Short diastereoselective synthesis of the C1-C13 (AB Spiroacetal) and C17-C28 fragments (CD spiroacetal) of spongistatin 1 and 2 through double chain-elongation reactions

Article abstract of DOI:10.1002/chem.201002204

A unique and practical synthetic sequence for rapid access to polyketides and to further the spiroacetals derived from them, which utilizes a bidirectional Hosomi-Sakurai allylation approach around key allylsilanes in the synthesis of the AB and CD ring s

Full text of DOI:10.1002/chem.201002204

DOI: 10.1002/chem.201002204
Short Diastereoselective Synthesis of the C1–C13 (AB Spiroacetal) and C17–
C28 Fragments (CD Spiroacetal) of Spongistatin 1 and 2 through Double
Chain-Elongation Reactions
Christopher L. Flowers and Pierre Vogel*[a]
Abstract: A unique and practical synthetic sequence for rapid access to poly-
ketides and to further the spiroacetals derived from them, which utilizes a bidirec-
tional Hosomi–Sakurai allylation approach around key allylsilanes in the synthesis
of the AB and CD ring systems of spongistatin 1 and 2, is reported. The synthesis
of the AB spiroacetal 9 requires 13 steps, with a longest linear sequence of seven
steps in an overall yield of 27%. The synthesis of the CD spiroacetal 13 requires
15 steps, with a longest linear sequence of 11 steps in an overall yield of 30%.
Both syntheses start from but-3-enol.
Keywords: double chain elonga-
tion · enantioselectivity · Hosomi–
Sakurai reaction · spiro compounds ·
spongistatin
Introduction
Spiroacetals, and in particular their 6,6-congeners, are key
structural elements of a variety of natural products of bio-
logical interest, for example, marine macrolides, ionophores
and polyether antibiotics.[1] The spiroacetal fragments are
often very important for the biological activity of the com-
pounds containing them. In particular, spongistatins (alto-
hyrtins, for example, 1–5), which were isolated from marine
sponges of the genus Spongia by three research groups in
1993,[2] display two highly oxygenated 6,6-spiroacetals in
their macrolactone skeleton (Figure 1). These marine mac-
rolides are potent cancer cell growth inhibitors and thus rep-
resent promising leads for the development of new anti-
cancer agents.[3,4]
In addition to seminal reports by the groups of Evans,[5]
Kishi,[6] Paterson,[7] Smith,[8] Crimmins,[9] Heathcock,[10] and
Ley[11] on the total syntheses of spongistatins 1 and 2, much
effort has been devoted to the implementation of straight-
forward and high-yielding pathways towards the ABCD
“northern” hemisphere[12] and the EF tetrahydropyran subu-
nits.[13] Our group has presented an early synthesis of the
[a] Dr. C. L. Flowers, Prof. Dr. P. Vogel
Laboratory of Glycochemistry and Asymmetric Synthesis (LGSA)
Swiss Institute of Technology (EPFL), Batochime
1015 Lausanne (Switzerland)
E-mail: pierre.vogel@epfl.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002204.
Figure 1. Representative members of the spongistatin (altohyrtin) family.
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FULL PAPER
C29–C51 fragments of spongistatin 1[14] and has developed a
noniterative approach to the asymmetric synthesis of fif-
teen-carbon polyketides, including advanced precursors of
AB[15] and CD[16] spiroacetals of spongistatin 1–3 starting
from 2,2’-methylidenedifuran.[17] Because of their limited
supply from nature[18] any clinical evaluation of spongistatins
must rely upon synthetic sources. Gram-scale synthesis of 1
and 3 is now a major priority, the group of Heathcock[19]
and, more recently, the group of Smith[20] have made sub-
stantial progresses toward this objective.[21] We disclose here
our efforts to realize quicker and more efficient access to
polyketides and to further the 6,6-spiroacetals (1,7-
provided an efficient means of masking one of the two bis-
allylating functionalities to circumvent concurrent and prob-
lematic hydrogen–ene reactions.[28]
CD spiroacetal: As common to most C17–C28 CD spiroace-
tal syntheses, our retrosynthesis identifies key acyclic precur-
sor 14 as the desired intermediate to the CD spiroacetal 13,
which upon ozonolysis and under kinetically controlled cyc-
lization conditions[29] should provide the required partially
anomerically stabilized spiroacetal. Accordingly, fragment
14 could be generated through two consecutive Hosomi–Sa-
kurai reactions by using optimized substrate/Lewis acid con-
ditions to set up the required polyketide precursor 14 rapid-
ly in a double elongation reaction sequence. Pivotal to this
approach was the use of a core bis-allyl silane 7[24] that pro-
vided an efficient means to the definition of the required
stereogenic centers at C4 and C8 in the carbon-forming
steps when amalgamated with known aldehydes 15[30] and
16[31] (Scheme 2).
dioxaspiroACHTUNGTRENNUNG[5,5]undecanes) derived from them. Based on bi-
directional, dissymmetrical double Hosomi–Sakurai allyla-
tions[22] of allylsilanes 6[23] and 7,[24,25] efficient syntheses of
C1–C13 and C17–C28 fragments of 1–3 have been realized
starting from inexpensive but-3-enol (8). C2-Symmetrical
long-chain polyketides have been prepared by Barrett and
co-workers by using a bidirectional symmetrical allylbora-
tion of aldehydes.[26]
Retrosyntheses
AB spiroacetal: The C1–C14 fragment of spongistatin 1 and
2 contains five stereogenic centers arrayed on a 6,6-spiroace-
tal framework. The configuration of the anomeric carbon
C7 of this system corresponds to the thermodynamically fa-
vored diaxial, double anomerically stabilized arrange-
ment.[27] The synthetic strategy adopted to tackle the synthe-
sis of the AB spiroacetal 9 was based upon a bidirectional
dissymmetrical allylation strategy around 2-((trimethylsilyl)-
methyl)allyl acetate (6).
We identified key polyketide precursor 10 as the desired
intermediate, which after ozonolysis and under thermody-
namically controlled cyclization conditions should provide
the required spiroacetal 9. Accordingly, fragment 10 could
be generated through two consecutive allylation reactions
by using optimized substrate/Lewis acid conditions
(Scheme 1). Central to this approach was the use of 6 that
Scheme 2. Retrosynthesis of CD spiroacetal 13.
Owing to the ß-silyl effect[32] (see the intermediate or lim-
iting structure of the transition state 21, Scheme 3) the bis-
silyl allyl reagent 7 was expected to react significantly faster
towards electrophiles, such as aldehyde 17, than the corre-
sponding monoallylsilane 18 that resulted from the sila-ene
reaction (k1 >k2, Scheme 3). Provided that reaction condi-
tions favor the Hosomi–Sakurai reaction over the hydro-
gen–ene reaction (7+17!20), which has been observed for
the reaction of allylsilane 7 with non-oxygen based electro-
philes,[33] this methodology should provide rapid access to
Scheme 3. Hosomi–Sakurai reactions (k1, k2) with (2-((trimethylsilyl)
methyl)allyl) trimethylsilane (7) and the competing hydrogen (ene) reac-
tion (k3). LA: Lewis acid.
