Exploiting quadrupolar interactions in the synthesis of the macrocyclic portion of longithorone C

Article abstract of DOI:10.1021/ol800821f

(Chemical Equation Presented) 2,3,4,5,6-Pentafluorobenzyl and 3,5-bistrifluoromethylbenzyl ester auxiliaries can enable difficult macrocyclizations to afford rigid all-carbon paracyclophanes. The effectiveness of these auxiliaries has been demonstrated in

Full text of DOI:10.1021/ol800821f

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2927-2930
Exploiting Quadrupolar Interactions in
the Synthesis of the Macrocyclic Portion
of Longithorone C
Joseph E. Zakarian, Yassir El-Azizi, and Shawn K. Collins*
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128 Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
shawn.collins@umontreal.ca
Received April 10, 2008
ABSTRACT
2,3,4,5,6-Pentafluorobenzyl and 3,5-bistrifluoromethylbenzyl ester auxiliaries can enable difficult macrocyclizations to afford rigid all-carbon
paracyclophanes. The effectiveness of these auxiliaries has been demonstrated in preparing the carbon skeleton of the macrocyclic natural
product longithorone C.
Longithorone C, 1, is a farnesylated quinone and a member
of the longithorone family of natural products isolated in
1999 by Schmitz and co-workers from the marine tunicate
Aplodium longithorax.1 Longithorone C, like most members
of the family, possesses a macrocyclic [12]paracyclophane
skeleton (Figure 1). The macrocycle, which resembles a cis-
farnesol unit wrapped about a quinone core, exhibits
restricted rotation which imparts an element of planar
chirality to the structure.1a Although no biological activity
for longithorone C has been reported, longithorone A has
Figure 1. Representative members of the longithorone family of
natural products.
been shown to display cytotoxicity against P388 murine
leukemia cells (IC50 ∼10 µg/mL) and longithorone J has
displayed minimal activity in some human cell lines.2 To
demonstrate the rigidity of the skeleton of longithorone C,
Schmitz and co-workers refluxed 1 in toluene for 7 days.
Some degradation was observed, but the optical rotation
remained unchanged.1a Few synthetic studies directed toward
the synthesis of these macrocyclic natural products have been
reported, perhaps denoting the significant synthetic challenge
associated with constructing the planar chiral carbon skeleton.
(1) For the isolation of longithorone C, see:(a) Fu, X.; Hossain, M. B.;
Schmitz, F. J.; van der Helm, D. J. Org. Chem. 1997, 62, 3810–3819For
the isolation of other family members, see: (b) Fu, X.; Ferreira, M. L.;
Schmitz, F. J. J. Nat. Prod. 1999, 62, 1306–1310. (c) Davis, R. A.; Carroll,
A. R.; Quinn, R. J. J. Nat. Prod. 1999, 62, 158–160. (d) Fu, X.; Hossain,
M. B.; van der Helm, D.; Schmitz, F. J. J. Am. Chem. Soc. 1994, 116,
12125–12126.
(2) Davis, R. A.; Carroll, A. R.; Watters, D.; Quinn, R. J. Nat. Prod.
Res., Part B 2006, 20, 1277–1282.
10.1021/ol800821f CCC: $40.75
Published on Web 06/24/2008
2008 American Chemical Society

