Total synthesis of the leucetta-derived alkaloid calcaridine a

Article abstract of DOI:10.1055/s-0029-1216929

A biomimetically guided total synthesis of the Leucettaderived aminoimidazole alkaloid, calcaridine A, is described. The synthesis relies on position selective metalations of a 4,5-diiodoimidazole derivative to provide a tetrasubstituted imidazole. Subjec

Full text of DOI:10.1055/s-0029-1216929

2970
PAPER
Total Synthesis of the Leucetta-Derived Alkaloid Calcaridine A
Total
S
ynthesi
a
s
of the Leu
n
cetta-Derive
d
d
A
lkaloidC
u
alcaridine
A
ka B. Koswatta, Rasapalli Sivappa, H. V. Rasika Dias,* Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA
Fax +1(817)2723808; E-mail: lovely@uta.edu; E-mail: dias@uta.edu
Received 12 June 2009
interest appears to stem from a report from Ireland and co-
workers describing the unique mode of action of naami-
dine A (3)6 and its potential use as an anticancer agent
coupled with the recognition that the 2-aminoimidazole
Abstract: A biomimetically guided total synthesis of the Leucetta-
derived aminoimidazole alkaloid, calcaridine A, is described. The
synthesis relies on position selective metalations of a 4,5-diiodo-
imidazole derivative to provide a tetrasubstituted imidazole. Sub-
jection of this polysubstituted imidazole derivative to oxidative may serve as a platform for medicinal chemistry endeav-
ors.14 Recently, reports from the Crews lab have appeared,
rearrangement with a Davis oxaziridine provides the corresponding
imidazolone core of calcaridine A.
first in 2003 describing calcaridine A (5),15,16 spirocalcar-
idines A (6) and B (7),15 and then in 2004 describing
Key words: 2-aminoimidazole, oxidative rearrangement, metal–
halogen exchange, oxaziridine, imidazolone
spiroleucettadine (8)17 (Scheme 1), which contain both
unique skeletons and higher levels of oxidation than the
naamidine-type systems, for example, 3 (Figure 1). Sev-
eral groups, including our own have initiated synthetic
programs in response to these reports.18 It is of note that
the structure of spiroleucettadine (8) has been revised on
the basis of three unsuccessful total synthesis campaigns,
A large number of sponge-derived 2-aminoimidazole-
containing natural products have been reported and have
served as targets in a number of total synthesis endeavors.
Two major families of alkaloids have been described that
possess this heterocycle; the oroidin1,2 and the Leucetta al-
kaloids.3 Both families of natural products have been the
subject of synthetic efforts, with the former having attract-
ed significantly more attention, presumably as a conse-
quence of the challenging structural intricacy of several
family members. The Leucetta-derived family, for exam-
ple, 1–4 (Figure 1),4–7 isolated from Leucetta or Clathrina
genera of sponges, have, until recently, received less at-
tention from the synthetic community.8–13 The increase in
X
OMe
16
19
1
15
5
4
N
17
14
6
H2N
2
20
3
18
OMe
N
7
OR
OH
Me
8
N
N
13
12
9
H2N
O
10
11
Me
OH
9: X = H, naamine A
10: X = OH, 14-hydroxynaamine A
11: X = OMe, 14-methoxynaamine A
6: R = H, spirocalcaridine A
7: R = Me, spirocalcaridine B
10→6/7
O
O
O
O
O
Me
11→5
N
9→10
N
HO
OMe
N
N
N
N
O
OMe
HN
H2N
H
N
N
O
H2N
O
O
Me
1: clathridine A
Me
OMe
N
N
O
2: preclathridine A
NHMe
Me
Me
O
5: calcaridine A
8: spiroleucettadine
Me
Me
OMe
N
O
N
O
O
N
N
H
OMe
OMe
OH
N
N
N
O
HN
N
O
N
N
Bn
[O]
13
H2N
Me
N
OMe
OR
OH
H
N
PG
Me
Me
O
4: kealiiquinone
3: naamidine A
12
N
S
N
H
Figure 1 Some Leucetta-derived alkaloids
O
14: R = H or Me
SYNTHESIS 2009, No. 17, pp 2970–2982
x
x.
x
x
.
2
0
0
9
Advanced online publication: 07.08.2009
DOI: 10.1055/s-0029-1216929; Art ID: C02709SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Biosynthetic relationships between naamines and other
Leucetta alkaloids

PAPER
Total Synthesis of the Leucetta-Derived Alkaloid Calcaridine A
2971
thus demonstrating the power of total synthesis as a means the biological potential of this natural product, neither of
to confirm or refute structural assignments.19 which was described in the original report.15
Similarly to the oroidin alkaloids,20 the biosynthetic ori- For some time our lab has pursued a strategy to the syn-
gins of the Leucetta alkaloids have not been elucidated ex- thesis of polysubstituted imidazoles, which relies on func-
perimentally, however, the relationships between them, if tionalization of a polyhaloimidazole derivative2,12,22 rather
not the details, are apparent.3,18 For example, 14-methoxy- than de novo synthesis of the heterocycle for the construc-
naamine A (11) may serve as a precursor for calcaridine A tion of polysubstituted imidazoles and this forms the basis
(5), which can be accessed through an oxidative rear- of the approach to calcaridine A (5) described herein. It
rangement (C4 → C5 migration). This type of rearrange- has been demonstrated that N-protected 4,5-dihaloimida-
ment with tetrahydrobenzimidazoles has recently been zoles can be functionalized sequentially at C5, then C4 by
demonstrated in our lab, for example, 12 → 13 treatment with Grignard reagents, and then electrophilic
(Scheme 1).21 The spirocalcaridines 6 and 7 can be envi- trapping.23,24 Subsequent C2-functionalization can then be
sioned as arising from an ipso substitution reaction (C8 → accomplished by lithiation, and electrophile quench, for
C14) from 14-hydroxynaamine A (10) and oxidation.3 example, with N3,25 thus providing a flexible and expedi-
Our lab has demonstrated previously that certain 2-ami- ent approach to a large number of these alkaloids.12,16,22
noimidazole derivatives undergo oxidative addition of The Ohta lab has reported in a number of publications the
water or methanol to produce systems related to these nat- use of a similar metalation-electrophilic quench sequence;
ural products 12 → 14 (Scheme 1).21 Finally, spiroleucet- these reports describe the use of organolithiums (either
tadine (8) can be formed through an oxidative cyclization deprotonation or halogen exchange), but require blocking
(C8 → O → C5) from naamine A (9). Although the details the more reactive C2-position, adding additional steps.8
of the biosynthesis of these natural products have not been Amongst other advantages, our strategy provides the op-
worked out, these formal relationships provide a basis for portunity for divergent functionalization, which should
the development of synthetic approaches. In this contribu- prove useful in probing structure–activity relationship
tion, we describe the development of a biomimetically (SAR). Based on this general analysis, the retrosynthesis
guided approach to calcaridine A (5) based on the oxida- depicted in Scheme 2 was envisioned in which 14-meth-
tive rearrangement of 14-methoxynaamine (Scheme 2).16 oxynaamine A (15: PG = H ≡ 11), the rearrangement pre-
In addition to exploring the generality of the oxidation cursor, is constructed through a series of metalation-
chemistry with substrates other than tetrahydrobenzimi- electrophile reactions. 14-Methoxynaamine A (11) has
dazoles, we were also interested in addressing questions not been described in the literature as occurring naturally,
of the both the relative (and absolute) stereochemistry and but the closely related 14-methoxynaamidine A (19) has
been reported (Scheme 2).26 Oxidative rearrangement of
the 4,5-disubstituted imidazole would then provide the
corresponding 5-imidazolone.21
HO
MeO
oxidative
rearrangement
N
In our initial approach, the 4,5-diiodoimidazole 18 was
metalated with EtMgBr in CH2Cl2, and then treated with
OMe
H2N
N
N
OMe
H2N
CuCN·2LiCl followed by the siloxybenzyl bromide deriv-
ative 20.24 However, rather than the required substituted
product 24, we obtained the imidazolium salt 21
(Scheme 3). Presumably, the organometallic species and
the alkylating agent do not react and upon quenching the
reaction, the reduced heterocycle undergoes N-alkylation.
To circumvent this issue we modified the approach to em-
ploy an aldehyde, the product of which would then be re-
duced to 24. Thus metalation of 18 with EtMgBr and then
reaction with the siloxybenzaldehyde 22 provided the ex-
pected doubly benzylic alcohol 23 (Scheme 3). Ionic re-
duction of 23 with Et3SiH in the presence of TFA
provided the reduced product with concomitant desilyla-
tion, thus the reduction product was treated with TBSCl/
NaH to afford 24. The resulting heterocycle was subjected
to a second round of metalation and treatment of the in situ
formed Grignard with anisaldehyde. However, rather than
obtaining the expected alcohol, we either obtained a com-
plex mixture of products when the reaction was conducted
in CH2Cl2, or the corresponding ketone derivative 25 in
approximately 50% yield along with a similar amount of
the 4-methoxybenzyl alcohol when the reaction was per-
formed in THF (Scheme 3). The latter outcome suggests
Me
N
O
OMe
Me
5: calcaridine A
MeO
15
OPG
N
I
N
metalation, then
anisaldehyde
C2-amination
N
N
OMe
Me
Me
16
17
OPG
OPG
Me
N
metalation
then ArCHO
I
I
O
N
N
O
MeO
OMe
N
N
N
HN
Me
18
OH
Me
19: 14-methoxynaamidine A
Scheme 2 Retrosynthetic analysis of calcaridine A
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

2972
P. B. Koswatta et al.
PAPER
OTBS
1. EtMgBr, CH2Cl2
I
I
I
N
N
N
N
EtMgBr, CH2Cl2
2. CuCN⋅2LiCl
then 20
then 22
90%
OH
I
N
Me
Me
23
18
N
Br
21
Me
OTBS
Et3SiH, TFA
OHC
OTBS
then
NaH, TBSCl
70%
20
OTBS
22
O
I
1. EtMgBr
THF
N
N
2. anisaldehyde
reflux
N
N
OMe
Me
Me
50%
24
OTBS
OTBS
25
Scheme 3 Grignard reactions on imidazole 18
that the initial (and required) alcohol is formed but then (Scheme 4). Addition of 4-methoxyphenylmagnesium
undergoes an Oppenhauer-type oxidation,27 providing ke- bromide (28) led to the formation of alcohol 29 in excel-
tone 25. Unfortunately, we were not able to find condi- lent yield, which was converted into methyl ether 30 by
tions that prevented the oxidation, and therefore we acid-catalyzed substitution.29 At this point, we decided to
adopted a slightly different tactic, in which the imidazole test whether the oxidative rearrangement was feasible on
was first formylated and then the remaining aromatic frag- this type of substrate, as all of the previously investigated
ment introduced via Grignard chemistry (Scheme 4).
examples were tetrahydrobenzimidazole derivatives.21
Gratifyingly, it was found upon treatment with 2.5 equiv-
alents of N-sulfonyloxaziridine 31 in methanol at 40 °C
that a smooth rearrangement took place providing imida-
Metalation was performed as before with EtMgBr and
then reaction with the N-methyl-N-(2-pyridyl)formamide
(26)28 provided the corresponding aldehyde 27
OH
CHO
I
N
N
N
N
N
EtMgBr, THF
28, THF
then 26
78%
reflux
99%
N
OMe
Me
27
Me
Me
29
24
OTBS
OTBS
OTBS
TFA, MeOH
40 °C
92%
TBSO
OMe
OMe
N
N
31
N
MeOH, 40 °C
~30%
OMe
N
O
OMe
Me
Me
32
30
OTBS
MgBr
OMe
O2N
O
NSO2Ph
CHO
N
N
H
26
Me
28
31
Scheme 4 Rearrangement feasibility studies
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

