Explorations on the total synthesis of the unusual marine alkaloid chartelline A

Article abstract of DOI:10.1021/jo060084f

In work directed toward a total synthesis of chartelline A (1a), a strategy was investigated to construct the 10-membered ring of this marine alkaloid via an intramolecular aldehyde/β-lactam cyclocondensation to form the macrocyclic enamide functionality.

Full text of DOI:10.1021/jo060084f

Explorations on the Total Synthesis of the Unusual Marine Alkaloid
Chartelline A
Cuixiang Sun, Xichen Lin, and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
smw@chem.psu.edu
ReceiVed January 16, 2006
In work directed toward a total synthesis of chartelline A (1a), a strategy was investigated to construct
the 10-membered ring of this marine alkaloid via an intramolecular aldehyde/â-lactam cyclocondensation
to form the macrocyclic enamide functionality. Therefore, spiro-â-lactam and imidazole fragments were
first prepared. Tribromooxindole â-lactam 24 was synthesized from commercially available 5-nitroisatin
(18) in seven steps and 30% overall yield via a Staudinger ketene-imine [2 + 2]-cycloaddition strategy.
The requisite 2-bromoimidazole subunit 40 bearing a terminal alkyne and a masked aldehyde was efficiently
prepared from the readily available imidazole ester 25 in 10 steps. With both advanced intermediates
available, the addition of the lithium acetylide generated from 2-bromoimidazole subunit 40 to the γ-lactam
carbonyl group of N-Boc-tribromooxindole 24 was investigated, affording the desired N-Boc-aminal 41.
Hydrolysis of the acetonide moiety of 41, followed by oxidative cleavage of the resulting diol, gave the
aldehyde 42. Unfortunately, treatment of aldehyde 42 with p-toluenesulfonic acid did not give the desired
10-membered macrocyclic (Z)-enamide 46, but rather the highly unsaturated seven-membered ring
compound 44.
Introduction and Background
by X-ray crystallography. Furthermore, the absolute configu-
ration of the stereogenic center at C(20) was also determined
by X-ray to be S. Chartellines B and C have also been assigned
the S configuration on the basis of comparisons of their CD
spectra with that of chartelline A. Due to the 2-bromoimidazole
ring, the chartellines can exist in two tautomeric forms derived
from prototropic exchange between N-5 and N-7. The N-5-H
isomer predominates in solution based upon NMR spectral
analysis, while the N-7-H isomer (as shown in the structures)
was observed in the solid state by X-ray analysis. According to
the crystal structure, the central 10-membered ring of chartelline
A adopts a rigid, tublike conformation, which indicates that there
is very little conjugation present between the ring systems (see
structure A). Thus, the indolenine system is almost perpendicular
to the spiro-â-lactam ring and is close to parallel to the imidazole
ring.
In the 1980s, Christophersen and co-workers reported the
isolation of a small group of unique, highly halogenated indole-
imidazole alkaloids, chartellines A (1a), B (1b), and C (1c),
from the marine bryozoan Chartella papyracea (Ellis and
Solander) collected in the North Sea.1-3 The structure and
stereochemistry of chartelline A was unambiguously established
(1) (a) Chevolot, L.; Chevolot, A.-M.; Gajhede, M.; Larsen, C.; Anthoni,
U.; Christophersen, C. J. Am. Chem. Soc. 1985, 107, 4542. (b) Anthoni,
U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen, C. J. Org.
Chem. 1987, 52, 4709. (c) Nielsen, P. H.; Anthoni, U.; Christophersen, C.
Acta Chem. Scand. 1988, B42, 489.
(2) The chartellamides are biogenetically related â-lactams isolated from
the same organism: Anthoni, U.; Bock, K.; Chevolot, L.; Larsen, C.;
Nielsen, P. H.; Christophersen, C. J. Org. Chem. 1987, 52, 5638. For
synthetic studies, see: Pinder, J. L.; Weinreb, S. M. Tetrahedron Lett. 2003,
44, 4141.
Chartelline A lacks any significant antimicrobial activity
against a representative series of microorganisms, including
Gram-negative and Gram-positive bacteria, as well as molds.1b
Chartelline A was also found to be inactive in the National
Cancer Institute leukemia screen (3PS31) at a dose level of 5.60
(3) Several additional related alkaloids that are not â-lactams have also
been isolated: (a) Rahbaek, L.; Anthoni, U.; Christophersen, C.; Nielsen,
P. H.; Petersen, B. O. J. Org. Chem. 1996, 61, 887. (b) Rahbaek, L.;
Christophersen, C. J. Nat. Prod. 1997, 60, 175. For synthetic work in this
area, see: Korakas, P.; Chaffee, S.; Shotwell, J. B.; Duque, P.; Wood, J. L.
Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 12054.
10.1021/jo060084f CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/07/2006
J. Org. Chem. 2006, 71, 3159-3166
3159

Sun et al.
SCHEME 1
mg/kg and exhibited an ED50 of 29 and 31 µg/mL in the in
vitro KB and PS tests, respectively.1b Despite this lack of
biological activity, however, the structural novelty and complex-
ity of the chartellines make them worthy targets for total
synthesis.
We have previously described some preliminary feasibility
studies on synthesis of the spiro-â-lactam unit of the chartellines
via a strategy involving a Staudinger [2 + 2]-cycloaddition.4
Moreover, the Isobe group has reported two other methods to
build model spiro-â-lactams related to these alkaloids.5 More
recently, Baran et al. have disclosed an elegant strategy for
construction of the pentacyclic ring system of the chartellines.6
In this paper are outlined some of our ongoing studies on these
natural products which we hope will ultimately lead to a total
synthesis of chartelline A.7
SCHEME 2
Retrosynthetic Plan
Our first-generation synthetic strategy for chartelline A is
outlined in Scheme 1. The plan was to prepare the 10-membered
enamide 2 via cyclodehydration of aldehyde â-lactam 3.
Enamide 2 would be â-chlorinated8 and the system further
manipulated to produce chartelline A (1a). Intermediate 3 would
ultimately arise from coupling of a metal acetylide like 5 with
an activated N-acyllactam 4 using methodology which we have
previously tested.4
AIBN and (TMS)3SiH provided the â-lactam 8 in 91% yield.11
Subsequent Cbz protection of the γ-lactam moiety of 8 and
removal of the PMP protecting group with ceric ammonium
nitrate at 0 °C gave the required NH â-lactam 9 in high overall
yield. We were pleased to find that reaction of â-lactam 9 with
phenylacetaldehyde in the presence of p-toluenesulfonic acid
as catalyst produced the desired model enamide 11 in good yield.
Although the configuration of the enamide here is E, we believe
that in the actual natural product system the (Z)-configuration
of the 10-membered enamide will result from the cyclocon-
densation of 3, since the (E)-isomer is considerably more
strained. It was also found that bis-NH-lactam 10 undergoes
selective condensation at the â-lactam moiety with phenylac-
etaldehyde under the same conditions to produce enamide 12
in moderate yield.
Results and Discussion
Preliminary Model Studies. Prior to executing the strategy
in Scheme 1, a simple nonhalogenated model system was
initially explored to test some of the important steps. Thus, isatin
(6) was first converted to the corresponding imine with
p-anisidine (Scheme 2). This imine was found to undergo
smooth Staudinger [2 + 2]-cycloaddition with chloroketene to
afford a high yield of a 5:1 mixture of stereoisomeric R-chloro-
â-lactams 7.9,10 Free radical dechlorination of the mixture 7 with
(4) Lin, X.; Weinreb, S. M. Tetrahedron Lett. 2001, 42, 2631.
(5) (a) Nishikawa, T.; Kajii, S.; Isobe, M. Chem. Lett. 2004, 33, 440.