Scheme 1. Retrosynthesis of AB spiroacetal 1.
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14075

P. Vogel and C. L. Flowers
polyketide fragments. In their convergent synthesis of polyol
chains, Rychnovsky and co-workers used allylsilane 7 to join
two different 4-acetoxy-1,3-dioxanes, demonstrating that
well-chosen electrophilic partners can lead to the required
chemoselectivities (k1 >k2 @k3).[25]
Results and Discussion
Construction of methyl ketone 11 was initiated with but-3-
enol (8), which was first protected as the benzyl ether fol-
lowed by ozonolysis to give aldehyde 22. A Brown allylation
gave a single enantiomer of the homoallylic alcohol 23 with
an enantiomeric excess (ee) greater than 95%.[7a] Homoal-
lylic alcohol 23 was then transformed to the methyl ketone
11 through a Wacker oxidation by using PdCl2, CuCl, and
oxygen[34] to give the desired product in acceptable yields
(Scheme 4).
Scheme 6. Synthesis of AB spiroacetal 9. Reagents and conditions:
a) SnCl4, 13 h, ꢀ788C, (94%); b) [Pd
2ACHTUNGTNER(NUNG dba)3], bis(pinacolacto)diborane,
DMSO, 16 h, RT, (77%, 4:1); c) O3, DMS, PPTS, DCM, ꢀ788C, (77%).
PPTS: pyridinium paratoluenesulfonate.
cause Allais and Cossy indicated in the case of unprotected
b-hydroxy aldehydes that high levels of 1,3-syn induction
are observed.[12n] This reaction has not yet been mechanisti-
cally investigated but it would appear that it does not occur
through a simple Lewis acid coordination/activation of the
carbonyl, but instead undergoes a transmetallation with the
allylsilane to produce an allyl stannane that is the active al-
lylating reagent. This is reinforced by our observation that
the reaction does not occur when a solution of SnCl4 is
added dropwise to the ketone and the allylsilane, but re-
quires overnight premixing with the allylsilane. The resulting
allyl acetate 26 was transformed and reacted through an in
situ allylboration, developed by Miyaura,[36] with aldehyde
12. The desired 1,3-syn-oxygenated system was formed in a
4:1 ratio with the desired polyol 27 arising from both a
Felkin control model, which was reinforced by 1,5-anti in-
duction.[37]
Scheme 4. Synthesis of methyl ketone 11. Reagents and conditions:
a) BnBr, NaH, THF, TBAI, 16 h, RT, (85%); b) O3, PPh3, DCM, ꢀ788C,
(94%); c) (ipc)2BOMe, allylmagnesium bromide, Et2O, 18 h, then NaOH,
H2O2, 1 h reflux, (98%); d) PdCl2, CuI, O2, DMF/H2O, 3 h, RT, (54%).
IPC: isopinocampheyl.
Assembly of the complementary 3-hydroxyaldehyde 12
commenced with the para-methoxybenzyl (PMB) protection
of 8 to give 24. In a similar manner to the preparation of
methyl ketone 11 (Scheme 4), fragment 25 was elaborated
with a Brown allylation in greater than 95% ee,[35] followed
by tert-butylsilyl (TBS) protection and ozonolysis to give the
desired aldehyde 12 in 58% yield over the five steps
(Scheme 5).
Successful elaboration of polyketide 9 involved a one-pot
ozonolysis/deprotection/cyclization sequence. The cycliza-
tion occurred smoothly under conditions previously used on
similar fragments to give the desired thermodynamic axial,
axial spiroacetal 9 (Scheme 6).[4] The relative configuration
of the latter could be verified through NOE correlation 2D
2-((Trimethylsilyl)methyl)allyl acetate (6)[23] and methyl
ketone 11 were smoothly reacted with SnCl4. The highly ste-
reocontrolled course of this transformation had significant
implications for ensuring the generation of diastereotopical-
ly pure allyl acetate 26 (Scheme 6). SnCl4 was chosen be-
1H NMR. Key NOEs between Hax C5 and Hax C11, Heq
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
C5 and Heq C11, along with H C8 and H C2 confirmed
the relative configuration of the AB spiroacetal. These ob-
servations were in agreement with the literature
(Figure 2).[4]
The synthesis of aldehyde 15 (Scheme 2) commenced with
but-3-enol (8), which was first TBS protected, then the ter-
minal olefin was exposed to ozone followed by reductive
workup, and the resulting aldehyde 28 was asymmetrically
allylated in 98% ee[7b] by applying conditions developed by
Brown.[38] The homoallylic alcohol 29 was protected as the
PMB ether 30 and the desired aldehyde 15 was obtained
through ozonolysis (five steps, 60% yield), with purifications
Scheme 5. Synthesis of aldehyde 12. Reagents and conditions: a) PMBCl,
NaH, THF, TBAI, 16 h, RT, (88%); b) O3, PPh3, DCM, ꢀ788C, (87%);
c) (ipc)2BOMe, allylmagnesium bromide, Et2O, 18 h, then NaOH, H2O2
1 h reflux, (96%); d) TBSCl, imidazole, DMF, RT, (91%); e) O3, PPh3,
DCM, ꢀ788C, (87%).
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Double Chain-Elongation Reactions
FULL PAPER
1
Figure 2. Diagnostic H NMR NOEs in AB spiroacetal 9.
required only for the allyl alcohol 29 and aldehyde 15
(Scheme 7).
Scheme 9. Synthesis of CD spiroacetal 13. Reagents and conditions:
a) 1 equiv. MgBr2·OEt2, CH2Cl2, 1 h, ꢀ788C, (97%); b) MeI, NaH, THF,
08C, (87%); c) 1equiv. BF3·OEt2, CH2Cl2, 1 h, ꢀ788C, (84%); d) TBSCl,
imidazole, CH2Cl2, 3 d, RT, (91%); e) O3, Me2S, CH2Cl2, ꢀ788C, (91%);
f) DDQ, CH2Cl2, 08C, (72%). DDQ: dichlorodicyanobenzoquinone.
substitution at C2 of the allylsilane, after the second reac-
tion in which Felkin-inducing conditions were used to form
the 1,3-syn relationship by using BF3·OEt2.[37b] With this ad-
vanced polyketide 14 in hand the final manipulations were
effected. The secondary alcohol was protected under stan-
dard conditions as the TBS silyl ether and ozonolysis of the
olefin moiety afforded ketone 35 in high yields. The final
one-pot deprotection/cyclization sequence was initiated with
5,6-dichloro-2,5-dicyanobenzoquinone and under these mild
conditions the dihydroxyketone spontaneously cyclized to
the desired “non-anomeric” equatorial, axial-spiroacetal 13
(Scheme 9).
