Evolution of a strategy for total synthesis of the marine fungal alkaloid (±)-communesin F

Article abstract of DOI:10.1021/jo100339k

A new synthetic strategy for construction of the heptacyclic marine fungal alkaloid (±)-communesin F has been devised. Key reactions include an intramolecular Heck cyclization of a tetrasubstituted alkene to generate a tetracyclic enamide bearing one of the quaternary carbon centers (C7) of the alkaloid, an intramolecular reductive cyclization of an N-Boc aniline onto the oxindole moiety to form a pentacyclic framework containing the southern aminal, a stereoselective N-Boc-lactam enolate C-allylation to introduce the second quaternary carbon center (C8), and an azide reduction/N-Boc-lactam-opening cascade leading to the northern aminal.

Full text of DOI:10.1021/jo100339k

pubs.acs.org/joc
Evolution of a Strategy for Total Synthesis of the Marine Fungal
Alkaloid (()-Communesin F
Jae Hong Seo, Peng Liu, and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
smw@chem.psu.edu
Received February 23, 2010
A new synthetic strategy for construction of the heptacyclic marine fungal alkaloid (()-communesin
F has been devised. Key reactions include an intramolecular Heck cyclization of a tetrasubstituted
alkene to generate a tetracyclic enamide bearing one of the quaternary carbon centers (C7) of the
alkaloid, an intramolecular reductive cyclization of an N-Boc aniline onto the oxindole moiety to
form a pentacyclic framework containing the southern aminal, a stereoselective N-Boc-lactam enolate
C-allylation to introduce the second quaternary carbon center (C8), and an azide reduction/
N-Boc-lactam-opening cascade leading to the northern aminal.
Introduction and Background
In 2003, Hemscheidt and co-workers described an alka-
loid, nomofungin (9), which was isolated from the fermen-
tation broth of an unidentified fungus derived from the
bark of Ficus microcarpa L., growing on the Manoa campus
of the University of Hawaii.2 The name nomofungin was
chosen because the fungus producing this alkaloid was lost
after isolation of the metabolite. Although nomofungin and
communesin B (5) have identical 1H and 13C NMR spectral
data, the metabolite was initially proposed to have struc-
ture 9, which has a lower N,O-acetal rather than the aminal
of communesin B. However, it was later found that this
assignment was incorrect and that nomofungin is actually
communesin B (5). It should be noted that the Hemscheidt
studies did establish both the configuration at C21 of 5
using Murata’s J-based NMR method, as well as the abso-
lute configuration of the molecule using the exciton chira-
lity method as being 6R,7R,8R,9S,11S,21R as shown.
Hemscheidt also found that communesin B has cyto-
toxic activity against LoVo and KB cells (MIC 2.0 μg/
mL, 4.5 μg/mL, respectively), which was shown to be due
Marine microbes are a relatively new source of unique
natural products, in contrast to terrestrial microorga-
nisms, which have been studied extensively for many
decades. In 1993, Numata and co-workers reported two
structurally unique polycyclic alkaloids, communesin A
(1) and B (5), which were isolated from a Penicillium
fungus growing on the marine alga Enteromorpha intesti-
nalis (Figure 1).1 Communesins A (1) and B (5) show
cytotoxicity against P-388 lymphocytic leukemia cells
with moderate to potent activity (ED50 = 3.5 μg/mL and
0.45 μg/mL, respectively). The structures of these alka-
loids were elucidated by extensive spectroscopic analysis.
Thus, the communesins have a novel heptacyclic skeleton
bearing two aminal functional groups, two vicinal quater-
nary carbon centers (C7, C8) and an epoxide moiety. The
relative stereochemistry of the communesins (except for
C21) was determined by NMR NOE studies, although the
absolute configurations of 1 and 5 could not be established
at that time.
(2) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt,
T. K. J. Org. Chem. 2001, 66, 8717. For the retraction of the putative
nomofungin structure, see: Ratnayake, A. S.; Yoshida, W. Y.; Mooberry,
S. L.; Hemscheidt, T. K. J. Org. Chem. 2003, 68, 1640.
(1) (a) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.;
Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron
Lett. 1993, 34, 2355.
DOI: 10.1021/jo100339k
r
Published on Web 03/24/2010
J. Org. Chem. 2010, 75, 2667–2680 2667
2010 American Chemical Society

Seo et al.
JOCArticle
FIGURE 1. Communesins and perophoramidine.
to the ability of the metabolite to cause microfilament dis-
ruption.
Extensive spectroscopic analysis showed that the compound
has a hexacyclic ring system (i.e., one less ring than the
heptacyclic skeleton of the communesins due to the absence
of the azepine-G-ring). Perophoramidine has a bis-amidine
rather than the bis-aminal functionality present in the com-
munesins, as well as three halogen atoms in the aromatic
rings. Perophoramidine also has adjacent quaternary car-
bons (C4, C20) similar to the communesins, but the relative
stereochemistry of these two stereogenic centers was found
to be opposite that of the communesins. The absolute stereo-
chemistry of perophoramidine has not yet been established.
Perophoramidine has cytotoxicity against the HCT116
colon carcinoma cell line (IC50 = 60 μM) due to induction
of apoptosis by poly(adenosine-50-diphosphateribose)poly-
merase (PARP) cleavage.
Although there is relatively little in the way of experimental
evidence to date for the biogenesis of these metabolites, it is
clear that they are derived from two tryptamines units, along
with an isoprenoid moiety in the case of the communesins.7
Structurally, the communesins and perophoramidine closely
resemble members of the calycanthaceous family of plant
alkaloids, whose biogenesis was suggested via an oxidative
dimerization of tryptamine many years ago.8 More recently,
Stoltz et al. have proposed an alternative pathway for forma-
tion of the communesins via a hetero-Diels-Alder step.9
The novel structures of the communesins and perophor-
amidine, as well as the promising biological activity of these
alkaloids, have caught the attention of a number of synthetic
chemists. To date, however, few successful total syntheses of
these complex metabolites have been reported, perhaps due
in part to difficulties in the stereoselective formation of the
Recently, several other communesins have been isolated,
including communesin C (6), D (7), E (2), F (8), G (3), and H
(4).3 These metabolites differ only in the substituents at N15
and N16, except for communesin F, which has a double bond
instead of an epoxide at C21,22. Communesins C and D,
along with communesin B, were isolated from a Penicillium
species growing on the sponge Axinella verrucosa.3a All three
compounds exhibit moderate antiproliferative activity
against a series of leukemia cell lines. Communesins A, B,
D, E, and F were also isolated from the fermentation broth of
okara (the insoluble residue of whole soybeans) with Peni-
cillium espansum Link MK-57.3b,4 These communesins show
insecticidal activity against the third instar larvae of silk-
worms (LD50=150, 5, 80, 300, and 80 μg/g for communesins
A, B, D, E, and F, respectively). Communesins G and H,
which were isolated from Penicillium rivulum Frisvad,3c were
found to be inactive in antimicrobial, antiviral, and anti-
cancer assays. Several additional communesin derivatives
have recently been detected by mass spectrometry in a
marine Penicillium, although the complete structures of these
new metabolites have not yet been determined.3d,5
In 2002, Ireland et al. reported the isolation of a related
metabolite, perophoramidine (10), from the tropical colo-
nial ascidian Perophora namei collected in the Philippines.6
(3) (a) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.;
Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004, 67, 78. (b) Hayashi, H.;
Matsumoto, H.; Akiyama, K. Biosci. Biotechnol. Biochem. 2004, 68, 753.
(c) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad, J. C.;
Christophersen, C. J. Nat. Prod. 2005, 68, 258. (d) Kerzaon, I.; Pouchus,
Y. F.; Monteau, F.; Le Bizec, B.; Nourrisson, M.-R.; Biard, J.-F.; Grovel, O.
Rapid Commun. Mass Spectrom. 2009, 23, 3928.
(4) There is some confusion about nomenclature since some structurally
different compounds were initially designated as the same communesins due
to simultaneous publication by two groups (see ref 3a,3b). The currently
accepted communesin nomenclature can be found in ref 3c.
(5) For a brief review of the communesins, see: Siengalewicz, P.; Gaich,
T.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2.
(7) For labeling studies on the biosynthesis of the communesins, see:
Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561.
(8) (a) Robinson, R.; Teuber, H. J. Chem. Ind. 1954, 783. (b) Woodward,
R. B.; Yand, N.; Katz, T. J. Proc. Chem. Soc., London 1960, 76.
(c) Hendrickson, J. B.; Rees, R.; Goschke, R. Proc. Chem. Soc., London
1962, 383.
(6) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.;
Ireland, C. M. J. Org. Chem. 2002, 67, 7124.
(9) (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44,
1203. (b) May, J. A.; Stoltz, B. M. Tetrahedron 2006, 62, 5262.
2668 J. Org. Chem. Vol. 75, No. 8, 2010

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SCHEME 1
SCHEME 2
SCHEME 3
adjacent quaternary carbon centers. Funk and Fuchs made a
breakthrough on these molecules by completing an elegant
total synthesis of racemic perophoramidine utilizing a key
biomimetically patterned hetero Diels-Alder reaction.10
Unnatural dehaloperophoramidine has also been synthe-
sized by Rainier and co-workers through a quite different
strategy.11 More recently, Qin et al. have published the first
total synthesis of racemic communesin F.12 In addition, a few
other preliminary synthetic approaches to the core ring
system of the communesins and perophoramidine have been
reported.13-15 Herein we report a new approach to the
communesins, culminating in a total synthesis of racemic
communesin F (8).16,17
form a tetracyclic enamine derivative 15 having the C7
quaternary carbon (Scheme 2). In this case, a carbonylation
is not necessary since the tetrahydropiperidine ring incorpo-
rates a carbon which will become C9 of the communesins.
Moreover, the cyclization product 15 has the enamine func-
tionality in a position to facilitate introduction of the second
(C8) quaternary center. It should be noted that we app-
roached this transformation with some trepidation, since
examples of intramolecular Heck reactions of tetrasubstituted
double bonds are relatively uncommon.19,20 In the work
described below, we have investigated three series of Heck
substrates 14 which differ in the substituent (X) at C12a in the
F-ring. These substituents were intended to provide suitable
functionality for eventual construction of the azepine-G-ring
and also allow some flexibility with regard to protecting group
compatibility during various steps in the synthesis.
In order to prepare the requisite substrates 14 for the Heck
reaction, we employed the three different F-ring anilines
shown in Scheme 3. Thus, known nitro benzyl alcohol 1621
was converted to the BOM ether 17a and the TBS ether 17b
via standard procedures in good yields. The corresponding
anilines 18a and 18b were then prepared conveniently by
iron-promoted reduction of the nitro compounds. The third
aniline required, 18c, is a known compound which was acces-
sed by the literature procedure.22
Results and Discussion
Our initial unified approach to synthesis of both the com-
munesins and perophoramidine was to rely on a tandem intra-
molecular Heck reaction/carbonylation of an acrylamide sub-
strate such as 11 to form a lactam ester like 12 (Scheme 1). This
compound would then be transformed to a tetracycle 13, where
the lactone carbonyl would become C9 of the communesins
(C24 of perophoramidine) and provide a handle to establish the
quaternary carbon at C8. In a series of publications, we have
described the implementation of this basic strategy.14 However,
we have found that the success of the key Heck/carbonylation
step was highly dependent upon the substituents in the two
aromatic rings of 11, and even in the optimal cases reproduci-
bility often was an issue, particularly for large-scale reactions.
As a result, we decided to investigate a new strategy which
would bypass this problematic step.
Thus, we considered the possibility of effecting a pivotal
intramolecular Heck reaction18 of a system such as 14 to
The B/C-ring component required for synthesis of the Heck
substrates 14 was easily prepared from commercially available
(10) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068.
(11) Sabhi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006,
45, 4317.
(12) (a) Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8,
2187. (b) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129,
13794.
(13) Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169.
(14) (a) Artman, G. D., III; Weinreb, S. M. Org. Lett. 2003, 5, 1523.
(b) Artman, G. D., III. Ph.D. Thesis, The Pennsylvania State University, University
Park, PA, 2004. (c) Seo, J. H.; Artman, G. D., III; Weinreb, S. M. J. Org. Chem.
2006, 71, 8891. (d) Evans, M. A.; Sacher, J. R.; Weinreb, S. M. Tetrahedron
2009, 65, 6712.
(15) George, J. H.; Adlington, R. M. Synlett 2008, 2093.
(16) A preliminary account of a portion of this work has appeared: Liu,
P.; Seo, J. H.; Weinreb, S. M. Angew. Chem., Int. Ed. 2010, 49, 2000.
(17) Taken from the Ph.D. theses of: (a) Seo, J. H. The Pennsylvania State
University, University Park, PA, 2008. (b) Liu, P. The Pennsylvania State
University, University Park, PA, 2010.
(19) For examples of intramolecular Heck reactions with substrates
bearing tetrasubstituted alkene moieties, see: (a) Grigg, R.; Sridharan, V.;
Stevenson, P.; Worakun, T. J. Chem. Soc., Chem. Commun. 1986, 1697.
(b) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133.
(c) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S. Tetrahedron
1989, 45, 3557. (d) Cheng, C.-Y.; Liou, J.-P.; Lee, M.-J. Tetrahedron Lett.
1997, 38, 4571. (e) Liou, J.-P.; Cheng, C.-Y. Tetrahedron Lett. 2000, 41, 915.
(f) Hsin, L.-W.; Chang, L.-T.; Chen, C.-W.; Hsu, C.-H.; Chen, H.-W.
Tetrahedron 2005, 61, 513. (g) Frey, D. A.; Duan, C.; Hudlicky, T. Org.
Lett. 1999, 1, 2085. (h) Fukuyama, Y.; Yuasa, H.; Tonoi, Y.; Harada, K.;
Wada, M.; Asakawa, Y.; Hashimoto, T. Tetrahedron 2001, 57, 9299.
(i) Nicolaou, K. C.; Roecker, A. J.; Follmann, M.; Baati, R. Angew. Chem.,
Int. Ed. 2002, 41, 2107.
(20) For an intermolecular example, see: Dyker, G.; Korning, J.; Jones,
P. G.; Bubenitschek, P. Angew. Chem., Int. Ed. 1993, 32, 1733.
(21) (a) Seno, K.; Hagishita, S.; Sato, T.; Kuriyama, K. J. Chem. Soc.
Perkin Trans. 1 1984, 2012. (b) Ozlu, Y.; Cladingboel, D. E.; Parsons, P. J.
Tetrahedron 1994, 50, 2183.
(18) For a review of the intramolecular Heck reaction, see: Link, J. T.
Org. React. 2002, 60, 157.
(22) Liedholm, B. Acta Chem. Scand. 1993, 47, 701.
J. Org. Chem. Vol. 75, No. 8, 2010 2669

