A formal total synthesis of the salicylihalamides

Article abstract of DOI:10.1021/jo035054g

The synthesis of the macrolactone 23 is described. The synthesis features a diastereoselective hydroboration of the chiral alkene 17 followed by a Suzuki cross-coupling reaction with the benzoate 5. The resulting seco acid 21 was converted to the macrolac

Full text of DOI:10.1021/jo035054g

A F or m a l Tota l Syn th esis of th e Sa licylih a la m id es
Christian Herb and Martin E. Maier*
Universita¨t Tu¨bingen, Institut fu¨r Organische Chemie, Auf der Morgenstelle 18,
72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received J uly 22, 2003
The synthesis of the macrolactone 23 is described. The synthesis features a diastereoselective
hydroboration of the chiral alkene 17 followed by a Suzuki cross-coupling reaction with the benzoate
5. The resulting seco acid 21 was converted to the macrolactone 23 by a Mitsunobu lactonization
using immobilized triphenylphosphine. The stereogenic centers in the alkene 17 were established
by a Noyori reduction of the â-keto ester 8 and an Evans aldol reaction. The synthesis illustrates
the conversion of a syn aldol product to the corresponding anti product by inversion of the methyl-
bearing center.
In tr od u ction
Polyketides comprise a large group among the biologi-
cally active natural products. They are characterized by
a substantial structural diversity, which is the result of
various folding patterns in ring-forming reactions during
biosynthesis. Thus, many polyketides contain one or more
aromatic rings with a characteristic distribution of the
oxygen functionality. A recently discovered group of
polyketides are the benzolactone enamides (Figure 1). In
addition to a benzoic acid substructure and a macrolac-
tone ring, these natural products feature an enamide side
chain. Some representative molecules from this family
include the salicylihalamides,1 the apicularens,2 the
lobatamides, the oximidines,3 YM-75518,4 and the mac-
rolides CJ -12,950 and CJ -13,357.5
As related macrolactones that lack the enamide side
chain, zearalenone,6 radicicol,7 C292,8 and queenslandon9
(1) Erickson, K. L.; Beutler, J . A.; Cardellina, J . H., II.; Boyd, M. R.
J . Org. Chem. 1997, 62, 8188-8192.
(2) (a) Kunze, B.; J ansen, R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H.
J . Antibiot. 1998, 51, 1075-1080. (b) J ansen, R.; Kunze, B.; Reichen-
bach, H.; Ho¨fle, G. Eur. J . Org. Chem. 2000, 913-919.
(3) Kim, J . W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J .
Org. Chem. 1999, 64, 153-155.
F IGURE 1. Structures of representative benzolactone ena-
mides.
can be mentioned. The benzolactone enamides show
potent activity against human cancer cell lines. For some
of the benzolactone enamides, it could be shown that the
antitumor activity is due to the inhibition of vacuolar
ATPase membrane bound enzymes.10,11 These enzymes
utilize the hydrolysis of ATP to generate a potential
across the membrane that can be used to transport ions
and small molecules. In contrast to other known V-
ATPase inhibitors, salicylihalamide A discriminates be-
tween nonmammalian and mammalian V-ATPases. There-
(4) Suzumura, K.-i.; Takahashi, I.; Matsumoto, H.; Nagai, K.;
Setiawan, B.; Rantiatmodjo, R. M.; Suzuki, K.-i.; Nagano, N. Tetra-
hedron Lett. 1997, 38, 7573-7576.
(5) Dekker: K. A.; Aiello, R. J .; Hirai, H.; Inagaki, T.; Sakakibara,
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1998, 51, 14-20.
(6) (a) Stob, M.; Baldwin, R. S.; Tuite, J .; Andrews, F. N.; Gillette,
K. G. Nature 1962, 196, 1318. (b) Urry, W. H.; Wehrmeister, H. L.;
Hodge, E. B.; Hidy, P. H. Tetrahedron Lett. 1966, 3109-3114. (c) Hidy,
P. H.; Baldwin, R. S.; Greasham, R. L.; Keith, C. L.; McMullen, J . R.
Adv. Appl. Microbiol. 1977, 22, 59-82. (d) Cordier, C.; Gruselle, M.;
J aouen, G.; Hughes, D. W.; McGlinchey, M. J . Magn. Reson. Chem.
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Nakajima, S. J . Nat. Prod. 1979, 42, 374-377. (c) Ayer, W. A.; Lee, S.
P.; Tsuneda, A.; Hiratsuka, Y. Can. J . Microbiol. 1980, 26, 766-73.
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(9) Hoshino, Y.; Ivanova, V. B.; Yazawa, K.; Ando, A.; Mikami, Y.;
Zaki, S. M.; Karam, A.-Z. A.; Youssef, Y. A.; Gra¨fe, U. J . Antibiot. 2002,
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(10) Boyd, M. R.; Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J . W.;
Hayakawa, Y.; Beutler, J . A.; McKee, T. C.; Bowman, B. J .; Bowman,
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(11) For reviews, see: (a) Nishi, T.; Forgac, M. Nature Rev. Mol.
Cell Biol. 2002, 3, 94-103. (b) Beutler, J . A.; McKee, T. C. Curr. Med.
Chem. 2003, 10, 787-796.
10.1021/jo035054g CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/23/2003
J . Org. Chem. 2003, 68, 8129-8135
8129

Herb and Maier
fore, these natural products are important leads for the
development of drugs that target this enzyme class. The
fact that the benzolactone enamides were found in
various sources additionally underscores the great po-
tential of V-ATPases as molecular targets since this mode
of action seems to be an efficient defense mechanism for
microorganisms. The new structural features combined
with the novel mode of action rendered these natural
products interesting targets for total synthesis. So far
total syntheses for salicylihalamide,12 apicularen A,13
lobatamides,14 and oximidine15 have been described. In
addition, synthetic studies were published.16,17,18,19 Our
group has contributed syntheses of the core structures
of apicularen A,17b,d salicylihalamide A,16e and oximidine.18a
In this paper, we disclose a formal total synthesis of
salicylihalamide A featuring the tactical combination of
a diastereoselective hydroboration with a Suzuki cross-
coupling reaction followed by a Mitsunobu macrolacton-
ization employing immobilized triphenylphosphine.
The macrolactone portion of salicylihalamide is unique
in that it features a double bond in allylic position to the
aromatic ring. Because of steric hindrance around the
carboxylic group and participation of the double bond, a
classical macrolactonization is difficult. So far most of
the syntheses of salicylihalamide A create the macrocyclic
ring by a ring-closing metathesis reaction. The Rizzacasa
group constructs the macrolactone ring by a nucleophilic
attack of an alkoxide on an acetal ester.12h Previously,
we had reported formation of the macrolactone ring of
the salicylihalamides by intramolecular Suzuki reaction.16e
F IGURE 2. Retrosynthetic analysis for salicylihalamide
featuring a Mitsunobu macrolactonization and a diasterose-
lective hydroboration/Suzuki cross coupling.
SCHEME 1. Syn th esis of th e Ben zoa te 5 w ith a
3-iod op r op -2-en yl Sid e Ch a in
(12) (a) Wu, Y.; Esser, L.; De Brabander, J . K. Angew. Chem. 2000,
112, 4478-4480. (b) Fu¨rstner, A.; Dierkes, T.; Thiel, O.; Blanda, G.
Chem.-Eur. J . 2001, 7, 5286-5298. (c) Labrecque, D.; Charron, S.;
Rej, R.; Blais, C.; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645-2648.
(d) Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817-1820. (e) Smith, A.
B., III.; Zheng, J . Synlett 2001, 1019-1023. (f) Smith, A. B., III.; Zheng,
J . Tetrahedron 2002, 58, 6455-6471. (g) Wu, Y.; Liao, X.; Wang, R.;
Xie, X.-S.; De Brabander, J . K. J . Am. Chem. Soc. 2002, 124, 3245-
3253. (h) Holloway, G. A.; Hu¨gel, H. M.; Rizzacasa, M. A. J . Org. Chem.
2003, 68, 2200-2204.
(13) (a) Bhattacharjee, A.; Seguil, O. R.; De Brabander, J . K.
Tetrahedron Lett. 2001, 42, 1217-1220. (b) Lewis, A.; Stefanuti, I.;
Swain, S. A.; Smith, S. A.; Taylor, R. J . K. Tetrahedron Lett. 2001, 42,
5549-5552. (c) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew. Chem.