PAPER
Total Synthesis of the Leucetta-Derived Alkaloid Calcaridine A
2973
zolone 32 in modest, but unoptimized, yield (Scheme 4). Unfortunately, at this stage (see below) we were unable to
A single stereoisomer was obtained in this reaction, and separate the two diastereomers, but it was clear from the
although we have not rigorously assigned the relative ste- NMR data that the minor of the two diastereomers corre-
reochemistry, we have tentatively assigned it as indicated sponds to calcaridine A (5).
1
in Scheme 4 based on the similarity of its H NMR data
compared to epi-calcaridine A (epi-5, see Scheme 6, vide
infra).
OMe
OMe
BuLi, THF
–78 °C, then
N
N
N
N
N3
Although the general feasibility of the strategy had been
demonstrated, issues with regard to the deprotection–
reprotection sequence (23 → 24, Scheme 3) prompted us
to make changes to the protecting group on the phenolic
oxygen and to use a benzyl group. The choice of this pro-
tecting group had the added advantage that it could be re-
moved by catalytic hydrogenation, which would be used
in the late-stage reduction of the 2-azido moiety and there-
fore would telescope the sequence to some extent. The di-
iodoimidazole 18 was converted into alcohol 34 through
metalation and reaction with the benzyl-protected alde-
hyde 33, Et3SiH-mediated reduction provided the net sub-
stitution product 35 (Scheme 5). Metalation at C4, and
reaction with N-methylformanilide provided the aldehyde
36, which reacts with 4-methoxyphenylmagnesium bro-
mide (28) to produce the required alcohol 37. Acid-cata-
lyzed ether formation provided 38 in excellent yield.
TsN3, 58%
OMe
OMe
Me
Me
39
38
BnO
OBn
N
Pd(OH)2/C, H2
EtOH, >95%
OMe
H2N
N
OMe
Me
31
11
OH
MeOH
40 °C
54%
HO
HO
OMe
OMe
I
N
N
I
+
I
N
N
N
N
N
N
N
EtMgBr, CH2Cl2
Et3SiH, TFA
H2N
H2N
OH
N
r.t., then 33
>95%
CHCl3, 55 °C
60%
OMe
OMe
O
O
I
Me
Me
Me
Me
epi-5
Me
5
18
Scheme 6 First-generation approach to epi-calcaridine A (epi-5)
and calcaridine A (5)
35
OBn
OBn
34
CHO
On analysis of stereochemical outcome of the oxidative
rearrangement, we believed that it might be possible to
improve the diastereoselectivity by switching the location
of the two benzylic substituents, thereby placing the pre-
existing stereocenter closer to the point of the oxygen
transfer, at C5 of the imidazole.30 To accomplish this ne-
cessitated a minor re-engineering of the synthetic se-
quence, but in reality required modifying the order of
addition, this is in fact one of the strengths of our ap-
proach. Accordingly, 18 was metalated at C5 and reacted
with p-anisaldehyde to provide the alcohol 40 in excellent
yield (Scheme 7), which was converted into the methyl
ether 41 by treatment with NaH followed by methyl io-
dide. Initially we attempted to introduce the remaining
benzyl fragment by metalation with EtMgBr, conversion
into the cuprate (CuCN·2LiCl), and then trapping with the
TBS-protected benzyl bromide derivative, but this strate-
gy again led to the formation of an imidazolium salt (43,
Scheme 7). Using benzaldehyde 22 as electrophile with
the Grignard derived from 41 in CH2Cl2 was partially suc-
cessful providing the ketone 44 and the desilylated ketone
45. The desilylated ketone 45 was subjected to reduction
under Wolff–Kischner conditions, but this experiment
was unsuccessful. Interestingly repetition of the Grignard
chemistry in THF provided the anticipated diol 46 as a 2:1
EtMgBr, THF
then N-methyl-
formanilide
66%
OBn
OR
33
CHO
N
N
N
4-MeOC6H4MgBr
THF, >95%
N
OMe
Me
Me
36
OBn
OBn
37: R = H
TFA, MeOH
55–60 °C
>95%
38: R = Me
Scheme 5 Preparation of benzyl-substituted precursor 38
At this stage the 2-amino substituent was introduced by
deprotonation of 38 at C2 with n-BuLi and reaction with
TsN3 affording 39 (Scheme 6).25 Treatment of 39 with
Pd(OH)2/H2 resulted in conversion of the azido moiety
into the amine and hydrogenolysis of the benzyl protect-
ing group providing 14-methoxynaamine A (11). Expo-
sure of this substrate to 31 in MeOH at 40 °C led to
oxidative rearrangement and the formation of a 2:1 mix-
ture of epi-calcaridine A (epi-5) and calcaridine A (5).
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

2974
P. B. Koswatta et al.
PAPER
mixture of diastereomers (stereochemistry unassigned) in complicated by concomittent reduction of the acetal, but
addition to the net reduction product 42. Attempts to re- it was found that deprotection of the acetal followed by re-
move the hydroxy group in 46 by radical based deoxygen- duction of the alcohol produced 50. Addition of 4-meth-
ation methods were also unsuccessful.
oxyphenylmagnesium bromide provided the expected
alcohol 51, which was converted into the methyl ether 52
upon treatment with NaH and MeI. Installation of the 2-
amino substituent was accomplished through lithiation at
C2 and reaction with TsN3 (Scheme 8).25 Catalytic hydro-
genation led to reduction of both the azide moiety to the
amino group and hydrogenolysis of the O-benzyl protect-
ing group providing the regioisomer 54 of 14-methoxy-
naamine A (11) (Scheme 9). Subjection of 54 to oxidative
rearrangement with the Davis reagent 31 provided a 1:1
mixture of calcaridine A and epi-calcaridine in low but
unoptimized yield. Although there had been some change
in the diastereoselectivity of the rearrangement, it was not
as substantial as hoped and the separation problem persist-
ed. Our earlier studies with the oxidative rearrangement
chemistry had demonstrated that 2-azido substituted imi-
dazoles would participate in the rearrangement21 and so
we subjected 53 to oxidation in the hope that the diastere-
omers resulting from this reaction might be more easily
separable. We were gratified to find that although there
was no change in the diastereoselectivity (1:1 mixture),
the resulting 2-azido imidazolones 55 and epi-55 were
separable by chromatography. Both diastereomers were
individually subjected to catalytic hydrogenation to pro-
vide in essentially quantitative yield calaridine A (5) and
epi-calcardine A (epi-5) as solids (Scheme 9). The NMR
spectra of one of the diastereomers matched that reported
in the literature.15 Once pure, as an added bonus, the non-
natural diastereomer provided suitable crystals for X-ray
analysis, which in addition to confirming the connectivity
provided the relative stereochemistry of this diastereomer
(Figure 2) and by analogy that of the natural product. We
were also able to use the crystalline non-natural diastereo-
mer as seeds to effect fractional crystallizations to purify
all of the previously prepared diastereomeric mixtures.
X
I
I
I
N
N
N
N
N
N
EtMgBr, CH2Cl2
NaH, then
MeI, 72%
OMe
OH
then
p-anisaldehyde
97%
Me
Me
Me
40
18
41: X = I
42: X = H
OR
OMe
OMe
EtMgBr, CH2Cl2
then 22
EtMgBr, CH2Cl2
then CuCN⋅2LiCl
then 20, 35%
N
O
OMe
N
EtMgBr, THF
then 22, 48%
OTBS
TBSO
Me
OMe
44: R = TBS, 19%
45: R = H, 5%
N
N
N
OH
OMe
OMe
N
Me
Me
43
46
OMe
OMe
Scheme 7 Unsuccessful approaches to the regioisomeric rearrange-
ment substrate
As these direct approaches were not successful we adopt-
ed the approach delineated in Scheme 8 to assemble the
inverted substrate. Thus, metalation of 18 and trapping
with N-methylformanilide provided the corresponding al-
dehyde 47, which was protected as an acetal with ethylene
glycol, providing 48. Metalation at C4 and reaction of the
resulting Grignard with 33 provided the alcohol 49. At-
tempted ionic reduction of the alcohol at this stage was
OH
I
I
I
ethylene
glycol
N
N
N
N
N
N
N
N
EtMgBr, CH2Cl2
EtMgBr, THF, r.t.
O
O
then 33, 87%
p-TsOH, PhH
reflux, 97%
r.t. then N-methyl-
formanilide
61–73%
OBn
O
I
Me
Me
Me
O
Me
H
O
48
47
18
49
1. HCl (aq), THF
reflux
OBn
OBn
2. Et3SiH
TFA, CH2Cl2
r.t., 65%
4-MeOC6H4MgBr
OMe
THF, reflux, 84%
BuLi, THF
–78 °C
OMe
N
N
N
N
N
N3
then TsN3
76%
N
OBn
CHO
Me
Me
Me
OMe
OR
50
53
NaH, THF, 0 °C
→ r.t. → 0 °C
then MeI, 84%
51: R = H
52: R = Me
Scheme 8 Preparation of precursor azide 53
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Total Synthesis of the Leucetta-Derived Alkaloid Calcaridine A
2975
OBn
OH
OMe
OMe
N
N
N
N
Pd(OH)2/C
N3
H2N
H2, EtOH
>95%
Me
Me
OMe
OMe
53
54
31, CHCl3
r.t.
31, MeOH
50 °C, 26%
BnO
HO
OMe
OMe
N
N
Pd(OH)2/C
N
N3
H2N
H2, EtOH
>95%
OMe
N
O
OMe
O
Me
Me
epi-55 (47%)
epi-5
BnO
HO
OMe
OMe
Pd(OH)2/C
N
N
N3
H2N
H2, EtOH
>95%
N
O
N
OMe
OMe
O
Me
Me
55 (46%)
5
Scheme 9 Completion of the synthesis of epi-calcaridine A (epi-5) and calcaridine A (5)
mers has allowed the assignment of the relative stereo-
chemistry of this natural product through an X-ray crystal
structure analysis of the non-natural diastereomer. In the
course of this project we have prepared quite large quan-
tities of both diastereomers, which have been submitted
for biological testing through the NCI Developmental
Therapeutics Program, and the NIH Molecular Libraries
Screening Centers Network. The results emerging from
these studies will be published elsewhere.
All chemicals were purchased from commercial vendors and were
used as received unless stated otherwise. All reactions were con-
ducted under an atmosphere of dry N2 in oven-dried glassware. Sol-
vents were dried using a Pure-Solv 400 solvent purification system
(Innovative Technologies Inc.), except for DMF, which was dried
over CaH2 and then distilled. 1H NMR spectra were acquired at 300
or 500 MHz in CDCl3, unless indicated otherwise, using residual
CHCl3 as reference. 13C NMR spectra were obtained at 75 or 125
MHz in CDCl3, unless otherwise indicated, using solvent as internal
standard. High-resolution mass spectra were obtained at the Univer-
sity of Florida by electrospray ionization (HRMS-ESI).
Figure 2 X-ray crystal structure of epi-calcaridine A (co-crystal-
lized molecule of methanol omitted)
In one last experiment to improve the overall efficiency
we attempted acid-catalyzed ether exchange to establish
whether either of the individual diastereomers of 5 or epi-
5 could be converted into the other. Unfortunately, we
found treatment of either diastereomer with catalytic HCl
in MeOH at various temperatures up to reflux led to no
discernable epimerization.
[4-(tert-Butyldimethylsiloxy)phenyl]-(5-iodo-3-methyl-1H-imi-
dazol-4-yl)methanol (23)
A 3.0 M solution of EtMgBr in Et2O (1.10 mL, 3.30 mmol) was
added to a solution of 1831 (1.00 g, 3.00 mmol) in anhyd CH2Cl2 (10
mL) at r.t. over 5 min. The resulting mixture was stirred at r.t. for 20
min and then 4-(tert-butyldimethylsilyloxy)benzaldehyde (22; 0.78
g, 3.30 mmol) was added and stirred at r.t. for 24 h. Then, half-sat.
aq NH4Cl (20 mL) was added, the resulting white solid was dis-
solved in EtOAc (100 mL), and the layers were separated. The or-
ganic layer was dried (Na2SO4) and concentrated to give a pale
In summary we have developed a biomimetically guided
total synthesis of the Leucetta-derived alkaloid calcari-
dine A using an oxidative rearrangement of 14-methoxy-
naamine A derivative. While the overall diastereo-
selectivity of the process is poor, access to both diastereo-
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