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SCHEME 4
materials. Therefore, known enol triflate 19,23 readily acces-
sible from the corresponding β-keto ester, was coupled in a
Suzuki-Miyaura reaction with o-nitrobenzeneboronic acid to
afford β-arylated-R,β-unsaturated ester 20 in excellent yield
(Scheme 4).24 This ester was converted to acid 21 by basic
hydrolysis and then to the corresponding acid chloride 22.
Without purification, 22 was combined with anilines 18a-c in
the presence of Hunig’s base to cleanly afford amides 23a-c,
respectively. It was found most convenient to replace the
N-benzyl group of these intermediates at this point with a carba-
mate protecting group. Thus, exposure of 23a-c to ethyl chlo-
roformate in methylene chloride at room temperature resulted
in high yields of ethyl carbamates 24a-c.25 All three compounds
could be transformed to the N-methylamides 25a-c in excellent
yields with sodium hydride and methyl iodide.
With the requisite substrates in hand, we proceeded to
explore the key intramolecular Heck cyclizations. We were
pleased to find that both O-protected hydroxymethyl-sub-
stituted systems 25a and 25b underwent rapid, high-yielding
Heck reactions under the conditions shown in Scheme 4 to
afford the desired spirocyclic enamides 26a and 26b, respec-
tively. On the other hand, the cyclization of the C12a
bromine-substituted substrate 25c proved to be much more
problematic.
Therefore, when compound 25c was exposed to the same
experimental conditions as used successfully for 25b, a 1:1
mixture of the desired Heck product 26c along with penta-
cyclic enamide 27 was formed in 74% total yield (Scheme 5).
The latter compound presumably arises from a subsequent
Heck arylation of bromide 26c. However, after some experi-
mentation, it was found that by lowering the reaction
temperature to 100 °C and allowing the reaction to proceed
for 1 h produced a mixture of 26c and 27 in a 6.7:1 ratio in
51% total yield, along with 40% of recovered starting
material 25c which could be recycled. Since compounds
26c and 27 were not easily separable by silica gel chroma-
tography, the crude mixture was reduced with iron/concen-
trated HCl to afford aniline 28, which could then be
separated from the amine derived from 27 (84% isolated
yield based on the amount of nitro compound 26c in the
mixture). This material was next converted to the Boc
derivative 29c in high yield.
(23) Ferraris, D.; Ficco, R. P.; Pahutski, T.; Lautar, S.; Huang, S.; Zhang,
J.; Kalish, V. Bioorg. Med. Chem. Lett. 2003, 13, 2513.
(24) For examples of Suzuki-Miyaura couplings with o-nitrobenzene-
boronic acid, see: (a) Ho, T.-L.; Hsieh, S.-Y. Helv. Chim. Acta 2006, 89, 111.
(b) Gonzalez, R. R.; Liguori, L.; Carrillo, A. M.; Bjorsvik, H.-R. J. Org.
Chem. 2005, 70, 9591. (c) Myers, A. G.; Herzon, S. B. J. Am. Chem. Soc. 2003,
125, 12080. (d) Ghosez, L.; Franc, C.; Denonne, F.; Cuisinier, C.; Touillaux,
R. Can. J. Chem. 2001, 79, 1827. (e) Murugesan, N.; Gu, Z.; Stein, P. D.;
Bisaha, S.; Spergel, S.; Girotra, R.; Lee, V. G.; Lloyd, J.; Misra, R. N.;
Schmidt, J.; Mathur, A.; Stratton, L.; Kelly, Y. F.; Bird, E.; Waldron, T.;
Liu, E. C.-K.; Zhang, R.; Lee, H.; Serafino, R.; Abboa-Offei, B.; Mathers, P.;
Giancarli, M.; Seymour, A. A.; Webb, M. L.; Moreland, S.; Barrish, J. C.;
Hunt, J. T. J. Med. Chem. 1998, 41, 5198. (f) Thompson, W. J.; Gaudino, J.
J. Org. Chem. 1984, 49, 5237.
(25) For examples of replacement of an N-benzyl group with a carbamate
moiety in a one-pot reaction, see: (a) Ottenbrite, R. M.; Alston, P. V. J. Org.
Chem. 1974, 39, 1115. (b) Ando, K.; Kankake, M.; Suzuki, T.; Kakayama, H.
Tetrahedron 1995, 51, 129. (c) Chenna, A.; Donnelly, J.; McCullough, K. J.;
Proctor, G. R.; Redpath, J. J. Chem. Soc., Perkin Trans. 1 1990, 261.
(d) Winkler, J. D.; Axten, J.; Hammach, A. H.; Kwak, Y.-S.; Lengweiler,
U.; Lucero, M. J.; Houk, K. N. Tetrahedron 1998, 54, 7045. (e) Pichon, N.;
Harrison-Marchand, A.; Mailliet, P.; Maddaluno, J. J. Org. Chem. 2004, 69,
7220.
The nitro groups of the two other Heck products 26a
and 26b were also converted to the corresponding amines,
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Seo et al.
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SCHEME 5
the desired pentacyclic Boc-protected aminals 30a-c in good
yields.
At this stage, we turned to introduction of the quaternary
carbon at C8 with the desired stereochemistry, along with
subsequently forming the upper aminal moiety. Initial stu-
dies were carried out with the TBS-protected enamide 30b,
which was treated with an excess of butyllithium at low
temperature, followed by addition of allyl iodide to afford
the desired C-allylated imine 32 as the major product along
with a small amount of the N-allyl enamine 33 (Scheme 7).
Reaction of the enamide 30b with the alkyllithium reagent
undoubtedly produces the intermediate lithio enamine 31,28
which undergoes alkylation from the less congested convex
face to form 32 having the required vicinal quaternary
carbon stereochemistry of the communesins. The structure
and stereochemistry of this intermediate were confirmed by
HMQC, HMBC, and NOESY-NMR experiments. It might
also be noted that we have been unable to alkylate 31 and
related systems (cf. 40, 50) with any two carbon electrophiles
such as nitroethylene, ethyl iodoacetate, iodoacetonitrile,
2-iodoethylazide, N-nosylaziridine, ethylene oxide, etc.17 In
addition, all attempted cyclopropanations of the enamide
also failed.29,30
SCHEME 6
Since it seemed possible that the C-allylation product 32
could arise via an aza-Cope rearrangement from the N-allyl
compound 33, we briefly probed this possibility in a related
series where the TBS group of 32 and 33 had been replaced by
a p-methoxyphenyl (PMP) protecting group.17a Thus, both
allyl pentacycles were first reexposed to the allylation con-
ditions, but no change was detected. In refluxing toluene
(bp 110 °C) both compounds were stable and no isomeriza-
tion occurred. At a higher temperature in refluxing o-xylene
(bp 143-145 °C), the N-allyl pentacycle began to decompose
but none of the C-allyl compound was detected. However, at
this same temperature the C-allyl pentacycle was slowly
converted to the N-allyl product, and after heating for
17 h, the ratio of C-allyl/N-allyl compounds in the mix-
ture was found to be 1:0.6. This unexpected conversion
can be rationalized by invoking a 1-aza-Cope rearrange-
ment, which is usually unfavorable relative to its counter-
part, a 3-aza-Cope rearrangement. However, in this speci-
fic system, relief of ring strain or of unfavorable steric
although each required a different reduction procedure.
The BOM-protected system 26a was reduced by catalytic
hydrogenation at 40 atm using 5% Pt/C to afford the corres-
ponding unstable aniline (without BOM hydrogenolysis),
which was immediately transformed to the Boc derivative
29a in 87% yield for the two steps (Scheme 6). In the case of
the TBS-protected compound 26b, catalytic hydrogenation
was best effected using 10% Pd/C at 1 atm, followed by Boc
protection to produce carbamate 29b in 85% overall yield.26
The next objective in the synthesis was to construct the
southern aminal functionality and the attendant D-ring
of the communesins via a partial reduction of the lactam
functionality of our three intermediates. After screening
several hydride reagents,27 it was discovered that alane-
dimethylethylamine complex effected lactam reduction/
cyclization of 29a-c in one operation to directly generate
(28) For deacylation of an enamide with an alkyllithium reagent, see:
(a) Obika, S.; Nishiyama, T.; Tatematsu, S.; Nishimoto, M.; Miyashita, K.;
Imanishi, T. Heterocycles 1997, 44, 537. (b) Fowler, F. W. J. Org. Chem.
1972, 37, 1321.
(26) Attempts to reduce the nitro group of the related PMP-protected
system i by chemical methods (e.g., Cu(acac)2/NaBH4/EtOH or SnCl2/
NaBH4/THF/EtOH) led to the N-hydroxyindole iii as the major product
along with some of the desired aniline ii.17a For related transformations, see:
(a) Stefanchi, A.; Leonetti, F.; Cappa, A.; Carotti, A. Tetrahedron Lett. 2003,
44, 2121. (b) Myers, A. G.; Herzon, S. B. J. Am. Chem. Soc. 2003, 125, 12080.
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Pavloff, A. M.; Lester, B. M.; Zirkle, C. L. J. Med. Chem. 1971, 14, 179.
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(d) Kaufman, M. D.; Grieco, P. A. J. Org. Chem. 1994, 59, 7197. (e) Grieco,
P. A.; Kaufman, M. D. J. Org. Chem. 1999, 64, 7586. (f) Gnad, F.; Poleschak,
M.; Reiser, O. Tetrahedron Lett. 2004, 45, 4277. (g) Bubert, C.; Cabrele, C.;
Reiser, O. Synlett 1997, 827. (h) Beumer, R.; Bubert, C.; Cabrele, C.;
Vielhauer, O.; Pietzsch, M.; Reiser, O. J. Org. Chem. 2000, 65, 8960.
(i) Beumer, R.; Reiser, O. Tetrahedron 2001, 57, 6497. (j) Huang, D.; Yan,
M.; Zhao, W.-J.; Shen, Q. Synth. Commun. 2005, 35, 745. (k) Wenkert, E.;
McPherson, A.; Sanchez, E. L.; Webb, R. L. Synth. Commun. 1973, 3, 255.
(l) Paulini, K.; Reibig, H.-U. Liebigs Ann. Chem. 1991, 455. (m) Tanny, S. R.;
Grossman, J.; Fowler, F. W. J. Am. Chem. Soc. 1972, 94, 6495.
(30) For examples of dichlorocarbene additions to enamides, see:
(a) Castro, J. L.; Castedo, L.; Riguera, R. J. Org. Chem. 1987, 52, 3579.
(b) Perchonock, C. D.; Lantos, I.; Finkelstein, J. A.; Holden, K. G.
J. Org. Chem. 1980, 45, 1950. (c) Lantos, I.; Bhattacharjee, D.; Eggleston,
D. S. J. Org. Chem. 1986, 51, 4147. (d) Manikumar, G.; Shamma, M. J. Org.
Chem. 1981, 46, 386.
(27) For related lactam reductions leading to aminals, see, for example:
(a) Govek, S. P.; Overman, L. E. J. Am. Chem. Soc. 2001, 123, 9468.
(b) Miyamoto, H.; Okawa, Y.; Nakazaki, A.; Kobayashi, S. Tetrahedron
Lett. 2007, 48, 1805. (c) Kawasaki, T.; Shinada, M.; Ohzono, M.; Ogawa, A.;
Terashima, R.; Sakamoto, M. J. Org. Chem. 2008, 73, 5959.
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SCHEME 7
SCHEME 8
interactions could be the driving force for the 1-aza-Cope
rearrangement.31
With intermediate imine 32 now in hand, our plan for
completion of the synthesis was to next construct the north-
ern aminal functionality of the metabolites containing the
A/B-ring system and then finally establish the azepine-G-
ring. Toward this end, it was necessary to oxidatively cleave
the allyl group, although this transformation could not be
directly effected on 32 due to the presence of the imine
functionality. In an attempt to protect the imine, compound
32 was treated with diethyl pyrocarbonate in EtOH,32 which
provided the desired R-ethoxycarbamate 34 as a mixture of
diastereomers, but to our surprise a significant amount of
aldehyde 35 was also produced (Scheme 8). The N,O-acetal
34 was also found to be rather sensitive to handling and
tended to rearrange to 35. Formation of this aldehyde can be
rationalized as occurring via an intermediate N-acyliminium
ion generated from the imine 32 and ethyl pyrocarbonate.
As can be seen from models, there is a close proximity
between the siloxymethyl group at C12a and the electrophilic
N-acyliminium ion functionality, which facilitates an intra-
molecular hydride transfer.33 In an attempt to decrease the
amount of 35 formed from the imine, the reaction conditions
were varied, but neither low temperature (-78 °C) nor
addition of bases (NEt3, K2CO3) caused any significant
improvement. It might also be noted that the PMP-protected
variant of silyl ether 32 was even more prone to undergo this
hydride migration.
SCHEME 9
We therefore decided to explore manipulating the termi-
nal olefin moiety of the crude 34/35 product mixture. It
was found that by three sequential reactions (i.e., dihydroxy-
lation, oxidative cleavage, and reduction), the desired
alcohol 36 could be obtained by chromatography as a 2:1
mixture of diastereomers in 45% yield based on imine 32,
along with diol 37 in 30% yield, which is derived from
aldehyde 35.
In an attempt to continue the synthesis, alcohol 36 was
first converted to the corresponding azide under Mitsunobu
conditions (Scheme 9). This azide was then reduced by
catalytic hydrogenation, and the resulting amine was pro-
tected in a one-pot reaction to afford N-Boc compound 38.
Unfortunately, we were unable to cyclize 38 to the desired
northern aminal 39, but rather under acidic conditions
only a rearranged aldehyde was observed which results via
a hydride migration from the C11 methylene group.
(31) For examples of 1-aza-Cope rearrangements, see: (a) Wu, P.-L.;
Chu, M.; Fowler, F. W. J. Org. Chem. 1988, 53, 963. (b) Wu, P.-L.; Fowler,
F. W. J. Org. Chem. 1988, 53, 5998. (c) Walters, M. A. Tetrahedron Lett.
1995, 36, 7055. (d) Wu, P.-L.; Wang, W.-S. J. Org. Chem. 1994, 59, 622.
(32) Kamatani, A.; Overman, L. E. Org. Lett. 2001, 3, 1229.
Since the primary difficulty with the sequence involving
the siloxymethyl series of compounds was due to the un-
desired hydride migrations outlined above, we decided to
eliminate any possibility of this rearrangement by replace-
ment of the C12a carbon substituent with a bromine. It might
also be noted that a bromine substituent was used as a C12a
functional handle to construct the azepine-G-ring in Qin’s
total synthesis of communesin F.12b We therefore returned
to brominated tetracyclic enamide 30c. Conversion of this
compound to the corresponding lithio enamine using the
butyllithium procedure described above (cf. Scheme 7) was
(33) For examples of intramolecular hydride transfers, see: (a) Bergmann,
R.; Gericke, R. J. Med. Chem. 1990, 33, 492. (b) Wessig, P.; Henning, H.-G.
Liebigs Ann. Chem. 1991, 983. (c) Vankar, Y. D.; Shah, K.; Bawa, A.; Singh,
S. P. Tetrahedron Lett. 1991, 47, 8883. (d) Marcuccio, S. M.; Elix, J. A. Aust.
J. Chem. 1985, 38, 1785. (e) Mitscher, L. A.; Gill, H.; Filppi, J. A.;
Wolgemuth, R. L. J. Med. Chem. 1986, 29, 1277. (f) Wu, A.; Ghakraborty,
A.; Witt, D.; Lagona, J.; Damkaci, F.; Ofori, M. A.; Chiles, J. K.; Fettinger,
J. C.; Isaacs, L. J. Org. Chem. 2002, 67, 5817. (g) Bartels, A. B.; Jones, P. G.;
Liebscher, J. Synthesis 2003, 67. (h) Padwa, A.; Wang, Q. J. Org. Chem. 2006,
71, 3210. (i) Kocienski, P. J.; Kirkup, M. J. Org. Chem. 1975, 40, 2998.
(j) Longridge, J. L.; Nicholson, S. J. Chem. Soc., Perkin Trans. 2 1990, 965.
(k) Ivanov, I. C.; Karagiosov, S. K. Synthesis 1995, 633. (l) Raucher, S.;
Lawrence, R. F. Tetrahedron 1983, 39, 3731. (m) Craze, G.-A.; Watt, I.
Tetrahedron Lett. 1982, 23, 975.
2672 J. Org. Chem. Vol. 75, No. 8, 2010

