Synthetic studies toward sarain A. Formation of the western macrocyclic ring

Article abstract of DOI:10.1021/jo026914g

Starting with the tricyclic core 2b, annulation to form the 13-membered western ring of sarain A has been achieved to afford the macrocycle 30a by initial construction of the sterically congested quaternary center at C-3, followed by elaboration of the C-

Full text of DOI:10.1021/jo026914g

Syn th etic Stu d ies tow a r d Sa r a in A. F or m a tion of th e Wester n
Ma cr ocyclic Rin g
Moo J e Sung, Hyoung Ik Lee, Hee Bong Lee, and J in Kun Cha*,†
Department of Chemistry, University of Alabama, Tuscaloosa, Alabama 35487
jcha@chem.wayne.edu
Received December 27, 2002
Starting with the tricyclic core 2b, annulation to form the 13-membered western ring of sarain A
has been achieved to afford the macrocycle 30a by initial construction of the sterically congested
quaternary center at C-3, followed by elaboration of the C-3 side-chain and ring-closing olefin
metathesis. Also included is a parallel conversion of tricycle 2c to macrocycle 30b containing a
functionalized side-chain at N-1 suitable for attachment of the eastern macrocyclic ring.
SCHEME 1
Sarains A-C (1A-C) belong to a new family of
structurally intricate alkaloids found in marine sponges.
They were isolated by Cimino and co-workers from the
sponge Reniera sarai1a,b and reported to possess moderate
antitumor, antibacterial, and insecticidal activity.1c The
biosynthesis of sarains has been postulated to involve
reductive condensation of a bispyridinium macrocycle,2
and their fascinating architecture has attracted consider-
able synthetic interest.3 The stereoselective synthesis of
the tricyclic core of sarain A has been achieved by three
groups and also in our laboratory.4-7 Although sarain A
has not succumbed to a total synthesis to date, the
Weinreb group reported the construction of the “western”
macrocyclic ring by employing a Grubbs’ ring-closing
olefin metathesis strategy.4c The “eastern” macrocyclic
ring assembly of sarains was addressed by the Heathcock
group in a synthesis of an appropriately designed model
system.5b Toward a total synthesis of 1A, we herein report
a successful annulation of a western macrocyclic ring onto
2b and 2c (Scheme 1) by adaptation of Weinreb’s previ-
ous work.
Resu lts a n d Discu ssion
† Current address: Department of Chemistry, Wayne State Uni-
versity, 5101 Cass Avenue, Detroit, MI 48202.
By a slight modification of our previously reported
synthesis of 2a ,7 we first secured multigram quantities
of the N-Boc-protected tricyclic core 2b in order to
facilitate removal of the N-substituent at a later stage
under mild conditions.8 Annulation to form the western
macrocyclic ring onto 2b required initial construction of
the quaternary center at C-3. Our initial plan was to
utilize Weinreb’s alkylation of a nitrile anion at C-3
(Scheme 2).4c The nitrile 5 was prepared as an epimeric
mixture via alcohol 4 by standard methods. Despite
considerable experimentation, alkylation of 5 afforded
none of the desired C-alkylation product 6; instead, the
amide 7 was isolated in 50% (unoptimized) yield, pre-
sumably arising from N-alkylation. This disappointing
result was in sharp contrast to Weinreb’s previous
observation that a nitrile bearing an exocyclic carbamate
functionality (rather than an endocyclic lactam in 5) was
amenable to C-3 alkylation; subtle, as yet unidentified,
(1) (a) Cimino, G.; Mattia, C. A.; Mazzarella, L.; Puliti, R.;
Scognamiglio, G.; Spinella, A.; Trivellone, E. Tetrahedron 1989, 45,
3863. (b) Guo, Y.; Madaio, A.; Trivellone, E.; Scognamiglio, G.; Cimino,
G. Tetrahedron 1996, 52, 8341. (c) Caprioli, V.; Cimino, G.; De Guilio,
A.; Madaio, A.; Scognamiglio, G.; Trivellone, E. Comp. Biochem.
Physiol. 1992, 103B, 293.
(2) Cf. (a) Baldwin, J . E.; Whitehead, R. C. Tetrahedron Lett. 1992,
33, 2059. (b) Baldwin, J . E.; Bischoff, L.; Claridge, T. D. W.; Heupel,
F. A.; Spring, D. R.; Whitehead, R. C. Tetrahedron 1997, 53, 2271. (c)
Gil, L.; Gateau-Olesker, A.; Marazano, C.; Das, B. C. Tetrahedron Lett.
1995, 36, 707. (d) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano,
C.; Das, B. C. J . Am. Chem. Soc. 1998, 120, 8026.
(3) Matzanke, N.; Gregg, R. J .; Weinreb, S. M. Org. Prep. Proc. Int.
1998, 30, 1.
(4) (a) Sisko, J .; Weinreb, S. M. J . Org. Chem. 1991, 56, 3210. (b)
Sisko, J .; Henry, J . R.; Weinreb, S. M. J . Org. Chem. 1993, 58, 4945.
(c) Irie, O.; Samizu, K.; Henry, J . R.; Weinreb, S. M. J . Org. Chem.
1999, 64, 587.
(5) (a) Henke, B. R.; Kouklis, A. J .; Heathcock, C. H. J . Org. Chem.
1992, 57, 7056. (b) Heathcock, C. H.; Clasby, M.; Griffith, D. A.; Henke,
B. R.; Sharp, M. J . Synlett 1995, 467. (c) Denhart, D. J .; Griffith, D.
A.; Heathcock, C. H. J . Org. Chem. 1998, 63, 9616.
(6) Downham, R.; Ng, F. W.; Overman, L. E. J . Org. Chem. 1998,
63, 8096.
(7) Sung, M. J .; Lee, H. I.; Chong, Y.; Cha, J . K. Org. Lett. 1999, 1,
2017.
(8) Sung, M. J . Ph.D. Dissertation, The University of Alabama,
December 2001.
10.1021/jo026914g CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/11/2003
J . Org. Chem. 2003, 68, 2205-2208
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Sung et al.
SCHEME 2
SCHEME 3
electronic factors seem to play an important role in the
successful nitrile alkylation.
The exclusive N-alkylation of the nitrile 5 prompted
us to investigate N-allylation in tandem with a 3-aza-
Claisen rearrangement of the presumed intermediate 8
(Scheme 3). Walters had shown that the Claisen re-
arrangement of 3-aza-1,2,5-hexatrienes could take place
under exceptionally mild conditions.9 Unfortunately, in
lieu of the 3-aza-Claisen rearrangement product 9, only
amide 10 was obtained in 50% yield. When the amide
10 was subjected to Walters’ rearrangement protocols [I2/
(EtO)3P/Et3N] or other dehydrating reagents, it was
recovered unchanged. Similarly, the Claisen rearrange-
ment of allyl ether 12, which was readily prepared by
palladium-mediated allylation of aldehyde 11,10 was also
futile under either thermal or Lewis-acid-catalyzed con-
ditions. It became apparent that these approaches to the
construction of the quaternary center at C-3 were thwarted
by severe steric congestion.11
tography) with an excess of aqueous formaldehyde in the
presence of sodium carbonate gave diol 15a in 90% yield,
along with minute amounts of the initial aldol product
14 (Scheme 4). Formation of 15a presumably involved a
Tishchenko reaction and subsequent in situ hydrolysis
of the resulting formate (structure not shown). The aldol
condensation-Tishchenko reaction sequence could not be
extended to other nonenolizable aldehydes such as 3-tri-
methylsilylpropargyl aldehyde and acrolein for easy
installation of a longer side chain. Elaboration of the side
chain of 15a proved to be challenging and required
intramolecularity to overcome unfavorable steric effects.
Toward this end, the two hydroxyl groups in 15a were
first differentiated by the THP protecting group to
provide an equal mixture of 16, 17, and 18. These were
easily separated by column chromatography, and 18 was
readily re-converted to 15a by a catalytic amount of
p-TsOH in MeOH for recycling. Treatment of 16 with
diethylphosphonoacetyl chloride (19) in the presence of
pyridine, followed by removal of the THP protecting
group with p-TsOH, afforded alcohol 20a . Dess-Martin
oxidation of 20a and subsequent intramolecular Wittig
olefination of 21a then provided δ-lactone 22a in excel-
Ultimately, treatment of aldehyde 11 (or its more
stable epimer obtained upon silica gel column chroma-
(9) (a) Walters, M. A.; McDonough, C. S.; Brown, P. S., J r.; Hoem,
A. B. Tetrahedron Lett. 1991, 32, 179. (b) Walters, M. A.; Hoem, A. B.;
Arcand, H. R.; Hegeman, A. D.; McDonough, C. S. Tetrahedron Lett.
1993, 34, 1453. (c) Walters, M. A.; Hoem, A. B. J . Org. Chem. 1994,
59, 2645.
(10) Inoue, Y.; Toyofuku, M.; Taguchi, M.; Okada, S.-i.; Hashimoto,
H. Bull. Chem. Soc. J pn. 1986, 59, 885.
(11) Several other unsuccessful approaches are discussed in
ref 8.
2206 J . Org. Chem., Vol. 68, No. 6, 2003