Scheme 7. Synthesis of aldehyde 15. Reagents and conditions: a) TBSCl,
imidazole, CH2Cl2, 2 h, RT, (97%); b) O3, Me2S, CH2Cl2, ꢀ788C, (89%);
c) (ipc)2BOMe, allylmagnesium bromide, Et2O, 18 h, then NaOH, H2O2,
1 h, reflux, (86%); d) NaH, PMBCl, DMF, 16 h, 08C, (84%); e) O3, PPh3,
CH2Cl2, ꢀ788C, (96%).
Aldehyde 16 was readily accessed through a standard pro-
cedure developed by Crimmins and co-workers.[31] (S)-Glyci-
dol 31 was protected as the benzyl ether prior to the epox-
ide being regioselectively opened by the vinyl cuprate gener-
ated from vinyl magnesium bromide. The chiral alcohol 32
was then sequentially PMB protected and reacted with
ozone, which after reductive workup gave the desired alde-
hyde 16 in 51% yield over the five steps (Scheme 8).
The relative configuration of the formed spiroacetal 13
1
was confirmed through H NMR NOE experiments. Critical
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
correlations between H C4 Heq C11, H C2 Heq C11, and
ꢀ
ꢀ
H C4 and H C2 confirmed the proposed relative configura-
tion and structure of 13 (Figure 3).
Scheme 8. Synthesis of aldehyde 16. Reagents and conditions: a) BnBr,
NaH, THF, 18 h, 08C, (90%); b) vinylmagnesium bromide, CuI, ꢀ208C,
20 min (86%); c) PMBCl, NaH, DMF, 08C, (84%); d) O3, Me2S, MeOH,
ꢀ788C, (79%).
With the key aldehyde fragments 15 and 16 in hand, their
union around 7 was investigated (Scheme 9). As expected,[37]
when MgBr2·OEt2 was stirred with the chiral aldehyde 15 in
CH2Cl2 at ꢀ788C, followed by the dropwise addition of bis-
silane 7, the desired allylation product was formed in high
yields as a single observable 1,3-anti diastereomer, as pre-
dicted from a chelating model with an appropriate Lewis
acid. This alcohol was methylated under conditions to pro-
vide key allylsilane 34 ready for a consecutive Hosomi–Sa-
kurai reaction with aldehyde 16. The advantage of this order
of the two successive allylations became clear, with heavy
1
Figure 3. Diagnostic H NMR NOEs in CD spiroacetal 13.
Conclusion
The present route to the C1–C13 AB spiroacetal ring system
9 is concise, convergent and highly stereocontrolled. The
key amalgamation was based around a bis-allyl core system
6 that allowed for an efficient and high yielding convergent
synthesis. Notably, the synthesis used a minimal number of
protecting groups, minimal redox fluctuations, and the qua-
Chem. Eur. J. 2010, 16, 14074 – 14082
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14077

P. Vogel and C. L. Flowers
sired diastereoisomer 27. [a]25859 =ꢀ14.1 (c=0.50, CHCl3); 1H NMR
(400 MHz, CDCl3) of 27 (major): d=7.38–7.30 (m, 5H; H-C(Bn)), 7.29
ternary center was set up in the skeletal carbon-forming re-
action and was not introduced in subsequent steps, as is
often employed in the synthesis of the AB spiroacetals. The
synthetic route to 9 was achieved in 13 steps with a longest
linear sequence of seven steps (overall yield of longest
linear sequence is 27%) from inexpensive but-3-enol (8).
A practical, efficient and highly convergent route has
been opened to the synthesis of the C17–C28 CD spiroacetal
13 of spongistatins in which the pseudo C2 symmetry, in the
terms of the carbon framework and functionality, has been
exploited around a core bis-silane 7 in a novel manner. The
synthetic route to 13 required 14 steps with a longest linear
sequence of 11 steps (overall yield of longest linear se-
quence is 30%), also from 8. The chemistry disclosed here
should be applied to the quick generation of long-chain
polyketides of other natural products and analogues of bio-
logical interest.
(d, 2H, J=8.2; H-C
ACHUTNGTRENNUG(PMB)), 6.89 (d, 2H, J=8.2 Hz; H-CCAHTUNGTRENNUNG
(brs, 1H; HA-C(1’)), 4.89 (brs, 1H; HB-C(1’)), 4.55 (m, 2H; H2-CACHTUNGTRENNUNG
4.44 (m, 2H; H2-C(Bn)), 4.29 (m, 1H; H-C(11)), 4.19 (m, 1H; H-C(3)),
4.09 (m, 1H; H-C(9)), 3.94 (brs, 1H; OH), 3.80 (brs, 1H; OH), 3.82 (s,
3H; MeO
(C13)), 2.40–2.20 (m, 4H; H2-C(6) and H2-C(8)), 1.93–1.76 (m, 4H; H2-
C(2) and H2-C(12)), 1.72–1.51 (m, 4H; H2-C(4) and H2-C(10)), 1.32 (s,
ACHTUNGTRENN(GNU PMB)), 3.75–3.69 (m, 3H; H2-C(1), OH), 3.51 (m, 2H; H2-C-
AHCTUNGTRENNUNG
3H; Me-C(5)), 0.90 (s, 9H; H-CACTHNUTRGENNG(U TBS)), 0.12 ppm (2ꢁs, 6H; H-CACHTUNGTRENNUNG(TBS));
13C NMR (100.6 MHz, CDCl3): d=146.3 (s, Carom), 143.7 (s, C(7)), 138.5
(s, Carom), 130.3 (s, Carom), 129.4, 129.3, 128.5, 127.7 (4d, Carom), 117.6 (t, C-
AHCTUNRTGENNG(UN 1’’)), 113.8 (d, Carom), 74.1 (s, C(5)), 73.1 (t, CH2-(Bn)), 72.7 (t, CH2-
(PMB)), 69.6 (d, CH-C(11)), 69.2 (d, CH-C(9)), 69.0 (d, CH-C(3)), 67.7
(t, CH2-C(1)), 66.4 (t, CH2-C(13)), 55.3 (q, CH3-(PMB)), 48.9 (t, CH2-
C(6)), 48.8 (t, CH2-C(8)), 45.4 (t, CH2-C(4)), 42.7 (t, CH2-C(10)), 37.5 (t,
CH2-C(2)), 37.5 (t, CH2-C(12)), 30.8 (s, C-(TBS)), 30.3 (q, CH3-C(1’)),
25.9 (q, CH3-(TBS)), ꢀ4.4 ppm (q, CH3-(TBS)); IR (film): n˜ =3402, 3050,
2927, 2855, 1708, 1512, 1371, 1246, 1088, 1034, 834, 731 cmꢀ1; HRMS
(MALDI): calcd for C36H59O7Si: 631.3952 [M+H]; found: 631.3943.