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SCHEME 10
SCHEME 11
problematic since some halogen-metal exchange occurred
under these conditions. However, the enamide could be
tranformed by basic hydrolysis to the unstable NH enamine
40, which without purification was treated with LDA and
allyl iodide to form the C-allyl imine 41 in 58% isolated yield
along with 29% of the corresponding N-allyl enamine.
With alkylated pentacycle 41 in hand, we subsequently
investigated the oxidative cleavage of the allyl group. As we
had hoped, exposure of imine 41 to diethyl pyrocarbonate in
ethanol cleanly produced R-ethoxycarbamate 42 (Scheme 10).
However, much to our surprise, dihydroxylation of 42 followed
by oxidative cleavage with periodate gave hexacyclic acetal 43
(42% overall yield for three steps from 41) as a mixture of
epimers instead of the desired aldehyde. The structure of the
cyclic acetal 43 was confirmed by 2D NMR studies (HMQC,
HMBC, and NOESY). Cyclic acetal 43 could then be hydro-
lyzed with aqueous acid to the hemiacetal 44 in good yield. With
the hope that there might be some aldehyde in equilibrium with
this hemiacetal, attempts were made at reductive aminations of
44, but to no avail. In view of these problems in forming the
northern aminal, along with some of the poor reaction yields
observed in the C12a bromine series of intermediates, the
synthetic strategy was revised again.
Because the many problems encountered in attempting
to form the upper aminal primarily involved an imine, it
was decided to avoid such functionality and instead utilize a
B-ring lactam. Moreover, we elected to adopt an approach
analogous to that of Qin,12b where the azepine-G-ring
was positioned prior to forming the A/B-ring northern
aminal. To investigate this new strategy, enamide 30a in
the BOM-protected series was first hydrolyzed to the un-
stable NH enamine 45, which without purification was
treated with cyanogen azide at room temperature to afford
the N-cyanoamidine 47 (Scheme 11).34 This transformation
is believed to occur via an initial [3 þ 2]-dipolar cyclo-
addition of the enamine to afford triazole 46, which then
rearranges with concomitant loss of nitrogen to form
product 47. It was then found that basic hydrolysis of
this amidine gave the lactam 48 as a single stereoisomer.
Subsequent base-mediated N-acylation of lactam 48 led
to N-Boc lactam 49, but also caused isomerization to a
3:1 mixture of epimers at C8, which was of no consequence
to the synthesis.
(34) (a) Marsh, F. D.; Hermes, M. E. J. Am. Chem. Soc. 1964, 86, 4506.
(b) Warren, B. K.; Knaus, E. E. J. Heterocycl. Chem. 1982, 19, 1259.
J. Org. Chem. Vol. 75, No. 8, 2010 2673