2002, 114, 3853-3856. (d) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith,
S. A.; Taylor, R. J . K. Org. Biomol. Chem. 2003, 1, 104-116.
(14) (a) Shen, R.; Lin, C. T.; Porco, J . A., J r. J . Am. Chem. Soc. 2002,
124, 5650-5651. (b) Shen, R.; Lin, C. T.; Bowman, E. J .; Bowman, B.
J .; Porco, J . A., J r. J . Am. Chem. Soc. 2003, 125, 7889-7901.
(15) Wang, X.; Porco, J . A., J r. J . Am. Chem. Soc. 2003, 125, 6040-
6041.
(16) Salicylihalamide studies: (a) Fu¨rstner, A.; Thiel, O. R.; Blanda,
G. Org. Lett. 2000, 2, 3731-3734. (b) Feutrill, J . T.; Holloway, G. A.;
Hilli, F.; Hu¨gel, H. M.; Rizzacasa, M. A. Tetrahedron Lett. 2000, 41,
8569-8572. (c) Wu, Y.; Seguil, O.; De Brabander, J . K. Org. Lett. 2000,
2, 4241-4244. (d) Georg, G. I.; Ahn, Y. M.; Blackman, B.; Farokhi, F.;
Flaherty, P. T.; Mossman, C. J .; Roy, S.; Yang, K. J . Chem. Soc., Chem.
Commun. 2001, 255-256. (e) Bauer, M.; Maier, M. E. Org. Lett. 2002,
4, 2205-2208.
(17) Apicularen studies: (a) Bhattacharjee, A.; De Brabander, J . K.
Tetrahedron Lett. 2000, 41, 8069-8073. (b) Ku¨hnert, S. M.; Maier, M.
E. Org. Lett. 2002, 4, 643-646. (c) Hilli, F.; White, J . M.; Rizzacasa,
M. A. Tetrahedron Lett. 2002, 43, 8507-8510. (d) Petri, A. F.; Ku¨hnert,
S. M.; Scheufler, F.; Maier, M. E. Synthesis 2003, 940-955.
(18) Oximidine studies: (a) Scheufler, F.; Maier, M. E. Synlett 2001,
1221-1224. (b) Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487-
3490.
In this project, we planned to invert the key reactions.
That is, the Suzuki cross-coupling reaction would be
intermolecular and the lactonization would be intramo-
lecular. The retrosynthetic analysis that features a
Suzuki reaction is shown in Figure 2. This analysis leads
to the vinyl iodide D and the alkenol derivative E. Since
macrolactonization reactions under Mitsunobu conditions
are well-known,14,16b,20 we wanted to apply this strategy
for the salicylihalamide core structure.
Resu lts a n d Discu ssion
The synthesis of the benzoate 2 carrying a propenyl
side chain started with the known benzoic acid 2.12f
Esterification of 2 with methyl iodide and DBU21 fur-
nished the corresponding ester 3 (Scheme 1). The vinyl
iodide was established by ozonolysis of the double bond
(19) Studies related to the enamide side chain: (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) Stefanuti,
I.; Smith, S. A.; Taylor, R. J . K. Tetrahedron Lett. 2000, 41, 3737-
3738. (d) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407-408. (e) Shen,
R.; Porco, J . A., J r. Org. Lett. 2000, 2, 1333-1336. (f) Fu¨rstner, A.;
Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3, 3955-3957.
(20) For some examples, see: (a) Selle´s, P.; Lett, R. Tetrahedron
Lett. 2002, 43, 4627-4631. (b) Liao, X.; Wu, Y.; De Brabander, J . K.
Angew. Chem. 2003, 115, 1686-1690; Angew. Chem., Int. Ed. 2003,
42, 1648-1652. (c) Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001,
3, 213-216. (d) Smith, A. B., III.; Noda, I.; Remiszewski, S. W.; Liverton,
N. J .; Zibuck, R. J . Org. Chem. 1990, 55, 3977-3979.
(21) Mal, D. Synth. Commun. 1986, 16, 331-335.
8130 J . Org. Chem., Vol. 68, No. 21, 2003

Formal Total Synthesis of the Salicylihalamides
SCHEME 2. Syn th esis of th e 6-m eth ylh ep t-6-en yl
Eth er 17
terminal alkenol subunit, the Evans strategy that we
developed earlier was used.16e,28 Accordingly, aldol reac-
tion29,30 of the chiral propionate 12 with aldehyde 11
using TiCl4 (1.05 equiv) in the presence of sparteine
(Crimmins variant)31 (2.5 equiv) provided a high yield of
the syn aldol product 13. After protection of the resulting
hydroxyl function as MOM ether, the chiral auxiliary was
removed by treatment of 14 with LiBH4 in methanol.32
We found that these conditions work sometimes better
than NaBH4 in THF/H2O.33 To introduce the terminal
double bond, the tosylate 16 was prepared by standard
conditions. Elimination to give the alkene 17 could be
smoothly accomplished by heating the tosylate 16 in
glyme in the presence of NaI and DBU.
For the combination of the two fragments 5 and 17, a
Suzuki coupling34 was employed (Scheme 3). First, the
alkene was subjected to a diastereoselective hydrobora-
tion using 9-BBN (1.2 equiv) in THF. Subsequently, the
solution of the intermediate borane was added to a
solution of the vinyl iodide 5 in a mixture of DMF/water
containing PdCl2(dppf) as catalyst, Ph3As as ligand, and
Cs2(CO3) as base.35 Under these conditions, a 65% yield
of the desired coupling product 18 could be secured. The
coupling was accompanied by the iodide 19 (11%).
Changing the base to NaOH and omitting Ph3As gave
similar results (63% of 18, 9% of 19). The stereochemical
course of the hydroboration reaction was assumed to
follow the Houk model (F , Scheme 3).36 The hydroxy acid
21 that functions as a substrate for the macrolactoniza-
tion was generated by cleavage of the silyl ether with
TBAF giving the hydroxy ester 20. Finally, basic hy-
drolysis of 20 provided the hydroxy acid 21. During the
workup of 21, strong acid conditions have to be avoided.
Otherwise, substantial amounts of the cyclic acetal 22
can be formed from the MOM protecting group. Initially,
the Mitsunobu macrolactonization was run in solutions
under high dilution (0.005 M). These conditions furnished
a 25% yield of the macrolactone 23. The yield could be
improved by the use of immobilized triphenylphosphine.37
This allowed the reaction to be run at a higher concen-
tration (0.02 M) and led to a 43% yield. If, however, the
azodicarboxylate was immobilized (5.0 equiv of polysty-
rene-DEAD resin, 1.3 equiv of PPh3, THF, 0.01 M), no
lactone could be observed. The NMR (1H, 13C) and other
spectroscopic data are in full accord with the literature
data.12b,g
followed by the Takai reaction22,12b of the resulting
aldehyde 4 providing the E-isomer 5 as the major product
(E/ Z ) 5:1).
The synthesis of the aliphatic sector corresponding to
E started with the C-3 aldehyde23 7 that can be attained
by Michael addition of p-methoxy benzyl alcohol to
acrolein (Scheme 2).24 Chain extension with ethyl diazo-
acetate in the presence of tin(II) chloride furnished the
3-keto ester 8.25,26 By application of Noyori conditions and
the use of (R)-(+)-BINAP as the chiral ligand, the keto
group was reduced to the secondary alcohol 9 (84%, >90%
enantiomeric excess (ee)).27 Protection of the alcohol as
tert-butyldimethylsilyl ether gave compound 10. Reduc-
tion of the ester group with DIBAL secured the chiral
aldehyde12g 11 in good overall yield. To establish the
(28) Phukan, P.; Bauer, M.; Maier, M. E. Synthesis 2003, 1324-
1328.
(29) (a) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 77-82. (b)
Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 83-91.
(30) For a review, see: Arya, P.; Qin, H. Tetrahedron 2000, 56, 917-
947.
(31) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J .
Org. Chem. 2001, 66, 894-902.
(32) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc.
1992, 114, 9434-9453.
(33) Prashad, M.; Kim, H.-Y.; Lu, Y.; Liu, Y.; Har, D.; Repic, O.;
Blacklock, T. J .; Giannousis, P. J . Org. Chem. 1999, 64, 1750-1753.
(34) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J . Angew. Chem. 2001,
113, 4676-4701; Angew. Chem., Int. Ed. 2001, 40, 4544-4568.
