Studies toward the synthesis of (-)-zampanolide: Preparation of the macrocyclic core

Article abstract of DOI:10.1002/adsc.200800247

Studies towards the synthesis of the macrocyclic core of (-)-zampanolide are reported. The synthetic approach features a one-pot reduction/vinylogous aldol reaction for construction of the C-15-C-20 fragment, an intramolecular silyl-modified Sakurai (ISMS) reaction for construction of the 2,6-cis-disubstituted exo-methylene pyran subunit, and use of an sp ²-sp³ Stille reaction for macrocyclization.

Full text of DOI:10.1002/adsc.200800247

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DOI: 10.1002/adsc.200800247
Studies toward the Synthesis of (À)-Zampanolide: Preparation of
the Macrocyclic Core
Dawn M. Troast,a Jiayi Yuan,a and John A. Porco Jr.a,*
a
Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
590 Commonwealth Avenue, Boston, MA 02215, USA
Fax : (+1)-617-358-2847; e-mail: porco@bu.edu
Received: April 24, 2008; Published online: July 9, 2008
Dedicated to Prof. Chi-Huey Wong on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Studies towards the synthesis of the macro- disubstituted exo-methylene pyran subunit, and use
cyclic core of (À)-zampanolide are reported. The of an sp2-sp3 Stille reaction for macrocyclization.
synthetic approach features a one-pot reduction/vi-
nylogous aldol reaction for construction of the C-15–
C-20 fragment, an intramolecular silyl-modified Sa- Keywords: allylsilanes; macrolide; exo-methylene
kurai (ISMS) reaction for construction of the 2,6-cis- pyrans; sp2-sp3 coupling; Stille reaction; zampanolide
Introduction
and 2 were found to be opposite, although, as pointed
out by Hoye and coworkers,[3] the propensity of the
The intriguing natural product (À)-zampanolide, aldehyde of 2 to hydrate may affect the accuracy of
(Figure 1, 1) was isolated in 1996 by Tanaka and Higa optical rotation measurements.[3] Regarding biological
from the Okinawan sponge, Fasciospongia rimosa, activity, (À)-zampanolide displayed cytotoxicity
collected off of the coast of Okinawa, Japan.[1] Zam- against P388, HT29, A549, and MEL28 cell lines (IC50
panolide is a 20-membered macrolide which contains 1–5 ng/mL). (+)-Dactylolide showed cytotoxicity
a high degree of unsaturation, a 2,6-disubstituted exo- toward L1210 and SK-OV-3 cell lines (63% and 40%
methylene pyran ring, and a N-acyl hemiaminal side- inhibition at 3.2 mgmLÀ1, respectively).[4]
chain. Both the relative stereochemistry at the C-20
Since the initial isolation and structure elucidation
stereocenter and the absolute stereochemistry were of (À)-zampanolide in 1996, researchers have been
determined via total synthesis in 2001 by Smithꢀs lab- unable to isolate additional amounts of the natural
oratory[2] which was further confirmed by Hoye and product from the Okinawan sponge or any other
Huꢀs synthesis in 2002.[3,4] The related natural product, source. Interest in this biologically interesting com-
(+)-dactylolide (2) was isolated in 2001 by Riccio and pound, as well as its challenging structural architec-
co-workers from the Vanuatu sponge Dactylospongia ture, has sparked a great deal of attention in the syn-
sp.[59 Interestingly, the absolute configurations of 1 thetic organic community. The first syntheses of zam-
panolide and dactylolide were published by Smith
and co-workers in 2001 and 2002, respectively.[2]
These initial reports were followed by Hoye and Huꢀs
syntheses of both molecules in 2003.[3] Other synthe-
ses of dactylolide have been published by Florean-
cig,[6] Keck,[7] Jennings,[8] and McLeod.[9] Our work in
this area was initiated by interest in the N-acyl hemia-
minal side chain and its apparent stabilization through
an intramolecular hydrogen bond network and en-
tailed preparation of a N-acyl hemiaminal model
system.[10] In this paper, we report our studies towards
Figure 1. (À)-Zampanolide and (+)-dactylolide.
the synthesis of the macrocyclic core of (À)-zampano-
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Figure 2. Retrosynthetic analysis.
lide featuring a one-pot reduction/vinylogous aldol re- tion at the ester bond gives the b-stannylacrylic acid
À
action, an intramolecular silyl-modified Sakurai reac- 7. Disconnection at the C-6 C-7 bond provides allylic
tion (ISMS), and use of an sp2-sp3 Stille reaction for acetate 8 and the pyran fragment 9. Pyran 9 may be
construction of the macrocyclic core.
formed using an intramolecular silyl-modified Sakurai
(ISMS)[15] reaction between allyl silane 10 and a,b-un-
saturated aldehyde 11. The C-15–C-20 fragment may
be constructed using a vinylogous aldol reaction[16] be-
tween protected serine derivative 12 and dienol ether
13.
