N-heterocyclic carbene catalyzed oxidative macrolactonization: Total synthesis of (+)-dactylolide

Article abstract of DOI:10.1002/anie.201201653

Three key steps constitute the total synthesis of (+)-dactylolide: the 1,6-oxa conjugate addition reaction of a 2,4-dienal for the facile synthesis of the 2,6-cis-2-(4-oxo-2-butenyl)tetrahydropyran subunit, the umpolung alkylation reaction of a cyanohydrin, and the NHC-catalyzed oxidative macrolactonization reaction for the synthesis of the 20-membered macrocyle. NHC=N-heterocyclic carbene. Copyright

Full text of DOI:10.1002/anie.201201653

Angewandte
Chemie
DOI: 10.1002/anie.201201653
Natural Products
N-Heterocyclic Carbene Catalyzed Oxidative Macrolactonization:
Total Synthesis of (+)-Dactylolide**
Kiyoun Lee, Hyoungsu Kim,* and Jiyong Hong*
(+)-Dactylolide (1, Figure 1) is a cytotoxic 20-membered
macrolide isolated from the Vanuatu sponge Dactylospongia
sp by Riccio and co-workers.[1] It possesses unique structural
features which include a 2,6-cis-2-(4-oxo-2-butenyl)tetra-
hydropyran, a highly unsaturated 20-membered macrolac-
carbene (NHC)-catalyzed oxidative macrolactonization reac-
tion for the synthesis of the 20-membered macrocyle in 1.
Our retrosynthetic plan for 1 is outlined in Scheme 1. In
pursuit of 1, we were particularly interested in addressing the
potential challenges associated with the formation of the
Figure 1. Structure of (+)-dactylolide (1) and (À)-zampanolide (2).
tone, and an a-chiral aldehyde. (+)-Dactylolide (1) displayed
modest tumor cell growth inhibitory activities in leukemia
and ovarian cancer cell lines[1] and the mode of action has not
been fully understood. Not surprisingly, as a result of the
architectural complexity, biological profile, and enantiomeric
relationship of the macrolactone core in 1 with natural (À)-
zampanolide (2, Figure 1),[2] 1[2b,3,5] and unnatural (À)-dacty-
lolide[2c–e,4,5] have attracted considerable interest from
a number of synthetic groups, thus culminating in the first
total synthesis by Smith and co-workers.[2b,3a] The syntheses of
1 reported to date focus on the diastereoselective construc-
tion of the 2,6-cis-disubstituted tetrahydropyran subunit and
the efficient formation of the 20-membered macrolactone
core in 1. Herein, we report a convergent synthesis of 1,
enlisting the 1,6-oxa conjugate addition reaction of a 2,4-
dienal for the facile synthesis of the 2,6-cis-2-(4-oxo-2-
butenyl)tetrahydropyran subunit in 1, the umpolung alkyla-
tion reaction of a cyanohydrin, and the N-heterocyclic
Scheme 1. Retrosynthetic plan for (+)-dactylolide (1). PMB=para-
methoxybenzyl, TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyl-
dimethylsilyl.
highly unsaturated 20-membered macrolactone. Dienoic
substrates are known to be ineffective for macrolactonization
under conventional reaction conditions.[6] In particular, the
macrolactonization of dienoic substrates for the synthesis of
1 either failed to proceed[3c] or gave the desired macrolactones
in unsatisfactory yields under Yamaguchi, Shiina, or Trost–
Kita conditions.[2d] We were also interested in the develop-
ment of a concise approach to the 2,6-cis-2-(4-oxo-2-bute-
nyl)tetrahydropyran subunit in 1.
We anticipated that the 20-membered macrolactone in
1 could be constructed by intramolecular oxidative macro-
lactonization of w-hydroxy aldehyde 3 catalyzed by an NHC.