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SCHEME 12
promote the desired conjugate addition to the enone. All
attempts to subsequently effect an aza-Michael addition of
the N-Boc carbamate in 58 to the R,β-unsaturated ketone
moiety to form the azepine ring under a variety of acidic or
basic conditions unfortunately also failed.
We therefore decided to generate the azepine ring of
communesin F using the strategy of Qin et al.12a,35 Thus,
exposure of ketone 58 to methyllithium in THF at low
temperature led to the (E)-allylic alcohol 59 in 73% yield
(Scheme 13). Subsequent treatment of this alcohol with
PPTS at room temperature promoted a stereoselective allylic
substitution reaction which produced the hexacyclic G-ring
product 61 having the communesin configuration at C11 in
62% isolated yield. In addition, a 24% yield of the diene 60
resulting from dehydration of starting alcohol 59 was
formed, similar to what was observed in the Qin system.
The stereochemical outcome of this cyclization is not sur-
prising since inspection of models indicates that the confor-
mation shown in 59 is preferred in order to minimize steric
interactions with the γ-lactam B-ring. Thus, an acid cata-
lyzed allylic substitution by the N-Boc group via this con-
formation produces the requisite communesin configuration
at C11 in 61.
To complete the total synthesis, it was now necessary to
form the northern aminal. Toward this end, γ-lactam 61 was
treated with commercially available triethyloxonium fluor-
oborate and DIEA in methylene chloride in order to form the
corresponding ethyl imidate, similar to the conditions repor-
ted by Qin et al.12b Although this reaction produced some of
the desired compound, a substantial amount of an unidenti-
fied byproduct was formed. Alternatively, the use of tri-
methyloxonium fluoroborate in the presence of Hunig’s base
cleanly generated the desired methyl imidate 62.
Since the upper Boc protecting group proved to be much
more labile toward acid than the one on the southern aminal,
it could be selectively removed with 5% trifluoroacetic acid
in methylene chloride. Upon neutralization of the resulting
amine TFA salt with aqueous sodium bicarbonate, cycliza-
tion occurred spontaneously to form the heptacyclic amidine
63.36 Reduction of this amidine with sodium borohydride in
acetic acid containing acetic anhydride occurred stereoselec-
tively from the less hindered face to give the N-acetyl aminal
64. Finally, removal of the Boc protecting group on the lower
aminal could then be effected with 40% TFA in methylene
chloride to afford racemic communesin F (8). This material,
which exists as a 2.6:1 mixture of acetamide rotamers in
CDCl3, had proton and carbon NMR spectral data identical
to that reported by the Qin group for the alkaloid.12b
In conclusion, we have achieved a stereoselective total
synthesis of the heptacyclic fungal alkaloid (()-communesin
F (8) in about 30 steps from readily prepared enol triflate 19
and commercially available o-nitrobenzeneboronic acid.
Notable reactions in the sequence include a rare example
of an intramolecular Heck cyclization of a tetrasubstituted
Gratifyingly, alkylation of the mixture of N-Boc lactams
49 could be effected with potassium tert-butoxide and allyl
iodide to afford the desired product 51 as a single C8
stereoisomer in excellent yield. This alkylation proceeds via
attack of the iodide on the N-Boc lactam enolate 50 from the
least congested convex face, analogous to the stereoselective
alkylations of the lithio enamines done previously (vide
supra). To continue the synthesis it was found best to
selectively remove the Boc group on the lactam at this point
by basic cleavage to produce 52.
In a straightforward series of reactions, the allyl group of
52 was oxidatively cleaved to the aldehyde which without
purification was reduced to the corresponding alcohol. This
alcohol could then be transformed into the mesylate 53 in
good overall yield for the three steps (Scheme 12). Removal
of the BOM group of 53 was effected by hydrogenolysis with
Pearlman’s catalyst and the resulting benzyl alcohol was
immediately oxidized with the Dess-Martin periodinane to
produce aldehyde 54. Displacement of the mesylate with
sodium azide in DMF afforded azido aldehyde 55.
We next investigated homologation of this compound
to the R,β-unsaturated ketone 56, but to our surprise, the
aldehyde was found to be unreactive in Wadsworth-Emmons-
Horner or Wittig condensations, perhaps for steric reasons.
However, it was discovered that aldehyde 55 underwent
a clean cross-aldol reaction with acetone in the presence
of aqueous sodium hydroxide to produce the desired (E)-
unsaturated ketone 56 in excellent yield. In order to activate
the δ-lactam for rearrangement in the next step, a Boc
group was installed to form 57. With enone 57 in hand,
our initial plan was to effect a one-pot tandem azide reduc-
tion, lactam opening, and subsequent aza-Michael addition
of the resulting N-Boc carbamate to the R,β-unsaturated
ketone moiety to sequentially form the A-ring and the
azepine-G-ring. Therefore, N-Boc lactam azide 57 was
reduced with trimethylphosphine in THF/water which led
to the γ-lactam 58 in good yield, but this procedure did not
(35) For closely related cyclizations, see: (a) Harrington, P. J.; Hegedus,
L. S.; McDaniel, K. F. J. Am. Chem. Soc. 1987, 109, 4335. (b) Yokoyama, Y.;
Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486. (c) Yokoyama,
Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur.
J. Org. Chem. 2004, 1244.
(36) Although Qin et al.12b have reported that it was necessary to stir this
amine with silica gel at 50 °C in order to effect cyclization to the amidine, we
observed that simple neutralization of the azepine TFA salt at room
temperature was sufficient to produce 63.
2674 J. Org. Chem. Vol. 75, No. 8, 2010

Seo et al.
JOCArticle
SCHEME 13
alkene to generate a spiro-tetracycle with the C7 quaternary
carbon center of the metabolite, a one-pot reductive cycliza-
tion of an N-Boc aniline onto an oxindole moiety to form a
pentacyclic system incorporating the southern aminal, a
stereoselective N-Boc lactam enolate C-allylation to intro-
duce the C8 quaternary carbon center, and an azide reduc-
tion/N-Boc-δ-lactam opening cascade eventually leading to
the northern aminal. In principle, it should be possible to
effect the key intramolecular Heck reaction of substrate
25a enantioselectively to ultimately produce the natural
(-)-enantiomer of communesin F.37 We hope to explore this
transformation in future work.
diluted with EtOAc and H2O and basified with solid Na2CO3.
The organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic phases were dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel (hexanes/EtOAc, 9/1) to provide the iodoaniline 18a (2.22 g,
76%): 1H NMR (300 MHz, CDCl3) δ 7.49-7.31 (m, 5H), 7.16
(br m, 1H), 6.89 (d, J=7.4 Hz, 1H), 6.77 (br s, 1H), 4.94 (s, 2H),
4.74 (s, 2H), 4.69 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 146.5,
141.0, 137.7, 128.8, 128.4, 127.9, 127.6, 119.2, 114.3, 94.2, 88.4,
74.2, 69.6; HRMS-ES (m/z) [M þ H]þ calcd for C15H17NO2I
370.0304, found 370.0295.
Synthesis of Ester 20. To a solution of enol triflate 1923 (763 mg,
1.94 mmol) and o-nitrobenzeneboronic acid (356 mg, 2.13
mmol) in DME (11.0 mL) and water (3.7 mL) were added
Pd(PPh3)4 (45 mg, 0.039 mmol) and Na2CO3 (617 mg, 5.82
mmol). The reaction mixture was stirred at 80 °C for 1 h and
then cooled to rt. The solution was diluted with H2O and
extracted with EtOAc. The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
(hexanes/EtOAc, 1/3) to give arylated compound 20 (697 mg,
98%): 1H NMR (300 MHz, CDCl3) δ 8.03 (dd, J=1.2, 8.2 Hz,
1H), 7.57 (ddd, J = 0.8, 7.6, 7.6 Hz, 1H), 7.46-7.39 (m, 3H),
7.36-7.26 (m, 3H), 7.19 (dd, J=1.3, 7.6 Hz, 1H), 3.87 (q, J=
7.2 Hz, 2H), 3.73 (q, J = 12.7 Hz, 2H), 3.48, 3.22 (ABq, J =
17.9 Hz, 2H), 2.83 (t, J=5.8 Hz, 2H), 2.60 (m, 2H), 0.88 (t, J=
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.6, 148.3,
144.7, 138.2, 137.1, 133.5, 130.1, 129.4, 128.8, 128.4, 127.7,
125.1, 124.6, 61. 8, 60.7, 58.6, 49.2, 26.0, 14.0; HRMS-ES (m/z)
[M þH]þ calcd for C21H23N2O4 367.1658, found 367.1651.
Synthesis of Carboxylic Acid 21. To a solution of ester 20
(18.23 g, 49.75 mmol) in MeOH (260 mL) and water (108 mL)
Experimental Section
Synthesis of BOM Ether 17a. To a solution of (2-iodo-3-nitro-
phenyl)methanol21 (16, 263 mg, 0.94 mmol) in THF (5.0 mL)
were added TBAI (70 mg, 0.19 mmol), DIPEA (0.25 mL, 1.41
mmol), and BOMCl (0.13 mL, 0.94 mmol). The reaction mixture
was heated at 70 °C for 14 h and quenched by the addition of
saturated aqueous NaHCO3. The solution was then extracted
with EtOAc. The combined organic layers were dried over
Na2SO4 and concentrated. The residue was purified by flash
column chromatography on silica gel (hexanes/EtOAc, 1/4) to
1
give the BOM ether 17a (232 mg, 62%): H NMR (300 MHz,
CDCl3) δ 7.67 (d, J=7.6 Hz, 1H), 7.58 (dd, J=1.5, 7.9 Hz, 1H),
7.49 (d, J = 7.7 Hz, 1H), 7.45-7.32 (m, 5H), 4.98 (s, 2H), 4.74
(s, 2H), 4.72 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 154.7,
143.8, 137.4, 131.0, 128.8, 128.4, 127.8, 127.7, 123.3, 94.4, 88.7,
73.9, 69.9; HRMS-ES (m/z) [M þ H]þ calcd for C15H15NO4I
400.0046, found 400.0039.
Synthesis of Aniline 18a. To a solution of nitro compound 17a
(3.16 g, 7.92 mmol) in EtOH (50.0 mL) were added iron powder
(2.21 g, 39.59 mmol) and AcOH (6.8 mL). The reaction mixture
was heated at 60 °C for 12 h and then cooled to rt. The mixture
was filtered, and the filtrate was concentrated. The residue was
was added LiOH H2O (10.45 g, 249.05 mmol). The reaction
3
mixture was stirred at 50 °C for 12 h before MeOH was remo-
ved under reduced pressure. The resulting aqueous solution
was acidified with 1 N HCl to pH 5-6 and extracted with
EtOAc. The combined organic phases were dried over Na2SO4
and concentrated. The residue was purified by flash column
chromatography on silica gel (MeOH/CH2Cl2, 1/10) to give the
(37) For a review, see: Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv.
Synth. Catal. 2004, 346, 1533.
J. Org. Chem. Vol. 75, No. 8, 2010 2675

