Asymmetric synthesis of the fully functional macrolide core of salicylihalamide: remote control of olefin geometry during RCM.

Article abstract of DOI:10.1021/ol006646d

A catalysis-based approach to the core region 24 of the antitumor agents salicylihalamides A and B is reported. Key steps are two asymmetric hydrogenations of beta-keto esters 13 and 16 catalyzed by [(R)-BINAP.RuCl(2)](2).NEt(3) and an RCM-based macrocyclization effected by the NHC-containing ruthenium carbene 21. The stereochemical outcome of the latter reaction is controlled by remote substituents on the phenolic OH group of the cyclization precursor 23.

Full text of DOI:10.1021/ol006646d

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3731-3734
Asymmetric Synthesis of the Fully
Functional Macrolide Core of
Salicylihalamide: Remote Control of
Olefin Geometry during RCM
Alois Fu1rstner,* Oliver R. Thiel, and Gaetano Blanda
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
fuerstner@mpi-muelheim.mpg.de
Received September 25, 2000
ABSTRACT
A catalysis-based approach to the core region 24 of the antitumor agents salicylihalamides A and B is reported. Key steps are two asymmetric
hydrogenations of â-keto esters 13 and 16 catalyzed by [(R)-BINAP‚RuCl2]2‚NEt3 and an RCM-based macrocyclization effected by the NHC-
containing ruthenium carbene 21. The stereochemical outcome of the latter reaction is controlled by remote substituents on the phenolic OH
group of the cyclization precursor 23.
Bioassay-guided fractionation of the extracts of an unidenti-
fied sponge of the Haliclona genus collected off the
Southwestern Australian coast led to the discovery of
salicylihalamides A (1) and B (2), potent cytotoxic mac-
action. These attractive biological properties render 1 and 2
priority targets for total synthesis and excellent templates
for the development and validation of new methodology.
In this context, several procedures for the formation of
the rather labile enamide entity of 1 have been reported,3
while no concise synthesis of the salicylate macrolide
segment has been described thus far. As part of our ongoing
program on the use of ring closing metathesis (RCM),4 we
have recently outlined an efficient entry into a truncated
(2) Since the discovery of salicylihalamide, several closely related
cytotoxic agents have been isolated which also combine a salicyclic acid
macrolide and a polyunsaturated enamide side chain, cf.: (a) Lobata-
mides: McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina, J. H.;
Laakso, J.; Ireland, C. M.; Murray, L.; Capon, R. J.; Boyd, M. R. J. Org.
Chem. 1998, 63, 7805. (b) Oximidines: Kim, J. W.; Shin-ya, K.; Furihata,
K.; Hayakawa, Y.; Seto, H. J. Org. Chem. 1999, 64, 153. (c) CJ-12,950
and CJ-13,357: Dekker: K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.;
Sakakibara, T.; Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.; Kojima, N. J.
Antibiot. 1998, 51, 14. (d) Apicularens: Jansen, R.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 2000, 913.
(3) (a) Shen, R.; Porco, J. A. Org. Lett. 2000, 2, 1333. (b) Snider, B. B.;
Song, F. Org. Lett. 2000, 2, 407. For additional methods for the construction
of enamides, see: (c) Hudrlick, P. F.; Hudrlick, A. M.; Rona, R. J.; Misra,
R. N.; Withers, G. P. J. Am. Chem. Soc. 1977, 99, 1993. (d) Alonso, D. A.;
Alonso, E.; Na´jera, C.; Yus, M. Synlett 1997, 491. (e) Ogawa, T.; Kiji, T.;
Hayami, K.; Suzuki, H. Chem. Lett. 1991, 1443. (f) Stefanuti, I.; Smith, S.
A.; Taylor, R. J. K. Tetrahedron Lett. 2000, 41, 3735.
rolides with a mean GI50 concentration of about 15 nM in
the NCI’s 60 cell line human tumor assay.1 More importantly,
these natural products are unique in the sense that their mean-
graph profile in this assay shows no significant correlation
to that of any other compound contained in the NCI
database,2 suggesting a hitherto unknown mechanism of
(1) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H.; Boyd, M. R. J.