(b) Nishikawa, T.; Kajii, S.; Isobe, M. Synlett 2004, 2025.
(6) Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed.
2005, 44, 3714.
(7) Taken from: (a) Lin, X. Ph.D. Thesis, The Pennsylvania State
University, University Park, PA, 2002. (b) Sun, C. Ph.D. Thesis, The
Pennsylvania State University, University Park, PA, 2005.
(8) See, for example: (a) Shrestha-Dawadi, P. B.; Lugtenburg, J. Eur.
J. Org. Chem. 2003, 4654. (b) Diller, D.; Bergmann, F. Chem. Ber. 1977,
110, 2956.
In some additional trial experiments, lactam 8 was converted
to the corresponding N-Boc γ-lactam, to which lithio tert-
butylacetylide could be added chemoselectively, producing 13
as a mixture of stereoisomers (Scheme 3).12 This adduct mixture
then underwent a Meyer-Schuster rearrangement13 promoted
by trifluoroacetic acid to generate vinylogous amide 14 in which
(9) For reviews of the Staudinger reaction, see: Palomo, C.; Aizpurua,
J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem. 1999, 3223 and
references therein.
(10) For Staudinger cycloadditions of isatin imines, see: (a) Singh, G.
S.; Mehrotra, K. N. Ind. J. Chem. 1985, 24B, 129. (b) Joshi, K. C.; Jain,
R.; Sharma, V. J. Ind. Chem. Soc. 1986, 430. (c) Skiles, J. W.; McNeil, D.
Tetrahedron Lett. 1990, 31, 7277. (d) Joshi, K. C.; Dandia, A.; Bhagat, S.
J. Fluorine Chem. 1990, 48, 169.
(11) Bandini, E.; Favi, G.; Martelli, G.; Panunzio, M.; Piersanti, G. Org.
Lett. 2000, 2, 1077.
(12) Padwa, A.; Dean, D. C.; Fairfax, D. J.; Xu, S. L. J. Org. Chem.
1983, 58, 4646.
(13) (a) Omar, E. A.; Tu, C.; Wigal, C. T.; Braun, L. L. J. Heterocycl.
Chem. 1992, 29, 947. (b) Mamouni, A.; Daich, A.; Decroix, B. Synth.
Commun. 1998, 28, 1839.
3160 J. Org. Chem., Vol. 71, No. 8, 2006

Total Synthesis of the Marine Alkaloid Chartelline A
SCHEME 3
SCHEME 4
the Boc protecting group had been lost. The (Z)-s-cis-geometry
of this compound was established by X-ray crystallography.14
An interesting alternative here is to effect the Meyer-Schuster
rearrangement of 13 under milder conditions using tetrabutyl-
ammonium perrhenate and p-toluenesulfonic acid via the
procedure of Narasaka et al.,15 which led to vinylogous amide
15 still bearing the Boc group.
To generate the R,â-unsaturated imine functionality of the
chartellines, the intention was to reduce the carbonyl group of
the vinylogous amide functionality of a compound such as 14
or 15, followed by elimination. Several reducing agents (e.g.,
NaBH4/CeCl3, Zn(BH4)2, DIBALH, etc.) were tried to convert
15 to the corresponding alcohol, and it was eventually found
that lithium borohydride was effective for this transformation,
giving 16 in moderate yield. Exposure of N-Boc alcohol 16 to
trifluoroacetic acid, however, afforded the interesting but
undesired product 17 in good yield. In future work, it will be
necessary to further investigate the transformation of an
intermediate like 16 to the requisite unsaturated imine.
extensive experimentation, however, it was found that slow
addition of a solution of chloroacetyl chloride (10 equiv) in
benzene to a mixture of the N-PMP imine derived from 18 and
TEA in benzene at reflux afforded R-chloro-â-lactam 19 as a
mixture of stereoisomers in good yield. Since problems again
arose here with the solubility of subsequent intermediates
bearing a γ-lactam NH, a Boc group was installed on 19 at this
point to produce 20. The nitro group of 20 was reduced to the
amine with zinc in acetic acid, which also partially removed
the chlorine in the â-lactam. The crude mixture was therefore
subjected to free-radical dehalogenation11 to generate aniline
21 in high overall yield. This compound could be halogenated
with benzyltrimethylammonium tribromide to afford dibromoa-
niline 22. The Doyle modification17 of the Sandmeyer reaction
was then used to transform aniline 22 in one pot to the tribromo
compound 23. Finally, the PMP protecting group could be
removed with ceric ammonium nitrate, yielding the requisite
free â-lactam 24.
Preparation of the Imidazole Fragment. The synthesis of
the imidazole unit began with known imidazole ester 25, which
is readily prepared from histidine.18 It was found that N-
protection of the imidazole 25 as a SEM or BOM derivative
afforded regioisomeric mixtures which were quite inconvenient
to use for subsequent steps. However, the imidazole could be
protected regioselectively as the N-trityl compound 26 (Scheme
5). R,R-Dimethylation of ester 26 could best be effected with
methyl iodide using potassium tert-butoxide as the base to afford
compound 27 in good yield. The ester functionality of 27 was
then reduced with lithium aluminum hydride, and the resulting
alcohol 28 was converted to the acetate 29. The next step in
the sequence was to elaborate the imidazole ring further via
bromination at C(5), but unfortunately, the trityl group proved
to be incompatible with this transformation. It was therefore
necessary at this point to switch protecting groups, and this could
be done simply by treating trityl compound 29 with benzyl-
oxymethyl chloride, leading to BOM-protected imidazole 30.
Synthesis of the Tribrominated â-Lactam Moiety. Our
original plan was to prepare the required tribromo â-lactam
segment 4 using the Staudinger cycloaddition approach outlined
in Scheme 2 starting from 4,5,6-tribromoisatin. Although this
isatin could be conveniently prepared,7a,16 it proved difficult to
use due to solubility issues, and more importantly, various
imines derived from this compound did not undergo a Staudinger
cycloaddition. Therefore, an alternative sequence was developed
commencing from commercially available 5-nitroisatin (18).
Condensation of 5-nitroisatin with p-anisidine gave the N-PMP
imine as a bright red solid. However, upon treatment of this
imine under the same Staudinger experimental conditions used
for the simple isatin-derived model system (cf. Scheme 2), no
desired â-lactam product 19 was observed (Scheme 4). After
(14) We are grateful to Dr. Louis J. Todaro (Single-Crystal X-ray Facility,
Department of Chemistry, Hunter College, CUNY) for the X-ray analysis
of compound 14.
(15) (a) Narasaka, K.; Kusama, H.; Hayashi, Y. Chem. Lett. 1991, 1413.
(b) Narasaka, K.; Kusama, H.; Hayashi, Y. Tetrahedron 1992, 48, 2059.
(16) Synthesized by a variation of the preparation of 4,6-dibromoisatin:
Jnaneshwar, G. K.; Deshpande, V. H. J. Chem. Res., Synop. 1999, 632.
(17) Doyle, M. P.; Van Lente, M. A.; Mowat, R.; Fobare, W. F. J. Org.
Chem. 1980, 45, 2570.
(18) Bauer, H.; Tabor, H. Biochem. Prepr. 1957, 5, 97.
J. Org. Chem, Vol. 71, No. 8, 2006 3161

Sun et al.
SCHEME 5
SCHEME 7
SCHEME 6
We were surprised to find, however, that in this product the
BOM group was on Na rather than Nb as anticipated on the
basis of literature analogy.19 This result, and a consideration of
the mechanism of the formation of 30 (vide infra), led us to
investigate a shorter, more efficient route to the desired
imidazole fragment.
