Ring-closing metathesis and photo-fries reaction for the construction of the ansamydn antibiotic kendomycin: Development of a protecting group free oxidative endgame

Article abstract of DOI:10.1002/chem.200902226

Two convergent total synthe-ses of the ansa-polyketide (-)-kendo-mycin (1) are described. The syntheses benefit from the use of readily avail-able and cheap starting materials. Highly complex diastereoselective Claisen-Ireland rearrangements were used to introduce the (E)-double bond and the C16-Me group. The ring clo-sure of the strained ansa macrocycle was achieved by ring-closing metathesis and a highly efficient combination of macrolactonization and photo-Fries re-action. A protecting group free end-game via an unstable o-quinone is pre-sented. Additionally some unsuccessful synthetic efforts towards the total synthesis of 1 are described.

Full text of DOI:10.1002/chem.200902226

FULL PAPER
DOI: 10.1002/chem.200902226
Ring-Closing Metathesis and Photo-Fries Reaction for the Construction of
the Ansamycin Antibiotic Kendomycin: Development of a Protecting Group
Free Oxidative Endgame
Thomas Magauer, Harry J. Martin, and Johann Mulzer*[a]
Abstract: Two convergent total synthe-
ses of the ansa-polyketide (ꢀ)-kendo-
mycin (1) are described. The syntheses
benefit from the use of readily avail-
able and cheap starting materials.
and the C16-Me group. The ring clo-
sure of the strained ansa macrocycle
was achieved by ring-closing metathesis
and a highly efficient combination of
macrolactonization and photo-Fries re-
action. A protecting group free end-
game via an unstable o-quinone is pre-
sented. Additionally some unsuccessful
synthetic efforts towards the total syn-
thesis of 1 are described.
Keywords: Claisen–Ireland
Highly
complex
diastereoselective
rearrangement
·
metathesis
·
Claisen–Ireland rearrangements were
used to introduce the (E)-double bond
natural products · polyketides
Introduction
Kendomycin [(ꢀ)-TAN 2162] (1) was first reported in
1996,[1] and re-isolated in 2000 by Zeeck and Bode during
their screening program for new metabolites from Actino-
mycetes.[2] Biological testing revealed 1 to be a potent endo-
thelin receptor antagonist and antiosteoperotic compound
with remarkable antibacterial and cytostatic activity,[2,3] most
likely through proteasome inhibition.[3a] Beside the diverse
pharmacological qualities, which have attracted (bio)-chem-
ists in the last years, kendomycin discloses an unique molec-
ular architecture with a fully carbogenic ansa-polyketide
chain, nine stereogenic centers, a pentasubstituted tetrahy-
dropyran ring and a remarkable p-quinone-methide chromo-
phore. The biosynthesis (Scheme 1)[2b,4] implies the forma-
tion of benzoic acid 2a or the corresponding quinoid nu-
cleus 2b from malonate subunits under the mediation of
chalcone synthase (CHS). This core unit is then loaded onto
the type I polyketide synthase (PKS) to form keto acid 3
which undergoes cyclization to ketone 4 under decarboxyla-
tion. Ketalization leads to 1 eventually.
Scheme 1. Biosynthesis of kendomycin.
The challenging framework and the promising pharmaco-
logical profile of 1 motivated us[5] and sometime later, a
number of other groups[6–8] to carry out studies towards its
synthesis. Thus far four total syntheses[6] and one formal
one[7] have been reported, along with a number of fragment
preparations.[8] All these approaches loosely follow the bio-
genetic pathway by starting with an aromatic polyphenol
[a] T. Magauer, Dr. H. J. Martin, Prof. J. Mulzer
Institute of Organic Chemistry, University of Vienna
Wꢀhringerstrasse 38, 1090 Vienna (Austria)
Fax : (+43)1-4277-52189
E-mail: johann.mulzer@univie.ac.at
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507

subunit, attaching a polyketide chain and then aiming for
cyclization. The main challenge has thus been the formation
of the strained macrocyclic ansa-ring and the late stage gen-
eration of the quinone and lactol units. So far, macrocycliza-
tions have been performed via RCM,[6b] C-glycosidation,[6a]
Barbier-type organometal addition,[6d] Prins reaction[7] and
Horner–Wadsworth–Emmons olefination.[8e] In continuation
of earlier reports[5] we now want to disclose our recent ef-
forts, which have culminated in two successful syntheses.[6e]
Results and Discussion
It is obvious that the formation of the quinone methide
chromophore should be deferred to the end of the synthesis,
via the oxidation of known[6a] benzofuran 5 (Scheme 2). A
further general consideration concerns the tetrahydropyran
ring which preferably should be installed after the macrocyc-
Scheme 3. Precursors for macrocyclizations.
lization—mainly because of restricted rotation around the
[5d]
ꢀ
C4a C5 bond which might be disadvantageous for subse-
quent ring closures.
elongation to the 10-olefin. ortho-Directed lithiation of C4a
and addition to aldehyde 12 should set the stage for the en-
visaged RCM reaction.
Scheme 2. Benzofuran precursor of kendomycin.
In this report we present four general approaches toward
the synthesis of the common precursor 5 (Scheme 3). Three
of them address the ring-closing metathesis (RCM) at differ-
ent sites as key steps. In the first approach (A), we intended
to combine olefinic carbons C9 and C10 of compound 6
through RCM, followed by an addition of C5-OH to C9 for
tetrahydropyran ring formation. In approaches B and C
using compounds 7 and 9, respectively, as RCM precursors,
the tetrahydropran ring should be generated by diastereose-
lective SN1 reaction of the C9-OH with an in situ generated
benzylic cation at C5.[9] The final approach (D) focuses on
the macrolactonization of compound 8 followed by a photo-
Fries reaction, and the tetrahydropyran should be formed by
C5-carbonyl reduction and SN1 cyclization. It should be
noted at this point, that only approaches C and D have been
successful, in contrast to route A where the RCM did not
work and B, where the RCM precursor 7 could not be made
at all.
Scheme 4. Retrosynthetic disconnections for route A.
Vinyliodide 10 was easily available from known aldehyde
13.[10] Colvinꢂs one carbon chain elongation[11] afforded the
corresponding alkyne, which was alkylated with MeI and
converted to 10 by hydrozirconation/iodination. Iodide 11
was prepared from known compound 14[9] via a two step
standard procedure. Pd0-assisted Negishi coupling[12] of io-
dides 10 and 11, followed by deprotection gave (E)-olefin 15
which was converted to 1,4-diene 16 via IBX oxidation and
Wittig methylenation (Scheme 5).
Aldehyde 12 was available from known alcohol 17[13] via
1,3 shift of the PMB protecting group and oxidation of the
primary alcohol with IBX (Scheme 6). MOM-directed
ortho-lithiation of 16 followed by nucleophilic addition to
aldehyde 12 afforded benzylic alcohols 18a and 18b as a
1.5:1 diastereomeric mixture. The configuration at the ben-
zylic carbon C5 was assigned by converting compound 18b
into cyclic iodoether 19. 2D NMR experiments (NOESY)
revealed that 19 and hence 18b have the desired R configu-
ration at C5.
RCM and trans-etherification (route A): Retrosynthetically,
the RCM precursor 6 was disconnected into vinyl iodide 10,
alkyl iodide 11 and aldehyde 12 (Scheme 4). The synthesis
of the Northern diene portion should be achieved by a Ne-
gishi cross-coupling of iodides 10 and 11, followed by chain
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Construction of the Ansamycin Antibiotic Kendomycin
FULL PAPER
Scheme 5. Synthesis of compound 16. a) TMSCHN2, LDA, THF, ꢀ788C
! RT, 82%; b) BuLi, MeI, THF, ꢀ788C ! RT, 95%; c) [Cp2ZrClH],
benzene, THF, I2, 83%; d) TBAF, THF, 94%; e) I2, PPh3, CH2Cl2, 88%;
Scheme 7. a) Grubbsꢂ II catalyst, 15 mol%, CH2Cl2, reflux, 16 h, 46%;
b) IBX, DMSO, RT, 96%.
f) 11, tBuLi, ZnCl2, Et2O/THF, 5 mol% [Pd
N
10 in THF; g) TBAF, THF, 67% 2 steps; h) IBX, DMSO, RT, 97%;
i) MePPh3Br, tBuOK, THF, 08C, 90%.
from styrene 23 and aldehyde 24, which could be formed by
an Evans aldol addition of aldehyde 25 and ketoimide 26
(Scheme 8). The installation of the C14/C15 double bond
should then be achieved by either Negishi coupling of io-
dides 27[7] and 28 or by esterification of acid 30 with alcohol
29 followed by an Ireland–Claisen rearrangement.
Scheme 6. a) DDQ, CH2Cl2, 3 ꢃ MS, 08C, 74%; b) DIBAL, CH2Cl2, ꢀ78
! ꢀ108C, 93%; c) CH2Cl2, DMSO, (COCl)2, NEt3, ꢀ788C, 99%; d) 16,
nBuLi, TMEDA, THF, ꢀ408C then 12, ꢀ78 ! ꢀ258C, 75% (d.r. 1.5:1);
e) tert-butyl-4-methylpyridine, I2, CH2Cl2, ꢀ78 ! ꢀ108C, 50%.
Subjecting 18b to Grubbsꢂ II catalyst[14] did not result in
the desired cyclization to 20b, but only decomposition of
starting material was observed (Scheme 7). In contrast, 18a
underwent the cyclization and afforded macrocyle 20a
which was used for test purposes. Unfortunately all attempts
to form the tetrahydropyran by iodination, oxymercuration
or selenocyclization failed. Additionally, as RCM of ketone
21 was not successful, we abandoned approach A at this
point[15] and turned to route B.
Scheme 8. Retrosynthetic disconnections for route B.
The synthesis started with known[6a] aldehyde 32, easily
available from citronellene 31 in two steps.[17] Pinnick oxida-
tion[18] to the corresponding acid 30 followed by amidation
afforded oxazolidinone 33 in good yield (Scheme 9). The
second methyl group was introduced via diastereoselective
alkylation with methyl iodide, and reductive removal of the
auxiliary afforded primary alcohol 34. Subsequent Finkel-
stein reaction delivered gram quantities of alkyl iodide 28 in
RCM reaction at C19/C20 (route B): Installation of the
13,14-(E)-double bond via Negishi coupling and C4/5 con-
nection via an o-lithiation aldehyde addition sequence have
proven to be reliable and efficient. Additionally, we envis-
aged the Ireland–Claisen rearrangement[16] as an appropriate
tool for generating the 13,14-(E)-olefin along with the C-16
methyl group. Thus seco-compound 7 should be available
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509

J. Mulzer et al.
excellent yield. Coupling of known vinyl iodide 27 with 28
smoothly afforded diene 35 as a key fragment.
Scheme 9. a) NaClO2, NaH2PO4, tBuOH, H2O, 73% from 31; b) DIC,
DMAP, Evansꢂ oxazolidinone, CH2Cl2, 82%; c) LHMDS, MeI, THF,
ꢀ788C ! RT, 74% (d.r. 10:1); d) LiAlH4, Et2O, 0 8C, 80%; e) MsCl,
NEt3, CH2Cl2, 08C; f) NaI, acetone, RT, 86% from 34; g) 2.2 equiv
tBuLi, ZnCl2, ꢀ78 ! 08C, then 27, Et2O/THF, 5 mol% [Pd
ACHTUNGTRNEN(UNG PPh3)4], 08C,
95%.
In another approach (Scheme 10) for the synthesis of 35
we decided to use an Ireland–Claisen reaction. This should
give access to the trisubstituted (E)-olefin and generate the
stereocenter at C16 with the desired configuration. For this
purpose, known aldehyde 36[6a] was treated with isopropenyl
bromide in a Hiyama–Kishi reaction to give a 1.4:1 mixture
of allylic alcohols 29.[19] The alcohols were separated and es-
terified with carboxylic acid 30 to afford compounds 37a
and 37b, respectively. Treatment of 37a with LDA in THF/
HMPA afforded a (Z)-silyl ketene acetal, which was rear-
ranged to the corresponding silyl ester 38 in good yield and
acceptable diastereoselectivity (see also Table 1).[20] Reac-
tion with potassium fluoride and subsequent reduction with
LiAlH4 furnished alcohol 30 which was reduced to give the
C16-methyl group in 35. Since the ester enolate geometry
strongly depends on the solvents, treatment of 37b with
LDA in THF should give the corresponding (Z)-enolate,
and thus, the rearrangement should likewise provide com-
pound 39 after desilylation and reduction. Disappointingly,
all attempts to rearrange the (Z)-enolate of 37b proved to
be low yielding.
