Formal total syntheses of the (-)-salicylihalamides A and B from D-glucose and L-rhamnose

Article abstract of DOI:10.1021/jo050750x

Two formal total syntheses of the (-)-salicylihalamides, based on chiral pool approaches, are reported. D-Glucose and L-rhamnose were used to prepare advanced intermediates 23 and 54, which can be converted in three or four steps, respectively, to the tar

Full text of DOI:10.1021/jo050750x

Formal Total Syntheses of the (-)-Salicylihalamides A and B From
D-Glucose and L-Rhamnose
Torsten Haack, KyoungLang Haack, Wibke E. Diederich, Burchelle Blackman, Subho Roy,
Srinivas Pusuluri, and Gunda I. Georg*
Department of Medicinal Chemistry, Center for Cancer Experimental Therapeutics and
Center for Drug Discovery, Higuchi Biosciences Center, University of Kansas,
1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582
georg@ku.edu
Received April 14, 2005
Two formal total syntheses of the (-)-salicylihalamides, based on chiral pool approaches, are
reported. D-Glucose and L-rhamnose were used to prepare advanced intermediates 23 and 54, which
can be converted in three or four steps, respectively, to the target compounds. The synthesis of 23
from a known D-glucose-derivative was accomplished in 12 steps and 17% overall yield, and the
synthesis of 54 from a known L-rhamnose-derivative was done in nine steps and 6% overall yield.
A key step in the synthesis was a ring-closing metathesis reaction to prepare the macrocyclic ring
system. It was demonstrated that the phenolic protecting group was critical for inducing the
preferential formation of the desired E isomer. It was further shown that the protecting group at
the C13 hydroxyl group had no significant influence on the E:Z ratio during the ring-closing
metathesis reaction.
Introduction
salicylihalamides displayed a striking and unique pattern
of differential cytotoxicity in the NCI 60 tumor cell line
assay, indicating a new mechanism of action. Further
investigations revealed that these compounds inhibit
mammalian V-ATPases with unprecedented specificity.5
Prior to considering these substances as potential drug
candidates, thorough investigations with respect to their
exact mechanism of action are necessary. To develop a
pharmacophore model, the syntheses of analogues to
probe structure-activity relationships as well as biologi-
cal probes to characterize the ligand binding site in the
multisubunit complex of the V-ATPases are required.
Novel structural features coupled with unique biological
activity prompted us to undertake the total synthesis.
Because the availability of the salicylihalamides from
natural sources is limited, the semisynthesis of structural
The salicylihalamides A (1) and B (2), isolated in 1997
from a marine sponge of the genus Haliclona sp.,1 are
the most extensively studied members of a novel class of
natural products that have as common structural fea-
tures a salicylic acid moiety, a macrolactone, and an
unusual dienyl enamide side-chain.
(3) McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina, J. H., II;
Lakkso, J.; Ireland, C. M.; Murray, L.; Capon, R. J.; Boyd, M. R. J.
Org. Chem. 1998, 63, 7805-7810.
Members of this class of natural products such as the
oximidines,2 the lobatamides,3 the apicularens,4 and the
(4) Jansen, R.; Kunze, B.; Reichenbach, H.; Ho¨fle, G. Eur. J. Org.
Chem. 2000, 6, 913-919.
(1) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R.
J. Org. Chem. 1997, 62, 8188-8192.
(2) Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J.
Org. Chem. 1999, 64, 153-155.
(5) 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.
10.1021/jo050750x CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/12/2005
7592
J. Org. Chem. 2005, 70, 7592-7604

Total Syntheses of the (-)-Salicylihalamides A and B
SCHEME 1
analogues from the natural product itself is restricted.
Thus, obtaining the salicylihalamides synthetically is of
interest. Several total syntheses of the salicylihalamides6
and related natural products have been reported. We7a,d-f
and others7b,c have employed a chiral pool approach
toward the synthesis of members of this class of com-
pounds.
A chiral pool approach can be especially advantageous
if larger amounts of the target compound have to be
prepared via total synthesis. The starting materials
already bearing the desired chiral centers are usually
inexpensive. Moreover, enantio- or diastereoselective
reactions, which might cause separation problems due
to complex diastereomeric mixtures, can be avoided. In
this paper, we describe the details of two efficient and
high-yielding formal total syntheses of the salicylihala-
mides A and B, both based on a chiral pool strategy.
Results and Discussion
The initially proposed absolute stereochemistry of the
salicylihalamides was revised by total synthesis6a at a
time when we were pursuing their synthesis via a chiral
pool approach, employing commercially available 1,2,5,6-
diacetone-D-glucose as the starting material. We there-
fore first focused on the completion of the synthesis of
the (+)-salicylihalamides. The formal total synthesis of
the (+)-salicylihalamides, the enantiomers of the natu-
rally occurring molecules, has been reported earlier by
our group.7e Subsequently, we adapted the chiral pool
approach strategy also toward the synthesis of the (-)-
salicylihalamides.
As a potential chiral source, L-glucose, the enantiomer
of the previously used D-glucose, could be easily employed
following our earlier developed synthetic route. Although
L-glucose is also commercially available, it is significantly
more expensive than the naturally occurring D-glucose,
limiting its usefulness as a starting material. Thus, we
modified our hitherto developed synthesis to prepare the
naturally occurring salicylihalamides, again employing
D-glucose as the chiral source. In addition, we developed
a closely related chiral pool approach, using readily
available L-rhamnose as the starting material.9 The
retrosynthetic approach of our synthesis of the (-)-
salicylihalamides is outlined in Scheme 1.
We reasoned that the labile enamide side-chain func-
tionality would be best installed at a very late stage of
our synthetic approach leading to aldehyde 3, which can
be transformed into salicylihalamides A and B following
a known procedure.6d
For the macrocyclic core structure 3, we considered
disconnection at the lactone functionality, at the endocy-
clic double bond, and at C16 resulting in fragments 4, 5,
and 6.
The aromatic part 4 can be obtained from commercially
available o-anisic acid in one step,7e the aliphatic building
block 5 is accessible from the known alcohols 7 or 8, and
the stabilized ylide 6, needed for the two-carbon homolo-
gation, is also commercially available. Alcohol 7 can be
prepared in five steps from 1,2,5,6-diacetone-D-glucose8
and diol 8 from L-rhamnose9 in four steps.
The first step in our synthetic approach to the (-)-
salicylihalamides starting from alcohol 7 was its conver-
sion to bromide 9 (Scheme 2).10 Subsequent reaction with
a higher order allylcuprate11 gave rise to allylated
compound 10 with overall retention of stereochemistry
at C12 in the two-step process. Hydrolysis of acetonide
10 with 70% acetic acid provided lactol 11, which was
oxidized selectively to lactone 12.
Esterification of the remaining hydroxyl function at
C15 with aromatic fragment 13 using DCC as the coupl-
ing reagent gave rise to lactone 14 in excellent yield
(Scheme 3). Selective reduction of 14 with DIBAL-H at
-78 °C furnished the corresponding lactol anomers 15,
which, employing a Wittig reaction with stabilized ylide
(6) (a) Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem., Int.
Ed. 2000, 39, 4308-4310. (b) Fu¨rstner, A.; Thiel, O. R.; Blanda, G.
Org. Lett. 2000, 2, 3731-3734. (c) Wu, Y.; Seguil, O. R.; De Brabander,
J. K. Org. Lett. 2000, 2, 4241-4244. (d) Labrecque, D.; Charron, S.;
Rej, R.; Blais, C.; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645-2648.
(e) Smith, A. B.; Zheng, J. Synlett 2001, 1019-1023. (f) Snider, B. B.;
Song, F. Org. Lett. 2001, 3, 1817-1820. (g) Fu¨rstner, A.; Dierkes, T.;
Thiel, O. R.; Blanda, G. Chem. Eur. J. 2001, 7, 5286-5298. (h) Wu,
Y.; Liao, X.; Wang, R.; Xie, X.; De Brabander, J. K. J. Am. Chem. Soc.
2002, 124, 3245-3253. (i) Smith, A. B.; Zheng, J. Tetrahedron 2002,
58, 6455-6471. (j) Bauer, M.; Maier, M. M. Org. Lett. 2002, 4, 2205-
2208. (k) Holloway, G. A.; Hu¨gel, H.; Rizzacasa, M. A. J. Org. Chem.
2003, 68, 2200-2204. (l) Herb, C.; Maier, M. M. J. Org. Chem. 2003,
68, 8129-8135.
(7) (a) Georg, G. I.; Ahn, Y. M.; Blackman, B.; Farokhi, F.; Flaherty,
P. T.; Mossman, C. J.; Roy, S.; Yang, K. L. J. Chem. Soc., Chem.
Commun. 2001, 255-256. (b) Lewis, A.; Stefanuti, I.; Swain, S. A.;
Smith, S. A.; Taylor, R. K. A. Tetrahedron Lett. 2001, 42, 5549-5552.
(c) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. K. A.
Org. Biomol. Chem. 2003, 1, 104-116. (d) Yang, K. L.; Haack, T.;
Blackman, B.; Diederich, W. E.; Roy, S.; Pusuluri, S.; Georg, G. I. Org.
Lett. 2003, 5, 4007-4009. (e) Yang, K. L.; Blackman, B.; Diederich,
W. E.; Flaherty, P. T.; Mossman, C. J.; Roy, S.; Ahn, Y. M.; Georg, G.
I. J. Org. Chem. 2003, 68, 10030-10039. (f) Haack, T.; Kurtkaya, S.;
Snyder, J. P.; Georg, G. I. Org. Lett. 2003, 5, 5019-5022.
(9) (a) Bols, M.; Lundt, I.; Ottosen, E. R. Carbohydr. Res. 1991, 222,
141-149. (b) Han, O.; Liu, W. Tetrahedron Lett. 1987, 28, 1073-1076.
(c) Varela, O.; Cirelli, A. F.; Lederkremer, R. M. Carbohydr. Res. 1980,
85, 130-135.
(10) Redlich, H.; Neumann, H. J. Chem. Ber. 1981, 114, 2029-2050.
(11) Lipshutz, B. H. In Organocopper Reagents; Taylor, R. J. K., Ed.;
Oxford University: New York, NY; 1994; pp 104-128.
(8) (a) Lee, W. M.; Chan, W. H.; Weng, H. C.; Wong, M. S. Synth.
Commun. 1989, 19, 547-552. (b) Iacono, S.; Rasmussen, R.; Card, P.
J.; Smart, B. E. Org. Synth. 1990, Collect. Vol. VII, 139-141. (c)
Patroni, J. J.; Stick, R. V. Aust. J. Chem. 1978, 31, 445-446.
J. Org. Chem, Vol. 70, No. 19, 2005 7593

Haack et al.
SCHEME 2a
SCHEME 4a
a Reagents and conditions: (a) PNBA, DEAD, PPh3, PhMe, -30
°C to rt, 1 d.
SCHEME 5a
a Reagents and conditions: (a) CBr4, PPh3, THF, 0 °C to rt, 6
h, 90%; (b) (allyl)2Cu(CN)Li2, THF, Et2O, -78 °C, 30 min, 83%;
(c) AcOH, water, 70 °C, 3 h, 85%; (d) Ag2CO3/Celite, PhH, reflux,
1 h, 81%.
SCHEME 3a
a Reagents and conditions: (a) [CuHPPh3]6, PhH, reflux, 45 min,
45%; (b) Grubbs I catalyst, CH2Cl2, reflux, 3 h, 89% (E:Z ) 18:1);
(c) BBr3, CH2Cl2, -78 °C, 30 min, 85%; (d) K2CO3, MeOH, rt, 5 h,
95%.
remaining starting material, we also isolated side prod-
ucts in which the alcohol function had been eliminated
in both cases. Presumably, the results observed above
are due to steric interference of the nitrile-containing side
chain, hampering the attack of the PNBA especially in
Z-isomer 17.
The only moderate yield (45%) of the following selective
hydrogenation of E-acryl nitrile 18 to saturated nitrile
20 (Scheme 5)13 might be caused by steric hindrance
under these conditions because, as shown later in Scheme
8, the hydrogenation of a structurally related cyclic
analogue 29 proceeded with excellent yield and enhanced
reaction rate. With compound 20 in hand, we intended
to close the macrocycle using ruthenium-catalyzed ring-
closing metathesis.14 Reaction of 20 with the first genera-
tion Grubbs catalyst effectively produced macrocycle 21
not only in excellent yield (89%) but also with a remark-
a Reagents and conditions: (a) DCC, DMAP, CH2Cl2, rt, 1 d,
95%; (b) DIBAL-H, Et2O, -78 °C, 30 min, 93%; (c) PhMe, 80 °C,
2 h, 96%.
triphenylphosphoranylidene acetonitrile 6, provided acryl
nitriles 16 and 17 in 96% yield with an E:Z ratio of 3.6:1.
The required inversion of the chiral center at C13 in
16 and 17 was achieved by esterification under Mit-
sunobu conditions utilizing p-nitrobenzoic acid (PNBA),
allowing mild cleavage of the resulting ester to the
desired alcohol functionality at a later stage of the
synthesis (Scheme 4).12 Surprisingly, we noticed a con-
siderable difference in the reactivity between 16 and 17
during the Mitsunobu esterification. Although both reac-
tions were rather sluggish, E-isomer 16 gave rise to the
inverted product 18 in 74% yield, whereas Z-isomer 17
only yielded 10% of the desired ester 19. Apart from
(13) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291-293.
(14) For review: (a) Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2037-2056. (b) Grubbs, R. H.; Chang, S. Tetra-
hedron 1998, 54, 4413-4450. (c) Fu¨rstner, A. Top. Organomet. Chem.
1998, 1, 37-72. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (e) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18-29.
(12) (a) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-
3020. (b) Dodge, J. A.; Jones, S. A. Rec. Res. Dev. Org. Chem. 1997, 1,
273-283.
7594 J. Org. Chem., Vol. 70, No. 19, 2005

