDS, HMPA, THF,
−78 ◦C, 2 h; (iii) 7, −78–25 ◦C, 15 h, 85%; (h) Li, NH3(l), THF, −78 ◦C,
3.5 h, MeOH–NH4Cl, 25 ◦C, 15 h, 95%; (i) DMP, CH2Cl2, 25 ◦C, 0.3 h,
98%; (j) (i) 5, PBu3, 3 h, 70 ◦C; (ii) NaHMDS, THF, 0 ◦C, 0.7 h; (iii)
4, 0 ◦C, 15 h, 83%; (k) THF–H2O–HCl (8 : 1 : 1), 0.3 h; (l) Pb(OAc)4,
benzene, 25 ◦C, 0.3 h, 70% (overall).
( )-4,4-Dimethyl-5-hydroxyhept-6-yn-3-one, C9H14O2, OH-11
A solution of the keto-aldehyde 11 (4.0 g, 31.2 mmol) in 60.0 mL
ether was cooled to 0 ◦C and ethynylmagnesium bromide
(31.5 mL, 1.0 M solution, 31.5 mmol) was added dropwise to
the reaction mixture. The reaction was warmed to 25 ◦C and
stirred for 2 h. After the completion of the reaction as indicated
by TLC, the reaction mixture was quenched with dilute HCl
and worked up with ether. The combined organic layers were
Conclusions
In conclusion, we have developed a simple and inexpensive
procedure for the large-scale synthesis of both antipodes of B-
c,c-dimethylallyldiisopinocampheylborane, and have examined
the reactivity of the reagent with a wide variety of aldehydes,
3 8 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4

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dried (MgSO4), concentrated under vacuum, and purified by
column chromatography (silica gel, hexanes–ethyl acetate, 5 : 1)
to obtain 2.9 g (69%) of the alcohol OH-11.
(3S)-4,4-Dimethylhex-5-ene-1,3-diol, C8H16O2, 18
A solution of the hydroxyketone 17 (2.4 g, 17.2 mmol) in 20.0 mL
ether was cooled to 0 ◦C, and 5.4 g (18.9 mmol) of diisopinocam-
pheylborane (Ipc2BH) was added to it. The reaction mixture
was warmed to room temperature. After the completion of the
reaction, as indicated by 11B NMR spectroscopy, the reaction
mixture was oxidized with NaOAc and H2O2 and worked up
with ether and water. The combined organic layers were dried
(MgSO4) and concentrated under vacuum. The crude alcohol
was purified by column chromatography (silica gel, hexanes–
ethyl acetate, 5 : 1) to obtain 1.9 g (76%) of the diol 18.
dH(300 MHz; CDCl3; Me4Si) 5.84–5.94 (1 H, m), 5.12–5.18 (2 H,
m), 3.75–3.85 (2 H, m), 3.54–5.64 (1 H, m), 2.9–3.1 (2 H, br s),
1.41–1.75 (2 H, m), 0.98 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si)
145.1, 113.4, 78.3, 62.1, 41.5, 32.8, 22.8, 22.1.
4,4-Dimethylhept-1-yn-3,5-dione, C9H12O2, 12
Procedure similar to that for keto-10, providing 12 in 87% yield.
dH(300 MHz; CDCl3; Me4Si) 3.36 (1 H, s), 2.46 (2 H, t, J 7.3),
1.38 (6 H, s), 1.05 (3 H, t, J 7.3).
(5S)-4,4-Dimethyl-5-hydroxyhept-6-yn-3-one, C9H14O2, 13
A solution of the diketone 12 (2.0 g, 13.2 mmol) in 25.0 mL
ether was cooled to 0 ◦C and 4.6 g (14.5 mmol) of B-
chlorodiisopinocampheylborane (DipCl) was added to it. The
reaction mixture was warmed to room temperature. After
the completion of the reaction as indicated by 11B NMR
spectroscopy, the reaction mixture was oxidized with NaOAc
and H2O2, and worked up with ether and water. The combined
organic layers were dried (MgSO4) and concentrated under vac-
uum. The crude alcohol was purified by column chromatography
(silica gel, hexanes–ethyl acetate, 5 : 1) to obtain 1.5 g (76%) of
the hydroxy-ketone 13. The ee was determined to be 96% by
HPLC analysis.
(3S)-1-p-Methoxybenzyloxy-4,4-dimethylhex-5-en-3-ol,
C16H24O3, PMB-18
Diol 18 (1.8 g, 12.5 mmol) was added dropwise to a suspension
of NaH (0.7 g, 50% dispersion in mineral oil, 15.0 mmol) in
30.0 mL ether at 0 ◦C and stirred for 2 h. 6.3 g (31.2 mmol)
of PMBBr was added dropwise to the reaction mixture and
stirred overnight at 25 ◦C. After the completion of the reaction as
indicated by TLC, the reaction mixture was quenched with 10%
HCl and worked up with ether and water. The combined organic
layers were dried, concentrated under vacuum and purified by
column chromatography (silica gel, hexanes–ethyl acetate, 5 :
1), to obtain 2.6 g (80%) of mono-protected alcohol PMB-18.
dH(300 MHz; CDCl3; Me4Si) 7.25 (1 H, d, J 8.2), 6.88 (2 H,
d, J 8.6), 5.86 (1 H, dd, J 6.1 and 11.1), 4.99–5.06 (2 H, m),
4.45 (2 H, s), 3.79 (3 H, s), 3.48–3.73 (3 H, m), 2.89 (1 H, br s),
1.55–1.92 (2 H, m), 1.05 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si)
159.3, 145.6, 130.1, 129.3, 113.9, 112.6, 77.9, 73.0, 69.7, 55.3,
41.3, 31.3, 22.9, 22.5.
( )-1-tert-Butyldimethylsilyloxy-4,4-dimethylhex-5-en-3-ol,
C14H30O2Si, 16
A solution of dimethylallylbromide 9 (10.0 g, 67.1 mmol) was
added to a suspension of zinc (6.6 g, 100.0 mmol) and aldehyde
15 (6.3 g, 33.6 mmol) in 60.0 mL THF. A saturated solution of
NH4Cl was added dropwise to the reaction mixture and stirred
◦
for 3 h at 25 C. After completion of the reaction as indicated
by TLC, the reaction mixture was filtered under suction and
the residue was worked up with ether and 10% NH4Cl. The
combined organic layers were dried (MgSO4), concentrated
under vacuum, and purified by column chromatography (silica
gel, pentane–ether, 4 : 1) to obtain 6.9 g (80%) of the homoallylic
alcohol 16. dH(300 MHz; CDCl3; Me4Si) 5.82–5.94 (1 H, m),
4.94–5.08 (2 H, m), 3.72–3.90 (2 H, m), 3.52 (1 H, m), 3.25 (1
H, br s), 1.44–1.72 (2 H, m), 1.02 (6 H, s), 0.89 (9 H, s), 0.05
(6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 145.7, 112.3, 78.5, 63.3,
33.4, 25.9, 22.9, 22.5, 18.2, −5.5.
(3S)-3-tert-Butyldimethylsilyloxy-1-p-methoxybenzyloxy-4,4-
dimethylhex-5-ene, C22H38O3Si, 19
Alcohol PMB-18 (2.5 g, 9.5 mmol) was dissolved in 38 mL
dimethylformamide. tert-Butyldimethylsilylchloride (1.7 g,
11.3 mmol) and imidazole (1.2 g, 17.0 mmol) were added at
0
◦C and the mixture stirred for 3 h. After the completion of
the reaction as indicated by TLC, the reaction mixture was
worked up with ether and water. The organic layer was dried
over MgSO4, concentrated under aspirator vacuum to obtain
2.8 g (80%) of silyl ether 19. dH(300 MHz; CDCl3; Me4Si) 7.25
(2 H, d, J 7.9), 6.88 (2 H, d, J 8.7), 5.86 (1 H, dd, J 10.4 and
18.0), 4.93–4.98 (2 H, m), 4.40 (2 H s), 3.81 (3 H, s), 3.42–3.52
(3 H, m), 1.53–1.93 (2 H, m), 0.97 (6 H, s), 0.89 (9 H, s), 0.04 (3
H, s), 0.03 (3 H, s); dC(75.5 MHz; CDCl3; Me4Si) 159.1, 146.1,
1-tert-Butyldimethylsilyloxy-4,4-dimethylhex-5-en-3-one,
C14H28O2Si, keto-16
Procedure similar to that of keto-10, providing keto-16 in 87%
yield. dH(300 MHz; CDCl3; Me4Si) 5.90 (1 H, dd, J 10.5 and
17.6), 5.12–5.18 (2 H, m), 3.85 (2 H, t, J 6.4), 2.67 (2 H, t, J
6.5), 1.22 (6 H, s), 0.87 (9 H, s), 0.04 (6 H, s); dC(75.5 MHz;
CDCl3; Me4Si) 211.6, 142.3, 114.5, 58.9, 50.9, 40.4, 25.9, 23.2,
18.3, −5.5.
130.8, 129.3, 113.8, 111.6, 76.4, 72.5, 67.8, 55.3, 42.5, 33.9, 26.2,
+
=
24.5, 22.6, 18.4, −3.8; EI-MS: 309 [(M − C(CH3)2CH CH2) ],
+
121 [100%, CH2C6H4OCH3], 73, 59; CI-MS: 379 [(M + H)+],
+
121 [100%, CH2C6H4OCH3 ], 81, 69; HRMS-CI: (M+) 378.2608
(actual), 378.2590 (calcd); (M + H)+ 379.2662 (actual), 379.2669
1-Hydroxy-4,4-dimethylhex-5-en-3-one, C8H14O2, 17
(calcd).