Nevertheless, the rearrangement of 37a had provided us
with gram quantities of diene 35 and so we focused on the
elongation sequence (Scheme 11). Deprotection and IBX
oxidation furnished aldehyde 25 in 77% yield over two
steps. Extended Evans aldol methodology[21] followed by
1,3-reduction[22] afforded stereotetrad (C6 to C9) 40 in good
yield and high diastereoselectivity. Base induced hydrolysis
to remove the auxiliary and treatment with camphorsulfonic
acid in 2,2-dimethoxypropane and methanol afforded the
methyl ester. Reduction with LiAlH4 and oxidation of the
resulting primary alcohol to aldehyde 24 paved the way for
testing the final key steps. Thus, known aryl bromide 41[23]
was formylated and then converted to styrene 23 via Wittig
methylenation. To obtain the desired RCM precursor 7, 23
Scheme 10. a) CrCl2 (4 equiv), NiCl2 (0.04 equiv), DMF, 08C ! RT, 86 %
(d.r. 1.4:1); b) DIC, DMAP, CH2Cl2, then 29a or 29b, 92%; c) LDA,
THF/HMPA (23%) then TBSCl, ꢀ788C ! reflux; d) LDA, THF, then
TBSCl-HMPA, ꢀ788C ! reflux; e) i) HMPA, KHCO3, KF, MeI, 08C; ii)
LiAlH4, Et2O, 0 8C, 63% from 37a (d.r. 5:1), 8% from 37b; f) i) MsCl,
NEt3, CH2Cl2, 08C; ii) LiAlH4, THF, 08C ! RT, 90 %.
and 24 had to be coupled as before, but unfortunately, addi-
tion of nBuLi to 23 did not give the expected ortho-lithiat-
ed[24] product but led to polymerization of the styrene unit.
So, with a heavy heart after so much experimentation, we
abandoned route B.
RCM reaction at C10/C11 (route C): In our final RCM ap-
proach we aimed for the generation of a C10/C11 olefin
which has subsequently to be reduced in presence of the
13,14-olefin. For the formation of the 13,14-trisubstituted
double bond we wanted to reapply the Ireland–Claisen ap-
proach using the known allylic alcohol 42[25] and carboxylic
acid 43 as simple precursors. Carboxylic acid 43 should be
assembled from epoxide 44 and known aryl bromide 45.[8e]
The missing tetrahydropyran side chain should be intro-
duced in the usual way by ortho-lithiation of the C4a posi-
tion and addition of aldehyde 46 (Scheme 12).
For the enantioselective preparation of allylic alcohol 42,
a Duthaler–Hafner crotylation[26] of methacrolein proved to
be the method of choice, as the asymmetric crotylation pro-
tocols by Roush[27] or Brown[28] lacked enantio- or diastereo-
selectivity in this case. The synthesis of acid 43 started from
aldehyde 32 (available from citronellene 31 in two steps, see
Supporting Information), which was reduced to the corre-
sponding alcohol and converted into silylether 47
(Scheme 13) and then into epoxide 44. Treatment of 44 with
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Construction of the Ansamycin Antibiotic Kendomycin
FULL PAPER
Scheme 11. a) TBAF, THF, RT, 87%; b) IBX, DMSO, RT, 95%; c) 26,
Sn
N
d) Me4NBH
A
e) LiOH, H2O2, THF/H2O 3:1, 92%; f) 2,2-dimethoxypropane, CSA,
16 h, RT, 90%; g) LiAlH4, Et2O, 0 8C, 99%; h) IBX, DMSO, RT, 99%; i)
tBuLi, DMF, 1n HCl, ꢀ788C ! RT, 83%; k) MePPh3Br, tBuOK, THF,
08C, 98%.
Scheme 13. a) LiAlH4, Et2O, 0 8C, 77% from citronellene 31;
b) TBDPSCl, imidazole, THF, RT, 90%; c) mCPBA, CH2Cl2, 08C, 96%;
d) 45, Mg, THF, reflux 2 h, ꢀ408C, CuI, then 44, ꢀ40 ! 08C, 4 h, 87 %;
e) DMSO, (COCl)2, NEt3, CH2Cl2, ꢀ788C, 95%; f) TfOH, toluene, 808C;
g) MOMCl, NaH, DMF, 95% from 47; h) TBAF, THF, RT, 89%; i) IBX,
DMSO, RT, 97%; j) NaClO2, NaH2PO4, tBuOH, H2O, 99%; k) DMAP,
EDCI·HCl, CH2Cl2, RT, 81%; l) i) LHMDS (4 equiv), HMPA, THF, then
50 dissolved in THF/TBSCl, ꢀ788C ! RT, then DMF, microwave,
15 min, 1808C; ii) LiAlH4, Et2O, 0 8C, 89% (d.r. 4:1); m) i) MsCl, CH2Cl2,
08C; ii) LiAlH4, Et2O, 0 8C, 89%.
quent removal of the auxiliary. Treatment with camphorsul-
fonic acid in dimethoxypropane furnished ester 55 which
was converted into aldehyde 46 by a reduction–oxidation se-
quence. ortho-Directed lithiation of 52 and addition of alde-
hyde 46 gave triolefin 9 as a 3.5:1 mixture of diastereomers
9a/9b, which was separated by chromatography. RCM of
the major diastereomer 9a with Grubbsꢂ second generation
catalyst induced smooth ring closure to 10,11-(E)-olefin 56
exclusively.
Scheme 12. Retrosynthetic disconnections for route C.
a cuprate reagent derived from bromide 45 gave the corre-
sponding alcohol as a mixture of diastereomers (ca. 1:1).
Oxidation led to ketone 48, which after treatment with trifl-
ic acid and reprotection with MOMCl furnished benzofuran
49 in good yield. Desilylation and two-step oxidation of the
primary alcohol afforded carboxylic acid 43 which was es-
terified with alcohol 42 to provide the rearrangement pre-
cursor 50. To our dismay, the Ireland–Claisen conditions we
had used for Route B did not work out as expected. In our
first tries, we had to struggle with moderate yields and very
low diasteroselectivities. Fortunately, after a lot of optimiza-
tion (see Table 1), yield and diasteroselectivity were im-
proved considerably. Subsequent reduction of the 16’-OH
finished the synthesis of 1,3-diolefin 52.
Site selective reduction of the 10,11-olefin with diimide,[29]
followed by acid-induced formation of the tetrahydropyran
ring and concomitant removal of the MOM group led to
key intermediate 5. Since the minor diastereomer 9b did
not undergo the RCM reaction and the SN1 tetrahydropyran
formation is independent of the configuration at C5 we con-
cluded that it might be advantageous to change the order of
the cyclization reactions (Scheme 15). Treatment of the 9a,b
mixture with HCl resulted in clean formation of tetrahydro-
pyran 59, which, not surprisingly showed the typical atropi-
somerism (1.5:1) of those compounds. Pleasingly, the subse-
quent RCM afforded the desired macrocyle in excellent
yield and almost exclusively as the (E)-isomer 60 (15:1).[30]
The success of this RCM came totally unexpected, as we
had anticipated major problems from the tetrahydropyran
Aldehyde 46 was obtained via Evans aldol addition of ke-
toimide 26 and acrolein (Scheme 14) to give adduct 53 in
good yield and diastereoselectivity. Lactonization to 54 was
performed via stereoselective carbonyl reduction and subse-
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J. Mulzer et al.
addition of a C9-aldehyde with ketoimide 26 should be used
for the C8–C5 chain elongation.
For ketone 48, which serves as the precursor of acid 43,
we developed a new route (Scheme 17). Starting with alde-
Scheme 16. Retrosynthesis for route D.
Scheme 14. a) Sn
91% (d.r. 5:1); b) Me4NBH
70% (d.r. 6:1); c) LiOH, H2O2, THF/H2O 2:1, RT, 72%; d) (CH3)2C-
(OMe)2, CSA, RT, 91%; e) LiAlH4, Et2O, 0 8C, 96%; f) pyridine·SO3,
NEt3, CH2Cl2/DMSO, ꢀ58C, 99%; g) nBuLi, TMEDA, THF, then 52,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
hyde 30, Colvinꢂs chain elongation furnished the correspond-
ing alkyne which was converted into vinyl iodide 61. Negishi
coupling with aryl bromide 45 furnished styrene 62, which,
after epoxidation was subjected to a Pd0-mediated rear-
rangement[31] to ketone 48.
ACHTUNGTRENNUNG
ꢀ78
! ꢀ308C, 90% (d.r. 3.5:1); h) Grubbsꢂ II catalyst, 20 mol%,
CH2Cl2, reflux, 16 h, 62% ((E) only).
ring. Diolefin 59 was reduced with high site selectivity to
compound 5 with diimide.
Macrolactonization and photo-Fries reaction to close the
C4a/C5 bond (route D): This approach (Scheme 16) was
centered around seco-acid 8 as a key intermediate. The
carbon skeleton should be assembled from the established
building blocks 43 and 29a which would give the (E)-13,14-
olefinic unit via Claisen–Ireland rearrangement. Evans aldol
Scheme 17. Synthesis of compound 48. a) TMSCHN2, nBuLi, THF,
ꢀ788C ! RT, 83%; b) [Cp2ZrHCl], benzene, 508C; I2, 08C, 76%; c) 45,
tBuLi, ZnCl2, Et2O/THF, ꢀ78 ! 08C, [Pd
ACHTUNGTREN(NNUG PPh3)4], then add 61, 67%; d)
DMDO, acetone, RT, 99%; e) PdACHTNUGTRENUNG(OAc)2, PBu3, tBuOH, reflux, 81%.
Allylic alcohol 29a was connected with acid 43 to furnish
ester 63 as the substrate of an Ireland–Claisen rearrange-
ment (Scheme 18). Treatment with excess LHMDS and re-
ductive work-up led to primary alcohol 64 as an easily sepa-
rable 4:1 diastereomeric mixture. Subsequent reduction of
the carboxyl to the methyl group followed by desilylation
and oxidation gave aldehyde 65 which was subjected to an
aldol addition with ketoimide 26. Diastereoselective 1,3-re-
duction followed by acid catalyzed lactonization furnished
lactone 66 which was converted into seco-acid 8 via the 7,9-
acetonide protected methyl ester. Macrolactonization of 8
Scheme 15. Synthesis of benzofuran 5 via RCM. a) N2ACTHNUGTRNE(UNG COOK)2, AcOH,
CH2Cl2, 40 h, reflux, 58%; b) 3n HCl, MeOH, RT, 96%; c) 3n HCl,
MeOH, RT, 71%; d) Grubbsꢂ II catalyst, 20 mol%, CH2Cl2, reflux, 16 h,
83% (E/Z 15:1); e) N2ACHTUNGTRENNUNG(COOK)2, AcOH, CH2Cl2, 5 h, reflux, 71%.
512
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Construction of the Ansamycin Antibiotic Kendomycin
FULL PAPER
under modified Boden–Keck conditions[32] worked nicely to
give 55% of monomer 67, which underwent clean photo-
Fries rearrangement to ketone 68. Reduction of the ketone
to the alcohol (diastereomeric mixture) followed by removal
of the acetonide and SN1 cyclization furnished key inter-
mediate 5.
a variety of conditions. Still convinced that it should be pos-
sible to work out a protecting group free endgame we tried
the direct oxidation of 5 with different oxidants, for instance
Fremyꢂs salt ((KSO3)2NO), CAN, Ag2O, PIDA, NaIO4 and
IBX. These experiments all failed, but finally we discovered
that DDQ in CH2Cl2/H2O cleanly oxidized 5 to o-quinone
71, which was immediately hydrolyzed to kendomycin (1)
on treatment with diluted hydrochloric acid.
Scheme 19. Oxidation of 5. a) TESOTf, Et3N, CH2Cl2, 08C, 82%; b) IBX,
DMF, RT, 24 h c) 0.1m HF, MeCN, RT, 30% (2 steps); d) DDQ, CH2Cl2/
H2O 10:1, RT, 52%; e) aq. HCl (1%), MeCN, 50%.
Scheme 18. Synthesis of benzofuran 5 via photo-Fries rearrangement.
a) EDCI, DMAP, 43, CH2Cl2, 85%; b) LHMDS, HMPA, TBSCl, ꢀ788C
! reflux; c) LiAlH4, Et2O, 0 8C, 84% from 63 (d.r. 4:1); d) i) MsCl, Et3N,
CH2Cl2, 08C; ii) LiAlH4, Et2O, 0 8C, 94% (2 steps); e) TBAF, THF, RT,
Conclusions
In conclusion we have presented four synthetic approaches,
two of which resulted in convergent total syntheses of ken-
domycin (1). For the stereoselective installation of the (E)-
13,14-olefin we investigated the experimental conditions for
three Ireland–Claisen reactions of unusual complexity, sum-
marized in Scheme 20 and Table 1, respectively.