Total Syntheses of the (-)-Salicylihalamides A and B
synthesized enantiomer ent-23,7e displayed identical
physical properties, except for its opposite optical rota-
tion. The conversion of ent-23 to ent-3 has already been
published by our group, and therefore the synthesis of
23 constitutes a formal total synthesis of the (-)-
salicylihalamides.7e
SCHEME 6a
Because the Mitsunobu inversion of Z-acryl nitrile 17
was low-yielding (Scheme 4), we decided to explore an
alternative route to convert 17 to saturated nitrile 20.
However, initial attempts to hydrogenate the cis-double
bond of 17 with hydrido(triphenylphosphine)-copper(I)
hexamer13 only resulted in intramolecular Michael ad-
dition leading to 24, which was isolated as a mixture of
diastereoisomers (Scheme 6). To prevent the Michael
addition, we protected the alcohol functionality in 17 to
form acetate 25 (Scheme 7). The subsequent hydrogena-
tion of 25 employing the above-described reaction condi-
tions now proceeded to 26 in very good yield (87%).
Cleavage of the acetate furnished alcohol 27, which was
then subjected to a Mitsunobu inversion with PNBA
providing the desired intermediate 20 in 48%.
a Reagents and conditions: (a) [CuHPPh3]6, PhH, rt, 5 min, 67%.
SCHEME 7a
Because the hydrogenation of 18 to 20 (Scheme 5) had
only proceeded in moderate yield, we decided to slightly
alter our synthetic route, in an effort to optimize the
overall yield of our synthetic sequence (Scheme 8). We
first subjected acryl nitrile 18 to an RCM reaction,
employing the first generation Grubbs catalyst, which
afforded macrocycle 28 in 92% yield and an excellent 24:1
E:Z ratio. After cleavage of the phenolic methyl ether and
removal of the Z-isomer, which led to 29 in 82% yield,
reduction of the exocyclic double bond in 29 with hydrido-
(triphenylphosphine)-copper(I) hexamer13 now proceeded
not only selectively but also at a significantly higher
reaction rate (2 vs 45 min for the formation of 20)
furnishing 22 in high yield (96%).
Because the observed E:Z selectivity in the reaction of
20 to 21 (Scheme 5) was higher (18:1) than in any other
hitherto published RCM reaction toward the synthesis
of the salicylihalamides, we decided to investigate the
stereochemical outcome of this particular RCM reaction
in more detail.
a Reagents and conditions: (a) Ac2O, DMAP, TEA, CH2Cl2, rt,
3 h, 97%; (b) [CuHPPh3]6, PhH, reflux, 45 min, 87%; (c) K2CO3,
MeOH, rt, 5 h, 89%; (d) PNBA, DEAD, PPh3, PhMe, -30 °C to rt,
1 day, 48%.
SCHEME 8a
To date, there has been no model described that can
reliably predict the stereochemical outcome of RCM
reactions. Thus, the optimization of the E:Z ratio con-
cerning the salicylihalamides was achieved empirically.6,7
In general, the presence of a protecting group at the
phenol functionality was found to be crucial to obtain
satisfactory amounts of the desired E-isomer. However,
the E:Z ratio in these reactions were dependent on the
substrate used in the RCM reaction.6,7 The first genera-
tion Grubbs catalyst was shown to be more effective in
producing a better E:Z ratio, as compared to the second
generation catalyst.7e
The results of our investigations are shown in Tables
1 and 2. We first probed the influence of the phenolic
protecting group on E:Z ratios (Table 1) with nitriles 20
and 30-32. All substrates carried a PNB protecting
group at the secondary alcohol function. The best result
was achieved with a methyl substituent favoring the
desired E-isomer with a 18:1 ratio (Table 1). Bulkier
protecting groups such as TBS or TBDPS as well as the
unprotected phenol resulted in inferior E:Z ratios in this
special case, as compared to other substrates in which
a Reagents and conditions: (a) Grubbs I catalyst, CH2Cl2, reflux,
3 h, 92% (E:Z 24:1); (b) BBr3, CH2Cl2, -78 to -30 °C, 30 min,
82%; (c) [CuHPPh3]6, PhH, reflux, 2 min, 96%.
able E:Z ratio of 18:1. Cleavage of the aromatic methyl
ether and separation from the undesired Z-isomer at this
stage provided 22 in high yield (85%). Subsequent
hydrolysis of the PNB group furnished the macrocyclic
core structure 23, which, in comparison with previously
J. Org. Chem, Vol. 70, No. 19, 2005 7595

Haack et al.
SCHEME 9a
TABLE 1. E and Z Ratios of PNB-Protected Nitriles 20
and 30-32 in RCM Reactions
a Reagents and conditions: (a) BaCO3, Br2, water, rt, 1 day, 99%;
(b) BzCl, pyridine, 0 °C to rt, 100%; (c) H2 (50 psi), 10% Pd/C, TEA,
EtOAc, rt, 1 day, 99%; (d) (i) NaOMe, MeOH, rt, 3 h; (ii)
1,4-dioxane, H2SO4, rt, 1 h, 87%.
substratea
R
product
yield (%)
E/Z ratiob
SCHEME 10a
30
20
31
32
H
38
21
39
40
41
89
94
75
1:3
18:1
7:1
Me
TBS
TBDPS
3:1
a Synthesis of substrates: 30 from 20, BBr3 (95%); 31 from 30,
TBSCl (82%); 32 from 30, TBDPSCl (88%). b Determined by
1
integration of the H NMR resonance of H8 and/or HPLC traces.
TABLE 2. E and Z Ratios of Me-Protected Nitriles 20
and 33-37 in RCM Reactions
a Reagents and conditions: (a) 13, EDCI, DMAP, CH2Cl2, rt,
14 h, 90%; (b) (i) DIBAL-H, PhMe, -78 °C, 15 min; (ii) HCl,
dioxane, MeOH, rt, 8 h, 74%.
substratea
R
product
yield (%)
E/Z ratiob
SCHEME 11a
33
34
35
36
20
37
H
41
42
43
44
21
45
44
87
84
94
89
94
29:1
26:1
23:1
22:1
18:1
16:1
Ac
MOM
Piv
PNB
TBS
a Synthesis of substrates: 33 from 20, K2CO3 (94%); 34 from
33, Ac2O (97%); 35 from 33, MOMCl (87%); 36 from 33, PivCl
(89%); 37 from 33, TBSOTf (83%). b Determined by integration of
the 1H NMR resonance of H8 and/or HPLC traces.
sterically demanding silyl protecting groups provided the
best E:Z ratios.7a,e
Having identified the methyl substituent as the best
protecting group at the phenolic moiety to achieve an
optimized E:Z ratio in our system, we investigated the
influence of different protecting groups at the C13
secondary alcohol employing substrates 20 and 33-37
(Table 2). Overall, we found that these groups had only
a minor effect on the E:Z ratios; however, all groups
resulted in outstandingly high E:Z ratios (Table 2),
including the reaction with the unprotected substrate 33.
Although this synthetic route already represented a
convenient and efficient formal chiral pool synthesis of
the (-)-salicylihalamides (12 steps from 7 to 23, 17%
overall yield), we sought to develop an even shorter
pathway starting from commercially available L-rham-
nose, using building block 8 (Schemes 1 and 9), which
was prepared in four steps by slight modifications of
known procedures (Scheme 9).9
a Reagents and conditions: (a) Tf2O, pyridine, 0 °C, 15 min; (b)
(allyl)2Cu(CN)Li2, -90 °C, 30% (two steps); (c) BCl3, CH2Cl2, -78
°C, 30 min, 48-72%.
lectivity (Scheme 10). Due to the lower steric restriction
of the constrained endocyclic alcohol as compared to the
more flexible exocyclic hydroxyl group, we were able to
achieve the esterification with 13 selectively at the C15
hydroxyl group of 8 to form 46 exclusively. Reduction of
the lactone moiety in 46 with DIBAL-H followed by
protection of the anomeric hydroxyl groups gave rise to
the methyl acetals 47 as a mixture of anomers.
Introduction of the allyl substituent at C12 was ac-
complished by activating the secondary hydroxyl group
as its triflate 48, followed by reaction with a higher order
allylcuprate (Scheme 11). This reaction did not proceed
as smoothly as the related allylation reaction of 9 to 10
(Scheme 3). As a side reaction, even at low temperature,
we observed that triflate displacement competed with
In contrast to the previously utilized alcohol 7, rham-
nose-derived diol 8 possesses the correct absolute config-
uration at C13 and C15, whereas an inversion at C12 is
required. The synthesis started with esterification of diol
8 with the aromatic building block 13, using EDCI as the
coupling reagent, and proceeded with excellent regiose-
7596 J. Org. Chem., Vol. 70, No. 19, 2005

Total Syntheses of the (-)-Salicylihalamides A and B
SCHEME 12a
groups. In all cases, we observed high E:Z ratios.
Furthermore, we demonstrated that the substituent at
the phenolic functionality had a significant impact on the
E:Z ratio. The methyl substituent provided the best E:Z
proportion in this specific case. Protecting groups at the
secondary alcohol function, however, had no significant
influence on E:Z ratios.
Experimental Section
General Methods. Tetrahydrofuran was dried by distilla-
tion from sodium/benzophenone. Methylene chloride was dried
by distillation from calcium hydride. All reactions involving
dry solvents were carried out under an argon atmosphere.
Extractive workups were carried out using the solvents
mentioned in the procedures and water (three extractions). The
combined organic layers were dried over magnesium sulfate,
filtered, and the filtrate was concentrated under reduced
pressure. Column chromatography was performed on silica gel
(0.040-0.063 mm, 230-400 mesh ASTM) with the solvent
systems indicated in the procedures.
7-((1S)-1-Bromoethyl)(1R,5R,7S)-3,3-dimethyl-2,4,6-
trioxabicyclo[3.3.0]octane (9). Carbon tetrabromide (1.96
g, 5.91 mmol) was added in portions to an ice-cooled solution
of 7 (371 mg, 1.97 mmol) and triphenylphosphine (1.65 g, 6.30
mmol) in THF (20 mL). The resulting yellow solution was
stirred for 1 h at 0 °C, for an additional 6 h at rt, and then
quenched with methanol (5 mL). The mixture was carefully
concentrated under reduced pressure and immediately loaded
onto a silica gel column. Column chromatography (EtOAc:
hexanes 1:4) afforded 444 mg (90%) of bromide 9 as a colorless
solid: mp 42-43 °C; 1H NMR (400 MHz, CDCl3) δ 5.85 (d,
1H, J ) 3.7 Hz), 4.76 (t, 1H, J ) 4.3 Hz), 4.27 (dt, 1H, J )
10.4, 4.7 Hz), 4.12 (dq, 1H, J ) 6.9, 5.0 Hz), 2.16 (dd, 1H, J )
13.4 Hz, 4.6 Hz), 1.77 (ddd, 1H, J ) 13.4, 10.4, 4.9 Hz), 1.71
(d, 3H, J ) 6.9 Hz), 1.52 (s, 3H), 1.32 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 111.4, 105.6, 81.2, 80.4, 49.9, 36.4, 26.8, 26.2,
22.0. The data are in accordance with reported values.10
7-((1S)-1-Methylbut-3-enyl)(1R,5R,7S)-3,3-dimethyl-2,4,6-
trioxabicyclo[3.3.0]octane (10). To a suspension of thor-
oughly dried copper(I) cyanide (4.0 g, 44.7 mmol) in dry THF
(30 mL) was added dropwise a solution of MeLi (59 mL, 1.5 M
in Et2O, 88.5 mmol) at -78 °C. The resulting greenish solution
was gradually warmed to 0 °C followed by the addition of neat
allyltributyltin (27 mL, 87 mmol). After being stirred for 30
min at 0 °C, the solution was again cooled to -78 °C. To this
reaction mixture was added a solution of 9 (3.68 g, 14.7 mmol)
in THF (30 mL) dropwise. The resulting mixture was stirred
at -78 °C for 1 h, and then carefully quenched by the addition
of a concentrated ammonium hydroxide solution, saturated
with NH4Cl, slowly warmed to rt, and stirred for an additional
3 h. Extractive workup followed by column chromatography
(EtOAc:hexanes 1:9) gave 2.57 g (83%) of 10 as a colorless and
a Reagents and conditions: (a) PPh3dCHCN, PhMe, 80 °C, 1
h, 98% (E:Z ) 23:2); (b) [CuHPPh3]6, PhH, 0 °C to rt, 15 min,
80%; (c) TBSOTf, pyridine, CH2Cl2, 0 °C to rt, 5 h, 91%; (d)
(PCy3)2Cl2RudCHPh, CH2Cl2, reflux, 12 h, 81% (E isomer) and
17% (Z isomer); (e) TBSOTf, pyridine, CH2Cl2, rt, 4 h, 97%.
ester cleavage. Nevertheless, the desired allylated prod-
uct 49 was obtained in 30% yield over two steps from
47. Cleavage of both methyl ethers in 49 provided lactol
50 in 48-72% yield as a mixture of anomers.
The remaining synthetic steps (Scheme 12) were
performed in analogy to our previous synthesis from
D-glucose. Wittig two carbon elongation of 50 with
triphenylphosphoranylidene acetonitrile (6) rendered
acryl nitrile 51 as a mixture of E:Z isomers. Selective
hydrogenation with hydrido(triphenylphosphine)-copper-
(I) hexamer13 afforded compound 52, which was protected
with a TBS group at both hydroxyl functionalities,
affording 53. Ring-closing metathesis with the first
generation Grubbs catalyst gave rise to macrocycle 54
in 98% yield (E and Z together, 81% of E-isomer was
isolated) and a 4.7:1 E:Z ratio (separable isomers).
Because this reaction yielded only slightly more of the
undesired Z-isomer in comparison to the reaction of 20
to 21, we refrained from exploring additional protecting
groups to improve the E:Z ratio.
volatile oil: [R]20 -14 (c 1.6 CHCl3); IR (neat) 3076, 2980,
D
1641, 1372, 1214, 1165, 1073, 1023 cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.78 (d, 1H, J ) 3.8 Hz), 5.79-5.71 (m, 1H), 5.05-
4.99 (m, 2H), 4.70 (t, 1H, J ) 4.3 Hz), 4.01 (ddd, 1H, J ) 10.9,
6.7, 4.2 Hz), 2.19 (ddt, 1H, J ) 13.7, 4.7, 1.5 Hz), 2.04 (dd, 1H,
J ) 13.3, 4.2 Hz), 1.85 (ddt, 1H, J ) 13.8, 7.9, 0.9 Hz), 1.73-
1.64 (m, 1H), 1.54 (ddd, 1H, J ) 13.3, 10.9, 4.8 Hz), 1.50 (s,
3H), 1.30 (s, 3H), 0.96 (d, 3H, J ) 6.7 Hz); 13C NMR (100 MHz,
CDCl3) δ 136.7, 116.2, 110.7, 105.1, 81.7, 80.4, 37.3, 36.6, 36.3,
26.6, 26.1, 15.9; HRMS m/z calcd for C12H24NO3 (M + NH4)
230.1756, found 230.1761.
5-((1S)-1-Methylbut-3-enyl)(3R,5S)oxolane-2,3-diol (11).
A solution of 10 (2.57 g, 12.1 mmol) in 70% aqueous acetic
acid was stirred at 70 °C for 3 h. The reaction mixture was
concentrated in vacuo and subsequently extracted with chlo-
roform. The organic layer was concentrated, and the residue
was treated with K2CO3 (6.91 g, 50 mmol) in MeOH (100 mL).
Evaporation of the solvent and subsequent column chroma-
tography (EtOAc) gave rise to 1.77 g (85%) of 11 as a colorless
To verify the correct structural assignment of 54, the
hydroxyl groups in 23 (from Scheme 5) were protected
as TBS ethers, also leading to core structure 54 (Scheme
12). This compound prepared via the two herein pre-
sented separate synthetic sequences exhibited identical
physical properties. The synthesis of 54 constitutes a
formal total synthesis of the (-)-salicylihalamides.7e
In summary, we have achieved two efficient formal
chiral pool syntheses of the salicylihalamides A and B.
In the first approach, the synthesis of macrocycle 23 from
known alcohol 7 was completed in 12 steps and 17%
overall yield. The second approach allowed the synthesis
of 54 from known diol 8 in nine steps and 6% overall
yield. In addition, we investigated the stereochemical
outcome of the ring-closing metathesis with our specific,
nitrile-containing substrates, using various protecting
J. Org. Chem, Vol. 70, No. 19, 2005 7597