Org. Chem. 1997, 62, 8188.
10.1021/ol006646d CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/27/2000

version of this core region and have evaluated its biological
activity.5 Described below is an extension of this work which
delivers the fully functional macrocycle 24 required for the
total synthesis of 1 and 2 and reveals a striking influence of
remote functionality on the stereochemical outcome of RCM.
The salicylic acid part is obtained from cheap 2,6-
dihydroxybenzoic acid 3 which is converted on a multigram
scale into triflate 5 by formation of the isopropylidene
derivative 46 and subsequent reaction with triflic anhydride
under standard conditions (Scheme 1).7 This compound can
Scheme 2a
Scheme 1a
a [a] acetone, SOCl2, DMAP, DME, 96%; [b] triflic anhydride,
pyridine, 85%; [c] 9-allyl-9-BBN, KOMe, PdCl2(dppf) cat., THF,
83%; [d] BCl3, CH2Cl2, 96%.
a [a] (i) LiHMDS, THF, -78 °C, 30 min; (ii) dimethylallyl
bromide, 0 °C, 16h, 85%; [b] LiOH, H2O2, THF/H2O, 0 °C, 99%;
[c] 12, CH2Cl2, 90 min; [d] (i) LDA, methyl acetate, THF, -78
°C, 1 h; (ii) addition of crude 11, rt, 2 h, 81%; [e] [(R)-
BINAP‚RuCl2]2‚NEt3 (0.8 mol %), H2 (4 atm), MeOH, 80 °C, 4 h,
96%; [f] MOMCl, iPr2NEt, DMAP cat., CH2Cl2, 40h, 90%; [g] (i)
LHMDS, tert-butyl acetate, THF, -45 f -30 °C, 90 min; (ii) 15,
-40 f -30 °C, 3 h, 98%; [h] [(R)-BINAP‚RuCl2]2‚NEt3 (1.2 mol
%), H2 (80 atm), MeOH, 25 °C, 6.5 h, 93%; [i] LiAlH4, Et2O, 0
°C, 6 h, 98%; [j] (i) NaH, DMF, 75 min; (ii) PMBCl, 90 min,
85%.
be subjected to allylation in high yield by a modified Suzuki-
type reaction8 according to a procedure previously developed
in this laboratory.9 Specifically, 9-allyl-9-BBN is treated with
KOMe to afford a mixture of borate complexes which rapidly
transfer the allyl group to the triflate in the presence of
catalytic amounts of PdCl2(dppf). Subsequent cleavage of
the isopropylidene group of 6 is best achieved with BCl3 in
CH2Cl2 at 0 °C, affording the desired salicyclic acid 7 in
almost quantitative yield.
The configuration of the chiral center at C-12 in the
aliphatic segment (salicylihalamide numbering) (Scheme 2)
is secured by means of an asymmetric alkylation reaction
of the oxazolidinone derivative 8 with prenyl bromide.10
Hydrolytic cleavage of the auxiliary affords acid 10, which
is converted into the corresponding acid chloride 11 under
strictly neutral conditions using the chloroenamine reagent
12 developed by Ghosez et al.11 Reaction of crude 11 with
the lithium enolate of methyl acetate at low temperature12
affords the â-keto ester 13 in 81% yield and sets the stage
for a ligand-controlled asymmetric reduction using [(R)-
BINAP‚RuCl2]2‚NEt3 as the catalyst (H2, 4 atm; 80 °C)
without concomitant hydrogenation of the alkene entity.13
O-Alkylation of the resulting diastereomerically pure (de g
99%) alcohol 14 with MOMCl, followed by chain extension
with lithio tert-butyl acetate,14 delivers â-keto ester 16
amenable to another double stereodifferentiating hydrogena-
(4) Recent reviews: (a) Fu¨rstner, A. Angew. Chem. 2000, 112, 3140;
Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (c) Schuster, M.; Blechert, S. Angew. Chem.