93%; f) IBX, DMSO, RT, 93%; g) 26, Sn
then ꢀ788C, then 65, 87% (d.r. 6:1); h) Me4NBH
2:1, ꢀ32 ! 08C, 72% (d.r. 20:1); i) LiOH, H2O2, THF/H2O 3:1, 96%;
j) 3n HCl, dioxane, 508C; k) (CH3)2C(OMe)2, CSA, RT, 85% 2 steps;
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
l) LiOH, THF/MeOH/H2O 2:1:1, 12 h, RT, 84%; m) EDCI, DMAP,
DMAP·HCl, CHCl3, reflux, 20 h, 55%; n) hn, 254 nm, cyclohexane,
50 min, 75%; o) NaBH4, MeOH, RT, then 0.5n HCl; p) TsOH, toluene,
608C, 71% from 68.
Completion of the total synthesis: With two successful ap-
proaches for benzofuran intermediate 5 in our hands, we fo-
cused on the crucial oxidative endgame (Scheme 19). Firstly,
we reproduced Leeꢂs endgame[6a] by starting with protection
of the C7-OH to give the corresponding TES ether which
was then oxidized with IBX to provide the unstable yet isol-
able o-quinone 69. On treatment of 69 with aqueous HF, the
silyl group was removed and 1,6-conjugate addition of water
occurred to furnish the target molecule 1. In an alternative
approach we tried to avoid the OTES protecting group. For
this purpose we envisaged a biomimetic pathway, by first
converting 5 into catechol 70, followed by oxidation to qui-
none 71 and spontaneous addition of water. Unfortunately
we could not remove the phenolic methyl ether even under
Scheme 20. Ireland–Claisen rearrangements.
For the formation of the tetrahydopyran ring a remarka-
bly efficient SN1 cyclization was used either before or after
the macrocyclization. Regarding the crucial issue of ring clo-
sure, our work not only demonstrates the so far unrecog-
nized capability of the photo-Fries ring contraction for the
formation of macrocycles, but also reemphasizes the unpar-
alleled potential of RCM for connecting monosubstituted
olefin residues. Additionally a protecting group free end-
Chem. Eur. J. 2010, 16, 507 – 519
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
513

J. Mulzer et al.
Table 1. Reaction conditions for Ireland–Claisen rearrangements.
Preparative HPLC was performed on
a Dynamix Model SD-1 equipped with
Compound
Base (equiv)/SiR3X (equiv)[a]
Reaction conditions[b]
Product
Yield [%][c]
d.r.[d]
a
Model UV-1 absorbance detector
37a
37b
50
50
50
50
50
50
50
50
50
63
63
63
63
63
63
LDA (1.2)/TBSCl (1.1)
LDA (1.2)/TBSCl (1.1)
LDA (1.25)/TBSCl (1.1)
LDA (1.25)/TBSOTf (1.1)
LDA (3.0)/TMSCl (3.0)
LDA (3.0)/TBSCl (10.0)
LDA (3.2)/TBSCl (5.5)
LDA (5.0)/TBSCl (7.0)
LHMDS (1.25)/TBSCl (1.2)
LHMDS (4.0)/TBSCl (6.0)
LHMDS (4.0)/TBSCl (6.0)
LDA (1.25)/TBSCl (6.0)
LDA (5.0)/TBSCl (5.5)
LHMDS (4.0)/TBSCl (6.0)
LHMDS (5.0)/TBSCl (6.0)
LHMDS (6.0)/TBSCl (7.0)
LHMDS (4.0)/TBSCl (6.0)
THF/HMPA, 2h
THF, 2 h
39
39
51
51
51
51
51
51
51
51
51
64
64
64
64
64
64
63
traces
20
35
17
59
19
46
traces
64
5:1
using a Supershere (60 ꢃ pore size,
4 mm particle size, Ø 25 mmꢄ250 mm)
at ambient temperature. Yields refer
to chromatographically purified com-
pounds, unless otherwise stated.
n.d.
n.d.
5:1
n.d.
1.1:1
4:1
10:1
n.d.
1:1
THF/HMPA, 3 h
THF/HMPA, 15 h
THF/HMPA, 14 h, RT
THF/HMPA/toluene,[e] 1 h
THF, 2 h
THF/HMPA, 3 h
THF/HMPA, 3 h[f]
THF/HMPA, 3 h
THF/HMPA, 3h[f]
THF/DMPU, 2 h[f]
THF/DMPU, 2 h
THF/HMPA, 3 h[f]
THF/HMPA, 4 h[f]
THF/HMPA, 2 h[f]
THF/HMPA; DMF[f,g]
(S)-tert-Butyl-(4-methylhex-5-enyloxy)-
diphenylsilane (47): b-(+)-Citronellene
(20.3 g, 147 mmol, 1.0 equiv) and
sodium acetate (12.6 g, 154 mmol,
1.05 equiv) were dissolved in CH2Cl2
(490 mL) and cooled to ꢀ208C. m-
CPBA (75%, 35.4 g, 154 mmol,
1.05 equiv) was added in small por-
tions and stirring was continued for
1.5 h, allowing the suspension to warm
to 08C. The reaction was quenched by
careful addition of saturated aqueous
NaHCO3 (200 mL) and extracted with
CH2Cl2 (3ꢄ70 mL). The combined or-
ganic fractions were washed with 1n
NaOH (100 mL), dried over MgSO4
and concentrated in vacuo. The crude
product was dissolved in Et2O
(245 mL), cooled to 08C and H5IO6
(50 g, 220 mmol, 1.5 equiv) in THF
84
4:1
n.d.
n.d.
47
63
58
n.d.
n.d.
2:1
2:1
2:1
89
4:1
[a] Enolization and silylketene acetal formation were performed at ꢀ788C. [b] The reactions were refluxed,
unless otherwise stated. All rearrangement products were treated with LiAlH4 after workup. [c] Yields were
determined after reductive workup. [d] The diastereomeric ratio (d.r.) was determined by 1H NMR. [e] In-
ternal quench conditions. [f] The silylketene acetal was isolated before rearrangement. [g] The starting materi-
al was added as a solution in THF/TBSCl. The rearrangement was performed under microwave irradiation at
1808C.
game for converting 5 into 1 was developed, which saves an-
(220 mL) was added within 45 min. Stirring was continued until TLC
analysis showed complete consumption of the starting material. The mix-
ture was diluted with Et2O (500 mL), H2O (300 mL) was added and the
phases were separated. The organic layer was washed twice with brine,
dried over MgSO4 and filtered. This solution was recooled to 08C and
LiAlH4 (4m in Et2O, 44 mL, 176 mmol, 1.2 equiv) was added via a drop-
ping funnel over 2 h. The solution was slowly quenched with ethyl acetate
(10 mL), 1n KHSO4 (200 mL) was carefully added and the aqueous layer
was extracted with Et2O (3ꢄ100 mL). The organic fraction was dried
over MgSO4, filtered and evaporated to dryness. Purification of the resi-
due by flash chromatography (pentane/diethyl ether 5:1) afforded the al-
cohol as a colorless oil (13.0 g, 77% over 3 steps). [a]2D0 = +18.8 (c =
1.25, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.69 (ddd, J=17.4, 10.2,
7.4 Hz, 1H), 4.99–4.90 (m, 1H), 3.63 (t, J=6.3 Hz, 2H), 2.20–2.07 (m,
1H), 1.62–1.51 (m, 2H), 1.40–1.32 (m, 2H), 1.31–1.25 (br, OH), 1.00 ppm
(d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=144.4, 112.8, 63.1,
37.6, 32.6, 30.5, 20.2 ppm; IR (film): n˜ = 3331, 3077, 2935, 1640, 1455,
1419, 1374, 1058 cmꢀ1; HRMS (ESI): m/z: calcd for C7H12: 96.0939,
found: 96.0919 [MꢀH2O]+.
other synthetic step.
Experimental Section
All solvents were distilled prior to use, except THF, which was purchased
from Acros Organics (99.85%, H2O <50 ppm) and used without further
purification. Et2O, toluene and benzene were distilled from sodium.
CH2Cl2 and CHCl3 were passed through an Al2O3/MgSO4 column or dis-
tilled over P2O5. Acetone was distilled over P2O5. DMF, DMSO, NEt3,
iPr2NH, iPr2NEt, TMEDA, HMPA and 2,6-lutidine were distilled from
CaH2. TBSCl was dissolved in hexane or THF (3m), treated with Et3N
(3%) and transferred via
a syringe filter to the reaction mixture.
[CpZrHCl] was prepared according to the Negishi procedure.[33] Solvent
degassing was achieved by repeated (at least four cycles) freeze–pump–
thaw cycles. All non-aqueous reactions were performed under an atmos-
phere of argon using oven-dried or flame-dried glassware and standard
syringe/septa techniques. 1H- and 13C NMR spectra were measured in
Above-prepared alcohol (3.30 g, 28.8 mmol, 1.0 equiv) in DMF (29 mL)
was cooled to 08C and imidazole (3.92 g, 57.6 mmol, 2 equiv) was added.
After 5 min TBDPSCl (7.4 mL, 28.8 mmol, 1.0 equiv) was transferred to
the solution via cannula and stirring was continued for 1 h at ambient
temperature. The reaction mixture was diluted with Et2O (200 mL),
quenched with NH4Cl (100 mL) and the phases were separated. The
aqueous layer was extracted with Et2O (3ꢄ50 mL), the organic layer was
washed with brine, dried over MgSO4 and concentrated in vacuo. Purifi-
cation by flash chromatography (hexane/ethyl acetate 10:1) afforded
compound 47 as a colorless oil (9.10 g, 90%). [a]2D0 = +6.7 (c = 1.10,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.71–7.64 (m, 4H), 7.45–7.33
(m, 6H), 5.68 (ddd, J=17.3, 10.1, 7.3 Hz, 1H), 4.96–4.88 (m, 1H), 3.65 (t,
J=6.6 Hz, 2H), 2.16–2.04 (m, 1H), 1.62–1.52 (m, 2H), 1.39–1.32 (m,
2H), 1.05 (s, 9H), 0.98 ppm (d, J=6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=144.7, 135.6, 134.2, 129.5, 127.6, 112.5, 64.1, 37.4, 32.7, 30.2,
26.9, 20.2, 19.2 ppm; IR (film): n˜ = 2932, 1639, 1589, 1473, 1427, 1389,
CDCl3 on
a Bruker Avance DRX-400 or DRX-600 at 400.13 MHz
(100.61 MHz) or 600.13 MHz (150.90 MHz), respectively. Chemical shifts
are given in ppm and were referenced to residual CHCl3 (1H, d=
7.26 ppm, 13C, d=77.00 ppm) or toluene (1H, d=7.09, 7.00, 6.98 ppm, 13C,
d=137.9, 129.2, 128.3, 125.5, 20.4 ppm). Data are reported as follows:
chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, br=broad), coupling constant in Hz, integration. Assign-
ments of proton resonances were confirmed by correlated spectroscopy.
IR spectra were recorded as thin films on a silicon plate on a Perkin–
Elmer 1600 FT-IR spectrometer. Mass spectra were measured on a Micro
mass, trio 200 Fisions Instruments. High-resolution mass spectra (HRMS)
were performed with a Finnigan MAT 8230 with a resolution of 10000.
Optical rotations were measured on a Perkin–Elmer 351 polarimeter at
208C (reported as follows: concentration (c in g per 100 mL), solvent).
The reaction progress was monitored on precoated TLC plates (Merck
Kieselgel 60 F254). Spots were visualized under UV light (254 nm) and/
or were stained with ceric ammonium molybdate (CAM), p-anisaldehyde
or potassium permanganate stain. Column chromatography was per-
formed with Merck silica gel 60 (230–400 mesh). Analytical HPLC was
performed on a Jasco System (PU-980 pump, UV 975 and RI 930) using
a Nucleosil 50 column (5 mm, Ø 4 mmꢄ241 mm) at ambient temperature.
1361, 1112 cmꢀ1
; HRMS (ESI): m/z: calcd for C19H23OSi: 295.1518,
found: 295.1522 [MꢀtBu]+.
(S)-tert-Butyl(4-(oxiran-2-yl)pentyloxy)diphenylsilane (44): Alkene 47
(5.91 g, 16.74 mmol, 1.0 equiv) was dissolved in CH2Cl2 (57 mL) and
cooled to 08C. m-CPBA (75%, 9.3 g, 40.17 mmol, 2.4 equiv) was added
514
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 507 – 519

Construction of the Ansamycin Antibiotic Kendomycin
FULL PAPER
in small portions and stirring was continued for 3 h. The reaction was fil-
tered over Celite, quenched by the careful addition of saturated aqueous
NaHCO3 (70 mL) and extracted with CH2Cl2 (3ꢄ70 mL). The combined
organic fractions were dried over MgSO4 and concentrated in vacuo. Pu-
rification of the residue by flash chromatography (hexane/ethyl acetate
10:1 ! 5:1) afforded epoxide 44 as a colorless oil (mixture of diastereo-
1.57 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.07 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=164.0, 147.9, 145.1, 142.4, 135.6, 134.0, 129.5,
127.6, 124.1, 113.8, 102.0, 100.7, 63.8, 61.4, 33.3, 31.6, 30.0, 26.9, 19.2, 19.1,
9.3 ppm; IR (film): n˜ = 3529, 2933, 2858, 1607, 1459, 1427, 1360, 1111,
864 cmꢀ1; HRMS (ESI): m/z: calcd for C31H38O4Si: 502.2539; found:
502.2537 [M]+.
