Synthesis of ent-Haterumalide NA (ent-Oocydin A) Methyl Ester

Article abstract of DOI:10.1021/ol0356789

(Equation presented) Stille coupling of allylic chloride 26 with vinylstannane 4a afforded 65% of 27 with the requisite skipped diene, vinyl chloride, and allylic oxygen functionality. Yamaguchi macrolactonization of 28 provided 65% of 29, which was elabo

Full text of DOI:10.1021/ol0356789

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4385-4388
Synthesis of ent-Haterumalide NA
(ent-Oocydin A) Methyl Ester
Yonghong Gu and Barry B. Snider*
Department of Chemistry, MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received September 2, 2003
ABSTRACT
Stille coupling of allylic chloride 26 with vinylstannane 4a afforded 65% of 27 with the requisite skipped diene, vinyl chloride, and allylic
oxygen functionality. Yamaguchi macrolactonization of 28 provided 65% of 29, which was elaborated to haterumalide NA methyl ester (32) by
a Nozaki−Hiyama−Kishi coupling with 31.
The macrolide haterumalide NA (1) was isolated in 1999
from an Okinawan sponge Ircinia sp.1 The same macrolide,
named oocydin A, was reported contemporaneously from a
strain of Serriatia marcescens growing as an epiphyte on
Rhyncholacis pedicillata, in a Venezuelan river,2 and in 2001
from a soil bacterium Serratia plymuthica in Sweden.3 The
closely related ester haterumalide B was isolated from the
Okinawan ascidian Lissoclinum sp.4 Haterumalide NA is
cytotoxic to P388 cells with an IC50 of 0.32 µg/mL,1 has
MICs of approximately 0.03 µg/mL against phytopathogenic
oomycetes,2 and suppresses apothecial formation of the plant
pathogen Sclerotinia sclerotiorum.3
for oocydin A.2 The absolute stereochemistry is also opposite
that originally proposed; structure 1 is the enantiomer of
haterumalide NA. Kigoshi reported that macrolactonization
could not be achieved. The macrolide was formed in 9%
yield by an intramolecular Reformatsky reaction of a
bromoacetate with an ꢀ-chloro-R,â,δ,ꢀ-dienal.5
We envisioned that the side chain of haterumalide NA (1)
could be introduced by the Nozaki-Hiyama-Kishi coupling
of aldehyde 2 with the appropriate vinyl iodide as shown in
Scheme 1. Macrolide 2 should be accessible by macrolac-
tonization of hydroxy acid 3 and adjustment of the oxygen
functionality. The key step in our route involved the Stille
coupling of allylic halide or acetate 5 with vinylstannane 4
to construct the skipped diene of 3.6,7 Finally, 5 should be
easily prepared from tetrahydrofuran 6, which has been
prepared by Yoshida by a diastereoselective iodoetherifica-
tion.8
As our work was nearing completion, Kigoshi reported
the first synthesis and revision of the structure of hateru-
malide NA.5 The stereochemistry at C15 of haterumalide NA
was revised to that shown in 1,1 as was originally proposed
(1) Takada, N.; Sato, H.; Suenaga, K.; Arimoto, H.; Yamada, K.; Ueda,
K.; Uemura, D. Tetrahedron Lett. 1999, 40, 6309.
(2) Strobel, G.; Li, J.-Y.; Sugawara, F.; Koshino, H.; Harper, J.; Hess,
W. M. Microbiology 1999, 145, 3557.
(3) Thaning, C.; Welch, C. J.; Borowicz, J. J.; Hedman, R.; Gerhardson,
B. Soil Biol. Biochem. 2001, 33, 1817.
(4) Ueda, K.; Hu, Y. Tetrahedron Lett. 1999, 40, 6305.
(5) Kigoshi, H.; Kita, M.; Ogawa, S.; Itoh, M.; Uemura, D. Org. Lett.
2003, 5, 957.
(6) (a) Sheffy, F. K.; Godschalx, J. P.; Stille, J. K. J. Am. Chem. Soc.
1984, 106, 4833. (b) Del Valle, L.; Stille, J. K.; Hegedus, L. S. J. Org.
Chem. 1990, 55, 3019.
(7) For applications of this reaction in natural product synthesis, see:
(a) Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508. (b)
White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem.
Soc. 2001, 123, 5407. (c) Vanderwal, C. D.; Vosburg, D. A.; Sorensen, E.
J. Org. Lett. 2001, 3, 4307.
10.1021/ol0356789 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/11/2003