2976
P. B. Koswatta et al.
PAPER
yellow solid, which was recrystallized from CH2Cl2–MeOH to give
23 (1.32 g, 99%) as a white solid; mp 202–205 °C.
and then p-anisaldehyde (0.20 mL, 1.64 mmol) was added at r.t. Af-
ter stirring at 40 °C for 32 h, half-sat. aq NH4Cl (10 mL) was added
to quench the reaction and the mixture was extracted with EtOAc (3
ꢀ 20 mL). The combined organic layers were dried (Na2SO4), and
concentrated to give the crude product, which was purified through
a short plug of silica gel (EtOAc–hexanes, 2:3) to give 25 (48.2 mg,
46%) as a pale yellow oil.
IR (KBr): 3418 (br), 3128, 2956, 2930, 2858, 1605, 1508, 1258,
1157, 1040, 916, 840, 784 cm–1.
1H NMR (DMSO-d6): d = 7.55 (s, 1 H), 7.11 (d, J = 8.8 Hz, 2 H),
6.80 (d, J = 8.8 Hz, 2 H), 6.17 (d, J = 4.1 Hz, 1 H), 5.76 (d, J = 4.1
Hz, 1 H), 3.33 (s, 3 H), 0.90 (s, 9 H), 0.13 (s, 6 H).
IR (neat): 2956, 2930, 2858, 1630, 1601, 1538, 1509, 1464, 1367,
1254, 1170, 903, 841, 783 cm–1.
13C NMR (DMSO-d6): d = 154.5, 141.9, 135.3, 135.2, 127.0, 120.1,
85.7, 66.4, 33.1, 26.1, 18.5, –4.0.
1H NMR: d = 8.28 (d, J = 8.7 Hz, 2 H), 7.39 (s, 1 H), 7.05 (d,
J = 8.2 Hz, 2 H), 6.95 (d, J = 8.7 Hz, 2 H), 6.73 (d, J = 8.2 Hz, 2
H), 4.40 (s, 1 H), 3.85 (m, 3 H), 3.44 (s, 3 H), 0.95 (s, 9 H), 0.15 (s,
6 H).
HR-ESIMS: m/z calcd for C17H26IN2O2Si [M + H]+: 445.0803;
found: 445.0790; for C17H25IN2O2Si + Na [M + Na]+: 467.0622;
found: 467.0608; for C34H50I2N4O4Si2 + Na [2 M + Na]+: 911.1352;
found: 911.1354.
13C NMR: d = 188.2, 162.8, 154.4, 138.7, 138.1, 136.6, 132.9,
131.6, 130.0, 129.4, 120.3, 113.3, 55.5, 31.7, 29.2, 25.7, 18.2,
–4.35.
4-(5-Iodo-3-methyl-3H-imidazol-4-ylmethyl)phenol
Et3SiH (8.00 mL, 50.18 mmol) and TFA (4.64 mL, 60.2 mmol)
were added to a solution of 23 (4.46 g, 10.0 mmol) in anhyd CHCl3
(50 mL) at r.t., then the resulting mixture was heated at 55–60 °C
for 30 h under N2, and quenched by the addition of sat. aq NaHCO3
(100 mL). The resulting yellow solid was then dissolved in acetone
(50 mL) and the mixture was extracted with CHCl3 several times
until the yellow color disappeared in the aqueous layer. The com-
bined organic solutions were dried (Na2SO4) and concentrated to
give a pale yellow solid, which was triturated with hexanes (30 mL)
to give the desilylated phenol (3.15 g, 96%); mp 179–181 °C.
HR-ESIMS: m/z calcd for C25H33N2O3Si [M + H]+: 437.2255; found
437.2306; for C25H32N2O3Si + Na [M + Na]+: 459.2074; found:
459.2108; for C50H64N4O6Si2 + Na [2 M + Na]+: 859.4257; found:
859.4179.
5-[4-(tert-Butyldimethylsilyloxy)benzyl]-1-methyl-1H-imida-
zole-4-carbaldehyde (27)
A 3.0 M solution of EtMgBr in Et2O (1.43 mL, 4.27 mmol) was
added to a solution of 24 (1.79 g, 4.19 mmol) in anhyd THF(40 mL)
at r.t. The resulting mixture was stirred at r.t for 30 min and then N-
methyl-N-(2-pyridyl)formamide (26; 0.50 mL, 4.27 mmol) was
added. After stirring for 2 h at r.t., half-sat. aq NH4Cl (20 mL) was
added to quench the reaction and the mixture was extracted with
EtOAc (3 ꢀ 40 mL). The combined organic layers were dried
(Na2SO4), and concentrated to give the crude product, which was
purified through a short plug of silica gel (EtOAc–hexanes, 2:3) to
give 27 as an off-white solid (1.18 g, 85%); mp 78–80 °C.
IR (KBr): 3422 (br), 2802, 2680, 2602, 1611, 1514, 1380, 1275,
1240, 1151, 990, 830, 766 cm–1.
1H NMR (DMSO-d6): d = 9.26 (s, 1 H), 7.56 (s, 1 H), 6.89 (d,
J = 8.7 Hz, 2 H), 6.65 (d, J = 8.7 Hz, 2 H), 3.78 (s, 2 H), 3.41 (s, 3
H).
13C NMR (DMSO-d6): d = 156.4, 140.5, 133.8, 129.4, 128.4, 115.9,
85.2, 32.6, 29.3.
HR-ESIMS: m/z calcd for C11H12IN2O [M + H]+: 314.9989; found:
314.9992; for C11H11IN2O + Na [M + Na]+: 336.9808; found:
336.9800.
IR (KBr): 2929, 2891, 2821, 1680, 1605, 1552, 1508, 1466, 1254,
1206, 902, 845, 782 cm–1.
1H NMR: d = 10.00 (s, 1 H), 7.42 (s, 1 H), 6.97 (d, J = 8.7 Hz, 2 H),
6.73 (d, J = 8.3 Hz, 2 H), 4.33 (s, 2 H), 3.44 (s, 3 H), 0.96 (s, 9 H),
0.16 (s, 6 H).
5-[4-(tert-Butyldimethylsilyloxy)benzyl]-4-iodo-1-methyl-1H-
imidazole (24)
13C NMR: d = 187.7, 154.7, 138.8, 138.3, 137.8, 129.3, 129.0,
120.5, 31.6, 28.6, 25.7, 18.3, –4.3.
NaH (60%, 1.67 g, 10.6 mmol) was added to a solution of the above
desilylated phenol (3.02 g, 9.61 mmol) in anhyd THF (30 mL) at r.t.
and the mixture was heated at 50 °C for 1.5 h, then the reaction was
allowed to come to r.t. tert-Butyldimethylsilyl chloride (1.59 g, 10.6
mmol) was added and the mixture stirred for 24 h at r.t. The mixture
was diluted with hexanes (40 mL) and washed with H2O (50 mL),
and brine (30 mL). The organic layer was dried (Na2SO4) and con-
centrated to give a pale yellow solid, which was recrystallized from
CHCl3–MeOH to afford 24 as a white solid (2.86 g, 70%); mp 202–
205 °C.
HR-ESIMS: m/z calcd for C18H27N2O2Si [M + H]+: 331.1836;
found: 331.1906; for C18H26N2O2Si + Na [M + Na]+: 353.1656;
found: 353.1692; for C36H52N4O4Si2 + Na [2 M + Na]+: 683.3419;
found: 683.3401.
{5-[4-(tert-Butyldimethylsilyloxy)benzyl]-1-methyl-1H-imida-
zol-4-yl}(4-methoxyphenyl)methanol (29)
A few drops of p-bromoanisole (from 3.25 mL, 26.0 mmol) was
added dropwise to a two-necked round-bottom flask containing
freshly crushed, oven-dried Mg turnings (0.62 g, 26.0 mmol) and a
small crystal of iodine in THF (20 mL). This mixture was then heat-
ed at 45 °C under N2 until the color of I2 faded. The remaining p-
bromoanisole was added dropwise over 10 min while heating at the
same temperature. After completion of the addition, the mixture
was heated to reflux for 1 h and cooled to r.t. Then, a solution of 27
(1.08 g, 3.25 mmol) in THF (10 mL) was added. The resulting mix-
ture was stirred at reflux for 7 h and cooled to 0 °C. Sat. aq NH4Cl
(20 mL) was added cautiously and the mixture was extracted with
EtOAc (3 ꢀ 30 mL). The combined organic layers were washed with
brine (30 mL), dried (Na2SO4), and concentrated to give thick
brown oil, which was purified through a short plug of silica gel
(EtOAc–hexanes, 4:1) to give 29 (1.42 g, quant) as a pale yellow
solid; mp 108–109 °C.
IR (KBr): 3077, 2929, 2857, 1610, 1510, 1471, 1269, 1174, 983,
838, 781 cm–1.
1H NMR (DMSO-d6): d = 7.61 (s, 1 H), 7.00 (d, J = 8.7 Hz, 2 H),
6.78 (d, J = 8.7 Hz, 2 H), 3.87 (s, 2 H), 3.44 (s, 3 H), 0.93 (s, 9 H),
0.16 (s, 6 H).
13C NMR (DMSO-d6): d = 154.2, 140.6, 133.6, 131.1, 129.6, 120.5,
85.2, 32.6, 29.3, 26.1, 18.4, –4.0.
HR-ESIMS: m/z calcd for C17H26IN2OSi [M + H]+: 429.0854;
found: 429.0857.
{5-[4-(tert-Butyldimethylsilyloxy)benzyl]-1-methyl-1H-imida-
zol-4-yl}(4-methoxyphenyl)methanone (25)
A 3.0 M solution of EtMgBr in Et2O (0.09 mL, 0.27 mmol) was
added dropwise to a solution of 24 (104 mg, 0.24 mmol) in anhyd
THF(2 mL) at r.t. The resulting mixture was stirred at r.t. for 15 min
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