1
mers) (5.91 g, 96%). H NMR (The asterisk denotes the minor diastereo-
Crude furan (13 g, 25.95 mmol, 1.0 equiv) in DMF (130 mL) was cooled
to 08C. Then NaH (1.5 g, 38.85 mmol, 1.5 equiv) was added in small por-
tions, followed by the careful addition of neat MOMCl (2.75 mL,
36.26 mmol, 1.4 equiv). The dark-brown solution was stirred for 1 h, di-
luted with Et2O (200 mL) and quenched with saturated aqueous NH4Cl
(150 mL). The product was extracted with Et2O/hexane 1:1 (3ꢄ50 mL),
washed with brine and dried over anhydrous MgSO4. The solvent was
evaporated and the pale yellow oil was purified by column chromatogra-
mer, 400 MHz, CDCl3): d=7.69–7.65 (m, 4H), 7.45–7.35 (m, 6H), 3.70–
3.63 (m, 2H), 2.75–2.64 (m, 2H), 2.51–2.47ACTHNUTRGNE(NUG m, 1H), 2.47–2.44* (m, 1H),
1.72–1.55 (m, 2H), 1.52–1.40 (m, 1H), 1.40–1.19 (m, 2H), 1.06 (s, 9H),
1.02 (d, J=6.6 Hz, 3H), 0.92* ppm (d, J=6.8, 3H); 13C NMR (The aster-
isk denotes the minor diastereomer, 100 MHz, CDCl3): d=135.6, 134.1*,
134.0, 129.6, 129.5*, 127.6, 64.1*, 64.0, 57.0, 56.9*, 46.9, 45.6*, 36.0, 35.8*,
30.7*, 30.1, 29.9*, 29.7, 26.9, 19.2, 17.1, 15.6* ppm; IR (film): n˜ = 3071,
3048, 2932, 1590, 1472, 1428, 1390, 1361, 1268, 1189, 1112 cmꢀ1; HRMS
(ESI): m/z: calcd for C21H25O2Si: 311.1467; found: 311.1464 [MꢀtBu]+.
(S)-6-(tert-Butyldiphenylsilyloxy)-1-(4-methoxy-2,5-bis(methoxyme-
thoxy)-3-methylphenyl)-3-methylhexan-2-one (48): Bromide 45 (11.3 g,
35.18 mmol, 3 equiv) was dissolved in THF (50 mL). Mg (855 mg,
35.18 mmol, 3 equiv), a crump of iodine and 2 drops of dibromoethane
were added and the mixture was heated to reflux until the Mg has been
completely consumed (1.5 h). The reaction was allowed to cool to room
temperature and transferred to a solution of CuI (223 mg, 1.17 mmol,
0.1 equiv) in THF (12 mL) at ꢀ508C. The resulting grey suspension was
stirred for 30 min at ꢀ308C and then cooled to ꢀ458C. Epoxide 44
(4.3 g, 11.7 mmol, 1 equiv) in THF (23 mL) was added dropwise and the
temperature was raised to 08C within 4 h. The reaction was quenched by
the addition of saturated aqueous NH4Cl (100 mL) and the phases were
separated. The aqueous layer was extracted with Et2O (4ꢄ50 mL), the
combined organic phases were dried over MgSO4, filtered and concen-
trated. Purification by flash chromatography (hexane/ethyl acetate 10:1
! 3:1) gave a diastereomeric mixture of the alcohols (6.2 g, 87%).
phy (hexane/ethyl acetate 3:1) to furnish furan 49 (13.4 g, 95%). [a]D20
=
1
+12.6 (c = 1.40, CH2Cl2); H NMR (400 MHz, CDCl3): d=7.68–7.62 (m,
4H), 7.44–7.31 (m, 6H), 7.07 (s, 1H), 6.22 (s, 1H), 5.21 (s, 2H), 3.84 (s,
3H), 3.67 (t, J=6.2 Hz, 2H), 3.55 (s, 3H), 2.93–2.86 (m, 1H), 2.40 (s,
3H), 1.90–1.80 (m, 1H), 1.71–1.59 (m, 1H), 1.63–1.54 (m, 2H), 1.29 (d,
J=7.1 Hz, 3H), 1.04 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
164.0, 149.2, 146.9, 145.5, 135.5, 134.0, 129.5, 127.6, 123.4, 115.3, 105.0,
100.8, 96.2, 63.8, 61.0, 56.1, 33.3, 31.6, 30.0, 26.8, 19.2, 19.1, 9.1 ppm; IR
(film): n˜
= 2932, 1684, 1653, 1559, 1473, 1427, 1260, 1153, 1112,
1044 cmꢀ1; HRMS (ESI): m/z: calcd for C33H42O5Si: 546.2802; found:
546.2792 [M]+.
(S)-4-(6-Methoxy-5-(methoxymethoxy)-7-methylbenzofuran-2-yl)penta-
noic acid (43):
A solution of benzofuran 49 (7.63 g, 13.93 mmol,
1.0 equiv) in THF (280 mL) was treated with TBAF (1m in THF,
15.33 mL, 15.33 mmol, 1.1 equiv) and stirred overnight at room tempera-
ture. Finally the reaction was quenched with NH4Cl (150 mL) and the
aqueous layer was extracted with Et2O (3ꢄ100 mL). The combined or-
ganic extracts were dried over MgSO4, filtered and evaporated to dry-
ness. Purification by column chromatography using gradient elution
(hexane/ethyl acetate 3: 1 ! 1:1) furnished the alcohol as a pale yellow
Oxalylchloride (1.72 mL, 20.30 mmol, 2 equiv) was dissolved in CH2Cl2
(50 mL), cooled to ꢀ788C and DMSO (2.88 mL, 40.60 mmol, 4 equiv)
was added dropwise. After 40 min, above alcohol (6.2 g, 10.15 mmol,
1 equiv) in CH2Cl2 (20 mL) was added via syringe and stirring was con-
tinued for additional 45 min. DIPEA (10.6 mL, 60.90 mmol, 6 equiv) was
added and the solution was warmed to 08C. The reaction was hydrolyzed
with saturated aqueous NH4Cl (100 mL), extracted with CH2Cl2 (3ꢄ
50 mL), washed with brine, dried over MgSO4 and filtered. Purification
by column chromatography (hexane/ethyl acetate 5:1 ! 3:1) afforded
1
oil (3.84 g, 89%). [a]2D0 = +13.4 (c = 1.60, CH2Cl2); H NMR (400 MHz,
CDCl3): d=7.07 (s, 1H), 6.27 (s, 1H), 5.21 (s, 2H), 3.84 (s, 3H), 3.64 (t,
J=6.3 Hz, 2H), 3.54 (s, 3H), 2.99–2.89 (m, 1H), 2.42 (s, 3H), 1.88–1.77
(m, 1H), 1.73–1.63 (m, 1H), 1.65–1.54 (m, 2H), 1.32 ppm (d, J=7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=163.7, 149.2, 146.9, 145.6, 123.4,
115.3, 105.0, 101.0, 96.2, 62.9, 61.0, 56.1, 33.5, 31.6, 30.3, 19.1, 9.1 ppm; IR
(film): n˜ = 3854, 3676, 2935, 1653, 1559, 1457, 1153, 1043 cmꢀ1; HRMS
(ESI): m/z: calcd for C17H24O5: 308.1624; found: 308.1620 [M]+.
ketone 48 (5.8 g, 95%). [a]D20
= +9.1 (c =
0.95, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=7.68–7.63 (m, 4H), 7.45–7.34 (m, 6H), 6.74 (s,
1H), 5.14 (s, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.73 (d, J=3.8 Hz, 2H), 3.63
(t, J=6.2 Hz, 2H), 3.51 (s, 3H), 3.48 (s, 3H), 2.68–2.58 (m, 1H), 2.20 (s,
3H), 1.80–1.70 (m, 1H), 1.56–1.47 (m, 2H), 1.48–1.39 (m, 1H), 1.09 (d,
J=6.8 Hz, 3H), 1.04 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
211.8, 150.0, 148.0, 146.9, 135.5, 134.0, 129.5, 127.6, 125.8, 123.5, 116.2,
99.7, 95.5, 63.7, 60.4, 57.4, 56.2, 45.0, 43.3, 30.1, 29.1, 26.8, 19.2, 16.5,
A
100 mL Schlenk flask was charged with above alcohol (3.57 g,
11.58 mmol, 1.0 equiv) and DMSO (60 mL, 0.2m). IBX (8.1 g,
28.94 mmol, 2.5 equiv) was added over a period of 20 min and stirring
was continued for 2 h at ambient temperature. The solution was diluted
with Et2O/hexane 1:1 (100 mL) and H2O (100 mL). The mixture was fil-
tered over Celite, the layers were separated and the aqueous layer was
extracted with Et2O/hexane 1:1 (3ꢄ50 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered and concentrated in vacuo.
The crude product was filtered over a plug of silica to give pure aldehyde
as a pale orange oil (3.43 g, 97%). [a]2D0 = +17.2 (c = 0.75, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=9.74 (t, J=1.4 Hz, 1H), 7.08 (s, 1H),
6.28 (s, 1H), 5.21 (s, 2H), 3.84 (s, 3H), 3.54 (s, 3H), 3.03–2.93 (m, 1H),
2.47 (dt, J=7.5, 1.4 Hz, 2H), 2.41 (s, 3H), 2.10–1.93 (m, 2H), 1.34 ppm
(d, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=202.0, 162.3, 149.3,
147.1, 145.8, 123.2, 115.4, 105.1, 101.6, 96.1, 61.0, 56.1, 41.6, 33.0, 27.7,
19.0, 9.1 ppm; IR (film): n˜ = 2932, 1723, 1653, 1559, 1457, 1340, 1219,
1153, 1119, 1090, 1042 cmꢀ1; HRMS (ESI): m/z: calcd for C17H22O5:
306.1467; found: 306.1464 [M]+.
10.4 ppm; IR (film): n˜
= 2933, 1710, 1559, 1481, 1237, 1155, 1112,
967 cmꢀ1; HRMS (ESI): m/z: calcd for C35H48O7Si: 608.3169; found:
608.3186 [M]+.
(S)-tert-Butyl(4-(6-methoxy-5-(methoxymethoxy)-7-methylbenzofuran-2-
yl)pentyloxy)diphenylsilane (49): Ketone 48 (15.8 g, 25.95 mmol,
1.0 equiv) and molecular sieves (4 ꢃ, 15.8 g) in of toluene/EtOH 4:1
(500 mL) were heated to 808C. After the addition of TfOH (689 mL,
7.79 mmol, 0.3 equiv) stirring was continued at 808C for 5 min and then
the mixture was rapidly cooled to 08C. The reaction was quenched by
the addition of saturated NaHCO3 (300 mL), filtered over Celite and the
mixture was extracted with Et2O (3ꢄ100 mL). The combined organic
layers were dried over anhydrous MgSO4 and the solvent was removed in
vacuo affording crude furan (13 g, 100%), which was used without fur-
ther purification in the next step. A small sample was purified by column
chromatography (hexane/ethyl acetate 5:1 ! 3:1) to obtain an analytical-
ly pure sample. [a]2D0 = +12.1 (c = 2.45, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.70–7.65 (m, 4H), 7.45–7.33 (m, 6H), 6.90 (s, 1H), 6.23 (d,
J=0.5 Hz, 1H), 5.52 (s, 1H), 3.84 (s, 3H), 3.69 (t, J=6.3 Hz, 2H), 2.96–
2.86 (m, 1H), 2.45 (s, 3H), 1.93–1.82 (m, 1H), 1.74–1.63 (m, 1H), 1.67–
Above aldehyde (3.43 g, 11.19 mmol, 1.0 equiv) was dissolved in tBuOH
(75 mL, 0.15m), treated with 2-methyl-2-butene (1 mLmmolꢀ1, 11.2 mL),
and cooled to 58C. NaClO2 (18.9 g, 167.85 mmol, 15 equiv) and 18.9 g
NaH2PO4 were dissolved in H2O (110 mL, 1.5m), transferred to a 250 mL
dropping funnel, and added over a period of 20 min. After 50 min at RT.