(35) Trost, B. M.; Lee, C. J . Am. Chem. Soc. 2001, 123, 12191-
12201.
(36) (a) Still, W. C.; Barrish, J . C. J . Am. Chem. Soc. 1983, 105,
2487-2489. (b) Houk, K. N.; Rondan, N. G.; Wu, Y.-D.; Metz, J . T.;
Paddon-Row, M. N. Tetrahedron 1984, 40, 2257-2274.
(37) Tunoori, A. R.; Dutta, D.; Georg, G. I. Tetrahedron Lett. 1998,
39, 8751-8754.
(22) (a) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986,
108, 7408-7410. (b) Okazoe, T.; Takai, K.; Utimoto, K. J . Am. Chem.
Soc. 1987, 109, 951-953.
(23) Matsuda, F.; Kito, M.; Sakai, T.; Ojkada, N.; Miyashita, M.;
Shirahama, H. Tetrahedron 1999, 55, 14369-14380.
(24) Wang, Y.; Farquhar, D. J . Med. Chem. 1991, 34, 197-203.
(25) Holmquist, C. R.; Roskamp, E. J . J . Org. Chem. 1989, 54, 3258-
3260.
(26) For a related keto ester, see: Nakatsuka, M.; Ragan, J . A.;
Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J . Am.
Chem. Soc. 1990, 112, 5583-5601.
(27) (a) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org.
Synth. 1992, 71, 1-13. (b) Kopecky, D. J .; Rychnovsky, S. D. J . Am.
Chem. Soc. 2001, 123, 8420-8421.
J . Org. Chem, Vol. 68, No. 21, 2003 8131

Herb and Maier
Meth yl 2-Allyl-6-m eth oxyben zoa te (3). To a cooled (0 °C)
solution of acid 2 (6.00 g, 31.2 mmol) in THF (150 mL) were
added 1,8-diazabicyclo-[5.4.0]-undec-7-en (DBU) (4.70 mL, 4.75
g, 31.2 mmol) and iodomethane (5.85 mL, 13.3 g, 93.6 mmol),
successively. After the mixture was stirred for 24 h at room
temperature, the precipitate was removed by filtration over
Celite and washed with Et2O (100 mL). The filtrate was
washed with H2O (30 mL), dried (MgSO4), filtered, and
concentrated. The residue was purified by flash chromatog-
raphy to yield 5.72 g (89%) of methyl ester 3 as a colorless oil.
TLC (petroleum ether/EtOAc, 10:1): Rf ) 0.41. IR (film): 1732,
SCHEME 3. Com bin a tion of th e F r a gm en ts 5 a n d
17 by Su zu k i Cr oss-Cou p lin g a n d Mitsu n obu
La cton iza tion of Hyd r oxy Acid 21
1
1470, 1267 cm-1. H NMR (400 MHz, CDCl3): δ 3.34 (d, J )
6.6 Hz, 2H), 3.80 (s, 3H), 3.87 (s, 3H), 5.01-5.08 (m, 2H), 5.83-
5.94 (m, 1H), 6.78 (d, J ) 8.3 Hz, 1H), 6.82 (d, J ) 7.6 Hz,
1H), 7.27 (dd, J ) 7.5, 8.3 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 37.6, 52.0, 55.8, 109.0 (C-5), 116.1, 121.6, 123.5,
130.4, 136.2, 138.5, 156.4, 168.5. MS (EI), m/z (%): 206 (51),
191 (24), 175 (100), 145 (26), 135 (99), 91 (27), 77 (43), 51 (17),
39 (11). HRMS (EI): [M]+ calcd for C12H14O3, 206.0943; found,
206.0928.
Meth yl 2-Meth oxy-6-(2-oxoeth yl)ben zoa te (4). Ozone
was passed through a solution of methyl 2-allyl-6-methoxy-
benzoate (3) (5.00 g, 31.2 mmol) in a 2:1 mixture of CH2Cl2/
MeOH (300 mL) at -78 °C until a slight blue color persisted
(∼1 h). The excess of ozone was removed by passing a stream
of nitrogen gas through the solution. Subsequently, Me2S (60
mL) was added at 0 °C and stirring was continued for 1 h at
this temperature. The reaction mixture was washed with brine
(2 × 100 mL), and the aqueous layer was extracted with CH2-
Cl2 (150 mL). The combined organic layers were dried (Na2-
SO4), filtered, and concentrated to yield 4.80 g (74%) of the
crude aldehyde 4, which was used for the Takai olefination
without further purification. For analytical purposes, a small
amount was purified by flash chromatography. TLC (petro-
leum ether/EtOAc, 1:1): Rf ) 0.60. IR (film): 1729, 1586, 1268
1
cm-1. H NMR (400 MHz, CDCl3): δ 3.61 (d, J ) 2.0 Hz, 2H),
3.81 (s, 3H), 3.85 (s, 3H), 6.80 (d, J ) 7.8 Hz, 1H), 6.88 (d, J
) 8.3 Hz, 1H), 7.33 (dd, J ) 7.8, 8.3 Hz, 1H), 9.64 (t, J ) 2.0
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 48.3, 52.2, 55.9, 110.5,
122.8, 123.8, 131.2, 131.4, 157.2, 167.8, 198.4. MS (EI), m/z
(%): 207 (3), 180 (40), 163 (9), 149 (58), 148 (100), 135 (42),
119 (11), 105 (17), 91 (22), 86 (29), 84 (48), 77 (25), 51 (28), 49
(58).
Meth yl 2-[(2E)-3-Iod op r op -2-en yl]-6-m eth oxy-ben zoa te
(5). To a vigorously stirred suspension of CrCl2 (17.1 g, 139
mmol) in THF (350 mL) was added dropwise a solution of the
crude aldehyde 4 (4.80 g, 23.1 mmol) and CHI3 (18.2 g, 46.2
mmol) in THF (120 mL) at 0 °C. The red-brown mixture was
stirred for another 12 h at 0 °C before it was diluted with Et2O
(250 mL) and washed with half-saturated aqueous Na2S2O3
solution (100 mL). After separation of the layers, the aqueous
phase was extracted with Et2O (3 × 100 mL). The combined
organic layers were washed with H2O (100 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography to yield 5.37 g (70%) of the
vinyl iodide 5 (E/ Z ) 5:1) as a slightly yellow oil. TLC
(petroleum ether/Et2O, 1:1): Rf ) 0.64. IR (film): 1731, 1471,
In summary, we present a synthesis of macrolactone
23 that represents a formal total synthesis of the sali-
cylihalamides. Macrolactone 23 served as an advanced
intermediate in the De Brabander12a,g and Fu¨rstner12b
syntheses. Our synthesis features an efficient synthesis
of the chiral alkene 17. The chiral centers were intro-
duced by a Noyori reduction of a keto ester and an Evans
aldol reaction on a derived aldehyde. This strategy also
illustrates how the methyl-bearing stereocenter in a syn
aldol product can be inverted by elimination and hy-
droboration. Finally, we demonstrated the advantage of
using immobilized triphenylphosphine for the Mitsunobu
lactonization in a complex setting.
1
1268 cm-1. H NMR (400 MHz, CDCl3): δ 3.32 (dd, J ) 1.5,
7.1 Hz, 2H), 3.80 (s, 3H), 3.88 (s, 3H), 6.08 (dt, J ) 1.5, 14.4
Hz, 1H), 6.58 (dt, J ) 7.1, 14.4 Hz, 1H), 6.78 (d, J ) 7.8 Hz,
1H), 6.80 (d, J ) 8.3 Hz, 1H), 7.28 (dd, J ) 7.8, 8.3 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 39.6, 52.2, 55.9, 76.8, 109.5,
121, 123.4, 130.7, 136.6, 143.4, 156.7, 168.2. MS (EI), m/z (%):
332 (20), 301 (10), 205 (58), 173 (85), 127 (23), 115 (100), 77
(23), 51 (16). HRMS (EI): [M]+ calcd for C12H13IO3, 331.9910;
found, 331.9921.