Kato et al. have reported on the synthesis of longithorone
B,3 and Shair and co-workers have prepared a dimeric
member of the longithorone family, longithorone A.4 Herein,
we report the first application of auxiliaries that engage in
quadrupolar interactions in a total synthesis objective: the
preparation of the macrocyclic portion of longithorone C.
The synthetic challenge of preparing extremely rigid
macrocycles, such as the [12]paracyclophane core of lon-
githorone C, in an efficient and asymmetric fashion encour-
aged us to develop new methods for enabling difficult
macrocyclizations.5 In 2006, we reported the use of perfluo-
robenzyl ester auxiliaries as conformational control elements
for macrocyclizations using olefin metathesis.6 In 2007, we
reported that 3,5-bistrifluoromethylbenzyl ester auxiliaries
were also effective and demonstrated their utility in en-yne
metathesis macrocyclizations.7 The fluoroarene auxiliaries
are believed to engage in noncovalent interactions with the
macrocyclic precursors, coercing the substrate into a con-
formation conducive to ring closure.8
Our initial studies into the use of these auxiliaries were
conducted using substrates that contained oxygen atoms
attached to the arene core that would become part of the
formed macrocycle. We had reported that molecular model-
ing studies suggested that the fluorinated rings of the
auxiliaries engage in 1p-π interactions with the lone pairs
of the oxygen atoms, resulting in a preference for a “closed”
conformation that is conducive to ring closure.6,9 The
molecular modeling studies also suggested that the 3,5-
bistrifluoromethylbenzyl ester auxiliaries would be more
effective in these model substrates. This hypothesis was also
proven correct through experiment.7 However, in the absence
of oxygen-containing substrates, like those found in the
longithorone family of natural products, the molecular
modeling studies suggested that the pentafluorobenzyl aux-
iliary would be more effective (Figure 2). Molecular model-
ing suggested that the ester 2 would prefer a conformation
2-S in which a quadrupolar interaction would be present,
Figure 2. Comparison of pentafluorobenzyl and 3,5-bistrifluoro-
methylbenzyl ester auxiliaries by molecular modeling.
over the conformation 2-O by -0.55 kcal/mol.10 Similarly,
the ester 3 would also prefer conformation 3-S over 3-O,
however, only by -0.41 kcal/mol.7 To investigate whether
the molecular modeling studies could be used to predict
which auxiliaries would be more effective for a given
substrate, we undertook the synthesis of the carbon skeleton
of longithorone C to probe the efficiency of our auxiliaries
and the results of the previous molecular modeling study.
Hence, the carbon skeleton of longithorone C, represented
by 4 (Figure 3), could arise from a macrocyclic relay ring
(3) Kato, T.; Nagae, K.; Hoshikawa, M. Tetrahedron Lett. 1999, 40,
1941–1944.
(4) (a) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc.
2002, 124, 773–775. (b) Morales, C. A.; Layton, M. E.; Shair, M. D. Proc.
Natl. Acad. Sci. 2004, 101, 12036–12041.
(5) Some difficult macrocyclizations have been aided by the use of
substituted methylenes as gearing elements. See reference 4 and: (a)
Commeureuc, A. G. J.; Murphy, J. A.; Dewis, M. L Org. Lett. 2003, 5,
2785–2788. (b) Kim, S. H.; Figueroa, I.; Fuchs, P. L. Tetrahedron Lett.
1997, 38, 2601–2604.
Figure 3. Retrosynthetic analysis of the carbon skeleton of
(6) (a) El-azizi, Y.; Schmitzer, A.; Collins, S. K. Angew. Chem., Int.
Ed. 2006, 45, 968–973. (b) Collins, S. K.; El-Azizi, Y. Pure Appl. Chem.
2006, 78, 783–789.
longithorone C.
(7) Collins, S. K.; El-Azizi, Y.; Schmitzer, A. R. J. Org. Chem. 2007,
72, 6397–6408.
closing metathesis (RRCM)11 of ester 5. The preparation of
the macrocyclization precursor 5 required the installation of
two carbon-arene bonds. We envisioned preparing these
bonds through copper-catalyzed Grignard reactions, made
possible by combining recent methods for Mg-I exchanges
(8) For some recent uses of quadrupolar interactions, see:(a) Marsella,
M. J.; Wang, Z.-Q.; Reid, R. J.; Yoon, K. Org. Lett. 2001, 3, 885–887. (b)
Gorske, B. C.; Blackwell, H. E. J. Am. Chem. Soc. 2006, 128, 14378–
14387. (c) Woll, M. G.; Hadley, E. B.; Mecozzi, S.; Gellman, S. H. J. Am.
Chem. Soc. 2006, 128, 15932–15933. (d) Watt, S. W.; Dai, C.; Scott, A. J.;
Burke, J. M.; Thomas, R. L.; Collings, J. C.; Viney, C.; Clegg, W.; Marder,
T. B. Angew. Chem., Int. Ed. 2004, 43, 3061–3063. (e) Collings, J. C.;
Batsanov, A. S.; Howard, J. A. K.; Dickie, D. A.; Clyburne, J. A. C.; Jenkins,
H. A.; Marder, T. B. J. Fluorine Chem. 2005, 126, 515–519. (f) Collings,
J. C.; Burke, J. M.; Smith, P. S.; Batsanov, A. S.; Howard, J. A. K.; Marder,
T. B. Org. Biomol. Chem. 2004, 2, 3172–3178.
(10) For a recent molecular modeling study on quadrupolar interactions
with pentafluorobenzenes, see: Gung, B. W.; Amicangelo, J. C. J. Org.
Chem. 2006, 71, 9261–9270.
(9) (a) Gung, B. W.; Xue, X.; Reich, H. J. J. Org. Chem. 2005, 70,
7232–7237. (b) Gung, B. W.; Xue, X.; Reich, H. J. J. Org. Chem. 2005,
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70, 3641–3644
.
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Org. Lett., Vol. 10, No. 14, 2008

