Total Synthesis of the Polyene-Polyol Macrolide RK-397, Featuring Cross-Couplings of Alkynylepoxide Modules

Article abstract of DOI:10.1021/ja039618+

The total synthesis of the natural product RK-397 is based on a new synthetic strategy for assembling polyacetate structures, by efficient cross-coupling of nucleophilic terminal alkyne modules with electrophilic epoxides bearing another alkyne at the opp

Full text of DOI:10.1021/ja039618+

Published on Web 02/07/2004
Total Synthesis of the Polyene-Polyol Macrolide RK-397,
Featuring Cross-Couplings of Alkynylepoxide Modules
Svetlana A. Burova and Frank E. McDonald*
Contribution from the Department of Chemistry, Emory UniVersity, 1515 Pierce DriVe,
Atlanta, Georgia 30322
Received November 15, 2003; E-mail: fmcdona@emory.edu
Abstract: The total synthesis of the natural product RK-397 is based on a new synthetic strategy for
assembling polyacetate structures, by efficient cross-coupling of nucleophilic terminal alkyne modules with
electrophilic epoxides bearing another alkyne at the opposite terminus. The natural product is constructed
from four principal modules: a polyene precursor for carbons 3-9, and three alkyne-terminated modules
for carbons 10-16, 17-22, and 23-33. Each module is prepared with control of all stereochemical elements,
and the alkynyl alcohols obtained from alkyne-epoxide couplings are converted into 1,3-diols by a sequence
of hydroxyl-directed hydrosilylation, C-Si bond oxidation, and stereoselective ketone reduction with induction
from the â-hydroxyl group. The highly convergent nature of our synthetic pathway and the flexibility of the
modular synthesis strategy for virtually any stereoisomer can provide access to other members of the
polyene-polyol macrolides, including stereoisomers of RK-397.
Introduction
Polyacetate structures in the form of 1,3,5-... alternating polyol
chains are found in a variety of natural products, such as the
polyene macrolides amphotericin B (1), nystatin (2), mycoticin
(3), and RK-397 (4) (Figure 1), which are well-known for their
antifungal activities.1,2 Relatively minor structural changes can
result in significant differences in biological activities. For
instance, amphotericin B (1) is used for severe systemic and
potentially fatal fungal infections but is also relatively toxic,
whereas nystatin (2) is much milder in activity and has virtually
no human toxicity.3 Mycoticin (3) and RK-397 (4) both exhibit
broad antimicrobial activities against filamentous fungi, yeast,
and bacteria at 50-100 µg/mL, yet only RK-397 (4) is reported
to have in vitro anticancer activity, inhibiting human leukemia
cell lines K-562 and HL-60 at 50 and 25 µg/mL, respectively.
The anticancer activity for RK-397 (4) vs the absence of activity
reported for mycoticin (3) is rather remarkable when the minor
differences in the two compound structures are considered,
specifically the additional methyl group at C14 of mycoticin
and differing relative stereochemistry of the C19 and C21
alcohols.
Polyacetate compounds are biosynthesized by building up the
linear carbon chain two atoms at the time using simple acetate
and propionate building blocks.4 In this regard, the Schreiber
(1) Maehr, H.; Yang, R.; Hong, L. N.; Liu, C. M.; Hatada, M. H.; Todaro, L.
J. J. Org. Chem. 1989, 54, 3816. (b) Wasserman, H. H.; Van Verth, J. E.;
McCaustland, D. J.; Borowitz, I. J.; Kamber, B. J. Am. Chem. Soc. 1967,
89, 1535. (c) Schreiber, S. L.; Goulet, M. T. J. Am. Chem. Soc. 1987, 109,
8120. (d) Lancelin, J. M.; Beau, J. M. Tetrahedron Lett. 1989, 30, 4521.
(2) Kobinata, K.; Koshino, H.; Kudo, T.; Isono, K.; Osada, H. J. Antibiot.
1993, 46, 1616. (b) Koshino, H.; Kobinata, K.; Isono, K.; Osada, H. J.
Antibiot. 1993, 46, 1619. (c) Suenaga, T.; Nakamura, H.; Koshino, H.;
Kobinata, K.; Osada, H.; Nakata, T. Tennen Yuki Kagobutsu Toronkai Koen
Yoshishu 1997, 39, 607 (Chem. Abstr. 1997, 131, 129786).