3-[(4-Meth oxyben zyl)oxy]p r op a n a l (7). A solution of
p-methoxybenzyl alcohol (18.0 mL, 20.0 g, 0.14 mol), monochlo-
roacetic acid (0.82 g, 8.69 mmol), and NaOH (0.35 g, 8.69
mmol) in H2O (1.8 mL) was added dropwise, with stirring over
5 min, to acrolein (12.0 mL, 10.2 g, 0.18 mol). Subsequently,
acetic acid (3.64 mL, 3.83 g, 63.7 mmol) was added, and the
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were recorded in CDCl3;
chemical shifts are calibrated to the residual proton and carbon
resonance of the solvent CDCl3 (δ H 7.25 ppm, δ C 77.00 ppm).
Atmospheric pressure ionization emission spectroscopy (API-
ES) MS: Agilent 1100 Series LC/MSD. HRMS (EI): modified
AMD Intectra MAT 711 A. HRMS (FT-ICR): Bruker Daltonic
APEX 2 with ESI. Flash chromatography: silica gel 43-60
µm. Solvents were distilled prior to use; petroleum ether, with
a boiling range of 40-60 °C, was used. The triphenylphosphine
resin was obtained from Fluka.
8132 J . Org. Chem., Vol. 68, No. 21, 2003

Formal Total Synthesis of the Salicylihalamides
solution was maintained at 40 °C for 6 days. After the solution
cooled to room temperature, the reaction mixture was diluted
with CH2Cl2 (500 mL) and washed with H2O (3 × 150 mL).
The organic layer was dried (MgSO4), filtered, and evaporated.
Volatile starting materials and byproducts were removed by
vacuum distillation at 120 °C (1.0 mm Hg), which left aldehyde
7 as light brown viscous oil, yielding 20.9 g (75%). Because it
appeared homogeneous by TLC and NMR analysis, it was used
for subsequent reactions without further purification. For
analytical purposes, a small amount was purified by flash
chromatography (diethyl ether). TLC (diethyl ether): Rf ) 0.68.
The ee determination was performed by HPLC using a
CHIRA-GROM 4 column, 8 µm, 60 × 2 mm, Part No. GS
CH40891K0602 (corresponds to CHIRACEL AS), eluent, n-hep-
tane/2-propanol (96:4); flow, 0.1 mL min-1; retention times,
major 35.5 min, minor 46.9 min.
Eth yl (3R)-3-{[ter t-Bu tyl(dim eth yl)silyl]oxy}-5-[(4-m eth -
oxyben zyl)oxy]p en ta n oa te (10). A stirred solution of 3-hy-
droxy ester 9 (6.70 g, 23.7 mmol), imidazole (4.04 g, 59.3
mmol), and DMAP (145 mg, 1.19 mmol) in dry dimethylfor-
mamide (100 mL) was treated with tert-butyldimethylsilyl
chloride (5.37 g, 35.6 mmol). The resulting solution was stirred
at ambient temperature for 48 h, diluted with water, and
extracted with ether (3 × 100 mL). The combined extracts were
dried with Na2SO4, filtered, and concentrated. Purification of
the residue by flash chromatography gave 8.33 g (89%) of the
silyl ether 10 as a colorless oil. TLC (petroleum ether/EtOAc,
5:1): Rf ) 0.76. [R]23D ) -2.5 (c 1.11, CH2Cl2). IR (film): 1737,
IR (film): 1724, 1612, 1514, 1248 cm-1 1H NMR (400 MHz,
.
CDCl3): δ 2.66 (t, J ) 6.1 Hz, 2H), 3.77 (t, J ) 6.1 Hz, 2H),
3.79 (s, 3H), 4.45 (s, 2H), 6.87 (d, J ) 8.6 Hz, 2H), 7.24 (d, J
) 8.6 Hz, 2H), 9.77 (s, 1H). 13C NMR (100 MHz, CDCl3): δ
43.8, 55.2, 63.4, 72.8, 113.7, 129.3, 129.8, 159.2, 201.2. MS (EI),
m/z (%): 194 (12), 138 (8), 137 (90), 136 (6), 135 (8), 122 (10),
121 (100), 109 (14), 94 (7), 91 (8), 89 (7), 78 (8), 77 (16), 51 (4).
HRMS (EI): [M]+ calcd for C11H14O3, 194.0943; found, 194.0951.
1514, 1250, 1097 cm-1 1H NMR (400 MHz, CDCl3): δ 0.03,
.
0.04 (2 s, 3H each), 0.85 (s, 9H), 1.24 (t, J ) 7.1 Hz, 3H), 1.81
(td, J ) 6.3, 6.1 Hz, 2H), 2.45 (d, J ) 6.2 Hz, 2H), 3.51 (t, J )
6.3 Hz, 1H), 3.79 (s, 3H), 4.10 (q, J ) 7.1 Hz, 2H), 4.28 (tt, J
) 6.2, 6.1 Hz, 1H), 4.38 (d, J ) 11.6 Hz, 1H), 4.42 (d, J ) 11.6
Eth yl 5-[(4-Meth oxyben zyl)oxy]-3-oxop en ta n oa te (8).
Ethyl diazoacetate (617 mg, 5.41 mmol) was added with
stirring at room temperature to a solution of anhydrous tin-
(II) chloride (98 mg, 0.52 mmol) in CH2Cl2 (10 mL). A few drops
of aldehyde 7 (1.0 g, 5.15 mmol) in CH2Cl2 (5 mL) were added
to the suspension. After nitrogen evolution had begun, the
remaining aldehyde solution was added dropwise over 10 min.
The solution continued to be stirred until the evolution of
nitrogen had stopped (∼1 h), and then the mixture was
transferred to a separatory funnel containing saturated brine
(20 mL) and diethyl ether (60 mL). After separation of the
layers, the aqueous phase was extracted with diethyl ether (2
× 80 mL). The organic layers were combined, dried (MgSO4),
filtered, and concentrated. Flash chromatography of the
remaining oil provided the â-keto ester 8, yielding 1.16 g (80%)
of a slightly yellow oil, keto-enol mixture. TLC (petroleum
ether/EtOAc, 2:1): Rf ) 0.46. IR (film): 1744, 1717, 1514, 1248
cm-1. 1H NMR (400 MHz, CDCl3, data for keto isomer): δ 1.26
(t, J ) 7.1 Hz, 3H), 2.81 (t, J ) 6.2 Hz, 2H), 3.47 (s, 2H), 3.72
(t, J ) 6.2 Hz, 2H), 3.80 (s, 3H), 4.18 (q, J ) 7.1 Hz, 2H), 4.43
(s, 2H), 6.87 (d, J ) 8.6 Hz, 2H), 7.24 (d, J ) 8.6 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ 14.0, 43.0, 49.6, 55.2, 61.3, 64.6,
72.8, 113.7, 129.3, 129.9, 159.2, 167.0, 201.4. MS (EI), m/z
(%): 262 (10), 206 (4), 205 (9), 189 (8), 176 (6), 138 (7), 137
(50), 136 (7), 135 (12), 122 (9), 121 (100), 109 (7), 99 (5), 91
(5), 78 (5), 77 (8), 73 (14), 57 (4), 45 (4). HRMS (ESI): [M +
Na]+ calcd for C15H20NaO5, 303.1203; found, 303.1203.
Hz, 1H), 6.86 (d, J ) 8.6 Hz, 2H), 7.24 (d, J ) 8.6 Hz, 2H). 13
C
NMR (100 MHz, CDCl3): δ -4.8, -4.7, 14.2, 17.9, 25.7, 37.4,
43.0, 55.2, 60.2, 66.2, 66.98, 72.5, 113.7, 129.2, 130.6, 159.1,
171.6. MS (EI), m/z (%): 196 (6), 195 (36), 143 (5), 122 (13),
121 (100), 91 (7), 77 (9), 57 (5). HRMS (ESI): [M + Na]+ calcd
for C21H36NaO5Si, 419.2224; found, 419.2220.
(3R)-3-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-5-[(4-m eth oxy-
ben zyl)oxy]p en ta n a l (11). To a stirred solution of ester 10
(7.06 g, 17.76 mmol) in dry CH2Cl2 (200 mL) was added DIBAH
(1.0 M in hexane, 20.4 mL) dropwise over 30 min at -78 °C.
After the mixture was stirred for 3.5 h at -78 °C, methanol
(5 mL) was added, the cooling bath was removed, and the
mixture was warmed to room temperature. Then water (30
mL) was added, and the mixture was extracted with Et2O (3
× 100 mL). The combined organic layers were washed with
water (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by flash chromatog-
raphy (petroleum ether/Et2O, 2:1) to yield 4.95 g (79%) of
aldehyde 11 as a pale-yellow oil. TLC (petroleum ether/EtOAc,
5:1): Rf ) 0.70. [R]D ) +7.1 (c 1.00, CH2Cl2). IR (film): 1726,
1613, 1514, 1250 cm-1 1H NMR (400 MHz, CDCl3): δ 0.05,
.