We therefore returned to imidazole ester 25 which was first
converted to a ∼2:1 mixture of regioisomeric BOM-protected
compounds 31 (Scheme 6). Without separation, this mixture of
esters was dimethylated as was done for 26 to generate a mixture
of regioisomeric alkylation products 32 and 33. Once again
without separation, this regioisomeric mixture was heated with
a catalytic amount of BOMCl in THF which caused complete
equilibration to the more stable BOM-isomer 32 in high yield.20
It seems likely that this equilibration proceeds via the bis-BOM
intermediate 34 and is thermodynamically driven. A similar
equilibration is probably occurring in the transformation of trityl
compound 29 to BOM-protected imidazole 30.19
To continue the synthesis, imidazole ester 32 was brominated
at C(5) to afford 35, which underwent a Stille coupling with
allyltributylstannane to afford allylated imidazole 36 (Scheme
7). The terminal double bond in intermediate 36 could be
cleaved to the corresponding aldehyde, but under no conditions
could an acetal of this compound be formed (cf. 5). A convenient
alternative was to first dihydroxylate olefin 3621 followed by
conversion of the diol to the well-behaved acetonide 37. It was
then possible to brominate imidazole 37 at C(2) with NBS to
produce 38 in high yield, and DIBALH reduction then produced
aldehyde 39. Using the Ohira modification of the Seyferth-
Gilbert reaction, aldehyde 39 could be converted directly into
terminal alkyne 40 in excellent yield.22-24
Coupling of the â-Lactam and Imidazole Segments. With
the requisite â-lactam and alkyne components in hand, we began
to investigate coupling procedures. In some preliminary studies,
it was discovered that â-lactams protected on nitrogen with
either TBS or tert-butyl groups did not react at the γ-lactam
functionality with the lithium acetylide derived from 40.
Moreover, a PMP group on the spiro-â-lactam could not be
removed after the coupling event. It was eventually found that
the best solution was simply to react unprotected â-lactam 24
with 2 equiv of the lithium acetylide generated from alkyne 40
to produce adduct 41 in good yield, along with the excess alkyne
which could be easily recovered by chromatography and
recycled (Scheme 8). The acetonide 41 was next hydrolyzed to
the corresponding diol in high yield and cleaved with lead
tetraacetate to generate aldehyde 42. Exposure of this aldehyde
to p-toluenesulfonic acid in toluene at room temperature
produced an unstable, bright yellow compound that did not
appear from spectral data to be the desired macrocyclic enamide
46, but which was tentatively assigned structure 44. We believe
that compound 44 probably arises via aldol-type cyclization of
vinylogous amide aldehyde intermediate 43 to produce the
seven-membered ring in the product. This material was con-
verted to the more stable bis-Boc compound 45, but due to the
(19) (a) Brown, T.; Jones, J. H.; Richards, J. D. J. Chem. Soc., Perkin
Trans. 1 1982, 1553. (b) Brown, T.; Jones, J. H. J. Chem. Soc., Chem.
Commun. 1981, 648. (c) Colombo, R.; Colombo, F.; Jones, J. H. J. Chem.
Soc., Chem. Commun. 1984, 292. (d) Fletcher, A. C. S.; Jones, J. H.;
Ramage, W. I.; Stachulski, A. V. J. Chem. Soc., Perkin Trans. 1 1979,
2261. (e) Hodges, J. C. Synthesis 1987, 20. (f) Chivikas, C. J.; Hodges, J.
C. J. Org. Chem. 1987, 52, 3591. (g) He, Y.; Chen, Y.; Du, H.; Schmid, L.
A.; Lovely, C. J. Tetrahedron Lett. 2004, 45, 5529. (h) Bhagavatula, L.;
Premchandran, R. H.; Plata, D. J.; King, S. A.; Morton, H. E. Heterocycles
2000, 53, 729.
(21) (a) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973. (b) Van Rheenen, V.; Cha, D. Y.; Hartley, W. M. Org.
Synth. 1988, 50, 342.
(22) (a) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971,
36, 1379. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997.
(23) For an example of the use of the Seyferth-Gilbert reagent with an
aldehyde having an adjacent quaternary center, see: Trost, B. M.; Fleitz,
F. J.; Watkins, W. J. J. Am. Chem. Soc. 1996, 118, 5146.
(24) Ohira, S. Synth. Commun. 1989, 19, 561.
(20) We thank Pooja Aggarwal for conducting the transformations shown
in Scheme 6.
3162 J. Org. Chem., Vol. 71, No. 8, 2006

Total Synthesis of the Marine Alkaloid Chartelline A
SCHEME 8
the (Z)-vinylogous amide geometry. Thus, nucleophilic attack
on the aldehyde functionality by the vinylogous amide to form
44 is the preferred mode of reaction.
Conclusion
In this paper, we have described the preparation of two key
building blocks which are potentially useful for a total synthesis
of the marine metabolite chartelline A (1a). Tribromo spiro-â-
lactam 24 can be synthesized in eight steps from commercially
available 5-nitroisatin (18) in about 30% overall yield. The
imidazole fragment 40 can be prepared from readily available
imidazole ester 25 in 10 steps. Although it is possible to couple
these units by chemoselective addition of the lithium acetylide
derived from alkyne 40 to the N-Boc γ-lactam functionality of
24, our first-generation strategy for formation of the 10-
membered ring of the natural product by a â-lactam/aldehyde
cyclocondensation failed. We are currently attempting to modify
the strategy to utilize intermediates described here to effect a
total synthesis of chartelline A (1a).
Experimental Section
Preparation of R-Chloro-â-lactam 19. A solution of 5-nitro-
isatin (18, 2.52 g, 12.7 mmol) and p-anisidine (1.58 g, 12.7 mmol)
in benzene (25 mL) was heated at reflux overnight with a Dean-
Stark trap. The reaction mixture was cooled to rt, and the solvent
was evaporated to give the imine as a red solid that was used
directly in the next step without purification.
To a refluxing solution of the above imine (104 mg, 0.35 mmol)
and triethylamine (0.49 mL, 3.5 mmol) in 10 mL of dry benzene
was added chloroacetyl chloride (0.279 mL, 3.5 mmol) dropwise
over 3 h. The solution was refluxed overnight and cooled to rt,
and saturated NaHCO3 solution was added. The mixture was
extracted with EtOAc, and the combined organic layers were dried
over MgSO4 and concentrated. The residue was purified by flash
column chromatography (30-50% EtOAc/hexanes gradient) to
yield R-chloro-â-lactam 19 (1:1 mixture of diastereoisomers, 97
mg, 74%) as an orange solid: IR (KBr) 3247, 1774, 1629, 1512
SCHEME 9
1
cm-1; H NMR (360 MHz, THF-d8) δ 10.74 (s, 0.5H), 10.69 (s,
0.5H), 8.44-8.27 (m, 2H), 7.16 (t, J ) 7.8 Hz, 1H), 7.04 (d, J )
7.4 Hz, 2H), 6.74 (d, J ) 7.4 Hz, 2H), 5.58 (s, 0.5 H), 5.40 (s,
0.5H), 3.64 (s, 3H); 13C NMR (75 MHz, THF-d8) δ 174.4, 172.3,
159.9, 159.8, 158.2, 158.1, 149.8, 149.1, 144.5, 144.1, 130.1, 128.7,
128.6, 125.1, 123.7, 122.8, 121.5, 119.5, 119.4, 115.3, 115.2, 111.7,
111.6, 67.3, 66.6, 64.8, 64.4, 55.6; HRMS (APCI+) calcd for
C17H13N3O5Cl (MH+) 374.0538, found 374.0555.