Figure 1. Representative polyene macrolide natural products.
chemical synthesis of mycoticin based on iterative aldol
equivalent addition to aldehydes might be considered to be an
(3) Drug Facts and Comparisons; Wolters Kluwer: St Louis, 1996; pp 2174,
2180.
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J. AM. CHEM. SOC. 2004, 126, 2495-2500
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A R T I C L E S
Burova and McDonald
Figure 2. Construction of polyacetates from two-carbon synthons: bio-
synthesis vs chemical synthesis.
Figure 3. Examples of four- and five-carbon synthons in the synthesis of
polyacetates.
imitation of this biosynthetic pathway (Figure 2).5 Note that a
linear synthesis of a 34-carbon chain from two-carbon synthons
requires 16 carbon-carbon bond-forming steps.
Thus, the number of carbon-carbon bond-forming steps can
be further reduced by using larger building blocks, such as
Carreira’s aldehyde condensation approach with four-carbon
acetoacetate synthons,6 or Rychnovsky’s sequential cross-
couplings of the five-carbon dibromides with 4-cyano-1,3-
dioxanes (Figure 3).7,8
We anticipated a more efficient modular approach for
polyacetate-alternating polyol structures by coupling larger
building blocks with six or more carbons in a linear chain,
(4) (a) Enzymatic Reaction Mechanisms, Walsh, C., Ed.; W. H. Freeman: San
Francisco, 1979; pp 909-916. (b) Staunton. J. Angew. Chem., Int. Ed. Engl.
1991, 30, 1302. (c) Cortes, J.; Haydock, S. F.; Roberts, G. A.; Bevitt, D.
J.; Leadlay, P. F. Nature 1990, 348, 176. (d) Donadio, S.; Staver, M. J.;
McAlpine, J. B.; Swanson, S. J.; Katz, L. Science 1999, 252, 675. (e) Tsoi,
C. J.; Khosla, C. Chem. Biol. 1995, 2, 355. (f) Rohr, J. Angew. Chem., Int.
Ed. Engl. 1995, 34, 881. (g) Bailey, J. E. Nat. Biotechnol. 1999, 17, 616.
(h) Cane, D. E.; Walsh, C. T.; Khosla, C. Science 1998, 282, 63. (i) Carreras,
C. W.; Santi, D. V. Curr. Opin. Biotechnol. 1998, 9, 403.
(5) Poss, C. S.; Rychnovsky, S. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993,
115, 3360. (b) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem.
Soc. 1990, 112, 6348. (c) Andersen, M. W.; Hildebrandt, B.; Dahmann,
G.; Hoffmann, R. W. Chem. Ber. 1991, 124, 2127.
Figure 4. Modular synthesis of polyol segment of RK-397 from six-carbon
synthons 5 and 6.
further reducing the number of carbon-carbon bond-forming
steps required for polyacetate synthesis. The optimal modular
synthesis would permit maximum variability in product struc-
tures with regard to functional groups and stereochemical
diversity, which is particularly important for combinatorial and
parallel synthetic strategies and methods. To this end we recently
reported a new strategy for assembling polyacetate structures
based on cross-coupling of six-carbon modules utilizing nu-
cleophilic epoxide opening of electrophilic epoxyalkynol 6 with
nucleophilic alkynyltriol 5 (Figure 4). Regioselective water
equivalent addition to the internal alkyne of the resulting diyne
7 produced â-hydroxyketone 8. Depending on the choice of
reducing reagent,9 stereoselective hydroxyl-directed reduction
of the â-hydroxyketone functionality in 8 afforded either 1,3-
syn or 1,3-anti diol products, therefore permitting rapid prepara-
tion of polyacetate structures 9 bearing twelve linear carbons
and separate control of all five stereocenters. Additionally, our
(6) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837.
See also (b) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (c) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1. (d)
Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586.
(e) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125,
2852. (f) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082. (g)
Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 1343. (h) Harris, T. M.;
Harris, C. M.; Kuzma, P. C.; Lee, J. Y. C.; Mahalingam, S.; Gilbreath, S.
G. J. Am. Chem. Soc. 1988, 110, 6186. (i) Yamaguchi, M.; Hasebe, K.;
Higashi, H.; Uchida, M.; Irie, A.; Minami, T. J. Org. Chem. 1990, 55,
1611. (j) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360.