Seo et al.
JOCArticle
carboxylic acid 21 (16.48 g, 86%): 1H NMR (300 MHz, CDCl3)
δ 12.6 (br s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.1 Hz,
1H), 7.33-7.26 (m, 6H), 7.13 (d, J=7.2 Hz, 1H), 4.03-3.90 (m,
2H), 3.73-3.51 (m, 2H), 3.00 (br s, 1H), 2.78 (br s, 1H), 2.47 (br
s, 2H); 13C NMR (75 MHz, CDCl3) δ 169.4, 148.5, 136.6, 135.6,
133.8, 131.8, 130.9, 130.7, 129.4, 129.3, 128.7, 127.3, 124.2, 58.6,
54.5, 46.6, 23.3; HRMS-ES (m/z) [M þ H]þ calcd for C19H19-
N2O4 339.1345, found 339.1325.
(m, 1H),3.86-3.72 (m, 1.3H), 3.45 (br s, 0.3H), 3.11 (s, 2H), 2.99
(s, 0.3H), 2.92 (s, 0.8H), 2.87 (s, 0.3H), 2.58 (s, 1.3H), 2.26 (s,
0.6H), 1.30 (t, J = 6.9 Hz, 2H), 1.17 (t, J = 7.1 Hz, 1H); 13C
NMR (75 MHz, CD3CN, 65 °C) δ 170.0, 156.6, 150.2, 147.0,
144.2, 139.7, 134.9, 134.2, 133.3, 132.0, 130.7, 130.6, 129.6,
129.3, 129.1, 128.8, 128.6, 126.1, 125.6, 103.1, 96.0, 75.3, 71.0,
62.5, 49.0, 48.1, 41.1, 39.0, 37.7, 27.2, 15.3; HRMS-ES (m/z)
[M þ H]þ calcd for C31H33N3O7I 686.1363, found 686.1371.
Synthesis of Tetracyclic Enamide 26a. To a solution of N-methyl
amide 25a (2.21 g, 3.23 mmol) in DMA (56.0 mL) were added
Pd(OAc)2 (145 mg, 0.65 mmol), PPh3 (339 mg, 1.29 mmol),
n-Bu4NBr (2.08 g, 6.45 mmol), and K2CO3 (892 mg, 6.48
mmol). The mixture was stirred at 150 °C for 25 min, cooled
to rt, and diluted with H2O. The aqueous solution was extrac-
ted with EtOAc. The combined organic extracts were dried
over Na2SO4 and concentrated. The residue was purified by
flash column chromatography on silica gel (hexanes/EtOAc,
1/2) to provide spirocyclic enamide 26a (1.88 g, 90%): 1H
NMR (300 MHz, CD3CN, 65 °C) δ 7.53-7.49 (m, 2H),
7.40-7.30 (m, 6H), 7.28-7.21 (m, 2H), 7.00 (d, J = 7.9 Hz,
1H), 6.80-6.84 (m, 2H), 4.85-4.80 (m, 2H), 4.36 (d, J = 11.9
Hz, 1H), 4.31, 4.26 (ABq, J=7.1 Hz, 2H), 4.07-3.99 (m, 2H),
3.23 (s, 3H), 2.64-2.53 (m, 1H), 1.98-1.89 (m, 1H), 1.34 (t, J=
7.1 Hz, 3H); 13C NMR (75 MHz, CD3CN, 65 °C) δ 178.8,
154.5, 150.9, 145.2, 139.7, 136.3, 132.6, 132.4, 132.15, 132.11,
130.1, 129.6, 129.4, 129.0, 128.8, 125.2, 124.9, 110.4, 109.1,
95.8, 70.9, 66.7, 63.8, 50.5, 38.9, 31.5, 27.5, 15.0; HRMS-ES
(m/z) [MþH]þ calcd for C31H32N3O7 558.2240, found 558.2238.
Synthesis of N-Boc Aniline 29a. To a beaker containing a
solution of the Heck product 26a (1.71 g, 3.07 mmol) in toluene
(30.0 mL) was added 5% platinum on carbon (514 mg). The
beaker was then transferred into a high-pressure reaction vessel
and flushed with H2. The hydrogen pressure was increased to
40 atm, and the reaction mixture was stirred at rt for 14 h. The
pressure was released, and the suspension was filtered through a
pad of Celite. The solvent was removed to give the aniline which
decomposed on standing and therefore was used immediately in
crude form.
To a solution of the freshly prepared crude aniline in THF
(90.0 mL) and H2O (30.0 mL) were added K2CO3 (8.49 g, 61.43
mmol) and (Boc)2O (10.05 g, 46.05 mmol). The mixture was
stirred at 60 °C for 20 h. The aqueous solution was extracted
with EtOAc. The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(hexanes/EtOAc, 1/4) to provide N-Boc aniline 29a (1.68 g,
87% for two steps): 1H NMR (300 MHz, CD3CN, 65 °C) δ 7.72
(d, J=8.9 Hz, 1H), 7.43-7.26 (m, 7H), 7.21 (s, 1H), 7.15-7.08
(m, 2H), 6.80-6.71 (m, 3H), 4.94, 4.91 (ABq, J = 6.7 Hz, 2H),
4.82, 4.73 (ABq, J=11.6 Hz, 2H), 4.70 (s, 2H), 4.26 (q, J=7.1
Hz, 2H), 4.17-4.01 (m, 2H), 3.11 (s, 3H), 2.60-2.48 (m, 1H),
2.10-1.99 (m, 1H), 1.55 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H); 13C
NMR (75 MHz, CD3CN, 65 °C) δ 180.1, 154.7, 154.5, 145.1,
139.6, 138.6, 136.1, 131.8, 131.7, 129.99, 129.94, 129.6, 129.1,
129.0, 128.8, 125.1, 123.7, 122.9, 112.0, 109.2, 96.1, 80.9, 71.1,
67.0, 63.5, 51.8, 39.3, 32.1, 29.0, 27.4, 15.1; HRMS-ES (m/z)
[M þ H]þ calcd for C36H42N3O7 628.3023, found 628.3022.
Synthesis of Pentacyclic Aminal 30a. To a solution of N-Boc
aniline 29a (302 mg, 0.48 mmol) in THF (15.0 mL) was added
Synthesis of Amide 23a. The acid 21 (11.33 g, 38.49 mmol) was
dissolved in SOCl2 (25.0 mL), and the solution was refluxed for
3 h. Excess SOCl2 was distilled off, and the resulting residue was
dried under high vacuum and then dissolved in CH2Cl2 (30.0 mL).
To a stirred solution of aniline 18a (9.16 g, 24.80 mmol) and
DIPEA (17.3 mL, 99.31 mmol) in CH2Cl2 (50.0 mL) was added
the above acid chloride 22 solution dropwise at rt. The reaction
mixture was further stirred at rt for 12 h and was diluted with
CH2Cl2 and saturated aqueous NaHCO3. The organic layer
was separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried over Na2SO4
and concentrated. The residue was purified by flash column
chromatography on silica gel (hexanes/EtOAc, 7/3) to give the
amide 23a (14.88 g, 87% based on aniline 18a): 1H NMR (300
MHz, CDCl3) δ 8.02 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 7.7 Hz,
1H), 7.85 (s, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.47-7.31 (m, 12H),
7.28-7.18 (m, 2H), 4.91 (s, 2H), 4.70 (s, 2H), 4.63 (s, 2H), 3.76
(br d, J = 5.5 Hz, 2H), 3.36, 3.14 (ABq, J = 16.9 Hz, 2H),
2.97-2.77 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 166.1, 147.6,
140.7, 137.9, 137.4, 137.3, 134.8, 133.5, 130.6, 129.3, 128.65,
128.59, 128.3, 128.13, 128.09, 127.6, 127.4, 127.0, 124.8, 124.4,
121.4, 94.01, 93.94, 73.9, 69.4, 61.1, 56.6, 48.5, 26.2; HRMS-
ES (m/z) [M þ H]þ calcd for C34H33N3O5I 690.1465, found
690.1472.
Synthesis of Ethyl Carbamate 24a. To a stirred solution of
amide 23a (3.13 g, 4.54 mmol) in CH2Cl2 (35.0 mL) was added
ClCO2Et (0.52 mL, 5.45 mmol) dropwise at 0 °C. After the
addition was complete, the ice bath was removed, and the mix-
ture was stirred at rt for 12 h before saturated aqueous NaHCO3
was added. The layers were separated. The aqueous layer was
extracted with CH2Cl2, and the combined organic phases were
dried over Na2SO4 and concentrated. The residue was purified
by flash column chromatography on silica gel (hexanes/EtOAc/
CH2Cl2, 5/3/2) to provide carbamate 24a (2.92 g, 96%): 1H
NMR (300 MHz, CDCl3) δ 8.06 (d, J = 7.9 Hz, 1H), 7.81 (dd,
J=1.3, 7.8 Hz, 1H), 7.73 (s, 1H), 7.63-7.58 (m, 1H), 7.47-7.27
(m, 7H), 7.24-7.14 (m, 2H), 4.86 (s, 2H), 4.65 (s, 2H), 4.58 (s,
2H), 4.41-4.09 (br m, 2H), 4.22 (q, J=7.0 Hz, 2H), 3.87-3.75
(br m, 2H), 2.85-2.68 (br m, 2H), 1.45-1.29 (br m, 3H); 13C
NMR (75 MHz, CDCl3) δ 165.7, 154.9, 147.6, 140.8, 137.7,
137.3, 133.8, 133.6, 130.7, 129.1, 128.4, 128.2, 127.6, 127.5,
125.1, 124.7, 121.5, 94.3, 94.0, 73.9, 69.4, 61.4, 47.1, 39.5, 25.8,
14.4; HRMS-ES (m/z) [M þ H]þ calcd for C30H31N3O7I
672.1207, found 672.1226.
Synthesis of N-Methyl Amide 25a. To a suspension of NaH
(192 mg, 60% dispersion in mineral oil, 4.79 mmol) in THF
(10.0 mL) was added a solution of amide 24a (2.92 g, 4.35 mmol)
in THF (30.0 mL) at 0 °C. The mixture was stirred at 0 °C for
15 min, and MeI (0.33 mL, 5.22 mmol) was added at this tem-
perature. The reaction mixture was warmed to rt and stirred for
12 h before the addition of saturated aqueous NaHCO3. The
aqueous mixture was extracted with EtOAc. The combined
organic layers were dried over Na2SO4 and concentrated. The
residue was purified by flash column chromatography on silica
gel (hexanes/EtOAc, 3/2) to provide N-methyl amide 25a (2.74
g, 92%). 1H NMR (300 MHz, CD3CN) δ 8.07 (dd, J=1.1, 8.1
Hz, 1H), 7.76-7.73 (m, 1H), 7.62-7.56 (m, 1.7H), 7.47-7.44 (br
m, 1H), 7.40-7.29 (m, 6H), 7.02 (br s, 0.3H), 6.40 (br s, 0.3H),
4.93 (s, 0.7H), 4.87 (s, 1.3H), 4.69 (s, 1H), 4.64 (s, 1.3H), 4.59
(s, 1.3H), 4.40 (br s, 1H), 4.20 (q, J=7.1 Hz, 1.5H), 4.11-4.00
AlH3 Me2NEt (1.44 mL, 0.5 M in toluene, 0.72 mmol) dropwise
3
at 0 °C. The reaction mixture was warmed to rt and stirred at rt
for 4 h before saturated aqueous Na2SO4 was added. The
aqueous mixture was extracted with EtOAc. The combined
organic phases were dried over Na2SO4 and concentrated.
The residue was purified by flash column chromatography on
silica gel (hexanes/EtOAc, 1/9) to give the aminal 30a (250 mg,
74%): 1H NMR (300 MHz, CDCl3) δ 7.42-7.29 (m, 6H), 7.19
(dd, J = 1.4, 7.3 Hz, 2H), 7.05 (br m, 1H), 6.97 (t, J = 7.8 Hz,
2676 J. Org. Chem. Vol. 75, No. 8, 2010