Synthesis of (2S,4S,6R,8S,10S)-2-(2-(benzyloxy)ethyl)-8-(2-(4-methoxy-
benzyloxy)ethyl)-4-methyl-1,7-dioxaspiro
G
(AB
spiroacetal 9): O3 was bubbled through a solution of a 4:1 mixture of
27:27’ (0.040 g, 0.077 mmol) in CH2Cl2 (5 mL) at ꢀ788C until the solution
was saturated (10 min), which was indicated by the solution turning blue.
The ozone generator was then turned off and O2 was bubbled through
the mixture for 10 min. The reaction was flushed with Ar and Me2S
(0.2 mL) was added dropwise at ꢀ788C. After stirring for 1 h at this tem-
perature the mixture was warmed to 258C and stirred for 1 h. The solvent
was removed under reduced pressure and the resulting oil suspension
was dissolved in CH2Cl2 (5 mL) and pyridinium p-toluenesulfonate
(2 mg, cat.) was added and the reaction was stirred for 16 h. The reaction
mixture was quenched with H2O (5 mL) and extracted with EtOAc (3ꢁ
10 mL). The combined organic phases were dried (MgSO4), filtered, and
evaporated under reduced pressure. The crude residue was purified by
column chromatography (petroleum ether/Et2O, 8:2) to give 9 (0.030 g,
Experimental Section
General methods
The general methods are described in the Supporting Information.
Synthesis of C1–C13 AB spiroacetal
Synthesis of (4R,6S)-8-(benzyloxy)-4,6-dihydroxy-4-methyl-2-methylene-
1-octyl acetate (26): SnCl4 (1.45 mL, 3.22 g, 12.37 mmol) was added drop-
wise to a solution of 2-((trimethylsilyl)methyl)allyl acetate (6, 2.63 mL,
2.32 g, 12.37 mmol) in CH2Cl2 (30 mL) and the solution was stirred at
258C for 12 h. The solution was transferred by a canula to a round-
bottom flask containing a solution of (4S)-6-(benzyloxy)-4-hydroxyhex-
an-2-one (11, 2.5 g, 11.25 mmol) in CH2Cl2 (10 mL) at ꢀ788C. The mix-
ture was allowed to stir for 1 h. The mixture was quenched with MeOH
(2 mL), saturated aqueous NH4Cl solution (5 mL), and extracted with
CH2Cl2 (3ꢁ20 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was puri-
77%) as
a
colorless oil. [a]52859 =ꢀ30.3 (c=0.88, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.38–7.25 (m, 5H; H-C(Bn)), 7.24 (d, 2H, J=8.2;
H-C
J=12.2 Hz; H2-C
C(10)), 4.19–4.12 (m, 1H; H-C(8)), 4.12–4.03 (m, 3H; H-C(2) and H-
OC(10) and H-OC(4)), 3.78 (s, 3H; MeO(PMB)), 3.56 (brt, 2H; J=
6.9 Hz, H-C(2’)), 3.55 (brt, 2H; J=6.5 Hz; H-C(2’’)), 2.03–1.75 (m, 8H;
Hax-C(3), HA-C(1’), A-C(1’’), Heq-C(5), Hax-C(9)), Heq-C(3), Heq-C(11),
and Hax-C(5)), 1.74–1.66 (m, 2H; HB-C(1’) and HB-C(1’’)), 1.56–1.50 (m,
A
ACHTUNGTNER(NUNG PMB)), 4.48 and 4.41 (2ꢁd, 2H;
AHCTUNGTRENNUNG
fied by flash chromatography (petroleum ether/AcOEt, 8:2) to give 26
25
(3.42 g, 94%) as a colorless oil. [a] =ꢀ8.5 (c=1.93, CHCl3); 1H NMR
589
AHCTUNGTRENNUNG
(400 MHz, CDCl3): d=7.40–7.30 (m, 5H: H-C(Bn)), 5.18 (brs, 1H; HA-
C(1’)), 4.98 (brs, 1H; HB-C(1’)), 4.88 (s, 2H; H2-C(1)), 4.55 (s, 2H; H2-
C(Bn)), 4.29 (brdtt, 1H, J=2.5, 8.5 Hz: H-C(6)), 3.91 (brs, 1H; OH),
3.75–3.69 (m, 3H; H2-C(8) and OH), 2.25 (s, 2H; H2-C(3)), 2.13 (s, 3H;
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
1H; Heq-C(9)), 1.49–1.45 (m, 1H; Hax-C(11)), 1.31 ppm (s, 3H; Me(C4));
13C NMR (100.6 MHz, CDCl3): d=158.3 (s, Carom), 138.3 (s, Carom), 136.5
(quat, Carom), 129.3, 128.3, 127.9, 127.6, 127.7 (5ꢁd, Carom), 113.7 (s, Carom),
96.5 (s, spiroacetal-C(6)), 73.1 (t, CH2-(Bn)), 72.7 (t, CH2-(PMB)), 67.5
(s, C(4)), 68.1 (t, CH2-C(2’)), 67.4 (t, CH2-CACTHNUTRGNE(UNG 2’’)), 66.1 (d, CH-C(10)),
64.9 (d, CH-C(2)), 62.1 (d, CH-C(8)), 55.2 (q, CH3-(PMB)), 39.7 (t, CH2-
C(3)), 38.0 (t, CH2-C(9)), 36.0 (t, CH2-C(5)), 35.5 (t, CH2-C(11)), 31.9 (t,
H3-C
Me-C(4)); 13C NMR (100.6 MHz, CDCl3): d=186.7 (s, C-(Ac)), 140.8 (s,
C(2)), 138.5 (s, Carom), 128.5, 127.8 (2d, Carom), 112.9 (t, CH2-C(1’’)), 73.4
ACHTUNGTRENNUNG(OAc)), 1.80–1.60 (m, 4H; H2-C(7) and H2-C(5)), 1.32 ppm (s, 3H;
AHCTUNGTRENNUNG
(t, CH2-(Bn)), 72.7 (s, C-C(4)), 69.1 (d, CH-C(6)), 68.8 (t, CH2-C(1)),
67.5 (t, CH2-C(8)), 47.7 (t, CH2-C(5)), 46.0 (t, CH2-C(3)), 37.2 (t, CH2-
C(7)), 26.3 (q, CH3-C(1’)), 21.0 ppm (q, CH3-(Ac)); IR (film): n˜ =3410,
3050, 2941, 1735, 1503, 1368, 1244, 1111, 1034, 735, 631 cmꢀ1; HRMS
(MALDI): calcd for C19H30O5 338.9937: [M+H]; found: 338.9939.
CH2-C
ACHTUNGTERNU(GNN 2’’)), 29.7 (t, CH2-CACHTUNRTGEGN(NNU 1’’)), 22.9 ppm (q, CH3-CACHTNUGRTEN(NUGN 1’’’)); IR (film): n˜ =
3402, 3050, 2927, 2855, 1624, 1589, 1571, 1246, 1088, 1034, 834, 731 cmꢀ1
;
Synthesis of a 4:1 mixture of (3S,5R,9R,11S)-1-(benzyloxy)-11-((tert-bu-
tyl)dimethylsilyloxy)-13-(4-methoxybenzyloxy)-5-methyl-7-methylenetri-
decane-3,5,9-triol (27) and (3S,5R,9S,11S)-1-(benzyloxy)-11-((tert-butyl)-
dimethylsilyloxy)-13-(4-methoxybenzyloxy)-5-methyl-7-methylenetride-
HRMS (MALDI): calcd for C29H41O7: 501.2574 [M+H]; found: 501.2583.