Results and Discussion
Retrosynthetic Analysis
Our retrosynthetic analysis for (À)-zampanolide, (À)-
1 is outlined in Figure 2. The N-acyl hemiaminal side- Synthesis of the C-15–C-20 Fragment
chain may be derived from the protected amino alco-
hol-bearing macrolide 4 and installed at a late stage The vinylogous aldol reaction is an efficient method
using our previously reported oxidative decarboxyla- for formation d-hydroxy-a,b-unsaturated esters which
tion-hydrolysis approach.[9] Further disconnection of are common motifs in natural products.[17] The vinylo-
the macrolide core affords three major fragments; (1) gous aldol reaction has the potential to generate three
the C-15–C-20 d-hydroxy-a,b-unsaturated portion, (2) elements of stereogenicity (two carbons and one
the 2,6-cis-disubstituted exo-methylene pyran ring, double bond) in a single transformation.[6,18] Litera-
and (3) the C-1–C-9 triene system. In an effort to in- ture examples indicate that the stereoselectivity of
stall the potentially sensitive 1,3-dienoate portion of this reaction can be dictated by either chelation or
the macrolide at a late stage of the synthesis, a less Felkin–Anh control as is the case for typical aldol re-
conventional disconnection was investigated. Rather actions. We employed a vinylogous aldol reaction for
than preparing 1,3-dienoate 4, we targeted prepara- construction of amino alcohol C-15–C-20 17 by con-
tion of the 1,4-dienoate 5. Subsequent isomerization densation of aldehyde 15 and silylketene acetal 16[19]
was imagined to occur under macrocyclic control.[11] [Scheme 1, Eq. (1)]. The reaction sequence involves
Installation of the dienoate in a “masked” format reduction of serine-derived methyl ester 12 and subse-
would allow for unveiling after construction of the quent oxidation to provide aldehyde 15. A number of
macrolide. Further disconnection of macrolide 5 at conditions to oxidize serine derivative 14 [e.g., Swern,
À
the C-3 C-4 bond affords the acyclic precursor 6 via IBX, IBX/Bu4NI, and Pd
U
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Studies toward the Synthesis of (À)-Zampanolide
Scheme 1. Vinylogous aldol reaction to access the C-15–C-20 fragment.
not proceed to completion, in particular on a larger 1.5 equiv. of Me2AlCl. The two-step process devel-
scale, (e.g., 10 g) which required investigation of alter- oped by Kiyooka[27] using DIBAL-H and TiCl2
(O-i-
ACHTREUNG
native routes. A number of tactics have been em- Pr)2 was next investigated. Reaction optimization pro-
ployed[23] to circumvent racemization of the a-chiral vided the desired vinylogous aldol product, 17 (dr=
stereocenter of a-amino aldehydes.[24] In particular, 16:1) in 68% yield from the methyl ester [(Scheme 1,
one-pot reduction/nucleophilic additions of esters in- Eq. (2)]. The three-step, one-pot protocol previously
volving DIBAL-H have been reported in the litera- employed resulted in a 44% overall yield of adduct 17
ture.[25] Polt and co-workers used this tactic for in situ [Eq. (1)] from the methyl ester without epimerization.
reduction of an ester, followed by addition of a nucle-
In order to assign stereochemistry of the vinylogous
ophile (RMgBr, RLi).[20a] In this case, DIBAL-H was aldol product, substrate 17 was treated with Oteraꢀs
used in conjunction with tri-iso-butylaluminum (i- distannoxane catalyst[28] (1,3-dichlorodistannoxane)
Bu3Al) to moderate its reactivity as well as to activate and subjected to microwave irradiation to afford
the substrate for the nucleophilic addition.[26] In a re- cyclic carbamate 18 (Scheme 2).[29] The minor anti-
lated approach, Kiyooka and co-workers found that diastereomer was also isolated and treated with
reduction with DIBAL-H, followed by addition of Oteraꢀs catalyst to afford the cyclic carbamate epi-18
TiCl2(O-i-Pr)2, also activated the alkoxyaluminum in- (Scheme 3 and Scheme 4). Analysis of coupling con-
G
termediate for nucleophilic addition.[27] Both of these stants between H-1 and H-2 showed J1,2 =4.8 Hz for
protocols avoided isolation of the aldehyde and are 18 and J1.2 =8.0 Hz for epi-18, which are within the
mild enough to be used with a number of different same range as similar substrates reported in litera-
nucleophiles without racemization.
ture.[30] The stereochemical assignment was further
After evaluation and optimization of the DIBAL- confirmed by NOE experiments. Carbamate 18
H/Me2AlCl system developed by Polt and co-workers, showed a 15% NOE between H-1 and the allylic
the highest yield of the desired homoallylic alcohol 17 methylene and a 5% NOE between H-2 and the
attained was 36% using 1.5 equiv. of DIBAL-H and other methylene (no NOE was observed between the
Scheme 2. Stereochemical assignment of the vinylogous aldol products.