PAPER
Total Synthesis of the Leucetta-Derived Alkaloid Calcaridine A
2977
IR (neat): 3189 (br), 3001, 2955, 2858, 1609, 1509, 1467, 1251,
1172, 1037, 1007, 840, 756 cm–1.
(50 mL) at r.t., then the resulting mixture was heated at 55–60 °C
for 24 h. After cooling to r.t., the reaction was quenched by the ad-
dition of sat. aq NaHCO3 (30 mL). The resulting mixture was ex-
tracted with CHCl3 (3 ꢀ 50 mL) and the combined extracts were
dried (Na2SO4), and concentrated. The residue was purified by
chromatography (hexanes–EtOAc, 1:1) to give 35 as a thick color-
less oil (1.61 g, 60%).
1H NMR: d = 7.38 (s, 1 H), 7.33 (d, J = 8.7 Hz, 2 H), 6.83–6.82 (d,
J = 8.7 Hz, 4 H), 6.68 (d, J = 8.7 Hz, 2 H), 5.74 (s, 1 H), 3.81 (s, 2
H), 3.77 (s, 3 H), 3.32 (s, 3 H), 0.96 (s, 9 H), 0.16 (s, 6 H).
13C NMR: d = 158.8, 154.3, 141.3, 136.9, 136.3, 130.6, 129.1,
127.9, 126.0, 120.3, 113.7, 69.5, 55.3, 31.7, 28.3, 25.8, 18.3, –4.3.
IR (neat): 3031, 2918, 1609, 1509, 1418, 1239, 1175, 1013, 816,
740, 697 cm–1.
HR-ESIMS: m/z calcd for C25H35N2O3Si [M + H]+: 439.2411;
found: 439.2390; for C25H34N2O3Si + Na [M + Na]+: 461.2207;
found: 461.2207; for C50H70N4O6Si2 + Na [2 M + Na]+: 899.4570;
found: 899.4611.
1H NMR: d = 7.42–7.30 (m, 6 H), 7.03 (d, J = 8.7 Hz, 2 H), 6.89 (d,
J = 8.7 Hz, 2 H), 5.02 (s, 2 H), 3.91 (s, 2 H), 3.41 (s, 3 H).
13C NMR: d = 157.8, 139.4, 137.0, 133.4, 129.6, 129.1, 128.7,
128.1, 1127.5, 115.2, 84.8, 70.2, 32.6, 30.0.
5-[4-(tert-Butyldimethylsilyloxy)benzyl]-4-[methoxy(4-meth-
oxyphenyl)methyl]-1-methyl-1H-imidazole (30)
HR-ESIMS: m/z calcd for C18H18IN2O [M + H]+: 405.0458; found:
405.0470; for C18H17IN2O + Na [M + Na]+: 427.0278; found:
427.0247.
TFA (0.80 mL, 10.2 mmol) was added to a solution of 29 (1.12 g,
2.55 mmol) in anhyd MeOH (30 mL) at r.t. and the resulting solu-
tion was then heated at 40 °C for 7 h. On completion of the reaction,
the organic layer was washed with sat. aq NaHCO3 (2 ꢀ 20 mL). Af-
ter ensuring that the pH of the solution was neutral, the aqueous lay-
er was extracted with EtOAc (3 ꢀ 30 mL). The combined organic
layers were washed with H2O (50 mL), brine (30 mL), dried
(Na2SO4), and concentrated to give 30 (1.15 g, quant) as a colorless
oil.
5-(4-Benzoyloxy)benzyl-1-methyl-1H-imidazole-4-carboxalde-
hyde (36)
EtMgBr (3.0 M in Et2O, 1.90 mL, 5.69 mmol) was added to a solu-
tion of 35 (2.19 g, 5.42 mmol) in anhyd THF (30 mL) at r.t., and the
resulting mixture was stirred at r.t. for 20 min. N-Methylformanilide
(0.74 mL, 5.96 mmol) was added and the resulting mixture was
stirred at r.t. overnight. Half-sat. aq NH4Cl (10 mL) was added to
quench the reaction and the mixture was extracted with EtOAc (3 ꢀ
50 mL), dried (Na2SO4), and concentrated to give the crude product.
This residue was purified through a short plug of silica gel (hex-
anes–EtOAc, 3:2) to give 36 as an off-white solid (1.09 g, 66%); mp
148–150 °C.
IR (neat): 2930, 2856, 1609, 1509, 1465, 1251, 1172, 1090, 1035,
916, 839, 782 cm–1.
1H NMR: d = 7.37 (d, J = 8.7 Hz, 3 H), 6.87–6.82 (m, 4 H), 6.70 (d,
J = 8.7 Hz, 2 H), 5.30 (s, 1 H), 3.93 (s, 2 H), 3.77 (s, 3 H), 3.34 (s,
3 H), 3.30 (s, 3 H), 0.96 (s, 9 H), 0.16 (s, 6 H).
13C NMR: d = 158.8, 154.2, 139.6, 137.1, 133.7, 130.9, 129.1,
128.2, 127.1, 120.2, 113.7, 79.5, 56.8, 55.3, 31.6, 28.4, 25.7, 18.3,
–4.4.
IR (KBr): 3107, 3032, 2859, 1674, 1510, 1244, 1175, 799, 780, 740,
698 cm–1.
1H NMR: d = 10.01 (s, 1 H), 7.51 (s, 1 H), 7.41–7.30 (m, 5 H), 7.05
(d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.02 (s, 2 H), 4.34 (s,
2 H), 3.47 (s, 3 H).
HR-ESIMS: m/z calcd for C26H37N2O3Si [M + H]+: 453.2568;
found: 453.2534.
5-(4-Benzyloxy)phenyl-(4-iodo-1-methyl-1H-imidazol-5-
yl)methanol (34)
13C NMR: d = 187.5, 157.9, 138.7, 138.0, 137.8, 136.9, 129.4,
128.7, 128.6, 128.1, 127.5, 115.3, 70.1, 31.7, 28.5.
EtMgBr (3.0 M solution in Et2O, 2.31 mL, 6.93 mmol) was added
to a solution of 18 (2.20 g, 6.60 mmol) in anhyd CH2Cl2 (15 mL) at
r.t. over ~5 min. The resulting mixture was stirred at r.t. for 20 min,
then 4-benzoyloxybenzaldehyde (33; 1.54 g, 7.25 mmol) in anhyd
CH2Cl2 (25 mL) was added and stirring was continued at r.t. over-
night. Sat. aq NH4Cl (10 mL) was added to the reaction mixture, the
resulting pale yellow solid was filtered, and the filtrate was parti-
tioned with CH2Cl2 (150 mL). The organic layer was dried
(Na2SO4) and concentrated to give a pale yellow solid. The resulting
solid was triturated with hexanes (30 mL), which was decanted
from the residue to give 34 (2.80 g, quant) as a white solid; mp 195–
198 °C.
HR-ESIMS: m/z calcd for C19H19N2O2 [M + H]+: 307.1441; found:
307.1462; for C19H18N2O2 + Na [M + Na]+: 329.1260; found:
329.1258.
{5-[4-(Benzoyloxy)benzyl]-1-methyl-1H-imidazol-4-yl}(4-meth-
oxyphenyl)methanol (37)
A few drops of p-bromoanisole (from 2.21 mL, 17.6 mmol) was
added dropwise to a two-necked round-bottom flask containing
freshly crushed oven-dried, Mg turnings (0.42 g, 17.6 mmol) and a
small crystal of iodine in THF (20 mL). This mixture was then heat-
ed at 45 °C under N2 until the color of I2 faded. The remainder of the
p-bromoanisole was added dropwise over 10 min while heating at
the same temperature. After the addition was complete, the mixture
was heated to reflux for 1 h and cooled to r.t. Then a solution of 36
(1.08 g, 3.52 mmol) in THF (10 mL) was added and the resulting
mixture was stirred at reflux overnight. After cooling to 0 °C, sat.
aq NH4Cl (20 mL) was added and the mixture was extracted with
EtOAc (3 ꢀ 50 mL). The combined organic layers were washed with
brine (30 mL), dried (Na2SO4), and concentrated to give a thick,
brown oil. The crude product was purified through a short plug of
silica gel (EtOAc) to give 37 as a pale yellow solid (1.47 g, quant);
mp 124–127 °C.
IR (KBr): 3189 (br), 3034, 2948, 2874, 1607, 1506, 1387,
1236,1166, 1006, 971, 744, 699 cm–1.
1H NMR (DMSO-d6): d = 7.58 (s, 1 H), 7.43 (d, J = 7.3 Hz, 2 H),
7.38 (t, J = 7.3 Hz, 2 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.17 (d, J = 8.7
Hz, 2 H), 6.99 (d, J = 8.7 Hz, 2 H), 6.22 (d, J = 4.1 Hz, 1 H), 5.80
(d, J = 4.1 Hz, 1 H), 5.07 (s, 2 H), 3.38 (s, 3 H).
13C NMR (DMSO-d6): d = 157.9, 141.9, 137.6, 135.4, 134.6, 129.0,
128.4, 128.3, 127.0, 115.1, 85.7, 70.0, 66.5, 33.2.
HR-ESIMS: m/z calcd for C18H18IN2O2 [M + H]+: 421.0408; found:
421.0392; for C18H17IN2O2 + Na [M + Na]+: 443.0227; found:
443.0194.
IR (KBr): 3198 (br), 3031, 2932, 2835, 1611, 1584, 1509, 1454,
1302, 1244, 1175, 1035, 801, 752, 698 cm–1.
1H NMR: d = 7.42–7.29 (m, 8 H), 6.89–6.76 (m, 6 H), 5.78 (s, 1 H),
5.00 (s, 2 H), 4.38 (br, 1 H), 3.78 (s, 2 H), 3.73 (s, 3 H), 3.28 (s, 3 H).
5-(4-Benzoyloxy)benzyl-4-iodo-1-methyl-1H-imidazole (35)
Et3SiH (5.36 mL, 33.55 mmol) and TFA (2.58 mL, 33.55 mmol)
were added to a solution of 34 (2.82 g, 6.71 mmol) in anhyd CHCl3
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