Synthesis of C17–C28 CD spiroacetal
Synthesis of (4R,6R)-8-((tert-butyl)dimethylsilyloxy)-6-(4-methoxybenzyl-
oxy)-2-((trimethylsilyl)methyl)oct-1-en-4-ol: Solid MgBr2·OEt2 (0.36 g,
1.41 mmol) was added portion-wise to a stirred mixture of (R)-5-(tert-bu-
cane-3,5,9-triol (27’): [Pd2ACHTUNGTENR(NUG dba)3] (0.022 g, 0.024 mmol, 4 mol%), 12
(0.251 g, 0.713 mmol), DMSO (10 mL), and 26 (0.200 g, 0.594 mmol)
were sequentially added to a round-bottomed flask and the resulting mix-
ture was mixed for 10 min at 258C. Bis(pinacolato)diboran (Miyauraꢂs re-
agent) (0.151 g, 0.594 mmol) was added portion-wise to this mixture. The
resulting greenish solution was stirred at 258C for 16 h. It was quenched
with H2O (5 mL) and stirred for 30 min. Et2O (20 mL) was added and
the organic phase was washed with brine (5ꢁ10 mL). The organic layer
was dried (Na2SO4), filtered, and evaporated under vacuum. The residue
was purified by flash chromatography (petroleum ether/Et2O, 1:1) to give
0.290 g (77%) as a colorless oil, which was a 4:1 mixture favoring the de-
tyldimethylsilyloxy)-3-(4-methoxybenzyloxy)pentanal
(15)
(0.50 g,
1.41 mmol) and 7[24b] (0.284 g, 1.41 mmol) at ꢀ788C in CH2Cl2 (100 mL).
The reaction was stirred at ꢀ788C for 1 h before being quenched with a
saturated aqueous solution of NH4Cl (50 mL) and allowed to warm to
258C. The reaction was diluted with Et2O (100 mL) and the aqueous
phase was extracted with Et2O (50 mL). The combined organic phases
were washed with brine (100 mL), dried (MgSO4), and evaporated. The
crude residue was purified by column chromatography (petroleum ether/
Et2O, 8:2) to give the product (2.10 g, 97%) of as a colorless oil. [a]52859
=
14078
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 14074 – 14082

Double Chain-Elongation Reactions
FULL PAPER
10.2 (c=0.17, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.27 (d, 2H, J=
7.3 Hz; 2ꢁH-C
J=7.3 Hz; H-C
C(1’)), 4.63 (2d, 2H, J=11.3 Hz; H2-C
H2-C(PMB)), 4.58 (s, 2H; H2-C(Bn)), 4.01 (m, 1H; H-C(2)), 3.94 (m,
1H; H-C(4)), 3.81 (2ꢁs, 6H; MeO(PMB) and MeO(PMB)), 3.75 (m,
G
ACHTUNGTREN(NUGN PMB)), 6.88 (d, 2H,
8.7 Hz; H-C
HA-C(1)), 4.67 (brs, 1H; HB-C(1)), 4.52 (s, 2H; H2-C
1H; H-C(6)), 3.90 (dt, 1H, J=6.8, 10.0 Hz; H-C(4)), 3.80 (s, 3H; MeO-
(PMB)), 3.73 (m, 2H; H2-C(8)), 2.10 (dddd, 2H, J=4.7, 5.5, 14.0 Hz;
A
U
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1H; H-C(8)), 3.75 (m, 2H; H2-C(1)), 3.60 (m, 1H; H-C(10)), 3.59 (m,
2H; H2-C(12)), 3.26 (s, 3H; MeO-C(8)), 2.43–2.27 (m, 1H; HA-C(5)),
2.26–2.08 (m, 3H; HB-C(5) and H2-C(11)), 1.90–1.50 (m, 6H; H2-C(9)
H2C(3)), 1.87 (ddd, 1H, J=6.3, 13.0 Hz; HA-C(7)), 1.74 (ddd, 1H, J=6.3,
13.3 Hz; HB-C(7)), 1.66 (m, 2H; H2-C(5)), 1.54 (s, 2H; H2C(1’)), 0.90 (s,
9H; H-C
13C NMR (100.6 MHz, CDCl3): d=144.5 (s, C(2)), 157.9, 136.8 (2ꢁs,
arom), 129.5, 113.8 (2ꢁd, Carom), 110.0 (t, C(1)), 74.9 (d, C(6)), 71.4 (t,
ACHTUNGTRENNUNG(TBS)), 0.06 (s, 6H; H-CACHTUNRTGENN(GUN TBS)), 0.03 ppm (s, 9H; H-CACHTNUGERTN(NUGN TMS));
and H2-C(7) and H2-C(3), 0.92 (s, 9H, H-C
(TBS)); 13C NMR (100.6 MHz, CDCl3): d=159.6, 159.5, 144.0 (3ꢁs,
arom), 138.7 (s, C(6)), 129.8, 129.6 (2ꢁs, Carom), 129.9, 128.8, 127.9, 114.3,
ACHTUNGTNER(NUNG TBS)), 0.08 ppm (s, 6H, H-C-
AHCTUNGTRENNUNG
C
C
CH2-(PMB)), 64.8 (d, C(4)), 59.7 (t, C(8)), 55.3 (q, CH3-(PMB)), 46.7 (t,
C(3)), 40.6 (t, C(5)), 37.3 (t, C(7)), 26.7 (t, C(1’)), 25.9 (q, CH3-(TBS)),
18.2 (s, C-(TBS)), ꢀ1.4 (q, CH3-(TMS)), ꢀ5.0 ppm (q, CH3-(TBS)); IR
114.2, 114.2, 114.1 (7ꢁd, Carom), 115.2 (t, C(1’), 77.4 (d, C(8)), 75.6 (d,
C(2)), 73.4 (t, CH2-(PMB)), 73.4 (d, C(10)), 73.2 (t, CH2-(PMB)), 72.4 (t,
CH2-(Bn)), 71.4 (t, C(1)), 66.3 (d, C(4)), 60.0 (t, C(12)), 56.9 (q, OMe),
55.8, 55.7 (2q, CH3-(PMB)), 45.5 (t, C(5)), 40.6 (t, C(7)), 39.5 (t, C(11)),
39.5 (t, C(3)), 38.2 (t, C(9)), 26.4 (q, CH3-(TBS)), 18.7 (s, C-(TBS)),
ꢀ4.9 ppm (q, CH3-(TBS)); IR (film): n˜ =3458, 3050, 2928, 2855,1612,
1513, 1463, 1248,1092, 1036, 835, 631 cmꢀ1; HRMS (MALDI): calcd for
C43H65O8S: 737.4370 [M+H]; found: 737.4371.