A solution of the ketone keto-16 (5.5 g, 21.5 mmol) was dissolved
in 40.0 mL of CH3OH, and 10.0 mL of 10% HCl was added
to the reaction mixture. After the completion of the reaction
as indicated by TLC, the reaction mixture was concentrated
in vacuo and worked up with ether and water. The combined
organic layers were dried (MgSO4), and concentrated under
reduced pressure. The crude hydroxyketone was purified by
column chromatography (silica gel, hexanes–ethyl acetate, 4 : 1)
to obtain 2.4 g (80%) of the pure hydroxyketone 17. dH(300 MHz;
CDCl3; Me4Si) 5.84–5.94 (1 H, m), 5.12–5.18 (2H, m), 3.79
(2 H, t, J 5.4), 2.71 (2 H, t, J 5.0), 2.52 (1 H, br s), 1.22 (6
H, s); dC(75.5 MHz; CDCl3; Me4Si) 214.3, 142.1, 114.8, 58.2,
50.9, 39.4, 23.4.
(3S)-3-tert-Butyldimethylsilyloxy-5-p-methoxybenzyloxy-2,2-
dimethylpentanal, C21H36O4Si, ald-19
Procedure similar to that of 11. 78% pure aldehyde ald-19 was
obtained. The resulting aldehyde was used for the next step
without further purification. dH(300 MHz; CDCl3; Me4Si) 9.54
(1 H, s), 7.25 (2 H, d, J 8.5), 6.88 (2 H, d, J 8.5), 4.40 (2 H, s),
3.96 (1 H, dd, J 3.51 and 7.41), 3.81 (3 H, s), 3.48 (2 H, dd, J
6.0 and 7.4), 1.61–1.91 (2 H, m), 1.05 (3 H, s), 1.00 (3 H, s),
0.85 (9 H, s), 0.05 (3 H, s), 0.03 (3 H, s); dC(75.5 MHz; CDCl3;
Me4Si) 206.3, 159.2, 130.4, 129.3, 113.8, 73.3, 72.6, 66.7, 55.3,
51.3, 33.6, 26.0, 19.1, 18.2, 17.6, −4.0, −4.2.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4
3 8 1 7

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(5S)-5-tert-Butyldimethylsilyloxy-7-p-methoxybenzyloxy-4,4-
dimethylheptan-3-ol, C23H42O4Si, OH-19
of a 0.5 M solution in ether–pentane) at −100 ◦C and maintained
at that temperature for 2 h. The progress of the reaction was
followed by 11B NMR spectroscopy (d 56). Upon completion,
the mixture was oxidized with 19.4 mL of 3.0 M NaOH and
19.4 mL of 30% H2O2, stirred for 4 h at room temperature and
extracted with ether. The organic layer was dried over MgSO4,
concentrated under vaccum, purified by column chromatogra-
phy (silica gel, hexanes–ethyl acetate, 3 : 2) to obtain 8.7 g (82%)
of the pure alcohol 24f. dH(300 MHz; CDCl3; Me4Si) 7.25 (2 H,
d, J 8.2), 6.88 (2 H, d, J 8.6), 5.86 (1 H, dd, J 6.1 and 11.1),
4.99–5.06 (2 H, m), 4.45 (2 H, s), 3.79 (3 H, s), 3.48–3.73 (3
H, m), 2.89 (1 H, d, J 2.7), 1.55–1.92 (2 H, m), 1.05 (6 H, s);
dC(75.5 MHz; CDCl3; Me4Si) 159.3, 145.6, 130.1, 129.4, 129.3,
113.9, 112.6, 77.9, 73.0, 69.7, 55.3, 41.3, 31.3, 22.9, 22.5.
Aldehyde ald-19 (1.0 g, 2.6 mmol) was dissolved in 5.0 mL THF
◦
and cooled to 0 C. Ethylmagnesium bromide (2.9 mL, 1.0 M
solution in THF, 2.9 mmol) was added to it dropwise and stirred
for 1 h. The reaction mixture was quenched with sat. NH4Cl,
worked up with ether and the combined organic layers were
dried (MgSO4), and concentrated under vacuum to obtain crude
alcohol OH-19, which was used for the next step without further
purification.
(5S)-5-tert-Butyldimethylsilyloxy-7-p-methoxybenzyloxy-4,4-
dimethylheptan-3-one, C23H40O4Si, 2
Procedure similar to that for keto-10, providing 2 (the C1–C6
subunit of epothilone) in 88% yield. dH(300 MHz; CDCl3; Me4Si)
7.24 (2 H, d, J 8.6), 6.87 (2 H, d, J 8.6), 4.40 (2 H, s), 4.05
(1 H, dd, J 3.1 and 7.4), 3.80 (3 H, s), 3.42–3.47 (2 H, m),
2.39–2.61 (2 H, m), 1.50–1.76 (2 H, m), 1.10 (3 H, s), 1.05 (3
H, s), 0.99 (3 H, t, J 7.1), 0.86 (9 H, s), 0.04 (3 H, s), 0.01 (3
H, s); dC(75.5 MHz; CDCl3; Me4Si) 159.2, 130.6, 129.2, 113.8,
74.0, 72.5, 67.3, 55.3, 53.0, 34.3, 31.7, 26.1, 22.0, 20.2, 18.3, 7.8,
−4.0, −4.1; EI-MS: m/z 309 [(M − C(CH3)2COCH2CH3)+], 121
[100%, +CH2C6H4OCH3], 77, 75; CI-MS: 409 [(M + H)+], 271,
121 [100%, +CH2C6H4OCH3], 81, 69; HRMS-CI: (M+) 408.2696
(calcd), 408.2677 (actual); (M + H)+ 409.2774 (calcd), 409.2787
(actual).
(2S,3S)-1-p-Methoxybenzyloxy-2,4,4-trimethylhex-5-en-3-ol,
C17H26O3, 24g
Procedure as described above for the dimethylallylboration of
aldehydes. dH(300 MHz; CDCl3; Me4Si) 7.23 (2 H, d, J 8.3), 6.87
(2 H, d, J 8.5), 5.98 (1 H, dd, J 6.8 and 10.8), 4.95–5.08 (2 H,
m), 4.41 (2 H, dd, J 6.3 and 7.1), 3.79 (3 H, s), 3.20–3.60 (4 H,
m), 1.91–2.07 (1 H, m), 1.05 (3 H, s), 1.05 (3 H, s), 0.94 (3 H, d,
J 6.9); dC(75.5 MHz; CDCl3; Me4Si) 159.3, 145.9, 129.3, 129.2,
113.8, 111.6, 83.2, 79.2, 76.5, 73.7, 73.0, 55.3, 42.3, 34.6, 24.2,
23.8, 18.4, 11.5.
(2S)-1-Benzyloxypent-4-en-2-ol, C12H16O2, Bn-OH-23h
B-c,c-Dimethylallyldiisopinocampheylborane 20
To a solution of B-allyldiisopinocampheylborane (20.0 mL,
1.0 M solution, 20.0 mmol) in ether–pentane was added
benzyloxyacetaldehyde (3.3 g, 22.0 mmol), and the mixture
stirred for 3 h at −100 ◦C. After the completion of the reaction as
indicated by 11B NMR spectroscopy (d 79), the reaction mixture
was oxidized using 8.0 mL of 3.0 M NaOH and 8.0 mL of 30%
H2O2, and the reaction mixture worked up with ether and water.
The combined organic layers were dried, concentrated and used
in the next step without further purification. dH(300 MHz;
CDCl3; Me4Si) 7.30–7.37 (5 H, m), 5.77–5.90 (1 H, m), 5.08–
5.17 (2 H, m), 4.57 (2 H, s), 3.85–3.93 (1 H, m), 3.52 (1 H, dd, J
3.4 and 9.4), 3.38 (1 H, dd, J 7.4 and 9.5), 2.24–2.30 (3 H, m);
dC(75.5 MHz; CDCl3; Me4Si) 138.0, 134.3, 128.5, 127.8, 127.7,
117.8, 73.9, 73.4, 69.8, 37.9.
1-Chloro-3-methyl-2-butene (90.2 mL, 1.0 mol) was added
dropwise to a stirred suspension of magnesium (120 g, 2.5 mol) in
200 mL ether and was stirred for 1 h. Meanwhile, a flame-dried
round-bottomed flask was cooled under an inert atmosphere
and B-methoxydiisopinocampheylborane (158.2 g, 0.5 mol)
was weighed into the flask under nitrogen.◦ The borinate was
dissolved in 500 mL ether and cooled to 0 C. The previously
made Grignard reagent was then transferred into the borinate
solution and stirred for 4 h. After the completion of the reaction
as monitored by 11B NMR (d 79), the reaction mixture was
filtered under nitrogen using a Kramer’s filter and was washed
repeatedly with ether. The organic layer was concentrated under
vacuum in nitrogen atmosphere. Spectroscopic grade pentane
was added to it using a cannula, stirred for 5 min and the
precipitate (unreacted Grignard reagent and the magnesium
salts) allowed to settle. The supernatant liquid was then trans-
ferred via a cannula into another round-bottomed flask under
nitrogen and the solvent was evaporated off under vacuum. After
repeated washing with pentane, the concentrate (90%, 159.4 g,
450.0 mmol) was dissolved in 450 mL pentane so as to prepare a
1 M stock solution of the reagent in pentane. This stock solution
was used for reaction with various aldehydes.
Typical procedure for the reaction of 20 with an aldehyde: B-
c,c-dimethylallyldiisopinocampheylborane, 20 (24.0 mL, 1.0 M
solution in pentane, 24.0 mmol) was dissolved in 24.0 mL ether
and cooled to −100 ◦C. The aldehyde (20.0 mmol) was dissolved
in 10.0 mL ether, cooled to −78 ◦C, and transferred to the
reaction mixture using a cannula. The reaction mixture was
monitored using 11B NMR (d 56). After completion, the reaction
mixture was oxidized using 3.0 M NaOH and 30% H2O2 and
stirred at room temperature for 6 h. The reaction mixture was
worked up with ether and water, the combined organic layers
were dried (MgSO4), concentrated under vacuum, and purified
by column chromatography (silica gel, hexanes–ethyl acetate) to
afford pure homoallylic alcohol.
