Enantioselective Biginelli Reaction of Aliphatic Aldehydes Catalyzed by a Chiral Phosphoric Acid: A Key Step in the Synthesis of the Bicyclic Guanidine Core of Crambescin A and Batzelladine A

Article abstract of DOI:10.1055/s-0036-1591567

An efficient chiral phosphoric acid catalyzed Biginelli reaction for the synthesis of optically pure 4-alkyl-3,4-dihydropyrimidin-2-(1 H)-ones has been developed, with a wide range of the desired products being obtained in moderate to high yields with good to excellent enantioselectivities (up to >99% ee after one recrystallization). The synthetic utility of this reaction is illustrated in various aliphatic bicyclic guanidine compounds, which is applied in the formal synthesis of the bicyclic guanidine core of crambescin A and batzelladine A.

Full text of DOI:10.1055/s-0036-1591567

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–M
paper
A
en
Y. Guo et al.
Paper
Synthesis
Enantioselective Biginelli Reaction of Aliphatic Aldehydes Cata-
lyzed by a Chiral Phosphoric Acid: A Key Step in the Synthesis of
the Bicyclic Guanidine Core of Crambescin A and Batzelladine A
Alk
catalyst
(1 mol%)
Alk CHO
Ar
Yongbiao Guo*
Zhenhua Gao
Chongxu Fan
Jisheng Chen
Junchen Li
CO2R
CO2R
H2N
O
+
HN
CHCl3
25 °C, 10 d;
then 50 °C, 1 d
O
O
O
NH2
O
P
O
N
H
OH
20 examples
up to 83% yield and 88% ee
up to >99% ee (recrystallization)
Ar
NH2
NH
NH2
NH
Ar = 3,5-(t-Bu)2-4-MeOC6H2
Yongpeng Huang
Guilan Huang
Huilan Yu
3 steps
catalyst
N
N
OH
n
Chuanpin Zou*
MeO
O
O
OMe
bicyclic guanidine
core of batzelladine A
15% total yield (4 steps)
bicyclic guanidine
core of crambescin A
8 examples
up to 16% total yield (4 steps)
Beijing Institute of Pharmaceutical Chemistry, No. 37,
Center South Street, Yangfang Town, Changping District,
Beijing 102205, P. R. of China
van87120@126.com
zou404@263.net
Received: 17.02.2018
O
O
Accepted after revision: 19.03.2018
Published online: 25.04.2018
DOI: 10.1055/s-0036-1591567; Art ID: ss-2018-f0091-op
HN
N
O
N
H
N
MeO
R
X
Abstract An efficient chiral phosphoric acid catalyzed Biginelli reac-
tion for the synthesis of optically pure 4-alkyl-3,4-dihydropyrimidin-2-
(1H)-ones has been developed, with a wide range of the desired prod-
ucts being obtained in moderate to high yields with good to excellent
enantioselectivities (up to >99% ee after one recrystallization). The syn-
thetic utility of this reaction is illustrated in various aliphatic bicyclic
guanidine compounds, which is applied in the formal synthesis of the
bicyclic guanidine core of crambescin A and batzelladine A.
MeO
F
OH
F
NH2
(S)-L-771688: X = N, R = H
SNAP-7941: X = CH, R = NHAc
N
O
NH
EtO2C
NH
n
N
H
O
OR
(S)-monastrol
crambescin A
NO2
NH2
Key words Biginelli reaction, dihydropyrimidinone, aliphatic alde-
hydes, crambescin, batzelladine
O
HN
O
NH
R1
4
iPrO2C
CO2R2
N
NH2
HN
*
n
N
O
3,4-Dihydropyrimidin-2-(1H)-one (DHPM) is a privi-
leged architecture in small-molecule active pharmaceutical
ingredients, such as calcium channel modulator,1 antihy-
pertensive agent,2 mitotic kinesin Eg5 inhibitor,3 α1 recep-
tor antagonist agent,4 melanin concentrating hormone re-
ceptor (MCH1-R) antagonist agent,5 HIVgp-120-CD4 inhibi-
tor,6 and sodium channel blocker (Figure 1).7 In this context,
the absolute configuration of the C4 stereogenic center in
DHPM motifs has a significant influence on the biological
activity, namely, the different enantiomers at C4 position
often exhibit diverse or even opposite biological activities.
For example, the R-enantiomer of crambescin A carboxylic
acid, a sodium channel blocker, exhibits >270-fold more po-
tent inhibitory activity in vitro than the other enantiomer.7d
Currently, our research group is focusing on the enantio-
selective total synthesis of crambescin A and batzelladine
A.8 Stereoselective construction of the bicyclic guanidine
structure in crambescin A and batzelladine A is a key issue
for the total synthesis of these natural products.6,7 Ret-
O
OR
X
N
H
H
crambescin B
(R)-SQ 32926
DHMP
NH2
NO2
HO
HN
NH
OR
O
O
EtO2C
n
N
OMe
O
N
NH2
NH
crambescin C
H
Ca2+ channel blocker
N
O
H
H
O
N
H
8
H2N
N
O
O
N
N
C9H19
3
H
NH2
batzelladine A
NH2
NH2
H C
R =
crambescin A–C
2
N
H
m
crambescin A–C carboxylic acid: R = H
Figure 1 Biologically active 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

B
Y. Guo et al.
Paper
Synthesis
rosynthetic analysis of crambescin A and batzelladine A is
illustrated in Scheme 1. The bicyclic guanidine core of
crambescin A and batzelladine A could be constructed from
optically pure 4-alkyl-DHPMs, and the enatioenriched 4-al-
kyl-DHPMs could be constructed via the enantioselective
Biginelli reaction, which consists of a 3-component conden-
sation reaction of urea, a β-keto ester, and an aliphatic alde-
hyde. In the past decades, versatile catalytic methodologies,
such as chiral Lewis acid catalyst,9 phosphoric acids,10 sec-
ondary amines,11 primary amines,12 bifunctional primary
amines,13 NbCl5/primary amines,14 self-assembled metha-
noproline-thiourea organocatalysts,15 or chiral 1,2-ben-
zenedisulfonimide,16 have been developed to improve the
synthesis of optically pure DHPMs by the enantioselective
Biginelli reaction. Whereas, to the best of our knowledge,
the aldehyde substrates of the enantioselective Biginelli re-
action are still mainly restricted to aromatic aldehydes,
except a few unique aliphatic aldehyde substrates, such as,
selective Biginelli reaction of aliphatic aldehydes and the
first synthesis of the bicyclic guanidine core of crambescin
A and batzelladine A via enantioselective Biginelli reaction.
Table 1 Synthesis of the DHPM Core of Crambescin A and Batzelladine
A: Initial Studiesa
O
OMe
H2N
O
NH2
2
Alk
*
O
+
O
cat. 1
(10 mol%)
CO2R2
O
O
HN
P
OH
CH2Cl2
25 °C, 10 d
OMe
O
N
H
3a
+
5a–i
Alk CHO
OMe
4a–i
cat. 1
2-phenylacetaldehyde,9b
cyclohexanecarbaldehyde,10a,b,d
Entry
Alk
Br(CH2)9
5
Yield (%)b
ee (%)c
isobutyraldehyde,11d and n-butyraldehyde,13a,15 were ap-
plied. Therefore, a highly stereoselective transformation for
the preparation of optically pure 4-alkyl-DHPMs with ali-
phatic aldehydes is in great demand.
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
30
48
54
47
46
52
35
46
50
85
85
85
85
85
85
86
86
86
n-C5H11
n-C6H13
n-C7H15
n-C8H17
n-C9H19
n-C10H21
n-C11H23
n-C12H25
NH2
N
NH
O
H
H
O
N
5g
5h
5i
H
8
H2N
N
O
O
N
N
C9H19
3
H
NH2
R
n
batzelladine A
CO2Me
a Reactions were run with urea (0.2 mmol), catalyst 1 (0.02 mmol), and al-
dehyde (0.24 mmol) in CH2Cl2 (2 mL) for 2 h. Methyl acetoacetate (3a; 0.6
mmol) was added, and the mixture was stirred at 25 °C for 10 d.
b Isolated yield based on urea.
HN
NH2
NH
H2N
N
N
O
c Determined by HPLC (Chiralcel OD-RH).
NH2
NH2
bicyclic guanidine
n
O
m
N
H
Synthesis of the Optically Pure 4-Alkyl-DHPMs via
the Enantioselective Biginelli Reaction
crambescin A
From the outset, we recognized that a mechanistic
study is necessary for the clear clarification of the reaction
profile, which was conducted by mass characterization of
intermediates (See Supporting Information, Figures S1, S2,
and S3). A reaction of urea, 10-bromodecanal, and methyl
acetoacetate catalyzed by 10 mol% of phosphoric acid was
carried out and monitored via HPLC-MS in sequential days.
In consideration of the reactive properties of the substrates,
we put forward a plausible mechanism for the five com-
pounds generated in the mixture on the basis of HPLC-MS
results and previous reports (Scheme 2).18 The N-acylimini-
um intermediate I formed by the dehydration of urea and
10-bromodecanal would subsequently participate in the
following process in three possible patterns: (i) path a, an-
other urea attacks the iminium I to generate a 1,1′-diurea II,
followed by the dehydration with 10-bromodecanal to give
a by-product IV; (ii) path b, another 10-bromodecanal re-
acts with I to generate a bis-iminium III, followed by the re-
R
n
enantioselective
Biginelli reaction
O
O
O
CO2Me
HN
OMe
H2N
NH2
+
O
N
H
Alk CHO
4-alkyl-DHPMs
Scheme 1 Retrosynthetic analysis of batzelladine A and crambescin A
Last year, we have reported a highly enantioselective
Biginelli reaction of aliphatic aldehydes using chiral phos-
phoric acid as catalyst, and a series of 4-alkyl-DHPMs were
obtained in moderate to high yields with good enantiose-
lectivities.17 However, when the more synthetically useful
aliphatic aldehydes were tried, the yields dropped dramati-
cally to 30–54% (Table 1). In order to improve the efficiency
of optically pure 4-alkyl-DHPMs synthesis, we herein re-
port a more efficient catalytic system for the highly enantio-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