(k) Evans, D. A.; Gauchet-Prunet J. A.; Carreira, E. M.; Charette, A. B. J.
Org. Chem. 1991, 56, 741.
(7) Rychnovsky, S. D.; Zeller, S.; Skalitzky, D. J.; Griesgraber, G. J. Org.
Chem. 1990, 55, 5550. (b) Rychnovsky, S. D.; Rogers, B. N.; Richardson,
T. I. Acc. Chem. Res. 1998, 31, 9, and refs 8h,j-l.
(8) For other synthetic work in the area of polyol-polyene macrolides, see:
Amphotericin B: (a) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.;
Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4696. (b) Nicolaou, K.
C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahatjis, D. P.; Chakraborty,
T. K. J. Am. Chem. Soc. 1988, 110, 4672. Mycoticin A: (c) see ref 5a. (d)
Dreher, S. D.; Leighton, J. L. J. Am. Chem. Soc. 2001, 123, 341.
Roxaticin: (e) Mori, Y.; Asai, M.; Kawade, J.-I.; Furukawa, H. Tetrahedron
1995, 51, 5315. (f) Mori, Y.; Asai, M.; Okumura, A.; Furukawa, H.
Tetrahedron 1995, 51, 5299. (g) Mori, Y.; Asai, M.; Kawade, J.-I.;
Okumura, A.; Furukawa, H. Tetrahedron Lett. 1994, 35, 6503. (h)
Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753. (i)
Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899.
Roflamycoin: (j) Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem.
Soc. 1997, 119, 2058. Dermostatin A: (k) Sinz, C. J.; Rychnovsky, S. D.
Tetrahedron 2002, 58, 6561. (l) Sinz, C. J.; Rychnovsky, S. D. Angew.
Chem., Int. Ed. 2001, 40, 3224. (m) Filipin III: Richardson, T. I.;
Rychnovsky, S. D. J. Am. Chem. Soc. 1997, 119, 12360.
(9) Syn-reduction of â-hydroxyketones: (a) Nakata, T.; Takao, S.; Fukui, M.;
Oishi, T. Tetrahedron Lett. 1983, 24, 3873. (b) Chen, K.-M.; Hardtmann,
G.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.
Anti-reduction of â-hydroxyketones: (c) Saksena, A. K.; Mangiaracina, P.
Tetrahedron Lett. 1983, 24, 273. (d) Evans, D. A.; Hoveyda, A. H. J. Am.
Chem. Soc. 1990, 112, 6447. (e) Keck, G. E.; Wager, C. A.; Sell, T.; Wager,
T. T. J. Org. Chem. 1999, 64, 2172.
9
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Total Synthesis of RK-397
A R T I C L E S
Scheme 1. Synthesis of C23-C31 Modulea
a Reagents and conditions: (a) Z-crotylborane-(-)-(Ipc)2, then H2O2,
3 N NaOH (50% yield, 77% ee); (b) p-methoxybenzyltrichloroacetimidate,
cat. CSA, CH2Cl2 (67% yield); (c) TBSCl, imidazole, DMF (60% yield);
(d) methyl acrylate (3 equiv), cat. 24 or 25, CH2Cl2 (see below); (e) DIBAL-
H, CH2Cl2, -78 °C (91% yield); (f) SO3-pyr, DMSO, CH2Cl2 (89% yield);
(g) 21, Et2O, -78° to -30 °C, then -78 °C, NaBH4, MeOH, then AcOH
quench, then H2O2, 3 N NaOH (97% yield, 4:1 dr); (h) K2CO3, MeOH. (i)
Me2C(OMe)2, cat. TsOH (75%, two steps).
Figure 5. Retrosynthetic analysis of RK-397.
methodology was applied in an iterative mode from 9 and
epoxyalkynol 6 to give the C11-C28 substructure of RK-
397.10,11
We have now completed the total synthesis of RK-397, based
on a modification of the modular synthesis approach outlined
above using iterative cross-couplings of terminal alkynes with
epoxyalkyne modules. In our retrosynthetic analysis, we decided
to introduce the light- and air-sensitive polyene at the end of
the synthesis a la Rychnovsky’s method of sequential Stille8k,l
and macrocyclic Horner-Emmons12 reaction from 11, which
in turn could be disconnected into the enyne 12, six-carbon
epoxyalkyne 13 (analogous to 6), and seven-carbon epoxyalkyne
14 (Figure 5).