(2S)-2-tert-Butyldimethyldimethylsilyloxy-1-benzyloxypent-4-
ene, C18H30O2, Bn-TBS-23h
Procedure similar to that for 19, providing the pure silyl ether
Bn-TBS-23h in 82% yield. dH(300 MHz; CDCl3; Me4Si) 7.30–
7.40 (5 H, m), 5.73–5.91 (1 H, m), 5.05–5.20 (2 H, m), 4.56 (2
H, s), 3.86–3.97 (1 H, m), 3.38 (2 H, s), 2.24–2.30 (2 H, m), 0.90
(9 H, s), 0.1 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 138.5, 135.0,
128.4, 127.6, 127.5, 117.1, 74.3, 73.4, 71.3, 39.5, 25.9, 18.3, −4.4,
−4.6.
(2S)-2-tert-Butyldimethyldimethylsilyloxypent-4-en-1-ol,
C11H24O2, OH-TBS-23h
The silylated benzyl ether Bn-TBS-23h (1.6 g, 5.9 mmol) was
dissolved in 12.0 mL THF and transferred to a pre-cooled
solution of lithium (0.2 g, 28.6 mmol) in liquid ammonia
◦
(60.0 mL) and stirred for 3 h at −78 C. The reaction mixture
was slowly quenched with NH4Cl and MeOH, warmed to room
temperature, stirred overnight and worked up with ether and
water. The organic layer was dried (MgSO4), concentrated under
aspirator vacuum, purified by column chromatography (silica
gel, hexanes–ethyl acetate, 5 : 1) to obtain 0.8 g (68%) of alcohol
OH-TBS-23h. dH(300 MHz; CDCl3; Me4Si) 5.65–5.86 (1 H, m),
4.94–5.15 (2 H, m), 3.37–3.78 (4 H, m), 2.24–2.30 (2 H, m), 0.90
(9 H, s), 0.10 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 134.5, 117.4,
71.2, 66.5, 37.6, 25.9, 18.3, −5.3, −5.4.
(3S)-1-p-Methoxybenzyloxy-4,4-dimethylhex-5-en-3-ol,
C16H24O3, 24f
Aldehyde 23f (7.8 g, 40.4 mmol) was added to a stirred solution
of (−)-B-c,c-dimethylallyldiisopinocampheylborane (96.9 mL
3 8 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4

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(2S)-Pent-4-ene-1,2-diol, C5H10O2, diol-23h
6-tert-Butyldimethylsilyloxy-5-methylhexan-1-ol, C13H30O2Si,
OH-31
A solution of the silyl alcohol OH-TBS-23h (0.5 g, 2.7 mmol)
was dissolved in 6.0 mL CH3OH, and 1.5 mL of 10% HCl added.
The reaction was stirred for 2 h, and monitored by TLC. The
reaction mixture was concentrated under vacuum, and worked
up with ether and water. The combined organic layers were dried,
concentrated and purified by column chromatography (silica gel,
hexanes–ethyl acetate, 2 : 3) to obtain 0.23 g (84%) of the diol
diol-23h. dH(300 MHz; CDCl3; Me4Si) 5.71–5.85 (1 H, m), 5.05–
5.11 (2 H, m), 3.83 (2 H, br s), 3.70 (1 H, ddd, J 2.9, 6.6 and
13.8), 3.59 (1 H, dd, J 2.9 and 11.5), 3.40 (1 H, dd, J 7.6 and
11.2), 2.19 (2 H, t, J 6.9); dC(75.5 MHz; CDCl3; Me4Si) 134.2,
117.8, 71.5, 66.1, 37.8; EI-MS: m/z 85 [M + H − H2O], 61, 43;
CI-MS: 103 [(M + H)+], 85 [(M + H − H2O)+], 67 [100%, M +
H − 2H2O].
Olefin 31 (3.5 g, 15.4 mmol) was dissolved in 30.0 mL ether.
BH3·Me2S (1.2 mL, 10 M solution, 12.0 mmol) was added at
0 ◦C and the mixture stirred overnight at room temperature. The
reaction mixture was oxidized with 14.4 mL of 3.0 M sodium
hydroxide and 14.4 mL of 30% hydrogen peroxide and stirred
for 10 h at 25 ◦C. The reaction mixture was worked up with
ether and water. The organic layer was dried over MgSO4, and
evaporated under aspirator vacuum to obtain 1.5 g (40%) of
alcohol OH-31. dH(300 MHz; CDCl3; Me4Si) 3.63 (2 H, t, J
7.0), 3.42 (1 H, dd, J 6.0 and 11.0), 3.35 (1 H, dd, J 7.0 and
11.0), 1.57–1.53 (3 H, m), 1.42–1.39 (3 H, m), 1.16–1.06 (1 H,
m), 0.88 (9 H, s), 0.85 (3 H, d, J 6.5), 0.03 (3 H, s), 0.02 (3 H, s);
dC(75.5 MHz; CDCl3; Me4Si) 68.2, 62.7, 35.6, 32.9, 32.8, 25.7,
23.0, 18.2, 16.5, −5.5; EI-MS: m/z 189, 171, 97, 75, 55 [100%,
C4H7 ], 47; CI-MS: m/z 247 [(M + H)+], 231, 189, 155, 143,
+
(2S)-1,2-Dimethoxypent-4-ene, C7H14O2, diMe-23h
133, 115 [M + H − HOSi(CH3)2C(CH3)3]; HRMS-CI: (M +
H)+ 247.2088 (actual), 247.2093 (calcd).
A solution of diol-23h (0.5 g, 5.0 mmol) in 10.0 mL ether was
added dropwise to a pre-cooled suspension of NaH (0.36 g,
50% dispersion in mineral oil, 7.5 mmol) in ether. CH3I (2.1 g,
15.0 mmol) was added to the reaction mixture and stirred
overnight at 25 ◦C. After the completion of the reaction, the
reaction mixture was quenched with dilute HCl and worked up
ether and water. The combined organic layers were dried over
MgSO4 and concentrated under vacuum. The crude product
was purified by column chromatography (silica gel, hexanes–
ethyl acetate, 4 : 1) to obtain 0.48 g (74%) of the dimethyl ether
diMe-23h.
6-tert-Butyldimethylsilyloxy-1-iodo-5-methylhexane,
C13H29OISi, 25
Alcohol OH-31 (1.5 g, 6.1 mmol) was dissolved in 12.0 mL
CH2Cl2. Iodine (3.1 g, 12.2 mmol), triphenylphosphine (3.2 g,
12.2 mmol) and imidazole (0.8 g, 12.2 mmol) were added to
the reaction mixture, which was stirred for 8 h. After the
completion of the reaction as indicated by TLC, the reaction
mixture was worked up with ether and water. The organic layers
were dried, concentrated under vacuum and purified by column
chromatography (silica gel, hexanes–ethyl acetate, 19 : 1) to
afford 1.7 g (80%) of 25. dH(300 MHz; CDCl3; Me4Si) 3.42 (1
H, dd, J 6.5 and 10.0), 3.38 (1 H, dd, J 6.0 and 10.0), 3.19
(2 H, t, J 7.0), 1.85–1.78 (2 H, m), 1.61–1.55 (1 H, m), 1.47–
1.33 (3 H, m), 1.10–1.02 (1 H, m), 0.89 (9 H, s), 0.87 (3 H, d,
J 6.7), 0.04 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 68.1, 35.4,
33.7, 31.8, 27.8, 25.8, 18.2, 16.5, 7.1, −5.5; EI-MS: m/z 299
[M − C4H9], 215, 185, 97 (100%), 75, 55; CI-MS: m/z 357 [(M +
H)+], 341, 299, 229 [M + H − HI], 133 [(HOSi(CH3)2C(CH3)3 +
H)+], 115; HRMS-CI: (M + H)+ 357.1103 (actual), 357.1111
(calcd).
(3S)-3,4-Dimethoxybutanal, C6H12O3, 23h
Procedure similar to that for 11, to provide the aldehyde 23h in
68% yield.
(2S,4S)-1, 2-Dimethoxy-5,5-dimethylhept-6-en-4-ol, C11H22O3,
24h
Procedure as described earlier for the dimethylallylboration of
aldehydes. dH(300 MHz; CDCl3; Me4Si) 5.85 (1 H, dd, J 5.7 and
11.1), 4.97–5.04 (2 H, m), 3.35–3.55 (5 H, m), 3.43 (3 H, s),
3.36 (3 H, s), 1.67–1.74 (1 H, m), 1.44–1.54 (1 H, m), 1.01 (6
H, s); dC(75.5 MHz; CDCl3; Me4Si) 145.5, 112.4, 80.9, 77.5,
74.2, 59.2, 57.4, 41.3, 33.3, 23.1, 22.1; EI-MS: m/z 157, 133,
125, 101 [100%], 89, 69, 59; CI-MS: 203 [M + H], 185 [(M +
H − H2O)+], 153, 133, 121, 101; HRMS-CI: (M + H − H2O)+
185.1547 (actual), 185.1542 (calcd).