There were many questions about the proposed Stille
coupling of 4 and 5. What is the best protecting group for
the alcohol of 4? What is the best leaving group X in 5? Is
the vinyl chloride of 5 compatible with the coupling? Will
the stereochemistry of the vinyl chloride be preserved? We
therefore carried out a model study, reacting 4 with (Z)-3-
chloro-2-octen-1-yl compounds 11 as shown in Table 1.
Scheme 1. Retrosynthetic Analysis of Haterumalide NA (1)
Table 1. Stille Coupling of 4 and 11
X
R
ligand
Ph3As
(o-furyl)3P
Ph3As
(o-furyl)3P
Ph3As
(o-furyl)3P
Ph3As
solvent
time
yield
Z/E ratio
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
TBS
TBS
TMS
TMS
Ac
Ac
TBS
TBS
THF
THF
THF
THF
THF
THF
C6H12
THF
17 h
48 h
42 h
48 h
48 h
65 h
14 h
48 h
70%
65%
50%
65%
55%
57%
75%
25%
85:15
85:15
85:15
85:15
79:21
76:24
74:26
variable
Vinylstannane 4a was prepared by the efficient five-step
sequence shown in Scheme 2. Addition of MeMgBr and CuI
Ph3As
Scheme 2. Synthesis of Vinylstannane 4a
Reduction of 2-octyn-1-ol with Red-Al at room temperature
and quenching with N-chlorosuccinimide (NCS)13 afforded
11, X ) OH. We found that coupling of 4a with 11, X )
Cl, under Farina conditions14 using AsPh3 and Pd2dba3
afforded 70% of a readily separable 85:15 mixture of the
desired product (Z)-12 and the isomerized product (E)-12.
The stereochemistry of the products was established by NOE
studies. It is noteworthy that the allylic chloride of 11 reacts
rapidly, while the vinyl chloride survives unchanged. Much
longer reaction times were required with tri-o-furylphosphine.
TMS was partially lost during the reaction, and stereocontrol
was worse with R ) Ac. Much lower yields were obtained
with X ) Br, and no product was obtained with X ) OAc.
Reaction in cyclohexane afforded higher yield, but lower
stereoselectivity.
Having established by this model study that the Stille
coupling of 4 and 5 should be viable, we turned our attention
to the preparation of 5 as shown in Scheme 3. Alcohol 13
has been prepared in optically pure form by Carreira’s aldol
procedure15 and by kinetic resolution of the racemic alcohol
with Sharpless asymmetric epoxidation.16 Heating 13 in
toluene containing MeOH at reflux afforded 85% of the keto
ester, which was reduced to give 93% of syn diol 14 with
Et2BOMe and NaBH4 in THF/MeOH at low temperature.
to propargyl alcohol and trapping with I2 afforded iodoallylic
alcohol 7,9 which was oxidized with MnO2 to yield the
unstable â-iodomethacrolein.10 Aldol reaction of ketene silyl
acetal 8 with the iodoaldehyde at -78 °C and oxazaboro-
lidinone 9 by Kiyooka’s procedure11 afforded 65% of 10 in
>80% ee.12 t-Butyldimethylsilylation and reaction with Me3-
SnSnMe3, Pd(PPh3)4, and i-Pr2EtN in toluene at 80 °C
afforded 91% of vinylstannane 4a.
(8) Tamaru, Y.; Hojo, M.; Kawamura, S.-i.; Sawada, S.; Yoshida, Z.-i.
J. Org. Chem. 1987, 52, 4062.
(9) Duboudin, J. G.; Jousseaume, B.; Bonakdar, A.; Saux, A. J.
Organomet. Chem. 1979, 168, 227.
(10) (a) Liu, F.; Negishi, E.-i. J. Org. Chem. 1997, 62, 8591. (b) He´naff,
N.; Whiting, A. Tetrahedron 2000, 56, 5193.
(11) (a) Kiyooka, S.-i.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano,
M. J. Org. Chem. 1991, 56, 2276. (b) Kiyooka, S.-i.; Kaneko, Y.; Kume,
K.-i. Tetrahedron Lett. 1992, 33, 4927. (c) Hena, M. A.; Kim, C.-S.; Horiike,
M.; Kiyooka, S.-i. Tetrahedron Lett. 1999, 40, 1161. (d) Kiyooka, S.-i.;
Hena, M. A. J. Org. Chem. 1999, 64, 5511.
(12) Lower enantiomeric excesses were obtained with tert-leucine or other
sulfonamides.
(13) Heathcock, C. H.; Mahaim, C.; Schlecht, M. F.; Utawanit, T. J.
Org. Chem. 1984, 49, 3264.
(14) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(15) (a) Anne´, S.; Yong, W.; Vandewalle, M. Synlett 1999, 1435. (b)
Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360.
(16) Sugita, Y.; Sakaki, J.-i.; Sato, M.; Kaneko, C. J. Chem. Soc., Perkin
Trans. 1 1992, 2855.
4386
Org. Lett., Vol. 5, No. 23, 2003