Synthetic Studies toward Sarain A
SCHEME 4
SCHEME 5
To set the stage for building a 13-membered ring by
ring-closing olefin metathesis, the saturated lactone 24a
was next prepared in 97% yield by hydrogenation of 22a
(Scheme 5). Following removal (91%) of the Boc protect-
ing group by either TBSOTf or TFA, amide 25a was
obtained by acylation with 5-hexenoyl chloride in 75%
yield. The other terminal olefin moiety was then intro-
duced by selective reduction (75%) of the lactone with
NaBH4, followed by indium-mediated allylation13 (88%)
of the resulting lactol 26a to provide 27a as a diastereo-
meric mixture. The key cyclization of the diene 27a took
place smoothly (a 0.4 mM solution in refluxing CH2Cl2)
using Grubbs’ second-generation catalyst14 to afford the
13-membered lactam 28a in 71% yield. Dehydration of
28a with the Martin sulfurane15 provided conjugated
(12) (a) Bestmann, H. J . Angew. Chem., Int. Ed. Engl. 1977, 16, 349.
(b) Bestmann, H. J .; Schobert, R. Tetrahedron Lett. 1987, 28, 6587.
(13) Yi, X.-H.; Meng, Y.; Li, C.-J . Tetrahedron Lett. 1997, 38, 4731.
(14) (a) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995,
28, 446. (b) Sanford, M. S.; Love, J . A.; Grubbs, R. H. J . Am. Chem.
Soc. 2001, 123, 6543. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18. For recent reviews, see: (d) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. 1997, 36, 2036. (e) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (f) Armstrong, S. K. J . Chem. Soc., Perkin
Trans. 1 1998, 371.
lent overall yields. Similarly, 17 was converted to 22a
via 23 in comparable yields. Treatment of 14 with
Bestmann’s ylide12 furnished the respective lactone (35%
yield) that was regioisomeric to 22a ; although the yield
was not high, this control experiment allowed us to
establish the regiochemistry of 16 and 17.
(15) (a) Arhart, R. J .; Martin, J . C. J . Am. Chem. Soc. 1972, 94,
5003. (b) Martin, J . C.; Franz, J . A.; Arhart, R. J . J . Am. Chem. Soc.
1974, 96, 4604.
J . Org. Chem, Vol. 68, No. 6, 2003 2207