Seo et al.
JOCArticle
2H), 6.56 (d, J=7.7 Hz, 1H), 6.24 (d, J= 7.8 Hz, 1H), 5.82 (s,
1H), 4.84 (s, 2H), 4.74-4.65 (m, 3H), 4.50 (d, J=11.6 Hz, 1H),
4.31-4.15 (m, 3H), 3.51 (br s, 1H), 3.00 (s, 3H), 2.50-2.35 (m,
2H), 1.53 (s, 9H), 7.1 (t, J=1.35 Hz, 3H); 13C NMR (75 MHz,
CD3CN, 65 °C) δ 154.3, 154.0, 151.8, 139.2,139.0, 134.4, 134.1,
130.4, 128.83, 128.76, 128.2, 127.9, 126.8, 125.7, 125.1, 124.5,
118.7, 116.8, 104.9, 94.9, 85.6, 81.5, 69.9, 65.5, 62.6, 52.0, 40.5,
34.6, 30.5, 28.0, 14.3; HRMS-ES (m/z) [M þ H]þ calcd for
C36H42N3O6 612.3074, found 612.3055.
Preparation of Cyanogen Azide. To a solution of cyanogen
bromide (536 mg, 5.06 mmol) in CH3CN (10.0 mL) was added
NaN3 (339 mg, 5.22 mmol) at 0 °C. The mixture was stirred at
0 °C for 4 h to give a solution of NCN3 in CH3CN (0.50 M)
which can be stored at 0 °C for several weeks without noticeable
decomposition.
Synthesis of N-Cyanoamidine 47. To a solution of enamide
30a (202 mg, 0.33 mmol) in EtOH (10.0 mL) was added 1 N
aqueous KOH solution (10.0 mL, 10.0 mmol). The mixture was
stirred at 94 °C for 3 h and then cooled to rt. After removal of
EtOH in vacuo, the cloudy aqueous solution was extracted with
EtOAc. The combined organic layers were dried over Na2SO4
and concentrated. Since the resulting enamine 45 was unstable
and decomposed during chromatographic purification, the
material was used directly in the next step.
organic layers were dried over Na2SO4 and concentrated. The
residue was purified by flash column chromatography on silica
gel (hexanes/EtOAc, 7/3) to give the N-Boc lactam (384 mg,
95%) as a 1:3 mixture of epimers 49a and 49b. For analytical
purposes, the N-Boc lactam mixture was carefully purified by
flash column chromatography on silica gel (hexanes/EtOAc, 9/1
then 7/3) to give pure samples of 49a and 49b.
49a: 1H NMR (300 MHz, CDCl3) δ 8.31 (d, J=5.7 Hz, 1H),
7.44-7.37 (m, 4H), 7.35-7.31 (m, 1H), 7.02-6.98 (m, 3H), 6.92
(t, J=7.8 Hz, 1H), 6.46 (d, J=7.7 Hz, 1H), 6.20 (d, J=7.8 Hz,
1H), 5.90 (s, 1H), 4.84, 4.80 (ABq, J = 6.8 Hz, 2H), 4.69, 4.61
(ABq, J = 12.0 Hz, 2H), 4.50, 4.42 (ABq, J = 11.7 Hz, 2H),
4.36-4.33 (m, 1H), 3.87 (s, 1H), 3.83-3.77 (m, 1H), 2.97 (s, 3H),
2.52-2.37 (m, 2H), 1.60 (s, 9H), 1.49 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 169.4, 154.2, 152.1, 151.4, 138.1, 137.8, 133.0,
130.6, 128.6, 128.4, 128.3, 128.1, 127.8, 127.5, 126.1, 125.8,
125.2, 119.4, 105.2, 93.7, 84.9, 83.3, 81.2, 69.2, 66.8, 56.6, 45.2,
42.7, 34.5, 30.7, 28.1, 28.0; HRMS-ES (m/z) [MþH]þ calcd for
C38H46N3O7 656.3336, found 656.3320.
49b: 1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m, 4H),
7.35-7.32 (m, 1H), 7.28 (br s, 1H), 7.19-7.12 (m, 2H), 7.03-
6.94 (m, 2H), 6.56 (d, J=5.7 Hz, 1H), 6.10 (s, 1H), 6.09 (d, J=
5.9 Hz, 1H), 4.91, 4.88 (ABq, J=5.1 Hz, 2H), 4.82, 4.69 (ABq,
J=8.8 Hz, 2H), 4.73 (d, J=1.4 Hz, 2H), 4.35 (s, 1H), 4.10-4.04
(m, 1H), 3.96-3.93 (m, 1H), 2.84-2.76 (m, 1H), 2.78 (s, 3H),
2.17 (d, J=10.6 Hz, 1H), 1.52 (s, 9H), 1.49 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 169.3, 152.8, 150.4, 137.5, 136.2, 132.6, 132.1,
129.7, 128.7, 128.3, 128.0, 127.63, 127.57, 127.3, 125.7, 125.5,
119.2, 104.4, 93.2, 82.8, 81.2, 79.7, 69.6, 65.7, 55.2, 51.6, 42.2,
32.3, 29.9, 28.0, 27.7; HRMS-ES (m/z) [M þ H]þ calcd for
C38H46N3O7 656.3336, found 656.3344.
Synthesis of C-Allyl Lactam 51. To a solution of N-Boc
lactams 49 (207 mg, 0.32 mmol) in THF (20.0 mL) was added
a solution of KO-t-Bu (42 mg, 0.38 mmol) in THF (1.5 mL)
dropwise at -78 °C, followed immediately by the addition of
allyl iodide (0.48 mL, 1.0 M in THF, 0.48 mmol). The dry
ice-acetone bath was removed, and the mixture was warmed to
rt and stirred for 40 min before aqueous saturated NaHCO3 was
added. The mixture was diluted with H2O and extracted with
EtOAc. The combined organic layers were dried over Na2SO4
and concentrated. The residue was purified by flash column
chromatography on silica gel (hexanes/EtOAc, 9/1 then 7/3) to
give the C-allyl lactam 51 (191 mg, 87%): 1H NMR (300 MHz,
CD3CN, 65 °C) δ 8.31 (dd, J=1.6, 7.7 Hz, 0.8H), 7.44-7.31 (m,
10H), 7.24(d, J=9.0 Hz, 1H), 7.10-7.03 (m, 2H), 6.98-6.88 (m,
5H), 6.53 (d, J=7.9 Hz, 1.8H), 6.36 (dd, J=1.0, 7.8 Hz, 0.8H),
6.21 (d, J=7.8 Hz, 1H), 5.75 (s, 1H), 5.70 (s, 1H), 5.64-5.55 (m,
1.8H), 5.13-5.03 (m, 2H), 4.93-4.83 (m, 4H), 4.80-4.75 (m,
2H), 4.67-4.52 (m, 5.8H), 4.35-4.17 (m, 4.8H), 3.84-3.77 (m,
0.8H), 3.73-3.62 (m, 0.8H), 3.13-3.02 (m, 1.7H), 3.00 (s, 2.8H),
2.93 (s, 3H), 2.91-2.84 (m, 1H), 2.70 (td, J=5.7, 13.7 Hz, 1H),
2.26 (s, 2.3H), 2.25-2.12 (m, 2H), 1.93-1.88 (m, 1H), 1.58 (s,
9H), 1.55 (s, 9H), 1.51 (s, 15H); 13C NMR (75 MHz, CD3CN, 65
°C) δ 173.0, 155.3, 155.2, 155.1, 154.4, 152.6, 152.3, 146.4, 140.3,
139.9, 139.8, 139.6, 135.4, 135.3, 134.8, 134.4, 130.7, 130.4,
130.0, 129.7, 129.6, 129.5, 129.1, 128.8, 128.7, 128.6, 127.6,
127.4, 127.3, 125.9, 125.2, 120.3, 118.8, 118.7, 118.4, 107.4,
106.2, 105.3, 96.0, 95.8, 86.5, 84.6, 84.0, 82.8, 82.6, 82.1, 70.94,
70.88, 70.7, 68.1, 66.1, 60.8, 55.9, 52.4, 45.1, 40.7, 37.4, 32.1,
31.1, 30.9, 28.92, 28.89, 28.8, 28.7; HRMS-ES (m/z) [M þ H]þ
calcd for C41H50N3O7 696.3649, found 696.3651.
To a solution of the crude enamine in MeCN (15.0 mL) was
added NCN3 (1.0 mL, 0.5 M in MeCN, 0.50 mmol, freshly
prepared). The solution was stirred at rt for 1 h and then concen-
trated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (hexanes/EtOAc, 2/3)
1
to give the N-cyanoamidine 47 (178 mg, 93%): H NMR (300
MHz, CDCl3) δ 7.68 (br s, 1H), 7.44-7.29 (m, 5H), 7.20 (d, J=
3.0 Hz, 2H), 7.13 (d, J=7.4 Hz, 1H), 7.06-7.00 (m, 1H), 6.96 (d,
J = 7.7 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 6.09 (d, J = 8.0 Hz,
1H), 6.07 (s, 1H), 4.92, 4.89 (ABq, J = 6.9 Hz, 2H), 4.81, 4.63
(ABq, J=11.7 Hz, 2H), 4.74 (s, 2H), 4.34 (s, 1H), 3.87-3.84 (m,
1H), 3.55-3.51 (m, 1H), 2.78 (s, 3H), 2.75-2.64 (m, 1H), 2.12
(dd, J = 3.5, 14.3 Hz, 1H), 1.51 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 172.3, 150.1, 150.6, 137.5, 136.4, 132.8, 132.3, 129.8,
129.1, 128.5, 127.8, 127.6, 127.5, 125.9, 125.7, 119.5, 116.3,
104.5, 93.3, 81.6, 78.8, 69.8, 65.9, 53.9, 46.8, 39.1, 30.5, 29.9,
28.1; HRMS-ES (m/z) [MþH]þ calcd for C34H38N5O4 580.2924,
found 580.2918.
Synthesis of Lactam 48. To a solution of N-cyanoamidine 47
(178 mg, 0.33 mmol) in EtOH (15.0 mL) was added 1 N aqueous
KOH solution (15.0 mL, 15.0 mmol). The mixture was stirred at
94 °C for 12 h and then cooled to rt. After removal of EtOH in
vacuo, the cloudy aqueous solution was extracted with EtOAc.
The combined organic layers were dried over Na2SO4 and
concentrated. The residue was purified by flash column chro-
matography on silica gel (hexanes/EtOAc, 1/1) to give the
lactam 48 (102 mg, 60%): 1H NMR (300 MHz, CDCl3) δ
7.45-7.29 (m, 5H), 7.19-7.16 (m, 3H), 7.05-6.95 (m, 2H),
6.58 (d, J=7.6 Hz, 1H), 6.44 (br s, 1H), 6.13 (s, 1H), 6.09 (d, J=
7.9 Hz, 1H), 4.92, 4.89 (ABq, J=6.9 Hz, 2H), 4.83, 4.72 (ABq,
J=11.6 Hz, 2H), 4.78 (s, 2H), 4.17 (s, 1H), 3.86 (t, J=11.7 Hz,
1H), 3.39-3.35 (m, 1H), 2.79 (s, 3H), 2.75-2.69 (m, 1H),
2.08-2.01 (m, 1H), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 170.7, 153.4, 150.5, 137.6, 136.3, 132.8, 132.5, 129.9, 128.7,
128.4, 128.3, 127.7, 127.6, 127.2, 125.6, 119.1, 104.3, 93.4, 81.1,
79.1, 69.6, 65.7, 54.6, 49.1, 38.2, 31.5, 30.0, 28.1; HRMS-ES
(m/z) [MþH]þ calcd for C33H38N3O5 556.2811, found 556.2820.
Synthesis of N-Boc Lactams 49. To a solution of lactam 48
(343 mg, 0.62 mmol) in THF (15.0 mL) was added LiHMDS
(0.93 mL, 1.0 M in THF, 0.93 mmol). The mixture was stirred at
rt for 10 min, and (Boc)2O (141 mg, 0.65 mmol) was added. The
reaction mixture was stirred at rt for another 10 min and
quenched with aqueous saturated NaHCO3. The mixture was
diluted with H2O and extracted with EtOAc. The combined
Synthesis of NH-Lactam 52. To a solution of the N-Boc
lactam 51 (191 mg, 0.27 mmol) in EtOH (28.0 mL) was added
1 N aqueous KOH solution (2.8 mL, 2.8 mmol). The mixture
was stirred at 80 °C for 13 h and then cooled to rt. After removal
of EtOH in vacuo, the cloudy aqueous solution was extracted
with EtOAc. The combined organic layers were dried over
Na2SO4 and concentrated. The residue was purified by flash
J. Org. Chem. Vol. 75, No. 8, 2010 2677