Haack et al.
solid (approximately 1:1 mixture of anomers): [R]20 +18 (c
1-((1E)-2-Cyanovinyl)(1R,3S,4S)-3-hydroxy-4-methyl-
hept-6-enyl 6-Methoxy-2-prop-2-enylbenzoate (16) and
1-((1Z)-2-Cyanovinyl)(1R,3S,4S)-3-hydroxy-4-methylhept-
6-enyl 6-Methoxy-2-prop-2-enylbenzoate (17). A mixture
of 15 (352 mg, 1.02 mmol) and (triphenylphosphoranylidene)-
acetonitrile (8, 398 mg, 1.32 mmol) in toluene (10 mL) was
stirred at 80 °C for 2 h. After being cooled, the mixture was
directly loaded on a silica gel column. Column chromatography
(EtOAc:hexanes 1:4) afforded 283 mg (75%) of the trans-isomer
16 (faster moving) and 77 mg (21%) of the cis-isomer 17 (slower
moving), each of them as a pale yellow oil.
D
1.2, CHCl3, 24 h); IR (KBr) 3377, 2929, 1703, 1641, 1035, 913
1
cm-1; H NMR (400 MHz, CDCl3, two anomers) δ 5.80-5.69
(m, 1H), 5.31 (s, 0.5H), 5.24 (s, 0.5H), 5.04-4.98 (m, 2H), 4.84
(s, br, 0.5H), 4.26 (s, br, 0.5H), 4.19-4.08 (m, 2H), 3.37 (d, br,
0.5H, J ) 4.7 Hz), 3.31 (s, br, 0.5 H), 2.21-2.12 (m, 1H), 1.98-
1.78 (m, 3H), 1.68-1.53 (m, 2H), 0.96 (d, 1.5H, J ) 6.6 Hz),
0.89 (d, 1.5H, J ) 6.7 Hz); 13C NMR (100 MHz, CDCl3, two
anomers) δ 136.6, 136.5, 116.2, 116.2, 102.2, 96.7, 83.9, 80.6,
76.4, 71.7, 38.7, 37.5, 37.3, 37.0, 35.6, 35.1, 15.9, 15.0; HRMS
(EI) m/z calcd for C9H16O3Li (M + Li) 179.1259, found
179.1254.
Compound 16: [R]20 -25 (c 1.5, CHCl3); IR (neat) 3520,
D
3074, 2970, 2929, 2841, 2227, 1732, 1639, 1585, 1471, 1439,
1269, 1109, 1070, 995, 915, 798, 757, 733 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.31 (t, 1H, J ) 8.0 Hz), 6.84 (d, 1H, J ) 7.7
Hz), 6.80 (d, 1H, J ) 7.8 Hz), 6.76 (d, 1H, J ) 4.9 Hz), 5.93-
5.80 (m, 1H), 5.77-5.71 (m, 3H), 5.09-4.98 (m, 4H), 3.81 (s,
3H), 3.71 (d, 1H, J ) 9.1 Hz), 3.35 (d, 2H, J ) 5.3 Hz), 2.38 (s,
br, 1H), 2.25-2.18 (m, 1H), 2.00-1.90 (m, 2H), 1.86-1.78 (m,
1H), 1.65-1.53 (m, 1H), 0.90 (d, 3H, J ) 6.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 166.7, 156.2, 151.5, 138.6, 136.8, 136.0,
130.9, 122.3, 122.0, 116.6, 116.4, 116.2, 109.0, 100.5, 72.2, 70.9,
55.7, 38.5, 38.2, 37.5, 37.1, 13.2; HRMS (FAB+) m/z calcd for
C22H28NO4 (M + H) 370.2018, found 370.1997.
Compound 17: [R]D -91 (c 1.2, CHCl3); IR (neat) 3543, 3076,
2966, 2929, 2224, 1732, 1639, 1585, 1471, 1438, 1269, 1243,
1110, 1068, 995, 916, 758 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.30 (t, 1H, J ) 8.0 Hz), 6.84 (d, 1H, J ) 7.7 Hz), 6.80 (d, 1H,
J ) 8.4 Hz), 6.48 (dd, 1H, J ) 11.1, 8.4 Hz), 5.95-5.74 (m,
3H), 5.50 (d, 1H, J ) 11.1 Hz), 5.07-4.99 (m, 4H), 3.82 (s,
3H), 3.84-3.80 (m, 1H), 3.41 (dd, 1H, J ) 15.6, 6.7 Hz), 3.32
(dd, 1H, J ) 15.3, 6.3 Hz), 2.48 (s, br, 1H), 2.28-2.24 (m, 1H),
2.05-1.94 (m, 2H), 1.89-1.83 (m, 1H), 1.68-1.65 (m, 1H), 0.92
(d, 3H, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 166.8, 156.4,
151.6, 139.0, 137.1, 136.1, 131.0, 122.3, 122.1, 116.4, 116.2,
114.7, 109.1, 100.7, 73.2, 71.4, 55.9, 38.5, 38.4, 37.7, 37.3, 13.3;
HRMS (FAB+) m/z calcd for C22H28NO4 (M + H) 370.2018,
found 370.2028.
5-((1S)-1-Methylbut-3-enyl)(3R,5S)-3-hydroxy-3,4,5-tri-
hydrofuran-2-one (12). A suspension of 11 (1.67 g, 9.70
mmol) and silver carbonate on Celite (25 g, 50 wt %, 45 mmol)
in benzene (100 mL) was refluxed for 1 h. The resulting
mixture was filtered through a pad of silica gel, and the filtrate
was concentrated in vacuo to give rise to 1.34 g (81%) of 12 as
a pale yellow oil after column chromatography (EtOAc:hexanes
2:3): [R]20 +102 (c 0.7, CHCl3); IR (neat) 3420, 2969, 2932,
D
1771, 1641, 1189, 1119, 995, 958, 918 cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.77-5.71 (m, 1H), 5.07 (d, 1H, J ) 15.7 Hz), 5.06
(d, 1H, J ) 11.5 Hz), 4.55 (dt, 1H, J ) 5.9, 6.9 Hz), 4.49 (t,
1H, J ) 7.4 Hz), 3.42 (s, br, 1H), 2.35-2.27 (m, 2H), 2.23-
2.16 (m, 1H), 1.98-1.91 (m, 1H), 1.79-1.72 (m, 1H), 0.96 (d,
3H, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 177.6, 135.4,
117.3, 82.1, 67.6, 37.6, 36.8, 33.4, 14.4; HRMS (EI) calcd for
C9H15O3 (M + H) 171.1021 found 171.1012.
5-((1S)-1-Methylbut-3-enyl)(3R,5S)-2-oxo-3-3,4,5-trihy-
drofuryl 6-Methoxy-2-prop-2-enylbenzoate (14). A solu-
tion of 12 (221 mg, 1.30 mmol), 2-allyl-6-methoxybenzoic acid
(13, 319 mg, 1.66 mmol), DCC (546 mg, 2.65 mmol), and DMAP
(156 mg, 1.28 mmol) in CH2Cl2 (2 mL) was stirred at rt for 24
h. A 1:9 mixture of EtOAc and hexanes (10 mL) was added,
and the resulting suspension was stirred for 5 min and then
loaded onto a silica gel column. Column chromatography
(EtOAc:hexanes 1:9) afforded 425 mg (95%) of 14 as a colorless
oil: [R]20D +40 (c 2.2, CHCl3); IR (neat) 3078, 2968, 2933, 2841,
2359, 2342, 2255, 1790, 1739, 1640, 1585, 1518, 1471, 1438,
1268, 1194, 1109, 1068, 996, 798, 733, 648 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.31 (t, 1H, J ) 8.0 Hz), 6.83 (d, 1H, J ) 7.6
Hz), 6.79 (d, 1H, J ) 8.3 Hz), 5.94-5.86 (m, 1H), 5.80-5.72
(m, 1H), 5.55 (dd, 1H, J ) 8.2, 6.0 Hz), 5.10-5.04 (m, 4H),
4.61-4.56 (m, 1H), 3.81 (s, 3H), 3.50-3.35 (m, 2H), 2.51-2.41
(m, 2H), 2.26-2.20 (m, 1H), 2.02-1.95 (m, 1H), 1.84-1.78 (m,
1H), 1.00 (d, 3H, J ) 6.7 Hz); 13C NMR (100 MHz, CDCl3) δ
172.2, 166.8, 156.7, 139.0, 136.1, 135.2, 131.1, 121.8, 121.7,
117.3, 116.4, 109.0, 81.8, 69.0, 55.9, 37.5, 37.3, 36.6, 32.0, 14.3;
HRMS (ES+) m/z calcd for C20H25O5 (M + H) 345.1702, found
345.1725.
(4E)-(1R,3R)-1-((1S)-1-Methylbut-3-enyl)-5-cyano-3-(6-
methoxy-2-prop-2-enylphenylcarbonyloxy)pent-4-enyl
4-Nitrobenzoate (18). To a solution of 16 (280 mg, 0.76 mmol)
and triphenylphosphine (755 mg, 2.88 mmol) in toluene (5 mL)
was added p-nitrobenzoic acid (487 mg, 2.91 mmol). The
resulting suspension was cooled to -30 °C. Diethyl azodicar-
boxylate (0.47 mL, 520 mg, 2.99 mmol) was added dropwise,
and the reaction mixture was allowed to reach rt overnight
and then stirred for an additional 24 h. The resulting solution
was directly loaded on a silica gel column. Column chroma-
tography (EtOAc:hexanes 1:9) afforded 290 mg (74%) of 18 as
a pale yellow oil: [R]20 +32 (c 0.90, CHCl3); IR (neat) 3075,
D
2972, 2226, 1726, 1640, 1585, 1527, 1471, 1348, 1274, 1103,
1069, 720 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 2H, J )
8.7 Hz), 8.11 (d, 2H, J ) 8.8 Hz), 7.27 (t, 1H, J ) 8.0 Hz), 6.81
(d, 1H, J ) 7.7 Hz), 6.73 (d, 1H, J ) 9.3 Hz), 6.73 (dd, 1H, J
) 15.1 Hz, 5.8 Hz), 5.94-5.70 (m, 4H), 5.32-5.29 (m, 1H),
5.08-5.00 (m, 4H), 3.80 (s, 3H), 3.35 (d, 2H, J ) 5.9 Hz), 2.23-
1.95 (m, 5H), 0.97 (d, 3H, J ) 6.7 Hz); 13C NMR (100 MHz,
CDCl3) δ 166.7, 163.9, 156.3, 150.7, 150.3, 138.7, 136.2, 135.6,
135.3, 130.8, 130.5, 123.4, 122.2, 121.8, 116.9, 116.5, 116.4,
108.7, 101.4, 74.4, 69.9, 55.6, 37.1, 36.8, 36.3, 34.1, 14.5; HRMS
(FAB+) m/z calcd for C29H34N3O7 (M + NH4) 536.2397, found
536.2391.
5-((1S)-1-Methylbut-3-enyl)(2R&2S,3R,5S)-2-hydroxy-
oxolan-3-yl 6-Methoxy-2-prop-2-enylbenzoate (15). To a
solution of 14 (2.20 g, 6.39 mmol) in diethyl ether (30 mL) was
added a solution of DIBAL-H (10 mL, 1.0 M in hexanes, 10
mmol) dropwise at -78 °C. The reaction mixture was stirred
at this temperature for 30 min, quenched at -78 °C with sat.
Rochelle’s solution, and warmed to rt. Extractive workup with
ether followed by column chromatography (EtOAc:hexanes 1:4)
gave 2.07 g (93%) of 15 as a colorless oil (approximately 1:5
mixture of anomers): [R]20D +5.9 (c 1.1, CHCl3, 24 h); IR (neat)
3420, 3076, 2929, 1732, 1639, 1585, 1471, 1438, 1268, 1116,
1
1072, 1005, 915, 755 cm-1; H NMR (400 MHz, CDCl3, major
anomer) δ 7.29 (t, 1H, J ) 8.1 Hz), 6.82 (d, 1H, J ) 7.6 Hz),
6.78 (d, 1H, J ) 8.4 Hz), 5.95-5.85 (m, 1H), 5.80-5.72 (m,
1H), 5.46 (d, 1H, J ) 3 Hz), 5.32 (s, br, 1H), 5.06-5.00 (m,
4H), 4.15-4.07 (m, 1H), 3.80 (s, 3H), 3.36 (d, 2H, J ) 6.4 Hz),
3.03 (s, br, 1H), 2.24-2.08 (m, 3H), 1.90-1.82 (m, 1H), 1.72-
1.63 (m, 1H), 0.99 (d, 3H, J ) 6.6 Hz); 13C NMR (100 MHz,
CDCl3, major anomer) δ 167.4, 156.6, 138.4, 136.5, 136.2,
130.7, 122.3, 121.7, 116.3, 116.2, 109.0, 100.1, 84.1, 79.6, 55.8,
38.4, 37.6, 37.4, 32.6, 15.8; HRMS (ES+) calcd for C20H27O5
(M + H) 329.1753 found 329.1739.
(4Z)-(1R,3R)-1-((1S)-1-Methylbut-3-enyl)-5-cyano-3-(6-
methoxy-2-prop-2-enylphenylcarbonyloxy)pent-4-enyl
4-Nitrobenzoate (19). To a solution of 17 (74 mg, 0.200 mmol)
and triphenylphosphine (210 mg, 0.80 mmol) in toluene (2 mL)
was added p-nitrobenzoic acid (134 mg, 0.80 mmol). The
resulting suspension was cooled to -30 °C. Diethyl azodicar-
boxylate (0.126 mL, 139 mg, 0.80 mmol) was added dropwise,
and the reaction mixture was allowed to reach rt within 5 h
and was then stirred for an additional 24 h. The resulting
solution was directly loaded on a silica gel column. Column
7598 J. Org. Chem., Vol. 70, No. 19, 2005