TLC analysis showed complete consumption and the reaction mixture
was partitioned between CH2Cl2 (150 mL) and brine (100 mL). The aque-
ous layer was extracted with three portions of CH2Cl2 (50 mL) and the
Chem. Eur. J. 2010, 16, 507 – 519
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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515

J. Mulzer et al.
combined organic extracts were dried over MgSO4. Evaporation of the
solvent gave crude acid, which was purified by flash chromatography
(hexane/ethyl acetate 3:1 ! 1:1) to give acid 43 as an orange-viscous oil
(3.60 g, 99%). [a]2D0 = +35.5 (c = 0.65, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.08 (s, 1H), 6.29 (s, 1H), 5.21 (s, 2H), 3.85 (s, 3H), 3.54 (s,
3H), 3.04–2.94 (m, 1H), 2.42–2.35 (m, 2H), 2.41 (s, 3H), 2.12–1.92 (m,
2H), 1.34 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
177.7, 162.4, 149.3, 147.0, 145.7, 123.2, 115.4, 105.1, 101.6, 96.2, 61.0, 56.1,
33.0, 31.4, 30.2, 19.0, 9.1 ppm; IR (film): n˜ = 3629, 2933, 1707, 1653,
1607, 1559, 1457, 1420, 1261, 1153, 1117, 1043 cmꢀ1; HRMS (ESI): m/z:
calcd for C17H22O6: 322.1416; found: 322.1421 [M]+.
416.2563; found: 416.2569 [M+Na]+. (R)-51: [a]D20 = ꢀ18.4 (c = 1.10,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d d=7.07 (s, 1H), 6.26 (s, 1H),
5.75 (ddd, J=17.0, 10.4, 6.4 Hz, 1H), 5.21 (s, 2H), 5.04 (dd, J=8.8,
1.0 Hz, 1H), 4.98 (dt, J=17.2, 1.6 Hz, 1H), 4.91 (dt, J=10.1, 1.5 Hz, 1H),
3.84 (s, 3H), 3.57–3.52 (m, 2H), 3.54 (s, 3H), 3.11–3.00 (m, 2H), 2.41 (s,
3H), 2.05 (dd, J=14.4, 6.8 Hz, 2H), 1.97 (dd, J=13.5, 6.4, 1H), 1.79–1.69
(m, 2H), 1.62–1.51 (m, 1H), 1.55 (d, J=1.3 Hz, 3H), 1.30 (d, J=6.8 Hz,
3H), 1.04 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
163.8, 149.2, 147.0, 145.6, 142.9, 133.2, 130.7, 123.4, 115.3, 112.0, 105.0,
101.0, 96.2, 65.7, 61.0, 56.1, 42.7, 36.9, 36.3, 36.0, 31.4, 20.6, 20.3, 16.1,
9.1 ppm; IR (film): n˜ = 3451, 2928, 1606, 1451, 1340, 1219, 1154, 1117,
1090, 1044 cmꢀ1; HRMS (ESI): m/z: calcd for C25H36O5: 416.2563; found:
416.2565 [M]+.
(S)-((3S,4S)-2,4-Dimethylhexa-1,5-dien-3-yl) 4-(6-methoxy-5-(methoxy-
methoxy)-7-methylbenzofuran-2-yl)pentanoate (50): A mixture of acid 43
(2.55 g, 7.91 mmol, 1.0 equiv), alcohol 42 (1.20 g, 9.51 mmol, 1.2 equiv),
EDCI·HCl (1.97 g, 10.28 mmol, 1.3 equiv) and DMAP (1.26 g,
10.31 mmol, 1.3 equiv) in CH2Cl2 (30 mL) was stirred at room tempera-
ture for 1.5 h. The reaction was diluted with CH2Cl2 (100 mL), quenched
with 1% HCl (20 mL) and washed with brine (2ꢄ50 mL). The organic
layer was dried over MgSO4, concentrated in vacuo and the residue was
purified by flash chromatography (hexane/ethyl acetate 15:1 ! 5:1) to
give ester 50 (2.75 g, 81%). [a]2D0 = +26.8 (c = 1.30, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=7.07 (s, 1H), 6.27 (s, 1H), 5.70 (ddd, J=17.2, 10.2,
8.0 Hz, 1H), 5.21 (s, 2H), 5.06–4.98 (m, 2H), 5.05 (d, J=7.8 Hz, 1H),
4.96–4.91 (m, 2H), 3.84 (s, 3H), 3.54 (s, 3H), 3.02–2.91 (m, 1H), 2.52–
2.43 (m, 1H), 2.41 (s, 3H), 2.36–2.30 (m, 2H), 2.10–1.99 (m, 1H), 1.99–
1.89 (m, 1H), 1.72 (s, 3H), 1.32 (d, J=7.1 Hz, 3H), 0.96 ppm (d, J=
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=172.5, 162.7, 149.3, 147.0,
145.7, 141.8, 139.8, 123.3, 115.2, 114.4, 113.4, 105.1, 101.4, 96.2, 80.3, 61.0,
56.1, 40.0, 33.0, 32.1, 30.5, 18.9, 18.2, 16.6, 9.1 ppm; IR (film): n˜ = 2967,
1734, 1700, 1684, 1653, 1559, 1457, 1152, 1117 cmꢀ1; HRMS (ESI): m/z:
calcd for C25H34O6Na: 453.2253; found: 453.2269 [M+Na]+.
6-Methoxy-5-(methoxymethoxy)-7-methyl-2-((2S,4S,8S,E)-4,6,8-trimethyl-
deca-6,9-dien-2-yl)benzofuran (52): Alcohol 51 (370 mg, 0.89 mmol,
1.0 equiv) was dissolved in CH2Cl2 (5 mL), cooled to 08C and treated
with Et3N (150 mL, 1.06 mmol, 1.2 equiv). After 5 min MsCl (80 mL,
1.06 mmol, 1.2 equiv) was added and stirring was continued for 30 min.
The solution was poured onto H2O (20 mL), extracted with CH2Cl2 (3ꢄ
10 mL), washed with brine and dried over MgSO4. The solvent was
evaporated under reduced pressure and the crude mesylate was immedi-
ately redissolved in Et2O (9 mL). LiAlH4 (4m in Et2O, 670 mL,
2.67 mmol, 3 equiv) was carefully added to the ice cooled solution and
the cloudy mixture was allowed to warm to room temperature over
30 min. After 2 h the reaction mixture was quenched at 08C by slow ad-
dition of ethyl acetate, diluted with Et2O (40 mL) and washed with 1%
HCl (10 mL). The aqueous layer was extracted with Et2O (3ꢄ10 mL),
and the combined organic fractions were washed with brine (10 mL),
dried over MgSO4 and the solvent was removed in vacuo. Purification by
flash chromatography (hexane/ethyl acetate 5:1) afforded diolefin 52 as a
an oil (310 mg, 89%). [a]D20
= +3.0 (c =
1.35, CH2Cl2); 1H NMR
ACHTUNGTRENNUNG(2S,6S,E)-2-((S)-2-(6-Methoxy-5-(methoxymethoxy)-7-methylbenzofuran-
(400 MHz, CDCl3): d=7.07 (s, 1H), 6.24 (s, 1H), 5.76 (ddd, J=17.2, 10.4,
6.1 Hz, 1H), 5.21 (s, 2H), 4.99–4.94, m 1H), 4.96 (dt, J=17.3, 1.7 Hz,
1H), 4.88 (dt, J=10.4, 1.6 Hz, 1H), 3.84 (s, 3H), 3.54 (s, 3H), 3.11–2.95
(m, 2H), 2.42 (s, 3H), 2.07 (dd, J=13.3, 5.2 Hz, 1H), 1.79 (dd, J=12.6,
8.1 Hz, 1H), 1.74–1.64 (m, 1H), 1.59–1.44 (m, 2H), 1.57 (d, J=1.3 Hz,
3H), 1.27 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 0.83 ppm (d, J=
6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=164.7, 149.1, 146.8, 145.8,
142.9, 133.3, 130.1, 123.5, 115.3, 111.7, 105.0, 100.4, 96.2, 61.0, 56.1, 48.0,
43.0, 36.3, 31.3, 28.3, 20.6, 19.5, 19.1, 16.1, 9.1 ppm; IR (film): n˜ = 2926,
1684, 1653, 1559, 1507, 1458, 1153, 1117, 1044 cmꢀ1; HRMS (ESI): m/z:
calcd for C25H36O4: 400.2614; found: 400.2607 [M]+.
2-yl)propyl)-4,6-dimethylocta-4,7-dien-1-ol (51): LHMDS (1m in THF,
11.1 mL, 12.08 mmol, 4 equiv) was diluted with THF (12 mL), cooled to
ꢀ788C and freshly distilled HMPA (7.5 mL) was slowly added via cannu-
la. After 5 min ester 50 (2.3 g, 3.28 mmol, 1.0 equiv) in THF (2.1 mL,
0.5 mL rinse) was transferred to a freshly prepared TBSCl solution (3m
in THF, 6.56 mL, 19.68 mmol, 6 equiv) and added dropwise to the above
LHMDS/HMPA mixture. The reaction mixture was stirred for 40 min at
ꢀ788C, allowed to warm to 08C over 15 min, stirred for additional 5 min
at room temperature and partitioned between H2O (100 mL) and Et2O
(3ꢄ70 mL). The combined organic fractions were washed with brine,
dried over MgSO4 and evaporated to dryness. The crude ketene silyl
acetal was dissolved in DMF (12 mL) and heated under microwave irra-
diation at 1808C for 15 min. The mixture was partitioned between H2O
(100 mL) and Et2O (100 mL), extracted with Et2O (3ꢄ50 mL), washed
with brine (50 mL), dried over MgSO4 and concentrated under reduced
pressure. The crude ester was dissolved in Et2O (30 mL), transferred to
an ice-bath and LiAlH4 (4m in Et2O, 1.51 mL, 6.04 mmol, 2 equiv) was
added carefully via cannula. After 30 min at room temperature TLC
analysis showed complete consumption of the starting material and the
reaction mixture was quenched at 08C by slow addition of ethyl acetate,
diluted with Et2O (100 mL) and washed with 1% HCl (100 mL). The
aqueous layer was extracted with Et2O (3ꢄ50 mL), and the combined or-
ganic fractions were washed with brine (50 mL), dried over MgSO4 and
the solvent was removed in vacuo. Purification by column chromatogra-
phy (hexane/ethyl acetate 10:1 ! 5:1) afforded alcohol 51 as a colorless
2R,4S,5R)-1-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-5-hydroxy-2,4-dimethyl-
hept-6-ene-1,3-dione (53): A 250 mL Schlenk flask was charged with
acid-free SnACHTNUTRGNEUNG(OTf)2 (5.3 g, 12.71 mmol, 1.1 equiv) and CH2Cl2 (42 mL,
0.3m). The white suspension was treated at ꢀ208C with Et3N (1.76 mL,
12.71 mmol, 1.1 equiv) whereupon the mixture turned pale yellow. After
5 min b-ketoimide 26 (3.34 g, 11.54 mmol, 1.0 equiv) in CH2Cl2 (19 mL,
0.6m) was added dropwise and the clear solution was stirred for 1 h at
ꢀ208C. Freshly distilled acrolein (2.31 mL, 34.62 mmol, 3 equiv) was dis-
solved in CH2Cl2 (35 mL, 1m) and slowly added at ꢀ788C. After 30 min
at ꢀ788C, the yellow-orange solution was poured onto a cooled (08C)
and vigorously stirred mixture of CH2Cl2/1m NaHSO4 1:1 (150 mL).
After 20 min at room temperature the aqueous phase was extracted with
CH2Cl2 (3ꢄ50 mL), the organic phase was washed with saturated aque-
ous NaHCO3, dried over MgSO4 and concentrated. Purification of the
residue by gradient flash chromatography (hexane/ethyl acetate 3:1 !