with copper-catalyzed allylic couplings. As such, the three
key carbon subunits necessary are the allylic electrophiles
6, 7, and 8 and the iso-propyl ester 9.
Scheme 2. Installation of Side Chains
The preparation of side chains 6 and 7 has been previously
reported.12 The synthesis of side chain 8 (Scheme 1) was
Scheme 1. Synthesis of Side Chain 8
of the newly formed Grignard reagent was added to a solution
of acetate 7 and a catalytic amount of Li2CuCl4 catalyst.15
Following workup, the iodide 16 was isolated in 80% yield.
The configuration of the benzylic olefin in 16 was confirmed
through an NOE study and was found to be identical to the
configuration in acetate 7. Other copper catalysts surveyed
(CuI, CuCN·LiCl) resulted in very low yields (<20%) of
16. The use of an allylic bromide 6 as a coupling partner
resulted in a 45% isolated yield of the iodide 16. All attempts
to adjust the reaction conditions using bromide 6 as the
coupling partner resulted in inseparable mixtures of 16 and
21. Consequently, the acetate 8 was used in the second
copper-catalyzed coupling reaction.
The Mg-I exchange in 16 was considerably more difficult.
The absence of the ester functional group ortho to the iodide
in 16 necessitated a larger quantity of i-PrMgBr and lower
temperatures to effect a clean and quantitative Mg-I
exchange. Following a similar protocol as described above,
the acetate 8 was added, and the product 17 was isolated in
65% yield. It was necessary to keep the reaction mixture as
concentrated as possible to maximize the yields. It should
be noted that the use of i-PrMgCl·LiCl promoted an
extremely rapid exchange; however, the yields of 17 were
unexplicably low (<10%).
adapted from a previous report on the synthesis of cis-
farnesol.13 Geranyl acetate 10 underwent selective ozonolysis
producing the corresponding aldehyde in good yield (72%).
Wittig reaction using the ylide generated from n-BuLi and
ethyltriphenylphosponium bromide followed by cleavage of
the acetate protecting group afforded alcohol 11. The alcohol
11 was subsequently converted to the corresponding bromide
12 in quantitative yield upon treatment with PBr3. The
bromide 12 was reacted with the Weiler dianion of ethyl
acetoacetate to afford the ꢀ-ketoester 13. The corresponding
phosphonate was formed from the enolate of 13 generated
from NEt3 in the presence of DMPU in 69% yield. Upon
treatment of the phosphonate with the cuprate generated from
a mixture of MeMgCl, MeLi, and CuI, the ester 14 was
obtained in 91% yield, and only the cis-isomer was observed
1
by H NMR. The reduction of 14 with DIBAL-H and
subsequent acetylation afforded the side chain 8.
The assembly of the carbon skeleton of longithorone C,
4, began with the esterification of 2,5-diiodobenzoic acid with
2-iodopropanol. The ester 9 was used in the subsequent
copper-catalyzed Grignard reactions. The corresponding
methyl esters or pentafluorobenzyl esters of 15 were incom-
patible in the following Mg-I exchange reaction, where the
esters normally underwent competitive nucleophilic attack.14
Treatment of ester 9 with i-PrMgBr at -40 °C lead to
complete Mg-I exchange in 10 min (Scheme 2). A solution
(14) For leading references on the Mg-I exchange, see: (a) Dohle, W.;
Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu,
V. A.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 4302–4320. (b)
Rottlander, M.; Boymond, L.; Berillon, L.; Lepretre, A.; Varchi, G.; Avolio,
S.; Laaziri, H.; Queguiner, G.; Ricci, A.; Cahiez, G.; Knochel, P.
Chem.-Eur. J. 2000, 6, 767–770. (c) Jensen, A. E.; Dohle, W.; Sapountzis,
I.; Lindsay, D. M.; Vu, V. A.; Knochel, P. Synthesis 2002, 4, 565–569. (d)
Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem. Commun. 2006, 6,
583–593. (e) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004,
25, 3333–3336. (f) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 1, 159–162.
(12) Amslinger, S.; Kis, K.; Hecht, S.; Adam, P.; Rohdich, F.; Arigoni,
D.; Bacher, A.; Eisenreich, W. J. Org. Chem. 2002, 67, 4590–4594.
(13) (a) Brown, R. C. D.; Bataille, C. J.; Hughes, R. M.; Kenney, A.;
Luker, T. J. J. Org. Chem. 2002, 67, 8079–8085. (b) Gibbs, R. A.; Eummer,
J. T.; Shao, Y. Org. Lett. 1999, 1, 627–630. (c) For an alternative synthesis
of cis-farnesol, see: Yu, J. S.; Kleckley, T. S.; Wiemer, D. F Org. Lett.
2005, 7, 4803–4806.
(15) For references on transmetallation to Cu and subsequent coupling,
see: (a) Rottlander, M.; Boymond, L.; Berillon, L.; Lepretre, A.; Varchi,
G.; Avolio, S.; Laaziri, H.; Queguiner, G.; Ricci, A.; Cahiez, G.; Knochel,
P. Chem.-Eur. J. 2000, 6, 767–770. (b) Backvall, J. E.; Sellen, M.; Grant,
B. J. Am. Chem. Soc. 1990, 112, 6615–6621.
Org. Lett., Vol. 10, No. 14, 2008
2929