1997, 109, 2124; Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Fu¨rstner,
A. Top. Catal. 1997, 4, 285.
(5) Fu¨rstner, A.; Seidel, G.; Kindler, N. Tetrahedron 1999, 55, 8215.
(6) Hadfield, A.; Schweitzer, H.; Trova, M. P.; Green, K. Synth. Commun.
1994, 24, 1025.
(7) (a) Fu¨rstner, A.; Konetzki, I. Tetrahedron 1996, 52, 15071. (b)
Fu¨rstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072. (c) Fu¨rstner, A.;
Nikolakis, K. Liebigs Ann. 1996, 2107.
(8) Review: Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(9) Fu¨rstner, A.; Seidel, G. Synlett 1998, 161.
(10) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(11) (a) Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.;
Ghosez, L. J. Chem. Soc., Chem. Commun. 1979, 1180. (b) Haveaux, B.;
Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.; Ghosez, L. Org. Synth.
1980, 59, 26. (c) For a previous application in total synthesis see: Fu¨rstner,
A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817.
(12) (a) Rathke, M. W.; Deitch, J. Tetrahedron Lett. 1971, 2953. (b)
Taber, D. F.; Deker, P. B.; Gaul, M. D. J. Am. Chem. Soc. 1987, 109,
7488.
(13) (a) Taber, D. F.; Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227.
(b) Ikariya, T.; Ishii, Y.; Kawano, H.; Arai, T.; Saburi, M.; Yoshikawa, S.;
Akutagawa, S. J. Chem. Soc., Chem. Commun. 1985, 922. (c) For a pertinent
review see: Noyori, R. Asymmetric Catalysis in Organic Synthesis,
Wiley: New York, 1994.
(14) Rathke, M. W.; Lindert, A. J. Am. Chem. Soc. 1971, 93, 2318.
3732
Org. Lett., Vol. 2, No. 23, 2000

tion reaction. While [(R)-BINAP‚RuCl2]2‚NEt3 as the catalyst
again serves this purpose very well, it turns out that optimal
results (de > 98%) are obtained under slightly modified
conditions by increasing the pressure of H2 to 80 atm but
lowering the reaction temperature to 25 °C.15 Compound 17
is then reduced with LiAlH4, and the resulting diol 18 is
converted into the mono-PMB ether derivative 19 by double
deprotonation with excess NaH and slow addition of 1 equiv
of PMBCl to the resulting dianion; under these conditions,
the alkylation of the primary alkoxide was found to be highly
favored over the competing protection of the secondary one.16
Esterification of alcohol 19 with acid 7 under Mitsunobu
conditions17 gives the desired ester 23a in 88% yield and
sets the stage for the crucial metathetic macrocyclization
(Scheme 3).
tion. Thus, compound 21 (Mes ) mesityl), its “saturated”
analogue 22, and congeners of this series were recently
reported to be superior metathesis catalysts.20 They have been
successfully applied to several handicaped cases beyond the
scope of the parent complex 20, including RCM of highly
substituted olefins.20,21 Therefore, these novel tools hold the
promise to effect the macrocyclization of substrate 23 as well.
In fact, diene 23a is cleanly converted into the desired
12-membered ring 24a on treatment with catalytic amounts
of ruthenium complex 21 in toluene at 80 °C.22 Surprisingly,
however, the product was obtained as a single isomer, which
was unambiguously assigned the (Z)-configuration on the
basis of its high-field NMR spectra.