(2S,3S)-3-(2-Methoxyethoxymethoxy)pent-4-en-2-ol, C9H18O4,
33
sec-Butyllithium (193.0 mL, 231.7 mmol) was added dropwise
to a well-stirred solution of allyloxymethoxyethoxymethane
32 (35.6 g, 243.8 mmol) in 500.0 mL THF at −78 ◦C
and stirred for 0.5 h. (+)-Ipc2BOMe ((+)-B-methoxy-
diisopinocampheylborane) (92.6 g, 292.7 mmol, 1.0 M solution
in THF) was added to the reaction mixture and stirred for 1 h
at −78 ◦C. BF3·Et2O (55.6 mL, 439.0 mmol) was added and the
reaction mixture was cooled to −100 ◦C. Acetaldehyde (13.7 mL,
243.9 mmol) dissolved in 25 mL THF was cooled to −78 ◦C
and was added dropwise to the reaction mixture. The reaction
was stirred at −100 ◦C for 2 h and then warmed to −78 ◦C
and stirred overnight. The reaction mixture was oxidized with
117.2 mL of 3.0 M sodium hydroxide and 117.2 mL of 30%
hydrogen peroxide and stirred for 10 h at room temperature.
The product was extracted with ether, washed with water, and
dried over MgSO4. The solvent was removed under aspirator
vacuum. The byproducts isopinocampheol and a-pinene were
vacuum-distilled and the crude product was purified by silica gel
column chromatography (hexane–ethyl acetate, 7 : 3) to obtain
33.0 g (75%) of the homoallylic alcohol 33. dH(300 MHz; CDCl3;
Me4Si) 5.64 (1 H, ddd, J 7.8, 10.6 and 17.8), 5.27–5.32 (2 H, m),
4.78 (1 H, d, J 7.0), 4.69 (1 H, d, J 7.0), 3.78–3.86 (2 H, m),
3.63–3.73 (2 H, m), 3.53–3.56 (2 H, m), 3.38 (3 H, s), 2.85 (1 H,
br s), 1.13 (3 H, d, J 6.3); dC(75.5 MHz; CDCl3; Me4Si) 134.7,
1-tert-Butyldimethylsilyloxy-2-methylhex-5-ene, C13H28OSi, 31
A solution of the iodide 30 (10.0 g, 3.2 mmol) was dis-
solved in 6.0 mL CH2Cl2 and cooled to −78 ◦C. Lithium
tetrachlorocuprate (16.0 mL, 0.1 M solution, 1.6 mmol) and
allylmagnesium bromide (6.4 mL, 1 M solution, 6.4 mmol) were
added to the reaction mixture and stirred at −78 ◦C for 4 h.
After complete reaction of the starting material, the reaction
mixture was worked up with NH4Cl and ether. The combined
organic layers were dried, concentrated in vacuo, and purified
by column chromatography (silica gel, hexanes–ethyl acetate, 9
: 1) to obtain 3.6 g (50%) of the olefin 31. dH(300 MHz; CDCl3;
Me4Si) 5.77–5.86 (1 H, m), 5.94–5.03 (2 H, m), 3.35–3.48 (2 H,
m), 1.96–2.17 (2 H, m), 1.44–1.65 (2 H, m), 1.09–1.22 (1 H, m),
0.90 (9 H, s), 0.88 (3 H, d, J 6.5), 0.05 (6 H, s); dC(75.5 MHz;
CDCl3; Me4Si) 139.3, 114.2, 68.2, 35.3, 32.2, 25.9, 19.0, 18.4,
16.6, −5.3; EI-MS: m/z 213 [M − CH3], 171 [M − C4H9], 141,
115, 99, 89, 75 [100%, (HOSi(CH3)2)+]; CI-MS: m/z 229 [(M +
H)+], 213 [M + H − CH4], 171, 145, 133, 115; HRMS-CI: (M +
H)+ 229.1982 (actual), 229.1988 (calcd).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4
3 8 1 9

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119.6, 92.9, 82.9, 71.7, 69.3, 67.3, 58.8, 18.5; EI-MS: m/z 89
m), 3.32 (3 H, s), 2.65 (3 H, s), 1.95 (3 H, s), 1.67–1.91 (2 H, m),
0.84 (9 H, s), 0.01 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 164.4,
152.9, 138.5, 121.3, 115.9, 92.8, 78.5, 71.8, 67.0, 59.7, 59.0, 37.3,
25.9, 19.2, 18.2, 13.6, −5.3, −5.4.
+
[100%, CH2OCH2CH2OCH3], 77, 70, 59, 45, 43; CI-MS: m/z
191 [(M + H)+], 115.
(3S)-3-(2-Methoxyethoxymethoxy)pent-4-en-2-one, C9H16O4,
35
4-((3S)-5-Hydroxy-3-(2-methoxyethoxymethoxy)-2-methylpent-
1-enyl)-2-methylthiazole, C14H23O4SN, 40
Procedure similar to that for keto-10, providing the ketone 35
in 76% yield. dH(300 MHz; CDCl3; Me4Si) 5.77 (1 H, ddd,
J 6.6, 10.3 and 17.1), 5.36–5.51 (2 H, m), 4.80 (1 H, d, J
6.9), 4.76 (1 H, d, J 6.9), 4.60 (1 H, d, J 6.6), 3.65–3.80
(2 H, m), 3.53 (2 H, t, J 4.4), 3.37 (3 H, s), 2.19 (3 H, s);
dC(75.5 MHz; CDCl3; Me4Si) 206.1, 132.3, 119.8, 93.6, 82.8,
71.6, 67.4, 58.8, 25.7; EI-MS: m/z 145 [(M − CH3CO)+], 113,
A solution of the silyl ether 39 (2.8 g, 6.7 mmol) was dissolved
in 10.0 mL of CH3OH, and 2.0 mL of AcOH was added to
the reaction mixture. After the completion of the reaction as
indicated by TLC, the reaction mixture was concentrated in
vacuo and worked up with ether and water. The combined
organic layers were dried (MgSO4), and concentrated under
reduced pressure. The crude hydroxyketone was purified by
column chromatography (silica gel, hexanes–ethyl acetate, 4 :
1) to obtain 1.7 g (83%) of the pure alcohol 39. dH(300 MHz;
CDCl3; Me4Si) 6.85 (1 H, s), 6.43 (1 H, s), 4.63 (1 H, d, J 6.9),
4.53 (1 H, d, J 6.9), 4.30 (1 H, dd, J 4.7 and 8.9), 3.45–3.83 (6 H,
m), 3.30 (3 H, s) 2.60 (3 H, s), 1.92 (3 H, s), 1.71–1.79 (2 H, m);
dC(75.5 MHz; CDCl3; Me4Si) 164.6, 152.6, 138.5, 120.8, 116.0,
92.3, 78.7, 71.8, 67.0, 59.1, 59.0, 36.8, 19.2, 14.0.
+
89 [100%, CH2OCH2CH2OCH3 ], 77, 59, 43; CI-MS: m/z 189
[(M + H)+], 113, 89 [100%, +CH2OCH2CH2OCH3].
(3S,4S)-3-(2-Methoxyethoxymethoxy)pentane-1,4-diol,
C9H20O5, 37
Olefin 33 (5.0 g, 26.3 mmol) was added to a suspension of
dicyclohexylborane (11.7 g, 65.8 mmol) in 60.0 mL ether at
◦
0 C and stirred overnight at room temperature. The reaction
mixture was oxidized with 26.2 mL of 3.0 M sodium hydroxide
and 26.2 mL of 30% hydrogen peroxide and stirred for 10 h at
room temperature. The reaction mixture was worked up with
ether and water. The organic layer was dried over MgSO4, and
evaporated under aspirator vacuum to obtain 4.1 g (76%) of
alcohol 37. dH(300 MHz; CDCl3; Me4Si) 4.72–4.84 (2 H, m),
3.62–3.78 (5 H, m), 3.46–3.58 (3 H, m), 3.37 (3 H, s), 2.90–3.10
(2 H, br s), 1.72–1.86 (1 H, m), 1.54–1.68 (1 H, m), 1.14 (3 H, d,
J 6.2); dC(75.5 MHz; CDCl3; Me4Si) 96.5, 82.1, 71.7, 69.6, 67.7,
59.0, 58.7, 33.9, 19.0.
4-((3S)-5-Oxo-3-(2-methoxyethoxymethoxy)-2-methylpent-1-
enyl)-2-methylthiazole, C14H21O4SN, 27
Procedure similar to that for keto-10, providing the aldehyde 27
in 85% yield. dH(300 MHz; CDCl3; Me4Si) 9.77 (1 H, s), 6.93
(1 H, s), 6.53 (1 H, s), 4.67–4.72 (2 H, m), 4.60 (1 H, d, J 6.9),
3.47–3.79 (4 H, m), 3.34 (3 H, s), 2.77 (1 H, ddd, J 2.9, 9.3 and
16.2), 2.66 (3 H, s), 2.52 (1 H, ddd, J 1.7, 4.0 and 16.2), 2.01 (3
H, s); dC(75.5 MHz; CDCl3; Me4Si) 200.7, 164.8, 152.3, 136.6,
121.8, 116.7, 92.6, 76.2, 71.7, 67.3, 59.0, 47.8, 19.2, 13.9.
4-((1E,3Z,5Z,10S)-11-tert-butyldimethylsilyloxy-2,10-
dimethylundeca-1,3,5-trienyl)-2-methylthiazole, C23H39OSNSi, 42
(2S,3S)-5-tert-Butyldimethylsilyloxy-3-(2-
methoxyethoxymethoxy)pentan-2-ol, C15H34O5Si, TBS-37
A mixture of iodide 25 (4.7 g, 13.1 mmol) and Ph3P (3.8 g,
14.4 mmol, 1.1 equiv.) was heated neat at 100 ◦C for 2 h to
provide the phosphonium salt (7.4 g, 91%) as a white solid: The
salt was dissolved in THF (120 mL, 0.1 M), and the solution
was cooled to 0 ◦C. Sodium hexamethyldisilylamide (NaHMDS,
12.0 mL, 12.0 mmol, 1 M solution in THF) was slowly added
at the same temperature, and the resulting mixture was stirred
for 15 min, before aldehyde 27 (3.2 g, 9.8 mmol) was slowly
added. Stirring was continued for another 15 min at 0 ◦C, and
then the mixture was quenched with saturated aqueous NH4Cl.