C
Y. Guo et al.
Paper
Synthesis
NH2
NH
O
O
O
O
H2N
NH2
Br
N
N
Br
Br
N
H
N
H
Br
O
8
8
8
8
H
H
III
IV
path b
Br
Br
O
8
8
O
O
O
NH2
O
H2N
NH2
H2N
NH2
O
NH
O
Br
N
NH2
O
8
H
H
path a
Br
N
NH2
Br
I
8
H
O
II
path c
OMe
Br
Br
8
8
CO2Me
CO2Me
HN
*
*
HN
O
O
N
H
NH2
O
V
5a
Scheme 2 Plausible reaction mechanism for the Biginelli reaction
action with urea to give IV; and (iii) path c, the β-keto ester
attacks I to generate an ureide V, which readily cyclizes to
amount of catalyst examined, 1 mol% of a catalyst was
found to be most suitable for the reaction, affording 31%
yield and 86% ee.
give the desired enantiomer 5a. Moreover, from the HPLC
chromatogram we observed that the corresponding peaks
of I–III decreased gradually, and the peaks of V and 5a in-
creased gradually in the meantime. On this basis, we be-
lieve that the conversion of I into V might be the chirality-
controlling and fast step, and the cyclization of V would be
the rate-determining (slow) step. Consequently, several fac-
tors, which might affect the reaction efficiency must be
considered: (1) catalyst dosage, (2) the amount of β-keto es-
ter to promote the transformation of I to V, (3) solvent, and
(4) temperature.
According to the mechanistic study, we initially investi-
gated the catalytic enantioselective Biginelli reaction in 10–
25 mol% of catalyst 1 in CH2Cl2 at 25 °C (Table 2). Although
the enantioselectivities were always high, poor yields were
obtained. Moreover, we found that the reaction took nearly
five days to reach completion. An increase of the catalyst
amount from 10 to 25 mol% had essentially no effect on
both yield and enantioselectivity. Therefore, the use of a
smaller amount of catalyst was investigated. Surprisingly,
when the amount of catalyst 1 was reduced from 10% to 5
mol%, the yield and enantioselectivity remained similar
(30% yield, 86% ee), whereas the reaction rate became slow-
er (Table 2, entries 1, 5, and 6). This result encouraged us to
optimize the amount of catalyst 1 further. Then a detailed
study of the amount of catalyst 1 allowed us to reduce the
catalyst from 10 mol% to 1 mol% with no deterioration of
yield and enantioselectivity (entries 7–11). Among the
Having identified 1 mol% as the optimal amount of cata-
lyst, we studied the effect of molar substrate (urea) concen-
tration on the reaction. Unfortunately, changing the con-
centration from 0.1 M to 0.2 M caused a distinct deteriora-
tion of the reaction rate and the yield of the product
reduced from 31% to 20% with a lower enantioselectivity
(Table 2, entries 10 and 12). When reducing the concentra-
tion to 0.05 M, reaction remained unsuccessful resulting in
a lower yield of 20% with a slightly better enantioselectivity
(87% ee) (entry 13). Accordingly, 0.1 M urea concentration
was chosen as the optimal concentration.
In order to improve the yield of DHPM, the amount of
methyl acetoacetate were investigated. Fortunately, with
the increased the amount of methyl acetoacetate, the yield
increased with no deterioration of enantioselectivity (Table
2, entries 14–16). The best result of yield (41%) with 86% ee
was observed when 7.5 equivalents of methyl acetoacetate
were used.
To further improve the yield of DHPM, the effect of sol-
vents was investigated. From our previous report,17 it was
known that a similar enantioselectivity was obtained when
the reaction was performed in CHCl3, whereas other sol-
vents such as xylene, toluene, benzene, 1,4-dioxane, or ace-
tone led to lower enantioselectivity. Surprisingly, the yield
was improved significantly from 41% to 58% with a slightly
higher enantioselectivity (88%, ee, Table 2, entry 17), when
CHCl3 was used. Furthermore, based on the results of HPLC-
MS, we found that intermediates I was almost completely
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

D
Y. Guo et al.
Paper
Synthesis
Table 2 Effect of Catalyst Loading and Time on the Enantioselective
the carbon chain of aliphatic aldehydes have a slight influ-
ence on the yield and enantioselectivity. Moreover, the sub-
stituent on the aldehydes had little effect on the reactivity
and stereoselectivity as demonstrated by reactions involv-
ing bromononyl-, 4-methoxyphenoxyl-, tert-butyldimethyl-
siloxyl- and phenyl-substituted aliphatic aldehydes (entries 1,
10, 11 and 17). For cyclohexanecarbaldehyde, good yield and
excellent enantioselectivities were achieved (entry 16).
We next studied the generality of β-keto esters in the
reaction. Ethyl (3b), isopropyl (3c), and tert-butyl 3-oxobu-
tanoate (3d) gave similar enantioselectivity to methyl ace-
toacetate (3a), but the yields were reduced with increasing
size of the R substituent.
Biginelli Reactiona
Br
O
O
O
cat. 1
(1–25 mol%)
8
H2N
NH2
Br
OMe
CO2Me
3a
2
HN
*
+
O
N
H
O
8
4a
5a
Entry 1 (mol%) Ratio 2/3a/4a Solvent
Time (d) Yield (%)b ee (%)c
1
2
10
15
20
25
5
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:5
1:1.2:7.5
1:1.2:10
1:1.2:7.5
1:1.2:7.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
5–6
5–6
5–6
5–6
5
30
30
29
29
23
30
19
31
29
31
20
20d
20e
36
41
40
58
86
86
86
86
86
86
86
86
86
86
86
83
87
86
86
86
88
88
3
Table 3 Scope of Chiral Phosphoric Acid Catalyzed Enantioselective
4
Biginelli Reactiona
5
6
5
8–9
5
O
Alk
O
O
CO2R
7
2.5
H2N
NH2
cat. 1 (1 mol%)
HN
OR
+
2
3
8
2.5
1
10–11
10
CHCl3, 25 °C, 10 d;
then 50 °C, 1 d
O
N
H
Alk CHO
9
5
4
10
11
12
13
14
15
16
17
18
1
12–13
15
0.5
1
Entry
Alk
R
5
Yield (%)b
76 (66)
ee (%)c
12–13
12
1
2
Br(CH2)9
n-C5H11
n-C6H13
n-C7H15
n-C8H17
n-C9H19
n-C10H21
n-C11H23
n-C12H25
TBSO(CH2)9
MPMO(CH2)9
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
5a
5b
5c
5d
5e
5f
88 (98)
85 (99)
85 (98)
85 (99)
85 (99)
85 (99)
86 (98)
86 (99)
86 (98)
86 (99)
86 (99)
80 (99)
73 (90)
87 (94)
87 (99)
85 (97)
85 (99)
85 (98)
82 (97)
80 (99)
1
72 (60)
76 (65)
75 (63)
76 (63)
71 (60)
75 (62)
73 (62)
76 (65)
75 (63)
70 (50)
65 (51)
63 (45)
78 (70)
71 (60)
70 (60)
82 (68)
83 (65)
75 (60)
65 (50)
1
12
3
1
12
4
1
12
5
1
10–11
6
1
CHCl3
10 + 1–2 78f
7
5g
5h
5i
a Reactions were run with urea (0.2 mmol), catalyst 1 (0.001–0.05 mmol),
and 10-bromodecanal (0.24 mmol) in CH2Cl2 (2 mL) for 2 h. Methyl acetoac-
etate (3a; 0.6 mmol) was then added and the mixture was stirred at 25 °C for
5–13 d.
8
9
b Yield was determined by HPLC analysis.
10
11
12
13
14
15
16
17
18
19
20
5j
c Determined by HPLC (Chiralcel AD-RH).
d Amount of urea used: 0.2 M.
5k
5l
e Amount of urea used: 0.05 M.
f Methyl acetoacetate (1.5 mmol), CHCl3, 10 days (25 °C), and then 1–2 days
(50 °C).
i-Pr
5m
5n
5o
5p
5q
5r
t-Bu
n-Bu
transformed into intermediate V, but the dehydration reac-
tion of intermediate V became very sluggish after ten days
of reaction, so the reaction temperature was increased after
that time. Increasing the reaction temperature from 25 to
50 °C did not affect the enantioselectivity, but resulted in a
higher yield (78%, entry 18). And on the basis of the results
of HPLC-MS, intermediate V was almost completely trans-
formed into DHPM after one day of reaction at 50 °C.
With our optimized catalyst system in hand, we applied
the approach to a variety of aliphatic aldehydes (Table 3, en-
tries 1–17) and methyl acetoacetate with urea. As shown in
Table 3, the corresponding DHPMs were obtained in moder-
ate to good yields (63–83%) with excellent enantioselectivi-
ties (73–88% ee) (entries 1–17). The length and the type of
cyclohexyl
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
i-Pr
5s
5t
t-Bu
a Reaction conditions: 2 (0.2 mmol), phosphoric acid catalyst 1 (0.002
mmol), and aldehyde 4 (0.24 mmol) in CHCl3 (2 mL) at 25 °C for 2 h, then
β-keto ester 3 (1.5 mmol) was added, and the mixture was stirred at 25 °C
for 10 d, then at 50 °C for 1 d. β-Keto ester: 3a R = Me; 3b R = Et; 3c R = i-Pr;
3d R = t-Bu.
b Isolated yield based on the urea. Total yield after one recrystallization
from MeCN is given in parentheses.
c Determined by HPLC (Chiralcel OD-RH) for 5a–p and HPLC (Chiralcel AS-RH)
for 5q–t; ee after one recrystallization from MeCN is given in parentheses.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