(PCy3)Cl2 2414 or the corresponding o-isopropoxybenzylidene-
ruthenium carbene 25.15 Catalyst 24 produced the R,â-unsatu-
rated ester 18 in 60% yield after 16 h at ambient temperatures.
However, the more reactive phosphine-free Ru catalyst 25 also
provided 18 in 66% yield after 5 h at 36 °C. More dramatic
results were observed in the reaction of tert-butyldimethylsilyl
ether 17 with methyl acrylate. Grubbs’s second generation
metathesis catalyst 24 was a very poor catalyst for this
transformation, generating a low yield (23%) of desired R,â-
unsaturated ester 19 even with 10 mol % loading of catalyst
24. In contrast, R,â-unsaturated ester 19 was obtained in good
yield (74%) when only 2 mol % of phosphine-free Ru catalyst
25 was applied. In all cases only the trans-alkene isomers 18
and 19 were obtained from olefin cross-metathesis. Enantio-
selective aldol addition of the unsaturated aldehyde 20 with the
enolborinate 21 (from 4-(trimethylsilyl)-3-butyn-2-one and (-)-
(Ipc)2BOTf/Et3N16) gave the expected â-hydroxyketone in low
yield. Recalling that Paterson successfully utilized a one-pot
boron aldol addition and stereoselective reduction of the
intermediate boron chelate with NaBH4,17 we applied the same
one-pot aldol-reduction procedure from 20 and 21 to provide
syn-diol 22 as an 4:1 mixture of diastereomers in excellent yield.
After basic methanolysis of the alkynylsilane 22 and acetonide
Results and Discussion
I. Synthesis of Modules 12, 13, and 14. The synthesis of
the C23-C31 module 12 began with synthesis of homoallylic
alcohol 15 from the reaction of isobutyraldehyde with (Z)-
crotyldiisopinocampheylborane13 (derived from commercially
available (1S)-(-)-R-pinene, 89% ee; Scheme 1). In our hands,
alcohol 15 was difficult to separate from the isopinocampheol
byproduct of auxiliary oxidation, therefore 15 was isolated in
75% purity and was taken to the next step without additional
purification. After protection of the free hydroxyl group as a
p-methoxybenzyl ether and purification, this compound 16
was subjected to ruthenium-catalyzed olefin cross-metathesis
with methyl acrylate.8d,14 This reaction can be catalyzed either
with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene Ru(dCHPh)-
(10) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2002, 124, 8188.
(11) For a different approach to the RK-397 polyol, see: Schneider, C.;
Tolksdorf, F.; Rehfeuter, M. Synlett 2002, 12, 2098.
(15) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron
Lett. 2000, 41, 9973.
(16) Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997. (b) Paterson,
I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.;
Norcross, R. D. Tetrahedron 1990, 46, 4663.
(17) Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992, 33, 801. (b) Paterson,
I.; Perkins, M. V. Tetrahedron 1996, 52, 1811.
(12) Nicolaou, K. C.; Seitz, S. P.; Pavia M. R. J. Am. Chem. Soc. 1982, 104,
2030. (b) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(13) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919. (b) For 15,
see ref 8d. (c) For compound ent-15, see: Ghosh, A. K.; Liu, W. J. Org.
Chem. 1997, 62, 7908.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
9
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A R T I C L E S
Burova and McDonald
Scheme 4. Coupling of C17-C22 and C23-C31 Modulesa
Scheme 2. Synthesis of the C17-C22 Modulea
a Reagents and conditions: (a) TBSCl, imidazole, DMF (85% yield);
(b) p-methoxybenzyl trichloroacetimidate, cat. CSA, CH2Cl2 (74% yield);
(c) m-CPBA, CH2Cl2 (79-83% yield); (d) (S,S)-salenCo(III)OAc (polymer-
supported), H2O (for R ) TBS, 46% yield epoxide (29) + 43% yield diol
(31); for R ) PMBn, 42% yield epoxide (30) + 54% yield diol (32, 4:1
dr)).
a Reagents and conditions: (a) 23, n-BuLi, THF, -50 °C, then BF3-
OEt2, -78 °C, then 29 or 30.