2978
P. B. Koswatta et al.
PAPER
13C NMR: d = 158.8, 157.5, 140.9, 137.1, 137.0, 136.2, 130.2,
129.1, 128.7, 128.1, 127.6, 125.9, 115.1, 113.7, 70.1, 69.5, 55.3,
31.8, 28.2.
IR (KBr): 3548, 3475, 3417, 2996, 2934, 1614, 1512, 1247, 1174,
1114, 823, 618 cm–1.
1H NMR (CD3OD): d = 7.28 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.2
Hz, 2 H), 6.83 (d, J = 8.7 Hz, 2 H), 6.67 (d, J = 8.2 Hz, 2 H), 5.25
(s, 1 H), 3.83 (s, 2 H), 3.74 (s, 3H), 3.31 (s, 3 H), 3.11 (s, 3 H).
HR-ESIMS: m/z calcd for C26H27N2O3 [M + H]+: 415.2016; found:
415.2016; for C26H26N2O3 + Na [M + Na]+: 437.1856; found:
437.1817.
13C NMR (CD3OD): d = 160.0, 156.3, 147.0, 130.8, 128.9, 127.8,
126.9, 124.3, 123.3, 115.4, 113.8, 75.1, 55.7, 54.5, 28.7, 27.0.
5-[4-(Benzoyloxy)benzyl]-4-[methoxy(4-methoxyphenyl)meth-
yl]-1-methyl-1H-imidazole (38)
HR-ESIMS: m/z calcd for C20H24N3O3 [M + H]+: 354.1827; found:
354.1812; for C20H23N3O3 + Na [M + Na]+: 376.1645; found:
376.1632.
TFA (0.53 mL, 6.81 mmol) was added to a solution of 37 (1.42 g,
3.41 mmol) in anhyd MeOH (20 mL) at r.t. and the mixture was then
heated at 55 °C for overnight. Sat. aq NaHCO3 (20 mL) was added
to the above reaction mixture and the aqueous layer was extracted
with EtOAc (3 ꢀ 30 mL). The combined organic layers were washed
with aq NaHCO3 (2 ꢀ 10 mL), H2O (50 mL), brine (30 mL), dried
(Na2SO4), concentrated to give 38 (1.58 g, quant) as a pale yellow
oil.
2-Amino-5-(4-hydroxybenzyl)-5-[methoxy(4-methoxyphe-
nyl)methyl]-3-methyl-3,5-dihydroimidazol-4-one (Calcaridine
A, 5)
Amine 11 (175 mg, 0.51 mmol) and 2-benzenesulfonyl-3-(4-nitro-
phenyl)oxaziridine (31; 311 mg, 1.02 mmol) were dissolved in
MeOH (5 mL) at r.t. Then, the mixture was heated at 40 °C for 4 h.
After checking TLC, the reaction was stopped, concentrated, and
purified by flash column chromatography using 10% MeOH in
EtOAc to give a pale yellow solid (100 mg, 54%) of a 1:2 mixture
of diastereomers calcaridine A (5) and epi-calcaridine A (epi-5).
IR (neat): 3032, 2971, 2916, 1610, 1509, 1244, 1174, 1011, 804,
742 cm–1.
1H NMR: d = 7.51 (s, 1 H), 7.42–7.29 (m, 7 H), 6.92–6.76 (m, 6 H),
5.35 (s, 1 H), 5.02 (s, 2 H), 3.95 (s, 2 H), 3.77 (s, 3 H), 3.35 (s, 3 H),
3.33 (s, 3 H).
4-Iodo-1-methyl-1H-imidazol-5-yl)(4-methoxyphenyl)meth-
anol (40)
13C NMR: d = 158.9, 157.5, 139.5, 137.2, 137.1, 133.7, 130.5,
129.2, 128.7, 128.2, 128.1, 127.6, 127.1, 115.0, 113.7, 79.5, 70.1,
56.8, 55.3, 31.7, 28.3.
A 3.0 M solution of EtMgBr in Et2O (3.31 mL, 9.93 mmol) was
added into a solution of 18 (3.01 g, 9.03 mmol) in anhyd CH2Cl2 (30
mL) at r.t. over 5 min. The resulting mixture was stirred at r.t. for 45
min under N2 and p-anisaldehyde (0.86 mL, 9.93 mmol) in anhyd
CH2Cl2 (10 mL) was added dropwise. After stirring at r.t. for 16 h,
half-sat. aq NH4Cl (100 mL) was added and the resulting white solid
was dissolved in EtOAc (100 mL) and the layers were separated.
The organic layer was dried (Na2SO4) and concentrated and the re-
sulting solid was triturated with hexanes to give 40 as a yellowish
white solid (2.79 g, 90%); mp 124–125 °C.
HR-ESIMS: m/z calcd for C27H29N2O3 [M + H]+: 429.2117; found:
429.2176; for C27H28N2O3 + Na [M + Na]+: 451.1992; found:
451.1955.
2-Azido-5-[4-(benzoyloxy)benzyl]-4-[methoxy(4-methoxyphe-
nyl)methyl]-1-methyl-1H-imidazole (39)
n-BuLi (1.6 M solution in hexanes, 0.72 mL, 1.14 mmol) was added
dropwise to a stirred solution of 38 (445 mg, 1.04 mmol) in anhyd
THF (8 mL) at –78 °C. The reaction mixture was stirred for 30 min
at the same temperature. The cooling bath was removed for 10 min,
then the mixture was re-cooled to –78 °C and TsN3 (246 mg, 1.25
mmol) in THF (1 mL) was added dropwise. After stirring for an ad-
ditional 10 min at –78 °C, the mixture was allowed to come to r.t.
and stirred for 40 min. The reaction was quenched by the careful ad-
dition of sat. aq NH4Cl (3 mL). The aqueous layer was extracted
with EtOAc (3 ꢀ 15 mL), and the combined organic extracts were
dried (Na2SO4), and concentrated to give a pale brown oil. The
crude product was purified through a short column of silica gel
(hexanes–EtOAc, 4:1) to give the unreacted starting material and 39
(283 mg, 58%) as a reddish brown oil.
IR (KBr): 3424 (br), 3158, 1608, 1510, 1242, 1032, 867, 838 cm–1.
1H NMR (DMSO-d6): d = 7.55 (s, 1 H), 7.13 (d, J = 8.4 Hz, 2 H),
6.88 (d, J = 8.4 Hz, 2 H), 6.18–6.17 (d, J = 3.9 Hz, 1 H), 5.78-5.77
(d, J = 3.9 Hz, 1 H), 3.70 (s, 3 H), 3.34 (s, 3 H).
13C NMR (DMSO-d6): d = 158.7, 141.9, 135.4, 134.3, 126.9, 114.2,
85.7, 66.5, 55.6, 33.1.
HR-ESIMS: m/z calcd for C12H14IN2O2 [M + H]+: 345.0095; found:
345.0086; for C12H13IN2O2 +Na [M + Na]+: 366.9914; found:
366.9904; for C24H26I2N4O4 + Na [2 M + Na]+: 710.9936; found:
710.9927.
IR (neat): 3032, 2933, 2835, 2137, 1610, 1509, 1244, 1173, 1088,
1033, 832, 744, 697 cm–1.
4-Iodo-5-[methoxy(4-methoxyphenyl)methyl]-1-methyl-1H-im-
idazole (41)
1H NMR: d = 7.49–7.34 (m, 7 H), 6.98–6.88 (m, 6 H), 5.23 (s, 1 H),
5.02 (s, 2 H), 3.85 (s, 2 H), 3.78 (s, 3 H), 3.35 (s, 3 H), 3.04 (s, 3 H).
NaH (60%, 0.21 g, 5.24 mmol) was added to a solution of 40 (1.65
g, 4.77 mmol) in anhyd THF (40 mL) at r.t. and the mixture was
heated at 60 °C for 2.5 h. The reaction was allowed to come to r.t.
and MeI (0.33 mL, 5.24 mmol) was added at 0 °C (ice/water) drop-
wise and stirred for 30 min, then it was allowed to come to r.t., and
stirred for 24 h. The mixture was quenched by adding H2O (20 mL)
and extracted with EtOAc (3 ꢀ 40 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated to give a thick brown
oil, which was purified through a short plug of silica gel (EtOAc–
hexanes, 3:7) to give 41 as a pale yellow oil (1.24 g, 72%).
13C NMR: d = 159.1, 157.6, 139.8, 137.1, 136.9, 133.4, 130.3,
129.2, 128.7, 128.5, 128.1, 127.6, 126.2, 115.1, 113.8, 79.2, 70.1,
56.9, 55.3, 29.5, 28.7.
HR-ESIMS: m/z calcd for C26H24N5O2 [M + H – MeOH]+:
438.1925; found: 438.1898; for C27H27N5O3 + Na [M + Na]+:
492.2006; found: 492.1977.
2-Amino-5-[4-hydroxybenzyl]-4-[methoxy(4-methoxyphe-
nyl)methyl]-1-methyl-1H-imidazole (14-Methoxynaamine A,
11)
Azide 39 (258 mg, 0.55 mmol) was dissolved in EtOH (3 mL) and
stirred under an H2 atmosphere (55 psi) in the presence of 20%
Pd(OH)2 on charcoal (77 mg) at r.t. for overnight. The catalyst was
filtered through a pad of Celite and the filtrate was concentrated to
give amine 11 (196 mg, quant) as a pale yellow solid; mp 91–95 °C.
IR (KBr): 2932, 1612, 1510, 1463, 1303, 1248, 1087, 1033, 951,
837, 784 cm–1.
1H NMR: d = 7.38 (s, 1 H), 7.20–7.18 (d, J = 8.7 Hz, 2 H), 6.86–
6.84 (d, J = 8.7 Hz, 2 H), 5.52 (s, 1 H), 3.79 (s, 3 H), 3.38 (s, 3 H),
3.33 (s, 3 H).
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