0.06 (2 s, 3H each), 0.86 (s, 9H), 1.76-1.89 (m, 2H), 2.47-
2.60 (m, 2H), 3.50 (t, J ) 6.3 Hz, 1H), 3.79 (s, 3H), 4.33-4.39
(m, 1H), 4.37 (d, J ) 11.4 Hz, 1H), 4.42 (d, J ) 11.4 Hz, 1H),
6.87 (d, J ) 8.6 Hz, 2H), 7.23 (d, J ) 8.6 Hz, 2H), 9.78 (t, J )
2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ -4.7, -4.6, 17.9,
25.7, 37.6, 51.0, 55.2, 65.6, 66.0, 72.6, 113.8, 129.2, 130.4, 159.2,
202.0. MS (EI), m/z (%): 137 (7), 136 (16), 135 (25), 131 (34),
122 (12), 121 (100), 101 (15), 83 (7), 77 (10), 75 (24), 59 (8).
HRMS (ESI): [M + Na]+ calcd for C19H32NaO4Si, 375.1962;
found, 375.1968.
Eth yl (3R)-3-Hyd r oxy-5-[(4-m eth oxyben zyl)oxy]p en -
ta n oa te (9). Dry, degassed DMF (3 mL) was added to a flask
containing benzeneruthenium(II) chloride dimer (45 mg, 0.09
mmol) and (R)-(+)-BINAP (112 mg, 0.18 mmol). The slurry
was heated to 90 °C with stirring for 20 min. The reddish-
brown solution was allowed to cool to room temperature and
was then added via cannula to a Parr flask containing a
degassed solution of â-keto ester 8 (8.4 g, 30.0 mmol) in dry
ethanol (15 mL). The hydrogenation flask was flushed a few
times with hydrogen and then pressurized with 4.0 bar
hydrogen at 90 °C and vigorous shaking for 20 h. After the
solution cooled to room temperature, the dark-red solution was
concentrated in vacuo and purified by flash chromatography
to provide the 3-hydroxy ester 9 (7.1 g, 84%, >90% ee) as a
pale-yellow liquid. TLC (petroleum ether/EtOAc, 2:1): Rf )
0.29. [R]23D ) -3.8 (c 1.00, CH2Cl2). IR (film): 3489, 1732, 1514,
(4R)-4-Ben zyl-3-{(2R,3R,5R)-5-{[ter t-bu tyl(d im eth yl)si-
lyl]oxy}-3-h yd r oxy-7-[(4-m eth oxyben zyl)oxy]-2-m eth yl-
h ep ta n oyl}-1,3-oxa zolid in -2-on e (13). To a stirred, cooled
(0 °C) solution of (4S)-4-(phenylmethyl)-3-propanoyl-1,3-ox-
azolidin-2-one (12) (2.86 g, 12.3 mmol) in CH2Cl2 (100 mL) was
added dropwise titanium(IV) chloride (1.42 mL, 2.44 g, 12.9
mmol), and the mixture was allowed to stir for 5 min.
Subsequently, (-)-sparteine (7.04 mL, 7.19 g, 30.7 mmol) was
added to the yellow slurry. The dark-red enolate solution was
stirred for 20 min at 0 °C before a solution of aldehyde 11 (4.76
g, 13.5 mmol) in CH2Cl2 (50 mL) was added dropwise and the
mixture stirred for 1 h at 0 °C. The reaction was quenched
with half-saturated ammonium chloride (20 mL). After separa-
tion of the layers, the organic layer was dried (Na2SO4),
filtered, and concentrated in vacuo. Purification of the residue
by flash chromatography afforded 5.67 g (79%) of the desired
product 13 as a colorless oil. TLC (petroleum ether/Et2O, 2:3):
Rf ) 0.33. [R]23D ) +44.0 (c 1.00, CH2Cl2). IR (film): 3529, 1783,
1
1249 cm-1. H NMR (400 MHz, CDCl3): δ 1.26 (t, J ) 7.1 Hz,
3H), 1.72-1.84 (m, 2H), 2.47 (d, J ) 6.3 Hz, 2H), 3.36 (s, br,
1H), 3.58-3.69 (m, 2H), 3.79 (s, 3H), 4.15 (q, J ) 7.1 Hz, 2H),
4.17-4.26 (m, 1H), 4.44 (s, 2H), 6.87 (d, J ) 8.6 Hz, 2H), 7.24
(d, J ) 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 14.1, 36.0,
41.6, 55.2, 60.5, 67.0, 67.6, 72.8, 113.8, 129.2, 130.1, 159.2,
172.4. MS (EI), m/z (%): 176 (5), 139 (7), 138 (75), 137 (100),
135 (16), 121 (75), 109 (52), 107 (16), 105 (11), 94 (26), 91 (12),
79 (13), 78 (13), 77 (33), 65 (8), 51 (8), 39 (8). HRMS (ESI): [M
+ Na]+ calcd for C36H56NaO8Si, 305.1365; found, 305.1362.
1
1696, 1513 cm-1. H NMR (400 MHz, CDCl3): δ 0.06, 0.07 (2
J . Org. Chem, Vol. 68, No. 21, 2003 8133

Herb and Maier
s, 3H each), 0.86 (s, 9H), 1.24 (d, J ) 6.8 Hz, 3H), 1.47-1.63
(m, 1H), 1.65-1.75 (m, 1H), 1.76-1.94 (m, 2H), 2.76 (dd, J )
13.3, 9.7 Hz, 1H), 3.21-3.28 (m, 2H), 3.46-3.58 (m, 2H), 3.69-
3.75 (m, 1H), 3.78 (s, 3H), 4.01-4.11 (m, 2H), 4.13-4.19 (m,
2H), 4.38 (d, J ) 11.4 Hz, 1H), 4.42 (d, J ) 11.4 Hz, 1H), 4.60-
4.69 (m, 1H), 6.86 (d, J ) 8.6 Hz, 2H), 7.16-7.21 (m, 2H),
7.21-7.29 (m, 3H), 7.29-7.36 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ -4.6, -4.5, 11.0, 17.9, 25.8, 37.1, 37.7, 40.8, 42.8,
55.2, 66.1, 66.3, 69.2, 69.8, 72.6, 113.7, 127.3, 128.9, 129.2,
129.4, 130.5, 135.1, 153.0, 159.1, 176.6. MS (EI), m/z (%): 233
(12), 148 (5), 142 (12), 122 (8), 121 (100), 91 (22), 57 (70). HRMS
(ESI): [M + Na]+ calcd for C32H47NNaO7Si, 608.3014; found,
608.3024.
(27), 176 (12), 145 (20), 137 (27), 135 (25), 131 (22), 123 (17),
122 (100), 101 (17), 99 (15), 91 (20), 89 (28), 77 (19), 75 (32),
73 (38), 59 (13), 57 (9), 45 (66). HRMS (ESI): [M + Na]+ calcd
for C24H44NaO6Si, 479.2799; found, 479.2794.
(2S,3R,5R)-5-{[ter t-Bu tyl(dim eth yl)silyl]oxy}-7-[(4-m eth -
oxyben zyl)oxy]-3-(m eth oxym eth oxy)-2-m eth ylh ep tyl 4-
m eth ylben zen esu lfon a te (16). To a stirred solution of
alcohol 15 (1.18 g, 2.58 mmol) in pyridine (5 mL) was added
p-toluenesulfonyl chloride (1.48 g, 7.75 mmol) at 0 °C. After
the solution was stirred for 2 h, the reaction was quenched by
addition of ice (0.5 g) and water (10 mL). The mixture was
diluted with Et2O (50 mL) and washed with 1 N HCl (20 mL),
saturated NaHCO3 solution (10 mL), and brine (10 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated
in vacuo. Filtration of the residue over a short pad of silica
gel and evaporation of the solvent gave the pure tosylate 16
as a slightly yellow oil, yield 1.54 g (98%). TLC (petroleum
(4R)-4-Ben zyl-3-[(2R,3R,5R)-5-{[ter t-bu tyl(d im eth yl)si-
lyl]oxy}-7-[(4-m eth oxyben zyl)oxy]-3-(m eth oxym eth oxy)-
2-m eth ylh ep ta n oyl]-1,3-oxa zolid in -2-on e (14). To a stirred,
cooled (0 °C) solution of alcohol 13 (4.01 g, 6.85 mmol) in CH2-
Cl2 (90 mL) were added N,N-diisopropylethylamine (15.4 mL,
11.6 g, 90.0 mmol), chloromethylmethyl ether (3.42 mL, 3.62
g, 45.0 mmol), and tetrabutylammonium iodide (665 mg, 1.80
mmol). The reaction mixture was protected from light and
allowed to reach room temperature within 12 h. After 3 days,
saturated aqueous NaHCO3 solution (100 mL) was added
followed by Et2O (150 mL). The organic layer was washed with
1 N HCl (50 mL) and brine (30 mL), and the basic aqueous
layer was extracted with Et2O (2 × 50 mL). The combined
organic extracts were dried (Na2SO4), filtered, and concen-
trated in vacuo. Flash chromatography of the residue provided
the MOM ether 14 as a slightly yellow oil, yield 3.48 g (81%).
ether/EtOAc, 2:1): Rf ) 0.76. [R]23 ) +7.7 (c 1.46, CH2Cl2).