1:1) yielded 53 as a viscous oil (3.64 g, 91%, d.r. 5:1 as determined by
oil (1.11 g, 89%, d.r. 4:1 as determined by 1H NMR). (S)-51: [a]2D0
=
+9.5 (c = 1.95, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.07 (s, 1H),
6.28 (s, 1H), 5.74 (ddd, J=17.1, 10.5, 6.4 Hz, 1H), 5.21 (s, 2H), 5.05 (d,
J=8.8 Hz, 1H), 4.95 (dt, J=17.2, 1.6 Hz, 1H), 4.89 (dt, J=10.2, 1.5 Hz,
1H), 3.84 (s, 3H), 3.54 (s, 3H), 3.49 (d, J=5.1 Hz, 2H), 3.12–2.97 (m,
2H), 2.41 (s, 3H), 2.13–1.99 (m, 2H), 1.88–1.78 (m, 1H), 1.78–1.69 (m,
1H), 1.62 (d, J=1.3 Hz, 3H), 1.49–1.41 (m, 1H), 1.42–1.36 (br, OH), 1.31
(d, J=7.1 Hz, 3H), 1.05 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=163.9, 149.2, 146.9, 145.6, 142.9, 133.3, 130.7, 123.4, 115.3,
112.0, 105.0, 100.9, 96.2, 66.1, 61.0, 56.1, 42.8, 37.7, 36.4, 36.2, 31.5, 20.5,
20.1, 16.2, 9.1 ppm; IR (film): n˜ = 3451, 2927, 1559, 1449, 1340, 1219,
1154, 1116, 1091, 1044 cmꢀ1; HRMS (ESI): m/z: calcd for C25H36O5:
HPLC and 1H NMR). [a]2D0
=
ꢀ115.3 (c
=
1.6, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=7.37–7.27 (m, 3H), 7.23–7.17 (m, 2H), 5.82 (ddd,
J=16.9, 10.7, 5.9 Hz, 1H), 5.31 (d, J=17.2 Hz, 1H), 5.20 (d, J=10.6 Hz,
1H), 4.87 (q, J=7.2 Hz, 1H), 4.80–4.72 (m, 1H), 4.49–4.43 (br, 1H),
4.30–4.24 (m, 1H), 4.19 (dd, J=9.1, 3.0 Hz, 1H), 3.30 (dd, J=13.5,
3.2 Hz, 1H), 2.93–2.84 (m, 1H), 2.78 (dd, J=13.5, 9.6 Hz, 1H), 2.46(d,
J=3.3 Hz, OH), 1.48 (d, J=7.3 Hz, 3H), 1.24 ppm (d, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=210.8, 170.4, 153.3, 137.5, 135.0, 129.3,
129.0, 127.4, 116.3, 72.7, 66.5, 55.3, 52.0, 48.9, 38.0, 12.8, 10.9 ppm; IR
(film): n˜ = 3629, 3510, 2984, 1773, 1684, 1653, 1559, 1456, 1362, 1214,
516
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 507 – 519

Construction of the Ansamycin Antibiotic Kendomycin
FULL PAPER
1121 cmꢀ1; HRMS (ESI): m/z: calcd for C19H23O5NNa: 368.1473; found:
368.1477 [M+Na]+.
quenched by slow addition of ethyl acetate, diluted with Et2O (80 mL)
and washed with 1% HCl (100 mL). The aqueous layer was extracted
with Et2O (3ꢄ50 mL), and the combined organic fractions were washed
with brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purifi-
cation by column chromatography (hexane/ethyl acetate 3:1) afforded
the alcohol as a colorless oil (761 mg, 96%). [a]2D0 = +11.8 (c = 0.80,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.80 (ddd, J=17.1, 10.1,
6.2 Hz, 1H), 5.26(dt, J=17.3, 1.6 Hz, 1H), 5.16 (dt, J=10.8, 1.6 Hz, 1H),
4.39–4.34 (m, 1H), 3.70–3.65 (m, 2H), 3.57 (dd, J=8.1, 2.7 Hz, 1H), 2.36
(t, J=5.4 Hz, OH), 2.01–1.92 (m, 1H), 1.90–1.81 (m, 1H), 1.38 (s, 3H),
1.35 (s, 3H), 0.99 (d, J=7.0 Hz, 3H), 0.83 ppm (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=135.7, 115.7, 100.6, 76.8, 71.1, 67.1, 37.2,
36.5, 25.4, 23.8, 13.0, 10.6 ppm; IR (film): n˜ = 3423, 2987, 1684, 1653,
1559, 1507, 1457, 1380, 1226, 1180, 1027 cmꢀ1; HRMS (ESI): m/z: calcd
for C11H19O3: 199.1334; found: 199.1332 [MꢀMe]+.
A solution of the above prepared alcohol (23 mg, 0.107 mmol, 1.0 equiv)
in CH2Cl2 (0.5 mL, 0.2m) was cooled to ꢀ58C. Et3N (45 mL, 0.321 mmol,
3 equiv) and subsequently SO3·Pyr (51 mg, 0.321 mmol, 3 equiv) in
DMSO (0.5 mL, 0.6m) were added dropwise. The mixture was stirred for
1.5 h at ꢀ58C and quenched with aqueous 1m KHSO4 solution (0.5 mL).
The phases were partitioned between brine and Et2O (1:1, 40 mL) and
the aqueous layer was extracted with Et2O (3ꢄ10 mL). The combined or-
ganic fractions were concentrated to 5 mL under reduced pressure, fil-
tered over a plug of silica and excess solvent was removed in vacuo to
afford aldehyde 46 (23 mg, 99%). [a]2D0 = ꢀ39.0 (c = 0.70, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=9.71 (d, J=1.0 Hz, 1H), 5.80 (ddd, J=
17.1, 10.7, 6.2 Hz, 1H), 5.27(dt, J=17.3, 1.7 Hz, 1H), 5.18 (dt, J=10.6,
1.6 Hz, 1H), 4.40–4.35 (m, 1H), 3.84 (dd, J=8.1, 3.3 Hz, 1H), 2.44 (ddq,
J=7.0, 3.2, 0.9 Hz, 1H), 2.04–1.94 (m, 1H), 1.36 (s, 3H), 1.33 (s, 3H),
1.17 (d, J=7.0 Hz, 3H), 0.87 ppm (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=204.2, 135.4, 115.9, 100.8, 73.2, 70.9, 48.6, 36.7,
25.1, 23.8, 12.7, 7.8 ppm; IR (film): n˜ = 2986, 1734, 1684, 1653, 1559,
1507, 1458, 1380, 1225 cmꢀ1; HRMS (ESI): m/z: calcd for C11H17O3:
197.1178; found: 197.1171 [MꢀMe]+.
(3R,4S,5R,6R)-4-Hydroxy-3,5-dimethyl-6-vinyltetrahydro-2H-pyran-2-
one (54): Me4NBHACHTUNGTRENNUNG(OAc)3 (2.85 g, 10.85 mmol, 5 equiv) was dissolved in
MeCN/AcOH 1.9:1 (360 mL), cooled to ꢀ328C and aldol product 53
(750 mg, 2.17 mmol, 1.0 equiv) in MeCN (6 mL) was added dropwise.
The reaction was stirred for 3 h at ꢀ328C, allowed to warm to 08C over-
night, diluted with CH2Cl2 (100 mL) and quenched by the addition of sa-
turated aqueous Rochelleꢂs salt (150 mL). Saturated aqueous NaHCO3
was carefully added to the vigorously stirred solution over 20 min. After
1 h no more gas evolution was observed and the two-phase mixture was
partitioned between CH2Cl2 (400 mL) and H2O (100 mL). The aqueous
layer was extracted with CH2Cl2 (3ꢄ100 mL), and the combined organic
fractions were dried over MgSO4, filtered and concentrated in vacuo. Pu-
rification of the residue by flash chromatography (hexane/ethyl acetate
3:1) afforded the diol as a viscous oil (527 mg, 70%, d.r. ꢁ 6:1 as deter-
mined by 1H NMR). [a]2D0
=
ꢀ30.5 (c
=
0.80, CH2Cl2); 1H NMR
(600 MHz, CDCl3): d=7.36–7.31 (m, 2H), 7.30–7.27 (m, 1H), 7.22–7.18
(m, 2H), 5.97 (ddd, J=16.9, 10.9, 5.8 Hz, 1H), 5.32 (d, J=17.4 Hz, 1H),
5.21 (d, J=10.6 Hz, 1H), 4.73–4.68 (m, 1H), 4.34–4.30 (br, 1H), 4.27–
4.22 (m, 1H), 4.20 (dd, J=8.7, 2.6 Hz, 1H), 3.98 (d, J=9.8 Hz, 1H), 3.84
(dq, J=7.1, 1.9 Hz, 1H), 3.80–3.76 (br, OH), 3.41–3.34 (br, OH), 3.24
(dd, J=13.5, 3.4 Hz, 1H), 2.80 (dd, J=13.5, 9.3 Hz, 1H), 2.03–1.96 (m,
1H), 1.28 (d, J=7.2 Hz, 3H), 0.84 ppm (d, J=7.2 Hz, 3H); 13C NMR
(150 MHz, CDCl3): d=178.0, 152.8, 137.9, 134.9, 129.4, 129.0, 127.5,
115.7, 75.7, 73.4, 66.2, 55.0, 39.3, 39.2, 37.8, 12.1, 9.7 ppm; IR (film): n˜ =
3448, 2976, 1780, 1700, 1559, 1456, 1388, 1211 cmꢀ1; HRMS (ESI): m/z:
calcd for C19H25O5NNa: 370.1630; found: 370.1644 [M+Na]+.
A solution of the diol (1.98 g, 5.71 mmol, 1.0 equiv) in THF/H2O 3:1
(80 mL) was treated at 08C with H2O2 (30% in H2O, 2.3 mL). LiOH
(383 mg, 9.14 mmol, 1.6 equiv) was added and stirring was continued for
1 h at ambient temperature. The reaction was acidified by the addition of
1n HCl (20 mL) and stirred for further 5 min. The biphasic mixture was
diluted with H2O (100 mL), extracted with Et2O (3ꢄ70 mL), dried over
MgSO4 and concentrated under reduced pressure. Purification by flash
(S)-1-(6-Methoxy-5-(methoxymethoxy)-7-methyl-2-((2S,4S,8S,E)-4,6,8-tri-
methyldeca-6,9-dien-2-yl)benzofuran-4-yl)-2-((4R,5S,6R)-2,2,5-trimethyl-
6-vinyl-1,3-dioxan-4-yl)propan-1-ol (9a,b): To a solution of benzofuran 52
(100 mg, 0.250 mmol, 1.4 equiv) in THF (0.6 mL) freshly distilled
TMEDA (80 mL, 0.535 mmol, 3 equiv) was added at ambient tempera-
ture. The solution was cooled to ꢀ788C and nBuLi (156 mL, 0.250 mmol,
1.4 equiv) was added dropwise. After 1.5 h at ꢀ308C the orange solution
was recooled to ꢀ788C and aldehyde 46 (38 mg, 0.178 mmol, 1.0 equiv)
in THF (0.5 mL) was added via cannula. The reaction mixture was
warmed to ꢀ258C over 2 h, diluted with Et2O (40 mL) and finally
quenched with saturated aqueous NH4Cl solution (10 mL). The reaction
mixture was extracted with diethyl ether (3ꢄ10 mL), dried over MgSO4
and the solvent was removed in vacuo. The residue was purified by
column chromatography (hexane/ethyl acetate 20:1 ! 5:1) to furnish al-
chromatography (hexane/ethyl acetate 3:1
!
1:1) gave lactone 54
(700 mg, 72%). [a]2D0 = +103.8 (c = 0.60, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=5.85 (ddd, J=17.2, 11.0, 5.7 Hz, 1H), 5.40 (d, J=17.2 Hz,
1H), 5.3 (d, J=10.6 Hz, 1H), 4.80–4.74 (m, 1H), 3.88 (dd, J=9.6, 4.0 Hz,
1H), 2.57–2.48 (m, 1H), 2.27–2.19 (m, 1H), 2.09–2.01 (br, OH), 1.41 (d,
J=7.1 Hz, 3H), 0.97 ppm (d, J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=173.2, 133.6, 117.4, 79.9, 73.7, 60.4, 40.1, 37.9, 21.0, 14.4, 14.2,
5.5 ppm; IR (film): n˜ = 3446, 2977, 1718, 1700, 1653, 1559, 1507, 1458,
1213, 1094 cmꢀ1; HRMS (ESI): m/z: calcd for C9H12O2: 152.0837; found:
152.0844 [MꢀH2O]+.
(R)-Methyl 2-((4S,5S,6R)-2,2,5-trimethyl-6-vinyl-1,3-dioxan-4-yl)propa-
noate (55): Lactone 54 (700 mg, 4.11 mmol, 1.0 equiv) was dissolved in
2,2-dimethoxypropane (40 mL), treated with camphorsulfonic acid
(96 mg, 0.41 mmol, 0.1 equiv) and stirred overnight at room temperature.
The solution was diluted with Et2O (100 mL), neutralized with saturated
aqueous NaHCO3 (50 mL), extracted with Et2O (3ꢄ50 mL), washed with
brine (70 mL) and dried over MgSO4. The solvent was removed in vacuo
and the residue was purified by flash chromatography (hexane/ethyl ace-
tate 10:1) to yield ester 55 (903 mg, 91%). [a]2D0 = ꢀ20.3 (c = 1.05,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.79 (ddd, J=17.1, 10.7,
6.1 Hz, 1H), 5.25 (dt, J=17.3, 1.7 Hz, 1H), 5.16 (dt, J=10.5, 1.6 Hz, 1H),
4.39–4.35 (m, 1H), 3.71–3.66 (m, 1H), 3.69 (s, 3H), 2.59 (dq, J=6.99,
4.99 Hz, 1H), 2.00–1.90 (m, 1H), 1.34 (s, 3H), 1.33 (s, 3H), 1.21 (d, J=
7.1 Hz, 3H), 0.83 ppm (d, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=174.8, 134.7, 115.7, 100.7, 75.1, 70.8, 51.7, 42.9, 37.4, 25.2, 23.7, 12.8,
11.4 ppm; IR (film): n˜ = 2988, 1740, 1700, 1653, 1559, 1458, 1301, 1226,
1176, 1025, 1001 cmꢀ1; HRMS (ESI): m/z: calcd for C12H19O4: 227.1283;
found: 227.1289 [MꢀMe]+.
