Total synthesis of haterumalides NA and NC via a chromium-mediated macrocyclization

Article abstract of DOI:10.1021/ja8043695

The syntheses of haterumalides NA and NC were accomplished via the macrocyclization of a chlorovinylidene chromium carbenoid onto a pendant aldehyde to generate the C8-C9 bond with the desired stereoisomer as the major product. Utilizing the latter chemistry enables access to both C9 hydroxylated (haterumalides NC and ND) and C9 deoxygenated forms (haterumalides NA, NB, and NE; via deoxygenation of the C9-hydroxyl). Copyright

Full text of DOI:10.1021/ja8043695

Published on Web 08/23/2008
Total Synthesis of Haterumalides NA and NC via a Chromium-Mediated
Macrocyclization
Jennifer M. Schomaker and Babak Borhan*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received June 9, 2008; E-mail: babak@chemistry.msu.edu
The haterumalides are a series of chlorinated macrolides isolated
from an Okinawan sea sponge of the species Ircinia (Figure 1).1,2
Kigoshi’s synthesis of haterumalide NA led to its structural
revision.3 The stereochemistry of the remaining haterumalides is
assumed to mimic that of haterumalide NA, and the stereochem-
istries in Figure 1 have been changed to reflect the corrections made
to the initial structure of haterumalide NA.
this chemistry has not been utilized in a natural product synthesis
and its participation in a macrocyclization has not been reported.
Synthesis of 1c commenced with preparation of the tetrahydro-
furan-containing aldehyde for intramolecular CrCl2-mediated cou-
pling (Scheme 1). 2-Deoxy-D-ribose 2 was converted to the
disilylated methyl acetal 3 in high yield. Addition of allyltrimeth-
ylsilane to 3 in the presence of tin tetrabromide by the method of
Woerpel and co-workers gave the allylated product in excellent
diastereoselectivity.10,11 Desilylation to yield 4 was followed by
protection of the primary alcohol as a trityl group, yielding 5 poised
for Mitsunobu esterification with carboxylic acid 9c.
Preparation of 9c began with the ring-opening of 6 with the anion
of chloroform to yield the corresponding alcohol.12 DMP oxidation
furnished the unstable, reactive, and volatile aldehyde 7, which was
immediately subjected to a Still-Gennari olefination to yield the
desired Z-acrylate.13 Reduction of the ester to the allylic alcohol 8
was followed by a rapid oxidation to the unsaturated aldehyde and an
immediate asymmetric Mukaiyama aldol reaction to furnish 9a.14 The
secondary alcohol was protected as a TBS ether, and the phenyl ester
was hydrolyzed to give the desired 1,1,1-trichloroalkane substrate 9c.
Mitsunobu esterification of alcohol 5 and carboxylic acid 9c
yielded 10a without incident. Both TBS-protected and acetylated
C3-OH compounds (10a and 10c) were carried forward for
comparative studies in later stages. Selective dihydroxylation of
the terminal alkene was followed by oxidative cleavage of the diol
with sodium periodate in a mixture of dioxane and water, yielding
aldehydes 11a and 11c. Presumably, the TBS and acetyl protecting
groups provide enough steric hindrance to prevent any undesired
oxidation of the trisubstituted olefin.
With the substrates 11a and 11c in hand, studies directed toward
the intramolecular CrCl2-mediated coupling were pursued (Scheme
2). Several different concentrations were screened, as studies with an
intermolecular approach (Cr-mediated coupling, followed by intramo-
lecular Mitsunobu lactonization, not shown) proved that higher reaction
concentrations gave much better yields, presumably due to an increased
rate in the desired reaction compared to the competing side reaction
caused by quenching of the vinylidene chromium carbenoid with water
or other proton sources present in the reaction (despite precautions
taken to dry all reagents and solvents carefully).
Figure 1. Structure of the haterumalides.
Figure 1 summarizes previous synthetic approaches to hateru-
malide NA. Kigoshi and co-workers utilized an intramolecular
Reformatsky reaction as a key step to form the macrolide.3 Snider
and Gu used an intermolecular Stille coupling reaction followed
by a Yamaguchi macrolactonization.4 Hoye and Wang reported the
first total synthesis of the correct enantiomer of haterumalide NA
using a Pd-mediated alkyne haloallylation reaction.5 Most recently,
Roulland and Kigoshi, in two separate reports, described the use
of variants of Suzuki-Miyaura cross-coupling along with macro-
lactonizations to achieve the synthesis of haterumalide NA.6,7 Our
approach entailed the construction of the C8-C9 bond, such that
any member of the haterumalide family could be accessed. Critical
to this assembly would be the ability to construct a nucleophilic
Z-vinyl chloride moiety that would participate in a macrocyclization