The reaction mixture was worked up with ether and water. The
combined organic layers were dried (MgSO4), and concentrated
under reduced pressure to afford the crude product. Purification
by column chromatography (silica gel, hexane–ethyl acetate, 9 :
1) furnished olefin 42 with extensive b-elimination.
Procedure similar to that for Bn-TBS-23h, providing the silyl
ether TBS-37 in 87% yield. dH(300 MHz; CDCl3; Me4Si) 4.80 (1
H, d, J 6.9), 4.76 (1 H, d, J 6.9), 3.45–3.82 (8 H, m), 3.36 (3 H, s),
1.73–1.83 (1 H, m), 1.53–1.64 (1 H, m), 1.14 (3 H, d, J 6.4), 0.86
(9 H, s), 0.02 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 96.5, 82.8,
71.7, 69.4, 67.7, 59.1 (2 carbons), 34.4, 25.9, 18.9, 18.2, −5.3,
−5.4.
(3S)-5-tert-Butyldimethylsilyloxy-3-(2-
methoxyethoxymethoxy)pentan-2-one, C15H32O5Si, 38
Procedure similar to that for keto-10, providing the ketone 38 in
80% yield. dH(300 MHz; CDCl3; Me4Si) 4.72 (2 H, s), 4.18 (1 H,
dd, J 4.5 and 7.5), 3.66–3.73 (4 H, m), 3.46–3.49 (2 H, m), 3.35
(3 H, s), 2.15 (3 H, s), 1.78–1.87 (2 H, m), 0.86 (9 H, s), 0.02 (6
H, s); dC(75.5 MHz; CDCl3; Me4Si) 209.1, 95.6, 79.5, 71.7, 67.6,
59.0, 58.5, 35.0, 26.4, 25.9, 18.9, −5.4, −5.5.
(2S,3S)-2-tert-Butyldimethylsilyloxy-3-(2-
methoxyethoxymethoxy)pent-4-ene, C15H32O4Si, 45
4-((3S)-5-tert-Butyldimethylsilyloxy-3-methoxyethoxymethoxy-
Procedure similar to that for 19, providing the silyl ether 45 in
89% yield. dH(300 MHz; CDCl3; Me4Si) 5.73 (1 H, ddd, J 6.8,
10.4 and 17.3), 5.20–5.27 (2 H, m), 4.74 (1 H, d, J 6.9), 4.70 (1
H, d, J 6.9), 3.73–3.94 (3 H, m), 3.58–3.64 (1 H, m), 3.50–3.54 (2
H, m), 3.36 (3 H, s), 1.07 (3 H, d, J), 0.86 (9 H, s), 0.04 (6 H, s);
dC(75.5 MHz; CDCl3; Me4Si) 134.9, 118.2, 93.6, 81.2, 71.8, 70.3,
66.8, 59.0, 25.9, 19.2, 18.1, −4.6, −4.7.
2-methylpent-1-enyl)-2-methylthiazole, C20H37O4SNSi, 39
Thiazolyl chloride 5 (2.1 g, 14.1 mmol) was heated at 80 ◦C with
tri-n-butylphosphine (42.3 mL of a 1.0 M solution, 42.3 mmol)
for 3 h. The reaction mixture was cooled to 0 ◦C and diluted with
30.0 mL THF. NaHMDS (13.4 mL, 1.0 M solution, 13.4 mmol)
was added dropwise to the reaction mixture and stirred at 0 ◦C
for 20 min. Ketone 38 (3.0 g, 9.4 mmol) was added to the
reaction mixture and stirred overnight. After the completion
of the reaction as indicated by TLC, the reaction mixture was
quenched with NH4Cl and worked up with ether and water. The
combined organic layers were dried, concentrated and purified
by column chromatography (silica gel, hexanes–ethyl acetate, 9
: 1) to obtain 2.9 g (74%) of the coupled olefin 39. dH(300 MHz;
CDCl3; Me4Si) 6.89 (1 H, s), 6.45 (1 H, s), 4.68 (1 H, d, J 6.7),
4.59 (1 H, d, J 6.8), 4.25 (1 H, dd, J 5.4 and 8.0), 3.47–3.80 (6 H,
(3S,4S)-4-tert-Butyldimethylsilyloxy-3-(2-
methoxyethoxymethoxy)pentan-1-ol, C15H34O5Si, OH-45
Procedure similar to that for 37, providing the alcohol OH-45
in 78% yield. dH(300 MHz; CDCl3; Me4Si) 4.83 (1 H, d, J 6.9),
4.73 (1 H, d, J 6.9), 3.53–3.90 (8 H, m), 3.38 (3 H, s), 3.00 (1 H,
br s), 1.86 (1 H, ddd, J 4.9, 9.6 and 14.4), 1.50–1.61 (1 H, m),
1.11 (3 H, d, J 6.3), 0.87 (9 H, s), 0.07 (3 H, s), 0.06 (3 H, s);
3 8 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4

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dC(75.5 MHz; CDCl3; Me4Si) 96.1, 80.0, 71.7, 70.2, 67.4, 59.4,
59.1, 32.6, 25.8, 18.3, 18.0, −4.7, −4.8.
1.02–1.10 (1 H, m), 0.88 (9 H, s), 0.86 (3 H, d, J 7.2), 0.04 (6
H, s); dC(75.5 MHz; CDCl3; Me4Si) 138.8, 131.9, 128.3, 127.6,
127.4, 125.8, 95.5, 79.9, 75.8, 71.8, 71.3, 68.4, 67.0, 59.0, 35.7,
32.9, 28.1, 27.8, 27.1, 26.0, 18.4, 16.8, 15.3, −5.3.
(3S,4S)-4-tert-Butyldimethylsilyloxy-3-(2-
methoxyethoxymethoxy)pentanal, C15H32O5Si, 46
(2S,3S,5Z,10S)-11-tert-Butyldimethylsilyloxy-3-(2-
methoxyethoxymethoxy)undec-5-en-2-ol, C22H46O5Si, OH-48
Procedure similar to that for keto-10, providing the pure
aldehyde 46 in 97% yield. dH(300 MHz; CDCl3; Me4Si) 9.72
(1 H, s), 4.71 (2 H,s), 3.95–4.04 (2 H, s), 3.59–3.62 (2 H, m),
3.47–3.49 (2 H, m), 3.33 (3 H, s), 2.43–2.68 (2 H, m), 1.05 (3
H, d, J 6.2), 0.81 (9 H, s), 0.01 (6 H, s); dC(75.5 MHz; CDCl3;
Me4Si) 201.2, 95.7, 76.5, 71.6, 68.6, 67.2, 59.0, 43.8, 25.7, 17.9,
17.5, −4.7, −4.9.
Procedure similar to that for OH-TBS-23h, providing the
alcohol OH-48 in 85% yield. dH(300 MHz; CDCl3; Me4Si) 5.32–
5.48 (2 H, m), 4.76 (2 H, s), 3.63–3.79 (3 H, m), 3.50–3.53 (2 H,
m), 3.27–3.42 (6 H, m), 2.85–2.89 (1 H, br s), 2.12–2.36 (2 H, m),
1.89–2.03 (2 H, m), 1.50–1.54 (1 H, m), 1.22–1.36 (3 H, m), 1.12
(3 H, d, J 6.3), 0.98–1.10 (1 H, m), 0.84 (9 H, s), 0.79 (3 H, d,
J 7.2), 0.01 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 132.3, 124.6,
95.8, 83.9, 71.7, 68.9, 68.3, 67.6, 59.0, 35.6, 32.8, 29.0, 27.7, 26.9,
25.9, 19.1, 18.3, 16.7, −5.4.
(2S,3S,5Z,10S)-2,11-Bis(tert-butyldimethylsilyloxy)-3-(2-
methoxyethoxymethoxy)undec-5-ene, C28H60O5Si2, 47
Procedure similar to that for 42, providing the olefin 47 in <5%
yield.
(3S,5Z,10S)-11-tert-Butyldimethylsilyloxy-3-(2-
methoxyethoxymethoxy)undec-5-en-2-one, C22H44O5Si, 28
(2S,3S)-2-Benzyloxy-3-(2-methoxyethoxymethoxy)pent-4-ene,
C16H24O4, Bn-33
Procedure similar to that for keto-10, providing the pure ketone
28 in 95% yield. dH(300 MHz; CDCl3; Me4Si) 5.28–5.52 (2 H,
m), 4.74 (1 H, d, J 7.0), 4.69 (1 H, d, J 7.0), 4.06 (1 H, dd, J 6.1
and 6.3), 3.66–3.70 (2 H, m), 3.47–3.50 (2 H, m), 3.28–3.42 (5
H, m), 2.42 (2 H, dd, J 5.9 and 6.6), 2.15 (3 H, s), 1.94–2.03 (2
H, m), 1.50–1.53 (1 H, m), 1.22–1.38 (3 H, m), 1.00–1.03 (1 H,
m), 0.86 (9 H, s), 0.82 (3 H, d, J 6.7), 0.01 (6 H, s); dC(75.5 MHz;
CDCl3; Me4Si) 209.2, 133.3, 123.3, 95.2, 82.1, 71.6, 68.3, 67.5,
59.0, 35.7, 32.8, 29.9, 27.7, 26.9, 26.6, 26.0, 18.3, 16.7, −5.4.