Synthesis of N-Boc Lactam 20. To a solution of the â-lactam
19 (129 mg, 0.35 mmol), DMAP (42 mg, 0.35 mmol), and
triethylamine (48 µL, 0.35 mmol) in 8 mL of dry methylene chloride
was added Boc anhydride (113 mg, 0.52 mmol) at rt. The solution
was stirred for 10 min at rt and then evaporated. The residue was
purified by flash column chromatography (10-20% EtOAc/
hexanes) to yield the N-Boc lactam 20 (105 mg, 64%) as a white
solid: IR (KBr) 2982, 1786, 1744, 1513 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.37-8.20 (m, 3H), 6.99-6.94 (m, 2H), 6.74-6.71 (m,
2H), 5.28 (s, 0.35H), 5.25 (s, 0.65H), 3.68 (s, 3H), 1.64 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 170.1, 167.2, 158.7, 158.5, 157.5,
157.4, 147.8, 147.6, 145.3, 144.9, 144.8, 144.5, 128.0, 127.9, 127.7,
127.6, 123.2, 122.1, 120.9, 119.3, 119.2, 119.1, 116.4, 116.2, 114.7,
114.6, 86.9, 86.6, 66.7, 65.7, 65.0, 64.6, 55.2, 27.7; HRMS (APCI+)
calcd for C22H21ClN3O7 (MH+) 474.1062, found 474.1093.
Synthesis of Aniline 21. To a solution of nitro R-chloro-â-lactam
20 (1.040 g, 2.20 mmol) in 50 mL of THF was added Zn dust
(4.32 g, 66.1 mmol) in one portion and AcOH (2.52 mL, 44.1
mmol) dropwise. The mixture was stirred at rt overnight and filtered,
and the filter cake was washed thoroughly with EtOAc. The
existence of Boc rotamers it was difficult to unambiguously
confirm its structure by NMR.
We therefore decided to investigate a related system where
cyclization to a 10-membered enamide like 46 was not possible
and which we thought might be more amenable to detailed NMR
analysis. Thus, terminal alkyne 48 was deprotonated with
n-butyllithium, and the resulting acetylide was combined with
N-Boc lactam 47, producing adduct 49 (Scheme 9). As was done
in Scheme 8, acetonide 49 was hydrolyzed to the diol and then
cleaved to afford aldehyde 50. Subsequent cyclization of this
compound with p-TsOH in toluene led to the bright yellow
pentacycle 51, which was immediately converted to the stable
mono-Boc compound 52. A series of 2D NMR experiments on
52 (HMQC, HMBC, NOESY, see the Supporting Information)
were then carried out to conclusively prove the structure of this
compound. We believe the failure of amido aldehyde 43 to
undergo cyclization to the desired enamide product 46 is
probably due to the strain in this macrocyclic system due to
J. Org. Chem, Vol. 71, No. 8, 2006 3163

Sun et al.
combined filtrate was concentrated, and saturated NaHCO3 solution
was added. The mixture was extracted with EtOAc. The organic
extract was dried over MgSO4 and concentrated to afford a mixture
of aniline 21 and undechlorination aniline (1:2) as a yellow solid,
which was used directly for the next reaction.
(1.02 mL, 7.40 mmol). The reaction mixture was stirred overnight
at rt and then evaporated. The residue was purified by flash column
chromatography (40% EtOAc/hexanes) to yield the protected
imidazole 26 (2.30 g, 96%) as a white solid: mp 152-153 °C; 1H
NMR (400 MHz, CDCl3) δ 7.37 (d, J ) 1.3 Hz, 1H), 7.29-7.26
(m, 9H), 7.14-7.11 (m, 6H), 6.77 (d, J ) 1.3 Hz, 1H), 4.11 (q, J
) 7.1 Hz, 2H), 3.58 (s, 2H), 1.19 (t, J ) 7.1 Hz, 3H); 13C NMR
(90 MHz, CDCl3) δ 170.8, 142.1, 138.0, 133.8, 129.4, 127.8, 127.7,
119.4, 74.9, 60.3, 34.4, 13.8; HRMS calcd for C26H24N2O2 (MH+)
397.1915, found 397.1936.
2-Methyl-2-(1-trityl-1H-imidazol-4-yl)propionic Acid Ethyl
Ester (27). To a solution of imidazole 26 (6.10 g, 15.4 mmol) in
dry THF (360 mL) were added t-BuOK (6.91 g, 61.6 mmol) and
18-crown-6 (0.814 g, 3.08 mmol) at -78 °C. The resulting solution
was stirred for 0.5 h at -78 °C, and MeI (3.83 mL, 61.6 mmol)
was then added. The mixture was stirred at -78 °C for 2 h, and
water was added. The mixture was extracted with ether, and the
organic extracts were dried over MgSO4 and concentrated. The
residue was purified by flash column chromatography (30-50%
EtOAc/hexanes gradient) to yield imidazole ester 27 (6.22 g, 95%)
as a white solid: mp 116-117 °C; 1H NMR (400 MHz, CDCl3) δ
7.35-7.31 (m, 10H), 7.14-7.10 (m, 6H), 6.64 (d, J ) 1.4 Hz,
1H), 4.09 (q, J ) 7.1 Hz, 2H), 1.52 (s, 6H), 1.16 (t, J ) 7.1 Hz,
3H); 13C NMR (90 MHz, CDCl3) δ 176.3, 145.3, 142.5, 138.0,
129.8, 128.0, 127.9, 117.5, 75.2, 60.6, 43.1, 25.4, 14.1; HRMS calcd
for C28H28N2O2 (MH+) 425.2228, found 425.2223.
The above mixture was dissolved in 25 mL of toluene, and
(TMS)3SiH (1.02 mL, 3.30 mmol) and a catalytic amount of AIBN
were added. The mixture was heated at 100 °C overnight. The
solution was evaporated in vacuo and the residue was purified by
flash column chromatography (2-5% MeOH/CH2Cl2 gradient) to
give the aniline â-lactam 21 (795 mg, 88%) as a yellow solid: IR
1
(KBr) 3476, 3381, 2986, 1782, 1766, 1514 cm-1; H NMR (300
MHz, CDCl3 + CD3OD) δ 7.74-7.71 (m, 1H), 6.78-6.95 (m, 2H),
6.74-6.69 (m, 4H), 3.68 (s, 3H), 3.52 (d, J ) 14.7 Hz, 1H), 3.20
(d, J ) 14.7 Hz, 1H), 2.26 (s, 2H), 1.60 (s, 9H); 13C NMR (75
MHz, CDCl3 + CD3OD) δ 172.5, 162.6, 156.5, 148.8, 144.4, 131.2,
129.8, 124.7, 118.4, 117.0, 116.9, 114.5, 109.6, 85.0, 60.5, 55.3,
50.7, 27.9; HRMS (APCI+) calcd for C22H24N3O5 (MH+) 410.1710,
found 410.1697.
Preparation of Dibromoaniline 22. To a solution of aniline 21
(1.47 g, 3.58 mmol) in a mixture of CH2Cl2-MeOH (60 mL:24
mL) were added benzyltrimethylammonium tribromide (2.93 g, 7.52
mmol) and calcium carbonate powder (896 mg, 8.96 mmol) at rt,
and the mixture was stirred for 30 min. The solid calcium carbonate
was filtered off, the filtrate was concentrated, and water was added
to the residue. The mixture was extracted with CH2Cl2. The organic
layer was then dried over MgSO4 and evaporated in vacuo. The
residue was purified by flash column chromatography (CH2Cl2) to
yield dibromo aniline 22 as a white solid (1.85 g, 91%): IR (KBr)
2-Methyl-2-(1-trityl-1H-imidazol-4-yl)propan-1-ol (28). To a
solution of imidazole ester 27 (0.80 g, 1.9 mmol) in dry THF (80
mL) was added LiAlH4 (1.0 M in Et2O, 2.3 mL, 2.3 mmol) at rt.