E
Y. Guo et al.
Paper
Synthesis
Due to the good results obtained, we next tried to im-
prove the enantiomeric excess of 4-alkyl-DHPMs by recrys-
tallization from acetonitrile. Fortunately, after recrystalliza-
tion, the corresponding DHPM derivatives were obtained in
moderate to good total yields (45–70%) with excellent en-
antioselectivities (90–99%, ee) as shown in Table 3. The op-
tically pure 4-alkyl-DHPMs (97–99%, ee) could be used
directly without further purification for the synthesis of
batzelladine A, crambescin A or other optically pure com-
pounds, except for 5m (90%, ee) and 5n (94%, ee).
was removed under these conditions, presumably as a re-
sult of propanoic acid assistance by the neighboring guani-
dine in 8j (Table 5). All products 8b–j were isolated as the
trifluoroacetate salts.
Table 5 Synthesis of 8b–j from 5b–ja
R
R
R
n
n
n
CO2Me
CO2Me
CO2Me
N
HN
HN
a
b
EtO
N
O
N
H
O
N
Synthesis of the Bicyclic Guanidine Core of Crambes-
cin A and Batzelladine A
5b–j
6b–j
7b–j
Another key step in our retrosynthetic analysis to the
bicyclic guanidine core of crambescin A and batzelladine A
(Scheme 1) was the coupling/cyclization reaction of 5b. Ini-
tially, we examined the coupling reaction of 5b by Singh’s
method19 utilizing n-BuLi and 1,2-dibromoethane, but the
yield of bicyclic intermediate 6b was very low (10%). Thus,
several bases and electrophiles for this conversion were fur-
ther investigated, and the results are summarized in Table
4. The best result of yield (42%) was observed when 5.0
equivalents of n-BuLi and 5.0 equivalents of 1,2-dibro-
moethane were used. Moreover, based on the results of
HPLC, we concluded that no racemization occurred during
the process, as the enantiomeric ratio was completely re-
tained. Then the bicyclic intermediates 6c–j were synthe-
sized according to the optimized reaction conditions (Table
5). The resulting bicyclic intermediates 6c–j were further
O-ethylated with triethyloxonium tetrafluoroborate to the
intermediates 7b–j, and then treatment with ammonium
propionate gave the bicyclic guanidine core of crambescin A
8b–i (Table 5). Serendipitously, the silyl protecting group
R
n
CO2Me
HN
c
H2N
N
8b–j
R
–
CF3CO2
Entry
5–8
n
Yield (%) Yield (%) Yield (%)
of 6b
of 7b
of 8b,c
1
2
3
4
5
6
7
8
9
b
c
d
e
f
H
3
42
38
40
42
45
40
43
39
45
86
89
89
85
87
75
99
75
80
61 (22)
65 (22)
60 (21)
65 (23)
60 (23)
70 (21)
61 (26)
60 (18)
65 (23)
H
H
H
H
H
H
H
4
5
6
7
g
h
i
8
9
10
7
j
TBSOd
a Reaction conditions: (a) 5b–j (1 mmol), n-BuLi (5 mmol), anhyd THF (10
mL), –20 °C to r.t., 3 h, then 1-bromo-2-chloroethane (6.0 mmol), r.t., 3 h;
(b) 6b–j (0.5 mmol), NaHCO3 (2.0 mmol), Et3O+BF4– (1.0 mmol), anhyd
CH2Cl2 (10 mL), r.t., 0.5 h; (c) 7b–j (0.3 mmol), ammonium propionate (1.0
g), 80 °C, 0.5 h.
Table 4 Investigation of Coupling Reaction of 5b to 6ba
b Isolated yield for the single step.
1. base, THF
c Overall yields from 5b–j are given in parentheses.
d For 8j, R = HO.
CO2Me
CO2Me
HN
HN
2. BrCH2CH2X
O
N
O
N
H
5b
6b
We proceeded to determine the absolute configuration
of our synthesized bicyclic guanidine core of crambescin A
and batzelladine A by a comparison of optical rotation. The
bicyclic guanidines 8h and 8j derived from 5h and 5j were
found to be identical in all respects including specific rota-
tions, to that reported6a,7d for the specific rotations of 8h
{[α]D24 +56 (c 0.2, MeOH, TFA salt), [α]D23 +58 (c 0.3, MeOH,
Entry
Base (equiv)
X
Yield (%)b
1
2
3
4
5
6
7
n-BuLi (3.5)
n-BuLi (3.5)
n-BuLi (4.0)
n-BuLi (5.0)
n-BuLi (6.0)
LDA (5.0)
Br
10
34
38
42
40
38
0
Cl
Cl
Cl
Cl
Cl
Cl
23
HCO2H salt), Lit.7d S [α]D –56.2 (c 0.28, MeOH)} and 8j
{[α]D24 +27 (c 0.5, MeOH, TFA salt), [α]D23 +30 (c 0.2, MeOH,
HCO2H salt), Lit.6a R [α]D23 +28.3 (c 0.2, MeOH)}, thereby es-
tablishing the absolute configuration of our synthesized bi-
cyclic guanidine core of crambescin A and batzelladine A to
be R. Moreover, based on this finding, we conclude that the ab-
solute configurations of all 4-alkyl-DHPMs in this paper are R.
LiHMDS (5.0)
a Reactions were run with DHMP 5b (0.5 mmol) and base (1.75–3.0 mmol)
in anhyd THF (5 mL) at r.t. under N2 atmosphere for 3 h. 1,2-Dibromo-
ethane or 1-bromo-2-chloroethane (3.0 mmol) was added, and the mixture
was stirred at 25 °C for 2 h.
b Isolated yield based on DHMP 5b.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

F
Y. Guo et al.
Paper
Synthesis
With the bicyclic guanidine core of crambescin A 8b–i
in hand, crambescin A could be synthesized according to
previously reported literature procedures (Scheme 3).
gum was purified by column chromatography on a silica gel column
[eluent: hexane/i-PrOH (15:1)] to afford 4-alkyl-DHMPs 5 as white
crystalline solids. Then the optically pure 4-alkyl-DHPMs were ob-
tained by recrystallization from MeCN.
NH2
Methyl (R)-4-(9-Bromononyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5a)
n
N
O
NH
O
CO2Me
HN
ref. 6e
18
Yield: 49 mg (66%); white solid; mp 82–85 °C; [α]D +100 (c 0.40,
n
H
4 steps
H2N
N
N
NH2
NH2
CH2Cl2).
m
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 5.8 min,
tR (major) = 8.8 min; 98% ee.
1H NMR (600 MHz, CDCl3): δ = 8.11 (s, 1 H), 5.75 (s, 1 H), 4.29 (s, 1 H),
3.71 (s, 3 H), 3.40 (t, J = 7.2 Hz, 2 H), 2.28 (s, 3 H), 1.86–1.82 (m, 2 H),
1.55–1.48 (m, 2 H), 1.42–1.38 (m, 3 H), 1.27 (s, 10 H).
8b–i
crambescin A
Scheme 3 Synthetic plan of crambescin A with reference to the litera-
ture
13C NMR (150 MHz, CDCl3): δ = 166.3, 154.4, 146.9, 101.5, 51.6, 51.2,
36.9, 34.0, 32.8, 29.4, 29.3, 29.2, 28.7, 28.1, 24.3, 18.6.
HRMS: m/z calcd for C16H28BrN2O3 [M + H]+: 375.1278; found:
375.1286.
In summary, a more efficient catalytic approach to high-
ly enantioselective Biginelli reaction of aliphatic aldehydes
using a very low amount of chiral phosphoric acid (1 mol%)
as catalyst has been developed. A wide range of optically
pure 4-alkyl-DHPMs were obtained in moderate to high
yields with good to excellent enantioselectivities (up to
>99% ee after one recrystallization). Moreover, through the
use of a novel synthetic strategy involving the enantioselec-
tive Biginelli reaction, the bicyclic guanidine core of
crambescin A and batzelladine A were accomplished in
highly convergent and stereoselective sequences. Further,
the enantioselective total synthesis of crambescin A and
batzelladine A are in progress in our laboratory.
Methyl (R)-4-Pentyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (5b)
18
Yield: 29 mg (60%); white solid; mp 156–158 °C; [α]D +150 (c 0.50,
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (40:60 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 4.7 min,
tR (major) = 6.9 min; 99% ee.
1H NMR (600 MHz, CDCl3): δ = 8.10 (s, 1 H), 5.77 (s, 1 H), 4.28 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.28 (s, 3 H), 1.56–1.47 (m, 2 H),
1.39–1.36 (m, 1 H), 1.29–1.22 (m, 5 H), 0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.3, 154.4, 146.9, 101.5, 51.6, 51.1,
36.9, 31.4, 24.0, 22.5, 18.6, 14.0.
HRMS: m/z calcd for C12H21N2O3 [M + H]+: 241.1547; found: 241.1554.
Reagents and solvents were purchased from common commercial
suppliers and were used without further purification. Column chro-
matography was generally performed on silica gel (200–300 mesh).
Melting points were determined with a Büchi B-545 melting point
apparatus. 600 MHz 1H NMR and 150 MHz 13C NMR spectra were re-
corded on Varian VMS-600 spectrometers, respectively. The chemical
shifts are reported in ppm (δ scale) relative to internal TMS, and cou-
pling constants are reported in hertz (Hz). Electrospray ionization
mass spectrometry (ESI-MS) was carried out on a Agilent 6410 LC/MS
spectrometer.
Methyl (R)-4-Hexyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (5c)
Yield: 33 mg (65%); white solid; mp 147–149 °C; [α]D18 +142 (c 0.54,
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (40:60 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 6.8 min,
tR (major) = 11.0 min; 98% ee.
1H NMR (600 MHz, CDCl3): δ = 8.17 (s, 1 H), 5.81 (s, 1 H), 4.28 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.28 (s, 3 H), 1.59–1.47 (m, 2 H),
1.39–1.33 (m, 1 H), 1.29–1.25 (m, 7 H), 0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.4, 154.5, 146.9, 101.2, 51.6, 51.1,
36.9, 31.7, 29.0, 24.3, 22.6, 18.6, 14.1.
HRMS: m/z calcd for C13H23N2O3 [M + H]+: 255.1703; found: 255.1707.
Study on Reaction Mechanism of Biginelli Reaction by HPLC-MS
In order to ensure that the reaction optimization became more effi-
cient, we studied the reaction mechanism by HPLC-MS at first. A mix-
ture of urea (2; 12 mg, 0.2 mmol), 10-bromodecanal (4a; 56 mg, 0.24
mmol) and methyl acetoacetate (3a; 70 mg, 0.6 mmol) was reacted in
the presence of 10 mol% of phosphoric acid A at 25 °C in CH2Cl2. After
2, 3, 5, and 10 days, the same amount of crude mixture was dissolved
in MeOH and filtered using a 0.45 μm filter, and then, each sample
was analyzed by HPLC-MS. The results are summarized in Figure S1,
S2, and S3 (see Supporting Information).
Methyl (R)-4-Heptyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (5d)
Yield: 34 mg (63%); white solid; mp 128–130 °C; [α]D18 +131 (c 0.50,
CH2Cl2).
4-Alkyl-DHMPs 5; General Procedure
After stirring a solution of urea (2; 12 mg, 0.2 mmol), phosphoric acid
catalyst 1 (1.6 mg, 0.002 mmol) and aliphatic aldehyde 4 (0.24 mmol)
in CHCl3 (2 mL) at 25 °C for 2 h, β-keto ester 3 (1.5 mmol) was added.
The reaction mixture was stirred at 25 °C for 10 days and then at 50
°C for 1 day. After evaporating the excess solvent, the resulting orange
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 3.4 min,
tR (major) = 5.1 min; 98% ee.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