A solution of homoallylic alcohol 33 (10.0 g, 52.6 mmol) was
added dropwise to a suspension of NaH (3.8 g, 50% dispersion
in mineral oil, 79.0 mmol) in 100.0 mL ether at 0 ◦C. Benzyl
bromide (12.0 mL, 105.2 mmol) was added to the reaction
mixture and stirred overnight at room temperature. The reaction
mixture was quenched with NH4Cl and worked up with ether
and water. The combined organic layers were dried (MgSO4),
concentrated under reduced pressure and purified by column
chromatography (silica gel, hexanes–ethyl acetate 19 : 1) to
obtain 11.5 g (78%) of the benzyl ether Bn-33. dH(300 MHz;
CDCl3; Me4Si) 7.24–7.42 (5 H, m), 5.81 (1 H, ddd, J 7.2, 10.3
and 17.6), 5.24–5.34 (2 H, m), 4.79 (1 H, d, J 6.8), 4.73 (1 H,
d, J 6.9), 4.65 (1 H, d, J 12.0), 4.60 (1 H, d, J 11.9), 4.14 (1
H, dd, J 5.7 and 6.4), 3.78–3.85 (1 H, m), 3.45–3.65 (4 H, m),
3.34 (3 H, s), 1.18 (3 H, d, J 6.3); dC(75.5 MHz; CDCl3; Me4Si)
138.9, 134.9, 128.3, 127.8, 127.5, 118.6, 93.2, 79.8, 76.8, 71.8,
71.6, 66.9, 58.9, 16.0; ESI-MS: 303 [Na adduct]; HRMS-ESI:
(Na adduct) 303.1573 (actual), 303.1572 (calcd).
4-((1E,3S,5Z10S)-11-tert-Butyldimethylsilyloxy-3-(2-
methoxyethoxymethoxy)-2,10-dimethylundeca-1,5-dienyl)-2-
methylthiazole, C27H49O4SNSi, 49
Procedure similar to that for 39, providing the coupled olefin 49
in 98% yield. dH(300 MHz; CDCl3; Me4Si) 6.93 (1 H, s), 6.48 (1
H, s), 5.32–5.48 (2 H, m), 4.72 (1 H, d, J 6.9), 4.64 (1 H, d, J
6.8), 4.13 (1 H, dd, J 6.6 and 6.9), 3.80–3.86 (1 H, m), 3.53–3.64
(3 H, m), 3.30–3.45 (5 H, m), 2.70 (3 H, s), 2.30–2.45 (2 H, m),
1.91–2.05 (5 H, m), 1.22–1.58 (4 H, m), 0.99–1.09 (1 H, m), 0.88
(9 H, m), 0.84 (3 H, d, J 6.8), 0.03 (6 H, s); dC(75.5 MHz; CDCl3;
Me4Si) 164.6, 152.8, 138.4, 132.0, 125.2, 121.5, 115.9, 92.8, 81.7,
71.8, 68.4, 67.0, 59.0, 35.7, 32.9, 31.9, 27.8, 27.1, 26.0, 19.3, 18.4,
16.8, 13.8, −5.3.
(3S,4S)-4-Benzyloxy-3-(2-methoxyethoxymethoxy)pentan-1-ol,
C16H26O5, Bn-OH-33
Procedure similar to that for 37, providing the alcohol Bn-OH-
33 in 82% yield. dH(300 MHz; CDCl3; Me4Si) 7.26–7.34 (5 H,
m), 4.85 (1 H, d, J 6.9), 4.76 (1 H, d, J 6.9), 4.62 (1 H, d, J 11.8),
4.51 (1 H, d, J 11.8), 3.52–3.89 (8 H, m), 3.38 (3 H, s), 2.74–2.84
(1 H, br s), 1.87 (1 H, ddd, J 4.6, 9.1 and 13.9), 1.63 (1 H, ddd,
J 4.6, 8.8 and 14.1), 1.18 (3 H, d, J 6.3); dC(75.5 MHz; CDCl3;
Me4Si) 138.5, 128.4, 127.7, 127.6, 96.0, 77.7, 76.5, 71.7, 71.3,
67.4, 59.1 (2 carbons), 32.9, 15.0; ESI-MS: 321 [Na adduct].
4-((1E,3S,5Z,10S)-11-Hydroxy-3-(2-methoxyethoxymethoxy)-
2,10-dimethylundeca-1,5-dienyl)-2-methylthiazole, C21H35O4SN,
OH-49
The silyl ether 49 (2.0 g, 3.9 mmol) was dissolved in 8.0 mL of
THF, and 2.0 mL of AcOH and 2.0 mL of H2O were added
to the reaction mixture. After the completion of the reaction
as indicated by TLC, the reaction mixture was concentrated
in vacuo and worked up with ether and water. The combined
organic layers were dried (MgSO4), and concentrated under
reduced pressure. The crude hydroxyketone was purified by
column chromatography (silica gel, hexanes–ethyl acetate, 4 : 1)
to obtain 1.2 g (80%) of the pure alcohol OH-49. dH(300 MHz;
CDCl3; Me4Si) 6.95 (1 H, s), 6.49 (1 H, s), 5.34–5.47 (2 H, m),
4.72 (1 H, d, J 6.9), 4.64 (1 H, d, J 6.8), 4.14 (1 H, t, J 6.9),
3.80–3.87 (1 H, m), 3.39–3.64 (5 H, m), 3.38 (3 H, s), 2.71 (3
H, s), 2.31–2.47 (2 H, m), 1.98–2.08 (6 H, m), 1.08–1.60 (5 H,
m), 0.89 (3 H, d, J 6.7); dC(75.5 MHz; CDCl3; Me4Si) 164.7,
152.7, 138.5, 131.9, 125.5, 121.5, 115.9, 92.8, 81.8, 71.8, 68.2,
67.0, 59.1, 35.7, 32.8, 31.9, 27.7, 19.2, 16.6, 13.8.
(3S,4S)-4-Benzyloxy-3-(2-methoxyethoxymethoxy)pentanal,
C16H24O5, 7
Procedure similar to that for keto-10, providing the pure
aldehyde 7 in 97% yield. dH(300 MHz; CDCl3; Me4Si) 9.72–
9.75 (1 H, m), 7.26–7.32 (5 H, m), 4.75 (2 H, s), 4.57 (1 H, d,
J 12.1), 4.44 (1 H, d, J 11.8), 4.18–4.25 (1 H, m), 3.46–3.72 (5
H, m), 3.33 (3 H, s), 2.52–2.75 (2 H, m), 1.15 (3 H, d, J 6.3);
dC(75.5 MHz; CDCl3; Me4Si) 201.1, 138.3, 128.4, 127.8, 127.7,
95.7, 75.0, 74.7, 71.6, 71.1, 67.3, 59.0, 44.5, 14.5.
(2S,3S,5Z,10S)-2-benzyloxy-11-tert-butyldimethylsilyloxy-3-
(2-methoxyethoxymethoxy)undec-5-ene, C29H52O5Si, 48
Procedure similar to that for 42, providing the olefin 48 in 58%
yield. dH(300 MHz; CDCl3; Me4Si) 7.25–7.33 (5 H, m), 5.42 (2
H, d, J 5.3), 4.79 (2 H, s), 4.61 (1 H, d, J 12.0), 4.50 (1 H, d,
J 11.9), 3.41–3.71 (8 H, m), 3.37 (3 H, s), 2.25–2.43 (2 H, m),
2.02–2.03 (2 H, m), 1.26–1.57 (4 H, m), 1.19 (3 H, d, J 5.3),
4-((1E,3S,5Z,10S)-3-(2-Methoxyethoxymethoxy)-2,10-dimethyl-
11-oxoundeca-1,5-dienyl)-2-methylthiazole, C21H33O4SN, 3
Procedure similar to that for keto-10, providing the pure
aldehyde 3 (the C7–C21 subunit of epothilone) in 98% yield.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4
3 8 2 1

View Article Online
dH(300 MHz; CDCl3; Me4Si) 9.58 (1 H, d, J 2.0), 6.94 (1 H, s),
6.47 (1 H, s), 5.39–5.43 (2 H, m), 4.71 (1 H, d, J 6.8), 4.63 (1 H, d,
J 6.9), 4.12 (1 H, t, J 6.8), 3.78–3.85 (1 H, m), 3.51–3.63 (3 H, m),
3.37 (3 H, s), 2.69 (3 H, s), 2.27–2.42 (3 H, m), 1.97–2.07 (5 H,
m), 1.33–1.41 (4 H, m), 1.06 (3 H, d, J 7.0); dC(75.5 MHz; CDCl3;
Me4Si) 205.1, 164.6, 152.8, 138.3, 131.1, 126.0, 121.5, 116.0, 92.8,
81.6, 71.8, 67.1, 59.1, 46.2, 32.0, 30.1, 27.4, 26.9, 19.3, 13.8, 13.3;
(2R,3S,4Z)-7-Benzyloxy-1,2-bis(tert-butyldimethylsilyloxy)-3-
methylhept-4-ene, C27H50O3Si2, 53
A mixture of 1-benzyloxy-3-iodopropane (2.0 g, 7.4 mmol)
and Ph3P (1.9 g, 7.4 mmol) was heated in xylene at 100 ◦C
for 10 h. Evaporation of the xylene provided white crystals
of the phosphonium salt. The solid was submerged in THF
◦
with occasional heating. The solution was cooled to 0 C and
+
EI-MS: m/z 256, 89 [100%, CH3OCH2CH2OCH2 ]; CI-MS: m/z
NaHMDS (6.9 mL, 6.9 mmol) was added slowly. The clear
red solution was stirred for 20 min at room temperature and
396 [(M + H)+], 290 [100%, M + H − HOCH2OCH2CH2OCH3],
256, 168, 89; HRMS-CI: (M + H) 396.2205 (actual), 396.2209
(calcd).