This outcome was totally unexpected for the following
reasons: (i) The vast majority of RCM-based macrocycliza-
tions reported in the literature provide (E,Z)-mixtures, with
the (E)-isomer usually being favored.4 (ii) This general
pattern was observed in our previous approach to a truncated
salicylihalmide core which has been obtained in an E:Z ratio
of 2.3:1.5,23 (iii) NHC-containing metathesis catalysts were
recently shown to be particularly (E)-selective, by enriching
the product initially formed in the thermodynamically more
favored alkene via subsequent isomerization.24(iv) Complex
21, when applied to the total synthesis of zearalenone 25a,
a fungal metabolite closely related to salicylihalamide from
the structural point of view, substantiated this notion, giving
exclusively the protected (E)-isomer 25b in excellent yield.25
Scheme 3a
In view of this precedence, we speculated which particular
conformational constraints within 23a are responsible for its
exclusive cyclization to (Z)-24a. Possible candidates are the
hydrogen bond between the phenolic OH and the COOR
group, preventing free rotation in this part of the molecule,
or the branches on the aliphatic chain which might force
this segment to adopt a strongly preferred conformation.26
While addressing these issues, it was noticed that protec-
tion of the seemingly remote phenolic OH group has a
a [a] DEAD, PPh3, Et2O, 20 h, 88%; [b] (i) TMSCH2N2, THF/
MeOH (2:1), 46 h, then AcOH, 54% (23b); or (ii) MOMCl, iPr2NEt,
CH2Cl2, 18 h, 84% (23c); or (iii) TBSCl, imidazole, DMF, 24 h,
89% (23d); [c] catalyst 21, see Table 1.
In view of the high degree of substitution on one of the
olefinic sites of 23, it was not surprising to find that the
classical Grubbs catalyst 2018 fails to afford any cyclized
material. Complex 20 is known to be very sensitive toward
(18) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
(19) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
(20) These “second generation” metathesis catalysts have been indepen-
dently and almost simultaneously reported by three groups, cf.: (a) Huang,
J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999,
121, 2674. (b) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247. (c) Ackermann, L.; Fu¨rstner, A.;
Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999, 40,
4787. (d) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (e) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751. (f)
Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich, D.; Herrmann, W. A.
Angew. Chem. 1999, 111, 2573.
the substitution pattern of the alkenes.19 Gratifyingly, how-
ever, exchange of one of the PCy3 ligands by an N-
heterocyclic carbene (NHC) helps to overcome this limita-
(21) (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S. P. J. Org. Chem. 2000, 65, 2204. (b) Ackermann, L.; El Tom, D.;
Fu¨rstner, A. Tetrahedron 2000, 56, 2195.
(15) For precedence see: Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin,
K.; Glunz, P. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 7050.
(16) See also: (a) McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999,
64, 1520. (b) Paquette, L. A.; Collado, I.; Purdie, M. J. Am. Chem. Soc.
1998, 120, 2553.
(22) It is important to quench the reaction mixture by addition of ethyl
vinyl ether in order to inactivate the catalyst prior to workup.
(23) Fu¨rstner, A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005.
(24) Lee, W. C.; Grubbs, R. H. Org. Lett. 2000, 2, 2145.
(25) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org.
Chem., in press.
(17) Review: Mitsunobu, O. Synthesis 1981, 1.
Org. Lett., Vol. 2, No. 23, 2000
3733

dramatic effect on the stereochemical outcome of the RCM-
refluxing CH2Cl2. These experimental facts indicate that the
configuration of the newly formed olefin is substrate- rather
than catalyst-controlled even if “second generation” carbene
complexes are used. The subtle effects on fairly distant sites
of the diene that are difficult to predict on the basis of our
present understanding of RCM28,29 clearly illustrate the need
for the development of truly stereoselective metathesis
protocols.30
based macrocyclization (Table 1).27 Thus, simple methylation
Table 1. RCM-Based Cyclization of 23 to 24. All Reactions
Were Carried Out Using Ruthenium Complex 21 (5 mol %) in
Toluene at 80°C unless Stated Otherwise
entry
substrate
t (h)
yield (%)
E:Z
In summary, we have developed a concise and high-
yielding approach to the fully functional core 24 of the potent
antitumor agents salicylihalamides A and B. The synthesis
is largely based on catalytic processes,31 both for the control
of the absolute and relative configuration as well as for the
preparation of the macrocyclic scaffold. Cleavage of the PMB
ether in (E)-24 with DDQ followed by oxidation of the
resulting primary alcohol to the corresponding aldehyde sets
the stage for the attachment of the enamide side chain
according to one of the procedures outlined in the literature.3
We are actively pursuing the end game of the total synthesis
of these highly relevant targets.