G
Y. Guo et al.
Paper
Synthesis
1H NMR (600 MHz, CDCl3): δ = 8.17 (s, 1 H), 5.80 (s, 1 H), 4.28 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.28 (s, 3 H), 1.57–1.48 (m, 2 H),
1.38–1.25 (m, 10 H), 0.87 (t, J = 6.6 Hz, 3 H).
1H NMR (600 MHz, CDCl3): δ = 7.98 (s, 1 H), 5.66 (s, 1 H), 4.28 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.28 (s, 3 H), 1.56–1.50 (m, 2 H),
1.38–1.24 (m, 18 H), 0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.4, 154.7, 147.0, 101.3, 51.5, 51.1,
13C NMR (150 MHz, CDCl3): δ = 166.3, 154.3, 146.8, 101.5, 51.6, 51.1,
36.9, 31.8, 29.5, 29.3, 29.2, 24.3, 22.6, 18.5, 14.1.
36.9, 31.9, 29.6, 29.6, 29.6, 29.5, 29.3, 29.3, 24.4, 22.7, 18.6, 14.1.
HRMS: m/z calcd for C14H25N2O3 [M + H]+: 269.1860; found: 269.1864.
HRMS: m/z calcd for C18H33N2O3 [M + H]+: 325.2486; found: 325.2490.
Methyl (R)-4-Octyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
Methyl (R)-4-Dodecyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (5e)
dine-5-carboxylate (5i)
20
Yield: 36 mg (63%); white solid; mp 134–136 °C; [α]D18 +125 (c 0.50,
Yield: 44 mg (65%); white solid; mp 127–129 °C; [α]D +110 (c 0.50,
CH2Cl2).
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 4.1 min,
tR (major) = 6.0 min; 99% ee.
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 10.1
min, tR (major) = 15.2 min; 98% ee.
1H NMR (600 MHz, CDCl3): δ = 8.44 (s, 1 H), 6.00 (s, 1 H), 4.28 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.70 (s, 3 H), 2.27 (s, 3 H), 1.55–1.49 (m, 2 H),
1.38–1.24 (m, 12 H), 0.86 (t, J = 6.6 Hz, 3 H).
1H NMR (600 MHz, CDCl3): δ = 8.09 (s, 1 H), 5.73 (s, 1 H), 4.28 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.28 (s, 3 H), 1.58–1.47 (m, 2 H),
1.38–1.24 (m, 20 H), 0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.4, 154.7, 147.0, 101.3, 51.5, 51.1,
13C NMR (150 MHz, CDCl3): δ = 166.3, 154.4, 146.9, 101.4, 51.5, 51.1,
36.9, 31.8, 29.5, 29.3, 29.2, 24.3, 22.6, 18.5, 14.1.
36.9, 31.9, 29.7, 29.6, 29.6, 29.6, 29.5, 29.3, 29.3, 24.4, 22.7, 18.6, 14.1.
HRMS: m/z calcd for C15H27N2O3 [M + H]+: 283.2016; found: 283.2021.
HRMS: m/z calcd for C16H29N2O3 [M + H]+: 339.2642; found: 339.2648.
Methyl (R)-4-Nonyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
Methyl (R)-4-[9-(tert-Butyldimethylsilyl)nonyl]-6-methyl-2-oxo-
dine-5-carboxylate (5f)
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5j)
Yield: 36 mg (60%); white solid; mp 117–119 °C; [α]D18 + 129 (c 0.40,
Yield: 54 mg (63%); white solid; mp 86–88; [α]D22 +93 (c 0.50, CH2Cl2).
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 12.1
min, tR (major) = 15.9 min; 99% ee.
1H NMR (600 MHz, CDCl3): δ = 7.55 (s, 1 H), 5.46 (s, 1 H), 4.31–4.25
(dt, J = 7.2, 3.6 Hz, 1 H), 3.72 (s, 3 H), 3.59 (t, J = 6.6 Hz, 2 H), 2.28 (s, 3
H), 1.57–1.45 (m, 4 H), 1.38–1.26 (m, 12 H), 0.89 (s, 9 H), 0.04 (s, 6 H).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 5.1 min,
tR (major) = 7.7 min; 99% ee.
1H NMR (600 MHz, CDCl3): δ = 8.30 (s, 1 H), 5.88 (s, 1 H), 4.27 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.27 (s, 3 H), 1.56–1.50 (m, 2 H),
1.38–1.24 (m, 14 H), 0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3) δ = 166.3, 153.9, 146.7, 101.6, 63.3, 51.7,
51.2, 36.9, 32.9, 29.6, 29.5, 29.4, 29.3, 26.0, 25.8, 24.4, 18.7, 18.4, –5.3.
13C NMR (150 MHz, CDCl3): δ = 166.4, 154.7, 147.0, 101.4, 51.6, 51.1,
36.9, 31.8, 29.5, 29.5, 29.3, 29.3, 24.3, 22.6, 18.6, 14.1.
HRMS: m/z calcd for C16H29N2O3 [M + H]+: 297.2173; found: 297.2177.
HRMS: m/z calcd for C22H43N2O4Si [M + H]+: 427.2987; found:
427.2987.
Methyl (R)-4-Decyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
Methyl (R)-4-{9-[(4-Methoxybenzyl)oxy]nonyl}-6-methyl-2-oxo-
dine-5-carboxylate (5g)
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5k)
Yield: 38 mg (62%); white solid; mp 131–133 °C; [α]D16 +101 (c 0.50,
Yield: 43 mg (50%); colorless oil; [α]D22 +75 (c 0.40, CH2Cl2).
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 8.4 min,
tR (major) = 13.7 min; 99% ee.
1H NMR (600 MHz, CDCl3): δ = 8.46 (s, 1 H), 7.28 (dd, J = 9.0, 2.4 Hz, 2
H), 6.89 (dd, J = 9.0, 2.4 Hz, 2 H), 6.03 (s, 1 H), 4.44 (s, 2 H), 4.28 (dt,
J = 7.2, 3.6 Hz, 1 H), 3.81 (s, 3 H), 3.73 (s, 3 H), 3.44 (t, J = 7.2 Hz, 2 H),
2.29 (s, 3 H), 1.62–1.49 (m, 4 H), 1.41–1.27 (m, 12 H).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 6.2 min,
tR (major) = 9.6 min; 98% ee.
1H NMR (600 MHz, CDCl3): δ = 8.16 (s, 1 H), 5.77 (s, 1 H), 4.28 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.28 (s, 3 H), 1.57–1.50 (m, 2 H),
1.38–1.24 (m, 16 H), 0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.3, 154.5, 146.9, 101.4, 51.6, 51.1,
36.9, 31.9, 29.6, 29.6, 29.5, 29.3, 29.3, 24.4, 22.7, 18.6, 14.1.
HRMS: m/z calcd for C17H31N2O3 [M + H]+: 311.2329; found: 311.2334.
13C NMR (150 MHz, CDCl3): δ = 166.3, 159.0, 154.6, 147.0, 130.7,
129.2, 113.7, 101.3, 72.4, 70.2, 55.2, 51.5, 51.1, 36.9, 29.7, 29.5, 29.4,
29.4, 26.1, 18.5.
HRMS: m/z calcd for C24H37N2O5 [M + H]+: 433.2697; found: 433.2635.
Methyl (R)-4-Undecyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (5h)
Methyl (R)-4-Ethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
18
5-carboxylate (5l)
Yield: 40 mg (62%); white solid; mp 116–118 °C; [α]D +111 (c 0.40,
CH2Cl2).
Yield: 20 mg (51%); white solid; mp 193–195 °C; [α]D20 +148 (c 0.15,
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 7.9 min,
tR (major) = 12.2 min; 99% ee.
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (20:80 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 5.0 min,
tR (major) = 6.8 min; 99% ee.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