Sung et al.
SCHEME 6
in 15b was more conveniently achieved by means of
chloroacetylation compared to the above-mentioned use
of the THP protecting group. The chloroacetate group was
chosen over the acetate because of its facile removal by
thiourea and Et3N.16 Protection of 15b with chloroacetic
anhydride was selective for -OR1 (in preference to
-OR2), but an excess of chloroacetic anhydride was used
for rapid processing. Thus, sequential treatment of 15b
with chloroacetic anhydride and diethylphosphonoacetyl
chloride (19) gave an easily separable mixture of 31
(45%), 32 (30%), and 33 (5-10%). The last two com-
pounds were recycled to afford 15b by basic hydrolysis
(K2CO3, MeOH) in nearly quantitative yield. Diene 27b
was then obtained by adaptation of the above-mentioned
procedure for 27a ; use of the Wilkinson catalyst was
necessary for conversion of 22b to 24b to avoid concomi-
tant hydrogenolysis of the PMB group. In contrast to
uncomplicated ring closure of 27a , it was surprising that
treatment of diene 27b with the Grubbs catalyst gave
28b in lower (42%) yield, along with formation of a dimer.
Silylation of 27b prior to ring-closing olefin metathesis
gave a reliably higher yield of the desired macrocycle,
and subsequent desilylation furnished 28b in 54% overall
yield. Upon treatment of 27b with TBSOTf, the second-
ary alcohol was selectively protected as the tert-butyldi-
methylsilyl ether, validating steric congestion around the
primary alcohol. Finally, 28b was converted smoothly to
the desired macrolactam 30b, which we plan to utilize
for installation of the eastern macrocyclic ring.
In summary, we have achieved the assembly of the
western macrocyclic ring by initial construction of the
sterically congested quaternary center at C3, followed by
elaboration of the side-chain and ring-closing olefin
metathesis. Refinement of the present approach to
streamline the overall steps, as well as formation of the
remaining eastern macrocycle in 30b, is currently in
progress to complete a total synthesis of sarain A.
diene 29a in 60% yield at 88% conversion. For conven-
ience, 27a , 28a , and 29a were used as obtained in
isomeric mixtures. These isomers complicated charac-
terization but were inconsequential: hydrogenation (10%
Pd/C) of 29a gave the macrolactam 30a (95%).
We next introduced an alkoxybutane N-substitutent
in place of the PMB group prior to the construction of
the pyrrolidinone ring so as to facilitate subsequent
annulation of the eastern macrocyclic ring (Scheme 6).
By this simple alteration in the amine starting material,
large amounts of 15b were prepared in comparable
yields.8 The requisite differentiation of the two alcohols
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM35956) for generous financial sup-
port.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and copies of 1H and 13C NMR spectra of key
intermediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O026914G
(16) Use of triethylamine in place of NaHCO3 was necessary:
Naruto, M.; Ohno, K.; Naruse, N.; Takeuchi, H. Tetrahedron Lett. 1979,
20, 251.
2208 J . Org. Chem., Vol. 68, No. 6, 2003