Seo et al.
JOCArticle
column chromatography on silica gel (hexanes/EtOAc, 7/3 then
EtOAc, 1/3) to give the aldehyde 54 (30 mg, 75% for two steps):
1H NMR (300 MHz, CDCl3) δ 10.08 (s, 1H), 8.11 (d, J=7.6 Hz,
1H), 7.06-6.88 (m, 4H), 6.78 (dd, J=1.0, 7.8 Hz, 1H), 6.50 (dd,
J = 1.0, 7.9 Hz, 1H), 6.25 (s, 1H), 5.70 (s, 1H), 4.55-4.46 (m,
1H), 4.03-3.92 (m, 1H), 3.41-3.32 (m, 1H), 3.17 (td, J = 4.5,
12.8 Hz, 1H), 3.01 (s, 3H), 2.74 (s, 3H), 2.60-2.49 (m, 3H), 1.96
(dd, J = 4.4, 13.8 Hz, 1H), 1.47 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 193.2, 172.6, 154.0, 151.1, 138.8, 134.6, 130.8, 130.0,
129.2, 127.6, 127.1, 126.2, 125.0, 117.4, 111.3, 82.6, 82.3,
67.9, 59.7, 46.8, 38.8, 36.7, 34.5, 31.2, 28.0, 27.9; HRMS-ES
(m/z) [M þ H]þ calcd for C28H34N3O7S 556.2117, found
556.2133.
Synthesis of Azide 55. To a solution of the mesylate 54 (25 mg,
0.045 mmol) in DMF (1.5 mL) was added NaN3 (50 mg, 0.77
mmol). The reaction mixture was stirred at 90 °C for 2 h and
diluted with H2O. The aqueous mixture was extracted with
Et2O. The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (hexanes/EtOAc, 1/1) to
give the azide 55 (14 mg, 61%): 1H NMR (300 MHz, CDCl3) δ
10.10 (s, 1H), 8.11 (dd, J=2.5, 7.6 Hz, 1H), 7.05-6.94 (m, 4H),
6.77 (dd, J=1.1, 7.8 Hz, 1H), 6.49 (dd, J=1.0, 7.9 Hz, 1H), 6.14
(s, 1H), 5.70 (s, 1H), 3.72-3.63 (m, 1H), 3.38-3.32 (m, 1H), 3.17
(td, J=4.7, 12.9 Hz, 1H), 3.00 (s, 3H), 2.92-2.82 (m, 1H), 2.55
(td, J=6.1, 13.3 Hz, 1H), 2.33 (t, J=8.8 Hz, 2H), 1.95 (dd, J=
4.5, 13.8 Hz, 1H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
193.4, 172.8, 154.0, 151.1, 138.6, 134.7, 131.2, 130.1, 129.1,
127.5, 126.9, 126.3, 125.1, 117.3, 111.1, 82.7, 82.0, 59.8, 48.7,
47.2, 38.8, 35.1, 31.1, 28.1, 28.0; HRMS-ES (m/z) [MþH]þ calcd
for C27H31N6O4 503.2407, found 503.2418.
Synthesis of r,β-Unsaturated Ketone 56. To a solution of the
aldehyde 55 (130 mg, 0.26 mmol) in acetone (20.0 mL) was
added 10% aqueous NaOH solution (2.4 mL). The reaction
mixture was stirred at 60 °C for 3 h and then cooled to rt. After
removal of acetone in vacuo, the cloudy aqueous mixture was
extracted with EtOAc. The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. The residue was puri-
fied by flash column chromatography on silica gel (hexanes/
EtOAc, 1/1) to give the R,β-unsaturated ketone 56 (130 mg,
93%): 1H NMR (300 MHz, CDCl3) δ 8.35 (dd, J=2.0, 6.6 Hz,
1H), 7.59 (d, J=16.0 Hz, 1H), 6.98-6.91 (m, 4H), 6.35 (t, J=
7.9 Hz, 2H), 6.20 (d, J=16.0 Hz, 1H), 5.74 (s, 1H), 5.63 (s, 1H),
3.66-3.59 (m, 1H), 3.29-3.26 (m, 1H), 3.16 (td, J=4.4, 12.7 Hz,
1H), 3.00 (s, 3H), 2.89-2.82 (m, 1H), 2.55-2.44 (m, 1H), 2.49 (s,
3H), 2.31 (t, J = 8.6 Hz, 2H), 2.02-1.95 (m, 1H), 1.45 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 199.9, 173.2, 154.0, 151.1, 145.1,
138.8, 132.7, 131.5, 131.2, 129.1, 128.6, 127.4, 126.9, 125.9,
124.7, 118.6, 107.8, 82.6, 81.9, 58.9, 48.8, 46.5, 39.4, 35.2, 31.1,
28.8, 28.1, 26.5; HRMS-ES (m/z) [M þ H]þ calcd for C30H35-
N6O4 543.2720, found 543.2720.
Synthesis of N-Boc Lactam 57. To a solution of lactam 56
(130 mg, 0.24 mmol) in THF (40.0 mL) were added LiHMDS
(0.26 mL, 1.0 M in THF, 0.26 mmol) and (Boc)2O (63 mg, 0.29
mmol). The reaction mixture was stirred at rt for 10 min and
quenched with aqueous saturated NaHCO3. The mixture was
diluted with H2O and extracted with EtOAc. The combined
organic layers were dried over Na2SO4 and concentrated. The
residue was purified by flash column chromatography on silica
gel (hexanes/EtOAc, 9/1, 3/1 then 1/1) to give N-Boc-lactam 57
(125 mg, 81%): 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J=7.2
Hz, 1H), 7.42 (d, J =16.0 Hz, 1H), 6.97-6.88 (m, 4H), 6.32 (t,
J=7.2 Hz, 2H), 6.21 (d, J=16.0 Hz, 1H), 5.61 (s, 1H), 3.63 (dd,
J=4.0, 13.3 Hz, 1H), 3.52-3.38 (m, 2H), 2.95 (s, 3H), 2.91-2.81
(m, 1H), 2.51 (td, J=5.6, 13.6 Hz, 1H), 2.37 (s, 3H), 2.37-2.30
(m, 2H), 2.01-1.96 (m, 1H), 1.48 (s, 9H), 1.43 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 198.9, 171.5, 153.9, 152.8, 150.8, 143.2,
138.5, 133.1, 132.7, 131.1, 129.2, 128.4, 127.5, 127.0, 125.5,
124.9, 118.7, 107.7, 83.9, 82.4, 81.9, 59.0, 48.4, 48.2, 44.0, 34.2,
1
1/1) to give the NH-lactam 52 (155 mg, 94%): H NMR (300
MHz, CDCl3) δ 8.27-8.22 (m, 1H), 7.40-7.24 (m, 5H),
6.97-6.82 (m, 4H), 6.53 (dd, J = 0.8, 7.8 Hz, 1H), 6.26 (dd,
J = 0.9, 7.8 Hz, 1H), 6.25 (s, 1H), 5.88-5.74 (m, 1H), 5.63 (s,
1H), 4.88-4.81 (m, 2H), 4.84, 4.77 (ABq, J=6.7 Hz, 2H), 4.70,
4.61 (ABq, J=11.9 Hz, 2H), 4.51 (d, J=12.1 Hz, 1H), 4.24 (d,
J=12.1 Hz, 1H), 3.49 (td, J=4.5, 12.8 Hz, 1H), 3.25-3.18 (m,
1H), 2.97 (s, 3H), 2.85 (d, J=7.0 Hz, 2H), 2.54 (td, J=6.0, 13.4
Hz, 1H), 1.95 (dd, J=4.2, 13.5 Hz, 1H), 1.45 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 173.4, 154.1, 150.8, 138.5, 137.8, 134.4,
133.8, 132.7, 128.8, 128.4, 128.3, 127.8, 127.6, 126.8, 126.3,
125.9, 124.0, 119.4, 116.9, 106.1, 94.2, 83.1, 81.2, 69.6, 66.6,
58.6, 48.7, 40.6, 39.3, 31.4, 28.4, 28.1; HRMS-ES (m/z) [MþH]þ
calcd for C36H42N3O5 596.3124, found 596.3136.
Synthesis of Mesylate 53. To a solution of allyl lactam 52 (155mg,
0.26 mmol) in THF (9.0 mL) and H2O (3.0 mL) were added
OsO4 (0.33 mL, 4 wt % solution in water, 0.052 mmol) and
NMO (152 mg, 1.30 mmol). The mixture was stirred at rt for
12 h, and then a solution of NaIO4 (278 mg) in H2O (3.0 mL)
was added. The mixture was further stirred at rt for 2 h. The
cloudy aqueous solution was diluted with H2O and extracted
with EtOAc. The combined organic layers were dried over
Na2SO4 and concentrated. The resulting aldehyde was not
purified and was used directly in the next step.
To a solution of the crude aldehyde in EtOH (20.0 mL) was
added NaBH4 (25 mg, 0.66 mmol) at 0 °C. The mixture was
stirred at 0 °C for 15 min and then quenched by the addition of
saturated aqueous NH4Cl. After removal of EtOH in vacuo, the
residue was diluted with H2O and extracted with EtOAc. The
combined organic layers were dried over Na2SO4 and concen-
trated. The alcohol was not purified and was used directly in the
next step.
To a solution of the above crude alcohol in CH2Cl2 (10.0 mL)
were added TEA (0.18 mL, 1.29 mmol) and MsCl (61 μL, 0.78
mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min and
then quenched by the addition of saturated aqueous NaHCO3.
The mixture was diluted with H2O and extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4 and
concentrated. The residue was purified by flash column chro-
matography on silica gel (hexanes/EtOAc/TEA, 2/3/0.1 then
3/7/0.1) to give the mesylate 53 (147 mg, 83% for three steps): 1H
NMR (300 MHz, CDCl3) δ 8.18 (d, J=7.4 Hz, 1H), 7.39-7.28
(m, 5H), 6.97-6.85 (m, 4H), 6.52 (d, J=7.7 Hz, 1H), 6.25 (d, J=
7.3 Hz, 1H), 5.82 (s, 1H), 5.58 (s, 1H), 4.81, 4.76 (ABq, J =
6.7 Hz, 2H), 4.68, 4.61 (ABq, J = 11.8 Hz, 2H), 4.51-4.43 (m,
1H), 4.44 (d, J=12.0 Hz, 1H), 4.14 (d, J=12.1 Hz, 1H), 3.50 (td,
J = 4.4, 12.5 Hz, 1H), 3.24-3.18 (m, 1H), 2.95 (s, 3H), 2.72 (s,
3H), 2.53-2.38 (m, 3H), 2.01 (dd, J=3.8, 13.3 Hz, 1H), 1.45 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 173.2, 150.9, 138.9, 137.8,
133.8, 130.8, 128.6, 128.5, 127.8, 127.2, 126.8, 126.2, 124.4,
119.7, 106.4, 94.1, 83.2, 82.0, 69.7, 68.1, 66.6, 59.0, 46.5, 39.4,
36.7, 34.5, 31.4, 28.3, 28.1; HRMS-ES (m/z) [MþH]þ calcd for
C36H44N3O8S 678.2849, found 678.2849.
Synthesis of Aldehyde 54. To a solution of mesylate 53 (49
mg, 0.072 mmol) in THF (5.0 mL) was added Pearlman’s
catalyst (50 mg). After being stirred under an atmosphere of
hydrogen for 14 h, the reaction mixture was filtered through a
pad of Celite and concentrated to give the corresponding
alcohol which was not purified but used directly in the next
step.
To a solution of the benzyl alcohol in CH2Cl2 (5.0 mL) was
added Dess-Martin periodinane (35 mg, 0.083 mmol). The
reaction was stirred at rt for 15 min and quenched by the addi-
tion of 10% aqueous Na2S2O3 solution. The aqueous mixture
was extracted with CH2Cl2. The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (hexanes/
2678 J. Org. Chem. Vol. 75, No. 8, 2010