H
Y. Guo et al.
Paper
Synthesis
1H NMR (600 MHz, CDCl3): δ = 8.07 (s, 1 H), 5.79 (s, 1 H), 4.27–4.24
(m, 1 H), 3.71 (s, 3 H), 2.28 (s, 3 H), 1.60–1.56 (m, 2 H), 0.91 (t, J = 7.2
Hz, 3 H).
1H NMR (600 MHz, CDCl3): δ = 8.64 (s, 1 H), 6.23 (s, 1 H), 4.17 (t, J = 3.6
Hz, 1 H), 3.70 (s, 3 H), 2.27 (s, 3 H), 1.72–1.61 (m, 4 H), 1.51–1.43 (m, 2
H), 1.24–0.96 (m, 5 H).
13C NMR (150 MHz, CDCl3): δ = 166.4, 154.5, 147.0, 100.9, 52.8, 51.1,
13C NMR (150 MHz, CDCl3): δ = 166.7, 155.3, 147.5, 99.7, 56.3, 51.1,
29.8, 18.6, 8.7.
44.6, 28.8, 26.3, 26.2, 26.1, 26.0, 18.5.
HRMS: m/z calcd for C9H15N2O3 [M + H]+: 199.1077; found: 199.1077.
HRMS: m/z calcd for C13H21N2O3 [M + H]+: 253.1574; found: 253.1553.
Methyl (R)-4-Isopropyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
Methyl (R)-6-Methyl-2-oxo-4-phenethyl-1,2,3,4-tetrahydropyrim-
dine-5-carboxylate (5m)
idine-5-carboxylate (5q)
20
20
Yield: 19 mg (45%); white solid; mp 191–193 °C; [α]D +130 (c 0.3,
Yield: 37 mg (68%); white solid; mp 160–162 °C; [α]D +120 (c 0.3,
CH2Cl2).
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (20:80 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 6.9 min,
tR (major) = 9.3 min; 90% ee.
The ee was determined by HPLC analysis: Chiralpak AS-RH;
MeCN/H2O (40:60 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 5.5 min,
tR (major) = 8.2 min; 99% ee.
1H NMR (600 MHz, CDCl3): δ = 7.39 (s, 1 H), 5.59 (s, 1 H), 4.23 (s, 1 H),
3.71 (s, 3 H), 2.29 (s, 3 H), 1.89–1.86 (m, 2 H), 0.92 (d, J = 6.6 Hz, 3 H),
0.86 (d, J = 6.6 Hz, 3 H).
1H NMR (600 MHz, CDCl3): δ = 8.30 (s, 1 H), 7.27–7.25 (m, 2 H), 7.18–
7.16 (m, 3 H), 6.06 (s, 1 H), 4.34 (s, 1 H), 3.89 (s, 3 H), 2.77–2.74 (m, 1
H), 2.66–2.61 (m, 1 H), 2.28 (s, 3 H), 1.93–1.88 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 166.5, 153.9, 146.8, 100.4, 57.1, 51.2,
13C NMR (150 MHz, CDCl3): δ = 166.2, 154.6, 147.3, 141.0, 128.4,
34.3, 18.4, 15.5.
128.3, 126.0, 101.1, 51.1, 38.2, 30.6, 18.7.
HRMS: m/z calcd for C10H17N2O3 [M + H]+: 213.1234; found: 213.1237.
HRMS: m/z calcd for C15H19N2O3 [M + H]+: 275.1390; found: 275.1397.
Methyl (R)-4-Isobutyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
Ethyl (R)-6-Methyl-2-oxo-4-phenethyl-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (5n)
dine-5-carboxylate (5r)
20
20
Yield: 32 mg (70%); white solid; mp 153–155 °C; [α]D +129 (c 0.3,
Yield: 37 mg (65%); white solid; mp 173–175 °C; [α]D +105 (c 0.3,
CH2Cl2).
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak AD-RH;
MeCN/H2O (30:70 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 5.9 min,
tR (major) = 7.3 min; 94% ee.
The ee was determined by HPLC analysis: Chiralpak AS-RH;
MeCN/H2O (40:60 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 6.5 min,
tR (major) = 9.9 min; 98% ee.
1H NMR (600 MHz, CDCl3): δ = 8.34 (s, 1 H), 5.96 (s, 1 H), 4.31 (dt,
J = 10.2, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.27 (s, 3 H), 1.72–1.68 (m, 1 H),
1.59–1.54 (m, 1 H), 1.28–1.24 (m, 1 H), 0.92 (d, J = 2.4 Hz, 3 H), 0.91
(d, J = 2.4 Hz, 3 H).
1H NMR (600 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.28–7.26 (m, 2 H), 7.19–
7.17 (m, 3 H), 5.95 (s, 1 H), 4.35 (dt, J = 7.8, 3.6 Hz, 1 H), 4.20–4.10 (m,
2 H), 2.79–2.74 (m, 1 H), 2.66–2.61 (m, 1 H), 2.29 (s, 3 H), 1.96–1.85
(m, 2 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.3, 154.6, 146.9, 102.1, 51.1, 49.5,
13C NMR (150 MHz, CDCl3): δ = 165.7, 154.4, 147.0, 141.0, 128.4,
45.6, 23.6, 23.5, 21.0, 18.5.
128.3, 126.0, 101.5, 59.9, 51.0, 38.1, 30.7, 18.6, 14.3.
HRMS: m/z calcd for C11H19N2O3 [M + H]+: 227.1390; found: 227.1394.
HRMS: m/z calcd for C16H21N2O3 [M + H]+: 289.1547; found: 289.1549.
Methyl (R)-4-Butyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
Isopropyl (R)-6-Methyl-2-oxo-4-phenethyl-1,2,3,4-tetrahydropy-
dine-5-carboxylate (5o)
rimidine-5-carboxylate (5s)
Yield: 27 mg (60%); white solid; mp 143–145 °C; [α]D18 +145 (c 0.55,
Yield: 36 mg (60%); white solid; mp 195–197 °C; [α]D20 +110 (c 0.15,
CH2Cl2).
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak AD-RH;
MeCN/H2O (30:70 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 6.7 min,
tR (major) = 11.1 min; >99% ee.
The ee was determined by HPLC analysis: Chiralpak AS-RH;
MeCN/H2O (40:60 v/v), 1.0 mL/min, l = 280 nm; tR (minor) = 7.7 min,
tR (major) = 12.5 min; 97% ee.
1H NMR (600 MHz, CDCl3): δ = 8.45 (s, 1 H), 6.05 (s, 1 H), 4.28 (dt,
J = 7.8, 3.6 Hz, 1 H), 3.71 (s, 3 H), 2.27 (s, 3 H), 1.58–1.48 (m, 2 H),
1.38–1.24 (m, 4 H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.4, 154.7, 147.0, 101.4, 51.5, 51.1,
36.6, 26.4, 22.4, 18.5, 13.9.
1H NMR (600 MHz, CDCl3): δ = 7.73 (s, 1 H), 7.28 (t, J = 7.8 Hz, 2 H),
7.27 (t, J = 7.8 Hz, 3 H), 5.74 (s, 1 H), 5.08–5.02 (m, 1 H), 4.33 (dt,
J =7.8, 3.6 Hz, 1 H), 2.79–2.74 (m, 1 H), 2.67–2.62 (m, 1 H), 2.29 (s, 3
H), 1.96–1.84 (m, 2 H), 1.23 (d, J = 6.0 Hz, 3 H), 1.22 (d, J = 6.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 165.1, 154.1, 146.6, 141.0, 128.5,
128.3, 126.0, 101.8, 67.3, 51.0, 38.1, 30.7, 22.0, 21.9, 18.6.
HRMS: m/z calcd for C17H23N2O3 [M + H]+: 303.1703; found: 303.1706.
HRMS: m/z calcd for C11H19N2O3 [M + H]+: 227.1390; found: 227.1394.
Methyl (R)-4-Cyclohexyl-6-methyl-2-oxo-1,2,3,4-tetrahydropy-
rimidine-5-carboxylate (5p)
tert-Butyl (R)-6-Methyl-2-oxo-4-phenethyl-1,2,3,4-tetrahydropy-
20
rimidine-5-carboxylate (5t)
Yield: 30 mg (60%); white solid; mp 224–226 °C; [α]D +111 (c 0.2,
20
CH2Cl2).
Yield: 32 mg (50%); white solid; 173–175 °C; [α]D +115 (c 0.3,
CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (40:60 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 4.5 min,
tR (major) = 5.4 min; 97% ee.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

I
Y. Guo et al.
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Synthesis
The ee was determined by HPLC analysis: Chiralpak AS-RH;
MeCN/H2O (40:60 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 5.1 min,
tR (major) = 8.4 min; 99% ee.
Methyl (R)-3-Heptyl-1-oxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (6d) Yield: 123 mg (42%); colorless oil;
[α]D20 +142 (c 0.2, CH2Cl2).
1H NMR (600 MHz, CDCl3): δ = 7.53 (s, 1 H), 7.27 (t, J = 7.8 Hz, 2 H),
7.18 (t, J = 7.8 Hz, 3 H), 5.67 (s, 1 H), 4.29 (dt, J = 8.4, 3.0 Hz, 1 H), 2.78–
2.73 (m, 1 H), 2.65–2.60 (m, 1 H), 2.25 (s, 3 H), 1.95–1.83 (m, 2 H),
1.45 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 165.0, 154.1, 145.7, 141.2, 128.5,
128.3, 126.0, 102.9, 80.4, 51.4, 38.3, 30.9, 28.3, 18.6.
The ee was determined by HPLC analysis: Chiralpak OD-H; MeCN/H2O
(60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 4.9 min, tR (major) =
6.8 min; 99% ee.
1H NMR (600 MHz, CDCl3): δ = 5.48 (s, 1 H), 4.27 (dt, J = 7.2, 3.6 Hz, 1
H), 3.71 (s, 3 H), 3.72–3.65 (m, 2 H), 3.20 (ddd, J = 18.0, 8.0, 4.2 Hz, 1
H), 3.00 (dt, J = 18.0, 8.0 Hz, 1 H), 2.06–1.91 (m, 2 H), 1.55–1.48 (m, 2
H), 1.38–1.24 (m, 10 H), 0.86 (t, J = 7.2 Hz, 3 H).
HRMS: m/z calcd for C18H25N2O3 [M + H]+: 317.1860; found: 317.1866.
13C NMR (150 MHz, CDCl3): δ = 166.2, 153.9, 153.1, 98.4, 51.9, 51.0,
46.6, 37.1, 31.9, 31.8, 29.2, 29.2, 24.4, 22.6, 21.4, 14.1.
HRMS: m/z calcd for C16H27N2O3 [M + H]+: 295.2016; found: 295.2029.
Bicyclic Intermediates 6; General Procedure
After stirring a solution of the respective 4-alkyl-DHPMs 5b–j (1
mmol) in anhyd THF (10 mL) under N2 atmosphere at –20 °C, n-BuLi
(2.4 M solution in hexanes, 2.1 mL, 5 mmol) was added dropwise at
–20 °C. After the addition, the reaction mixture was warmed to r.t.
and stirred for an additional 1 h. Then 1-bromo-2-chloroethane (6
mmol) was added dropwise using a cannula at r.t. and the mixture
was stirred at r.t. for 3 h. Afterwards, sat. aq NH4Cl was introduced to
terminate the reaction. The mixture was extracted with Et2O (3 × 25
mL), and the combined organic layers were sequentially washed with
brine and H2O, dried (anhyd Na2SO4), and filtered. After evaporating
the excess of solvent, the resulting orange gum was purified by col-
umn chromatography on a silica gel column [eluent: hexane/EtOAc (3:1)]
to afford the respective bicyclic intermediate 6b–j as a colorless oil.
Methyl (R)-3-Octyl-1-oxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (6e) Yield: 139 mg (45%); colorless oil;
[α]D15 +134 (c 0.2, CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 6.1 min,
tR (major) = 8.8 min; >99% ee.
1H NMR (600 MHz, CDCl3): δ = 5.43 (s, 1 H), 4.27 (dt, J = 7.2, 3.6 Hz, 1
H), 3.71 (s, 3 H), 3.73–3.66 (m, 2 H), 3.20 (ddd, J = 18.0, 8.0, 4.2 Hz, 1
H), 3.01 (dt, J = 18.0, 8.0 Hz, 1 H), 2.05–1.93 (m, 2 H), 1.54–1.48 (m, 2
H), 1.42–1.25 (m, 12 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.2, 153.9, 153.2, 98.4, 51.9, 51.0,
46.6, 37.2, 31.9, 31.8, 29.5, 29.3, 29.2, 24.4, 22.6, 21.4, 14.1.
HRMS: m/z calcd for C17H29N2O3 [M + H]+: 309.2173; found: 309.2185.
Methyl (R)-1-Oxo-3-pentyl-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (6b)
Yield: 101 mg (38%); colorless oil; [α]D20 +176 (c 0.35, CH2Cl2).
Methyl (R)-3-Nonyl-1-oxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (6f) Yield: 129 mg (40%); colorless oil;
[α]D20 +130 (c 0.4, CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-H; MeCN/H2O
(40:60 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 5.5 min, tR (major) =
6.9 min; 99% ee.
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, l = 280 nm; tR (minor) = 7.7 min,
tR (major) = 10.9 min; >99% ee.
1H NMR (600 MHz, CDCl3): δ = 5.59 (s, 1 H), 4.27 (dt, J = 6.0, 3.0 Hz, 1
H), 3.70 (s, 3 H), 3.71–3.65 (m, 2 H), 3.20 (ddd, J = 18.0, 8.0, 4.2 Hz, 1
H), 3.01 (dt, J = 18.0, 8.0 Hz, 1 H), 2.05–1.91 (m, 2 H), 1.53–1.49 (m, 2
H), 1.37–1.23 (m, 14 H), 0.86 (t, J = 7.2 Hz, 3 H).
1H NMR (600 MHz, CDCl3): δ = 5.45 (s, 1 H), 4.28 (dt, J = 7.2, 3.6 Hz, 1
H), 3.71 (s, 3 H), 3.73–3.67 (m, 2 H), 3.20 (ddd, J = 18.0, 8.4, 4.2 Hz, 1
H), 3.01 (dt, J = 18.0, 8.0 Hz, 1 H), 2.05–1.92 (m, 2 H), 1.55–1.48 (m, 2
H), 1.38–1.21 (m, 6 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.3, 153.9, 153.2, 98.4, 51.9, 51.1,
46.6, 37.1, 31.9, 31.4, 24.0, 22.6, 21.4, 14.0.
HRMS: m/z calcd for C14H23N2O3 [M + H]+: 267.1703; found: 267.1718.
13C NMR (150 MHz, CDCl3): δ = 166.2, 153.9, 153.2, 98.4, 51.8, 51.0,
46.6, 37.1, 31.9, 31.8, 29.5, 29.5, 29.3, 29.3, 24.4, 22.6, 21.4, 14.1.
HRMS: m/z calcd for C18H31N2O3 [M + H]+: 323.2329; found: 323.2340.
Methyl (R)-3-Hexyl-1-oxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (6c)
Yield: 112 mg (40%); colorless oil; [α]D15 +161 (c 0.44, CH2Cl2).
Methyl (R)-3-Decyl-1-oxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (6g)
Yield: 144 mg (43%); colorless oil; [α]D20 +128 (c 0.1, CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-H; MeCN/H2O
(60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 5.0 min, tR (major) =
5.8 min; 98% ee.
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, l = 280 nm; tR (minor) = 9.9 min,
tR (major) = 14.7 min; 99% ee.
1H NMR (600 MHz, CDCl3): δ = 5.29 (s, 1 H), 4.27 (s, 1 H), 3.71 (s, 3 H),
3.73–3.66 (m, 2 H), 3.20 (ddd, J = 18.0, 8.0, 4.2 Hz, 1 H), 3.01 (dt,
J = 18.0, 8.0 Hz, 1 H), 2.06–1.92 (m, 2 H), 1.54–1.48 (m, 2 H), 1.37–1.24
(m, 16 H), 0.87 (d, J = 7.2 Hz, 3 H).
1H NMR (600 MHz, CDCl3): δ = 5.58 (s, 1 H), 4.27 (s, 1 H), 3.71 (s, 3 H),
3.72–3.65 (m, 2 H), 3.20 (ddd, J = 18.0, 8.0, 4.0 Hz, 1 H), 3.00 (dt,
J = 18.0, 8.0 Hz, 1 H), 2.05–1.92 (m, 2 H), 1.55–1.46 (m, 2 H), 1.38–1.21
(m, 8 H), 0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.3, 154.0, 153.3, 98.4, 51.9, 51.1,
46.6, 37.2, 32.0, 31.8, 29.7, 29.0, 24.4, 22.6, 21.4, 14.1.
HRMS: m/z calcd for C15H25N2O3 [M + H]+: 281.1560; found: 281.1878.
13C NMR (150 MHz, CDCl3): δ = 166.2, 153.9, 153.1, 98.4, 51.92, 51.1,
50.8, 46.6, 37.2, 31.9, 31.9, 29.7, 29.6, 29.5, 29.3, 29.3, 24.4, 22.7, 14.1.
HRMS: m/z calcd for C19H33N2O3 [M + H]+: 337.2486; found: 337.2496.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