(film): n˜ =3452, 3050, 2952, 1556, 1346, 1098, 857, 697, 660, 611, 567 cmꢀ1
;
HRMS (MALDI): calcd for C26H49O4Si2: 481.3091 [M+H]; found:
481.3091.
Synthesis of tert-butyl ((3R,5R)-5-methoxy-3-(4-methoxybenzyloxy)-
7((trimethylsilyl)methyl)oct-7-enyloxy)dimethylsilane (34): NaH (0.110 g,
2.75 mmol) was added portionwise to a solution of (4R,6R)-8-((tert-bu-
tyl)dimethylsilyloxy)-6-(4-methoxybenzyloxy)-2-((trimethylsilyl)methyl)-
oct-1-en-4-ol (0.66 g, 1.37 mmol) and MeI (1.95 g, 13.73 mmol) in THF
(10 mL) at 08C. After stirring at 08C for 1 h the mixture was stirred at
258C for 16 h. The reaction mixture was quenched with dropwise addi-
tion of a saturated aqueous solution of NH4Cl (15 mL) and extracted
with ether (50 mL). The organic layers were washed with brine (20 mL),
dried (MgSO4), filtered, and concentrated. The crude residue was puri-
Synthesis of (2R,4R,8R,10R)-1-(benzyloxy)-4,12-bis((tert-butyl)dimethyl-
silyloxy)-8-methoxy-2,10-bis(4-methoxybenzyloxy)-6-methylenedodecane:
Imidazole (0.028 g, 0.407 mmol) was added to a solution of tert-butyl-di-
methylchlorosilane (0.061 g, 0.407 mmol) in CH2Cl2 (5 mL) at 258C. Al-
cohol 14 (0.200 g, 0.271 mmol) was added dropwise to this mixture. Upon
completion of the addition, the mixture was stirred for 2 h. The mixture
was diluted with Et2O (20 mL) and washed with H2O (3ꢁ10 mL). The
combined organic phase was washed with brine (10 mL), dried (MgSO4),
and evaporated. The crude was purified by column chromatography (pe-
troleum ether/Et2O, 9:1) to give the product (0.210 g, 91%) as a colorless
fied by flash chromatography (petroleum ether/Et2O, 95:5) to give 34
25
(0.590 g, 87%) as a colorless oil. [a] =9.3 (c=0.23, CHCl3); 1H NMR
589
(400 MHz, CDCl3): d=7.28 (d, 2H, J=8.1 Hz; H-C
J=8.1 Hz, H-C(PMB)), 4.64 (brs, 1H; HA-C(8)), 4.59 (brs, 1H; HB-
C(8)), 4.50 (2ꢁd, 2H; J=11.1 Hz; H2-C(PMB)), 3.80 (s, 3H; MeO-
(PMB)), 3.72 (m, 1H; H-C(5)), 3.72 (m, 2H; H2-C(1)), 3.51 (m, 1H; H-
ACHTUNGTREN(NUGN PMB)), 6.88 (d, 2H;
oil. [a] =10.3 (c=0.34, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.35–
25
589
ACHTUNGTRENNUNG
7.30 (m, 5H; H-C(Bn)), 7.26 (2ꢁd, 4H; J=8.4 Hz, 2ꢁH-C
(2ꢁd, 4H, J=8.4 Hz; 2ꢁH-C(PMB)), 4.82 (brs, 2H; HA-C(1’) and HB-
C(1’)), 4.55 (s, 2H; H2-C(Bn)), 4.49 (2ꢁd, 2H, J=12.0 Hz; H2-C(PMB)),
4.44 (2ꢁd, 2H, J=11.0 Hz; H2-C(PMB)), 4.07 (m, 1H; H-C(2)), 3.80 (m,
1H; H-C(4)), 3.80 (s, 3H; MeO(PMB)), 3.79 (s, 3H; MeO(PMB)), 3.75
ACHTUNGTRENUN(NG PMB)), 6.86
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
C(3)), 3.27 (s, 3H; MeO-C(5)), 2.31 (dd, 1H, J=6.4, 14.0 Hz; HA-C(6)),
1.97 (dd, 1H, J=7.0, 14.0 Hz; HB-C(6)), 1.74 (m, 2H; H2-C(2)), 1.76 (m,
1H; HA-C(4)), 1.53 (m, 1H; HB-C(4)), 1.55 (s, 2H; H2-C(1’)), 0.91 (s,
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(m, 1H; H-C(8)), 3.75 (m, 2H; H2-C(1)), 3.62 (m, 1H; H-C(10)), 3.59
(m, 2H; H2-C(12)), 3.22 (s, 3H; MeO(C8)), 2.40–2.25 (m, 2H; H2-C(7)),
2.20–1.93 (m, 2H; H2-C(11)), 1.84–1.62 (m, 4H; H2-C(9) and H2-C(5)),
9H; H-C
13C NMR (100.6 MHz, CDCl3): d=144.6 (s, C-(7)), 156.9, 132.2 (2ꢁs,
arom), 129.5, 113.8 (2ꢁd, Carom), 109.3 (t, C(8)), 88.2 (d, C(5)), 73.9 (d,
ACHTUNGTRENNUNG(TBS)), 0.06 (s, 6H; H-CACHTUNRTGENN(GUN TBS)), 0.03 ppm (s, 9H; H-CACHTNUGERTN(NUGN TMS));
C
1.54–1.41 (m, 2H; H2-C(3)), 0.92 (s, 9H; H-C
ACHTUNGTRENNUNG
C(3)), 71.3 (t, CH2-(PMB)), 64.8 (t, C(1)), 59.6 (q, OMe), 55.2 (q, CH3-
(PMB)), 46.7 (t, C(6)), 40.6 (t, C(4)), 35.7 (t, C(2)), 26.7 (t, CH2-C(1’)),
25.8 (q, CH3-(TBS)), 18.2 (s, C-(TBS)), ꢀ1.4 (q, CH3-(TMS)), ꢀ5.3 ppm
(q, CH3-(TBS)); IR (film): n˜ =3050, 2927, 2855,1729, 1513, 1463, 1361,
1247, 1093, 835, 633 cmꢀ1; HRMS (MALDI): calcd for C27H51O4Si2:
95.3247 [M+H]; found: 495.3258.
