Total synthesis of (-)-salicylihalamide A.

Article abstract of DOI:10.1021/ol015822v

[see structure]. A 16-step synthesis of the novel cytotoxin salicylihalamide A (1E) has been achieved in 3.3% overall yield using ring closing metathesis to generate the macrolide and addition of (1Z,3Z)-hexadienylcuprate (2), which was generated in situ from ethylcuprate and acetylene, to alkenyl isocyanate 3 to form the side chain.

Full text of DOI:10.1021/ol015822v

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1817-1820
Total Synthesis of (−)-Salicylihalamide A
Barry B. Snider* and Fengbin Song
Department of Chemistry MS015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received March 9, 2001
ABSTRACT
A 16-step synthesis of the novel cytotoxin salicylihalamide A (1E) has been achieved in 3.3% overall yield using ring closing metathesis to
generate the macrolide and addition of (1Z,3Z)-hexadienylcuprate (2), which was generated in situ from ethylcuprate and acetylene, to alkenyl
isocyanate 3 to form the side chain.
The novel cytotoxic macrolide salicylihalamide A (1E) was
isolated from the sponge Haliclona sp. in 1997 by Boyd,
Erickson, and co-workers (see Scheme 1).1 Salicylihalamide
A was accompanied by a small amount of salicylihalamide
B (1Z) with a Z-enamide double bond. The structure was
determined by NMR spectroscopic methods, and the absolute
stereochemistry was assigned by the use of Mosher esters.
The structure was originally assigned as the enantiomer as
a result of the failure to take into account the priority order
change on conversion of the acid chloride to the ester.2 De
Brabander corrected the absolute stereochemistry assignment
in the first synthesis of 1E.3,4
no significant correlations to those of any other antitumor
compounds contained in the NCI database, suggesting a new
mechanism of action.
Scheme 1. Retrosynthetic Analysis
Salicylihalamide A shows a striking pattern of differential
cytotoxicity in the NCI 60-cell line screen. The mean GI50
concentration was approximately 15 nM with a range of
differential sensitivity e 103.1 The melanoma cell lines
showed the highest average sensitivity (GI50 7 nM, TGI 60
nM). More importantly, the mean-graph profiles of 1E show
(1) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R. J.
Org. Chem. 1997, 62, 8188-8192.
(2) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R. J.
Org. Chem. 2001, 66, 1532.
(3) (a) Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem., Int. Ed.
2000, 39, 4308-4310. (b) Wu, Y.; Seguil, O. R.; De Brabander, J. K. Org.
Lett. 2000, 2, 4241-4244. We thank Professor De Brabander for com-
municating this information prior to publication and for copies of the spectra
of key intermediates.
(4) For other syntheses, see: (a) Labrecque, D.; Charron, S.; Rej, R.;
Blais, C.; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645-2648. (b) Smith,
A. B., III; Zheng, J. Synlett, in press.
10.1021/ol015822v CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/18/2001