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Scheme 3. Vinylogous aldol reaction using a highly racemized aldehyde substrate.
Scheme 4. Further advancement of the vinylogous aldol product
Scheme 5. Synthesis of the hydroxyallylsilane reagent.
two methylene groups). Substrate epi-18 showed a Synthesis of the exo-Methylene Pyran Subunit
13% NOE between the two methylenes.
To rule out racemization during the reaction, we A number of syntheses of zampanolide and dactyo-
conducted a vinylogous aldol reaction using a largely lide[3,7] have utilized the intramolecular silyl-modified
racemized sample of aldehyde 15 to provide a vinylo- Sakurai (ISMS) reaction[15] for construction of the 2,6-
gous aldol product (Æ)-17 (35% ee. dr=7:1, disubstituted exo-methylene pyran subunit. For our
Scheme 3). Comparison of this product to material synthetic route, the requisite allylsilane 10 for an
obtained using the one-pot DIBAL-H reduction/vinyl- ISMS reaction was obtained from Cu(I)-mediated ad-
ogous aldol process (Scheme 1) by chiral HPLC, indi- dition[32] of vinyl-Grignard reagent 21[33] to chiral ep-
cated that the latter process proceeded without race- oxide 20 (Scheme 5). Compound 20 was prepared by
mization of the intermediate aldehyde or equivalent addition of trimethylsilylacetylene anion to (S)-epi-
to afford adduct 17 in >99% ee and dr=16:1.
chlorohydrin followed by epoxide formation from the
Vinylogous aldol substrate 17 was next advanced to subsequent chlorohydrin.[34] Subsequent desilylation
the a,b-unsaturated aldehyde, 11 (Scheme 4). Amino and alkyne reduction to the terminal olefin with
alcohol 17 was protected as the N,O-acetonide 19 Cp2Zr(H)Cl (Schwartzꢀs reagent[35]) afforded hydroxy-
which was followed by reduction of the methyl ester allylsilane 10 in good overall yield.
with DIBAL-H. Subsequent oxidation with 4-acetami-
With aldehyde 11 and silane 10 in hand, the ISMS
do-2,2,6,6-tetramethylpiperidine-1-oxoammonium tet- reaction was next explored. After evaluation of a
rafluoroborate (Bobbitt reagent)[3,31] afforded enal 11. number of Brønsted and Lewis acid catalysts, we
[36]
Initially, Dess–Martin reagent was used for this oxida- found that Bi(OTf)3 (1.5 equiv.) in conjunction with
G
tion; however, formation of an unidentified by-prod- 2,6-di-tert-butylpyridine as a triflic acid scavenger[37]
uct caused lower yields in the subsequent pyran annu- was found to mediate the desired reaction to cleanly
lation (vide infra).
afford pyran 24 as a single diastereomer (68%). The
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Studies toward the Synthesis of (À)-Zampanolide
Scheme 6. ISMS reaction to construct the exo-methylene pyran.
relative stereochemistry of exo-methylene pyran 24 CBr4/MeOH[46]] afforded a low yield of the N-Boc-
was determined to be syn by NOE studies. Elabora- amino alcohol product or decomposition of the start-
tion of the terminal olefin by cross-metathesis[38] using ing material. Finally, treatment of 26 with 50% formic
the Grubbs-Hoveyda second generation catalyst[39] acid in CH2Cl2[47] provided the desired secondary alco-
provided a,b-unsaturated aldehyde 9 as a single olefin hol in 60% yield. Esterification of 27 with 7[48] provid-
isomer in 66% yield (Scheme 6).
ed the macrocylization precursor 6 in 80% yield.