A
U
(100.6 MHz, CDCl3): d=159.0, 158.9, (2ꢁs, Carom), 138.4 (s, C(6)), 129.4,
129.3, 129.2 (3ꢁs, Carom), 128.9, 128.3, 128.1, 127.6, 127.5, 113.7, 113.6 (7ꢁ
d, Carom) 115.2 (t, C(1’)), 76.4 (d, C(8)), 76.2 (d, C(2)), 75.2 (d, C(10)),
73.5 (t, CH2-(PMB)), 73.2 (t, CH2-(PMB)), 72.8 (t, CH2-(Bn)), 72.7 (t,
C(1)), 68.0 (d, C(4)), 59.7 (t, C(12)), 56.4 (q, OMe), 55.2, 55.2 (2q, CH3-
(PMB)), 45.1 (t, C(5)), 40.7 (t, C(7)), 40.6 (t, C(11)), 39.8 (t, C(3)), 37.9
(t, C(9)), 26.0 (q, CH3-(TBS)), 25.6 (q, CH3-(TBS)), 18.3 (s, C-(TBS)),
18.0 (s, C-(TBS)), ꢀ4.5 (q, CH3-(TBS)), ꢀ5.3 ppm (q, CH3-(TBS)); IR
(film): n˜ =3050, 2951, 2927, 2855, 1613, 1514, 1463, 1248, 1092, 1039, 834,
774, 632, 541 cmꢀ1; HRMS (MALDI): calcd for C49H79O8Si: 851.5835
[M+H]; found: 851.5842.
Synthesis of (2R,4R,8R,10R)-1-(benzyloxy)-12-((tert-butyl)dimethylsilyl-
ACHTUNGTRENNUNGoxy)-8-methoxy-2,10-bis(4-methoxybenzyloxy)-6-methylenedodecan-4-ol
(14):
Method A: BF3·OEt2 (0.267 g, 0.380 mL, 0.808 mmol) was added drop-
wise to a stirred solution of 16[31, 47] (0.305 g, 0.970 mmol) and allyl silane
34 (0.400 g, 0.808 mmol) at ꢀ788C in CH2Cl2 (50 mL). The mixture was
stirred at ꢀ788C for 1 h before being quenched with a saturated aqueous
solution of NH4Cl (20 mL) and allowed to warm to 258C. The mixture
was diluted with Et2O (100 mL) and the aqueous phase was extracted
with Et2O (50 mL). The combined organic phases were washed with
brine (50 mL), dried (MgSO4), and evaporated. The crude residue was
Synthesis of (2R,4R,8R,10R)-1-(benzyloxy)-4,12-bis((tert-butyl)dimethyl-
silyloxy)-8-methoxy-2,10-bis(4-methoxybenzyloxy)-6-methylenedodecan-
6-one (35): O3 was bubbled through a solution of the olefin obtained
above (0.210 g, 0.285 mmol) in CH2Cl2 (6 mL) at ꢀ788C until the solu-
tion was saturated (5 min), which was indicated by the solution turning
blue. The ozone generator was then turned off and O2 was bubbled
through the solution for 10 min. The reaction was flushed with Ar and
Me2S (0.50 mL) was added dropwise at ꢀ788C. After stirring for 1 h at
this temperature the reaction was warmed to 258C and stirred for 1 h.
The solvent was removed under reduced pressure. The crude was purified
by column chromatography (petroleum ether/Et2O, 9:1) to give 35
purified by column chromatography (petroleum ether/Et2O, 8:2) to give
25
589
14 (0.502 g, 84%) as a colorless oil. [a] =14.2 (c=0.23, CHCl3).
Method
B:
3,5-Bis(trifluoromethyl)phenylboronic
acid
(11 mg,
0.004 mmol) was added to a solution of mono(2,6-diisopropoxybenzoyl)
tartrate (16 mg, 0.044 mmol) in dry propionitrile (1 mL) at 258C and the
mixture was stirred for 30 min. The mixture cooled to ꢀ788C. Aldehyde
16 (0.070 g, 0.222 mmol) and allyltrimethylsilane 34 (0.110 g, 0.222 mmol)
were added to this solution. After being stirred for 12 h, the reaction mix-
ture was poured into brine (5 mL) and extracted with Et2O (5 mL, 3
times), dried (MgSO4), and concentrated. The crude residue was purified
(0.192 g, 91%) as s colorless oil. [a] =8.4 (c=0.2, CHCl3); 1H NMR
25
589
(400 MHz, CDCl3): d=7.38–7.33 (m, 5H; H-C(Bn)), 7.29 (d, 2H, J=
7.7 Hz; H-C
J=7.7 Hz; H-C
H2-C(Bn)), 4.67–4.35 (m, 4H, 2ꢁH2-C
(2ꢁs, 6H; 2ꢁMeO(PMB)), 3.72 (m, 1H; H-C(8)), 3.71 (m, 1H; H-C(4)),
3.71 (m, 2H, H2-C(1)), 3.70 (m, 2H; H2-C(12)), 3.55 (m, 1H; H-C(10)),
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
by column chromatography (petroleum ether/Et2O, 9:1) to give 14
AHCTUNGTRENNUNG
25
(0.121 g, 74%) as a colorless oil. [a] =16.1 (c=0.30, CHCl3); 1H NMR
ACHTUNGTRENNUNG
589
(400 MHz, CDCl3): d=7.38–7.30 (m, 5H; H-C(Bn)), 7.29 (2ꢁd, 4H, J=
Chem. Eur. J. 2010, 16, 14074 – 14082
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14079

P. Vogel and C. L. Flowers
3.25 (s, 3H; MeO(C8)), 2.71–2.53 (m, 3H; H2-C(7) and HA-C(5)), 2.51–
2.41 (m, 1H; HB-C(5)), 1.90–1.77 (m, 2H; H2-C(11)), 1.77–1.68 (m, 2H;
Hill, A. Sutherland, Nat. Prod. Rep. 2009, 26, 725–728; K. L. Jack-
son, J. A. Henderson, A. J. Phillips, Chem. Rev. 2009, 109, 3044–
3079; T. Pitterna, J. Cassayre, O. F. Hꢃter, P. M. J. Jung; P. Maien-
fisch, F. Murphy Kessabi, L. Quaranta, H. Tobler, Bioorg. Med.
Chem. 2009, 17, 4085–4095; P. Maienfisch, F. Murphy Kessabi, L.
Quaranta, H. Tobler, Bioorg. Med. Chem. 2009, 17, 4085–4095.
[2] a) G. R. Pettit, Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd,
J. M. Schmidt, J. N. A. Hooper, J. Org. Chem. 1993, 58, 1302–1304;
b) G. R. Pettit, Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd, J.
Chem. Soc. Chem. Commun. 1993, 1166–1168; c) M. Kobayashi, S.
Aoki, H. Sakai, K. Kawazoe, N. Kihara, T. Sasaki, I. Kitagawa, Tet-
rahedron Lett. 1993, 34, 2795–2798; d) M. Kobayashi, S. Aoki, H.
Sakai, N. Kihara, T. Sasaki, I. Kitagawa, Chem. Pharm. Bull. 1993,
41, 989–991; e) M. Kobayashi, S. Aoki, I. Kitagawa, Tetrahedron
Lett. 1994, 35, 1243–1246; f) M. Kobayashi, S. Aoki, K. Gato, I. Ki-
tagawa, Chem. Pharm. Bull. 1996, 44, 2142–2149; g) N. Fusetani, K.