PAPER
Total Synthesis of the Leucetta-Derived Alkaloid Calcaridine A
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13C NMR: d = 159.0, 141.4, 131.8, 131.2, 126.9, 113.9, 88.0, 76.4,
56.9, 55.4, 33.0.
1H NMR (acetone-d6): d = 9.51 (s, 1 H), 8.84 (d, J = 8.7 Hz, 2 H),
8.06 (s, 1 H), 7.80 (d, J = 8.7 Hz, 2 H), 7.39–7.36 (m, 4 H), 7.00 (s,
1 H), 4.23 (s, 3 H), 4.00 (s, 3 H), 3.86 (s, 3 H).
HR-ESIMS: m/z calcd for C13H16IN2O2 [M + H]+: 359.0251; found:
359.0261; for C13H15IN2O2 + Na [M + Na]+: 381.0055; found:
381.0076; for C26H30I2N4O4 + Na [2 M + Na]+: 739.0249; found:
739.0244.
13C NMR (acetone-d6): d = 187.0, 161.3, 159.0, 140.5, 138.6, 137.3,
133.5, 131.7, 130.4, 127.0, 114.5, 113.6, 74.7, 56.5, 54.7, 32.6.
HR-ESIMS: m/z calcd for C20H20N2O4 + Na [M + Na]+: 375.1315;
found: 375.1314.
1-[4-(tert-Butyldimethylsilyloxy)benzyl]-4-[methoxy(4-meth-
oxyphenyl)methyl]-3-methyl-3H-imidazol-1-ium Bromide (43)
A 3.0 M solution of EtMgBr in Et2O (1.00 mL, 3.00 mmol) was
added to a solution of 41 (1.00 g, 2.78 mmol) in anhyd CH2Cl2 (10
mL) at r.t. The resulting mixture was stirred at r.t. for 45 min and 1
M solution of CuCN·2LiCl (3.20 mL) was added followed by 4-
(tert-butyldimethylsilyloxy)benzyl bromide (20; 1.00 g, 3.32
mmol) in anhyd CH2Cl2 (5 mL). The yellow reaction mixture was
stirred at r.t. for 15 h and poured into half-sat. aq NH4Cl (30 mL).
The mixture was stirred for 10 min, the layers were separated, and
the aqueous phase was extracted with CH2C12 (3 ꢀ 30 mL). The
combined organic extracts were dried (Na2SO4) and evaporated.
The residue was purified by flash chromatography (EtOAc–hex-
anes, 2:3) to yield the imidazolium bromide 43 (0.54 g, 35%) as a
green solid, which turned to liquid upon exposure to air.
[4-(tert-Butyldimethylsilyloxy)phenyl]-{5-[methoxy(4-meth-
oxyphenyl)methyl]-1-methyl-1H-imidazol-4-yl}methanol (46)
A 3.0 M solution of EtMgBr in Et2O (0.5 mL, 1.5 mmol) was added
to a solution of 41 (420 mg, 1.17 mmol) in anhyd THF (5 mL) at r.t.
over 5 min. The resulting mixture was stirred at r.t. for 15 min and
4-(tert-butyldimethylsilyloxy)benzaldehyde (22; 691 mg, 2.92
mmol) in anhyd THF (1 mL) was added at r.t. After completion of
the addition, the mixture was heated to reflux for 45 h, at which time
H2O (5 mL) was added to quench the reaction and the mixture was
extracted with EtOAc (3 ꢀ 15 mL). The combined organic layers
were dried (Na2SO4) and concentrated to give the crude product,
which was purified through a short plug of silica gel (EtOAc–hex-
anes, 3:1) to give 46 as a yellow solid (264 mg, 48%) as a 2:1 mix-
ture of diastereomers; mp 102–104 °C.
IR (neat): 3392 (br), 2932, 2858, 1610, 1512, 1463, 1252, 1173,
1083, 913, 838, 754 cm–1.
IR (neat): 3175 (br), 2932, 2858, 1609, 1508, 1251, 1087, 914 cm–1.
1H NMR: d = 7.35 (s, 1 H), 7.31–7.28 (d, J = 8.7 Hz, 2 H), 7.10–
7.08 (d, J = 8.4 Hz, 1 H), 7.01–6.99 (d, J = 8.7 Hz, 1 H), 6.82–6.79
(d, J = 8.7 Hz, 2 H), 6.77–6.74 (m, 2 H), 5.82–5.81 (s, 1 H), 5.40–
5.39 (s, 1 H), 3.78–3.76 (s, 3 H), 3.29 (s, 3 H), 3.32, 3.07 (s, 3 H),
0.95 (s, 9 H), 0.14 (s, 6 H).
1H NMR: d = 10.45 (br, 1 H), 7.27 (d, J = 8.2 Hz, 2 H), 7.22 (d,
J = 8.2 Hz, 2 H), 6.90 (d, J = 8.2 Hz, 2 H), 6.80 (d, J = 8.2 Hz, 2
H), 6.57 (s, 1 H), 5.39 (d, J = 11.9 Hz, 1 H), 5.31–5.27 (m, 3 H),
3.90 (s, 2 H), 3.80 (s, 3 H), 3.44 (s, 3 H), 3.28 (s, 3 H), 0.94 (s, 9 H),
0.15 (s, 6 H).
13C NMR: d = 159.0 (158.9), 155.1 (155.0), 144.2 (144.5), 138.0
(138.2), 136.9, 131.6 (131.5), 128.1 (127.9), 127.4 (127.3), 125.1
(125.2), 120.0, 113.8 (113.7), 74.8 (74.5), 69.9 (69.7), 56.7 (56.7),
55.3 (55.3), 32.8, 25.8, 18.3, –4.3.
13C NMR: d = 160.4, 156.7, 138.5, 136.3, 130.6, 128.8, 127.2,
125.6, 121.0, 119.9, 114.6, 75.3, 56.8, 55.5, 53.0, 35.1, 25.7, 18.2,
–4.4.
HR-ESIMS: m/z calcd for C26H37N2O3Si [M]+: 453.2568; found:
453.2591.
HR-ESIMS: m/z calcd for C26H37N2O4Si [M + H]+: 469.2517;
found: 469.2534; for C26H36N2O4Si + Na [M + Na]+: 491.2337;
found: 491.2319; for C52H72N4O8Si2 + Na [M + Na]+: 959.4781;
found: 959.4781.
[4-(tert-Butyldimethylsilyloxy)phenyl]-{5-[methoxy(4-meth-
oxyphenyl)methyl]-1-methyl-1H-imidazol-4-yl}methanone (44)
A 3.0 M solution of EtMgBr in Et2Or (1.16 mL, 3.47 mmol) was
added to a solution of 41 (1.14 g, 3.15 mmol) in anhyd CH2Cl2 (10
mL) at r.t. over 5 min. The resulting mixture was stirred at r.t. for 30
min and 4-(tert-butyldimethylsilyloxy)benzaldehyde (22; 1.49 g,
6.30 mmol) in anhyd CH2Cl2 (5 mL) was added at r.t. After comple-
tion of the addition, the mixture was heated to reflux for 45 h, after
which H2O (20 mL) was added to quench the reaction. The organic
layer was separated, washed once with aq 10% Na2SO3 (50 mL) and
brine (30 mL). The organic layer was dried (Na2SO4) and concen-
trated to give the crude product, which was purified by column
chromatography using gradient elution (EtOAc–hexanes 1:9 →
EtOAc) to give 44 as a pale brown oil (284 mg, 19%).
In addition to the alcohol, the net reduction product 42 was obtained
from the above reaction as a light brown oil (119 mg, 43%).
5-[Methoxy(4-methoxyphenyl)methyl]-1-methyl-1H-imidazole
(42)
IR (KBr): 2935, 1611, 1511, 1464, 1249, 1172, 1079, 1032, 828
cm–1.
1H NMR: d = 7.41 (s, 1 H), 7.27–7.24 (d, J = 8.7 Hz, 2 H), 6.90–
6.87 (d, J = 8.7 Hz, 2 H), 6.71 (s, 1 H), 5.24 (s, 1 H), 3.81 (s, 3 H),
3.50 (s, 3 H), 3.32 (s, 3 H).
13C NMR: d = 159.4, 139.6, 131.6, 130.7, 129.9, 128.2, 113.9, 76.5,
56.5, 55.4, 32.2.
1H NMR: d = 8.23 (d, J = 8.5 Hz, 2 H), 7.39 (s, 1 H), 7.33 (d,
J = 8.5 Hz, 2 H), 6.91 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 8.5 Hz, 2 H),
6.54 (s, 1 H), 3.79 (s, 3 H), 3.49 (s, 3 H), 3.44 (s, 3 H), 0.99 (s, 9 H),
0.23 (s, 6 H).
HR-ESIMS: m/z calcd for C13H17N2O2 [M + H]+: 233.1285; found:
233.1265.
1-Methyl-4-iodoimidazole-5-carboxaldehyde (47)
13C NMR: d = 188.4, 159.8, 158.9, 140.2, 138.3, 137.8, 133.0,
131.7, 131.3, 127.1, 119.6, 115.4, 113.8, 74.7, 57.4, 55.4, 33.4,
25.7, 18.3, –4.2.
A solution of EtMgBr (3.0 M in Et2O, 2.62 mL, 7.86 mmol) was
added to a solution of 18 (2.50 g, 7.50 mmol) in anhyd CH2Cl2 (20
mL) at r.t. over 10 min. The resulting mixture was stirred at r.t. un-
der N2 with monitoring by TLC to ensure that all starting material
had reacted with the Grignard reagent. Then, N-methylformanilide
(1.01 mL, 8.23 mmol) was added dropwise to the above mixture and
stirred at r.t. for a further 16 h. Half-sat. aq NH4Cl (10 mL) was add-
ed and the resulting suspension was extracted with CH2Cl2 (3 ꢀ 30
mL). The combined organic layers were dried (Na2SO4), concen-
trated, and the resulting residue was purified by flash chromatogra-
In addition to the ketone, the desilylated product 45 was obtained as
a white solid (60 mg, 5%).
(4-Hydroxyphenyl)-{5-[methoxy(4-methoxyphenyl)methyl]-1-
methyl-1H-imidazol-4-yl}methanone (45)
Mp 197–200 °C.
IR (KBr): 2932, 1633, 1606, 1510, 1439, 1248, 1163, 1081, 910
cm–1.
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