Scheme 5. Hydroxyl-Directed Hydrosilylation-Oxidationa
Scheme 3. Synthesis of C10-C16 Modulea
a Reagents and conditions: (a) Vinylmagnesium bromide, CuBr, THF,
-70° to -40 °C (84% yield); (b) KOH (81% yield); (c) TMS-acetylene/
n-BuLi/BF3-OEt2, THF, -78 °C (75% yield); (d) m-CPBA, CH2Cl2 (77%
yield, 1.2:1 dr); (e) NaH, PMBnCl, Bu4NI, DMF (73% yield); (f) n-BuLi,
TMSCl, THF, -55° to -40 °C (55% yield); (g) 10% (S,S)-salenCo(III)OAc,
THF/H2O (36, 32% yield + 37, 47% yield).
protection of the 1,3-diol, the diastereomeric mixture was
purified by silica gel flash chromatography to provide single
diastereomer 23 (corresponding to generalized structure 12).18,19
The C17-C22 module was prepared as previously described
from the (S)-enynol 26.10 Epoxidation of either the silyl ether
27 or p-methoxybenzyl ether 28 gave a ca. 1:1 mixture of
diastereomers, and single diastereomers 29 and 30 could be
prepared by Jacobsen’s hydrolytic kinetic resolution procedure20
(Scheme 2).
The seven-carbon C10-C16 module was constructed from
(R)-epichlorohydrin and copper bromide-promoted addition of
vinylmagnesium bromide followed by subsequent distillation
from KOH to give 33,21 which was converted into the enynol
a Reagents and conditions: (a) (Me2SiH)2NH, 100 °C; (b) cat. Pt(DVDS),
THF; (c) 30% aq. H2O2, KHCO3, KF, MeOH/THF (42, 43% yield + 43,
13% yield); (d) Et2BOMe, THF/MeOH, NaBH4, -78 °C; (e) K2CO3,
MeOH; (f) Me2C(OMe)2, cat. TsOH, 3Å MS (67% yield, three steps).
34 (Scheme 3). We originally first protected the hydroxyl as a
p-methoxybenzyl ether, followed by epoxidation, but the mixture
of epoxides was determined to contain the desired diastereomer
36 as the minor component of a 1.7:1 mixture of diastereomers.
However, when epoxidation was conducted on the alcohol 34
followed by PMBn ether formation (desilylation also occurred
under the basic conditions, which required resilylation of the
epoxyalkyne) the mixture of epoxides favored 36 in a 1.2:1
diastereomeric ratio. Hydrolytic kinetic resolution provided 36
as a single stereoisomer which was easily separated from the
more polar diol 37.
(18) Although a similar reaction sequence could be accomplished from 19 to
give the silyl ether analogue of 23, the mixture of diastereomers could not
be efficiently separated.
(19) Relative and absolute configuration of 23 was confirmed by X-ray
diffraction analysis of the secondary alcohol resulting from DDQ oxidative
removal of the p-methoxybenzyl ether protective group. Please see
Supporting Information for details.
(20) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 4147. (b)
Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
6776. (c) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 1307.
(21) Schuda, A.; Mazzocchi, P. H.; Fritz, G.; Morgan, T. Synthesis 1986, 309.
(b) For a different enantioselective synthesis of 34, see: Zemribo, R.; Mead,
K. T. Tetrahedron Lett. 1998, 39, 3895.
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Total Synthesis of RK-397
A R T I C L E S
Scheme 6. Coupling to C10-C16 Module and Alkyne Hydration
Scheme 7. Coupling of C10-C31 to Polyene and Completion of
OPMBa
RK-397 Synthesisa
a Reagents and conditions: (a) n-BuLi, THF, -78°C, then BF3-OEt2,
-78 °C, then 36 (59% yield); (b) (Me2SiH)2NH, 100 °C; (c) cat. Pt(DVDS),
THF. (d) 30% aq H2O2, KHCO3, KF, MeOH/THF (65% yield, three steps);
(e) Et2BOMe, THF/MeOH, NaBH4, -78 °C; (f) K2CO3, MeOH; (g)
Me2C(OMe)2, cat. TsOH, 3Å MS (80% yield, three steps).