Total Syntheses of the (-)-Salicylihalamides A and B
chromatography (EtOAc:hexanes 1:9) afforded 10 mg (10%) of
18 as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.23-
8.18 (m, 4H), 7.26 (t, 1H, J ) 8.0 Hz), 6.78 (d, 1H, J ) 7.7
Hz), 6.71 (d, 1H, J ) 8.3 Hz), 6.59 (dd, 1H, J ) 11.2 Hz, 7.7
Hz), 5.92-5.75 (m, 3H), 5.53 (dd, 1H, J ) 11.2, 1.2 Hz), 5.34-
5.29 (m, 1H), 5.06-4.98 (m, 4H), 3.80 (s, 3H), 3.31 (d, 2H, J )
6.5 Hz), 2.23-2.10 (m, 5H), 0.98 (d, 3H, J ) 6.7 Hz).
2.75 (m, 1H), 2.69-2.60 (m, 1H), 2.40-2.27 (m, 2H), 2.11-
1.84 (m, 5H), 0.91 (d, 3H, J ) 6.5 Hz); 13C NMR (100 MHz,
acetone-d6) δ 168.9, 164.7, 156.2, 151.5, 140.5, 137.0, 131.6,
131.5, 130.8, 130.7, 124.4, 122.6, 122.4, 120.3, 115.2, 78.0, 72.8,
38.3, 38.2, 34.5, 34.2, 32.4, 13.9, 13.6; HRMS (FAB+) m/z calcd
for C26H30N3O7 (M + NH4) 496.2084 found 496.2109.
(8E)-3-((3S,5R,6S)-5,14-Dihydroxy-6-methyl-1-oxo-
2,3,4,5,6,7,10-heptahydrobenzo[d][12]-annulen-3-yl)pro-
panenitrile (23). A mixture of 22 (31 mg, 65 µmol) and
potassium carbonate (72 mg, 0.52 mmol) in methanol (4 mL)
was stirred at rt for 5 h. The suspension was neutralized with
2 N HCl. Extractive workup with ethyl acetate and column
chromatography (acetone:hexanes 2:3) gave rise to 20 mg (95%)
of the desired product 23 as a colorless solid: mp 198-200 °C
1-[(2S)-4-Cyano-2-(6-methoxy-2-prop-2-enylphenyl-
carbonyloxy)butyl](1R,2S)-2-methylpent-4-enyl 4-Nitro-
benzoate (20 from 18). To a refluxing solution of 18 (303
mg, 0.58 mmol) in benzene (10 mL) were added water (0.3 mL,
17 mmol) and hydrido(triphenylphosphine)copper(I) hexamer
(371 mg, 0.19 mmol). Refluxing was continued for 45 min. The
mixture was filtered through a pad of silica gel, and the
resulting solution was concentrated under reduced pressure.
Column chromatography (EtOAc:hexanes 1:4) gave rise to 43
mg (14%) of starting material 18 and 137 mg (45%) of product
(MeOH, dec); [R]20 -30 (c 1.1, MeOH); IR (KBr) 3440-3185,
D
2247, 2247, 1701, 1680, 1469, 1294, 1047, 778 cm-1; 1H NMR
(400 MHz, acetone-d6) δ 9.21 (s, br, 1H), 7.13 (t, 1H, J ) 7.8
Hz), 6.81 (d, 1H, J ) 8.1 Hz), 6.68 (d, 1H, J ) 7.4 Hz), 5.36-
5.21 (m, 3H), 4.13-4.10 (m, 1H), 3.67-3.65 (m, 1H), 3.53 (dd,
1H, J ) 16.0, 8.3 Hz), 3.31 (d, 1H, J ) 16.2 Hz), 2.73-2.65
(m, 2H), 2.24-2.21 (m, 1H), 2.00-1.66 (m, 5H), 1.32-1.25 (m,
1H), 0.81 (d, 3H, J ) 6.7 Hz); 13C NMR (100 MHz, acetone-d6)
δ 168.9, 155.9, 140.4, 131.8, 131.1, 129.6, 123.0, 122.5, 120.4,
115.0, 73.7, 70.8, 38.5, 38.3, 38.1, 37.5, 32.9, 13.6, 13.4; HRMS
(FAB+) m/z calcd for C19H24NO4 (M + H) 330.1705, found
330.1701.
20 as a pale yellow oil: [R]20 +35 (c 1.3, CHCl3); IR (neat)
D
3077, 2971, 2247, 1724, 1637, 1585, 1527, 1471, 1439, 1349,
1
1274, 1104, 1069, 917, 720 cm-1; H NMR (400 MHz, CDCl3)
δ 8.24 (d, 2H, J ) 8.6 Hz), 8.16 (d, 2H, J ) 8.5 Hz), 7.29 (t,
1H, J ) 8.0 Hz), 6.83 (d, 1H, J ) 7.7 Hz), 6.76 (d, 1H, J ) 8.4
Hz), 5.99-5.89 (m, 1H), 5.81-5.71 (m, 1H), 5.34-5.26 (m, 2H),
5.09-5.00 (m, 4H), 3.82 (s, 3H), 3.38 (d, 2H, J ) 6.2 Hz), 2.64-
2.51 (m, 2H), 2.24-2.19 (m, 1H), 2.14-2.02 (m, 5H), 1.98-
1.94 (m, 1H), 0.97 (d, 3H, J ) 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 167.5, 164.1, 156.3, 150.4, 138.5, 136.4, 135.9, 135.6,
130.7, 130.6, 123.5, 122.9, 121.9, 119.2, 116.8, 116.4, 108.8,
75.0, 69.7, 55.7, 37.1, 36.9, 36.3, 34.3, 30.6, 14.6, 13.1; HRMS
(FAB+) m/z calcd for C29H36N3O7 (M + NH4) 538.2553, found
538.2559.
5-((1S)-1-Methylbut-3-enyl)(2R&2S,3S,5S)-2-(cyano-
methyl)oxolan-3-yl 2-Methoxy-6-prop-2-enylbenzoate (24).
To a solution of 17 (30 mg, 0.080 mmol) in benzene (1 mL)
was added hydrido(triphenylphosphine)copper(I) hexamer (130
mg, 0.067 mmol), and the mixture was stirred at rt for 30 min.
The mixture was filtered through a pad of silica gel, washed
several times with benzene, and the filtrate was concentrated
under reduced pressure. Column chromatography (EtOAc:
hexanes 1:9) gave 20 mg (67%) of 24 as a mixture of diastereo-
(8E&8Z)-(3S,5R,6S)-3-(2-Cyanoethyl)-14-methoxy-6-
methyl-1-oxo-2,3,4,5,6,7,10-heptahydrobenzo[f][12]-
annulen-5-yl 4-Nitrobenzoate (21). A solution of 20 (52 mg,
100 µmol) and bis(tricyclohexylphosphine)benzylidene ruthe-
nium(IV) dichloride (Grubbs I catalyst, 20 mg, 24 µmol) in
degassed CH2Cl2 (30 mL) was refluxed for 3 h. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography (EtOAc:hexanes 1:4) to
give 44 mg (89%) of 21 as a pale yellow oil (inseparable 18:1
1
mers (approximately 1:1). H NMR (400 MHz, CDCl3) δ 7.31
(t, 1H, J ) 8.0 Hz), 6.84 (d, 1H, J ) 7.7 Hz), 6.81 (d, 1H, J )
8.4 Hz), 5.95-5.87 (m, 1H), 5.80-5.74 (m, 1H), 5.22-5.20 (m,
1H), 5.09-4.99 (m, 4H), 4.18-4.15 (m, 1H), 3.95-3.93 (m, 1H),
3.82 (s, 3H), 3.37-3.35 (d, 2H, J ) 6.4 Hz), 2.85 (t, 2H, J )
4.5 Hz), 2.28-2.20 (m, 1H), 2.15 (ddd, 1H, J ) 13.8 Hz, 5.1
Hz, 1.3 Hz), 2.10-2.05 (m, 1H), 1.96-1.85 (m, 1H), 1.81-1.73
(m, 1H), 1.00 (d, 3H, J ) 6.7 Hz).
mixture of E/Z-isomers): [R]20 -40 (c 1.5, CHCl3); IR (neat)
D
2962, 2247, 1725, 1598, 1583, 1526, 1468, 1439, 1349, 1272,
1116, 971, 756, 721 cm-1. E-isomer: 1H NMR (400 MHz,
CDCl3) δ 8.30 (d, 2H, J ) 8.9 Hz), 8.22 (d, 2H, J ) 8.9 Hz),
7.28 (t, 1H, J ) 8.1 Hz), 6.83 (d, 1H, J ) 9.1 Hz), 6.81 (d, 1H,
J ) 8.3 Hz), 5.73 (dd, 1H, J ) 9.2, 3.2 Hz), 5.68-5.65 (m, 1H),
5.42 (ddd, 1H, J ) 15.1, 9.3, 2.2 Hz), 5.21 (ddd, 1H, J ) 11.0,
8.6, 3.7 Hz), 3.80 (s, 3H), 3.37 (d, 1H, J ) 16.1 Hz), 2.76-2.69
(m, 1H), 2.54-2.46 (m, 1H), 2.42-2.30 (m, 3H), 2.12-1.99 (m,
3H), 1.89-1.77 (m, 2H), 0.93 (d, 3H, J ) 6.6 Hz); 13C NMR
(100 MHz, CDCl3) δ 167.7, 164.0, 156.3, 150.4, 139.2, 135.9,
130.7, 130.6, 130.4, 129.2, 123.6, 123.5, 123.0, 119.2, 109.4,
77.0, 71.7, 55.6, 37.6, 37.5, 34.2, 33.4, 31.8, 13.6, 13.1; HRMS
(FAB+) m/z calcd for C27H32N3O7 (M + NH4), 510.2240 found
510.2268.
1-((1S)-1-Methylbut-3-enyl)(1S,3R)(4Z)-5-cyano-3-(6-
methoxy-2-prop-2-enylphenylcarbonyloxy)pent-4-enyl
Acetate (25). A solution of 17 (523 mg, 1.42 mmol), triethyl-
amine (0.3 mL, 218 mg, 2.15 mmol), acetic anhydride (0.2 mL,
216 mg, 2.12 mmol), and a catalytic amount of DMAP in CH2-
Cl2 (5 mL) was stirred at rt for 3 h. The reaction mixture was
quenched by addition of methanol (1 mL). Evaporation under
reduced pressure and column chromatography (EtOAc:hexanes
1:4) gave 565 mg (97%) of 25 as colorless oil: [R]20 -49 (c
D
0.90, CHCl3); IR (neat) 3076, 2973, 2936, 2842, 2360, 2342,
2223, 1732, 1640, 1585, 1471, 1438, 1372, 1268, 1238, 1107,
1067, 916, 758 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.30 (t, 1H,
J ) 8.0 Hz), 6.81 (d, 1H, J ) 8.4 Hz), 6.79 (d, 1H, J ) 8.4 Hz),
6.43 (dd, 1H, J ) 11.1, 8.5 Hz), 5.83-5.93 (m, 2H), 5.78-5.69
(m, 1H), 5.54 (d, 1H, J ) 11.2 Hz), 5.07-4.94 (m, 5H), 3.82 (s,
3H), 3.35 (d, 2H, J ) 6.5 Hz), 2.28-2.20 (m, 2H), 2.07 (s, 3H),
2.02-1.97 (m, 1H), 1.91-1.84 (m, 2H), 0.94 (d, 3H, J ) 6.5);
13C NMR (100 MHz, CDCl3) δ 170.5, 166.8, 156.6, 150.3, 138.6,
136.3, 136.1, 130.8, 122.5, 121.7, 116.5, 114.5, 109.0, 102.2,
77.2, 72.6, 70.6, 55.8, 37.4, 37.0, 35.9, 34.6, 21.2, 14.0; HRMS
(FAB+) m/z calcd for C24H30NO5 (M + H) 412.2124, found
412.2103.
(8E)-(3S,5R,6S)-3-(2-Cyanoethyl)-14-hydroxy-6-methyl-
1-oxo-2,3,4,5,6,7,10-heptahydro-benzo[f][12]annulen-5-
yl 4-Nitrobenzoate (22). To a solution of 21 (49 mg, 99 µmol)
in CH2Cl2 (4 mL) was added boron tribromide (0.2 mL, 1 M in
CH2Cl2, 0.20 mmol) at -78 °C, and the resulting mixture was
stirred at -78 °C for 30 min. The reaction mixture was
quenched at -78 °C with sat. K2CO3 solution. Extractive
workup with ether and column chromatography (acetone:
hexanes 3:7) afforded 40 mg (85%) of product 22 as a colorless
solid: mp 97-100 °C; [R]20D -38 (c 1.7, MeOH); IR (neat) 3349,
2969, 2931, 2249, 1724, 1607, 1589, 1527, 1465, 1349, 1288,
1-[(2S)-4-Cyano-2-(6-methoxy-2-prop-2-enylphenyl-
carbonyloxy)butyl](1S,2S)-2-methylpent-4-enyl Acetate
(26). To a refluxing solution of 25 (555 mg, 1.35 mmol) in
benzene (15 mL) containing a drop of water was added
hydrido(triphenylphosphine)copper(I) hexamer (1.5 g, 0.76
mmol), and the solution was refluxed for an additional 45 min.
The mixture was filtered through a pad of silica gel, and the
1
1118, 1063, 970, 721 cm-1; H NMR (400 MHz, acetone-d6) δ
9.28 (br s, 1H), 8.31 (d, 2H, J ) 8.9 Hz), 8.28 (d, 2H, J ) 8.8
Hz), 7.16 (t, 1H, J ) 7.9 Hz), 6.83 (d, 1H, J ) 8.1 Hz), 6.72 (d,
1H, J ) 7.4 Hz), 5.64 (dd, 1H, J ) 8.9, 2.4 Hz), 5.57-5.51 (m,
1H), 5.43-5.37 (m, 1H), 5.23 (dd, 1H, J ) 14.4, 7.2 Hz), 3.64
(dd, 1H, J ) 16.2, 8.5 Hz), 3.39 (d, 1H, J ) 16.3 Hz), 2.81-
J. Org. Chem, Vol. 70, No. 19, 2005 7599