afforded primary iodide 19. Unfortunately, all attempts to
displace the iodide with a lithium acetylide led only to
elimination product 21. We hypothesized that the basic
tetrahydrofuran oxygen of 19 complexed to the lithium
acetylide to give complex 20 in which the acetylide is
positioned to effect elimination to give 21, rather than the
desired substitution to generate the carbon skeleton of 5.
If this analysis is correct, changing the order of the steps
so that the propargylic alcohol is introduced before the
iodoetherification forms the tetrahydrofuran should solve this
problem. Protection of the diol of 14 as the acetonide (95%),
reduction of the ester with LAH (95%), and reaction with
MsCl and Et3N and then NaI in acetone (83%) afforded
iodide 22 (see Scheme 4). The propargylic alcohol was now
Scheme 3. Unsuccessful Route to 5
Scheme 4. Preparation of Stille Coupling Precursor 26
Iodoetherification as described by Yoshida8 afforded 79%
of iodomethyltetrahydrofuran 6 in >95% de.
To our surprise, displacement of the iodide of 6 with an
oxygen nucleophile proved to be surprisingly difficult.
Mixtures of substitution and elimination products were
obtained under most conditions. Eventually, we found that
Reich’s oxidative substitution protocol17 effected substitution
without elimination. Oxidation of the TBS ether of 6 with
m-CPBA in CH2Cl2 generated the reactive iodoso compound
that was displaced by the OTBS oxygen to give 80% of
oxetane 15 after loss of the TBS group. We reasoned that
changing the protecting group could prevent formation of
the oxetane. The analogous oxidation of the acetate of 6 led
to cation 16, which reacted with water to give 82% of a
mixture of hydroxy acetates 17. Basic hydrolysis of this
mixture (100%), tritylation of the primary alcohol (88%),
and silylation of the secondary alcohol (93%) afforded 18.
LiBH4 reduction of the ester of 18 (99%) and reaction of
the primary alcohol with PPh3, I2, and imidazole (90%)
successfully introduced in 92% yield by displacement with
LiCtCCH2OTBS in THF/HMPA and resilylation of the
partially deprotected primary alcohol. Deprotection of the
acetonide with BF3‚Et2O and propanedithiol18 afforded 79%
of diol 23 at 80% conversion.
Iodoetherification of 23 afforded 81% of iodomethyltet-
rahydrofuran 24 in >90% de. Acetylation (95%), oxidation
with m-CPBA,17 and hydrolysis of the hydroxyacetate
mixture (65% two steps) afforded diol 25. Formation of the
(17) (a) Reich, H. J.; Peake, S. L. J. Am. Chem. Soc. 1978, 100, 4888.
(b) Be´res, J.; Sa´gi, Gy.; Baitz-Ga´cs, E.; To¨mo¨sko¨zi, I.; O¨ tvo¨s, L. Tetrahedron
1988, 44, 6207.
(18) Konosu, T.; Oida, S. Chem. Pharm. Bull. 1991, 39, 2212.
Org. Lett., Vol. 5, No. 23, 2003
4387