The solution was stirred for 3 h and quenched with 1.0 mL of 15%
KOH solution. The resulting solution was stirred overnight, dried
over MgSO4, and concentrated. The residue was purified by flash
column chromatography (80% EtOAc/hexanes) to yield alcohol 28
1
3466, 3368, 2980, 1774, 1735, 1512 cm-1; H NMR (300 MHz,
CD2Cl2) δ 8.19 (s, 1H), 6.99-6.96 (m, 2H), 6.79-6.74 (m, 2H),
4.60 (br s, 2H), 3.71 (s, 3H), 3.60 (d, J ) 14.6 Hz, 1H), 3.40 (d,
J ) 14.6 Hz, 1H), 1.62 (s, 9H); 13C NMR (75 MHz, CD2Cl2) δ
171.6, 162.2, 157.1, 148.7, 140.5, 132.6, 130.6, 122.0, 119.8, 118.3,
114.9, 110.2, 105.8, 85.9, 62.0, 55.7, 48.2, 28.1; HRMS (APCI+)
calcd for C22H22BrN3O5 (MH+) 565.9921, found 565.9886.
Synthesis of Tribromide 23. To a solution of dibromo aniline
22 (1.25 g, 2.20 mmol) in 55 mL of MeCN was added CuBr2 (2.46
g, 11.0 mmol), followed by t-BuONO (437 µL, 3.31 mmol), and
the solution was then heated at 50 °C for 1 h. The reaction mixture
was diluted with saturated NaHCO3 solution, extracted with EtOAc,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (20-50% EtOAc/
hexanes) to yield tribromide 23 as a white solid (1.22 g, 88%) along
with the γ-lactam product (109 mg, 9%), which had lost the Boc
1
(0.7 g, 99%) as a white solid: mp 143-144 °C; H NMR (300
MHz, CDCl3) δ 7.34-7.30 (m, 10H), 7.14-7.10 (m, 6H), 6.55 (d,
J ) 1.4 Hz, 1H), 3.57 (s, 2H), 1.21 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 149.0, 142.4, 138.1, 129.7, 128.1, 128.0, 116.3, 75.2,
73.0, 36.1, 24.9; HRMS calcd for C26H26N2O (MH+) 383.2122
(MH+), found 383.2121.
Acetic Acid 2-Methyl-2-(1-trityl-1H-imidazol-4-yl)propyl Es-
ter (29). To a solution of the above alcohol 28 (0.680 g, 1.78 mmol)
in dry CH2Cl2 (45 mL) were added pyridine (0.288 mL, 3.56 mmol),
acetyl chloride (0.165 mL, 2.31 mmol), and a catalytic amount of
DMAP at rt. The solution was stirred overnight, and brine was
added. The organic layer was washed with brine, dried over MgSO4,
and concentrated. The residue was purified by flash column
chromatography (40% EtOAc/hexanes) to yield acetate 29 (0.730
g, 97%) as a pale yellow oil: 1H NMR (360 MHz, CDCl3) δ 7.35-
7.30 (m, 10H), 7.14-7.11 (m, 6H), 6.55 (s, 1H), 4.10 (s, 2H), 1.96
(s, 3H), 1.26 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 170.9, 146.7,
142.5, 138.2, 129.7, 127.9, 117.0, 75.1, 72.1, 35.4, 24.6, 20.8;
HRMS calcd for C28H28N2O2 (MH+) 425.2224, found 425.2209.
Acetic Acid 2-(1-Benzyloxymethyl-1H-imidazol-4-yl)-2-
methylpropyl Acid Ester (30). To a solution of trityl-protected
imidazole 29 (1.24 g, 2.92 mmol) in MeCN (136 mL) was added
BOMCl (3.24 mL, 23.4 mmol). The reaction mixture was heated
and stirred in an oil bath at 90 °C for 48 h. Saturated NaHCO3 was
then added, and the resulting solution was stirred for 10 min. The
organic layer was washed with brine, dried over MgSO4, and
concentrated. The residue was purified by flash column chroma-
tography (50-100% EtOAc/hexanes gradient) to yield the BOM-
protected imidazole 30 (763 mg, 86%) as a colorless oil: IR (film)
3034, 2971, 1733, 1500 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.51
(d, J ) 1.3 Hz, 1H), 7.36-7.27 (m, 5H), 6.82 (d, J ) 1.3 Hz, 1H),
5.27 (s, 2H), 4.44 (s, 2H), 4.15 (s, 2H), 2.02 (s, 3H), 1.32 (s, 6H);
13C NMR (90 MHz, CDCl3) δ 170.9, 149.0, 136.7, 136.2, 128.5,
128.1, 127.8, 114.0, 75.0, 72.0, 70.0, 35.4, 24.5, 20.8; HRMS calcd
for C17H22N2O3 (MH+) 303.1703, found 303.1700.
1
group: IR (KBr) 2980, 1781, 1736, 1512 cm-1; H NMR (300
MHz, CD2Cl2) δ 8.44 (s, 1H), 6.97-6.94 (m, 2H), 6.76-6.73 (m,
2H), 3.68 (s, 3H), 3.64 (d, J ) 14.7 Hz, 1H), 3.44 (d, J ) 14.7 Hz,
1H), 1.64 (s, 9H); 13C NMR (75 MHz, CD2Cl2) δ 170.9, 161.8,
157.1, 148.3, 141.4, 130.3, 128.3, 124.9, 123.2, 122.9, 120.3, 118.3,
114.9, 86.6, 61.8, 55.6, 48.2, 28.0; HRMS (ESI+) calcd for C22H20-
Br3N2O5 (MH+) 628.8917, found 628.8862.
Synthesis of â-Lactam 24. To a solution of â-lactam 23 (322
mg, 0.510 mmol) in 7 mL of MeCN was added dropwise CAN
(839 mg, 1.53 mmol) in 5 mL of water at 0 °C. The solution was
stirred for 1.5 h at 0 °C, and saturated Na2SO3 was added. The
mixture was extracted with EtOAc, and the organic layer was dried
over MgSO4 and concentrated. The residue was purified by flash
column chromatography (15-25% EtOAc/hexanes gradient) to
yield â-lactam 24 (241 mg, 90%) as a white solid: IR (KBr) 3222,
1
2980, 1785, 1744, 1584 cm-1; H NMR (360 MHz, THF-d8) δ
8.37 (s, 1H), 7.46 (br s, 1H), 3.50 (d, J ) 14.4 Hz, 1H), 3.20 (dd,
J ) 1.8, 14.4 Hz, 1H), 1.60 (s, 9H); 13C NMR (75 MHz, THF-d8)
δ 173.1, 165.2, 149.7, 142.5, 127.6, 127.2, 124.4, 123.3, 119.9,
85.5, 58.2, 28.1; HRMS (APCI+) calcd for C15H14Br3N2O4 (MH+)
522.8498, found 522.8499.
(1-Trityl-1H-imidazol-4-yl)acetic Acid Ethyl Ester (26). To a
solution of imidazole ester 25 (0.95 g, 6.17 mmol) in CH2Cl2 (100
mL) at rt were added trityl chloride (2.05 g, 7.40 mmol) and NEt3
3164 J. Org. Chem., Vol. 71, No. 8, 2006

Total Synthesis of the Marine Alkaloid Chartelline A
(1-Benzyloxymethyl-1H-imidazol-4-yl)acetic Acid Ethyl Ester
and (3-Benzyloxymethyl-3H-imidazol-4-yl)acetic Acid Ethyl
Ester (31). To a solution of imidazole ester 25 (3.0 g, 19.5 mmol)
in 24 mL of THF were added triethylamine (9.2 mL, 66.2 mmol)
and 94% BOMCl (4.9 mL, 33.1 mmol) at 0 °C. The resulting
solution was then warmed to rt and stirred for 1.5 h. The mixture
was concentrated in vacuo, and the residue was dissolved in CH2Cl2.