To investigate the macrocyclization with both the pen-
tafluorobenzyl ester and 3,5-bistrifluoromethylbenzyl ester
auxiliaries, the esters 19 and 20 were synthesized and their
macrocyclization investigated using both the Grela catalyst
2516 and the Blechert catalyst 22.17 To construct the
fluorinated esters, the iso-propyl ester 17 was first saponified
using NaOH in refluxing MeOH/PhMe to yield the corre-
sponding carboxylic acid 18 in 95% yield. Alkylation with
the corresponding benzyl bromides afforded the esters 19
and 20 in excellent overall yields following purification by
chromatography. Some decomposition of 20 was observed
over time, and it was usually stored in frozen benzene at
-18 °C.
only trace amounts of the desired macrocycle were obtained.
Last, the use of any other ester other than the fluoroarenes
discussed here resulted in the formation of only dimers and
oligomers.
Treatment of the pentafluorophenyl benzyl ester 20 with
catalyst 25 in PhMe afforded a 32% isolated yield of the
rigid macrocycle 4. Changing the solvent to CH2Cl2 and
using the more reactive Blechert catalyst 22 afforded slightly
higher yields of the corresponding macrocycle (37-40%).
The ester 19 containing a bis-1,3-trifluoromethylbenzyl ester
auxiliary did not afford higher yields than the corresponding
pentafluorobenzyl ester 20. Treatment of 19 with catalyst
25 in either CH2Cl2 or PhMe afforded 20-23% yields of
the isolated macrocycle. In all cases, the reactions afforded
24 as the major product, where the relay ring closing
metathesis side chain has been consumed but no productive
macrocyclization has occurred. These results are in agreement
with the molecular modeling results discussed earlier. The
pentafluorobenzyl ester 2 was calculated to have only a
slightly higher energetic preference for its “stacked” con-
former 2-S (∼0.1 kcal/mol) compared to the 3,5-bistrifluo-
romethylbenzyl ester. Although this represents a seemingly
small energetic difference, it accounts for approximately 20%
higher yields in the formation of macrocyclization products.
With the two esters 19 and 20 in hand, their macrocy-
clization was investigated (Table 1). It should be noted that
Table 1. Macrocyclization to Form the Carbon Skeleton of
Longithorone C
In summary, we have synthesized the highly rigid mac-
rocyclic carbon skeleton of the natural product longithorone
C. The synthesis of the carbon skeleton 4 highlights the
effectiveness of quadrupolar interactions as synthetically
useful noncovalent interactions capable of controlling the
conformation of molecules for macrocyclization. The com-
bination of Mg-I exchange and copper-catalyzed Grignard
reactions allowed the stereocontrolled installation of the
olefinic chains for macrocyclization. It is likely that this
strategy would be of use in the preparation of other natural
products. The success of these auxiliaries opens the way to
the development of chiral gearing elements to induce
atropisomerism.
substrate
cat.
solvent
yield (%)a
20
20
19
19
25
22
25
25
PhMe
CH2Cl2
PhMe
32
37
20
23
CH2Cl2
a Represents isolated yield after chromatography.
Acknowledgment. We thank the NSERC (Canada),
FQRNT (Que´bec), CFI (Canada), Boehringer Ingelheim
(Canada) Ltd., Merck Frosst Centre for Therapeutic Re-
search, AstraZeneca, and the Universite´ de Montre´al for
generous financial support. The authors thank Sylvie Bilo-
deau (Universite´ de Montre´al) for help in acquiring the NMR
spectra of 4.
three structural features of 19 and 20 are essential for
successful macrocyclization. First, the relay ring closing
metathesis strategy was necessary, otherwise only dimeriza-
tion of the starting material was observed. Second, esters
19 and 20 were prepared with a cis-olefin as the metathesis
partner. If this olefin was substituted for a terminal olefin,
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Bieniek, M.; Michrowska, A.; Gulajski, L.; Grela, K. Organome-
tallics 2007, 26, 1096–1099.
(17) (a) Buschmann, N.; Wakamatsu, H.; Blechert, S. Synlett 2004, 4,
667–670. (b) Dunne, A. M.; Mix, S.; Blechert, S. Tetrahedron Lett. 2003,
44, 2733–2736.
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