Construction of a Macrolide Precursor
Model Studies for the Stille Macrocyclization
As described in our retrosynthetic analysis (Figure 2), Conditions for the critical sp2-sp3 Stille macrocycliza-
we planned to prepare vinylstannane 6 in order to tion were first examined in an intermolecular fashion
evaluate sp2-sp3 Stille macrocyclization for construc- employing model system 38 (Table 1). Initial screen-
À
tion of the macrocyclic core. Construction of the C-6
ing of the palladium source [Pd
A
ACHTREUNG
C-7 bond via allylation to install an allylic acetate PdCl
A
ACHTREUNG
function was more difficult than anticipated. Howev- showed Pd
ACHTREUNG
er, we found that activation of the aldehyde as an coupling of 28A and B and b-stannyl acrylate 7.[49] Ini-
oxocarbenium ion with BnOTMS led to good conver- tial screening with Cu(I) and N,N-diisopropylethyla-
sion while simultaneously protecting the emerged hy- mine (DIEA) (entries 1–3) afforded only the 1,4-
droxy group (Scheme 7). Optimization of reaction diene product 29 in low conversion. Replacing the al-
conditions led to the identification of TMSOTf as a lylic acetate with a chloride was examined using NMP
promoter for allylation of 9 with the Trost trimethyle- as solvent (entry 4) which afforded 44% of the 1,4-
nemethane (TMM) reagent 25[40] in the presence of product, 29 along with numerous side products. In an
BnOTMS which cleanly afforded allylic acetate 26 attempt to accelerate the reaction and increase the
(83% yield, dr=1:1).
conversion, use of tetrabutylammonium iodide
Removal of the acetonide protecting group was (TBAI) as an additive[50] was investigated (entries 5–
next attempted using standard conditions. Traditional 8). Quaternary ammonium salts have been employed
methods for acetonide deprotection including AcOH/ to accelerate metal-mediated couplings involving al-
MeOH,[41] PPTS/MeOH,[42] and TsOH/MeOH[43] led kynes,[51] alkenes,[52] and alkyl[53] substrates. When
to incomplete conversion, loss of the TBDPS ether, TBAI was employed for the coupling of acetate 28
or loss of the allylic acetate functionality. All attempts and model vinylstannane 7, the reaction proceed to
to remove the acetonide under other conditions [e.g., completion and provided the 1,3-diene product 30 as
CeCl /
3 (CO2H)2/MeCN,[44] BiCl3/aqueous MeCN,[45] the sole product. When Bu4NCl[54] was used in place
G
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Scheme 7. Synthesis of a macrocyclization substrate.
Table 1. Model Stille reactions.
Entry
X
Additive
Solvent/Temperature
Result
1
2
3
4
5
6
7
8
OAc
OAc
OAc
Cl
OAc
OAc
Cl
CuI
DIEA
PhMe/reflux
PhMe/reflux
PhMe/reflux
NMP/608C
PhMe/reflux
PhMe/reflux
PhMe/reflux
PhMe/reflux
only 29[a]
1:2; 29:30
DIEA, CuI
DIEA, CuTC
DIEA, CuI, Bu4NI
DIEA, Bu4NI
DIEA, Bu4NI
DIEA, Bu4NCl
29 (trace 30)[a]
44% 29[a,b]
57% 30[b]
62% 30[b]
44% 30[b]
OAc
mixture of 29 and 30
[a]
Significant impurity present.
Isolated yields after silica gel chromatography.
[b]
of TBAI, a mixture of 1,4- and 1,3-product was ob- Macrocyclization via sp2-sp3 Coupling
served. According to a literature precedent, the addi-
tive TBAI may form an anionic Pd(0) species which is Optimized conditions for sp2-sp3 coupling derived
highly reactive in oxidative addition.[55] One possible from the model studies (Table 1) were evaluated for
pathway for the isomerization is shown in Scheme 8. the construction of the zampanolide macrolide core
The initially formed 1,4-diene (A) may undergo a b- (Scheme 9). After considerable experimentation, we
hydride elimination to form the p-allyl species B, fol- found that macrocyclization of vinylstannane
lowed by reductive elimination, to afford the more (0.005M in toluene) could be achieved using 20% Pd-
stable 1,3-diene C. (PPh3)4, 3.0 equiv. of Bu4NI, and DIEA (2 equiv.)
(48 h, reflux) to afford macrolactone 5 in 50% yield.
6
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Studies toward the Synthesis of (À)-Zampanolide
Scheme 8. Isomerization to a 1,3-diene.
Scheme 9. Stille macrocyclization.