2980
P. B. Koswatta et al.
PAPER
phy (EtOAc–hexanes, 1:4) to give a white solid (1.09 g, 61%);
mp 69–72 °C.
starting material was consumed (2 h), the reaction was worked up
following the above procedure giving the pure aldehyde (1.95 g,
quant), as a cream colored solid; mp 135 °C.
IR (KBr): 2811, 1666, 1504, 1338, 1243, 964, 782, 707 cm–1.
1H NMR: d = 9.62 (d, J = 0.5 Hz, 1 H), 7.55 (s, 1 H), 3.91 (s, 3 H).
13C NMR: d = 181.3, 145.0, 130.0, 100.3, 34.5.
IR (KBr): 3327 (br), 3088, 3009, 2862, 1655, 1513, 1352, 1297,
1245, 1045, 1014, 807, 786, 741, 715 cm–1.
1H NMR: d = 9.90 (s, 1 H), 7.46 (s, 1 H), 7.41–7.31 (m, 7 H), 6.94
(d, J = 8.7 Hz, 2 H), 6.01 (s, 1 H), 5.03 (s, 2 H), 3.87 (s, 3 H).
HR-ESIMS: m/z calcd for C5H6IN2O [M + H]+: 236.9519; found:
236.9527; for C5H5IN2O + Na [M + Na]+: 258.9339; found:
258.9362.
13C NMR: d = 180.4, 158.7, 156.8, 142.1, 137.0, 135.1, 128.7,
128.1, 128.0, 127.5, 126.6, 115.1, 70.9, 70.1, 34.5.
5-[1,3]Dioxolan-2-yl-4-iodo-1-methyl-1H-imidazole (48)
p-Toluenesulfonic acid monohydrate (140 mg, 0.74 mmol) and eth-
ylene glycol (95%, 4.10 mL, 73.7 mmol) were added to a solution
of 47 (3.48 g, 14.7 mmol) in toluene (75 mL). The reaction mixture
was heated to reflux for 22 h using a Dean–Stark condenser. The
mixture was cooled to r.t., and then the mixture was washed with
sat. aq NaHCO3 (3 ꢀ 25 mL) and H2O (30 mL). The resulting tolu-
ene solution was dried (Na2SO4), concentrated and purified by chro-
matography (hexanes–EtOAc, 65:35) to give 48 (4.02 g, 97%) as an
off-white solid; mp 115–118 °C.
HR-ESIMS: m/z calcd for C19H19N2O3 [M + H]+: 323.1390; found:
323.1382; for C19H18N2O3 + Na [M + Na]+: 345.1210; found:
345.1198.
4-(4-Benzyloxy)benzyl-1-methyl-1H-imidazole-5-carbaldehyde
(50)
Et3SiH (3.86 mL, 24.2 mmol) and TFA (2.80 mL, 36.3 mmol) were
added to a solution of the aldehyde prepared above (1.95 g, 6.05
mmol) in anhyd CHCl3 (100 mL) under N2 at r.t. The resulting mix-
ture was stirred for 24 h while monitoring the reaction progress by
TLC. The reaction was then quenched with sat. aq NaHCO3 (50
mL). The mixture was extracted with CHCl3 (3 ꢀ 50 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated to
give a yellowish white solid, which was purified over silica gel with
(EtOAc–hexanes, 3:1) to give 50 as a pale yellow solid, (1.21 g,
65%); mp 85–86 °C.
IR (KBr): 2951, 2887, 1578, 1494, 1473, 1370, 1245, 1217, 1085,
952, 815 cm–1.
1H NMR: d = 7.39 (s, 1 H), 5.79 (s, 1 H), 4.15 (m, 2 H), 4.04 (m, 2
H), 3.69 (s, 3 H).
13C NMR: d = 141.9, 127.0, 98.8, 87.8, 65.3, 33.2.
HR-ESIMS: m/z calcd for C7H10IN2O2 [M + H]+: 280.9782; found:
280.9791; for C7H9IN2O2 + Na [M + Na]+: 302.9610; found:
302.9612.
IR (KBr): 3121, 3058, 3028, 2915, 2826, 2746, 1763, 1665, 1520,
1332, 1247, 1171, 1009, 845, 744, 699, 633 cm–1.
1H NMR: d = 9.85 (s, 1 H), 7.47 (s, 1 H), 7.40–7.30 (m, 5 H), 7.18
(d, J = 8.7 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 5.01 (s, 2 H), 4.12 (s,
2 H), 3.85 (s, 3 H).
(4-Benzyloxyphenyl)(5-[1,3]dioxolan-2-yl-1-methyl-1H-imida-
zol-4-yl)methanol (49)
13C NMR: d = 179.1, 157.6, 155.8, 142.9, 137.1, 131.3, 129.7,
128.6, 128.0, 127.5, 127.0, 115.2, 70.1, 34.4, 33.2.
A solution of EtMgBr (3.0 M in Et2O, 2.67 mL, 8.02 mmol) was
added to a solution of 48 (2.14 g, 7.64 mmol) in anhyd THF(20 mL)
at r.t. over 10 min. The resulting mixture was stirred at r.t. until all
the starting material had reacted (TLC analysis, ca. 30 min) and then
4-benzyloxybenzaldehyde (1.78 g, 8.40 mmol) in anhyd THF (10
mL) was added at r.t. followed by stirring for 38 h. Sat. aq NH4Cl
(10 mL) was added to quench the reaction and the mixture was ex-
tracted with EtOAc (3 ꢀ 40 mL) and the combined organic layers
were washed with brine (30 mL). The EtOAc solution was dried
(Na2SO4) and concentrated to give the crude product, which was pu-
rified by column chromatography (EtOAc → EtOH–EtOAc, 1:9) to
give 49 as a white solid (2.46 g, 87%); mp 160–162 °C.
HR-ESIMS: m/z calcd for C19H19N2O2 [M + H]+: 307.1441; found:
307.1444; for C19H18N2O2 + Na [M + Na]+: 329.1266; found:
329.1207.
4-(4-Benzyloxybenzyl)-5-[hydroxy(4-methoxyphenyl)methyl]-
1-methyl-1H-imidazole (51)
A few drops of p-bromoanisole (from 1.98 mL, 15.8 mmol) was
added dropwise to a two-neck round-bottom flask containing fresh-
ly crushed, oven-dried Mg turnings (0.38 g, 15.8 mmol) and a small
crystal of I2 in THF (25 mL). This mixture was then heated at 45 °C
under N2 until the color of I2 faded. The rest of the p-bromoanisole
was added dropwise over 10 min while heating at the same temper-
ature. After completion of the addition, the mixture was heated at
reflux for 1 h and cooled to r.t. A solution of 50 (1.21 g, 3.95 mmol)
in THF (10 mL) was added. The resulting mixture was stirred at re-
flux for overnight and cooled to 0 °C. Sat. aq NH4Cl (20 mL) was
added and the mixture was extracted with EtOAc (3 ꢀ 40 mL). The
combined organic layers were washed with brine (30 mL), dried
(Na2SO4), and concentrated to give a thick brown oil, which was pu-
rified through a short plug of silica gel with 100% EtOAc to give a
white solid (1.64 g, 84%); mp 148–149 °C.
IR (KBr): 3176 (br), 3120, 2918, 1606, 1511, 1419, 1226, 1076,
1035, 951, 843, 698 cm–1.
1H NMR: d = 7.40–7.27 (m, 8 H), 6.92 (d, J = 8.3 Hz, 2 H), 5.90 (s,
1 H), 5.84 (s, 1 H), 5.03 (s, 2 H), 4.00 (m, 2 H), 3.92 (m, 2 H), 3.66
(s, 3 H).
13C NMR: d = 158.1, 145.0, 138.8, 137.2, 136.2, 128.6, 128.0,
127.9, 127.5, 121.8, 114.7, 97.3, 70.1, 69.5, 65.1, 33.0.
HR-ESIMS: m/z calcd for C21H23N2O4 [M + H]+: 367.1652; found:
367.1662; for C21H22N2O4 + Na [M + Na]+: 389.1472; found:
389.1469.
IR (KBr): 3200 (br), 3115, 2998, 2908, 2834, 1611, 1510, 1459,
1238, 1173, 1032, 804, 697 cm–1.
4-[(4-Benzyloxyphenyl)hydroxymethyl)-1-methyl-1H-imida-
zole-5-carboxaldehyde
1H NMR: d = 7.41–7.25 (m, 6 H), 7.16 (d, J = 8.5 Hz, 2 H), 7.10 (d,
J = 8.5 Hz, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2
H), 6.05 (s, 1 H), 4.99 (s, 2 H), 3.88 (s, 2 H), 3.78 (s, 3 H), 3.34 (s,
3 H).
Aq 10% HCl (10 mL) was added to a solution of acetal 49 (2.23 g,
6.09 mmol) in THF (100 mL) and the resulting cloudy reaction mix-
ture was heated at 55 °C (the reaction mixture became clear after 10
min), while the reaction progress was monitored by taking 0.5 mL
aliquots and neutralizing with sat. aq NaHCO3 (2 mL). The aqueous
layer was extracted with EtOAc (1 ꢀ 3 mL), and the combined or-
ganic layers were dried (Na2SO4) and concentrated to give the crude
product, which was evaluated by 1H NMR spectroscopy. After all
13C NMR: d = 159.0, 157.3, 138.4, 137.2, 132.61, 132.55, 129.7,
129.0, 128.6, 128.0, 127.5, 127.0, 115.1, 113.9, 70.1, 65.5, 55.4,
33.4, 32.1.
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