◦
recooled to 0 C. Aldehyde 52 (1.7 g, 4.9 mmol) was added to
◦
the solution and stirred at 0 C for 2 h. The reaction mixture
was extracted with ether and water. The combined organic
layers were dried, concentrated under vacuum and purified by
column chromatography (silica gel, hexanes–ethyl acetate, 9 : 1)
to provide 1.8 g (77%) of olefin 53. dH(300 MHz; CDCl3; Me4Si)
7.26–7.38 (5 H, m), 5.33–5.45 (2 H, m), 4.51 (2 H, s), 3.41–3.56
(5 H, m), 2.64–2.76 (1 H, m), 2.32–2.46 (2 H, m), 0.93 (3 H, d, J
6.8), 0.89 (18 H, s), 0.05 (12 H, s); dC(75.5 MHz; CDCl3; Me4Si)
138.6, 129.5, 128.4, 127.6, 127.5, 124.7, 76.9, 72.9, 70.1, 65.7,
34.2, 28.2, 26.1, 26.0, 18.4, 18.3, 15.0, −4.0, −4.7, −5.2, −5.3.
(2R,3S)-1-tert-Butyldimethylsilyloxy-3-methylpent-
4-en-2-ol, C12H26O2Si, 51
Potassium tert-butoxide (56.7 mL, 1.0 M solution, 56.7 mmol)
◦
was dissolved in 100.0 mL THF at −78 C and trans-2-butene
(12.0 mL, 128.9 mmol) was added to it. n-Butyllithium (22.7 mL,
2.5 M solution, 56.7 mmol) was added to it and stirred for 20 min
at −45 ◦C. The reaction mixture was cooled to −78 ◦C and (+)-
B-methoxydiisopinocampheylborane [(+)-Ipc2BOMe] (22.0 g,
69.6 mmol) dissolved in 50.0 mL THF was added to it and
stirred for 1 h. Aldehyde 50 (9.0 g, 51.6 mmol) was dissolved
in 20.0 mL of THF pre-cooled to −78 ◦C, transferred to the
reaction mixture via a cannula at −78 ◦C and stirred for 3 h.
The reaction mixture was oxidized with 27.8 mL 3 M NaOH
and 27.7 mL 30% H2O2 and stirred overnight. The reaction
mixture was worked up with ether and water. The organic layer
was dried over MgSO4, concentrated under vacuum and purified
by column chromatography (silica gel, hexane–ethyl ether, 3 : 2)
to obtain 9.7 g (82%) of pure alcohol 51. dH(300 MHz; CDCl3;
Me4Si) 5.66–5.78 (1 H, m), 4.98–5.07 (2 H, m), 3.61–3.68 (1 H,
m), 3.40–3.49 (2 H, m), 2.48 (1 H, d, J 2.8), 2.22–2.34 (1 H, m),
1.08 (3 H, d, J 6.8), 0.89 (9 H, s), 0.06 (6 H, s); dC(75.5 MHz;
CDCl3; Me4Si) 140.5, 114.9, 74.7, 64.2, 41.0, 25.9, 18.3, 16.0,
−5.4.
(5S,6R)-6,7-Bis(tert-butyldimethylsilyloxy)-5-methylheptan-1-
ol, C20H46O3Si2, OH-6
Benzyl ether 53 (1.6 g, 3.3 mmol) was dissolved in ethyl acetate
(10.0 mL). 0.15 g of 10% w/v palladium-on-charcoal was added
to it and hydrogen gas bubbled through the reaction mixture for
6 h. The reaction mixture was filtered over silica gel and purified
by column chromatography (silica gel, hexanes–ethyl acetate,
3 : 1) to obtain 0.78 g (60%) of pure alcohol OH-6. dH(300 MHz;
CDCl3; Me4Si) 3.65 (2 H, t, J 6.6), 3.57–3.61 (1 H, m), 3.47 (2
H, d, J 6.4), 1.51–1.67 (3 H, m), 1.30–1.45 (2 H, m), 1.16–1.29
(2 H, m), 0.88 (9 H, s), 0.87 (9 H, s), 0.82 (3 H, d, J 6.8), 0.04 (12
H, s); dC(75.5 MHz; CDCl3; Me4Si) 75.9, 65.3, 63.1, 35.3, 33.4,
33.1, 26.0, 25.9, 23.8, 18.2 (2 carbons), 13.3, −3.9, −4.8, −5.2,
−5.4.
(2R,3S)-1,2-Bis(tert-butyldimethylsilyloxy)-7-iodo-
3-methylheptane, C20H45IO2Si2, 6
(2R,3S)-1,2-Bis(tert-butyldimethylsilyloxy)-3-methylpent-4-ene,
C18H40O2Si2, TBS-51
Alcohol OH-6 (0.3 g, 0.8 mmol) was dissolved in CH2Cl2. Iodine
(0.3 g, 1.15 mmol), triphenylphosphine (0.3 g, 1.2 mmol) and
imidazole (0.2 g, 2.3 mmol) were added and stirred for 8 h. After
the completion of the reaction as indicated by TLC, the reaction
mixture was worked up with ether and water. The organic layers
were dried, concentrated under vacuum and purified by column
chromatography (silica gel, hexanes–ethyl acetate, 19 : 1) to
afford 0.3 g (78%) of 6. dH(300 MHz; CDCl3; Me4Si) 3.57–3.62
(1 H, m), 3.47 (2 H, d, J 6.1), 3.47 (2 H, t, J 7.0), 1.77–1.86 (2 H,
m), 1.60–1.70 (1 H, m), 1.34–1.47 (3 H, m), 1.15–1.19 (1 H, m),
0.89 (9 H, s), 0.88 (9 H, s), 0.82 (3 H, d, J 6.6), 0.05 (12 H, s);
dC(75.5 MHz; CDCl3; Me4Si) 75.8, 65.2, 35.1, 33.8, 32.5, 28.6,
26.0, 25.9, 18.4 (2 carbons), 13.3, 7.2, −3.9, −4.8, −5.2, −5.3.
Procedure similar to that for 19, providing the silyl ether TBS-
51 in 89% yield. dH(300 MHz; CDCl3; Me4Si) 5.79–5.91 (1 H,
m), 4.96–5.09 (2 H, m), 3.44–3.62 (2 H, m), 2.39–2.45 (1 H, m),
0.98 (3 H, d, J 6.9), 0.90 (9 H, s), 0.89 (9 H, s), 0.06 (12 H, s).;
dC(75.5 MHz; CDCl3; Me4Si) 142.3, 113.7, 76.5, 75.4, 40.3, 26.0,
25.9, 18.4, 18.2, 13.6, −4.7 (2 carbons), −5.3, −5.4.
(2R,3R)-3,4-Bis(tert-butyldimethylsilyloxy)-2-methylbutanal,
C17H38O3Si2, 52
NMO (6.8 g, 58.2 mmol) was added to the olefinic ether TBS-51
(10.0 g, 29.1 mmol) dissolved in acetone–water (4 : 1, 60.0 mL)
at 0 ◦C. OsO4 (0.7 g, 2.9 mmol) was added to the above solution
and stirred for 6 h at room temperature, and the product
was extracted with ether, washed with a saturated solution of
sodium sulfite and dried over MgSO4. The solvent was removed
under aspirator vacuum. The crude product was dissolved in
acetone–water (4 : 1, 50.0 mL) and stirred at room temperature,
followed by the slow addition of NaIO4 (12.4 g, 58.2 mmol).
The mixture was stirred for 0.5 h at room temperature and the
product was extracted with ether, and washed with a saturated
solution of sodium thiosulfate. The solvent was removed under
aspirator vacuum and the crude product was purified by column
chromatography (silica gel, hexane–ethyl acetate, 3 : 2) to obtain
9.0 g (90%) of 52. dH(300 MHz; CDCl3; Me4Si) 9.77 (1 H, s),
4.12–4.18 (1 H, m), 3.62 (1 H, dd, J 4.8 and 10.0), 3.50 (1 H, dd,
J 6.0 and 9.0), 2.54–2.62 (1 H, m), 1.06 (3 H, d, J 6.9), 0.87 (9
H, s), 0.86 (9 H, s), 0.05 (12 H, s); dC(75.5 MHz; CDCl3; Me4Si)
204.6, 72.2, 64.4, 49.6, 25.9, 25.7, 18.3, 18.0, 7.6, −4.2, −4.9,
−5.4 (2 carbons).
(2S,3S,5Z,10S,11R)-2-Benzyloxy-11,12-bis(tert-
butyldimethylsilyloxy)-3-(2-methoxyethoxymethoxy)-10-
methyldodec-5-ene, C36H68O6Si2, 54
Procedure similar to that for 42, providing the olefin 54 in 85%
yield. dH(300 MHz; CDCl3; Me4Si) 7.26–7.36 (5 H, m), 5.43 (2
H, ddd, J 6.4, 11.4 and 17.4), 4.79 (2 H, s), 4.61 (1 H, d, J 11.9),
4.50 (1 H, d, J 11.8), 3.47–3.53 (4 H, m), 3.57–3.73 (5 H, m),
3.37 (3 H, s), 2.23–2.44 (2 H, m), 1.96–2.08 (2 H, m), 1.62–1.65
(1 H, m), 1.27–1.43 (3 H, m), 1.09–1.42 (1 H, m), 1.19 (3 H, d,
J 5.5), 0.90 (9 H, s), 0.89 (9 H, s), 0.81 (3 H, d, J 6.6), 0.05 (6
H, s), 0.04 (6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 138.8, 132.0,
128.3, 127.6, 127.4, 125.7, 95.5, 79.9, 75.9, 71.8, 71.3, 67.0, 65.4,
59.0 (2 carbons), 35.3, 33.5, 28.1, 27.7 (2 carbons), 26.0, 25.9,
18.4, 18.2, 15.3, 13.4, −4.0, −4.7, −5.2, −5.3. ESI: m/z 675 [Na
adduct]; HRMS-ESI: (Na adduct) 675.4460 (actual), 675.4452
(calcd).