Interestingly, only 1,4-diene product 5 was observed core for further studies and to probe the effect of the
in these experiments with no evidence of isomerized C-7 stereocenter on the dienoate geometry. Further
dienoate products formed. This is likely due to the studies involving oxidative deprotection of the allylic
constraints of the macrolide on olefin isomerization. benzyl ether[58] will be evaluated in order to obtain
In the cyclization, the two C-7 diastereomers of 5 the (À)-zampanolide macrolide core and should pro-
were found to be separable though this is inconse- vide materials for final oxidative decarboxylation-hy-
quential for the reaction sequence as the secondary drolysis protocols[10] for the late stage introduction of
alcohol will later be oxidized to a ketone in the final the sensitive N-acylheminal side-chain.
product. Subsequent treatment with DBU in THF at
458C afforded the 1,3-diene 4 in quantitative yield as
a 1:1 mixture of E,Z and E,E-isomers. In an effort to Conclusions
perform the reaction at
a lower temperature,
NaHMDS was evaluated, but gave no reaction, even Herein, we have reported the synthesis of the zampa-
with higher equivalents of base. DBU isomerization nolide macrolide core which features a one-pot reduc-
has been performed in i-PrOH[56] which allows for tion/vinylogous aldol reaction, an intramolecular silyl-
olefin isomerizations at room temperature due to as- modified Sakurai (ISMS) reaction to construct the
sumed carbonyl activation by the protic solvent. Inter- 2,6-disubstituted exo-methylene pyran, and sp2-sp3
estingly, the latter conditions produced the 2,4-diene Stille reaction employing a vinylstannane/allylic ace-
31 as the only product (inset). Isomerization using a tate substrate for macrocyclization. Initial studies
phosphazene base, BEMP[57] was also evaluated, but have been performed to isomerize the 1,4-diene mac-
no reaction was observed in this case. Other reactions rolactone product to the requisite 1,3-diene. Further
may be examined to produce the E,Z-dienoate, how- studies on the completion of the synthesis of (À)-zam-
ever, access to both olefin isomers is also useful in panolide are in progress and will be reported in due
terms of obtaining the E,E-dienoate macrolactone course.
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Experimental Section[59]
purged with argon and sealed. Reaction was subjected to
microwave irradiation (temperature: 1808C, 250 W power)
for 30 min. The reaction mixture was cooled to room tem-
perature and concentrated under vacuum. Purification on
silica gel (10–30% EtOAc in hexane) provided cyclic carba-
mate 18 as a colorless oil; yield: 40.1 mg (0.86 mmol, 95%).
Methyl 3-(Diphenyl-tert-butylsilyl)oxy-2-tert-butoxy-
carbonylaminopropanoate 12
N-(tert-Butoxycarbonyl)-l-serine methyl ester (9.54 g,
43.5 mmol, 1.0 equiv.) was dissolved in 44 mL of DMF. tert-
Butyldiphenylsilyl chloride (17 mL, 65.2 mmol, 1.5 equiv.)
and imidazole (5.92 g, 87 mmol, 2.0 equiv.) were added. The
reaction was stirred at room temperature for 5 h. EtOAc
was used to dilute the reaction mixture. The organic layer
was washed by pH 7 buffer, water, and saturated aqueous
NaCl. The combined organic layers were dried over NaSO4,
filtered, and concentrated under vacuum. Purification on
silica gel (5% ether in hexane was used to remove
TBDPSOH, then 20% EtOAc in hexane) provided methyl
ester 12 as a colorless viscous oil; yield: 19.5 g (42.6 mmol,
98%).
tert-Butyl 4-[(Diphenyl-tert-butyl-silyl)oxymethyl]-5-
(3-methoxycarbonyl-2-methylprop-2-enyl)-2,2-dimeth-
yloxazolidine-3-carboxylate 19
Methyl ester 17 (5.70 g, 10.5 mmol, 1.0 equiv.) was dissolved
in 53 mL of CH2Cl2 (0.2M). 3 Š Molecular sieves (2.1 g)
and 2,2-dimethoxypropane (6.5 mL, 52.6 mmol, 5.0 equiv.),
followed by (+/-)-CSA (488.8 mg, 2.10 mmol, 0.2 equiv.).
The reaction mixture was stirred at room temperature for
36 h, diluted with EtOAc, and the organic layer washed with
saturated aqueous NaHCO3 and saturated aqueous NaCl.
The organic layers were dried over Na2SO4, filtered, and
concentrated under vacuum. Purification on silica gel (10–
20% EtOAc in hexane) provided the acetonide 19 as a col-
orless oil; yield: 5.14 g (8.84 mmol, 84%).