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Total Synthesis of the Leucetta-Derived Alkaloid Calcaridine A
2981
HR-ESIMS: m/z calcd for C26H27N2O3 [M + H]+: 415.2016; found:
415.2034; for C26H26N2O3 + Na [M + Na]+: 437.1836; found:
437.1819.
through a pad of Celite and the filtrate was concentrated to give
amine 54 (91 mg, 97%) as a pale yellow solid; mp 91–95 °C.
IR (KBr): 3400, 1611, 1512, 1248, 1175, 1030 cm–1.
1H NMR (CD3OD): d = 7.20 (d, J = 7.8 Hz, 2 H), 7.00 (d, J = 7.8
Hz, 2 H), 6.88 (d, J = 7.8 Hz, 2 H), 6.74 (d, J = 7.4 Hz, 2 H), 5.49
(s, 1 H), 3.83 (s, 2 H), 3.75 (s, 3 H), 3.37 (s, 3 H), 3.20 (s, 3 H).
4-(4-Benzyloxybenzyl)-5-[methoxy(4-methoxyphenyl)methyl]-
1-methyl-1H-imidazole (52)
NaH (60%, 162 mg, 4.05 mmol) was added portionwise to a stirred
mixture of alcohol 51 (1.12 g, 2.70 mmol) in anhyd THF (25 mL) at
0 °C. After completion of the addition, the resulting mixture was
stirred for 10 min at the same temperature. The reaction was
warmed to r.t. and stirred for 1.5 h and then re-cooled (0 °C) fol-
lowed by the dropwise addition of MeI (0.20 mL). After 10 min, the
reaction was allowed to come to r.t. and stirred for 36 h. H2O (20
mL) was added to the mixture and the aqueous layer was extracted
with EtOAc (3 ꢀ 30 mL). The combined organic solution was dried
(Na2SO4), concentrated, and the residue was purified through short
plug of silica gel with (EtOAc–hexanes, 3:1) to give the 52 as a pale
yellow oil (0.97 g, 84%).
13C NMR (CD3OD): d = 159.6, 156.3, 147.2, 130.0, 129.3, 128.0,
127.3, 125.9, 121.6, 115.4, 113.8, 74.2, 56.0, 54.5, 29.7, 28.3.
(4R*,8S*) and (4R*,8R*)-2-Azido-4-(4-benzyloxybenzyl)-4-
[methoxy(4-methoxyphenyl)methyl]-1-methyl-1,5-dihydroimi-
dazol-5-one (55) and epi-55
3-(4-Nitrophenyl)-2-(phenylsulfonyl)oxaziridine (31; 254 mg, 0.83
mmol) was added to a stirred solution of azide 53 (255 mg, 0.54
mmol) in CHCl3 (3 mL) at r.t. and stirred overnight. On completion
of the reaction, the solvent was removed and the yellow residue was
purified by gravity column chromatography (CH2Cl2–toluene, 1:1)
to give epi-55 (123 mg, 47%) as a pale yellow semi-solid and 55
(121 mg, 46%) as a pale yellow solid.
IR (neat): 3032, 2931 1609, 1509, 1246, 1174, 1086, 1031, 805,
741, 698 cm–1.
1H NMR (CDCl3): d = 7.41–7.25 (m, 6 H), 7.20 (d, J = 8.3 Hz, 2
H), 7.09 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.3 Hz, 2 H), 6.81 (d,
J = 8.7 Hz, 2 H), 5.48 (s, 1 H), 5.01 (s, 2 H), 3.94 (s, 2 H), 3.76 (s,
3 H), 3.27 (s, 3 H), 3.23 (s, 3 H).
epi-55
IR (neat): 2931, 1764, 1599, 1512, 1455, 1250, 1177, 1098, 1029,
834, 797, 738, 698 cm–1.
1H NMR: d = 7.36–7.26 (m, 5 H), 6.95 (d, J = 8.7 Hz, 2 H), 6.78 (d,
J = 8.7 Hz, 2 H), 6.72 (d, J = 8.7 Hz, 2 H), 6.68 (d, J = 8.7 Hz, 2 H),
4.90 (s, 2 H), 4.78 (s, 1 H), 3.92 (d, J = 14.2 Hz, 1 H), 3.72 (s, 3 H),
3.35 (d, J = 14.2 Hz, 1 H), 3.33 (s, 3 H), 2.76 (s, 3 H).
13C NMR: d = 158.9, 157.2, 142.1, 138.4, 137.3, 133.3, 132.0,
129.7, 128.6, 127.9, 127.5, 127.3, 125.2, 114.9, 113.8, 75.0, 70.1,
56.6, 55.3, 33.0, 32.7.
HR-ESIMS: m/z calcd for C27H29N2O3 [M + H]+: 429.2173; found:
429.2181; for C27H28N2O3 + Na [M + Na]+: 451.1992; found:
451.1951.
13C NMR: d = 173.7, 160.2, 158.4, 158.3, 136.7, 130.7, 128.9,
128.6, 128.1, 127.6, 125.4, 124.5, 115.0, 114.0, 84.1, 79.0, 70.0,
57.7, 55.3, 38.3, 27.1.
HR-ESIMS: m/z calcd for C27H28N5O4 [M + H]+: 486.2136; found:
486.2141.
2-Azido-4-(4-benzyloxybenzyl)-5-[methoxy(4-methoxyphe-
nyl)methyl]-1-methyl-1H-imidazole (53)
n-BuLi (1.33 M solution in hexanes, 1.87 mL, 2.49 mmol) was add-
ed dropwise to a stirred solution of 52 (888 mg, 2.07 mmol) in an-
hyd THF (10 mL) at –78 °C. The reaction mixture was stirred for 45
min at the same temperature. Then, the ice/acetone bath was re-
moved for 5 min followed by re-cooling to –78 °C and dropwise ad-
dition of TsN3 (491 mg, 2.49 mmol). After stirring for 1 h at –78 °C,
the reaction was quenched by the careful addition of sat. aq NH4Cl
(3 mL). The aqueous layer was extracted with EtOAc (3 ꢀ 25 mL),
the combined organics were dried (Na2SO4), and concentrated to
give a pale brown oil, which was purified through a short column of
silica gel (hexanes–EtOAc, 4:1) to give 53 (972 mg, 76%) as a thick
pale yellow oil.
55
Mp 54–56 °C.
IR (neat): 2931, 1764, 1599, 1512, 1455, 1250, 1177, 1098, 1029,
834, 797, 738, 698 cm–1.
1H NMR: d = 7.35–7.26 (m, 7 H), 6.99 (d, J = 8.7 Hz, 2 H), 6.65 (m,
4 H), 4.90 (s, 2 H), 4.77 (s, 1 H), 3.85 (s, 3 H), 3.25 (d, J = 14.2 Hz,
1 H), 3.13 (s, 3 H), 3.05 (s, 3 H), 2.94 (d, J = 14.2 Hz, 1 H).
13C NMR: d = 175.4, 160.7, 159.1, 158.3, 136.7, 130.5, 130.1,
128.6, 128.1, 127.6, 125.3, 123.6, 114.9, 114.3, 84.2, 79.0, 69.9,
57.1, 55.4, 38.4, 27.4.
HR-ESIMS: m/z calcd for C27H28N5O4 [M + H]+: 486.2136; found:
486.2138.
IR (neat): 2932, 2835, 2136, 1610, 1509, 1248, 1172, 1085, 1033,
833, 738, 697 cm–1.
1H NMR: d = 7.42–7.31 (m, 5 H), 7.20 (d, J = 8.7 Hz, 2 H), 7.07 (d,
J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 6.79 (d, J = 8.7 Hz, 2 H),
5.37 (s, 1 H), 5.03 (s, 2 H), 3.90 (s, 2 H), 3.78 (s, 3 H), 3.21 (s, 3 H),
3.02 (s, 3 H).
(4R*,8R*)-epi-Calcaridine (epi-5)
Azide epi-55 (94 mg, 0.20 mmol) was dissolved in EtOH (3 mL)
and stirred under an H2 atmosphere (55 psi) in the presence of 20%
Pd(OH)2 on charcoal (40 mg) at r.t. overnight. The catalyst was fil-
tered through a pad of Celite and the filtrate was concentrated to
give epi-calcaridine A (epi-5) (73 mg, quant) as an off-white solid;
mp 218–220 °C.
13C NMR: d = 158.9, 157.3, 140.8, 139.6, 137.3, 133.0, 131.8,
129.7, 128.6, 128.0, 127.5, 127.3, 124.3, 114.9, 113.8, 75.0, 70.1,
56.5, 55.3, 32.8, 30.4.
HR-ESIMS: m/z calcd for C27H28N5O3 [M + H]+: 470.2187; found:
470.2191; for C27H27N5O3 + Na [M + Na]+: 492.2006; found:
492.1969.
IR (KBr): 3311 (br), 3001, 2830, 1770, 1693, 1613, 1560, 1513,
1440, 1309, 1256, 1089, 1032, 832, 793, 718 cm–1.
1H NMR (CD3OD): d = 7.20 (d, J = 8.7 Hz, 2 H), 6.94 (d, J = 8.7
Hz, 2 H), 6.89 (d, J = 8.7 Hz, 2 H), 6.66 (d, J = 8.7 Hz, 2 H), 4.59
(s, 1 H), 3.77 (s, 3 H), 3.43 (d, J = 14.2 Hz, 1 H), 3.31 (s, 3 H), 3.18
(d, J = 14.2 Hz, 1 H), 2.51 (s, 3 H).
2-Amino-4-[4-hydroxybenzyl]-5-[methoxy(4-methoxyphe-
nyl)methyl]-1-methyl-1H-imidazole (54)
Azide 53 (100 mg, 0.26 mmol) was dissolved in EtOH (5 mL) and
stirred overnight under an H2 atmosphere (55 psi) in the presence of
20% Pd(OH)2 on charcoal (30 mg) at r.t. The catalyst was filtered
13C NMR (CD3OD): d = 172.2, 160.5, 157.8, 156.8, 130.9, 129.0,
126.2, 124.40 114.9, 113.5, 84.1, 73.5, 56.3, 54.4, 38.3, 24.1.
Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York

2982
P. B. Koswatta et al.
PAPER
Yamashita, M.; Ohta, S. J. Chem. Soc., Perkin Trans. 1
2002, 1061. (g) Kawasaki, I.; Sakaguchi, N.; Fukushima, N.;
Fujioka, N.; Nikaido, F.; Yamashita, M.; Ohta, S.
Tetrahedron Lett. 2002, 43, 4377. (h) Kawasaki, I.;
Sakaguchi, N.; Khadeer, A.; Yamashita, M.; Ohta, S.
Tetrahedron 2006, 62, 10182.
HR-ESIMS: m/z calcd for C20H24N3O4 [M + H]+: 370.1761; found:
370.1761; for C20H23N3O4 + Na [M + Na]+: 392.1586; found:
392.1512.
(4R*,8S*)-Calcaridine A (5)
Following the procedure above, azide 55 (102 mg, 0.21 mmol) and
20% Pd(OH)2 on charcoal (40 mg) in EtOH (3 mL) under an H2 at-
mosphere gave calcaridine A (5) (78 mg, quant) as a pale yellow
solid; mp 163–165 °C.
(9) Giles, R. L.; Sullivan, J. D.; Steiner, A. M.; Looper, R. E.
Angew. Chem. Int. Ed. 2009, 48, 3116.
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IR (KBr): 3265 (br), 2833, 1781, 1692, 1612, 1560, 1513, 1449,
1346, 1250, 1093, 1023, 836, 799 cm–1.
1H NMR (CD3OD): d = 7.37 (d, J = 8.3 Hz, 2 H), 7.03 (d, J = 8.3
Hz, 2 H), 6.86 (d, J = 8.3 Hz, 2 H), 6.64 (d, J = 8.3 Hz, 2 H), 4.58
(s, 1 H), 3.82 (s, 3 H), 3.16 (s, 3 H), 3.16 (d, J = 14.2 Hz, 1 H), 2.83
(s, 3 H), 2.50 (d, J = 14.2 Hz, 1 H).
(12) Koswatta, P. B.; Lovely, C. J. Tetrahedron Lett. 2009, 50,
4998.
(13) Ermolat’ev, D. S.; Alifanov, V. L.; Rybakov, V. B.; Babaev,
E. V.; van der Eycken, E. V. Synthesis 2008, 2083.
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13C NMR (CD3OD): d = 173.3, 160.7, 158.7, 156.9, 130.8, 129.4,
126.1, 123.0, 114.9, 114.1, 84.2, 73.1, 56.1, 54.6, 37.9, 24.6.
HR-ESIMS: m/z calcd for C20H24N3O4 [M + H]+: 370.1761; found:
370.1761.
(16) Koswatta, P. B.; Sivappa, R.; Dias, H. V. R.; Lovely, C. J.
Org. Lett. 2008, 10, 5055.
Acknowledgment
(17) Ralifo, P.; Crews, P. J. Org. Chem. 2004, 69, 9025.
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We are grateful to The Robert A. Welch Foundation [Y-1362
(C.J.L.) and Y-1289 (H.V.R.D.)] and in part NIH (GM065503) for
funding our programs. The NSF provided funding (CHE-9601771
and CHE-0234811) for the purchase of NMR spectrometers used in
the course of this work.
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Synthesis 2009, No. 17, 2970–2982 © Thieme Stuttgart · New York