D
IR (film): 1613, 1514, 1363, 1250, 1177 cm-1
.
1H NMR (400
MHz, CDCl3): δ 0.01, 0.02 (2 s, 3H each), 0.81 (d, J ) 13.9
Hz, 3H), 0.84 (s, 9H), 1.53-1.62 (m, 2H), 1.63-1.78 (m, 2H),
2.00-2.08 (m, 1H), 2.42 (s, 3H), 3.23 (s, 3H), 3.47 (t, J ) 6.3
Hz, 2H), 3.60-3.66 (m, 1H), 3.78 (s, 3H), 3.81-3.90 (m, 2H),
4.06 (dd, J ) 9.4, 6.3 Hz, 1H), 4.36 (d, J ) 11.4 Hz, 1H), 4.40
(d, J ) 11.4 Hz, 1H), 4.46 (d, J ) 6.6 Hz, 1H), 4.50 (d, J ) 6.6
Hz, 1H), 6.85 (d, J ) 8.6 Hz, 2H), 7.22 (d, J ) 8.6 Hz, 2H),
7.31 (d, J ) 8.2 Hz, 2H), 7.77 (d, J ) 8.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ -4.7, -4.6, 10.9, 17.6, 21.5, 25.7, 36.1,
36.8, 38.8, 55.1, 55.6, 66.4, 66.7, 72.3, 72.5, 75.0, 96.1, 113.6,
127.8, 129.1, 129.7, 130.5, 133.0, 144.6, 159.02. MS (EI), m/z
(%): 189 (16), 148 (15), 147 (100), 121 (8), 73 (9). HRMS
(ESI): [M + Na]+ calcd for C31H50NaO8SSi, 633.2888; found,
633.2885.
TLC (petroleum ether/EtOAc, 2:1): Rf ) 0.60. [R]23 ) +69.8
D
(c 1.54, CH2Cl2). IR (film): 1781, 1700, 1514 cm-1 1H NMR
.
(400 MHz, CDCl3): δ 0.03, 0.06 (2 s, 3H each), 0.87 (s, 9H),
1.20 (d, J ) 6.8 Hz, 3H), 1.61-1.74 (m, 2H), 1.74-1.84 (m,
1H), 1.86-1.97 (m, 1H), 2.76 (dd, J ) 13.3, 9.7 Hz, 1H), 3.23-
3.34 (m, 4H), 3.53 (t, J ) 6.32 Hz, 2H), 3.77 (s, 3H), 3.81-
3.89 (m, 1H), 3.91-4.02 (m, 2H), 4.10-4.16 (m, 2H), 4.37 (d,
J ) 11.4 Hz, 1H), 4.42 (d, J ) 11.4 Hz, 1H), 4.51-4.64 (m,
3H), 6.85 (d, J ) 8.6 Hz, 2H), 7.17-7.22 (m, 2H), 7.22-7.28
(m, 3H), 7.28-7.36 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
-4.8, -4.4, 12.0, 18.0, 25.8, 36.4, 37.7, 41.3, 41.8, 55.2, 55.8,
56.2, 66.0, 66.6, 66.6, 72.5, 76.4, 96.6, 113.6, 127.3, 128.9, 129.2,
129.4, 130.7, 135.4, 153.2, 159.0, 174.7. MS (EI), m/z (%): 233
(10), 182 (7), 149 (8), 142 (16), 135 (10), 122 (17), 121 (100), 92
(16), 85 (54), 83 (78), 57 (70), 45 (41). HRMS (ESI): [M + Na]+
calcd for C34H51NNaO8Si, 652.3276; found, 652.3278.
1-({[(3R,5R)-3-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-5-(m eth -
oxym eth oxy)-6-m eth ylh ep t-6-en yl]oxy}m eth yl)-4-m eth -
oxyben zen e (17). A mixture of tosylate 16 (1.30 g, 2.13 mmol),
NaI (797 mg, 5.32 mmol), and DBU (1.60 mL, 1.62 g, 10.6
mmol) in glyme (40 mL) was refluxed with stirring for 3 h.
After that, the solution was cooled to room temperature,
diluted with Et2O (80 mL), and washed with saturated
NaHCO3 solution (15 mL), 1 N HCl (15 mL), and brine (15
mL). The organic layer was dried (Na2SO4), filtered, and
concentrated in vacuo. Filtration of the residue over a short
pad of silica gel gave 783 mg of the pure alkene 17 in 84%
yield as a slightly yellow oil. TLC (petroleum ether/EtOAc,
5:1): Rf ) 0.76. [R]23D ) +64.7 (c 1.25, CH2Cl2). IR (film): 3073,
(2S,3R,5R)-5-{[ter t-Bu tyl(dim eth yl)silyl]oxy}-7-[(4-m eth -
oxyben zyl)oxy]-3-(m eth oxym eth oxy)-2-m eth ylh ep ta n -1-
ol (15). To a stirred, cooled (0 °C) solution of 14 (500 mg, 0.79
mmol) in THF (10 mL) was added methanol (0.13 mL, 102 mg,
3.17 mmol) followed by LiBH4 (2.0 M in THF, 1.98 mL, 3.96
mmol). The reaction mixture was stirred at 0 °C for 5 min,
allowed to warm to room temperature, and stirred overnight.
The reaction was quenched by addition of saturated aqueous
NH4Cl solution (10 mL), and the mixture was stirred for 1 h
followed by extraction with EtOAc (3 × 20 mL). The combined
organic layers were washed with saturated NaHCO3 solution
(15 mL) and brine (15 mL), dried (MgSO4), filtered, and
concentrated in vacuo. The crude alcohol 15 was purified by
flash chromatography to give 280 mg (77%) of the alcohol 15
as a colorless oil. TLC (petroleum ether/EtOAc, 2:1): Rf ) 0.40.
1
1650, 1613, 1514, 1249 cm-1. H NMR (400 MHz, CDCl3): δ
0.04, 0.05 (2 s, 3H each), 0.88 (s, 9H), 1.57-1.68 (m, 4H), 1.69-
1.94 (m, 3H), 3.32 (s, 3H), 3.53 (t, J ) 6.6 Hz, 2H), 3.79 (s,
3H), 3.92-3.99 (m, 1H), 4.12 (dd, J ) 8.3, 5.0 Hz, 1H), 4.36-
4.46 (m, 3H), 4.57 (d, J ) 6.6 Hz, 1H), 4.91 (s, 2H), 6.87 (d, J
) 8.6 Hz, 2H), 7.24 (d, J ) 8.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ -4.6, -4.4, 16.8, 18.0, 25.9, 36.7, 41.7, 55.2, 55.6,
66.6, 66.8, 72.6, 76.6, 93.4, 113.6, 114.0, 130.7, 143.9, 159.0.
MS (EI), m/z (%): 389 (4), 357 (5), 245 (9), 199 (6), 189 (9),
176 (11), 147 (10), 145 (11), 137 (27), 135 (31), 131 (27), 122
(83), 121 (100), 89 (29), 75 (23), 73 (24), 59 (9), 45 (55). HRMS
(ESI): [M + Na]+ calcd for C24H42NaO5Si, 461.2694; found,
461.2694.