Silylketene Acetal 16
To
a solution of methyl 3,3-dimethylacrylate (5.0 mL,
38.2 mmol, 1.0 equiv.) in 120 mL THF at À788C was added
NaHMDS (45.0 mL, 45.9 mmol, 1.0M in THF, 1.0 equiv.)
dropwise. The reaction was stirred at À788C for 1 h then
freshly distilled TMSCl (6.3 mL, 49.7 mmol, 1.3 equiv.) was
added. The reaction mixture was brought to room tempera-
ture then concentrated under vacuum. The residue was dis-
solved in dry hexanes, filtered, and concentrated under
vacuum. Purification by high vacuum distillation provided
silylketene acetal 16; yield: 4.98 g (26.7 mmol, 70%). Spec-
tral data were found to match data reported in the litera-
ture.[19]
tert-Butyl 4-[(Diphenyl-tert-butylsilyloxy)methyl]-5-
(4-hydroxy-2-methylbut-2-enyl)-2,2-dimethyloxazol-
idine-3-carboxylate 31
Methyl ester 19 (1.46 g, 2.52 mmol, 1.0 equiv.) was dissolved
in 12.6 mL of CH2Cl2 and cooled to À788C. A solution of
DIBAL-H (1.0M in hexanes) (7.55 mL, 7.55 mmol,
3.0 equiv.) was added dropwise. After 1 h, the reaction mix-
ture was quenched with saturated aqueous Rochelleꢀs salt
and warmed to room temperature. The mixture was stirred
for three hours at room temperature. The reaction mixture
was diluted with EtOAc and the organic layer washed with
saturated aqueous NaCl, dried over Na2SO4, filtered, and
concentrated under vacuum. Purification on silica gel (20%
EtOAc in hexane) provided allylic alcohol 31 as a colorless
oil; yield: 1.34 g (2.42 mmol, 96%).
Methyl 7-(Diphenyl-tert-butylsilyl)oxy-5-hydroxy-3-
methyl-6-tert-butoxycarbonylaminohept-2-enoate 17
Methyl ester 12 (4.88 g, 10.7 mmol, 1.0 equiv.) was dissolved
in 53 mL of CH2Cl2 and cooled to À788C. A solution of
DIBAL-H (1.0M in hexanes) (16.0 mL, 15.0 mmol,
1.5 equiv.) was added dropwise. After 1 h at À788C, a solu-
a,b-Unsaturated Aldehyde 11
tion of TiCl2
A
and Ti(O-i-Pr)4, 1.0M in CH2Cl2, 20 min 08C to room tem-
G
Allylic alcohol 33 (1.35 g, 2.45 mmol, 1.0 equiv.) was dis-
solved in 24 mL of CH2Cl2. 2.0 g of silica gel (1.5% wt) were
added followed by addition of the solid Bobbitt reagent
(809.4 mg, 2.69 mmol, 1.1 equiv.) at room temperature. The
heterogeneous bright yellow mixture was stirred for 6 h. The
reaction mixture was filtered through a silica plug and
washed thoroughly with CH2Cl2. The filtrate was concentrat-
ed under vacuum to provide a,b-unsaturated aldehyde 11 as
a viscous oil; yield: 1.14 g (2.08 mmol, 85%).
perataure) was added dropwise at À788C. After five mi-
nutes, silylketene acetal 16 (6.15 g, 33.0 mmol, 3.1 equiv.)
was added. After 2 h, the reaction was slowly warmed from
À788C to À208C over 3 h. The total reaction time was 24 h
from addition of the silylketene acetal. The reaction mixture
was quenched at À788C with Rochelleꢀs salt and brought to
room temperature, diluted with EtOAc, and the organic
layer washed with saturated aqueous NaHCO3 and saturated
aqueous NaCl. The organic layers were dried over Na2SO4,
filtered, and concentrated under vacuum. Purification on
silica gel (10–20% EtOAc in hexane) provided d-hydroxy-
a,b-unsaturated ester 17 as a colorless oil; yield: 3.93 g
(7.25 mmol, 68%).
Chlorohydrin 32
Trimethylsilylacetylene (6.0 mL, 43.4 mmol, 1.5 equiv.) was
dissolved in 116 mL hexane. After cooling the reaction mix-
ture to 08C, n-butyllithium (2.3M, 12.6 mL, 28.9 mmol,
1.0 equiv.) was added, reaction was stirred for 10 min.
Et2AlCl (28.9 mL, 28.9 mmol, 1.0M in hexane, 1.0 equiv.)
was added, reaction was stirred for 30 min at 08C. The (S)-
epichlorohydrin (2.68 g, 28.9 mmol, 1.0 equiv.) in hexane
was transferred into a reaction flask via cannula. After 2.5 h
at 08C, reaction mixture was quenched with 1N aqueous
Methyl 4-{4-[(Diphenyl-tert-butyl-silyl)oxymethyl]-2-
oxooxazolidin-5-yl}-3-methylbut-2-enoate 18
Methyl ester 17 (64.2 mg, 0.119 mmol, 1.0 equiv.) was dis-
solved in 1.2 mL PhCl. Oteraꢀs catalyst (13.1 mg, 1.19”
10À2 mmol, 0.1 equiv.) was added and the reaction was
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Studies toward the Synthesis of (À)-Zampanolide
HCl and was extracted with ether. Then the organic layers
were washed with saturated aqueous NaCl. The combined
organic layers were dried over Na2SO4, filtered, and concen-
trated under vacuum to afford of chlorohydrins 34; yield:
5.16 g (27.0 mmol, 94%). The material was carried on to
next step without further purification.