The organic layer was washed with water, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (0-20% MeOH/EtOAc gradient) to
yield a mixture of BOM-protected imidazole regioisomers 31 as a
clear yellow-brown oil (2.94 g, 55%): 1H NMR (300 MHz, CDCl3)
(∼2:1 mixture of regioisomers) δ 7.5 (s, 1H, major and minor),
7.43-7.19 (m, 5H, major and minor), 7.02 (s, 1H, minor), 6.98 (s,
1H, major), 5.33 (s, 2H, major), 5.25-5.24 (m, 2H, minor), 4.41
(s, 2H, minor), 4.37 (s, 2H, major), 4.20-4.06 (m, 2H, major and
minor), 3.69 (s, 2H, major), 3.64 (s, 2H, minor), 1.29-1.13 (m,
3H, major and minor).
2-(1-Benzyloxymethyl-1H-imidazol-4-yl)-2-methylpropionic
Acid Ethyl Ester (32) and 2-[3-(Benzyloxy)methyl-3H-imidazol-
4-yl]-2-methylpropionic Acid Ethyl Ester (33). To a solution of
BOM-protected imidazole regioisomers 31 (2.65 g, 9.66 mmol) in
80 mL of THF at -78 °C were added t-BuOK (6.50 g, 57.97 mmol)
and 18-crown-6 (0.84 g, 2.42 mmol). After the solution was stirred
for 30 min at -78 °C, MeI (3.0 mL, 48.30 mmol) was added, and
the resulting solution was stirred for 1 h at -78 °C. The reaction
mixture was diluted with water and warmed to rt, and the aqueous
layer was extracted with ether. The extract was dried over MgSO4
and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (0-20% MeOH/EtOAc gradient) to
afford a mixture BOM-protected imidazole regioisomers 32 and
33 as a clear light yellow oil (2.44 g, 84%): 1H NMR (300 MHz,
CDCl3) (mixture of regioisomers) δ 7.52 (s, 1H, major), 7.51-
7.26 (m, 5H, major), 6.92 (s, 1H, major), 5.27 (s, 2H, major), 4.49
(s, 2H, major), 4.14 (q, J ) 7.1 Hz, 2H, major), 1.58 (s, 6H, major),
1.22 (t, J ) 7.1 Hz, 3H, major); 13C NMR (100 MHz, CDCl3) δ
137.9, 136.4, 128.9, 128.6, 128.5, 128.2, 128.1, 124.3, 114.7, 75.5,
70.7, 32.7, 27.7, 25.7, 14.3; HRMS calcd for C17H22N2O3 (MH+)
302.3724, found 303.1717.
136.5, 136.0, 128.3, 127.9, 127.5, 98.8, 73.8, 70.0, 60.6, 43.1, 25.0,
13.9; HRMS (APCI+) calcd for C17H22N2O3Br (MH+) 381.0814,
found 318.0794.
2-(5-Allyl-1-benzyloxymethyl-1H-imidazol-4-yl)-2-methylpro-
pionic Acid Ethyl Ester (36). Under an atmosphere of argon, a
solution of 5-bromoimidazole 35 (303 mg, 0.795 mmol) in 5 mL
of dioxane and a solution of t-Bu3P (121 µL, 0.040 mmol, 10% in
hexane) were added sequentially to a Schlenk tube charged with
Pd2(dba)3 (15 mg, 0.016 mmol) and CsF (266 mg, 1.75 mmol).
Allyltributylstannane (271 µL, 0.875 mmol) was then added by
syringe, the Schlenk tube was sealed and placed in a 100 °C oil
bath, and the mixture was stirred overnight. The reaction mixture
was then cooled to rt, diluted with EtOAc, and filtered through a
pad of silica gel. The silica gel was washed thoroughly with EtOAc,
and the combined washings were concentrated in vacuo. The residue
was purified by flash column chromatography (50-80% EtOAc/
hexanes gradient) to yield allyl imidazole 36 as a colorless oil (217
mg, 80%): 1H NMR (300 MHz, CDCl3) δ 7.42 (s, 1H), 7.35-
7.23 (m, 5H), 5.87-5.74 (m, 1H), 5.18 (s, 2H), 5.02 (dd, J ) 10.2,
1.2 Hz, 1H), 4.86 (d, J ) 17.2 Hz, 1H), 4.38 (s, 2H), 4.09 (q, J )
7.1 Hz, 2H), 3.42-3.40 (m, 2H), 1.58 (s, 6H), 1.17 (t, J ) 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 176.6, 142.3, 136.2, 135.6,
134.6, 128.4, 127.9, 127.7, 123.3, 115.9, 73.3, 69.4, 60.4, 43.2,
27.2, 26.0, 13.8.
2-[1-Benzyloxymethyl-5-(2,2-dimethyl[1,3]dioxolan-4-ylmethyl)-
1H-imidazol-4-yl]-2-methylpropionic Acid Ethyl Ester (37). To
a mixture of N-methylmorpholine N-oxide (371 mg, 3.17 mmol)
and allyl imidazole 36 (217 mg, 0.634 mmol) in water (7 mL) and
acetone (3.5 mL) was added osmium tetraoxide (193 µL, 0.032
mmol, 4% in water) at rt. The mixture was stirred overnight. The
solution was then concentrated, and the mixture was extracted with
CH2Cl2. The organic layer was dried over MgSO4 and evaporated
in vacuo. The residue was purified by flash column chromatography
(0-10% MeOH/EtOAc gradient) to yield the diol (235 mg, 99%)
as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.33-7.21 (m,
6H), 5.53 (d, J ) 11.0 Hz, 1H), 5.18 (d, J ) 11.0 Hz, 1H), 4.38 (s,
2H), 4.09 (q, J ) 6.9 Hz, 2H), 3.95 (br s, 2H), 3.83-3.80 (m, 1H),
3.58 (dd, J ) 3.0, 11.1 Hz, 1H), 3.42 (dd, J ) 6.4, 10.8 Hz, 1H),
2.78 (d, J ) 6.4 Hz, 2H), 1.56 (s, 6H), 1.17 (t, J ) 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 177.0, 141.9, 136.1, 128.4, 128.0,
127.7, 123.9, 73.8, 71.6, 69.7, 65.9, 60.8, 43.6, 27.1, 26.2, 26.0,
13.8.
To a stirred solution of the above diol (224 mg, 0.596 mmol) in
21 mL of dry acetone was added concentrated H2SO4 (87 µL). The
reaction mixture was stirred for 2 d, and saturated NaHCO3 was
slowly added. Acetone was evaporated, and the residue was
extracted with CH2Cl2. The organic extracts were dried over MgSO4
and concentrated. The residue was purified by preparative TLC
(50-100% EtOAc/hexanes gradient) to yield acetonide 37 (184
mg, 74%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.45
(s, 1H), 7.35-7.24 (m, 5H), 5.67 (d, J ) 11.0 Hz, 1H), 5.20 (d, J
) 11.0 Hz, 1H), 4.38 (s, 2H), 4.40 (ABq, J ) 18.0, 11.8 Hz, 2H),
4.19-4.02 (m, 4H), 3.55 (t, J ) 7.8 Hz, 1H), 2.92-2.89 (m, 2H),
1.61 (s, 3H), 1.60 (s, 3H), 1.40 (s, 3H), 1.28 (s, 3H), 1.20 (t, J )
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 176.6, 142.2, 136.3,
136.2, 128.4, 128.0, 127.7, 123.3, 109.2, 75.8, 74.0, 69.5, 69.0,
60.6, 43.5, 27.3, 26.6, 26.4, 26.0, 25.4, 14.0; HRMS (APCI+) calcd
for C23H33N2O5 (MH+) 417.2390, found 417.2364.