Meth yl 2-[(2E,5S,6R,8R)-8-{[ter t-Bu tyl(d im eth yl)silyl]-
oxy}-10-[(4-m eth oxyben zyl)oxy]-6-(m eth oxym eth oxy)-5-
m eth yld ec-2-en yl]-6-m eth oxyben zoa te (18). To a solution
of alkene 17 (720 mg, 1.64 mmol) in THF (16 mL) was added
9-BBN (0.5 M solution in THF, 3.93 mL, 1.97 mmol), and the
reaction was stirred for 4 h at room temperature. In a separate
flask, to a solution of vinyl iodide 5 (653 mg, 1.97 mmol) were
added Cs2CO3 powder (1.16 g, 3.28 mmol), AsPh3 (25 mg, 0.082
mmol), PdCl2(dppf) (67 mg, 0.082 mmol), and H2O (0.88 mL,
49.1 mmol) successively under vigorous stirring. This mixture
was stirred for 5 min before the borane solution was added to
it. After the solution was stirred for 12 h, the reaction mixture
was diluted with saturated aqueous NH4Cl. The mixture was
[R]23 ) -9.4 (c 1.54, CH2Cl2). IR (film): 3466, 1613, 1514,
D
1250 cm-1. H NMR (400 MHz, CDCl3): δ 0.04, 0.05 (2 s, 3H
1
each), 0.79 (d, J ) 7.1 Hz, 3H), 0.87 (s, 9H), 1.58-1.68 (m,
1H), 1.68-1.78 (m, 2H), 1.78-1.87 (m, 1H), 1.88-1.99 (m, 1H),
2.69 (dd, J ) 7.5, 4.7 Hz, 1H), 3.35 (s, 3H), 3.46-3.54 (m, 3H),
3.56-3.64 (m, 1H), 3.75-3.84 (m, 4H), 3.88-3.96 (m, 1H), 4.37
(d, J ) 11.4 Hz, 1H), 4.42 (d, J ) 11.4 Hz, 1H), 4.59 (d, J )
6.6 Hz, 1H), 4.63 (d, J ) 6.6 Hz, 1H), 6.86 (d, J ) 8.6 Hz, 2H),
7.23 (d, J ) 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ -4.6,
-4.4, 11.04, 18.0, 25.9, 37.0, 37.7, 39.1, 55.3, 55.9, 65.3, 66.6,
66.9, 72.6, 76.7, 96.4, 113.7, 129.3, 130.6, 159.1. MS (EI), m/z
(%): 309 (5), 279 (14), 275 (7), 247 (12), 215 (6), 199 (11), 189
8134 J . Org. Chem., Vol. 68, No. 21, 2003

Formal Total Synthesis of the Salicylihalamides
extracted with CH2Cl2 (3 × 30 mL), and the organic layer was
washed with H2O (20 mL) and brine (10 mL), dried with
MgSO4, filtered, and concentrated. Purification of the residue
by flash chromatography (CH2Cl2/acetone, 30:1) afforded cou-
pling product 18, yielding 687 mg (65%) as a slightly yellow
(10 mL), dried (MgSO4), filtered, and concentrated to give 107
mg (91%) of the desired acid 21 as a slightly yellow oil. TLC
(petroleum ether /EtOAc, 1:3): Rf ) 0.58. [R]23 ) +25.4 (c
D
1.15, CH2Cl2). IR (film): 3447, 1726, 1584, 1512, 1472 cm-1
.
1H NMR (400 MHz, CDCl3): δ 0.83 (d, J ) 6.1 Hz, 3H), 1.46-
1.62 (m, 2H), 1.66-1.84 (m, 3H), 1.85-2.00 (m, 2H), 1.91-
2.02 (m, 1H), 3.35-3.45 (m, 4H), 3.45-3.71 (m, 4H), 3.74-
3.80 (m, 5H), 3.82 (s, 3H), 3.88-3.95 (m, 1H), 4.45 (s, 2H), 4.61
(d, J ) 6.9 Hz, 1H), 4.77 (d, J ) 6.9 Hz, 1H), 5.34-5.43 (m,
1H), 5.44-5.54 (m, 1H), 6.75-6.83 (m, 2H), 6.85 (d, J ) 8.3
Hz, 2H), 7.22-7.26 (m, 3H). 13C NMR (100 MHz, CDCl3): δ
14.0, 35.2, 35.5, 36.4, 36.6, 37.1, 55.3, 55.7, 56.0, 67.7, 69.5,
72.8, 78.3, 94.2, 109.2, 113.8, 122.6, 122.8, 129.4, 129.6, 129.8,
130.1, 130.7, 139.8, 156.8, 159.2, 169.1. MS (EI), m/z (%): 345
(4), 199 (4), 187 (8), 177 (7), 164 (7), 162 (7), 156 (7), 137 (14),
135 (9), 122 (13), 121 (100), 77 (4), 45 (14). HRMS (ESI): [M
+ Na]+ calcd for C29H40NaO8, 539.2615; found, 539.2616.
Da ta for Aceta l 22. Colorless oil, TLC (petroleum ether/
oil. TLC (CH2Cl2/acetone, 30:1): Rf ) 0.44. [R]23 ) +20.6 (c
D
1.49, CH2Cl2). IR (film): 1733, 1514, 1471 cm-1. 1H NMR (400
MHz, CDCl3): δ 0.01, 0.03 (2 s, 3H each), 0.81-0.89 (m, 12H),
1.42-1.52 (m, 1H), 1.53-1.68 (m, 2H), 1.71-1.89 (m, 2H),
1.93-2.07 (m, 2H), 3.26 (d, J ) 6.1 Hz, 2H), 3.29 (s, 3H), 3.44-
3.53 (m, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 3.85 (s, 3H), 3.90-4.02
(m, 1H), 4.35 (d, J ) 11.6 Hz, 1H), 4.39 (d, J ) 11.6 Hz, 1H),
4.52-4.59 (m, 2H), 5.33-5.43 (m, 1H), 5.44-5.54 (m, 1H), 6.73
(d, J ) 8.3 Hz, 1H), 6.79 (d, J ) 7.8 Hz, 1H), 6.83 (d, J ) 8.6
Hz, 2H), 7.18-7.26 (m, 3H). 13C NMR (100 MHz, CDCl3): δ
-4.8, -4.4, 14.1, 18.0, 25.9, 35.7, 36.3, 36.4, 36.6, 38.2, 52.0,
55.2, 55.7, 55.9, 66.7, 67.1, 72.5, 78.1, 95.7, 108.8, 113.7, 121.5,
123.4, 129.1, 129.2, 130.4, 130.7, 130.8, 139.3, 156.4, 159.1,
168.5. MS (EI), m/z (%): 121 (8), 88 (10), 86 (64), 84 (100), 49
(13), 47 (17). HRMS (ESI): [M + Na]+ calcd for C36H56NaO8-
Si, 667.3637; found, 667.3636.
1
EtOAc, 1:3): Rf ) 0.54. IR (film): 1783, 1730 cm-1. H NMR
(400 MHz, CDCl3): δ 0.82 (d, J ) 6.8 Hz, 3H), 1.29-1.38 (m,
1H), 1.44-1.55 (m, 1H), 1.58-1.69 (m, 1H), 1.69-179 (m, 1H),
1.79-1.96 (m, 2H), 2.17-2.28 (m, 1H), 1.91-2.02 (m, 1H),
3.28-3.38 (m, 1H), 3.38-3.48 (m, 2H), 3.50-3.63 (m, 2H),
3.64-3.73 (m, 1H), 3.77 (s, 3H), 3.83 (s, 3H), 4.44 (s, 2H), 4.62
(d, J ) 6.3 Hz, 1H), 5.04 (d, J ) 6.9 Hz, 1H), 5.32-5.48 (m,
1H), 5.48-5.63 (m, 1H), 6.78 (d, J ) 8.1 Hz, 1H), 6.83-6.90
(m, 3H), 7.24 (d, J ) 8.3 Hz, 2H) 7.29 (t, J ) 8.1 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 14.4, 34.1, 35.2, 35.9, 36.6, 37.6,
55.2, 55.9, 65.6, 72.5, 73.6, 79.8, 93.3, 108.9, 113.7, 122.0, 122.3,
129.4, 129.5, 130.0, 130.2, 130.9, 140.3, 156.6, 159.1, 171.7.