ture was diluted with Et2O and washed with saturated aque-
ous NaCl. The organic layers were dried over Na2SO4, fil-
tered, and concentrated under vacuum. Purification on silica
gel (5% ether in pentane) provided terminal olefin 10 as a
light yellow oil; yield: 300 mg (1.51 mmol, 71%).
2,6-Disubstituted Pyran 24
Epoxide 20
Bi(OTf)3 (3.10 g, 4.60 mmol, 1.5 equiv.), 2,6-di-tert-butyl-4-
A
Chlorohydrin 34 (5.16 g, 27.0 mmol, 1.0 equiv.) was dissolved
in 135 mL of Et2O, and powdered NaOH (1.6 g, 40.6 mmol,
1.5 equiv.) was added. The reaction was stirred for 24 h at
room temperature. The reaction was filtered through Celite,
the organic layer was washed with pH 7 buffer, dried over
Na2SO4, filtered, and concentrated under vacuum. The
chiral epoxide (3.33 g, 21.6 mmol, 80%) was used without
further purification. Attempts to purify on silica gel caused
product decomposition. Spectral data for epoxide 20
matched literature data.[34]
methylpyridine (377.9 mg, 1.84 mmol, 0.6 equiv.), and 4 Š
molecular sieves (614.0 mg) were azeotroped under vacuum
with toluene. 30.7 mL of Et2O were added and reaction mix-
ture was cooled to À788C. Aldehyde 11 (1.69 g, 3.07 mmol,
1.0 equiv.) and allylsilane 10 (852.0 mg, 4.296 mmol,
1.4 equiv.) were added as a solution in ether and the mixture
was stirred at À788C for 24 h. The reaction was quenched
with N,N,N’-trimethylethylenediamine (1.8 mL, 13.8 mmol,
4.5 equiv.) and brought to room temperature. The reaction
mixture was diluted with EtOAc, washed with saturated
aqueous NaCl, dried over Na2SO4, filtered, and concentrat-
ed under vacuum. Purification on silica gel (0–10% EtOAc
in hexane) provided pyran 24 as an oil; yield: 1.56 g
(2.37 mmol, 77%).
Allylsilane 22
(2-Bromoallyl)trimethylsilane (16.8 g, 87.1 mmol, 1.0 equiv.)
was dissolved in 51 mL of ether at À788C. tert-Butyllithium
(1.70M, 102 mL, 174.2 mmol, 2.0 equiv.) was added and re-
action mixture was stirred for 1 h at À788C. MgBr2·Et2O
(1M, 95.8 mL, 1.1 equiv.) was added and stirring was contin-
ued for 30 min at À788C to afford the Grignard reagent
(21) in situ. In a separate flask, flame-dried CuI (772.0 mg,
4.05 mmol, 0.1 equiv.) was mixed with 203 mL of Et2O, and
the reaction mixture was cooled to À308C. The Grignard re-
agent (184.8 mL, 0.329M, 1.5 equiv.) described above was
transferred into the flask via cannula and stirred for 15 min.
Then (S)-epoxide 20 (6.25 g, 40.5 mmol, 1.0 equiv.) in Et2O
was added, and the reaction mixture was stirred for 24 h at
À308C. The reaction mixture was quenched with saturated
aqueous NH4Cl at À308C and was warmed to room temper-
ature and diluted with EtOAc. The organic layer was
washed with saturated aqueous NaCl, dried over Na2SO4, fil-
tered, and concentrated under vacuum. Purification on silica
gel (5% ether in hexane) provided allylsilane 22 as a light
yellow oil; yield: 8.39 g (31.2 mmol, 77%).
a,b-Unsaturated Aldehyde 9
Pyran 24 (364.8 mg, 0.55 mmol, 1.0 equiv.) and freshly dis-
tilled acrolein (110.8 mL, 1.66 mmol, 3.0 equiv.) were dis-
solved in 5.5 mL of CH2Cl2. Hoveyda-Grubbs 2nd generation
catalyst (35.2 mg, 5.53”10À2 mmol, 0.1 equiv.) wase added
and reaction mixture was refluxed for 12 h. The mixture was
cooled to room temperature and concentrated under
vacuum. Purification on silica gel (0–10% EtOAc in hexane)
provided a,b-unsaturated aldehyde 9 as a light yellow oil;
yield: 251 mg (0.367 mmol, 66%).