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Y. Guo et al.
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Synthesis
Methyl (R)-1-Oxo-3-undecyl-1,2,3,5,6,7-hexahydropyrrolo[1,2-
c]pyrimidine-4-carboxylate (6h) Yield: 137 mg (39%); colorless oil;
[α]D20 +125 (c 0.7, CH2Cl2).
Methyl (R)-1-Ethoxy-3-pentyl-3,5,6,7-tetrahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (7b)
Yield: 126 mg (86%); colorless oil; [α]D15 +148 (c 0.4, MeOH).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 12.9
min, tR (major) = 18.6 min; 98% ee.
1H NMR (600 MHz, CDCl3): δ = 5.45 (s, 1 H), 4.27 (dd, J = 7.2, 3.6 Hz, 1
H), 3.70 (s, 3 H), 3.73–3.66 (m, 2 H), 3.20 (ddd, J = 18.0, 8.0, 4.2 Hz, 1
H), 3.01 (dt, J = 18.0, 8.0 Hz, 1 H), 2.06–1.92 (m, 2 H), 1.55–1.48 (m, 2
H), 1.38–1.24 (m, 18 H), 0.86 (d, J = 7.2 Hz, 3 H).
1H NMR (600 MHz, CDCl3): δ = 4.47 (dd, J = 6.0, 4.8 Hz, 1 H), 4.20 (dq,
J = 10.8, 7.2 Hz, 1 H), 4.12 (dq, J = 10.8, 7.2 Hz, 1 H), 3.66 (s, 3 H), 3.65–
3.61 (m, 1 H), 3.47–3.43 (m, 1 H), 3.16 (ddd, J = 18.0, 8.4, 3.0 Hz, 1 H),
2.86 (dt, J = 18.6, 9.0 Hz, 1 H), 2.02–1.85 (m, 2 H), 1.47–1.37 (m, 3 H),
1.30–1.21 (m, 8 H), 0.85 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.5, 149.8, 97.4, 62.4, 55.0,
50.6, 47.4, 37.8, 32.0, 31.0, 24.3, 22.7, 21.8, 14.3, 14.1.
13C NMR (150 MHz, CDCl3): δ = 166.2, 153.9, 153.1, 98.4, 51.9, 51.0,
46.6, 37.2, 31.9, 31.9, 29.6, 29.6, 29.5, 29.3, 29.3, 24.4, 22.7, 21.4, 14.1.
HRMS: m/z calcd for C16H27N2O3 [M + H]+: 295.2016; found: 295.2018.
HRMS: m/z calcd for C20H35N2O3 [M + H]+: 351.2642; found: 351.2659.
Methyl (R)-1-Ethoxy-3-hexyl-3,5,6,7-tetrahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (7c)
Yield: 137 mg (89%); colorless oil; [α]D16 +138 (c 0.4, MeOH).
Methyl (R)-3-Dodecyl-1-oxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-
c]pyrimidine-4-carboxylate (6i) Yield: 164 mg (45%); colorless oil;
[α]D20 +109 (c 0.32, CH2Cl2).
1H NMR (600 MHz, CDCl3): δ = 4.47 (dd, J = 6.0, 4.8 Hz, 1 H), 4.20 (dq,
J = 10.8, 7.2 Hz, 1 H), 4.12 (dq, J = 10.8, 7.2 Hz, 1 H), 3.66 (s, 3 H), 3.65–
3.61 (m, 1 H), 3.47–3.43 (m, 1 H), 3.16 (ddd, J = 18.0, 8.4, 3.0 Hz, 1 H),
2.86 (dt, J = 18.6, 9.0 Hz, 1 H), 2.02–1.85 (m, 2 H), 1.47–1.37 (m, 3 H),
1.29–1.24 (m, 10 H), 0.85 (t, J = 7.2 Hz, 3 H).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (60:40 v/v), 1.0 mL/min, λ = 280 nm; tR (minor) = 18.6
min, tR (major) = 23.7 min; 98% ee.
1H NMR (600 MHz, CDCl3): δ = 5.75 (s, 1 H), 4.27 (s, 1 H), 3.70 (s, 3 H),
3.73–3.64 (m, 2 H), 3.20 (ddd, J = 18.0, 8.4, 4.2 Hz, 1 H), 3.01 (dt,
J = 18.0, 8.0 Hz, 1 H), 2.05–1.90 (m, 2 H), 1.54–1.48 (m, 2 H), 1.37–1.19
(m, 20 H), 0.86 (d, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.6, 149.8, 97.4, 62.4, 55.0,
50.6, 47.4, 37.9, 31.9, 31.0, 29.5, 24.6, 22.7, 21.8, 14.3, 14.1.
HRMS: m/z calcd for C17H29N2O3 [M + H]+: 309.2173; found: 309.2182.
13C NMR (150 MHz, CDCl3): δ = 166.2, 153.9, 153.3, 98.4, 51.8, 51.0,
46.5, 37.1, 31.9, 31.9, 29.6, 29.6, 29.6, 29.6, 29.5, 29.3, 29.3, 24.4, 22.6,
21.4, 14.1.
Methyl (R)-1-Ethoxy-3-heptyl-3,5,6,7-tetrahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (7d)
Yield: 143 mg (89%); colorless oil; [α]D25 +122 (c 0.5, MeOH).
1H NMR (600 MHz, CDCl3): δ = 4.47 (dd, J = 6.0, 4.8 Hz, 1 H), 4.20 (dq,
J = 10.8, 7.2 Hz, 1 H), 4.12 (dq, J = 10.8, 7.2 Hz, 1 H), 3.67 (s, 3 H), 3.65–
3.62 (m, 1 H), 3.48–3.43 (m, 1 H), 3.16 (ddd, J = 18.0, 8.4, 3.0 Hz, 1 H),
2.87 (dt, J = 18.6, 9.0 Hz, 1 H), 2.03–1.85 (m, 2 H), 1.46–1.35 (m, 3 H),
1.30–1.24 (m, 12 H), 0.85 (t, J = 7.2 Hz, 3 H).
HRMS: m/z calcd for C21H37N2O3 [M + H]+: 365.2799; found: 365.2810.
Methyl (R)-3-[9-(tert-Butyldimethylsilyl)nonyl]-1-oxo-1,2,3,5,6,7-
hexahydropyrrolo[1,2-c]pyrimidine-4-carboxylate (6j)
Yield: 203 mg (45%); colorless oil; [α]D22 +102 (c 1.0, CH2Cl2).
The ee was determined by HPLC analysis: Chiralpak OD-RH;
MeCN/H2O (70:30 v/v), 1.0 mL/min, l = 280 nm; tR (minor) = 9.7 min,
tR (major) = 12.4 min; 99% ee.
1H NMR (600 MHz, CDCl3): δ = 5.44 (s, 1 H), 4.27 (dt, J = 7.2, 3.6 Hz, 1
H), 3.71 (s, 3 H), 3.70–3.66 (m, 2 H), 3.58 (t, J = 6.6 Hz, 2 H), 3.20 (ddd,
J = 18.6, 8.4, 4.8 Hz, 1 H), 3.01 (dt, J = 18.6, 9.0 Hz, 1 H), 2.03–1.94 (m,
2 H), 1.52–1.46 (m, 4 H), 1.36–1.25 (m, 12 H), 0.88 (d, J = 2.7 Hz, 9 H),
0.03 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.6, 149.8, 97.4, 62.4, 55.0,
50.6, 47.4, 37.9, 31.9, 31.0, 29.7, 29.3, 24.7, 22.6, 21.8, 14.3, 14.1.
HRMS: m/z calcd for C18H31N2O3 [M + H]+: 323.2329; found: 323.2336.
Methyl (R)-1-Ethoxy-3-octyl-3,5,6,7-tetrahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (7e)
Yield: 143 mg (85%); colorless oil; [α]D25 +125 (c 0.25, MeOH).
1H NMR (600 MHz, CDCl3): δ = 4.48 (dd, J = 6.0, 4.8 Hz, 1 H), 4.21 (dq,
J = 10.8, 7.2 Hz, 1 H), 4.13 (dq, J = 10.8, 7.2 Hz, 1 H), 3.67 (s, 3 H), 3.66–
3.62 (m, 1 H), 3.48–3.43 (m, 1 H), 3.17 (ddd, J = 18.0, 8.4, 3.0 Hz, 1 H),
2.87 (dt, J = 18.6, 9.0 Hz, 1 H), 2.03–1.86 (m, 2 H), 1.45–1.41 (m, 3 H),
1.30–1.20 (m, 14 H), 0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.2, 153.9, 153.1, 98.4, 63.3, 51.9,
51.0, 46.6, 37.2, 32.8, 31.9, 29.6, 29.5, 29.4, 29.3, 26.0, 25.7, 24.4, 21.4,
18.3, –5.3.
HRMS: m/z calcd for C24H45N2O4Si [M + H]+: 453.3143; found:
453.3149.
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.6, 149.9, 97.5, 62.5, 55.1,
47.4, 37.9, 31.9, 31.0, 29.8, 29.6, 29.3, 24.7, 22.7, 22.6, 21.8, 14.4, 14.1.
HRMS: m/z calcd for C19H33N2O3 [M + H]+: 337.2486; found: 337.2496.
Intermediates 7b–j; General Procedure
To a mixture of the respective bicyclic intermediate 6b–j (0.5 mmol)
and NaHCO3 (168 mg, 2.0 mmol) in anhyd CH2Cl2 (10 mL) was added
dropwise Et3O+BF4– (0.2 M CH2Cl2 solution, 5 mL, 1.0 mmol) under N2
atmosphere at r.t. The resulting solution was stirred at r.t. for 0.5 h
and then H2O (20 mL) was added at r.t. The aqueous layer was extract-
ed with CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with brine (10 mL), dried (anhyd Na2SO4), and filtered. After the ex-
cess solvent was evaporated, the resulting orange gum was purified
by column chromatography on a silica gel column [eluting with hex-
ane/EtOAc (6:1)] to obtain the respective intermediate 7b–j as a col-
orless oil.
Methyl (R)-1-Ethoxy-3-nonyl-3,5,6,7-tetrahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (7f)
Yield: 152 mg (87%); colorless oil; [α]D23 +131 (c 0.5, MeOH).
1H NMR (600 MHz, CDCl3): δ = 4.45 (dd, J = 6.0, 4.8 Hz, 1 H), 4.18 (dq,
J = 10.8, 7.2 Hz, 1 H), 4.10 (dq, J = 10.8, 7.2 Hz, 1 H), 3.61 (ddd, J = 10.8,
8.4, 3.0 Hz, 1 H), 3.44 (td, J = 10.0, 7.2 Hz, 1 H), 3.14 (ddd, J = 18.6, 9.0,
3.0 Hz, 1 H), 2.85 (dt, J = 18.6, 9.0 Hz, 1 H), 2.09–1.75 (m, 2 H), 1.50–
1.33 (m, 3 H), 1.36–1.13 (m, 18 H), 0.84 (t, J = 7.2 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