(3S,5R,6S)-14-Meth oxy-3-{2-[(4-m eth oxyben zyl)oxy]eth -
yl}-5-(m eth oxym eth oxy)-6-m eth yl-3,4,5,6,7,10-h exah ydr o-
1H-2-ben zoxa cyclod od ecin -1-on e (23). To a cooled (0 °C)
solution of hydroxy acid 21 (80 mg, 155 µmol) in THF (7.5 mL)
was added polymer-bound PPh3 (3 mmol P/g resin, 330 mg,
990 µmol). After 15 min at room temperature, the slurry was
recooled to 0 °C and treated dropwise with DEAD (∼40%
solution in toluene, 150 µL, 60 mg, 345 µL). Within 15 h of
stirring, the reaction mixture was warmed to room tempera-
ture. The resin was filtered off and washed thoroughly with
THF. After evaporation of the solvent, the residue was purified
by flash chromatography (CH2Cl2/acetone, 20:1) to give 33 mg
(43%) of the desired lactone 23 as a colorless oil. TLC
As a byproduct, iodide 19 was isolated. This compound does
contain some unreacted alkene 17 (123 mg, 3.9:1 molar ratio,
colorless oil). TLC (petroleum ether/EtOAc, 5:1): Rf ) 0.74.
IR (film): 1613, 1513, 1250 cm-1. 1H NMR (400 MHz, CDCl3):
δ 0.04, 0.05 (2 s, 3H each), 0.87 (s, 9H), 0.98 (d, J ) 6.8 Hz,
3H), 1.50-1.94 (m, 4H), 1.97-2.08 (m, 1H), 2.93-3.05 (m, 1H),
3.31-3.42 (m, 4H), 3.47-3.55 (m, 2H), 3.63-3.74 (m, 1H), 3.80
(s, 3H), 3.87-3.99 (m, 1H), 4.36-4.46 (m, 2H), 4.55-4.65 (m,
2H), 6.86 (d, J ) 8.6 Hz, 2H), 7.24 (d, J ) 8.6 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ -4.6, -4.3, 11.4, 15.3, 18.0, 25.87,
36.8, 38.8, 40.3, 55.3, 55.8, 66.5, 66.8, 72.6, 77.8, 96.4, 113.7,
129.3, 130.6, 159.1. MS (EI), m/z (%): 389 (8), 357 (9), 189
(11), 137 (29), 121 (100), 89 (18), 77 (12), 75 (14), 45 (51). MS
(FD), m/z (%): 438.0 (100), 565.9 (69).
Met h yl 2-[(2E,5S,6R,8R)-8-H yd r oxy-10-[(4-m et h oxy-
ben zyl)oxy]-6-(m eth oxym eth oxy)-5-m eth yld ec-2-en yl]-6-
m eth oxyben zoa te (20). To a solution of 18 (355 mg, 0.55
mmol) in THF (5.5 mL) was added TBAF (1 M in THF, 1.65
mL, 1.65 mmol) at 0 °C. After the mixture was stirred for 2
days, saturated aqueous NaHCO3 solution (10 mL) was added
and the mixture extracted with Et2O (3 × 20 mL). The
combined organic extracts were dried (Na2SO4), filtered, and
concentrated. Flash chromatography of the residue gave 296
mg (100%) of the desired alcohol 20 as a colorless oil. TLC
(petroleum ether /EtOAc, 2:1): Rf ) 0.64. [R]23 ) -46.9 (c
D
0.85, CH2Cl2) (ref 12g, [R]20 ) -49.5 (c 1.30, CHCl3); ref 12b
D
[R]20 ) -21.0 (c 1.00, benzene)). IR (film): 1724, 1613, 1584,
D
(Et2O): Rf ) 0.55. [R]23 ) +15.9 (c 1.27, CH2Cl2). IR (film):
D
1468 cm-1. 1H NMR (400 MHz, CDCl3): δ 0.85 (d, J ) 6.6 Hz,
3H), 1.44 (dd, J ) 9.4, 15.4 Hz, 1H), 1.63-1.79 (m, 2H), 1.84-
1.95 (m, 1H), 1.97-2.07 (m, 1H), 2.08-2.17 (m, 1H), 2.30 (d,
br, J ) 13.1 Hz, 1H), 3.31 (d, br, J ) 16.7 Hz, 1H), 3.42 (s,
3H), 3.64 (t, J ) 9.6 Hz, 2H), 3.69 (s, 3H), 3.67-3.76 (m, 1H),
3.78 (s, 3H), 4.14 (dd, J ) 3.3, 9.3 Hz, 1H), 4.46 (s, 2H), 4.78
(d, J ) 6.8 Hz, 1H), 4.87 (d, J ) 6.8 Hz, 1H), 5.29-5.38 (m,
1H), 5.41-5.52 (m, 2H), 6.72-6.80 (m, 2H), 6.85 (d, J ) 8.3
Hz, 2H), 7.21 (t, J ) 8.8 Hz, 1H), 7.26 (d, J ) 8.3 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ 13.3, 34.0, 35.7, 36.4, 37.7, 37.7,
55.3, 55.3, 55.5, 66.6, 72.3, 72.6, 79.2, 96.8, 109.2, 113.7, 122.8,
124.5, 128.5, 129.0, 129.9, 130.7, 131.3, 139.1, 156.4, 159.1,
168.2. MS (EI), m/z (%): 202 (3), 176 (4), 147 (3), 130 (5), 104
(3), 84 (4), 59 (5), 45 (6), 44 (100). HRMS (ESI): [M + Na]+
calcd for C29H38NaO7, 521.2510; found, 521.2510.
3514, 1732, 1513, 1471 cm-1. H NMR (400 MHz, CDCl3): δ
1
0.86 (d, J ) 6.6 Hz, 3H), 1.43-1.53 (m, 1H), 1.53-1.66 (m,
1H), 1.66-1.75 (m, 2H), 1.75-1.90 (m, 2H), 1.91-2.02 (m, 1H),
3.27 (d, J ) 6.1 Hz, 2H), 3.36 (s, 3H), 3.50-3.72 (m, 4H), 3.78
(s, 3H), 3.80 (s, 3H), 3.87 (s, 3H), 3.87-3.94 (m, 1H), 4.43 (s,
2H), 4.60 (d, J ) 6.8 Hz, 1H), 4.68 (d, J ) 6.8 Hz, 1H), 5.34-
5.44 (m, 1H), 5.44-5.54 (m, 1H), 6.75 (d, J ) 8.3 Hz 1H), 6.80
(d, J ) 7.6 Hz, 1H) 6.86 (d, J ) 8.6 Hz, 2H), 7.21-7.28 (m,
3H). 13C NMR (100 MHz, CDCl3): δ 13.7, 35.8, 36.0, 36.4, 36.4,
36.8, 52.1, 55.2, 55.9, 55.9, 67.8, 69.4, 72.8, 80.6, 95.5, 108.8,
113.8, 121.5, 123.3, 129.3, 129.4, 130.4, 130.4, 131.0, 139.2,
156.4, 159.2, 168.6. MS (EI), m/z (%): 149 (4), 135 (8), 121
(11), 109 (6), 107 (5), 77 (7), 57 (5), 44 (100). HRMS (ESI): [M
+ Na]+ calcd for C30H42NaO8, 553.2772; found, 553.2773.
2-[(2E,5S,6R,8R)-8-Hydr oxy-10-[(4-m eth oxyben zyl)oxy]-
6-(m eth oxym eth oxy)-5-m eth yldec-2-en yl]-6-m eth oxyben -
zoic a cid (21). A solution of methyl ester 20 (121 mg, 0.23
mmol) in a mixture of THF (2 mL), EtOH (4 mL), and H2O (4
mL) was treated with LiOH‚H2O (96 mg, 2.28 mmol), and the
mixture was stirred at 70 °C for 3 days. After the mixture
cooled to room temperature, it was diluted with Et2O (30 mL)
and water (20 mL). The organic layer, containing unreacted
starting material and side products, was separated. The
aqueous layer was acidified (pH ∼ 3) by addition of hydro-
chloric acid (1 M solution, 2.2 mL) and extracted with EtOAc
(3 × 25 mL). The combined extracts were washed with water
Ack n ow led gm en t. Financial support by the Deut-
sche Forschungsgemeinschaft (Grant Ma 1012/10-1) and
the Fonds der Chemischen Industrie is gratefully ac-
knowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra of all key intermediates in PDF format. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J O035054G
J . Org. Chem, Vol. 68, No. 21, 2003 8135