Allyllic Acetate 26
2,6-Di-tert-butyl-4-methylpyridine
(2.9 mg,
0.014 mmol,
0.1 equiv.) and 4 Š molecular sieves (28.0 mg) were azeo-
troped under vacuum with toluene. 1.4 mL of Et2O were
added and the reaction mixture was cooled to À788C. Alde-
hyde 9 (95.7 mg, 0.14 mmol, 1.0 equiv.) and 2-((trimethylsi-
lyl)methyl)-2-propen-1-yl acetate 25 (34.6 mL, 0.167 mmol,
1.2 equiv.) were added as a solution in ether followed by
BnOTMS (35.6 mL, 0.18 mmol, 1.2 equiv,) and TMSOTf
(5.0 mL, 2.80”10À2 mmol, 0.2 equiv.) and the mixture was
stirred at À788C for 24 h. Purification on silica gel (0–10%
EtOAc in hexane) provided allylic acetate 26 as a light
yellow oil; yield: 98.3 mg (0.110 mmol, 79%).
Terminal Alkyne 23
Trimethylsilylalkyne 22 (1.45 g, 5.39 mmol, 1.0 equiv.) was
dissolved in 26 mL of MeOH at room temperature. K2CO3
(744.2 mg, 5.39 mmol, 1.0 equiv.) was added and reaction
mixture was stirred for 12 h at room temperature. The reac-
tion mixture was quenched with pH 7 buffer and extracted
with EtOAc. The organic layer was washed with saturated
aqueous NaCl, dried over Na2SO4, filtered, and concentrat-
ed under vacuum. Purification on silica gel (5% Et2O in
pentane) provided allylsilane 23 as a light yellow oil; yield:
8.39 g (31.2 mmol, 77%).
Secondary Alcohol 27
To a solution of acetonide 26 (77.3 mg, 8.66”10À2 mmol,
1.0 equiv.) in 870 mL CH2Cl2 at 08C was added 870 mL
formic acid and the reaction stirred for 3 h at 08C. Reaction
mixture was diluted with EtOAc, washed with saturated
aqueous NaHCO3 and saturated aqueous NaCl. Organic
layers were dried over Na2SO4, filtered, and concentrated
under vacuum. Purification on silica gel (10–20% EtOAc in
hexane) provided secondary alcohol 27 as a light yellow oil;
yield: 48.0 mg (5.63”10À2 mmol, 66%).
Terminal Olefin 10
Alkyne 23 (418.1 mg, 2.13 mmol, 1.0 equiv.) was dissolved in
10 mL THF at 08C. Cp2Zr(H)Cl (1.15 g, 4.47 mmol,
2.1 equiv.) was added and the reaction mixture was stirred
for 1 h at 08C. The reaction mixture was quenched with
H2O and warmed to room temperature. The reaction mix-
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DEDICATED CLUSTER
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Dawn M. Troast et al.
References
Stannyl Ester 6
Alcohol 27 (47.2 mg, 5.54”10À2 mmol, 1.0 equiv.), b-stanny-
lacrylic acid 7 (44.0 mg, 0.122 mmol, 2.2 equiv.), DMAP
(0.5 mg, 3.9”10À3 mmol, 0.07 equiv.), and DMAP·HCl
(1.1 mg, 7.2”10À3 mmol, 0.13 equiv.) in 1.1 mL CH2Cl2 were
cooled to 08C. DIC (8.7 mL, 0.122 mmol, 2.2 equiv.) was
added and the reaction mixture was stirred at room temper-
ature for 18 h. The reaction mixture was diluted with
EtOAc, washed with saturated aqueous NaHCO3, saturated
aqueous NaCl, dried over Na2SO4, filtered, and concentrat-
ed under vacuum. Purification on silica gel (5–20% EtOAc
in hexane) provided secondary alcohol 6 as a light yellow
oil; yield: 52.3 mg (4.38”10À2 mmol, 79%).
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To a flame-dried Schlenk tube was added Pd(PPh3)4 (7.9 mg,
G
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1,3-Diene Lactone 4
1,4-Diene lactone 5 (12.9 mg, 1.52”10À2 mmol, 1.0 equiv.)
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Acknowledgements
We thank the National Institutes of Health General Medical
Sciences (RO1GM-62842), Bristol-Myers Squibb, Novartis,
Wyeth, and Merck for research support and Professor Scott
Schaus (Boston University) for helpful discussions.
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Adv. Synth. Catal. 2008, 350, 1701 – 1711
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