K
Y. Guo et al.
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Synthesis
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.5, 149.8, 97.4, 62.3, 55.0,
50.6, 47.3, 37.8, 31.8, 31.0, 29.7, 29.6, 29.6, 29.3, 24.6, 22.6, 21.8, 14.3,
14.0.
Bicyclic Guanidine Core of Crambescin A 8b–i and Batzelladine A
8j Trifluoroacetate Salts; General Procedure
A mixture of the respective 7b–j (0.3 mmol) and ammonium propio-
nate (1.0 g, 11 mmol) was stirred at 80 °C under N2 atmosphere for 3
h and then the mixture was concentrated under reduced pressure.
The resulting orange gum was purified by column chromatography
on a silica gel column [eluent: EtOAc/MeOH/CF3CO2H (100:10:1)] to
obtain the respective trifluoroacetate salt 8b–j as a colorless oil.
HRMS: m/z calcd for C20H35N2O3 [M + H]+: 351.2642; found: 351.2654.
Methyl (R)-3-Decyl-1-ethoxy-3,5,6,7-tetrahydropyrrolo[1,2-c]py-
rimidine-4-carboxylate (7g)
Yield: 137 mg (75%); colorless oil; [α]D25 +114 (c 0.25, MeOH).
1H NMR (600 MHz, CDCl3): δ = 4.48 (dd, J = 6.0, 4.8 Hz, 1 H), 4.21 (dq,
J = 10.8, 7.2 Hz, 1 H), 4.13 (dq, J = 10.8, 7.2 Hz, 1 H), 3.67 (s, 3 H), 3.65–
3.62 (m, 1 H), 3.48–3.44 (m, 1 H), 3.16 (ddd, J = 18.0, 8.4, 3.0 Hz, 1 H),
2.87 (dt, J = 18.6, 9.0 Hz, 1 H), 2.02–1.86 (m, 2 H), 1.45–1.39 (m, 3 H),
1.30–1.24 (m, 18 H), 0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.5, 149.9, 97.5, 62.5, 55.0,
50.6, 47.4, 37.9, 31.9, 31.0, 29.8, 29.7, 29.7, 29.6, 29.3, 24.7, 22.7, 21.8,
14.4, 14.1.
(+)-Crambescin A Methyl Ester 8b (R = n-C5H11
)
18
Yield: 70 mg (61%); colorless oil; [α]D +55 (c 0.50, MeOH, CF3CO2H
salt).
1H NMR (600 MHz, CDCl3): δ = 9.92 (s, 1 H), 5.94 (s, 1 H), 4.44 (s, 1 H),
3.85 (t, J = 8.4 Hz, 1 H), 3.75 (s, 3 H), 3.68 (dd, J = 11.4, 8.4 Hz, 1 H),
3.34 (ddd, J = 18.0, 8.4, 3.0 Hz, 1 H), 2.95 (dt, J = 18.6, 9.6 Hz, 1 H),
2.26–2.20 (m, 1 H), 2.13–2.06 (m, 1 H), 1.58–1.48 (m, 2 H), 1.40–1.22
(m, 6 H), 0.87 (t, J = 7.2 Hz, 3 H).
HRMS: m/z calcd for C21H37N2O3 [M + H]+: 365.2799; found: 365.2807.
13C NMR (150 MHz, CDCl3): δ = 165.0, 151.9, 150.3, 102.5, 51.7, 50.1,
47.4, 36.6, 31.3, 30.7, 23.6, 22.4, 21.9, 13.9.
HRMS: m/z calcd for C14H24N3O2 [M + H]+: 266.1863; found: 266.1870.
Methyl (R)-1-Ethoxy-3-undecyl-3,5,6,7-tetrahydropyrrolo[1,2-
c]pyrimidine-4-carboxylate (7h) Yield: 187 mg (99%); colorless oil;
[α]D25 +115 (c 0.8, MeOH).
(+)-Crambescin A Methyl Ester 8c (R = n-C6H13
)
1H NMR (600 MHz, CDCl3): δ = 4.47 (dd, J = 6.0, 4.8 Hz, 1 H), 4.20 (dq,
J = 10.8, 7.2 Hz, 1 H), 4.13 (dq, J = 10.8, 7.2 Hz, 1 H), 3.67 (s, 3 H), 3.64
(ddd, J = 10.8, 8.0, 3.0 Hz, 1 H), 3.52–3.39 (m, 1 H), 3.16 (ddd, J = 18.6,
8.4, 3.0 Hz, 1 H), 2.87 (dt, J = 18.6, 9.0 Hz, 1 H), 2.05–1.86 (m, 2 H),
1.55–1.36 (m, 3 H), 1.31–1.21 (m, 20 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.6, 149.8, 97.4, 62.4, 55.1,
50.6, 47.4, 37.9, 31.9, 31.0, 29.8, 29.7, 29.7, 29.7, 29.6, 29.3, 24.7, 22.7,
21.8, 14.4, 14.1.
20
Yield: 77 mg (65%); colorless oil; [α]D +50 (c 0.35, MeOH, CF3CO2H
salt).
1H NMR (600 MHz, CDCl3): δ = 10.11 (s, 1 H), 4.42 (dt, J = 7.2, 3.6 Hz, 1
H), 3.85 (t, J = 8.4 Hz 1 H), 3.74 (s, 3 H), 3.68 (dd, J = 11.4, 8.4 Hz, 1 H),
3.33 (ddd, J = 18.0, 8.4, 3.0 Hz, 1 H), 2.93 (dt, J = 18.6, 9.6, 1 H), 2.25–
2.19 (m, 1 H), 2.10–2.05 (m, 1 H), 1.57–1.49 (m, 2 H), 1.36–1.24 (m, 8
H), 0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 165.1, 152.0, 150.4, 102.3, 51.6, 50.0,
HRMS: m/z calcd for C22H39N2O3 [M + H]+: 379.2955; found: 379.2961.
47.4, 36.7, 31.5, 30.7, 28.8, 23.9, 22.5, 21.8, 14.0.
Methyl (R)-3-Dodecyl-1-ethoxy-3,5,6,7-tetrahydropyrrolo[1,2-
c]pyrimidine-4-carboxylate (7i) 147mg, yield 75%; colorless oil,
[α]D25 +112 (c 0.48, MeOH).
HRMS: m/z calcd for C15H26N3O2 [M + H]+: 280.2020; found: 280.2027.
(+)-Crambescin A Methyl Ester 8d (R = n-C7H15
)
1H NMR (600 MHz, CDCl3): δ = 4.47 (dd, J = 6.0, 4.8 Hz, 1 H), 4.21 (dq,
J = 10.8, 7.2 Hz, 1 H), 4.13 (dq, J = 10.8, 7.2 Hz, 1 H), 3.67 (s, 3 H), 3.64
(ddd, J = 10.8, 8.4, 3.0 Hz, 1 H), 3.46 (td, J = 10.8, 7.2 Hz, 1 H), 3.16
(ddd, J = 18.6, 8.4, 3.0 Hz, 1 H), 2.87 (dt, J = 18.6, 9.0 Hz, 1 H), 2.03–
1.85 (m, 2 H), 1.48–1.36 (m, 3 H), 1.33–1.20 (m, 22 H), 0.87 (t, J = 7.2
Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.6, 149.8, 97.4, 62.4, 55.1,
50.7, 47.4, 37.9, 31.9, 31.0, 29.8, 29.7, 29.7, 29.7, 29.6, 29.3, 24.7, 22.7,
21.8, 14.4, 14.1.
21
Yield: 73 mg (60%); colorless oil; [α]D +47 (c 0.20, MeOH, CF3CO2H
salt).
1H NMR (600 MHz, CDCl3): δ = 10.12 (s, 1 H), 4.43 (s, 1 H), 3.87 (t,
J = 8.4 Hz, 1 H), 3.75 (s, 3 H), 3.69 (dd, J = 11.4, 8.4 Hz, 1 H), 3.33 (ddd,
J = 18.0, 8.4, 3.0 Hz, 1 H), 2.94 (dt, J = 18.6, 9.6 Hz, 1 H), 2.25–2.19 (m,
1 H), 2.13–2.06 (m, 1 H), 1.58–1.48 (m, 2 H), 1.40–1.25 (m, 10 H), 0.87
(t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 165.1, 152.0, 150.4, 102.3, 51.6, 50.1,
47.4, 36.7, 31.7, 30.7, 29.1, 29.0, 23.9, 22.6, 21.8, 14.0.
HRMS: m/z calcd for C23H41N2O3 [M + H]+: 393.3112; found: 393.3116.
HRMS: m/z calcd for C16H28N3O2 [M + H]+: 294.2176; found: 294.2177.
Methyl (R)-3-[9-(tert-Butyldimethylsilyl)nonyl]-1-ethoxy-3,5,6,7-
tetrahydropyrrolo[1,2-c]pyrimidine-4-carboxylate (7j)
Yield: 192 mg (80%); colorless oil; [α]D23 +75 (c 0.10, MeOH).
(+)-Crambescin A Methyl Ester 8e (R = n-C8H17
)
22
Yield: 82 mg (65%); colorless oil; [α]D +51 (c 0.34, MeOH, CF3CO2H
salt).
1H NMR (600 MHz, CDCl3): δ = 4.49 (dd, J = 5.4, 4.8 Hz, 1 H), 4.23–4.10
(m, 2 H), 3.68 (s, 3 H), 3.66–3.63 (m, 1 H), 3.59 (t, J = 6.6 Hz, 2 H),
3.49–3.45 (m, 1 H), 3.17 (ddd, J = 18.6, 8.4, 3.0 Hz, 1 H), 2.88 (dt,
J = 18.6, 9.0 Hz, 1 H), 2.01–1.90 (m, 2 H), 1.52–1.40 (m, 4 H), 1.31–1.26
(m, 15 H), 0.89 (s, 9 H), 0.04 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 167.4, 154.5, 149.9, 97.5, 63.3, 62.5,
55.0, 50.7, 47.4, 37.9, 32.9, 31.0, 29.8, 29.7, 29.6, 29.5, 26.0, 25.8, 24.7,
21.8, 18.4, 14.4, –5.3.
1H NMR (600 MHz, CDCl3): δ = 10.08 (s, 1 H), 4.44 (s, 1 H), 3.85 (s, 1
H), 3.75 (s, 3 H), 3.69 (s, 1 H), 3.34 (ddd, J = 18.0, 8.4, 3.0 Hz, 1 H), 2.95
(dt, J = 18.6, 9.6 Hz, 1 H), 2.25–2.20 (m, 1 H), 2.13–2.04 (m, 1 H), 1.58–
1.46 (m, 2 H), 1.37–1.24 (m, 12 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 165.0, 152.0, 150.4, 102.4, 51.7, 50.1,
47.4, 36.7, 31.8, 30.7, 29.3, 29.2, 23.9, 22.6, 21.8, 14.1.
HRMS: m/z calcd for C17H30N3O2 [M + H]+: 308.2333; found: 308.2343.
HRMS: m/z calcd for C26H49N2O4Si [M + H]+: 481.3456; found:
481.3478.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