Shinoda, S. Matsunaga, J. Am. Chem. Soc. 1993, 115, 3977–3981.
[3] a) R. K. Pettit, S. C. Mc Allister, G. R. Pettit, C. L. Herald, J. M.
Johnson, Z. A. Cichacz, Int. J. Antimicrob. Agents 1998, 1902; b) R.
Bai, Z. A. Cichacz, C. L. Herald, G. R. Pettit, E. Hamel, Mol. Phar-
macol. 1993, 44, 757–766; c) R. Bai, G. F. Taylor, J. M. Schmidt,
M. D. Williams, J. A. Kepler, G. R. Pettit, E. Hamel, Mol. Pharma-
col. 1995, 47, 965–976; d) R. Bai, G. F. Taylor, Z. A. Cichacz, C. L.
Herald, J. A. Kepler, G. R. Pettit, E. Hamel, Biochemistry 1995, 34,
9714–9721; e) R. F. LudueÇa, M. C. Roach, V. Prasad, G. R. Pettit,
C. L. Herald, Drug Dev. Res. 1995, 35, 40–48; f) E. Nogales, M. Wit-
taker, R. A. Milligan, K. H. Downing, Cell 1999, 96, 79–88; g) E.
Nogales, S. G. Wolf, K. H. Downing, Nature 1998, 391, 199- 203;
h) A. S. Rothmeier, I. Ischenko, J. Joore, D. Garczarczyk, R. Fꢃrst,
C. J. Bruns, A. M. Vollmar, S. Zahler, FASEB J. 2009, 23, 1127–
1137.
H2-C(9), 1.68–1.57 (m, 2H; H2-C(3)), 0.91 (s, 9H; H-C
ACHTUNGTRENNUNG
9H; H-C(TBS)), 0.07 (s, 6H; H-C(TBS)), 0.03 ppm (s, 6H; H-CACHTUNGTRENNUNG
A
U
13C NMR (100.6 MHz, CDCl3): d=207.6 (s, C(6)), 159.1, 159.0, 138.3,
131.7, 131.0 (5ꢁs, Carom), 129.7, 129.3, 129.2, 128.4, 127.6, 113.8, 113.6 (7ꢁ
d, Carom), 75.2 (d, C(8)), 75.1 (d, C(10)), 73.3 (t, CH2-(PMB)), 73.0 (d,
C(2)), 72.8 (t, CH2-(PMB)), 71.2 (t, C(1)), 70.7 (t, CH2-(Bn)), 66.3 (d,
C(4)), 59.6 (t, C(12)), 57.1 (q, OMe), 55.2 (q, CH3-(PMB)), 55.2 (q, CH3-
(PMB)), 52.3 (t, C(5)), 49.1 (t, C(7)), 40.6 (t, C(11)), 40.5 (t, C(3)), 37.7
(t, C(9)), 25.9 (q, CH3-(TBS)), 25.8 (q, CH3-(TBS)), 18.3 (s, C-(TBS)),
18.0 (s, C-(TBS)), ꢀ4.6 (q, CH3-(TBS)), ꢀ5.3 ppm (q, CH3-(TBS)); IR
(film): n˜ =3050, 2928, 1698, 1601, 1512, 1249, 1093, 834, 776, 632,
539 cmꢀ1; HRMS (MALDI): calcd for C48H77O9Si2: 853.5128 [M+H];
found: 853.5125.
Synthesis of (2-((2R,4S,6R,8R,10S)-8-(benzyloxymethyl)-4-methoxy-10-
((tert-butyl)dimethylsilyloxy)-2–2-(tert-butyl)dimethylsilyoxy)ethyl)-1,7-
dioxaspiro
ACHTUNGTRENNUNG
1,4-benzoquinone (0.015 g, 0.064 mmol) was added to
a
ketone 35 (0.050 g, 0.059 mmol) in 1:1 CH2Cl2/H2O (5 mL) at 08C. The
solution was stirred for 1 h at 08C before it was allowed to warm to 258C
and stirred for another 1 h. TLC indicated the consumption of the start-
ing material and the mono-deprotection; the reaction mixture was stirred
for 16 h. The solvent was removed under reduced pressure. The crude
residue was purified by column chromatography (petroleum ether/Et2O,
7:3) to give 13 (0.025 g, 72%) as a colorless oil. [a]25859 =ꢀ15.1 (c=0.34,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.38–7.35 (m, 5H; H-C(Bn)),
4.59 (s, 2H; H2-C(Bn)), 4.20 (m, 1H; H-C(8)), 3.89 (m, 1H; H-C(10)),
3.79 (m, 1H; HA-C(2’)), 3.71 (m, 1H; HB-C(2’)), 3.59–3.51 (m, 2H; H-
C(2) and HA-CACHTUNGTRENNUNG(1’’)), 3.50–3.44 (m, 2H; H-C(4) and HB-CACHTUGNTREN(NUGN 1’’)), 3.36 (s,
3H; MeO), 2.29 (dd, 1H, J=3.9, 13.4 Hz; Heq-C(11)), 2.16 (dd, 1H, J=
3.4, 12.0 Hz; Heq-C(5)), 2.06 (dd, 1H, J=3.4, 11.5 Hz; Hax-C(5)), 1.93 (m,
1H; Heq-C(9)) 1.90 (m, 1H; HA-C(1’)), 1.74–1.69 (m, 2H; HB-C(1’) and
Hax-C(9)), 1.40 (m, 1H; Heq-C(3)), 1.39–1.25 (m, 2H; Hax-C(11) and Hax-
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(3)), 0.90 (2ꢁs, 9H; H-C
6H; H-C(TBS)), 0.06 ppm (2ꢁs, 6H; H-C
CDCl3): d=138.4 (s, Carom), 128.3, 127.7, 127.4 (3ꢁd, Carom), 99.7 (s,
spiroC-C(6)), 74.1 (d, C(4)), 73.4 (t, CH2-(Bn)), 72.9 (t, C(1’’)), 68.9 (d,
A
ACHTUNGTREN(NUGN TBS)), 0.07 (2ꢁs,
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
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(TBS)), ꢀ4.5 (q, CH3-(TBS)), ꢀ5.2 ppm (q, CH3-(TBS)); IR (film): n˜ =
3050, 2927, 2825, 1603, 1589, 1513, 1462, 1360, 1247, 1093, 835, 633 cmꢀ1
;
HRMS (MALDI): calcd for C32H59O6Si2: 595.3792 [M+H]; found:
595.3790.
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Acknowledgements
We thank the TEC Top Achievers Grand and the Swiss National Science
Foundation for its generous financial support. We are grateful to Martial
Rey (NMR spectrometry service, ISIC, EPFL), Dr. Laure Menin, and
Francisco Sepulveda (MS service, ISIC, EPFL) for technical help.
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Received: August 1, 2010
Published online: October 20, 2010
14082
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Chem. Eur. J. 2010, 16, 14074 – 14082