1
cohols 9a and 9b (97 mg, 90%, d.r. 4:1 as determined by H NMR). Sep-
aration of the diastereomers for analytical purpose was done by HPLC,
yielding diastereomer 9a and 9b as light orange, viscous oils. 9a: [a]D20
=
ꢀ3.9 (c = 0.95, CH2Cl2); 1H NMR (600 MHz, CDCl3): d=6.63 (s, 1H),
5.79–5.72 (m, 2H), 5.21 (dt, J=17.0, 1.7 Hz, 1H), 5.17 (dd, J=6.0, 4.9 Hz,
1H), 5.13 (dt, J=10.6, 1.7 Hz, 1H), 5.10 (d, J=5.7 Hz, 1H), 5.09 (d, J=
5.7 Hz, 1H), 4.98–4.95 (m, 1H), 4.95 (dt, J=17.4, 1.7 Hz, 1H), 4.88 (dt,
J=10.2, 1.5 Hz, 1H), 4.33 (t, J=5.7 Hz, 1H), 3.77 (s, 3H), 3.56 (s, 3H),
3.44 (d, J=4.5 Hz, OH), 3.32 (d, J=8.5, 1.3 Hz, 1H), 3.09–3.03 (m, 1H),
3.03–2.96 (m, 1H), 2.39 (s, 3H), 2.35–2.29 (m, 1H), 2.09 (dd, J=12.8,
5.7 Hz, 1H), 1.98–1.91 (m, 1H), 1.78 (dd, J=13.2, 7.9 Hz, 1H), 1.72–1.65
(m, 1H), 1.61–1.54 (m, 1H), 1.58 (d, J=1.1 Hz, 3H), 1.50–1.44 (m, 1H),
1.33 (s, 3H), 1.26 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.8 Hz, 3H), 1.11 (s,
3H), 1.05 (d, J=6.8 Hz, 3H), 0.82 (d, J=6.4 Hz, 3H), 0.72 ppm (d, J=
6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=164.0, 150.1, 147.0, 144.0,
143.3, 135.8, 133.3, 130.1, 125.1, 123.0, 115.5, 114.2, 111.7, 101.3, 100.5,
99.9, 76.8, 74.2, 71.7, 60.6, 57.4, 47.9, 43.0, 40.7, 37.1, 36.3, 31.2, 28.3, 25.3,
23.7, 20.6, 19.5, 19.1, 16.0, 12.4, 9.1, 8.8 ppm; IR (film): n˜ = 3497, 2965,
2930, 1844, 1636, 1458, 1381, 1224, 1159, 1116, 1054 cmꢀ1; HRMS (ESI):
m/z: calcd for C37H56O7Na: 635.3924; found: 635.3919 [M+Na]+. 9b:
(R)-2-((4S,5S,6R)-2,2,5-Trimethyl-6-vinyl-1,3-dioxan-4-yl)propanal (46):
Ester 55 (900 mg, 3.71 mmol, 1.0 equiv) in Et2O (40 mL) was cooled to
08C and LiAlH4 (4m in Et2O, 1.49 mL, 5.57 mmol, 1.5 equiv) was careful-
ly added via cannula. After 30 min at 08C TLC analysis showed complete
consumption of the starting material and the reaction mixture was
1
[a]2D0 = ꢀ13.1 (c = 0.90, CH2Cl2); H NMR (600 MHz, CDCl3): d=6.51-
Chem. Eur. J. 2010, 16, 507 – 519
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
517

J. Mulzer et al.
A
115.2*, 114.3*, 111.7, 98.9*, 82.8*, 80.2*,76.8*, 61.3*, 48.1*, 47.9, 42.9,
39.1, 37.7*, 36.3, 31.3, 28.3, 20.6, 19.5, 19.2, 16.0, 13.6*, 9.2, 6.6* ppm; IR
(film): n˜ = 3391, 2964, 2927, 1636, 1604, 1455, 1405, 1384, 1284, 1114,
1048 cmꢀ1; HRMS (ESI): m/z: calcd for C32H46O5: 510.3345; found:
510.3331 [M]+.
6.0 Hz, 1H), 5.27 (dt, J=17.4, 1.7 Hz, 1H), 5.17 (dd, J=10.8, 1.6 Hz,
1H), 5.13–5.08 (m, 3H), 4.98–4.95 (m, 1H), 4.96 (dt, J=17.4, 1.7 Hz,
1H), 4.88 (dt, J=10.2, 1.7 Hz, 1H), 4.40 (t, J=5.5 Hz, 1H), 3.97 (dd, J=
7.9, 1.5 Hz, 1H), 3.79 (s, 3H), 3.60 (s, 3H), 3.24–3.10 (br, OH), 3.10–3.03
(m, 1H), 3.03–2.97 (m, 1H), 2.40 (s, 3H), 2.35–2.29 (m, 1H), 2.07 (dd,
J=13.0, 5.9 Hz, 1H), 2.03–1.97 (m, 1H), 1.79 (dd, J=12.8, 8.3 Hz, 1H),
1.73–1.67 (m, 1H), 1.58–1.54 (m, 1H), 1.57 (d, J=1.5 Hz, 3H), 1.53–1.49
(m, 1H), 1.44 (s, 3H), 1.39 (s, 3H), 1.28 (d, J=6.8 Hz, 3H), 1.05 (d, J=
6.8 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.72 ppm
(d, J=6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=164.2, 150.1, 147.5,
144.4, 143.3, 136.1, 133.3, 130.1, 125.5, 123.0, 115.6, 114.4, 111.7, 100.6,
100.4, 100.2, 73.5, 71.4, 70.7, 60.7, 57.7, 48.0, 42.8, 41.0, 36.8, 36.3, 31.2,
28.2, 25.6, 24.1, 20.6, 19.4, 18.9, 16.0, 12.9, 10.7, 9.1 ppm; IR (film): n˜ =
3469, 2965, 2930, 1457, 1380, 1340, 1226, 1160, 1116, 1023 cmꢀ1; HRMS
(ESI): m/z: calcd for C37H56O7Na: 635.3924; found: 635.3915 [M+Na]+.
Diolefin 60: Compound 59 (50 mg, 0.098 mmol, 1.0 equiv) was dissolved
in degassed CH2Cl2 (100 mL) and heated to reflux (458C outside temper-
ature). Grubbsꢂ II catalyst (16.6 mg, 0.020 mmol, 0.2 equiv) in degassed
CH2Cl2 (13 mL) was added via syringe pump within 16 h. After comple-
tion of the addition the mixture was stirred for another 30 min. The tem-
perature was lowered to room temperature and air was bubbled through
the solution to destroy excess catalyst. The solvent was evaporated and
purification by column chromatography (hexane/ethyl acetate 5:1 ! 3:1)
afforded macrocycle 60 (39 mg, 83%, E/Z 15:1). The mixture was used in
the next step without further purification. 1H NMR (400 MHz, CDCl3):
d=6.66 (s, 1H), 5.59 (ddd, J=15.6, 8.7, 2.0 Hz, 1H), 5.54 (s, OH), 5.33
(dd, J=15.5, 2.1 Hz, 1H), 4.92 (d, J=9.1 Hz, 1H), 4.74 (d, J=10.1 Hz,
1H), 4.27 (dd, J=4.4, 2.1 Hz, 1H), 3.81 (s, 3H), 3.76–3.69 (m, 1H), 3.17–
3.04 (m, 1H), 3.04–2.93 (m, 1H), 2.44 (s, 3H), 2.12–2.04 (m, 1H), 1.95
(dd, J=12.8, 4.9 Hz, 2H), 1.87–1.79 (m, 1H), 1.79–1.71 (m, 1H), 1.69 (s,
3H), 1.66–1.45 (m, 2H), 1.55 (br, OH), 1.33 (d, J=7.1 Hz, 3H), 1.04 (d,
J=7.1 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H),
0.95 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.0,
148.3, 141.8, 136.8, 133.0, 130.2, 125.2, 122.4, 115.5, 112.9, 104.6, 76.7,
75.7, 61.4, 44.4, 43.4, 38.9, 38.4, 35.8, 31.0, 28.8, 22.1, 21.3, 19.2, 18.1, 12.8,
9.4, 7.0 ppm; IR (film): n˜ = 3450, 2967, 1683, 1653, 1456, 1404, 1380,
1321, 1109 cmꢀ1; HRMS (ESI): m/z: calcd for C30H42O5: 482.3032; found:
482.3023 [M]+.
Macrocycle 56: Compound 9a (80 mg, 0.131 mmol, 1.0 equiv) was dis-
solved in degassed CH2Cl2 (130 mL) and heated to reflux. Grubbsꢂ II cat-
alyst (22 mg, 0.026 mmol, 0.2 equiv) in degassed CH2Cl2 (15 mL) was
added via syringe pump within 16 h. After completion of the addition the
mixture was stirred for another 30 min. The temperature was lowered to
room temperature and air was bubbled through the solution to destroy
excess catalyst. The solvent was evaporated and purification by column
chromatography (hexane/ethyl acetate 10:1 ! 5:1) afforded macrocycle
56 (47 mg, 62%, rotamers) as a white foam. [a]2D0 = +53.9 (c = 1.20,
CH2Cl2); H NMR (600 MHz, CDCl3): d=6.42 (s, 1H), 5.78 (dd, J=15.5,
4.2 Hz, 1H), 5.31 (dd, J=15.5, 9.1 Hz, 1H), 5.10 (dd, J=9.3, 4.7 Hz, 1H),
5.09 (d, J=5.7 Hz, 1H), 5.03–4.95 (br, 1H), 4.82 (d, J=8.7 Hz, 1H), 4.16
(dd, J=8.7, 6.0 Hz, 1H), 3.78 (s, 3H), 3.58 (s, 3H), 3.54 (dd, J=9.6,
3.6 Hz, 1H), 3.11–3.04 (m, 1H), 3.04–2.98 (m, 1H), 2.46–2.37 (m, 1H),
2.42 (s, 3H), 2.21 (d, J=14.7 Hz, 1H), 2.11–2.03 (br, 1H), 2.02–1.92 (br,
1H), 1.72–1.58 (br, 2H), 1.51 (s, 3H), 1.48–1.41 (m, 1H), 1.29–1.18 (m,
12H), 1.01–0.95 (m, 6H), 0.72–0.53 ppm (br, 3H); 1H NMR (400 MHz,
C7D8, 350 K): d=6.44 (s, 1H), 5.65 (ddd, J=15.5, 4.9 Hz, 1H), 5.44 (ddd,
J=15.5, 8.2, 1.7 Hz, 1H), 5.32 (d, J=8.2 Hz, 1H), 5.03 (d, J=5.6 Hz,
1H), 4.99 (d, J=5.6 Hz, 1H), 4.88 (d, J=8.8 Hz, 1H), 4.23 (dd, J=8.0,
6.1 Hz, 1H), 3.69 (dd, J=8.8, 4.5 Hz, 1H), 3.66 (s, 3H), 3.33 (s, 3H),
2.99–2.89 (m, 2H), 2.72–2.63 (br, OH), 2.59–2.49 (m, 1H), 2.40 (s, 3H),
2.16–2.07 (m, 2H), 1.94 (ddd, J=13.7, 8.9, 5.4 Hz, 1H), 1.80–1.70 (m,
1H), 1.70–1.60 (m, 1H), 1.52–1.41 (m, 1H), 1.50 (s, 3H), 1.47 (d, J=
6.6 Hz, 3H), 1.34 (s, 3H), 1.26 (d, J=6.9 Hz, 3H), 0.99 (d, J=6.4 Hz,
3H), 0.94 (d, J=6.8 Hz, 3H), 0.90 (s, 3H), 0.70 ppm (d, J=7.0 Hz, 3H);
13C NMR (100 MHz, C7D8, 350 K): d=163.6, 149.0, 146.6, 139.5, 137.9,
133.4, 128.6, 127.9, 127.2, 122.8, 114.9, 102.5, 100.9, 99.1, 75.2, 71.9, 60.6,
57.5, 45.4, 43.4, 40.4, 35.4, 34.8, 32.6, 30.0, 29.2, 26.1, 21.4, 21.2, 21.0, 19.3,
17.0, 13.2, 11.8, 9.5 ppm; IR (film): n˜ = 3440, 2960, 1683, 1652, 1557,
1455, 1378, 1163, 1113 cmꢀ1; HRMS (ESI): m/z: calcd for C35H52O7Na:
607.3612; found: 607.3616 [M+Na]+.