1
2
3
4
23a
23b
23c
23d
20
1.5
3
69a
93
0:100
66:34
68:32
40:60
91a
1
91
a Using 10 mol % of the catalyst.
completely alters the stereochemical bias and leads to the
preferred formation of the (E)-isomer in excellent yield. A
MOM or a TBS group exerts similar effects. The E/Z ratio
did not change during the course of the reaction, nor did we
observe any further enrichment in one isomer24 if purified
24d was reexposed to 20 mol % of catalyst 22 for 40 h in
Acknowledgment. Generous financial support by the
Deutsche Forschungsgemeinschaft (Leibniz award to A.F.)
and the Fonds der Chemischen Industrie is gratefully
acknowledged. We thank Dr. R. Mynott for his help with
the unambiguous assignment of the alkene stereochemistry
of our RCM products.
(26) For a pertinent review on how branches on an acyclic compound
affect the conformation, see: Hoffmann, R. W. Angew. Chem., Int. Ed.
2000, 39, 2054 and literature cited therein. We have briefly studied if
changing the relative configuration between the Me and the OMOM branch
of the cyclization precursor from anti to syn has an influence on the
stereochemical outcome of RCM but found no appreciable effect. Details
will be reported in a forthcoming full paper.
(27) For a previous example of the influence of remote substituents on
the stereochemical course of RCM, see: (a) Fu¨rstner, A.; Langemann, K.
J. Org. Chem. 1996, 61, 3942. (b) Fu¨rstner, A.; Langemann, K. Synthesis
1997, 792.
Supporting Information Available: Full experimental
section containing the analytical and spectroscopic data of
all new compounds. This material is available free of charge
via the Internet at http:pubs.acs.org.
(28) We believe that the cyclizations reported herein provide a unique
opportunity to reach a better understanding of the transition state of RCM
reactions because (i) mechanistically well behaved catalysts are employed,
(ii) the substrates have a defined site of initiation (the terminal rather than
the trisubstituted alkene), and (iii) the strong stereochemical preferences
allow to match the results by molecular modeling. Theoretical investigations
along these lines are underway.
(29) Another explanaton for the different stereoselectivity in RCM of
the O-protected substrates (23b-d) as compared to the O-unprotected diene
23a relates to the possible in situ formation of phenolate substituted
metathesis catalysts in the latter case. Such compounds are known to be
catalytically active (cf: Chang, S.; Jones, L.; Wang, C.; Henling, L. M.;
Grubbs, R. H. Organometallics 1998, 17, 3460). We thank the referee for
pointing out this possibility which is presently studied in our laboratory.
OL006646D
(30) Thus far, only macrocyclic (Z)-alkenes can be selectively and
predicatably formed by metathesis via a new protocol comprising alkyne
metathesis followed by Lindlar reduction, cf.: (a) Fu¨rstner, A.; Seidel, G.
Angew. Chem. 1998, 110, 1758; Angew. Chem., Int. Ed. 1998, 37, 1734.
(b) Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999,
121, 9453. (c) Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem.
Soc. 1999, 121, 11108. (d) Fu¨rstner, A.; Grela, K. Angew. Chem. 2000,
112, 1292; Angew. Chem., Int. Ed. 2000, 39, 1234. (e) Fu¨rstner, A.; Rumbo,
A. J. Org. Chem. 2000, 65, 2608. (f) Fu¨rstner, A.; Seidel, G. J. Organomet.
Chem. 2000, 606, 75. (g) Fu¨rstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463.
(31) For a discussion, see: Fu¨rstner, A. Synlett 1999, 1523.
3734
Org. Lett., Vol. 2, No. 23, 2000