Haack et al.
resulting solution was concentrated under reduced pressure.
Column chromatography (EtOAc:hexanes 3:7) afforded 488 mg
prop-2-enenitrile (29). A solution of 28 (48 mg, 98 µmol) in
CH2Cl2 (6 mL) was charged at -78 °C with boron tribromide
(0.3 mL, 1 M in CH2Cl2, 0.30 mmol). The resulting mixture
was allowed to reach -30 °C and was stirred at this tempera-
ture for 30 min. The yellow mixture was recooled to -78 °C
and quenched with 0.3 M Na2HPO4 solution (30 mL). Extrac-
tive workup with ethyl acetate followed by column chroma-
tography (acetone:hexanes 3:7) afforded 38 mg (82%) of product
(87%) of 26 as a colorless oil: [R]20 -19 (c 1.3, CHCl3); IR
D
(neat) 3077, 2972, 2936, 2841, 2247, 1731, 1640, 1585, 1471,
1439, 1371, 1264, 1241, 1113, 916, 756 cm-1 1H NMR (400
;
MHz, CDCl3) δ 7.30 (t, 1H, J ) 8.0 Hz), 6.84 (d, 1H, J ) 7.6
Hz), 6.80 (d, 1H, J ) 8.3 Hz), 5.97-5.89 (m, 1H), 5.80-5.69
(m, 1H), 5.16-4.99 (m, 6H), 3.82 (s, 3H), 3.37 (d, 2H, J ) 6.4
Hz), 2.60-2.42 (m, 2H), 2.20-2.11 (m, 3H), 2.09 (s, 3H), 1.95-
1.75 (m, 4H), 0.93 (d, 3H, J ) 6.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 170.8, 167.4, 156.3, 138.3, 136.1, 136.1, 130.6, 123.0,
121.8, 119.1, 116.6, 116.5, 108.8, 72.6, 70.5, 55.7, 37.4, 37.2,
36.3, 35.7, 29.5, 21.0, 13.9, 13.1; HRMS (FAB+) m/z calcd for
C24H32NO5 (M + H) 414.2280, found 414.2287.
29 as a colorless solid: mp 100-103 °C; [R]20 +8.9 (c 1.1,
D
MeOH); IR (neat) 3339, 2969, 2929, 2227, 1724, 1527, 1349,
1
1281, 1105, 720 cm-1; H NMR (400 MHz, acetone-d6) δ 9.32
(s, 1H), 8.26-8.30 (m, 4H), 7.21 (t, 1H, J ) 7.9 Hz), 6.96 (dd,
1H, J ) 16.1, 3.3 Hz), 6.86 (d, 1H, J ) 8.2 Hz), 6.76 (d, 1H, J
) 7.5 Hz), 6.07 (dd, 1H, J ) 16.2, 2.2 Hz), 5.90 (d, 1H, J ) 8.2
Hz), 5.61-5.52 (m, 2H), 5.38 (dd, 1H, J ) 14.9, 8.2 Hz), 3.65
(dd, 1H, J ) 16.0 Hz, J ) 8.6 Hz), 3.38 (dd, 1H, J ) 16.0, J )
2.4 Hz), 2.40-2.24 (m, 2H), 2.20 (dd, 1H, J ) 15.8, 8.9 Hz),
2.02-1.99 (m, 1H), 1.90 (dt, 1H, J ) 13.4, 10.4 Hz), 0.95 (d,
3H, J ) 6.6 Hz); 13C NMR (100 MHz, acetone-d6) δ 168.2,
164.8, 156.4, 153.4, 151.5, 140.8, 136.9, 131.9, 131.7, 131.0,
130.8, 124.4, 122.6, 121.9, 117.7, 115.4, 100.5, 77.6, 71.9, 38.1,
38.0, 34.6, 34.4, 14.5; HRMS (FAB+) m/z calcd for C26H28N3O7
(M + NH4) 494.1927, found 494.1916.
(1S,3S,4S)-1-(2-Cyanoethyl)-3-hydroxy-4-methylhept-
6-enyl 6-Methoxy-2-prop-2-enylbenzoate (27). A mixture
of 26 (480 mg, 1.61 mmol) and potassium carbonate (321 mg,
2.32 mmol) in methanol (10 mL) was stirred at rt for 5 h. The
suspension was neutralized with acetic acid (0.22 mL) and
concentrated under reduced pressure. Column chromatogra-
phy (EtOAc:hexanes 3:7) yielded 385 mg (89%) of the desired
alcohol 27 as a colorless oil: [R]20D -21 (c 1.2, CHCl3); IR (neat)
3508, 3076, 2967, 2841, 2248, 1731, 1640, 1585, 1480, 1439,
1277, 1115, 1070, 995, 915, 756 cm-1 1H NMR (400 MHz,
;
(8E)-(3S,5R,6S)-3-(2-Cyanoethyl)-14-hydroxy-6-methyl-
1-oxo-2,3,4,5,6,7,10-heptahydrobenzo[f][12]annulen-5-
yl 4-Nitrobenzoate (22 from 29). To a refluxing solution of
29 (23 mg, 48 µmol) in benzene (2 mL) containing a drop of
water was added hydrido(triphenylphosphine)copper(I) hex-
amer (80 mg, 41 µmol). Heating was continued for 2 min. The
mixture was filtered through a pad of silica gel, washed with
benzene, the filtrate was concentrated under reduced pressure,
and the residue was purified by column chromatography
(acetone:hexanes 3:7) to yield 22 mg (96%) of 22 as a colorless
solid. For data, refer to the previous synthesis of 22 above.
CDCl3) δ 7.31 (t, 1H, J ) 8.0 Hz), 6.85 (d, 1H, J ) 7.7 Hz),
6.80 (d, 1H, J ) 8.3 Hz), 5.95-5.88 (m, 1H), 5.85-5.76 (m,
1H), 5.33-5.29 (m, 1H), 5.09-5.00 (m, 4H), 3.83 (s, 3H), 3.76-
3.73 (m, 1H), 3.37 (d, 2H, J ) 6.2 Hz), 2.60-2.41 (m, 2H),
2.24-1.90 (m, 6H), 1.77-1.72 (m, 1H), 1.68-1.59 (m, 1H), 0.91
(d, 3H, J ) 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 167.6, 156.2,
138.5, 137.0, 136.2, 130.7, 123.0, 122.1, 119.3, 116.5, 116.3,
109.0, 72.6, 71.5, 55.8, 38.5, 38.3, 37.8, 37.2, 30.1, 13.3, 13.1;
HRMS (FAB+) m/z calcd for C22H30NO4 (M + H) 372.2175,
found 372.2185.
1-[(2S)-4-Cyano-2-(6-methoxy-2-prop-2-enylphenyl-
carbonyloxy)butyl](1R,2S)-2-methylpent-4-enyl 4-Nitro-
benzoate (20 from 27). To a solution of 27 (351 mg, 1.01
mmol) and triphenylphosphine (1.06 mg, 4.04 mmol) in toluene
(40 mL) was added p-nitrobenzoic acid (675 mg, 4.04 mmol),
and the suspension was cooled to -30 °C. Diethyl azodicar-
boxylate (0.65 mL, 719 mg, 4.13 mmol) was added dropwise,
and the mixture was allowed to reach rt overnight and then
stirred for an additional 24 h. The resulting solution was
directly loaded on a silica gel column. Column chromatography
(EtOAc:hexanes 1:4) afforded 238 mg (48%) of 20 as pale yellow
oil. For data, see above.
(2E,8E&8Z)-3-((3R,5R,6S)-5-Hydroxy-14-methoxy-6-
methyl-1-oxo(2,3,4,5,6,7,10-heptahydro-benzo[d][12]-
annulen-3-yl))prop-2-enenitrile (28). A solution of 18 (390
mg, 0.75 mmol) and bis(tricyclohexylphosphine)benzylidene
ruthenium(IV) dichloride (Grubbs I catalyst, 130 mg, 0.16
mmol) in degassed CH2Cl2 (100 mL) was heated at reflux
temperature for 3 h. The solvent was removed under reduced
pressure, and the residue was purified by column chroma-
tography (EtOAc:hexanes 15:85) to give 339 mg (92%) of 28
as a pale yellow oil as an inseparable 96:4 mixture of E/Z-
isomers: [R]20D -1.5 (c 1.0, CHCl3); IR (neat) 2962, 2928, 2226,
1725, 1527, 1275, 1114, 1074, 758, 720 cm-1. E-28: 1H NMR
(400 MHz, CDCl3) δ 8.28 (d, 2H, J ) 8.7 Hz), 8.20 (d, 2H, J )
8.6 Hz), 7.31 (t, 1H, J ) 8.0 Hz), 6.86 (d, 1H, J ) 8.5 Hz), 6.81
(d, 1H, J ) 7.6 Hz), 6.71 (dd, 1H, J ) 16.2 Hz, 2.8 Hz), 5.92-
5.88 (m, 2H), 5.71-5.63 (m, 2H), 5.40 (dd, 1H, J ) 15.2, 9.7
Hz), 3.84-3.78 (m, 1H), 3.79 (s, 3H), 3.35 (d, 1H, J ) 16.1
Hz), 2.42-2.32 (m, 2H), 2.04-1.94 (m, 2H), 1.81 (dt, 1H, J )
14.1 Hz, 11.0 Hz), 0.96 (d, 3H, J ) 6.7 Hz); 13C NMR (100
MHz, CDCl3) δ 167.0, 164.0, 156.5, 151.6, 150.5, 139.5, 135.7,
130.8, 130.7, 130.5, 129.6, 123.6, 123.2, 122.9, 116.8, 109.4,
100.2, 76.8, 70.6, 55.6, 37.4, 37.3, 34.1, 33.8, 14.1; HRMS
(FAB+) m/z calcd for C27H27N2O7 (M + H) 491.1818, found
491.1798.
(1S,3R,4S)-1-(2-Cyanoethyl)-4-methyl-3-(4-nitrophen-
ylcarbonyloxy)hept-6-enyl 6-Hydroxy-2-prop-2-enylben-
zoate (30). Boron tribromide (1 M in CH2Cl2, 0.37 mL, 0.37
mmol) was added dropwise at -78 °C to a solution of 20 (38
mg, 75 µmol) in CH2Cl2. After being stirred for 30 min, the
reaction was quenched by addition of a sat. solution of K2CO3
at -78 °C. Extractive workup with ether followed by column
chromatography (EtOAc:hexanes 3:7) afforded 35 mg (95%) of
30 as a colorless oil: [R]20D +62 (c 1.5, CHCl3); IR (neat) 3078,
2975, 2933, 2361, 2248, 1724, 1658, 1607, 1527, 1450, 1348,
1273, 1119, 1103, 917, 760, 719 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 10.92 (s, 1H), 8.22 (d, 2H, J ) 8.9 Hz), 8.10 (d, 2H,
J ) 8.9 Hz), 7.29 (t, 1H, J ) 7.9 Hz), 6.84 (d, 1H, J ) 7.3 Hz),
6.65 (d, 1H, J ) 7.5 Hz), 6.02-5.92 (m, 1H), 5.80-5.71 (m,
1H), 5.46-5.40 (m, 1H), 5.22 (dd, 1H, J ) 12.4, 5.5 Hz), 5.07-
5.03 (m, 2H), 5.00 (m, 1H), 5.87 (ddd, 1H, J ) 17.1, 3.3, 1.6
Hz), 3.71 (dd, 1H, J ) 16.1, 5.7 Hz), 3.50 (dd, 1H, J ) 16.1,
5.5 Hz), 2.45-2.41 (m, 2H), 2.25-1.95 (m, 7H), 0.99 (d, 3H, J
) 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 170.8, 164.0, 163.0,
150.5, 141.8, 137.4, 135.6, 135.1, 134.7, 130.5, 123.5, 122.7,
118.5, 117.0, 116.5, 115.7, 111.5, 74.5, 70.4, 40.0, 37.0, 36.2,
34.3, 30.6, 14.8, 13.9; HRMS (FAB+) m/z calcd for C28H31N2O7
(M + H) 507.2131, found 507.2119.
1-{(2S)-4-Cyano-2-[2-prop-2-enyl-6-(1,1,2,2-tetrameth-
yl-1-silapropoxy)phenylcarbonyl-oxy]butyl}(1R,2S)-2-
methylpent-4-enyl 4-Nitrobenzoate (31). A solution of 30
(37 mg, 73 µmol), TBSCl (42 mg, 0.28 mmol), and imidazole
(60 mg, 0.88 mmol) in DMF (1 mL) was stirred at 50 °C for 3
h. Extractive workup with ether and subsequent column
chromatography (EtOAc:hexanes 1:9) gave 37 mg (82%) of silyl
ether 31 as a colorless oil: [R]20D +17 (c 1.4, CHCl3); IR (neat)
3078, 2959, 2931, 2858, 2248, 1728, 1640, 1608, 1582, 1594,
1529, 1464, 1348, 1275, 1103, 1025, 916, 838, 784, 739, 720
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.20 (d, 2H, J ) 8.9 Hz),
8.12 (d, 2H, J ) 8.9 Hz), 7.14 (t, 1H, J ) 8.0 Hz), 6.75 (d, 1H,
J ) 7.6 Hz), 6.66 (d, 1H, J ) 8.1 Hz), 5.95-5.85 (m, 1H), 5.80-
5.70 (m, 1H), 5.30-5.25 (m, 1H), 5.21-5.15 (m, 1H), 5.09-
5.00 (m, 4H), 3.32 (d, 2H, J ) 6.3 Hz), 2.54-2.45 (m, 2H),
(2E,8E)-3-((3R,5R,6S)-5,14-Dihydroxy-6-methyl-1-oxo-
(2,3,4,5,6,7,10-heptahydro-benzo[d][12]annulen-3-yl))-
7600 J. Org. Chem., Vol. 70, No. 19, 2005