Since the discovery of the salicylihalamides, an emerging
class of structurally related, novel, cytotoxic salicylate
macrolides has been isolated. This family includes the
apicularens with an identical enamide side chain5 and the
lobatamides A-F,6 oximidines I and II,7 CJ-12,950, and CJ-
13,3578 with an enamide side chain terminating in an
O-methyl oxime.
The novel structure and potent biological activity of
salicylihalamide A has prompted intense synthetic interest
culminating in syntheses by De Brabander,3,9 Labrecque,4a
and Smith4b and several routes to the ring system.10-12 All
of these routes used ring closing metathesis (RCM) to form
the macrolide.
We thought that the N-(1E-alkenyl)-(2Z,4Z)-heptadiena-
mide side chain posed the major challenge in the synthesis
of salicylihalamide A. We therefore started by developing a
procedure for the introduction of the side chain. Taylor
reported that organocuprates add to acetylene at -50 °C to
give the (1Z)-alkenylcuprate.13 At -10 to 0 °C, the (1Z)-
alkenylcuprate adds to a second equivalent of acetylene to
give a (1Z,3Z)-alkadienylcuprate (see Scheme 2). This
hexenyl isocyanate to give 28% of the desired heptadiena-
mide 10, 15% of the pentenamide 9, and 9% of the
nonatrienamide 11.14 De Brabander used a similar strategy
to introduce the side chain, using (1Z,3Z)-hexadienyllithium,
which was prepared by halogen metal exchange from the
difficultly accessible (1Z,3Z)-1-bromohexadiene.3 Similar
lithium based strategies have been reported for the O-methyl
oxime terminated side chain of the lobatamides.15
Our approach to salicylihalamide A (1E) was developed
to minimize the use of protecting groups and functional group
interchanges. The key alkenyl isocyanate 3 should be
available from the R,â-unsaturated ester. The macrolide will
be formed by RCM of 4b. Hydrolysis of the acetal of 5,
Wittig reaction, and protection will provide 4b. The ester
linkage of 5 will be prepared by Mitsunobu esterification of
6 with 6-allylsalicylic acid. Finally, 6 will be prepared by
an asymmetric aldol reaction of dienyl silyl ether 7 and
aldehyde 8 by Carreira’s procedure.16
Amide 12 was prepared by Myers’ procedure from allyl
bromide and (-)-pseudoephedrine propanamide (see Scheme
3).17 Reduction of 12 with LiNH2BH3 gives 99% of the
17
Scheme 3. Preparation of Alcohol 6
Scheme 2. Introduction of the Side Chain
cuprate adds to a wide variety of electrophiles. We reported
last year that (1Z,3Z)-hexadienylcuprate (2) adds to (1E)-
(5) (a) Kunze, B.; Jansen, R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1998, 51, 1075-1080. (b) Jansen, R.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 2000, 913-919.
(6) (a) Galinis, D. L.; McKee, T. C.; Pannell, L. K.; Cardellina, J. H.,
II; Boyd, M. R. J. Org. Chem. 1997, 62, 8968-8969. (b) McKee, T. C.;
Galinis, D. L.; Pannell, L. K.; Cardellina, J. H., II; Laasko, J.; Ireland, C.
M.; Murray, L.; Capon, R. J.; Boyd, M. R. J. Org. Chem. 1998, 63, 7805-
7810. (c) Suzumura, K.-i.; Takahashi, I.; Matsumoto, H.; Nagai, K.;
Setiawan, B.; Rantiamodjo, R. M.; Suzuki, K.-i.; Nagano, N. Tetrahedron
Lett. 1997, 38, 7573-7576.
alcohol, which undergoes Swern oxidation to provide 76%
of aldehyde 8.18 Asymmetric aldol reaction of 719 with
aldehyde 8 by the Carreira procedure using Cu(OTf)2, (S)-
(7) Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J.
Org. Chem. 1999, 64, 153-155.
(8) 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, 14-20.
(9) For the synthesis of apicularen A, see: (a) Bhattacharjee, A.; De
Brabander, J. K. Tetrahedron Lett. 2000, 41, 8069-8073. (b) Bhattacharjee,
A.; Seguil, O. R.; De Brabander, J. K. Tetrahedron Lett. 2001, 42, 1217-
1220.
(10) (a) Fu¨rstner, A.; Seidel, G.; Kindler, N. Tetrahedron 1999, 55,
8215-8230. (b) Fu¨rstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2,
3731-3734.
(11) Georg, G. I.; Ahn, Y. M.; Blackman, B.; Farokhi, F.; Flaherty, P.
T.; Mossman, C. J.; Roy, S.; Yang, K. Chem. Commun. 2001, 255-256.
(12) Feutrill, J. T.; Holloway, G. A.; Hilli, F.; Hu¨gel, H. M.; Rizzacasa,
M. A. Tetrahedron Lett. 2000, 41, 8569-8572.
(13) Furber, M.; Taylor, R. J. K.; Burford, S. C. J. Chem. Soc., Perkin
Trans. 1 1986, 1809-1815.
(14) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407-408.
1818
Org. Lett., Vol. 3, No. 12, 2001