3 8 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4

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(2S,3S,5Z,10S,11R)-11,12-Bis(tert-butyldimethylsilyloxy)-3-
(2-methoxyethoxymethoxy)-10-methyldodec-5-en-2-ol,
C29H62O6Si2, OH-54
water. The combined organic layers were dried over MgSO4 and
concentrated under vacuum. The crude product was purified
by column chromatography (silica gel, hexanes–ethyl acetate,
4 : 1), to provide the required C7–C21 subunit of epothilone 3 in
0.2 g (70% overall yield for the two steps). dH(300 MHz; CDCl3;
Me4Si) 9.58 (1 H, d, J 2.0), 6.94 (1 H, s), 6.47 (1 H, s), 5.39–5.43
(2 H, m), 4.71 (1 H, d, J 6.8), 4.63 (1 H, d, J 6.9), 4.12 (1 H, t, J
6.8), 3.78–3.85 (1 H, m), 3.51–3.63 (3 H, m), 3.37 (3 H, m), 2.69
(3 H, s), 2.27–2.42 (3 H, m), 1.97–2.07 (5 H, m), 1.33–1.41 (4
H, m), 1.06 (3 H, d, J 7.0); dC(75.5 MHz; CDCl3; Me4Si) 205.1,
164.6, 152.8, 138.3, 131.1, 126.0, 121.5, 116.0, 92.8, 81.6, 71.8,
67.1, 59.1, 46.2, 32.0, 30.1, 27.4, 26.9, 19.3, 13.8, 13.3; EI-MS:
Procedure similar to that for OH-TBS-23h, providing OH-54
in 95% yield. dH(300 MHz; CDCl3; Me4Si) 5.35–5.51 (2 H, m),
4.79 (2 H, s), 3.67–3.82 (3 H, m), 3.52–3.60 (3 H, m), 3.44–3.46
(2 H, m), 3.37 (3 H, s), 3.35–3.36 (1 H, m), 2.95–2.97 (1 H,
br s), 2.18–2.38 (2 H, m), 1.98–2.05 (2 H, m), 1.58–1.66 (1 H,
m), 1.16–1.41 (4 H, m), 1.14 (3 H, d, J 6.4), 0.87 (9 H, s), 0.86
(9 H, s), 0.79 (3 H, d, J 6.8), 0.03 (3 H, s), 0.02 (3 H, s), 0.01
(6 H, s); dC(75.5 MHz; CDCl3; Me4Si) 132.4, 124.5, 95.8, 84.0,
75.8, 71.7, 68.9, 67.6, 59.0, 35.2, 33.4, 29.1, 27.7, 27.6, 26.0, 25.9,
19.1, 18.3, 18.2, 13.3, −4.0, −4.8, −5.3, −5.4; ESI: m/z 585 [Na
adduct]; HRMS-ESI: (Na adduct) 585.3981 (actual), 585.3983
(calcd).
+
m/z 256, 89 [100%, CH3OCH2CH2OCH2 ]; CI-MS: m/z 396
[(M + H)+], 290 [100%, M + H − HOCH2OCH2CH2OCH3],
256, 168, 89; HRMS-CI: (M + H) 396.2205 (actual), 396.2209
(calcd).
(3S,5Z,10S,11R)-11,12-Bis(tert-butyldimethylsilyloxy)-3-(2-
methoxyethoxymethoxy)-10-methyldodec-5-en-2-one,
C29H60O6Si2, 4
Acknowledgements
This paper is dedicated to the memory of Professor Ian P. Roth-
well. Financial assistance from the Herbert C. Brown Center
for Borane Research28 and the Aldrich Chemical Company are
gratefully acknowledged.
Procedure similar to that for keto-10, providing the pure
aldehyde 4 in 98% yield. dH(300 MHz; CDCl3; Me4Si) 5.48–
5.56 (1 H, m), 5.32–5.40 (2 H, m), 4.77 (1 H, d, J 7.1), 4.73 (1
H, d, J 7.1), 4.09 (1 H, t, J 6.2), 3.45–3.73 (6 H, m), 3.37 (3
H, s), 2.45 (2 H, t, J 6.6), 2.17 (3 H, s), 1.99–2.05 (2 H, m),
1.61–1.64 (1 H, m), 1.12–1.42 (4 H, m), 0.88 (9 H, s), 0.87 (9
H, s), 0.80 (3 H, d, J 6.8), 0.07 (3 H, s), 0.04 (6 H, s), 0.03
(3 H, s); dC(75.5 MHz; CDCl3; Me4Si) 209.2, 133.3, 123.2, 95.2,
82.1, 75.8, 71.7, 67.5, 65.3, 59.0, 35.2, 33.4, 29.9, 27.6, 27.5, 26.5,
26.0, 25.9, 18.3, 18.2, 13.3, −4.0, −4.8, −5.3, −5.4; EI-MS: m/z
References and notes
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J. Abraham, Curr. Pharm. Des., 2002, 8, 1707; (b) S. J. Stachel, K.
Biswas and S. J. Danishefsky, Curr.. Pharm. Des., 2001, 7, 1277; (c) J.
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Roschanger and D. Vourloumis, Angew. Chem., Intl. Ed., 1998, 37,
2015; (e) M. R. V. Finlay, Chem. Ind., 1997, 991; (f) L. Wessjohann,
Angew. Chem., Intl. Ed. Engl., 1997, 36, 715, and references therein.
For total syntheses, see:; (g) A. Balog, D. F. Meng, T. Kamenecka, P.
Bertinato, D. S. Su, E. J. Sorensen and S. J. Danishefsky, Angew.
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Winssinger, J. Pastor, S. Ninkovic, F. Sarabia, Y. He, D. Vourloumis,
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(i) D. Schinzer, A. Limberg, A. Bauer, O. M. Bohm and M. Cordes,
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Y. He, D. Vourloumis, H. Vallberg, F. Roschangar, F. Sarabia, S.
Ninkovic, Z. Yang and J. I. Trujillo, J. Am. Chem. Soc., 1997, 119,
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3 For recent analog syntheses, see: (a) D. Schinzer, E. Bourguet and S.
Ducki, Chem. Eur. J., 2004, 10, 3217; (b) D. Schinzer, O. M. Bohm,
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+
427, 147, 133, 89 [100%, CH2OCH2CH2OCH3 ], 73, 59; CI-MS:
m/z 561 [(M + H)+], 485 [(M + H − HOCH2CH2OCH3)+],
353 [(M + H − HOCH2CH2OCH3 − HOSi(CH3)2C(CH3)3)+],
+
221, 89 [100%, CH2OCH2CH2OCH3 ]; HRMS-CI: (M + H)
561.4008 (actual), 561.4007 (calcd).
4-(((1E,3S,5Z,10S,11R)-11,12-Bis(tert-butyldimethylsilyloxy)-
3-(2-methoxyethoxymethoxy)-2,10-dimethyldodeca-1,5-dienyl)-
2-methylthiazole, C34H65O5SNSi2, 55
Procedure similar to that for 39, providing the coupled olefin 55
in 83% yield. dH(300 MHz; CDCl3; Me4Si) 6.92 (1 H, s), 6.48
(1 H, s), 5.40 (2 H, ddd, J 6.9, 12.2 and 18.7), 4.71 (1 H, d. J
6.9), 4.63 (1 H, d, J 6.9), 4.12 (1 H, t, J 6.8), 3.78–3.86 (1 H,
m), 3.52–3.63 (4 H, m), 3.45–3.47 (2 H, m), 3.37 (3 H, s), 2.69
(3 H, s), 2.30–2.46 (2 H, m), 1.94–2.05 (5 H, m), 1.58–1.63 (1
H, m), 1.07–1.43 (4 H, m), 0.87 (9 H, s), 0.86 (9 H, s), 0.79 (3
H, d, J 6.9), 0.03 (6 H, s), 0.02 (6 H, s); dC(75.5 MHz; CDCl3;
Me4Si) 164.5, 152.8, 138.4, 132.0, 125.2, 121.5, 115.9, 92.7, 81.7,
75.8, 71.8, 67.0, 65.3, 59.0, 35.2, 33.4, 31.9, 27.8, 27.7, 26.0,
25.9, 19.2, 18.4, 18.2, 13.8, 13.4, −4.0, −4.8, −5.3, −5.4; ESI:
m/z 656, 678 [Na adduct]; HRMS-ESI: (Na adduct) 656.4202
(actual), 656.4200 (calcd).
4-((1E,3S,5Z,10S)-3-(2-Methoxyethoxymethoxy)-2,10-
dimethyl-11-oxoundeca-1,5-dienyl)-2-methylthiazole,
C21H33O4NS, 3
The silyl ether 55 (0.5 g, 0.7 mmol) was dissolved in 2.0 mL of
THF, and 0.5 mL of AcOH and 0.5 mL of H2O were added
to the reaction mixture. After the completion of the reaction
as indicated by TLC, the reaction mixture was concentrated
in vacuo and worked up with ether and water. The combined
organic layers were dried (MgSO4), and concentrated under
reduced pressure. The crude diol OH-55 was utilized for the
next step without further purification. The diol OH-55 was
dissolved in benzene (4.0 mL) and stirred at 25 ◦C. Pb(OAc)4
(0.7 g, 1.5 mmol) was added to the reaction mixture and stirred
for 20 min. After the completion of the reaction as indicated
by TLC, the reaction mixture was worked up with ether and
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4
3 8 2 3

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28 Contribution #38 from the Herbert C. Brown Center for Borane
Research.
3 8 2 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 1 2 – 3 8 2 4