event with a pendant aldehyde. Thus, we explored the utility of
the chlorovinylidene chromium carbenoids developed by Falck and
Mioskowski (see Figure 1, box).8,9 To the best of our knowledge,
Gratifyingly, treatment of the substrates shown in Scheme 2 with
4.0 equiv of CrCl2 at the indicated concentrations gave the desired
Scheme 1. Synthesis of 11a and 11ca
a (a) MeOH, cat. HCl, quant.; (b) TBSCl, imid, DMF, 98%; (c) allyltrimethylsilane, SnBr4, CH2Cl2, -78 °C, 93%, dr > 95:5; (d) TBAF, THF, 90%; (e)
TrCl, py, DMAP, CH2Cl2, rt, 87%; (f) nBuLi, CHCl3, BF3 ·OEt2, THF, -94 °C, 96%; (g) DMP, NaHCO3, 0 °C, 86%; (h) (TFEO)2P(O)CH(CH3)CO2Et,
KHMDS, 18-crown-6, THF, -78 °C, 91%; (i) DIBAL, THF, -20 °C, 93%; (j) MnO2, CH2Cl2, then add to D-N-Ts-valine, BH3 ·THF, CH2C(OPh)OTMS,
t
64%, 80% ee; (k) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 89%; (l) KOH, BuOH, H2O, 90%; (m) DIAD, PPh3, THF, 74%; (n) TBAF, THF, 0 °C, 88%; (o)
Ac2O, py, DMAP, CH2Cl2, 99%; (p) AD-mix R, tBuOH/H2O, rt, 90% for 10a, 88% for 10c; (q) NaIO4, dioxane/H2O, 78% for 11a, 87% for 11c.
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10.1021/ja8043695 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Formal Synthesis of Haterumalide NA (1a)a
Scheme 2. Chromium Carbenoid-Mediated Macrocyclization
Scheme 3. Synthesis of Haterumalide NC (1c)a
a (a) NaH, THF, CS2, then MeI, 98% for 12a, 95% for 12c.
yield of 21a, along with several unidentifiable byproducts (Scheme
4). Lowering the reaction temperature to 80 °C improved the yield
substantially; however, no further gains were observed at 60 °C.
Compounds 21a and 21c were obtained as the major product of the
deoxygenation, along with olefin-isomerized 22a or 22c as side products.
Compound 21a constitutes a formal synthesis of haterumalide NA.4
In summary, the first total synthesis of haterumalide NC was
accomplished in 16 linear steps (longest route) with an overall yield
of 6.2% via an unprecedented macrocyclization of an aldehyde and
a chlorovinylidene chromium carbenoid to construct the C8-C9
bond. Deoxygenation of the latter product led to the formal synthesis
of haterumalide NA.
Acknowledgment. We are grateful to the NIH (Grant No. R01-
GM082961) for support of this research. J.M.S. thanks the ACS
Division of Organic Chemistry for a Graduate Fellowship sponsored
by Eli Lilly, Michigan State University for a University Distin-
guished Fellowship, and a graduate fellowship sponsored by the
Dow Chemical Company Foundation.
a (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 94%; (b) 80% AcOH, 40 °C,
63%; (c) DMP, NaHCO3, CH2Cl2; (d) CrCl2, cat. NiCl2, DMSO, rt, 52%,
9:1 dr; (e) HF/py, THF, 91%; (f) AlMe3, Cp2ZrCl2 (cat.), I2, 84%; (g) DMP,
NaHCO3, CH2Cl2, rt; (h) nBuOH, CrO3, AcOH/H2SO4, 0 °C, 51%.
Supporting Information Available: Experimental procedures and
spectral data for 1c-21c. This material is available free of charge via
the Internet at http://pubs.acs.org.
C-C bond formation, with 0.025 M leading to the highest yields.
Most importantly, the macrocyclization products 12a and 12c were
obtained as one major diastereomer (9:1 for 12a, 4:1 for 12c), with
minor side products 13a and 13c resulting from proto-demetalation.
The stereochemistry of the newly generated C9 center matched the
stereochemistry of the natural product, haterumalide NC, according
to the chemical shift data obtained via 1H NMR.2 This was further
verified through modified Mosher ester analysis of the products
(Supporting Information).
The final piece for installation of the side chain of haterumalide
NC was prepared as illustrated in Scheme 3 in a fashion similar to
that reported in prior syntheses for haterumalide NA. Treatment of
3-butyn-1-ol (16) under Negishi’s conditions gave the desired
E-iodoalkene 17.15 Conversion of the alcohol to aldehyde with DMP
in the presence of excess NaHCO3 was immediately followed by
further oxidation to the n-butyl ester 18. The macrocycle 12c was
prepared for the upcoming NHK coupling by protection of the C9
alcohol with TBSOTf, removal of the trityl group, and oxidation
of the primary alcohol to the aldehyde with DMP. The crude
aldehyde 15 was immediately subjected to NHK coupling with the
vinyl iodide 18 to give the alcohol 19 as a 9:1 mixture of
diastereomers at C15.3-5 Deprotection of the C9 TBS group with
HF/py in THF provided haterumalide NC (1c).
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Next, we turned our attention toward the deoxygenation of the
C9-OH, which would lead to haterumalide NA. Xanthates 20a and
20c were synthesized as illustrated in Scheme 4.16 Radical-induced
fragmentation of 20a with AIBN in refluxing toluene led to a low
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