2-[1-Benzyloxymethyl-2-bromo-5-(2,2-dimethyl[1,3]dioxolan-
4-ylmethyl)-1H-imidazol-4-yl]-2-methylpropionic Acid Ethyl
Ester (38). To a solution of imidazole 37 (108 mg, 0.260 mmol)
in dry THF (10 mL) was added NBS (69 mg, 0.40 mmol) at 0 °C.
The mixture was stirred at 0 °C overnight, and 10% Na2S2O3
solution was added. The mixture was extracted with EtOAc, and
the organic extracts were dried over MgSO4 and concentrated. The
residue was purified by flash column chromatography (20-30%
EtOAc/hexanes gradient) to yield 2-bromoimidazole 38 (122 mg,
95%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.35-7.27
(m, 5H), 5.73 (d, J ) 11.2 Hz, 1H), 5.33 (d, J ) 11.2 Hz, 1H),
2-(1-Benzyloxymethyl-1H-imidazol-4-yl)-2-methylpropionic
Acid Ethyl Ester (32). To a solution of BOM imidazole regioi-
somers 32 and 33 (2.19 g, 7.27 mmol) in 24 mL of THF was added
a catalytic amount of 94% BOMCl (54 µL, 0.36 mmol) at rt. The
resulting solution was then warmed and stirred in an oil bath at 70
°C for 3 h. The mixture was concentrated in vacuo, and the residue
was purified by flash column chromatography on silica gel (EtOAc)
to yield BOM imidazole 32 as a clear light yellow oil (1.89 g,
1
86%): IR (film) 2980, 2935, 1727, 1500, 1455, 1455 cm-1; H
NMR (300 MHz, CDCl3) δ 7.52 (s, 1H), 7.51-7.26 (m, 5H), 6.92
(s, 1H), 5.27 (s, 2H), 4.49 (s, 2H), 4.14 (q, J ) 7.1 Hz, 2H), 1.58
(s, 6H), 1.22 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
137.9, 136.4, 128.9, 128.6, 128.5, 128.2, 128.1, 124.3, 114.7, 75.5,
70.7, 32.7, 27.7, 25.7, 14.3; HRMS calcd for C17H22N2O3 (MH+)
302.3724, found 303.1717.
2-(1-Benzyloxymethyl-5-bromo-1H-imidazol-4-yl)-2-methyl-
propionic Acid Ethyl Ester (35). To a solution of imidazole 32
(379 mg, 1.25 mmol) in 42 mL of CH2Cl2/MeOH (5:2) were added
benzyltrimethylammonium tribromide (672 mg, 1.72 mmol) and
CaCO3 powder (215 mg, 2.15 mmol) at rt. The mixture was stirred
until the orange color faded (∼4 h). The solid calcium carbonate
was filtered off, the filtrate was concentrated, and water was then
added to the residue. The mixture was extracted with CH2Cl2. The
organic layer was dried over MgSO4 and evaporated in vacuo. The
residue was purified by flash column chromatography (50-100%
EtOAc/hexanes gradient) to yield 5-bromoimidazole 35 as a
colorless oil (303 mg, 63%): IR (film) 2978, 2919, 1725 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.31-7.24 (m, 5H), 5.26
(s, 2H), 4.46 (s, 2H), 4.14 (q, J ) 7.1 Hz, 2H), 1.59 (s, 6H), 1.19
(t, J ) 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.4, 143.0,
J. Org. Chem, Vol. 71, No. 8, 2006 3165

Sun et al.
4.38 (ABq, J ) 15.5, 11.8 Hz, 2H), 4.18-4.03 (m, 4H), 3.54 (t, J
) 7.6 Hz, 1H), 2.89 (d, J ) 6.0 Hz, 2H), 1.58 (s, 3H), 1.57 (s,
3H), 1.39 (s, 3H), 1.28 (s, 3H), 1.21 (t, J ) 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 176.3, 142.9, 136.7, 128.4, 128.0, 127.6, 126.9,
118.3, 109.4, 75.7, 74.3, 70.2, 69.0, 60.8, 43.6, 28.0, 26.6, 26.5,
26.1, 25.4, 14.0; HRMS (APCI+) calcd for C23H32N2O5Br (MH+)
495.1495, found 495.1494.
and concentrated. The residue was purified by flash column
chromatography (30-100% EtOAc/hexanes gradient) to provide
the diol (19 mg, 99%) as a white solid: 1H NMR (300 MHz, THF-
d8) δ 8.25-8.23 (m, 1H), 7.31-7.01 (m, 6H), 5.72-5.65 (m, 1H),
5.42-5.34 (m, 1H), 4.53 (m, 3H), 3.98-3.10 (m, 8H), 1.65-1.62
(m, 3H), 1.58-1.56 (m, 12H); HRMS (APCI+) calcd for C34H37-
Br4N4O7 (MH+) 928.9390, found 928.9334.
2-[1-Benzyloxymethyl-2-bromo-5-(2,2-dimethyl[1,3]dioxolan-
4-ylmethyl)-1H-imidazol-4-yl]-2-methylpropionaldehyde (39). To
a solution of ester 38 (157 mg, 0.318 mmol) in CH2Cl2 (15 mL)
was added DIBALH (3.18 mL, 1.0 M in CH2Cl2) dropwise at -78
°C. The mixture was stirred at -78 °C overnight, and an additional
1.59 mL of DIBALH was added. After 7 h at -78 °C, EtOAc and
saturated NH4Cl were added, and the mixture was stirred at rt
overnight. The reaction mixture was filtered and concentrated. The
residue was purified by flash column chromatography (20-30%
EtOAc/hexanes gradient) to yield the aldehyde 39 (140 mg, 98%)
as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.52 (s, 1H),
7.39-7.28 (m, 5H), 5.73 (d, J ) 11.2 Hz, 1H), 5.36 (d, J ) 11.2
Hz, 1H), 4.56 (ABq, J ) 15.0, 12.0 Hz, 2H), 4.16-4.05 (m, 2H),
3.55-3.50 (m, 1H), 2.92-2.79 (m, 2H), 1.46 (s, 3H), 1.458 (s,
3H), 1.41 (s, 3H), 1.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
201.7, 139.6, 136.6, 128.7, 128.5, 128.0, 127.6, 119.4, 109.6, 75.9,
74.4, 70.6, 69.1, 47.9, 28.0, 26.5, 25.4, 22.2, 21.9; HRMS (APCI+)
calcd for C21H28N2O4Br (MH+) 451.1213, found 451.1236.
1-Benzyloxymethyl-2-bromo-5-(2,2-dimethyl[1,3]dioxolan-4-
ylmethyl)-4-(1,1-dimethylprop-2-ynyl)-1H-imidazole (40). To a
solution of Ohira’s diazoketophosphonate24 (142 mg, 0.741 mmol)
in 8 mL of MeOH at 0 °C were added K2CO3 (136 mg, 0.99 mmol)
and imidazole aldehyde 39 (223 mg, 0.494 mmol) in 8 mL of
MeOH. The mixture was stirred for 30 min at 0 °C and at rt for 4
h. The reaction was quenched with saturated NH4Cl solution and
diluted with CH2Cl2. The organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (10-25% EtOAc/hexanes
gradient) to yield acetylene 40 (212 mg, 96%) as a colorless oil:
1H NMR (360 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 5.68 (d, J )
11.2 Hz, 1H), 5.38 (d, J ) 11.2 Hz, 1H), 4.54 (ABq, J ) 13.3,
12.1 Hz, 2H), 4.41-4.34 (m, 1H), 4.06 (dd, J ) 8.1, 6.1 Hz, 1H),
3.62 (t, J ) 7.9 Hz, 1H), 3.55 (dd, J ) 15.5, 3.3 Hz, 1H), 3.08 (dd,
J ) 15.5, 8.4 Hz, 1H), 2.30 (s, 1H), 1.62 (s, 3H), 1.61 (s, 3H),
1.38 (s, 3H), 1.31 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 142.9,
136.8, 128.5, 128.0, 127.6, 126.6, 118.3, 109.3, 90.6, 76.5, 74.3,
70.4, 70.1, 68.9, 31.8, 31.4, 31.2, 27.7, 26.6, 25.5; HRMS (APCI+)
calcd for C22H28N2O3Br (MH+) 447.1283, found 447.1262.