Tetrahydropyran 5: To
a vigorously stirred refluxing solution of 60
(37 mg, 0.076 mmol, 1.0 equiv) and AcOH (11 mL, 0.192 mmol, 2.5 equiv)
in CH2Cl2 (7 mL) was added dipotassium azodicarboxylate (89 mg,
0.460 mmol, 6 equiv) over a period of 6 h. The mixture was cooled to
room temperature, filtered over Celite and concentrated in vacuo. The
crude product was purified by HPLC (hexane/ethyl acetate 4:1) to give 5
as a white foam (28 mg, 76%). All analytical data matched with those re-
ported by Lee[6a] and Rychnovsky.[7] [a]D20 = +19.4 (c = 0.17, CHCl3);
1H NMR (600 MHz, CDCl3): d=6.55 (s, 1H), 5.53 (s, 1H), 4.60 (d, J=
9.5 Hz, 1H), 4.54 (d, J=10.2 Hz, 1H), 3.83 (s, 3H), 3.67–3.62 (m, 1H),
3.44 (ddd, J=11.0, 2.3, 1.1 Hz, 1H), 3.11–3.04 (m, 1H), 2.47–2.41 (m,
1H), 2.45 (s, 3H), 2.26–2.19 (m, 1H), 1.93–1.88 (m, 1H), 1.84–1.77 (m,
1H), 1.62 (s, 3H), 1.61–1.54 (m, 1H), 1.53–1.49 (br, OH), 1.48–1.41 (m,
2H), 1.38 (d, J=6.8 Hz, 3H), 1.35–1.18 (m, 5H), 1.04 (d, J=7.0 Hz, 3H),
0.90 (d, J=6.6 Hz, 3H), 0.81 ppm (d, J=6.4 Hz, 3H), 0.76 (d, J=6.4 Hz,
3H); 13C NMR (150 MHz, CDCl3): d=159.7, 148.2, 141.6, 141.5, 131.5,
129.0, 122.1, 115.7, 112.5, 104.7, 77.8, 77.3 (2ꢄCH), 61.4, 43.8, 41.8, 39.6,
38.6, 33.7, 32.5, 31.5, 31.1, 27.5, 21.8, 21.0, 19.6, 18.7, 12.8, 9.4, 6.6 ppm;
IR (film): n˜ = 3463, 2924, 2854, 1457, 1375, 1325, 1109, 1001 cmꢀ1; HRMS
(ESI): m/z: calcd for C30H44O5Na: 507.3086; found: 507.3082 [M+Na]+.
4-((2R,3R,4S,5R,6R)-4-Hydroxy-3,5-dimethyl-6-vinyltetrahydro-2H-
pyran-2-yl)-6-methoxy-7-methyl-2-((2S,4S,8S,E)-4,6,8-trimethyldeca-6,9-
dien-2-yl)benzofuran-5-ol (59): A mixture of 9a,b (200 mg, 0.326 mmol)
was dissolved in MeOH (7 mL) and treated with 3 drops of 3n HCl. The
reaction mixture was stirred at room temperature overnight, diluted with
H2O (50 mL) and extracted with CH2Cl2 (4ꢄ20 mL). The organic ex-
tracts were dried over MgSO4, concentrated in vacuo and purified by
flash chromatography (hexane/ethyl acetate 5:1 ! 3:1) to afford tetrahy-
O-quinone 71: Macrocycle 5 (6 mg, 0.012 mmol, 1 equiv) was dissolved in
CH2Cl2/H2O 10:1 (1 mL) and treated with DDQ (4.2 mg, 0.019 mmol,
1.5 equiv) at room temperature. The color of the solution turned dark
purple within 15 min, whereas TLC analysis showed complete consump-
tion of the starting material. The mixture was directly loaded onto a
silica column and eluted (hexane/ethyl acetate 3:1 ! 2:1), to collect
purple-blue fractions. The solvent was carefully evaporated to afford
labile o-quinone 71 (3 mg, 52%) as a violet-blue compound. 1H NMR
(400 MHz, CDCl3): d=6.11 (s, 1H), 4.72 (d, J=9.8 Hz, 1H), 4.17 (d, J=
10.0 Hz, 1H), 3.55–3.48 (m, 1H), 3.32–3.26 (m, 1H), 2.97–2.87 (m, 1H),
2.34–2.27 (m, 1H), 2.27–2.21 (m, 1H), 1.90 (s, 3H), 1.88–1.80 (m, 1H),
1.81–1.73 (m, 1H), 1.68–1.54 (m, 3H), 1.62 (s, 3H), 1.47–1.37 (m, 1H),
1.44–1.31 (m, 1H), 1.36–1.24 (m, 2H), 1.19–1.09 (m, 1H), 1.25 (d, J=
6.8 Hz, 3H), 0.91 (d, J=6.1 Hz, 3H), 0.90 (d, J=6.8 Hz, 3H), 0.89 (d, J=
6.5 Hz, 3H), 0.80 ppm (d, J=6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=177.2, 173.7, 164.3, 147.4, 131.3, 129.1, 125.4, 113.7, 105.3, 78.3, 76.4,
75.8, 42.1, 41.7, 39.4, 38.2, 33.8, 32.5, 32.1, 29.7, 27.7, 21.8, 21.0, 19.6, 17.9,
17.0, 13.0, 8.2, 6.4 ppm; IR (film): n˜ = 3625, 2924, 2359, 17.32, 1699,
1652, 1584, 1455, 1377, 1326, 1094 cmꢀ1; HRMS (ESI): m/z: calcd for
C31H43O5NNa: 532.3039; found: 532.3058 [M+MeCN+Na]+.
dropyran 59 (120 mg, 72%, 1.5:1 rotamers) as a white foam. [a]D20
+87.2 (c = 1.75, CH2Cl2); 1H NMR (rotamers, 600 MHz, CDCl3): d=
7.67 (br, 0.5OH)+5.60 (br, 0.5OH), 6.55(br, 0.5H)+6.18(br, 0.5H),
5.88–5.79 (m, 1H), 5.76 (ddd, J=17.4, 10.2, 6.0 Hz, 1H), 5.27 (d, J=
16.6 Hz, 1H), 5.17 (br, 1H), 4.98–4.93 (m, 2H), 4.90–4.87 (m, 1H), 4.75
(br, 0.5H)+4.49 (br, 0.5H), 4.23 (dd, J=4.0, 1.7 Hz, 1H), 3.84 (br, 3H),
3.70 (br, 1H), 3.10–3.02 (m, 1H), 3.02–2.96 (m, 1H), 2.42 (s, 3H), 2.25–
1.95 (br, 1H), 2.16–2.11 (br, 1H), 2.08 (dd, J=13.0, 5.5 Hz, 1H), 1.78
(dd, J=12.3, 8.5 Hz, 1H), 1.73–1.65 (m, 1H+OH), 1.63–1.55 (m, 1H),
1.57 (s, 3H), 1.51–1.45 (m, 1H), 1.27 (d, J=6.8 Hz, 3H), 1.09 (br, 3H),
1.05 (d, J=6.8 Hz, 3H), 0.83 (d, J=6.4 Hz, 3H), 0.82 ppm (d, J=6.4 Hz,
3H); 13C NMR (The asterisk denotes signals not apparent in the 13C-
spectrum, 150 MHz, CDCl3): d=163.7, 146.9*, 143.3, 136.4*, 133.3, 130.1,
518
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 507 – 519

Construction of the Ansamycin Antibiotic Kendomycin
FULL PAPER
Kendomycin (1): O-quinone 71 (2 mg, 0.0043 mmol) was dissolved in
MeCN (2 mL) and treated with one drop of 1% HCl. The initial blue so-
lution turned yellow within 15 min and the reaction mixture was parti-
tioned between etyhlacetate (50 mL) and brine (15 mL). The aqueous
phase was extracted with ethyl acetate (3ꢄ10 mL), the organic layer was
dried over MgSO4 and concentrated in vacuo. Purification by flash chro-
matography (hexane/ethyl acetate 3:1 ! 2:1) gave kendomycin 1 (1 mg,
50%) as a yellow solid. M.p. 226–2278C (authentic sample: 235–2368C);
[a]D20 = ꢀ76.4 (c = 0.11, MeOH), (lit. [a]D20 = ꢀ80 (c = 2.71, MeOH),[2]
Green, M. M. B. Marques, H. J. Martin, Proc. Natl. Acad. Sci. USA
2004, 101, 11980.
[9] S. Pichlmair, M. M. B. Marques, M. P. Green, H. J. Martin, J. Mulzer,
Org. Lett. 2003, 5, 4657.
[10] J. Uenishi, R. Kawahama, O. J. Yonemitsu, J. Org. Chem. 1997, 62,
1691.
[11] E. W. Colvin, B. J. Hamill, J. Chem. Soc. Chem. Commun. 1973, 151.
[12] a) E. Negishi, C. Kotora, C. Xu, J. Org. Chem. 1997, 62, 8957;
b) Review: E. Negishi, Q. Hu, Z. Huang, M. Qian, G. Wang, Aldri-
chimica Acta 2005, 38, 71.
[13] W.-H. Jung, C. Harrison, Y. Shin, J.-H. Fournier, R. Balachandran,
B. S. Raccor, R. P. Sikorski, A. Vogt, D. P. Curran, B. W. Day, J.
Med. Chem. 2007, 50, 2951.
[14] a) M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953; b) B. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc.
1996, 118, 100.
[15] At that time we became aware that the White group had unsuccess-
fully pursued a related approach for the tetrahydropyran formation:
H. Smits, PhD Thesis, Oregon State University, 2007.
[16] a) R. E. Ireland, D. Habich, D. W. Norbeck, J. Am. Chem. Soc. 1985,
107, 3271; b) R. E. Ireland, P. Wipf, J. D. Armstrong, J. Org. Chem.
1991, 56, 650; c) R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am.
Chem. Soc. 1976, 98, 2868; d) A. M. M. Castro, Chem. Rev. 2004,
104, 2939.
[a]2D0
=
ꢀ79.3 (c
=
0.135, MeOH),[2b–d] [a]D20
=
ꢀ82.4 (c
= 0.514,
MeOH)[2a]), 1H NMR (600 MHz, CD3COCD3): d=8.10 (s, 1H), 7.19 (s,
1H), 6.54 (s, 1H), 4.64 (d, J=10.0 Hz, 1H), 4.36 (d, J=10.3 Hz, 1H),
3.95 (d, J=4.5 Hz, 1H), 3.56 (m, 1H), 3.53 (ddd, J=11.0, 2.3, 1.1 Hz,
1H), 2.42 (m, 1H), 2.36 (m, 1H), 2.12 (brd, J=17.0 Hz, 1H), 1.96 (m,
1H), 1.88 (m, 1H), 1.84 (s, 3H), 1.71 (m, 1H), 1.67 (m, 1H), 1.64 (m,
1H), 1.61 (s, 3H), 1.57 (m, 1H (10-Ha)[34]), 1.45 (ddd, J=12.9, 11.4,
2.9 Hz, 1H), 1.33 (m, 2H (11-H2)), 1.25 (m, 10-Hb), 0.95 (d, J=7.0 Hz,
3H), 0.94 (d, J=6.5 Hz, 3H), 0.89 (d, J=6.5 Hz, 3H), 0.87 (d, J=6.5 Hz,
3H), 0.71 ppm (d, J=7.0 Hz, 3H); 13C NMR (150 MHz, CD3COCD3):
d=182.1, 168.6, 146.8, 141.3, 132.1, 130.2, 129,9, 119.1, 111.0, 104.2, 78.7,
77.8, 76.2, 46.1, 41.4, 40.8, 39.8, 38.1, 35.9, 33.6, 33.5, 26.5, 22.7, 19.9, 19.7,
13.3, 12.7, 7.6, 7.2 ppm; IR (film): n˜ = 3322, 2926, 1670, 1614, 1585, 1329,
1098 cmꢀ1; HRMS (ESI): m/z: calcd for C29H42O6: 486.2981; found:
486.2975 [M]+.
[17] a) K. Mori, Tetrahedron 2008, 64, 4060; b) A. G. M. Barrett, R. A. E.
Carr, S. V. Attwood, G. Richardson, N. D. A. Walshe, J. Org. Chem.
1986, 51, 4840.
Acknowledgements
[18] B. S. Bal, W. E. Childers, H. W. Pinnick, Tetrahedron 1981, 37, 2091.
[19] a) Y. Okude, S. Hirano, T. Hiyama, H. Nozaki, J. Am. Chem. Soc.
1976, 98, 3179; b) A. Fꢅrstner, N. Shi, J. Am. Chem. Soc. 1996, 118,
12349; c) 29a and 29b were obtained as an easily separable 1.4:1
mixture. 29b was recycled by oxidation to the ketone and reduction
with NaBH4 (d.r. 2:1).
We thank Professor Zeeck, University of Gçttingen, for authentic sam-
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Received: August 10, 2009
Published online: November 30, 2009
Chem. Eur. J. 2010, 16, 507 – 519
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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