II. Coupling of C17-C22 and C23-C31 Modules and
Hydration of the Internal Alkyne. Cross-coupling of the
lithium acetylide from 23 with either electrophilic epoxides 29
a Reagents and conditions: (a) Cp2ZrCl2, LiEt3BH, THF; then I2 (90%
yield); (b) DDQ, CH2Cl2 (61% yield); (c) 2,2-dimethoxypropane, TsOH
(0.8 equiv), H2O (1.5 equiv), 3 d (86% yield); (d) HO2CCH2P(O)(OEt)2,
BOP, DMAP, CH2Cl2 (91% yield); (e) all-trans-7-(tributylstannyl)-2,4,6-
heptatrien-1-ol, cat. Pd2(dba)3-CHCl3, Ph3As, i-Pr2NEt, THF (32% yield
+ 27% recovered iodide); (f) Dess-Martin periodinane, NaHCO3, CH2Cl2;
(g) LiCl, DBU, MeCN, 2 d (29% yield, two steps); (h) Dowex 50W acidic
resin, MeOH (73% yield).
22
or 30 could be accomplished with BF3-OEt2 to provide the
corresponding homopropargylic alcohols 38 or 39 (Scheme 4).
Care was taken to avoid using more than 1 equiv of n-BuLi for
deprotonation of 23, as deprotonation on the aromatic ring of
the PMBn protective group resulted in diminished yields of
coupling products.
Several approaches were explored for hydration of the C23-
C24 alkyne including iodocyclization of a carbonate derivative
of 38,10,23,24 before we settled on hydroxyl-directed hydro-
silylation/Si-C bond oxidation, which had been reported by
Tamao and more recently Marshall.25 As our initial studies
indicated that TBS ether protective groups were incompatible
with siloxane carbon-silicon bond oxidation, we began by
forming the hydrodimethylsilyl ether substrate 40 (Scheme 5)
from p-methoxybenzyl ether-protected alkynyl alcohol 39. The
organic soluble catalyst complex Pt(0)-1,3-divinyl-1,1,3,3-
tetramethyldisiloxane complex (Pt(DVDS))26 completely con-
verted 40 to the cyclic siloxane 41,27 which was directly oxidized
with aqueous hydrogen peroxide in the presence of KF to furnish
â-hydroxyketones as a mixture of TMS-protected alkyne 42 and
its unprotected counterpart 43 in 56% yield for three steps
starting from alcohol 39. Hydroxyl-directed reduction of the
mixture of â-hydroxyketones 42 and 43 with NaBH4/Et2BOMe,9b
and sequential acetylenic TMS deprotection and acetonide
formation, gave product 44 in good yield.
(22) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(23) Marshall, J. A.; Yanik, M. M. J. Org. Chem. 1999, 64, 3798.
(24) Iodocyclization of the tert-butyl carbonate derivative of the alcohol of 38
was successful. However radical deiodination resulted in a product attributed
to radical cyclization onto the C28-C29 alkene. Please see Supporting
Information for more discussion.
(26) Denmark, S. E.; Wang, Z. Org. Lett. 2001, 3, 1073.
(27) Incomplete conversion of 40 to cyclic siloxane intermediate 41 was observed
during intramolecular hydrosilylation of 40 catalyzed by chloroplatinic acid
(H2PtCl6) even after extended reaction time. Cyclic siloxane 41 suffered
significant decomposition upon prolonged exposure to silica gel; therefore,
it was taken to the next step without purification.
(25) Tamao, K.; Maeda, K.; Tanaka, T.; Ito, Y. Tetrahedron Lett. 1988, 29,
6955. (b) Marshall, J. A.; Yanik, M. M. Org. Lett. 2000, 2, 2173.
9
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A R T I C L E S
Burova and McDonald
Conclusions
III. Coupling to the C10-16 Module and Completion of
the Synthesis of RK-397. The coupling of terminal alkyne 44
and the C10-C16 epoxyalkyne module 36 proceeded smoothly
to afford diyne 45, which underwent the identical sequence of
hydrosilylation-oxidation to 46 and chelation-controlled reduc-
tion to provide regio- and stereoselective introduction of the
C17-alcohol, protected as the acetonide 47 (Scheme 6).
The first synthesis of RK-397 (4) also demonstrates the merit
of our modular synthesis approach to this natural product, via
the advanced intermediate 47 bearing all 10 chiral centers.