Preparation of Alkyne 41. To a solution of imidazole alkyne
40 (245 mg, 0.548 mmol) in 4 mL of dry THF was added LiHMDS
(575 µL, 1.0 M in THF, 0.575 mmol) at -78 °C. The solution was
stirred at -78 °C for 30 min and at rt for 5 min and recooled to
-78 °C. A solution of N-Boc lactam 24 (144 mg, 0.274 mmol) in
1 mL of dry THF was added at -78 °C. The mixture was stirred
for 2 h at -78 °C, and water was added. The mixture was extracted
with Et2O, and the organic extracts were dried over MgSO4 and
concentrated. The residue was purified by flash column chroma-
tography (20-50% EtOAc/hexanes gradient) to provide alkyne 41
(mixture of diastereoisomers, 242 mg, 91%) as a white solid: 1H
NMR (300 MHz, CDCl3) δ 8.10-8.08 (m, 1H), 7.37-7.27 (m,
5H), 6.31 (br s, 0.25H), 6.28 (br s, 0.25H), 5.85 (br s, 0.25H), 5.70
(br s, 0.25H), 5.57-5.43 (m, 1H), 5.34-5.27 (m, 1H), 4.58-4.52
(m, 2H), 4.45-4.20 (m, 1H), 4.03-3.96 (m, 1H), 3.92-3.76 (m,
2H), 3.64-3.57 (m, 0.5H), 3.39-3.25 (m, 1.5H), 3.10-3.02 (m,
1H), 1.65-1.51 (m, 15H), 1.41-1.38 (m, 3H), 1.30-1.26 (m, 3H);
HRMS (APCI+) calcd for C37H41Br4N4O7 (MH+) 968.9703, found
968.9690.
To a solution of the above diol(12 mg, 0.013 mmol) in dry
benzene (1 mL) was added Pb(OAc)4 (6 mg, 0.014 mmol) under
argon at rt. The mixture was stirred for 10 min, diluted with EtOAc,
and washed with saturated NaHCO3. The organic phase was dried
over MgSO4 and concentrated to afford the aldehyde 42, which
was used directly for the next reaction: 1H NMR (300 MHz, CDCl3)
δ 9.62 (s, 0.5H), 9.56 (s, 0.5H), 8.10 (br s, 1H), 7.40-7.31 (m,
5H), 7.01 (s, 0.5H), 6.22 (s, 0.5H), 5.30 (d, J ) 12.1 Hz, 2H), 4.52
(d, J ) 10.6 Hz, 2H), 4.09-3.94 (m, 2.5H), 3.77 (d, J ) 15.0 Hz,
0.5H), 3.41 (d, J ) 15.0 Hz, 0.5H), 3.12 (d, J ) 15.0 Hz, 0.5H),
1.66-1.46 (m, 15H); HRMS (APCI+) calcd for C34H37Br4N4O7
(MH+) 928.9390, found 928.9334.
Synthesis of Seven-Membered-Ring Compound 44. To a
solution of aldehyde 42 (0.013 mmol) in dry toluene (10 mL) were
added flame-dried 4 Å molecular sieves and p-TsOH (29 mg, 0.15
mmol) at rt. The mixture was stirred at rt overnight. Saturated
NaHCO3 was added, and the mixture was extracted with EtOAc.
The organic layer was dried over MgSO4 and concentrated to yield
the unstable seven-membered vinylogous amide 44 (6 mg) as a
yellow solid, which was used directly for the next reaction without
further purification: 1H NMR (300 MHz, CD2Cl2) δ 12.66 (br s,
1H), 7.31-7.26 (m, 5H), 7.12 (d, J ) 11.6 Hz, 1H), 6.58 (d, J )
11.6 Hz, 1H), 6.15 (br s, 1H), 5.40 (s, 2H), 4.56 (s, 2H), 3.70-
3.68 (m, 2H), 1.55 (m, 3H), 1.28 (m, 3H); HRMS (APCI+) calcd
for C28H23Br4N4O3 (MH+) 778.8498, found 778.8566.
Synthesis of the Bis-N-Boc Lactam 45. To a solution of the
vinylogous amide 44 (6 mg, 0.008 mmol), DMAP (1.5 mg, 0.012
mmol), and triethylamine (1.6 µL, 0.012 mmol) in 1 mL of dry
CH2Cl2 was added Boc anhydride (3.3 mg, 0.015 mmol) at rt. The
solution was stirred at rt overnight and then evaporated. The residue
was purified by preparative TLC (hexanes/EtOAc/CH2Cl2 ) 4:2:
1) to yield the N-Boc lactam 45 (7 mg, 55% for three steps) as a
yellow solid: 1H NMR (300 MHz, CD2Cl2) δ 8.19 (s, 1H), 7.37-
7.27 (m, 5H), 6.58 (d, J ) 11.6 Hz, 1H), 6.02 (br d, J ) 11.6 Hz,
1H), 5.39 (ABq, J ) 20.0, 11.4 Hz, 2H), 4.57 (s, 2H), 4.03 (br s,
1H), 3.40 (br s, 1H), 1.59 (s, 3H), 1.45 (s, 9H), 1.23 (s, 3H), 1.10
(br s, 9H); 1H NMR (300 MHz, toluene-d8, 70 °C) δ 7.20 (s, 1H),
7.13-6.97 (m, 5H), 6.29 (d, J ) 11.6 Hz, 1H), 5.90 (d, J ) 11.6
Hz, 1H), 4.82 (ABq, J ) 13.8, 11.3 Hz, 2H), 4.18 (s, 2H), 3.92 (d,
J ) 15.1 Hz, 1H), 2.96 (d, J ) 15.1 Hz, 1H), 1.97 (s, 3H), 1.42 (s,
3H), 1.30 (s, 9H), 1.25 (br s, 9H); 13C NMR (75 MHz, toluene-d8,
70 °C) δ 199.3, 162.0, 150.0, 149.5, 144.8, 143.6, 137.2, 130.4,
130.4, 130.2, 128.8, 128.7, 128.3, 127.9, 126.7, 122.4, 121.5,
121.24, 121.19, 114.4, 84.9, 83.5, 74.1, 71.0, 65.8, 54.0, 49.4, 28.2,
28.0, 21.7, 21.4; LRMS (APCI+) calcd for C38H39Br4N4O7 (MH+)
978.95, found 978.9.
Acknowledgment. We are grateful to the National Science
Foundation (CHE-0404792) for financial support of this re-
search.
Supporting Information Available: Experimental procedures
for the compounds in Schemes 2, 3, and 9 and copies of proton
and carbon NMR spectra of new compounds. Also included are
X-ray data for compound 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
Preparation of Aldehyde 42. To a stirred solution of acetonide
41 (242 mg, 0.249 mmol) in 10 mL of THF/H2O (4:1) was added
dropwise 2.64 mL of TFA at rt. The mixture was stirred at rt
overnight. The reaction was quenched with saturated NaHCO3 and
extracted with Et2O. The organic extracts were dried over MgSO4
JO060084F
3166 J. Org. Chem., Vol. 71, No. 8, 2006