Conventional macrolactonization procedures require the use
of a stoichiometric amount of activating agents and often
need a protection/deprotection sequence. Recently, several
[*] K. Lee, Prof. Dr. J. Hong
Department of Chemistry, Duke University
Durham, NC 27708 (USA)
E-mail: jiyong.hong@duke.edu
Prof. Dr. H. Kim
College of Pharmacy, Ajou University
Suwon 443-749 (Korea)
E-mail: hkimajou@ajou.ac.kr
[**] We are grateful to Duke University for funding this work, to the
North Carolina Biotechnology Center (NCBC; Grant No. 2008-IDG-
1010) for funding of the NMR instrumentation, and to the National
Science Foundation (NSF) MRI Program (Award ID No. 0923097)
for funding mass spectrometry instrumentation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201653.
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examples of inter- and intramolecular NHC-catalyzed oxida-
tive esterification of aldehydes have been reported[7] and
clearly provide a new opportunity for the development of
catalytic acyl transfer agents in macrolactonization reactions
of w-hydroxy aldehydes in the presence of oxidants.
13 provided aldehyde 8. With aldehyde 8 in hand, we
attempted to stereoselectively install the C15 secondary
carbinol by an asymmetric organozinc addition.[14] We
expected that the asymmetric addition of a highly function-
alized bromozinc reagent derived from 7 to aldehyde 8 would
be challenging because of the possible chelation of the oxygen
atoms to zinc. Indeed, following the procedure described by
Shair and co-workers,[14b] the reaction gave 14 only with
modest stereoselectivity (d.r. = 3.5:1). After an extensive
search for the optimal reaction conditions, we were delighted
to find that the slow addition (4 h) of 8 to a mixture of the
corresponding bromozinc reagent of 7 and lithiated (1S,2R)-
NME provided 14 in good stereoselectivity and yield (d.r. =
7.7:1, 71%).[15]
Removal of the TBS group in 14 and MnO2 oxidation of
the resulting allyl alcohol provided the w-hydroxy 2,4-dienal
6, thus setting the stage for the key intramolecular 1,6-oxa
conjugate addition reaction. When 6 was treated with (S)-
15[16] at 08C, the organocatalytic 1,6-oxa conjugate addition
reaction proceeded smoothly to provide the desired 2,6-cis-2-
(4-oxo-2-butenyl)tetrahydropyran 5 with excellent stereo-
selectivity and yield (d.r. > 20:1, 98%).[17,18] When 6 was
treated with either piperidine or (R)-15, the organocatalytic
1,6-oxa conjugate addition reaction provided 5 in 89% (d.r. =
10:1) and 98% (d.r. = 2:1), respectively (see the Supporting
Information for details). To the best of our knowledge, this
work is the first successful example of the construction of
a tetrahydropyran through an intramolecular 1,6-oxa conju-
gate addition reaction.[19] Having successfully prepared the
desired 2,6-cis-tetrahydropyran enal 5 by employing the
intramolecular 1,6-oxa conjugate addition reaction, we pro-
ceeded to install the C1–C6 fragment of the natural product
using an acyl anion equivalent (Scheme 3). After extensive
experimentation, we used a TBS-protected cyanohydrin[20]
The substrate for the macrolactonization reaction could
be prepared by umpolung alkylation of the corresponding
TBS-protected cyanohydrin of 2,6-cis-tetrahydropyran enal 5
with dienyl chloride 4. We further envisioned that 5 could be
constructed in a stereoselective manner through an intra-
molecular 1,6-oxa conjugate addition reaction of w-hydroxy
2,4-dienal 6.[8] Despite the great potential as an elegant
solution to the facile synthesis of 2-(4-oxo-2-butenyl) cyclic
ethers, the 1,6-oxa conjugate addition has been extremely
underutilized in natural product synthesis.[9] Further analysis
suggested that 6 could be accessible by the asymmetric
addition of vinyl iodide 7 to aldehyde 8 in a reagent-
controlled manner.