Tol-BINAP, and (Bu4N)Ph3SiF2 gives 64% of an inseparable
4.2:1 mixture of 13 and the diastereomer that was carried
on through the RCM that gives 18. Carreira developed this
procedure for conjugated aldehydes and reported that un-
branched aliphatic aldehydes give low yields of aldol
products in high ee.16 We obtain an acceptable yield, but
only modest de, with branched aldehyde 8. Although the
inherent Cram selectivity with aldehyde 8 is low, 13 is the
anti-Cram product. The chiral catalyst must overcome a slight
preference for the diastereomer of 13. A 6:1 mixture favoring
the diastereomer of 13 is obtained in the matched case with
(R)-Tol-BINAP. We briefly investigated other routes to
13. Condensation of 7 and 8 by the Sato procedure using
Ti(O-i-Pr)4 and binaphthol proceeds in lower yield with
reduced selectivity.20 Coupling of the lithium enolate pre-
pared from the menthone-diketene adduct21 with 8 affords
selectivity comparable to that of the Carreira procedure.
phine (TFP) (87%)3,29,30 and hydrolysis of the acetonide in
a 1:1 mixture of 1 M KOH and THF at reflux to give 96%
of 17 (see Scheme 4). Mitsunobu coupling of 17 with 6 using
DEAD and Ph3P in ether affords 79% of 5.
Scheme 4. Completion of the Synthesis
Heating 13 with MeOH in toluene at reflux22 provides 85%
of â-keto ester 14,23,24 which is reduced to the syn alcohol
with Et2BOMe and NaBH4 in 98% yield.25,26 Lactonization
of the dihydroxy ester with catalytic HF in CH3CN27 yields
96% of hydroxylactone 15. Elimination to the unsaturated
lactone is the only reaction on attempted Mitsunobu coupling
of 15 with salicylate 17. Therefore, the lactone carbonyl
group was reduced prior to coupling. Reduction of 15 with
DIBAL-H affords the lactol, which is protected as the methyl
ether with TsOH and molecular sieves in MeOH to give 83%
of 6 as 2.6:1 mixture of â- and R-methoxy anomers that were
separated, and both were carried on to give the same mixture
of lactols from hydrolysis of 5.
6-Allylsalicylic acid (17) is prepared by Stille coupling
of 1628 with allyltributyltin using Pd2(dba)3 and trifurylphos-
(15) (a) Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett 2000, 397-
399. (b) Raw, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2000, 41, 10357-
10361. (c) Approaches using amide substitution on an alkenyl iodide have
also been reported: Shen, R.; Porco, J. A. Jr. Org. Lett. 2000, 2, 1333-
1336.
(16) Kru¨ger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838.
(17) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(18) Lin, N.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.; Sharp,
M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062-9072.
(19) Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinaman, S. W.;
Parlow, J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.; Daffner, M.; Stevens, J.
E. J. Org. Chem. 1991, 56, 91-95.
(20) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995,
41, 1435-1444.
(21) Ohmori, K.; Suzuki, T.; Miyazawa, K.; Nishiyama, S.; Yamamura,
S. Tetrahedron Lett. 1993, 34, 4981-4984.
RCM of 5 did not proceed, presumably because the
diequatorial substituents on the tetrahydropyran ring keep
the alkenes too far apart. Hydrolysis of 5 in 1:1 AcOH/H2O
at reflux yields 80% of the lactol, which is treated with
Ph3PdCHCO2Me to give 76% of 4a and 10% of the easily
separable Z isomer. RCM of 4a with (Cy3P)2PhCHdRhCl2
in CH2Cl2 requires reaction for 3-4 d and gives mainly the
undesired Z isomer. Since the alcohol and phenol need to
be protected before addition of cuprate 2 to the alkenyl
isocyanate, we converted 4a to bis TBS ether 4b in 99%
(22) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pharm. Bull.
1994, 42, 839-845.
(23) The stereochemical assignment of the diastereomers was confirmed
by comparison of the chemical shifts of the methyl group and the CHOH
proton with a series of 3-hydroxy-4-methylalkanoates of known relative
stereochemistry.24
(24) (a) Mochizuki, K.; Ohmori, K.; Harumi, T.; Shizuri, Y.; Nishiyama,
S.; Miyoshi, E.; Yamamura, S. Bull. Chem. Soc. Jpn. 1993, 66, 3041-
3046. (b) Flippin, L. A.; Brown, P. A.; Jalali-Araghi, K. J. Org. Chem.
1989, 54, 3588-3596. (c) Murai, A.; Amino, Y.; Ando, T. J. Antibiot. 1985,
38, 1610-1613.
(25) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repicˇ, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155-158.
(26) The minor diastereomer present in the mixture is reduced to the
syn diol with the opposite stereochemistry at both alcohol centers.
(27) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(29) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595.
(30) This compound has also been prepared from 16 by a Suzuki
coupling: Fu¨rstner, A.; Seidel, G. Synlett 1998, 161-162.
(28) Fu¨rstner, A.; Konetzki, I. Tetrahedron 1996, 52, 15071-15078.
Org. Lett., Vol. 3, No. 12, 2001
1819