acetonide, cleavage of the TBS ether with TBAF (85% two
steps), reduction of the propargylic alcohol with Red-Al
followed by NCS quench (70%),13 and conversion of the
allylic alcohol to the chloride with MsCl, Et3N, and then
LiCl in acetone (90%) afforded the required Stille coupling
precursor 26.
Stille coupling of 26 with 4a using the conditions
developed in the model study with Pd2dba3 and AsPh3 in
THF at 60 °C afforded 65% of 27 and 10% of the
corresponding (E)-isomer (see Scheme 5). Hydrolysis of the
to a solution of DMAP in toluene at 25 °C to give 65% of
the desired macrolide 29 and 15% of dimer and trimer.20
Addition of the mixed anhydride to DMAP in toluene at
higher temperatures afforded no dimer and trimer but gave
a lower yield of 29, suggesting that it is thermally unstable.
If DMAP was added to the mixed anhydride, only 15-20%
of 29 was formed, with dimer and trimer being the major
products formed in 50-60% yield.
Kigoshi reported that he was unable to effect macrolac-
tonization of a substrate that differs from 28 only in that the
primary alcohol is protected as a TBDPS rather than a trityl
ether and the secondary alcohol is protected as an acetate
rather than a TBS ether.5 Clearly the choice of protecting
groups is crucial for the success of the macrolactonization.
The â-acetoxy mixed anhydride may undergo elimination.
The primary TBDPS ether may undergo migration.
Hydrolysis of the TBS ether of 29 with TBAF in THF
(85%), acetylation of the alcohol (AcCl, pyr, DMAP), and
hydrolysis of the trityl ether in 80% AcOH at 40 °C for 12
h (78% for two steps) afforded primary alcohol 30. The 1H
NMR spectrum of 30 is identical to that kindly provided by
Prof. Kigoshi.
Scheme 5. Completion of the Synthesis of Haterumalide NA
Methyl Ester (32)
The synthesis of haterumalide NA methyl ester (32) was
completed as described by Kigoshi.5 Oxidation with Dess-
Martin periodinane and Nozaki-Hiyama-Kishi coupling
with iodide 315,21 afforded 30-40% of haterumalide NA
methyl ester after HPLC purification. The 1H NMR and CD
spectra of 32 are identical to those reported by Kigoshi for
ent-haterumalide NA methyl ester.
In conclusion, we have completed an efficient, convergent
synthesis of haterumalide NA methyl ester (32) that will be
equally suitable for the preparation of the natural enantiomer.
The key step is the Stille coupling of 4a with 26 to give
65% of 27 containing the desired skipped diene, vinylic
chloride, and allylic oxygen functionality. The successful
Yamaguchi macrolactonization of 28 to give 29, despite
earlier reports to the contrary with similar substrates,5
demonstrates the critical effect of protecting groups on the
success of the cyclization.
Acknowledgment. We thank the National Institutes of
Health (GM-50151) for financial support. We thank Prof.
H. Kigoshi for a copy of the 1H NMR spectrum of macrolide
alcohol 30.
Supporting Information Available: Full experimental
1
13
details and copies of H and C NMR spectral data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
acetonide of 27 with CSA (85%), tritylation of the primary
alcohol (91%), and basic hydrolysis of the phenyl ester (93%)
afforded hydroxy acid 28.
OL0356789
Macrolactonization was achieved efficiently by the Yamagu-
chi protocol.19 Addition of trichlorobenzoyl chloride and Et3N
afforded the mixed anhydride, which was added over 15 h
(20) For related macrolactonization by slow addition of the mixed
anhydride to DMAP and toluene, see: (a) Nicolaou, K. C.; Li, Y.;
Fylaktakidou, K. C.; Mitchell, H. J.; Sugita, K. Angew. Chem., Int. Ed.
2001, 40, 3854. (b) Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125,
2374.
(19) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(21) Thibonnet, J.; Launay, V.; Abarbri, M.; Ducheˆne, A.; Parrain, J.-L.
Tetrahedron Lett. 1998, 39, 4277.
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Org. Lett., Vol. 5, No. 23, 2003