The synthesis of 1 started with the preparation of the w-
hydroxy 2,4-dienal 6 for the key intramolecular 1,6-oxa
conjugate addition reaction (Scheme 2). The coupling of the
dithiane 10, prepared by THP protection of the known 1,3-
dithiane-2-ethanol (9),[10] and dienyl chloride 11[11] in the
presence of nBuLi and nBu2Mg[12] proceeded smoothly to
provide 12.[13] Exposure of the THP ether 12 to ZnCl2 with
subsequent Parikh–Doering oxidation of the resulting alcohol
Scheme 2. A stereoselective synthesis of 2,6-cis-2-(4-oxo-2-butenyl)-
tetrahydropyran: a) 3,4-dihydro-2H-pyran, camphorsulfonic acid,
CH2Cl2, 08C, 1 h, 92%; b) nBuLi/nBu2Mg (4:1), THF, 258C, 1 h; 11,
À78 to 08C, 1.5 h, 72%; c) ZnCl2, CH2Cl2, 258C, 3 h, 62% (75%
brsm); d) SO3·pyridine, DMSO, iPr2NEt, CH2Cl2, 08C, 1 h, 85%;
e) tBuLi, Et2O, À788C, 1 h; ZnBr2, Et2O, 08C, 1 h; nBuLi/(1S,2R)-NME,
toluene, 08C, 1 h; 8, À208C, 4 h, 71%, d.r. =7.7:1; f) pyridinium
p-toluenesulfonate, EtOH, 258C, 9 h, 69% (81% brsm); g) MnO2,
CH2Cl2, 258C, 20 min, 84%; h) (S)-15 (20 mol%), benzoic acid
(20 mol%), toluene, 08C, 10 h, 98%, d.r.>20:1. brsm=based on
recovered starting material, DMSO=dimethylsulfoxide, (1S,2R)-
NME=(1S,2R)-N-methylephedrine, THF=tetrahydrofuran,
THP=tetrahydropyranyl, TMS=trimethylsilyl.
Scheme 3. Preparation of w-hydroxy aldehyde 3 for NHC-catalyzed
oxidative macrolactonization: a) TBSCN, KCN, 18-crown-6, CH2Cl2,
258C, 1 h, 99%; b) 4, NaHMDS, THF, À788C, 20 min, 87%; c) DDQ,
pH 7 phosphate buffer/CH2Cl2 (1:10), 0 to 258C, 1.5 h, 96%.
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, HMDS=hexa-
methyldisilazide.
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because of the easy preparation[21] and preference for a-
alkylation[22] of the corresponding vinyl cyanohydrin anion.
After the formation of the TBS-protected cyanohydrin 16 by
treatment of 5 with TBSCN, the coupling of 16 and dienyl
chloride 4 gave 17 in 87%. Concomitant removal of the PMB
group and C1 oxidation of 17 was accomplished by treatment
with DDQ to afford the w-hydroxy aldehyde 3, which set the
stage for the pivotal NHC-catalyzed oxidative macrolactoni-
zation.
elaborating the C13 exo-methylene group, unveiling the C7
carbonyl group, and oxidizing the C20 hydroxy group to the
corresponding aldehyde (Scheme 5). Hydrolysis of the 1,3-
With the requisite w-hydroxy aldehyde 3 in hand, we
directed our attention to NHC-catalyzed oxidative macro-
lactonization (Scheme 4). Initial attempts for the macro-
Scheme 5. Completion of total synthesis of (+)-dactylolide (1): a) MeI,
CaCO3, CH3CN/H2O (3:1), 408C, 30 h, 81%; b) CH3Ph3P+IÀ, nBuLi,
THF, À78 to 258C, 1 h, 79%; c) TBAF, THF, À78 to 258C, 3 h, 75%;
d) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 to 258C, 1 h, 90%.
TBAF=tetra-n-butylammonium flouride.
dithiane group of 18 and Wittig olefination of the resulting
ketone gave 19. Concomitant removal of the TBS and TBDPS
groups with subsequent Dess–Martin oxidation of alcohol 20
afforded 1, which was identical in all respects to the natural
product.