yield by reaction with TBSOTf and 2,6-lutidine for 14 h.
RCM of 4b proceeded completely in 5 h, giving a 4:1
mixture of E/Z isomers. The desired product 18 was isolated
free of the Z isomer and diastereomer in 57% yield (71%
based on 4b in the 4.2:1 mixture of diastereomers) by
chromatography on silver nitrate impregnated silica gel.
Protection of the phenol is crucial for the formation of
the desired E isomer. RCM of the monosilyl ether with a
free phenol, which was prepared by reaction of 4a with
TBSOTf and 2,6-lutidine for 1 h, is also sluggish and gives
mainly the Z isomer. Fu¨rstner has also noted that the Z isomer
is obtained exclusively in related substrates with a free
phenol,10b and De Brabander found that protecting groups
have a marked effect on the stereoselectivity of the RCM.3
Basic hydrolysis of the methyl ester of 18 could not be
achieved without hydrolysis of the TBS ethers; the phenolic
TBS ether is especially sensitive. Selective hydrolysis of the
methyl ester is accomplished in 81% yield (94% yield based
on recovered 18) by heating with (Bu3Sn)2O in toluene for
2 d.31 Reaction of the acid with DPPA as described by De
Brabander gives the acyl azide (91%), which is heated in
benzene at reflux for 4 h to give alkenyl isocyanate 3 (94%)
that can be used without purification.
1E are identical to those previously reported;1,3 the optical
rotation, [R]25 ) -41 (c ) 0.067, MeOH), is larger than
D
that reported for the natural product,1 [R]25 ) -35 (c )
D
0.7, MeOH), and its enantiomer,3a [R]25D ) +20.8 (c ) 0.12,
MeOH).
De Brabander has shown that the nature of the enamide
side chain is not crucial for the cytotoxicity of salicylihala-
mide A derivatives but does play a role. The analogue with
a saturated heptanamide side chain is 15-20% as potent as
salicylihalamide A (1E).3b Our synthetic 1E and analogues
22 and 23 were evaluated at NCI to further define the role
of the side chain in the biological activity. Synthetic 1E has
essentially the same potency as the natural product, while
22 and 23 are about 20% as potent.32,33
In conclusion, we have completed the synthesis of (-)-
salicylihalamide A (1E) in 16 steps from aldehyde 8 in 3.3%
overall yield with minimal use of protecting groups. The key
step is the efficient introduction of the unsaturated side chain
by addition of (1Z,3Z)-hexadienylcuprate (2), which was
generated in situ from ethylcuprate and acetylene, to alkenyl
isocyanate 3.
Acknowledgment. We are grateful to the NIH for
generous financial support (GM-46470).
Addition of 3 to excess (1Z,3Z)-hexadienylcuprate (2),
which is prepared in situ from EtLi, CuBr‚Me2S, and
acetylene,13,14 affords 22% of enamide 19, 43% of protected
salicylihalamide A 20, and 9% of trienamide 21, which are
easily separable by chromatography on silver nitrate im-
pregnated silica gel. Deprotection of 19-21 as described by
De Brabander3 with HF‚pyridine and pyridine in THF for 3
d provides enamide 22 (70%), salicylihalamide A (1E, 78%),
and trienamide 23 (70%), respectively. The spectral data of
Supporting Information Available: Experimental details
and NMR spectral data for selected compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL015822V
(32) We thank Dr. Michael Boyd, National Cancer Institute, for arranging
for the evaluation of our samples.
(33) For a recent study on the biological activity, see: Boyd, M. R.;
Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J. W.; Hayakawa, Y.; Beutler,
J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E. J. J. Pharmacol. Exp.
Ther. 2001, 297, 114-120.
(31) Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. J. Org. Chem. 1994,
59, 7259-7266.
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