Total Syntheses of the (-)-Salicylihalamides A and B
2.29-2.19 (m, 1H), 2.14-1.97 (m, 6H), 0.98 (d, 3H, J ) 6.5
Hz), 0.95 (s, 9H), 0.22 (s, 3H), 0.21 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.5, 164.1, 152.5, 150.4, 138.2, 136.2, 135.8, 135.4,
130.6, 130.1, 125.7, 123.5, 122.0, 118.8, 117.0, 116.9, 116.6,
75.1, 70.7, 37.4, 36.7, 36.5, 34.2, 29.9, 25.8, 18.4, 14.9, 13.7,
-4.0, -4.2; HRMS (FAB+) m/z calcd for C34H45N2O7Si (M +
H) 621.2996, found 621.3008.
solution of 33 (8.5 mg, 23 µmol) and chloromethyl methyl ether
(0.1 mL, 106 mg, 1.32 mmol) in diisopropylethylamine (2 mL)
was stirred at rt for 1 day. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography (EtOAc:hexanes 1:4) to afford 8.3 mg (87%)
of 35 as a colorless oil: [R]20 +23 (c 0.40, CHCl3); IR (neat)
D
3076, 2931, 2360, 2341, 1728, 1585, 1471, 1267, 1112, 1036,
1
916, 755 cm-1; H NMR (400 MHz, CDCl3) δ 7.31 (t, 1H, J )
1-{(2S)-2-[6-(2,2-Dimethyl-1,1-diphenyl-1-silapropoxy)-
2-prop-2-enylphenylcarbonyloxy]-4-cyanobutyl}(1R,2S)-
2-methylpent-4-enyl 4-Nitrobenzoate (32). A solution of 30
(7 mg, 14 µmol), TBDPSCl (0.1 mL, 106 mg, 0.39 mmol), and
imidazole (50 mg, 0.73 mmol) in DMF (1 mL) was stirred at
80 °C for 6 h. Extractive workup with ether followed by column
chromatography (EtOAc:hexanes 1:9) gave rise to 9 mg (88%)
of silyl ether 32 as a colorless oil: [R]20D -8.9 (c 0.40, CHCl3);
IR (neat) 3074, 2932, 2858, 1725, 1528, 1463, 1276, 1114, 824,
8.0 Hz), 6.85 (d, 1H, J ) 7.7 Hz,), 6.80 (d, 1H, J ) 8.3 Hz),
6.00-5.88 (m, 1H), 5.79-5.68 (m, 1H), 5.39-5.33 (m, 1H), 5.08
(dd, 1H, J ) 10.1, 1.4 Hz), 5.03 (dd, 1H, J ) 17.1, 1.6 Hz),
4.97 (dd, 1H, J ) 18.6, 1.4 Hz), 4.94 (d, 1H, J ) 9.5 Hz), 4.72
(d, 1H, J ) 6.9 Hz), 4.68 (d, J ) 6.9 Hz, 1H), 3.84 (s, 3H), 3.66
(ddd, 1H, J ) 10.1, 3.7, 1.8 Hz), 3.41 (s, 3H), 3.37 (dd, 2H, J
) 6.1 Hz, 1.1 Hz), 2.62-2.44 (m, 2H), 2.22-2.12 (m, 1H), 2.09-
1.91 (m, 3H), 1.84 (dt, 1H, J ) 13.1, 7.9 Hz), 1.76 (ddd, 1H, J
) 14.5, 9.3, 1.8 Hz), 1.62 (ddd, 1H, J ) 14.5, 10.2, 3.0 Hz),
0.90 (d, 3H, J ) 6.7 Hz); 13C NMR (100 MHz, CDCl3) δ 167.9,
156.2, 138.2, 136.8, 136.3, 130.6, 123.4, 121.9, 119.5, 116.6,
116.1, 108.8, 96.7, 78.0, 70.9, 56.0, 55.7, 37.6, 37.2, 36.2, 34.4,
31.2, 13.5, 13.1; HRMS (FAB+) m/z calcd for C24H37N2O5 (M
+ NH4) 433.2702, found 433.2726.
1
719, 702 cm-1; H NMR (400 MHz, CDCl3) δ 8.15 (d, 2H, J )
9.1 Hz), 8.11 (d, 2H, J ) 9.1 Hz), 7.74-7.69 (m, 4H), 7.44-
7.35 (m, 6H), 6.83 (t, 1H, J ) 8.0 Hz), 6.62 (d, 1H, J ) 7.7
Hz), 6.31 (d, 1H, J ) 8.2 Hz), 5.94-5.84 (m, 1H), 5.83-5.78
(m, 1H), 5.33 (dt, 1H, J ) 9.5, 4.4 Hz), 5.24-5.18 (q, 1H, J )
5.8 Hz), 5.10-5.00 (m, 4H), 3.38-3.26 (m, 2H), 2.53-2.43 (m,
2H), 2.29-1.94 (m, 7H), 1.04 (s, 9H), 0.99 (d, 3H, J ) 6.5 Hz);
13C NMR (100 MHz, CDCl3) δ 167.4, 164.2, 152.3, 150.4, 138.1,
136.0, 135.9, 135.4, 135.3, 132.2, 132.0, 130.6, 130.2, 129.9,
127.9, 125.0, 123.5, 121.8, 118.8, 117.2, 117.0, 116.7, 77.2, 75.3,
71.3, 37.5, 36.7, 36.5, 34.1, 29.7, 26.5, 19.4, 15.0, 13.6; HRMS
(FAB+) m/z calcd for C44H52N3O7Si (M + NH4) 762.3575, found
762.361.
1-[(2S)-4-Cyano-2-(6-methoxy-2-prop-2-enylphenyl-
carbonyloxy)butyl](1R,2S)-2-methyl-pent-4-enyl 2,2-Di-
methylpropanoate (36). A solution of 33 (3.5 mg, 9.4 µmol),
pivaloyl chloride (0.15 mL, 146 mg, 1.21 mmol), triethylamine
(0.17 mL, 123 mg, 1.22 mmol), and 4-(dimethylamino)pyridine
(5 mg, 41 µmol) in CH2Cl2 (0.5 mL) was heated at reflux
temperature for 1 day. The solvent was removed under reduced
pressure, and the residue was purified by column chroma-
tography (EtOAc:hexanes 1:4) to afford 3.8 mg (89%) of
pivaloate 36: [R]20D +23 (c 0.20, CHCl3); IR (neat) 3077, 2971,
2931, 2248, 1727, 1585, 1471, 1268, 1160, 1110, 1068, 914
(1S,3R,4S)-1-(2-Cyanoethyl)-3-hydroxy-4-methylhept-
6-enyl 6-Methoxy-2-prop-2-enyl-benzoate (33). To a solu-
tion of 20 (26 mg, 53 µmol) in MeOH (2 mL) was added K2CO3
(100 mg, 0.72 mmol), and the mixture was stirred at rt for 3
h. Extractive workup with ether followed by column chroma-
tography (EtOAc:hexanes 3:7) resulted in 17 mg (94%) of 33
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.30 (t, 1H, J ) 8.0 Hz),
6.85 (d, 1H, J ) 7.7 Hz), 6.79 (d, 1H, J ) 8.4 Hz), 6.01-5.92
(m, 1H), 5.77-5.70 (m, 1H), 5.24-5.18 (m, 1H), 5.09-4.97 (m,
4H), 4.95-4.91 (m, 1H), 3.84 (s, 3H), 3.38 (d, 2H, J ) 6.2 Hz),
2.65-2.44 (m, 2H), 2.20-2.08 (m, 2H), 2.08-1.98 (m, 1H),
1.93-1.75 (m, 4H), 1.23 (s, 9H), 0.87 (d, 3H, J ) 6.7 Hz); 13C
NMR (100 MHz, CDCl3) δ 177.6, 167.5, 156.3, 138.6, 136.5,
136.3, 130.6, 123.2, 122.0, 119.3, 116.5, 116.3, 108.8, 72.8, 69.8,
55.7, 38.9, 37.1, 36.9, 35.9, 33.9, 30.9, 27.2, 14.2, 13.1; HRMS
(FAB+) m/z calcd for C27H38NO5 (M + H) 456.2750, found
456.2750.
as a colorless oil: [R]20 +19 (c 1.7, CHCl3); IR (neat) 3520,
D
3076, 2966, 2930, 2248, 1724, 1639, 1585, 1471, 1439, 1267,
1116, 1070, 915, 756 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.32
(t, 1H, J ) 8.0 Hz), 6.85 (d, 1H, J ) 7.7 Hz), 6.82 (d, 1H, J )
8.3 Hz), 5.96-5.78 (m, 1H), 5.83-5.73 (m, 1H), 5.44-5.38 (m,
1H), 5.09-4.99 (m, 4H), 3.83 (s, 3H), 3.60-3.56 (m, 1H), 3.37
(d, 2H, J ) 6.0 Hz), 2.75 (s, br, 1H), 2.63-2.42 (m, 2H), 2.35-
2.28 (m, 1H), 2.10-2.03 (m, 2H), 1.96 (dt, 1H, J ) 13.8, 7.9
Hz), 1.83-1.76 (m, 1H), 1.70-1.60 (m, 2H), 0.89 (d, 3H, J )
6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 168.7, 156.1, 138.2,
137.0, 136.1, 130.8, 122.9, 122.1, 119.2, 116.6, 116.2, 108.9,
71.3, 70.5, 55.7, 38.7, 38.6, 37.2, 37.0, 30.9, 15.3, 13.3; HRMS
(FAB+) m/z calcd for C22H30NO4 (M + H) 372.2175, found
372.2188.
(1S,3R,4S)-1-(2-Cyanoethyl)-4-methyl-3-(1,1,2,2-tetra-
methyl-1-silapropoxy)hept-6-enyl 6-Methoxy-2-prop-2-
enylbenzoate (37). To a solution of 33 (3.5 mg, 9.4 µmol) and
2,6-lutidine (50 µL, 0.43 mmol) in CH2Cl2 (0.5 mL) was added
tert-butyldimethylsilyl trifluoromethanesulfonate (0.1 mL, 115
mg, 0.44 mmol), and the mixture was stirred at rt for 1 day.
The solvent was removed under reduced pressure, and the
residue was purified by column chromatography (EtOAc:
hexanes 1:9) to give 3.8 mg (83%) of silyl ether 37: [R]20D -13
(c 0.20, CHCl3); IR (neat) 3077, 2929, 2856, 2248, 1731, 1585,
1471, 1263, 1111, 1068, 837, 776, 668 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.30 (t, 1H, J ) 8.0 Hz), 6.84 (d, 1H, J ) 7.7 Hz),
6.80 (d, 1H, J ) 8.3 Hz), 5.93 (ddt, 1H, 16.9, 10.2, 6.4 Hz),
5.74 (ddt, 1H, J ) 17.1, 10.1, 3.9 Hz), 5.25 (tt, 1H, J ) 7.7, 3.9
Hz), 5.10-4.93 (m, 4H), 3.84-3.81 (m, 1H), 3.83 (s, 3H), 3.36
(d, 2H, J ) 6.3 Hz), 2.59-2.45 (m, 2H), 2.20-2.15 (m, 1H),
2.07-1.97 (m, 2H), 1.87-1.67 (m, 3H), 1.58-1.51 (m, 1H), 0.91
1-[(2S)-4-Cyano-2-(6-methoxy-2-prop-2-enylphenyl-
carbonyloxy)butyl](1R,2S)-2-methyl-pent-4-enyl Acetate
(34). A solution of 33 (8.5 mg, 23 µmol), triethylamine (20 µL,
14.5 mg, 0.14 mmol), acetic anhydride (14 µL, 15.1 mg, 0.15
mmol), and a catalytic amount of 4-(dimethylamino)pyridine
in CH2Cl2 was stirred at rt for 12 h. The solvent was removed
under reduced pressure, and the residue was purified by
column chromatography (EtOAc:hexanes 3:7) to give 9.2 mg
(97%) of acetyl ester 34 as colorless oil: [R]20 +21 (c 0.40,
D
CHCl3); IR (neat) 3076, 2970, 2932, 2247, 1731, 1585, 1470,
1267, 1243, 1111, 1068, 915, 756 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.30 (t, 1H, J ) 8.0 Hz), 6.85 (d, 1H, J ) 7.8 Hz),
6.79 (d, 1H, J ) 8.3 Hz), 6.03-5.93 (m, 1H), 5.78-5.66 (m,
1H), 5.26-5.22 (m, 1H), 5.09-4.92 (m, 5H), 3.84 (s, 3H), 3.39
(d, 2H, J ) 6.3 Hz), 2.66-2.46 (m, 2H), 2.16-2.08 (m, 2H),
2.05 (s, 3H), 1.92-1.76 (m, 5H), 0.87 (d, 3H, J ) 6.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 170.5, 167.6, 156.3, 138.6, 136.5,
136.3, 130.7, 123.2, 122.0, 119.4, 116.5, 116.4, 108.8, 73.2, 69.9,
55.8, 37.1, 37.0, 36.1, 34.1, 30.9, 21.1, 14.4, 13.0; HRMS
(FAB+) m/z calcd for C24H35N2O5 (M + NH4) 431.2546, found
431.2539.
(s, 9H), 0.87 (d, 3H, J ) 6.7 Hz), 0.13 (s, 3H), 0.08 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 167.7, 156.3, 138.2, 137.0, 136.2,
130.6, 123.5, 121.8, 119.4, 116.6, 116.0, 108.9, 72.2, 71.8, 55.7,
39.1, 37.5, 37.3, 36.3, 31.3, 25.9, 18.1, 13.4, 13.0, -4.2, -4.5;
HRMS (FAB+) m/z calcd for C28H47N2O4Si (M + NH4) 503.3305,
found 503.3295.
General Procedure for the RCM Reactions of Sub-
strates 20, 30-37 To Determine the E:Z Ratios in Prod-
uct Mixtures 21, 38-45. A solution of the RCM substrate
(20, 30-37) (10 µmol) and bis(tricyclohexylphosphine)ben-
zylidene ruthenium(IV) dichloride (Grubbs I catalyst, 2 mg, 2
(1S,3R,4S)-1-(2-Cyanoethyl)-3-(methoxymethoxy)-4-me-
thylhept-6-enyl 6-Methoxy-2-prop-2-enylbenzoate (35). A
J. Org. Chem, Vol. 70, No. 19, 2005 7601