Although all three â-hydroxyketones (precursor to 22, com-
pounds 42 and 46) were reduced to syn-1,3-diols by chelation-
controlled reductions, the option of obtaining 1,3-anti-diols9c
by hydroxyl-directed reduction at any of these stages and the
availability of any isomer of 23 (four chiral centers, 16 isomers),
30 (four isomers) and 36 (four isomers) makes it not unrealistic
to consider that any of the 210 (1024) isomers of advanced
intermediate 47 can be prepared, and barring possible confor-
mational restrictions on the polyene macrocyclization, perhaps
any isomer of RK-397 can be prepared. Thus more efficient
conversions of the hydroxyalkynes 39 and 45 to â-hydroxy-
ketones 42 and 46, respectively, might enable practical parallel
synthesis of a library of RK-397 stereoisomers. Extensions of
this strategy to the synthesis of polypropionates are also in
progress.
From this stage, we sought to validate our methodology by
completing the total synthesis of RK-397, introducing the
polyene and closing the macrocycle following the strategy previ-
ously demonstrated for dermostatin by Sinz and Rychnovsky.8k-l
The terminal alkyne of 47 underwent hydrozirconation-
iodination28 to the trans-vinyl iodide 48 in excellent yield
(Scheme 7). Subsequent deprotection of the PMBn ethers to
49 and protective group equilibration with wet 2,2-dimethoxy-
propane and catalytic TsOH provided the desired tetracetonide
50 in good yield, with only the C31 alcohol unprotected. After
esterification with diethylphosphonoacetic acid, Stille coupling
with all-trans-7-(tributylstannyl)-2,4,6-heptatrien-1-ol29 to 51
and oxidation of the primary alcohol provided the correspond-
ing aldehyde which successfully underwent Horner-Emmons
macrocyclization under Masamune-Roush conditions12b to
provide the known tetraacetonide derivative 522c of RK-397.
Acidic methanolysis of the acetonide protective groups provided
synthetic RK-397 (4). Our synthetic RK-397 and tetraacetonide
52 were both identical with natural RK-397 and the derived
tetraacetonide 52 with regard to proton NMR spectra in CD3OD,
and UV-spectroscopy.30 Thus the unambiguous nature of our
synthesis with regard to setting stereocenters confirms Nakata’s
assignment of stereochemistry for RK-397.
Acknowledgment. This research was supported in part by a
seed grant from the Emory University Research Committee, as
well as the National Institutes of Health (CA-59703). Major
instrumentation for research (high-field NMR, mass spectrom-
etry, and X-ray crystallography) was provided by grants from
the National Institutes of Health, National Science Foundation,
and the Georgia Research Alliance. We also thank Drs.
Shaoxiong Wu and Bing Wang (NMR), Frederick H. Strobel
(MS), Kenneth I. Hardcastle and Mr. Wade A. Neiwert (X-
ray) for their expert assistance in support of this research.
Supporting Information Available: Complete experimental
details and compound characterizations, crystallographic data
for a derivative of compound 23 (includes cif data), discussion
of attempted hydration from iodocyclization of the tert-butyl
carbonate derivative of 38, and comparison of spectral data of
synthetic and natural RK-397 (4) and tetraacetonide derivative
52. This material is available free of charge via the Internet at
http://pubs.acs.org.
(28) Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron Lett. 1990, 31, 7257.
Cp2Zr(H)Cl has a poor shelf life. In our hands, commercial samples of
this reagent gave mostly or only the terminal alkene, probably from
disproportion to Cp2ZrH2 and inactive Cp2ZrCl2. (b) Review: Wipf, P.;
Jahn, H. Tetrahedron 1996, 52, 12853.
(29) Prepared in two steps from known all-trans-5-(tributylstannyl)-2,4-penta-
dienal (Dominguez, B.; Iglesias, B.; Lera, A. R. Tetrahedron 1999, 55,
15071): (a) Ph3PdCHCO2Et, CH2Cl2 (95% yield); (b) DIBAL, CH2Cl2,
-78 °C (75% yield).
(30) 1H NMR spectra and ultraviolet spectra of natural RK-397 (4) and its
tetraacetonide derivative 52 were generously provided by Dr. Tadashi
Nakata and Dr. Hiroyuki Koshino from The Institute of Physical and
Chemical Research (RIKEN), Japan.
JA039618+
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2500 J. AM. CHEM. SOC. VOL. 126, NO. 8, 2004