Seo et al.
JOCArticle
31.0, 29.4, 28.0, 27.6, 26.4; HRMS-ES (m/z) [MþH]þ calcd for
C35H43N6O6 643.3244, found 643.3247.
(d, J=7.3 Hz, 1H), 6.61 (d, J=15.8 Hz, 1H), 5.97 (s, 1H), 5.88
(d, J = 7.6 Hz, 1H), 4.96 (s, 1H), 4.85 (s, 1H), 4.42 (br s, 1H),
3.48-3.42 (m, 1H), 3.26 (t, J=9.8 Hz, 1H), 3.01-2.94 (m, 2H),
2.82 (br s, 1H), 2.52 (s, 3H), 2.46-2.37 (m, 1H), 2.03-1.86 (m,
1H), 1.91 (s, 3H), 1.53 (s, 9H), 1.38 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 175.8, 155.4, 151.3, 142.3, 138.2, 137.2, 131.5, 129.1,
128.2, 126.6, 126.1, 125.3, 125.1, 123.5, 116.7, 114.4, 103.9, 82.9,
81.4, 79.2, 61.5, 52.7, 40.1, 37.8, 35.2, 30.6, 28.4, 28.3, 19.2;
HRMS-ES (m/z) [M þ H]þ calcd for C36H47N4O5 615.3546,
found 615.3554.
Synthesis of Methyl Imidate 62. To a solution of the hexacycle
61 (12.0 mg, 0.020 mmol) in CH2Cl2 (10.0 mL) were added
DIPEA (34 μL, 0.20 mmol) and Me3OBF4 (29 mg, 0.20 mmol).
The reaction mixture was stirred at rt for 30 min and quenched
with saturated aqueous NaHCO3. The solution was diluted with
H2O and extracted with CH2Cl2. The combined organic layers
were dried over Na2SO4 and concentrated. The residue was
purified by preparative TLC (hexanes/acetone, 2/1) to give the
methyl imidate 62 (10.5 mg, 86%): 1H NMR (300 MHz, CDCl3)
δ 7.25 (d, J = 5.4 Hz, 1H), 7.13 (td, J = 1.4, 7.5 Hz, 1H),
6.95-6.89 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.33 (br s, 1H), 5.96
(d, J=6.8 Hz, 1H), 5.68 (s, 1H), 5.18 (br s, 1H), 3.92-3.65 (m,
4H), 3.78 (s, 3H), 3.48-3.36 (br m, 1H), 3.26-3.14 (br m, 1H),
2.98-2.73 (br m, 2H), 2.38 (s, 3H), 2.24-2.15 (m, 1H), 1.84 (s,
3H), 1.74 (s, 3H), 1.51 (s, 9H), 1.50 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 171.1, 155.8, 153.5, 150.7, 140.3, 136.8, 128.4, 126.3,
125.0, 124.9, 124.8, 124.5, 116.9, 103.5, 81.4, 80.2, 59.1, 57.9,
55.6, 51.1, 40.1, 38.4, 31.2, 29.7, 28.5, 28.4, 25.7, 18.8; HRMS-
ES (m/z) [M þ H]þ calcd for C37H49N4O5 629.3703, found
629.3723.
Synthesis of Amidine 63. To a solution of the imidate 62 (13.0 mg,
0.021 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.25 mL).
The reaction mixture was stirred at rt for 45 min and quenched
with saturated aqueous NaHCO3. The solution was extracted
with CH2Cl2. The combined organic layers were dried over
Na2SO4 and concentrated. The residue was purified by pre-
parative TLC (hexanes/acetone, 2/1) to give the amidine 63 (9.0
mg, 88%): 1H NMR (300 MHz, CDCl3) δ 7.07-6.96 (m, 2H),
7.05 (dd, J=1.4, 7.4 Hz, 1H), 6.86 (t, J=8.5 Hz, 1H), 6.78 (t,
J=7.7 Hz, 1H), 6.05 (dd, J=7.9, 12.9 Hz, 2H), 5.79 (br s, 0.6H),
5.61 (br s, 0.4H), 5.36-5.31 (m, 1H), 4.81 (d, J = 8.7 Hz, 1H),
3.83-3.73 (m, 2H), 3.36-3.29 (m, 1H), 3.26-3.18 (m, 1H), 2.90 (s,
3H), 2.87-2.77 (m, 1H), 2.29-2.20 (m, 1H), 2.07-2.00 (m, 1H),
1.85 (br s, 1H), 1.78 (s, 3H), 1.71 (s, 3H), 1.42 (br s, 5H), 1.23 (s,
4H); 13C NMR (75 MHz, CDCl3) δ 180.0, 154.0, 149.6, 137.7,
136.6, 134.3, 130.2, 129.7, 128.5, 127.5, 126.6, 124.6, 123.9, 121.9,
116.9, 104.3, 81.0, 79.1, 60.1, 58.6, 54.9, 54.8, 45.5, 38.3, 30.4, 28.3,
27.0, 25.7, 18.6; HRMS-ES (m/z) [MþH]þ calcd for C31H37N4O2
497.2917, found 497.2918.
Synthesis of (()-Communesin F (8). To a solution of the
amidine 63 (14.0 mg, 0.028 mmol) in acetic acid (0.8 mL) and
acetic anhydride (0.8 mL) was added NaBH4 (90 mg, 2.38 mmol)
at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and
quenched with saturated aqueous Na2CO3. The aqueous solu-
tion was extracted with CH2Cl2. The combined organic layers
were dried over Na2SO4 and concentrated. The resulting
N-acetyl-N-Boc-bis-aminal 64 was not purified and was used
directly in the next step.
Synthesis of Spiro-γ-lactam 58. To a solution of the N-Boc
lactam 57 (140 mg, 0.22 mmol) in THF (60.0 mL) and H2O
(12.0 mL) was added PMe3 (2.0 mL, 1.0 M in THF, 2.0 mmol).
The reaction mixture was stirred at 70 °C for 13 h and then
cooled to rt. After removal of THF in vacuo, the cloudy aqueous
mixture was extracted with EtOAc. The combined organic
layers were dried over Na2SO4 and concentrated. The residue
was purified by flash column chromatography on silica gel
(hexanes/EtOAc, 1/3) to give the spiro-γ-lactam 58 (118 mg,
88%): 1H NMR (300 MHz, CDCl3) δ 8.29 (br s, 0.5H), 7.80 (d,
J=16.0 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.20 (br s, 0.8H), 7.12
(t, J=7.6 Hz, 1H), 6.98-6.93 (m, 1H), 6.88 (t, J=7.8 Hz, 1H),
6.80 (d, J=7.3 Hz, 1H), 6.49 (d, J=16.0 Hz, 1H), 6.04 (s, 1H),
5.94 (d, J=7.5 Hz, 1H), 4.66 (s, 0.8H), 3.44-3.38 (m, 1H), 3.21
(t, J = 9.7 Hz, 1H), 2.99-2.92 (m, 2H), 2.78 (br s, 2H), 2.37 (s,
3H), 2.42-2.37 (br m, 1H), 2.05-1.98 (m, 1H), 1.52 (s, 9H), 1.35
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 199.5, 176.0, 155.4, 153.8,
151.6, 143.5, 137.5, 136.9, 134.1, 129.3, 126.7, 125.9, 125.4,
125.3, 114.5, 105.6, 82.3, 81.6, 79.2, 62.1, 52.8, 40.1, 37.7, 35.5,
34.6, 30.0, 28.3, 28.2, 27.4; HRMS-ES (m/z) [MþH]þ calcd for
C35H45N4O6 617.3339, found 617.3342.
Synthesis of Allylic Alcohol 59. To a solution of the spiro-
γ-lactam 58 (113 mg, 0.18 mmol) in THF (30.0 mL) was added
MeLi (0.57 mL, 1.6 M in Et2O, 0.91 mmol) dropwise at -78 °C.
The reaction mixture was stirred at -78 °C for 15 min and then
quenched with saturated aqueous NaHCO3. After removal of
THF in vacuo, the residue was diluted with H2O and extracted
with EtOAc. The combined organic layers were dried over
Na2SO4 and concentrated. The residue was purified by flash
column chromatography on silica gel (EtOAc) to give the allylic
alcohol 59 (85 mg, 73%): 1H NMR (300 MHz, CDCl3) δ 7.45 (d,
J=7.5 Hz, 1H), 7.27 (br s, 0.8H), 7.21 (br s, 0.6H), 7.12 (td, J=
1.2, 7.4 Hz, 1H), 6.99-6.89 (m, 2H), 6.85 (d, J = 7.8 Hz, 1H),
6.69 (d, J=7.8 Hz, 1H), 6.10 (d, J=11.2 Hz, 1H), 5.90 (s, 0.8H),
5.87 (d, J = 7.8 Hz, 1H), 4.80 (br s, 0.8H), 4.27 (br s, 0.8H),
3.46-3.40 (m, 1H), 3.24 (t, J = 9.7 Hz, 1H), 3.09 (br s, 1H),
2.99-2.91 (m, 1H), 2.83-2.79 (m, 1H), 2.72-2.64 (br m, 1H),
2.47 (s, 3H), 2.18-2.06 (m, 1H), 1.92-1.84 (m, 1H), 1.51 (s, 9H),
1.41 (s, 3H), 1.37 (s, 9H), 1.31 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 175.5, 155.7, 153.9, 150.8, 138.9, 138.3, 137.6, 137.1,
129.0, 126.4, 126.1, 125.2, 124.9, 123.4, 114.7, 103.7, 82.8, 81.3,
79.6, 70.5, 60.4, 52.8, 40.1, 38.1, 35.4, 35.1, 30.7, 30.0, 28.8,
28.4, 28.3; HRMS-ES (m/z) [M þ H]þ calcd for C36H49N4O6
633.3652, found 633.3647.
Synthesis of Hexacyclic γ-Lactam 61 and Diene 60. To a
solution of the allylic alcohol 59 (83 mg, 0.13 mmol) in CHCl3
(20.0 mL) was added PPTS (3.3 mg, 0.013 mmol). The reaction
mixture was stirred at rt for 1.5 h. After removal of CHCl3 in
vacuo, the residue was purified by flash column chromatogra-
phy on silica gel (hexanes/acetone, 5/1) to give the hexacycle 61
(51 mg, 62%) and diene 60 (20 mg, 24%).
Hexacycle 61: 1H NMR (300 MHz, CDCl3) δ 7.36-7.32 (br
m, 1H), 7.26-7.23 (br m, 1H), 7.13 (t, J=7.7 Hz, 1H), 6.92 (td,
J=1.3, 7.7 Hz, 1H), 6.88 (t, J=7.9 Hz, 1H), 6.28 (br d, J=6.7
Hz, 1H), 5.98 (br s, 1H), 5.89 (d, J = 7.6 Hz, 1H), 5.84 (s, 1H),
5.55 (br s, 1H), 5.10 (br s, 1H), 3.91 (br s, 1H), 3.47 (br d, J=9.0
Hz, 1H), 3.14-2.90 (m, 4H), 2.45 (s, 3H), 2.14-2.09 (br m, 1H),
1.98-1.92 (br m, 1H), 1.84 (s, 3H), 1.75 (s, 3H), 1.51 (s, 9H), 1.48
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.3, 156.2, 153.5, 150.6,
139.3, 137.3, 133.3, 128.8, 126.4, 125.9, 125.1, 125.0, 124.3,
116.9, 103.2, 89.5, 81.2, 79.6, 61.2, 59.7, 52.3, 41.0, 39.2, 36.1,
30.7, 28.6, 28.4, 25.6, 18.9; HRMS-ES (m/z) [MþH]þ calcd for
C36H47N4O5 615.3546, found 615.3560.
To a solution of the bis-aminal 64 in CH2Cl2 (5.0 mL) was
added TFA (2.0 mL). The reaction mixture was stirred at rt for
12 h and quenched with saturated aqueous Na2CO3. The
aqueous solution was extracted with CH2Cl2. The combined
organic layers were dried over Na2SO4 and concentrated. The
residue was purified by flash column chromatography on silica
gel (hexanes/acetone, 5/1 then 2/1) to give (()-communesin F (8)
(8.2 mg, 66% for two steps).
Diene 60: 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=7.7 Hz,
1H), 7.45 (br s, 1H), 7.14 (t, J=7.5 Hz, 1H), 6.97 (td, J=1.4, 7.8
Hz, 1H), 6.88 (t, J=7.8 Hz, 1H), 6.78 (d, J=14.6 Hz, 1H), 6.74
As described by the Qin group,6 (()-communesin F exists as
two amide rotamers in a ratio of 2.6: 1 in CDCl3 as shown by 1H
J. Org. Chem. Vol. 75, No. 8, 2010 2679

Seo et al.
JOCArticle
NMR. Only the NMR data for the major rotamer is listed (see
the Supporting Information for copies of the spectra).
30.8, 29.6, 26.0, 22.6, 18.5; HRMS-ES (m/z) [MþH]þ calcd for
C28H33N4O 441.2654, found 441.2635.
Major rotamer of 8: 1H NMR (300 MHz, CDCl3) δ 6.98 (d,
J=1.7, 7.7 Hz, 1H), 6.80 (t, J=7.7 Hz, 1H), 6.72-6.64 (m, 3H),
6.06 (d, J=7.7 Hz, 1H), 5.84 (d, J=7.6 Hz, 1H), 5.21 (br d, J=
8.9 Hz, 1H), 5.09 (s, 1H), 5.03 (d, J=8.8 Hz, 1H), 4.64 (s, 1H),
3.83 (dd, J=8.8, 11.4 Hz, 1H), 3.76 (br s, 0.5H), 3.34-3.27 (m,
1H), 3.25-3.17 (m, 1H), 3.04-2.96 (m, 1H), 2.80 (s, 3H),
2.75-2.70 (m, 1H), 2.38 (s, 3H), 2.30-2.18 (m, 2H),
1.97-1.91 (m, 1H), 1.83 (d, J = 1.2 Hz, 3H), 1.76 (d, J = 1.1
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.6, 150.1, 142.7,
140.6, 136.1, 132.7, 131.3, 128.3, 127.3, 124.6, 123.2, 120.6,
117.0, 114.7, 100.7, 82.6, 79.5, 64.4, 51.8, 51.2, 44.2, 37.8, 36.2,
Acknowledgment. We are grateful to the National Insti-
tutes of Health (CA-034303) and the National Science
Foundation (CHE-0806807) for financial support of this
research.
Supporting Information Available: Copies of proton and
carbon NMR spectra of new compounds and experimental
procedures for some sequences. This material is available free
of charge via the Internet at http://pubs.acs.org.
2680 J. Org. Chem. Vol. 75, No. 8, 2010