Haack et al.
µmol) in degassed CH2Cl2 (2 mL) was refluxed for 3 h. The
solution was filtered through a pad of silca gel, and the filtrate
containing the product mixtures 21, 38-45 was concentrated
under reduced pressure. E/Z ratios were determined by 1H
NMR spectroscopy and HPLC analysis (see Supporting Infor-
mation). For NMR analysis, the integral of the characteristic
doublet of one of the H8 protons appearing at around δ 3.4
ppm, which belongs to the E-isomer, was compared to the
corresponding H8 proton of the Z-isomer, which typically
appears at δ 3.1 ppm. HPLC analysis was carried out on a
silica gel column with a gradient of ethyl acetate and hexanes.
Peaks were detected at 280 nm. Specific information for each
example is provided with the 1H NMR spectra in the Support-
ing Information.
Hz), 5.10-5.05 (m, 2H), 4.40 (ddd, 1H, J ) 9.9, 5.7, 3.5 Hz,
1H), 4.19 (dq, 1H, J ) 6.4, 3.4 Hz), 3.83 (s, 3H), 3.45 (dq, 2H,
J ) 15.6, 6.6 Hz), 2.76 (ddd, 1H, J ) 12.6, 8.9, 5.9 Hz), 2.44
(dt, 1H, J ) 12.5, 10.4 Hz), 2.14 (bs, 1H), 1.20 (d, 3H, J ) 6.5
Hz); 13C NMR (100 MHz, CDCl3) δ 171.8, 166.9, 156.8, 139.1,
136.2, 131.1, 121.8, 122.7, 116.5, 109.0, 79.8, 69.1, 66.5, 56.0,
37.4, 27.9, 17.3; HRMS (FAB+) m/z calcd for C17H21O6 (M +
H) 321.1338, found 321.1326.
(2R,3R,5R)-5-((1S&1R)-1-Hydroxyethyl)-2-methoxyox-
olan-3-yl 6-Methoxy-2-prop-2-enylbenzoate (47). To a
solution of 46 (1.2 g, 3.75 mmol) in toluene (10 mL) under
argon atmosphere was slowly added diisobutylaluminum
hydride (7.9 mL, 1 M in toluene, 7.9 mmol) at -78 °C. After
15 min, MeOH (5 mL) was added to quench the reaction at
-78 °C, followed by the addition of 4 N HCl in dioxane (20
mL) at rt. The reaction was stirred for an additional 8 h. Water
(5 mL) was then added, and the majority of the solvents were
removed under reduced pressure. Extractive workup with
CH2Cl2 and aqueous NaHCO3 followed by column chroma-
tography (EtOAc:hexanes 4:1) provided 934 mg of 47 (74%):
(3R,5R,6S)-3-Hydroxy-5-(hydroxyethyl)-3,4,5-trihydro-
furan-2-one (8).9 To a suspension of L-rhamnose (25 g, 0.14
mol) and BaCO3 (35 g, 0.18 mol) in water (250 mL) in a round-
bottom flask, wrapped with aluminum foil, was carefully added
Br2 (7.7 mL, 0.15 mol) by syringe over 30 min. The brown
suspension was stirred overnight, turning into a yellow
solution the following day. Additional Br2 (0.3 mL, 5.8 mmol)
was added to force the reaction to completion. After 1 h, the
solution was acidified with concentrated HCl to pH 3. The
reaction mixture was then filtered through a fine glass filter,
and the filtrate was evaporated to remove water. The concen-
trated residue was dried further over MgSO4, filtered, followed
by flash column chromatography (MeOH:CH2Cl2 1:9). 22 g
(99%) of the lactone (3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl-
3H-4,5,6-trihydropyran-2-one was obtained. To a solution of
the lactone (1.5 g, 9.3 mmol) in pyridine (3 mL) was added
benzoyl chloride (3.33 mL, 28.7 mmol) at 0 °C. The mixture
was allowed to reach rt and was kept for 30 min. An extractive
workup with ether and brine was carried out, and the
concentrated residue was purified by silica gel column
chromatography (EtOAc:hexanes 3:7) to afford 4.4 g of
(3R,4R,5R,6S)-6-methyl-2-oxo-4,5-diphenylcarbonyloxy-3H-
4,5,6-trihydropyran-3-yl benzoate (100%). To a solution of this
tribenzoate (4.2 g, 8.9 mmol) and 10% Pd/C (350 mg) in EtOAc
(25 mL) equipped with a H2 balloon was added TEA (1.85 mL,
13.3 mmol) at rt. The resulting suspension was stirred for 1
day and filtered through Celite with EtOAc and concentrated
in vacuo. Flash column chromatography (EtOAc:hexanes 1:4)
provided 3.1 g of (3R,5R,6S)-6-methyl-2-oxo-5-phenylcarbony-
loxy-3H-4,5,6-trihydropyran-3-yl benzoate as a foaming solid
(99%). The dibenzoate (2.1 g, 5.9 mmol) was treated with
NaOMe (0.5 M in MeOH, 40 mL) and stirred for 30 min. MeOH
was evaporated in vacuo, followed by the addition of 1,4-
dioxane (100 mL) and H2SO4 (50% aq. 4 mL). The mixture was
dried over MgSO4, filtered through Celite, and concentrated.
Column chromatography (MeOH:CH2Cl2 1:9) gave rise to diol
[R]20 -28 (c 0.90, CHCl3); IR (neat) 3461, 1728, 1267, 1107,
D
1071 cm-1; 1H NMR (400 MHz, CDCl3, two anomers) δ 7.31-
7.26 (m, 1H), 6.84-6.77 (m, 2H), 5.96-5.86 (m, 1H), 5.27 (d,
0.6H, J ) 5.6 Hz), 5.16 (s, 0.4H), 5.08-5.03 (m, 2.6H), 4.65 (s,
0.4H), 4.12 (ddd, 0.6H, J ) 8.5, 5.8, 2.9 Hz), 4.08-4.02 (m,
0.6H), 3.82 (s, 3H), 3.66-3.54 (m, 0.8H), 3.42 (s, 1.2H), 3.38
(s, 1.8H), 3.42-3.68 (m, 2H), 2.40 (0.6 H, quintet, J ) 7.4 Hz),
2.25-2.22 (m, 0.4H), 2.22 (s, 0.6H), 2.06 (dd, 0.6H, J ) 13.3,
4.8 Hz), 1.93 (ddd, 0.4H, J ) 13.8, 10.8, 3.1 Hz), 1.50 (d, 0.4H,
J ) 5.5 Hz), 1.27 (d, 1.2H, J ) 5.7 Hz), 1.13 (d, 1.8H, J ) 6.51
Hz); 13C NMR (100 MHz, CDCl3, two anomers) δ 167.8, 167.6,
157.1, 157.1, 139.3, 139.0, 136.8, 136.7, 131.2, 131.0, 123.7,
123.2, 122.3, 122.1, 116.8, 116.7, 109.5, 109.5, 107.0, 97.6, 82.4,
78.5, 71.7, 69.6, 68.5, 67.6, 56.3, 56.3, 55.2, 55.0, 37.9, 33.1,
29.0, 18.8, 18.0; HRMS (FAB+) m/z calcd for C18H25O6 (M +
H) 337.1651, found 337.1644.
(3R,5R)-5-((1S)-1-Methylbut-3-enyl)-2-methoxyoxolan-
3-yl 6-Methoxy-2-prop-2-enylbenzoate (49). To a solution
of 47 (49 mg, 0.15 mmol) in CH2Cl2 (5 mL) were added at 0 °C
pyridine (0.025 mL, 0.29 mmol) and triflic anhydride (0.037
mL, 0.22 mmol). After 5 min of stirring, the mixture was
quenched with saturated NaHCO3 (2 mL) and extracted with
CH2Cl2 (50 mL). The organic layer was dried over MgSO4,
concentrated, and filtered through Celite. The crude triflate
48 was dried under vacuum at 0 °C for 1 h. 1H NMR (500 MHz,
CDCl3) δ 7.30 (t, 1H, J ) 8.0 Hz), 6.82 (d, 1H, J ) 7.5 Hz),
6.79 (d, 1H, J ) 8.4 Hz), 5.90 (ddt, 1H, J ) 16.9, 10.2, 6.5 Hz,
1H), 5.30 (dd, 1H, J ) 6.8, 2.1 Hz, 1H), 5.11-5.04 (m, 3H),
5.01 (q, 1H, J ) 1.7 Hz), 4.26 (ddd, 1H, J ) 9.5, 5.0, 4.7 Hz),
3.81 (s, 3H), 3.41 (s, 3H), 3.36 (d, 2H, J ) 6.5 Hz), 2.63 (ddd,
1H, J ) 14.4, 8.2, 7.0 Hz), 1.96 (ddd, 1H, J ) 14.3, 6.0, 2.1
Hz), 1.52 (d, 3H, J ) 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ
167.8, 157.1, 138.9, 136.6, 131.2, 123.1, 122.1, 116.8, 109.4,
107.8, 87.3, 79.1, 77.9, 77.6, 56.2, 55.3, 37.8, 32.0, 17.4. In
another flask, CuCN (25 mg, 0.29 mmol) was heated under
vacuum for 5 min and suspended in anhydrous THF (20 mL)
at -78 °C. MeLi (0.36 mL, 1.6 M in Et2O, 0.58 mmol) was
added slowly. The mixture was allowed to reach 0 °C, then
allyltributyltin (0.18 mL, 0.58 mmol) was added, and the
resulting solution was stirred for 30 min. After being cooled
to -78 °C, the mixture was added to a solution of the triflate
48 in THF (5 mL) at -90 °C. After being stirred for 1 h, the
reaction mixture was quenched by careful addition of concen-
trated aqueous NH4OH solution saturated with NH4Cl (10 mL)
and stirred at rt overnight. Extractive workup with ether
followed by column chromatography (EtOAc:hexanes 1:19)
8 (750 mg, 87%): [R]20 +2.2 (c 1.2, water); IR (neat) 3379,
D
1770, 1125 cm-1
;
1H NMR (400 MHz, MeOH-d4) δ 4.54 (dd,
1H, J ) 10.8, 8.7 Hz), 4.27 (quintet, 1H, J ) 4.7 Hz), 3.98-
3.92 (m, 1H), 2.55 (ddd, 1H, J ) 12.3, 8.6, 5.6 Hz), 2.05 (q,
1H, J ) 10.6 Hz), 1.17 (d, 3H, J ) 6.5 Hz); 13C NMR (100 MHz,
MeOH-d4) δ 179.3, 81.3, 69.5, 68.4, 32.8, 18.8; HRMS (FAB+)
m/z calcd for C6H10O4 (M + H) 147.0657, found 147.0807.
(3R,5R)-5-((1S)-1-Hydroxyethyl)-2-oxo-3-3,4,5-trihydro-
furyl 6-Methoxy-2-prop-2-enylbenzoate (46). To a solution
of 8 (86 mg, 0.59 mmol) in CH2Cl2 (5 mL) was added a mixture
of DMAP (89 mg, 0.71 mmol), EDCI (136 mg, 0.71 mmol), and
13 (136 mg, 0.71 mmol) in CH2Cl2 (2 mL) at 0 °C, and the
reaction mixture was stirred for 5 h at rt. Additional DMAP
(89 mg, 0.71 mmol), EDCI (136 mg, 0.71 mmol), and 13 (136
mg, 0.71 mmol) in CH2Cl2 (2 mL) was added to drive the
reaction to completion. After 9 h, the solvent was evaporated
and the crude mixture was purified by column chromatography
(MeOH/CH2Cl2 1:19) to produce 170 mg (90%) of desired ester
46: [R]20D +12 (c 1.0, CHCl3); IR (neat) 3453, 1793, 1736, 1268,
gave 16 mg (30% for two steps) of allylated product 49: [R]20
D
-16 (c 0.80, CHCl3); IR (neat) 1731, 1267, 1107, 1070 cm-1
;
1H NMR (400 MHz, CDCl3, R-anomer) δ 7.28 (t, 1H, J ) 8.2
Hz), 6.82 (d, 1H, J ) 7.8 Hz), 6.77 (d, 1H, J ) 8.3 Hz), 5.94
(ddt, 1H, J ) 17.0, 10.1, 6.7 Hz), 5.81 (dddd, 1H, J ) 17.4,
9.7, 7.8, 6.7 Hz), 5.17 (ddd, 1H, J ) 11.0, 7.9, 4.2 Hz), 5.12-
1
1118 cm-1; H NMR (400 MHz, CDCl3) δ 7.32 (t, 1H, J ) 8.1
Hz), 6.85 (d, 1H, J ) 7.7 Hz), 6.80 (d, 1H, J ) 8.4 Hz), 5.93
(ddq, 1H, J ) 16.8, 10.2, 6.6 Hz), 5.72 (dd, 1H, J ) 10.5, 9.1
7602 J. Org. Chem., Vol. 70, No. 19, 2005