In conclusion, the total synthesis of (+)-dactylolide (1) has
been accomplished in 19 steps for the longest sequence from
commercially available 1,3-dithiane with an overall yield of
1.4% (1.9% brsm). Highlights of the synthesis include the
organocatalytic 1,6-oxa conjugate addition reaction for the
stereoselective synthesis of 2,6-cis-2-(4-oxo-2-butenyl)tetra-
hydropyran and the NHC-catalyzed oxidative lactonization
for the construction of the 20-membered macrolactone. Other
notable features in the synthesis are highly efficient carbon–
carbon bond formations, including a 1,3-dithiane coupling
reaction, asymmetric addition of an alkenylzinc reagent, and
cyanohydrin alkylation, which allow a convergent approach
to the carbon skeleton in 1. We strongly believe that the
NHC-catalyzed oxidative macrolactonization provides a new
approach to a diverse set of macrolactones. The application of
the NHC-catalyzed oxidative macrolactonization to other
macrolactones and macrolide-containing natural products is
underway and will be reported in due course.
Scheme 4. NHC-catalyzed oxidative macrolactonization: a) 1,4-
dimethyl-4H-1,2,4-triazolium iodide (30 mol%), 3,3’,5,5’-tetra-tert-butyl-
diphenoquinone, DBU, DMAP, 4 ꢀ M.S., CH2Cl2, 258C, 20 h, 65%.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP=4-(dimethylamino)-
pyridine, M.S.=molecular sieves.
lactonization in the presence of dimethyltriazolium iodide,
DBU, MnO2, and 4 ꢀ molecular sieves in CH2Cl2 provided 18
in poor yield (< 10%). We were pleased to find that, however,
the addition of DMAP,[23] the use of 3,3’,5,5’-tetra-tert-
butyldiphenoquinone as an oxidant,[24] and a slow addition
of 3 (2 h) proved to be highly effective, thus leading to higher
yield (65%).[25] Since NHCs have not yet been exploited as
acyl transfer agents in macrolactonization reactions, our
report, therefore, constitutes the first example of the NHC-
catalyzed oxidative macrolactonization of w-hydroxy alde-
hydes. Because of significant benefits of the reaction, includ-
ing the catalytic nature and mild reaction conditions of the
reaction, the NHC-catalyzed oxidative macrolactonization
reaction would provide a significant advance in the field of
macrolactonization.
Received: February 29, 2012
Published online: && &&, &&&&
Keywords: lactones · natural products ·
.
N-heterocyclic carbenes · total synthesis · umpolung
Having successfully assembled the macrolactone 18, we
embarked on the completion of the synthesis of 1 by
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[18] It should be noted that the 1,4-oxa conjugate addition reaction of
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[19] For attempts for the synthesis of a tetrahydropyran by the 1,6-
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[25] The macrolactonization reaction of the corresponding carbox-
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details). Since structurally similar substrates without the cyano-
hydrin group failed to afford the corresponding macrolactone[3c]
or resulted in low to modest yields (21–48%) under a variety of
macrolactonization conditions,[2d] it is noteworthy to mention
that TBS-protected cyanohydrin at the C7-position plays an
important role in the NHC-catalyzed oxidative macrolactoniza-
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knowledge, this is the first example where a cyanohydrin elicits
the gem-disubstituent effect.[26]
[26] During the review of the manuscript, an independent report on
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Natural Products
Three key steps constitute the total syn-
thesis of (+)-dactylolide: the 1,6-oxa
conjugate addition reaction of a 2,4-
dienal for the facile synthesis of the 2,6-
cis-2-(4-oxo-2-butenyl)tetrahydropyran
subunit, the umpolung alkylation reaction
of a cyanohydrin, and the NHC-catalyzed
oxidative macrolactonization reaction for
the synthesis of the 20-membered mac-
rocyle. NHC=N-heterocyclic carbene.
K. Lee, H. Kim,* J. Hong*
&&&& — &&&&
N-Heterocyclic Carbene Catalyzed
Oxidative Macrolactonization: Total
Synthesis of (+)-Dactylolide
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