Total Syntheses of the (-)-Salicylihalamides A and B
5.01 (m, 5H), 3.86-3.80 (m, 1H), 3.82 (s, 3H), 3.40 (s, 3H),
3.40-3.39 (m, 2H), 2.47-2.42 (m, 1H), 2.37 (ddd, 1H, J ) 11.8,
7.8, 6.4 Hz), 2.02-1.90 (m, 2H), 1.74-1.70 (m, 1H), 0.83 (d,
3H, J ) 6.8 Hz); 13C NMR (125 MHz, CDCl3, R-anomer) δ
167.6, 157.1, 138.9, 136.7, 131.0, 123.6, 122.1, 116.7, 109.4,
97.6, 71.7, 69.5, 68.4, 56.3, 56.2, 55.1, 37.8, 32.9, 18.0; 1H NMR
(400 MHz, CDCl3, â-anomer) δ 7.29 (t, 1H, J ) 8.0 Hz), 6.82
(d, 1H, J ) 7.6 Hz), 6.77 (d, 1H, J ) 8.3 Hz), 5.90 (ddt, 1H, J
) 17.7, 9.5, 6.6 Hz), 5.79 (dddd, 1H, J ) 17.5, 9.7, 7.7, 6.6
Hz), 5.27 (dd, 1H, J ) 7.2, 2.8 Hz), 5.07-5.00 (m, 5H), 3.93 (q,
1H, J ) 7.6 Hz), 3.81 (s, 3H), 3.37 (s, 3H), 3.37-3.35 (m, 2H),
2.52 (dt, 1H, J ) 13.9, 7.3 Hz), 2.39-2.33 (m, 1H), 1.99-1.89
(m, 1H), 1.82-1.77 (m, 1H), 1.73 (ddd, 1H, J ) 14.1, 7.5 Hz),
0.87 (d, 3H, J ) 6.8 Hz); 13C NMR (125 MHz, CDCl3, â-anomer)
δ 167.5, 156.6, 138.4, 136.6, 136.2, 130.6, 123.2, 122.6, 116.4,
116.2, 109.0, 106.6, 81.4, 79.0, 55.8, 54.3, 37.7, 37.4, 37.4, 33.8,
29.7, 14.9; HRMS (ES+) m/z calcd for C21H32N1O5 (M + NH4)
378.2280, found 378.2293.
hexanes 1:3) afforded the saturated nitrile 52 (12 mg, 80%):
[R]20 -15 (c 0.30, CHCl3); IR (neat) 3446, 3076, 2926, 2249,
D
1
1656, 1606, 1450, 1249, 1220, 1120, 914, 817 cm-1; H NMR
(500 MHz, CDCl3) δ 11.0 (s, 1H), 7.36 (t, 1H, J ) 7.9 Hz), 6.91
(d, 1H, J ) 8.2 Hz), 6.8 (d, 1H, J ) 7.42 Hz), 5.99 (ddt, 1H, J
) 17.1, 10.3, 5.6 Hz), 5.8 (ddt, 1H, J ) 17.1, 9.9, 7.2 Hz), 5.54
(ddt, 1H, J ) 9.0, 6.1, 2.8 Hz), 5.07-4.98 (m, 3H), 4.88 (dq,
1H, J ) 17.2, 1.6 Hz), 3.67 (d, 2H, J ) 5.5 Hz), 3.48 (s, 1H),
2.51-2.39 (m, 3H), 2.44 (dt, 1H, 13.8, 6.0 Hz), 2.14 (q, 2H, J
) 7.3 Hz), 1.97-1.87 (m, 2H), 1.69 (ddd, 1H, J ) 13.9, 10.8,
2.7 Hz, 1H), 1.67-1.61 (m, 1H), 0.89 (d, 3H, J ) 6.8 Hz); 13C
NMR (125 MHz, CDCl3) δ 171.3, 162.9, 142.2, 137.5, 136.8,
134.8, 123.0, 118.7, 116.6, 116.4, 115.6, 111.6, 72.3, 71.0, 40.0,
38.8, 38.4, 37.0, 30.9, 15.1, 13.9; HRMS (FAB+) m/z calcd for
C21H28N1O4 (M + H) 358.2018, found 358.1999.
(1S,3S,4S)-1-(2-Cyanoethyl)-4-methyl-3-(1,1,2,2-tetra-
methyl-1-silapropoxy)hept-6-enyl 2-Prop-2-enyl-6-(1,1,2,2-
tetramethyl-1-silapropoxy)benzoate (53). To a solution of
52 (35 mg, 0.1 mmol) in CH2Cl2 (5 mL) were added pyridine
(0.08 mL, 0.98 mmol) and TBSOTf (0.18 mL, 0.78 mmol) at 0
°C, and the mixture was stirred for 5 h. The solvent was
removed in vacuo, and the residue was subjected to column
chromatography (EtOAc:hexane 1:9) to result in 52 mg of
compound 53 (91%): [R]20D +10 (c 0.50, CHCl3); IR (neat) 2244,
1726, 1583, 1465, 1255, 830 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.19 (t, 1H, J ) 7.91 Hz), 6.81 (d, 1H, J ) 7.7 Hz), 6.74 (d,
1H, J ) 8.2 Hz), 5.92 (ddt, 1H, J ) 16.8, 10.2, 6.4 Hz), 5.75
(ddt, 1H, J ) 7.01, 10.04, 17.04 Hz, 1H), 5.10-4.96 (m, 5H),
3.87 (dt, 1H, J ) 9.1, 2.8 Hz), 3.38-3.29 (m, 2H), 2.44 (ddq,
1H, J ) 16.4, 10.0, 5.6 Hz), 2.22-2.13 (m, 1H), 2.10-2.02 (m,
2H), 1.88-1.80 (m, 2H), 1.78-1.68 (m, 1H), 1.59 (ddd, 1H, J
) 14.4, 9.1, 5.7 Hz), 0.98 (s, 9H), 0.91 (s, 9H), 0.88 (d, 3H, J )
6.7 Hz), 0.25 (s, 3H), 0.24 (s, 3H), 0.12 (s, 3H), 0.08 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 168.1, 152.9, 138.5, 137.4, 136.5,
130.5, 126.5, 122.3, 119.5, 117.4, 117.0, 116.4, 73.2, 73.0, 39.4,
37.9, 37.7, 36.5, 31.5, 26.3, 26.2, 18.8, 18.4, 13.9, 13.8, -3.6,
-3.7, -3.8, -3.9; HRMS (ES+) m/z calcd for C33H56 N1O4Si2
(M + H) 586.3748, found 586.3738.
(3R,5R)-5-((1S&1R)-1-Methylbut-3-enyl)-2-hydroxyox-
olan-3-yl 6-Hydroxy-2-prop-2-enylbenzoate (50). To a
solution of 49 (77 mg, 0.21 mmol) in CH2Cl2 (6 mL) was added
BCl3 (1 M in CH2Cl2, 2.0 mL) at -78 °C, and the mixture was
stirred for 30 min. Water was added to stop the reaction.
Extractive workup with CH2Cl2 (50 mL) and subsequent
column chromatography (EtOAc:hexanes 1:3) gave 34 mg
(48%) of 50 as a mixture of anomers: [R]20 -1.0 (c 0.40,
D
CHCl3, 24 h); IR (neat) 3417, 1660, 1607, 1450 cm-1; 1H NMR
(500 MHz, CDCl3) δ 11.0 (s, 0.75H), 10.6 (s, 0.25H), 7.34 (t,
0.75H, J ) 7.9 Hz), 7.33 (t, 0.25H, J ) 7.8 Hz), 6.90-6.87 (m,
1H), 6.77-6.74 (m, 1H), 6.05 (ddt, 0.25H, J ) 17.1, 10.3 6.0
Hz), 5.98 (ddt, 0.75H, J ) 17.1, 10.3, 6.0 Hz), 5.83-5.74 (m,
1H), 5.58 (d, 0.75H, J ) 1.6 Hz), 5.54 (t, 0.25H, J ) 4.4 Hz),
5.35 (dd, 0.75H, J ) 7.2, 3.1 Hz), 5.27 (ddd, 0.25H, J ) 9.9,
7.7, 4.3 Hz), 5.06-4.91 (m, 4H), 4.14 (q, 0.75H, J ) 7.6 Hz),
3.85-3.80 (m, 0.25H), 3.74-3.64 (m, 2H), 3.11 (d, 0.25H, J )
4.7 Hz), 2.79 (d, 0.75H, J ) 2.3 Hz), 2.61 (dt, 0.75H, J ) 14.1,
7.3 Hz), 2.46-2.35 (m, 1.25H), 2.05-1.91(m, 1.25H), 1.82-1.76
(m, 1.75H), 0.89 (d, 3H, J ) 6.8 Hz); 13C NMR (125 MHz,
CDCl3) δ 171.3, 170.1, 163.3, 162.3, 143.1, 143.1, 138.3, 137.9,
136.8, 136.8, 123.1, 123.0, 116.8, 116.7, 116.7, 116.0, 115.9,
112.8, 112.1, 100.9, 94.6, 82.3, 81.1, 80.7, 75.1, 40.5, 40.1, 39.5,
38.1, 38.1, 38.0, 34.1, 31.5, 15.4, 15.1; HRMS (FAB+) m/z calcd
for C19H25O5 (M + H) 333.1702, found 333.1717.
3-[(3S,5R,6S)-5,14-Bis(1,1,2,2-tetramethyl-1-silapropoxy)-
6-methyl-1-oxo-2,3,4,5,6,7,10-heptahydrobenzo[d]-
[12]annulen-3-yl]propanenitrile (E-54 from 53). To a
solution of 53 (52 mg, 0.09 mmol) in CH2Cl2 (20 mL) was added
Grubbs I catalyst (3.7 mg, 0.0045 mmol), and the solution was
heated at reflux temperature for 12 h. Catalyst (3.7 mg, 0.0045
mmol) was added every 1 h for another three times, and after
completion of the reaction the solvent was removed under
reduced pressure. Column chromatography (EtOAc:hexane
1:19) gave 40 mg (81%) of the E-isomer 54 and 17% of the
1 - ((1E&1Z)- 2- Cyanovinyl)(4S,1R,3R)- 3- hydroxy- 4-
methylhept-6-enyl 6-Hydroxy-2-prop-2-enylbenzoate (51).
To a solution of 50 (58 mg, 0.17 mmol) in toluene (5 mL) was
added (triphenylphosphoranylidene)-acetonitrile (68 mg, 0.23
mmol), and the mixture was stirred at 80 °C for 1 h. After
cooling, the solution was directly loaded on a silica gel column.
Column chromatography (EtOAc:hexanes 3:7) afforded 65 mg
(98%, E:Z 23:2) of acryl nitrile 51: [R]20D -10 (c 0.20, CHCl3);
Z-isomer. E-54: [R]20 +2.5 (c 1.2, CHCl3); IR (neat) 2249,
D
1
1726, 1255, 1055 cm-1; H NMR (500 MHz, CDCl3) δ 7.14 (t,
IR (neat) 3451, 3075, 2228, 1661, 1606, 1450, 1216 cm-1
.
1H, J ) 7.9 Hz), 6.76 (d, 1H, J ) 8.3 Hz), 6.74 (d, 1H, J ) 8.8
Hz), 5.44-5.31 (m, 2H), 5.20 (q, 1H, J ) 6.3 Hz), 4.26 (dd, 1H,
J ) 8.2, 3.2 Hz, 1H), 3.66 (dd, 1H, J ) 16.4, 9.5 Hz, 1H), 3.33
(ddt, 1H, J ) 16.2, 3.3, 1.8 Hz), 2.45 (ddq, 2H, J ) 16.6, 9.4,
6.5), 2.28 (d, 1H, J ) 12.0 Hz), 2.07-2.07 (m, 2H), 1.82 (oct,
1H, J ) 5.5 Hz), 1.74 (dd, 1H, J ) 15.1, 8.3 Hz), 1.69 (q, 1H,
J ) 11.7 Hz), 1.33 (dd, 1H, J ) 14.9, 9.1 Hz, 1H), 0.98 (s, 9H),
0.92 (s, 9H), 0.84 (d, 3H, J ) 6.75 Hz), 0.24 (s, 3H), 0.19 (s,
3H), 0.16 (s, 3H), 0.13 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
168.5, 153.1, 139.0, 131.7, 130.0, 128.6, 127.6, 123.8, 119.6,
118.6, 72.8, 72.2, 38.5, 37.2, 32.5, 26.3, 26.2, 18.8, 18.4, 13.9,
13.4, -3.6, -4.0, -4.0, -4.1; HRMS (FAB+) m/z calcd for
C31H52 N1O4 Si2 (M + H) 558.3435, found 558.3442. Z-54: 1H
NMR (400 MHz, CDCl3) δ 7.18 (t, 1H, J ) 7.9 Hz), 6.79 (d,
1H, J ) 7.5 Hz), 6.74 (d, 1H, J ) 8.2 Hz), 5.36-5.26 (m, 3H),
3.99 (d, 1H, J ) 8.4 Hz), 3.90 (dd, 1H, J ) 15.7, 8.5 Hz), 3.01
(d, 1H, J ) 15.2 Hz), 2.41-2.31 (m, 2H), 2.08-1.95 (m, 3H),
1.90-1.85 (m, 2H), 1.75-1.70 (m, 1H), 1.49 (dd, 1H, J ) 15.0,
8.9 Hz), 0.97 (s, 9H), 0.90 (s, 9H), 0.90 (m, 3H), 0.25 (s, 3H),
0.24 (s, 3H), 0.19 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.7, 153.7, 140.4, 130.8, 129.4, 129.1, 126.3, 123.4,
E-isomer: 1H NMR (400 MHz, CDCl3) δ 10.9 (s, 0.08H), 10.8
(s, 0.92H), 7.38 (t, 1H, J ) 7.9 Hz), 6.92 (d, 0.92H, J ) 8.3
Hz), 6.88 (d, 0.08H, J ) 8.3 Hz), 6.54 (dd, 0.08H, J ) 11.5, 8.1
Hz), 6.03-5.93 (m, 2H), 5.78 (ddt, 1H, J ) 17.0, 10.0, 7.2 Hz),
5.62 (d, 0.92H, J ) 16.4 Hz), 5.52 (d, 0.08H, J ) 11.0 Hz),
5.08-5.02 (m, 3H), 4.89 (dd, 1H, J ) 17.2, 1.3 Hz), 3.68 (d,
2H, J ) 5.5 Hz), 3.61-3.54 (m, 1H), 2.23 (t, 1H, J ) 13.3, 6.1
Hz), 2.03 (d, 1H, J ) 4.8 Hz), 2.00-1.93 (m, 2H), 1.78 (ddd,
1H, J ) 13.9, 10.7, 3.0 Hz), 1.68 (quintett, 1H, J ) 6.8 Hz),
0.92 (d, 2.76H, J ) 6.8 Hz), 0.89 (d, 0.24H, J ) 6.8 Hz); 13C
NMR (100 MHz, CDCl3, E-isomer) δ 170.4, 162.9, 151.2, 142.2,
137.4, 136.6, 135.1, 123.0, 116.7, 116.3, 115.9, 111.5, 101.4,
71.7, 71.0, 40.0, 38.9, 38.0, 37.8, 37.1, 15.2; HRMS (ES+) m/z
calcd for C21H26N1O4 (M + H) 356.1862, found 356.1875.
(1S,3R,4S)-1-(2-Cyanoethyl)-3-hydroxy-4-methylhept-
6-enyl 6-Hydroxy-2-prop-2-enyl-benzoate (52). To a solu-
tion of 51 (15 mg, 0.04 mmol) in benzene (10 mL) was added
[Ph3PCuH]6 (41 mg, 0.02 mmol) at 0 °C. The solution was
allowed to reach rt and was stirred for an additional 10 min.
Evaporation of the solvent and column chromatography (EtOAc:
J. Org. Chem, Vol. 70, No. 19, 2005 7603

Haack et al.
119.4, 117.7, 72.3, 70.7, 39.9, 38.8, 33.0, 32.2, 30.1, 26.3, 26.0,
14.2, 13.3, -3.7, -4.1, -4.1, -4.3.
Postdoctoral Program of the German Academic Ex-
change Service (DAAD), a fellowship from an NIH
training grant (GM07775) and a fellowship from the
American Foundation for Pharmaceutical Education
(B.B.), and a postdoctoral fellowship from the Deutsche
Forschungsgemeinschaft (W.E.D.).
3-[(3S,5R,6S)-5,14-Bis(1,1,2,2-tetramethyl-1-silapropoxy)-
6-methyl-1-oxo-2, 3,4,5,6,7,10-heptahydrobenzo[d][12]-
annulen-3-yl]propanenitrile (E-54 from 23). A solution of
23 (33 mg, 0.10 mmol), TBSOTf (0.23 mL, 1.0 mmol), and
pyridine (1 mL) in CH2Cl2 (6 mL) was stirred for 4 h. The
mixture was directly loaded on a silica gel column. Column
chromatography (EtOAc:hexane 1:9) afforded 54 mg (97%) of
54. For data, refer to the previous synthesis of 54 above.
1
Supporting Information Available: Copies of H NMR
spectra for compounds 8-12, 14-23, 25-54. Copies of 13C
NMR spectra for compounds 8-12, 14-18, 20-23, 25-37,
46-54. HPLC traces for compounds 21, 38-45. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge fi-
nancial support from the NIH (CA84173). This work
was also supported by a fellowship (T.H.) within the
JO050750X
7604 J. Org. Chem., Vol. 70, No. 19, 2005