L
Y. Guo et al.
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Synthesis
(+)-Crambescin A Methyl Ester 8f (R = n-C9H19
)
13C NMR (150 MHz, CDCl3): δ = 165.1, 152.0, 150.4, 102.3, 51.6, 50.0,
47.4, 36.7, 31.9, 30.7, 29.6, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 23.9, 22.7,
21.8, 14.1.
24
Yield: 78 mg (60%); colorless oil; [α]D +57 (c 0.29, MeOH, CF3CO2H
salt).
HRMS: m/z calcd for C21H38N3O2 [M + H]+: 364.2959; found: 364.2962.
1H NMR (600 MHz, CDCl3): δ = 10.27 (s, 1 H), 4.43 (dt, J = 7.2, 3.6 Hz, 1
H), 3.86(t, J = 7.8 Hz, 1 H), 3.74 (s, 3 H), 3.69 (dd, J = 13.8, 8.0 Hz, 1 H),
3.33 (ddd, J = 18.6, 8.4, 4.8 Hz, 1 H), 3.00 (dt, J = 18.6, 9.6 Hz, 1 H),
2.25–2.20 (m, 1 H), 2.13–2.04 (m, 1 H), 1.57–1.47 (m, 2 H), 1.37–1.24
(m, 14 H), 0.86 (t, J = 7.2 Hz, 3 H).
Bicyclic Guanidine Core of Batzelladine A 8j (R = n-C9H19
)
Prepared from 8j and ammonium propionate according to the general
procedure; yield: 88 mg (65%); colorless oil; [α]D25 +27 (c 0.5, MeOH,
CF3CO2H salt).
13C NMR (150 MHz, CDCl3): δ = 165.1, 152.0, 150.4, 102.3, 51.6, 50.0,
1H NMR (600 MHz, CDCl3): δ = 10.09 (s, 1 H), 4.41 (s, 1 H), 3.88–3.85
(m, 1 H), 3.75 (s, 3 H), 3.71–3.62 (m, 1 H), 3.33 (ddd, J = 18.6, 8.4, 2.4
Hz, 1 H), 3.09 (s, 1 H), 2.95 (dt, J = 18.6, 9.6 Hz, 1 H), 2.26–2.20 (m, 1
H), 2.12–2.06 (m, 1 H), 1.58–1.50 (m, 4 H), 1.37–1.27 (m, 12 H).
13C NMR (150 MHz, CDCl3): δ = 165.0, 152.0, 150.4, 102.4, 62.98, 51.7,
50.1, 47.4, 36.6, 30.7, 29.1, 29.1, 29.0, 28.9, 25.5, 23.7, 21.9.
47.4, 36.7, 31.8, 30.7, 29.5, 29.4, 29.3, 29.2, 23.9, 22.6, 21.8, 14.1.
HRMS: m/z calcd for C18H32N3O2 [M + H]+: 322.2489; found: 322.2499.
(+)-Crambescin A Methyl Ester 8g (R = n-C10H21
)
24
Yield: 94 mg (70%); colorless oil; [α]D +52 (c 0.5, MeOH, CF3CO2H
salt).
HRMS: m/z calcd for C18H32N3O3 [M + H]+: 338.2438; found: 338.2446.
1H NMR (600 MHz, CDCl3): δ = 10.20 (s, 1 H), 4.43 (dt, J = 7.2, 3.6 Hz, 1
H), 3.86 (t, J = 8.4 Hz, 1 H), 3.75 (s, 3 H), 3.69 (dd, J = 16.8, 8.0 Hz, 1 H),
3.49 (s, 1 H), 3.33 (ddd, J = 18.6, 8.4, 4.8 Hz, 1 H), 3.00 (dt, J = 18.6, 9.6
Hz, 1 H), 2.25–2.20 (m, 1 H), 2.13–2.04 (m, 1 H), 1.58–1.48 (m, 2 H),
1.37–1.24 (m, 16 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 165.1, 152.0, 150.4, 102.3, 51.6, 50.1,
47.4, 36.7, 31.9, 29.6, 29.5, 29.4, 29.3, 29.3, 29.2, 23.9, 22.7, 21.8, 14.1.
Bicyclic Guanidine Core of Batzelladine A 8j (R = n-C9H19) Formic
Acid Salt
A mixture of trifluoroacetate salt 8j (45 mg, 0.1 mmol) and Et3N (20
mg, 0.2 mmol) in anhyd CH2Cl2 (0.5 mL) was stirred at 25 °C under N2
atmosphere for 0.5 h. Formic acid (23 mg, 0.5 mmol) was then added
and the mixture was stirred at 25 °C for 0.5 h. The crude mixture was
purified directly by column chromatography on a silica gel column
[eluting with EtOAc/MeOH/HCO2H (100:10:1)] to obtain 8j formic
acid salt as a colorless oil; yield: 35 mg (91%); [α]D23 +30 (c 0.2, MeOH,
HCO2H salt).
HRMS: m/z calcd for C19H34N3O2 [M + H]+: 366.2645; found: 336.2650.
(+)-Crambescin A Methyl Ester 8h (R = n-C11H23
)
24
Yield: 85 mg (61%); colorless oil; [α]D +56 (c 0.2, MeOH, CF3CO2H
salt).
1H NMR (600 MHz, CDCl3): δ = 10.33 (s, 1 H), 4.43 (dt, J = 7.2, 3.6 Hz, 1
H), 3.86 (td, J = 9.0, 2.4 Hz, 1 H), 3.74 (s, 3 H), 3.69 (dd, J = 17.4, 9.6 Hz,
1 H), 3.33 (ddd, J = 18.6, 8.4, 4.8 Hz, 1 H), 2.94 (dt, J = 18.6, 9.6 Hz, 1 H),
2.24–2.19 (m, 1 H), 2.12–2.05 (m, 1 H), 1.57–1.49 (m, 2 H), 1.37–1.24
(m, 18 H), 0.87 (t, J = 7.2 Hz, 3 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591567.
S
u
p
p
o
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f
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u
p
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ortiInfogrmoaitn
13C NMR (150 MHz, CDCl3): δ = 165.1, 152.0, 150.5, 102.3, 51.6, 50.0,
47.4, 36.7, 31.9, 30.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 23.9, 22.7, 21.8,
14.1.
References
HRMS: m/z calcd for C20H36N3O2 [M + H]+: 350.2802; found: 350.2809.
(1) (a) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.;
DiMarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.; McCarthy,
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(b) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.;
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Dzwonczyk, S.; McMullen, D. M.; Normandin, D. E.; Parham, C.
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Schreiber, S. L.; Mitchison, T. J. Science 1999, 286, 971.
(b) Haggarty, S. J.; Mayer, T. U.; Miyamoto, D. T.; Fathi, R.; King,
R. W.; Mitchison, T. J.; Schreiber, S. L. Chem. Biol. 2000, 7, 275.
(4) Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle,
K. E.; Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.;
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Chem. 2000, 43, 2703.
(+)-Crambescin A Methyl Ester 8h (R = n-C11H23) Formic Acid Salt
A mixture of trifluoroacetate salt 8h (46 mg, 0.1 mmol) and Et3N (20
mg, 0.2 mmol) in anhyd CH2Cl2 (0.5 mL) was stirred at 25 °C under N2
atmosphere for 0.5 h. Formic acid (23 mg, 0.5 mmol) was then added
and the mixture was stirred at 25 °C for 0.5 h. The crude mixture was
purified directly by column chromatography on a silica gel column
[eluent: EtOAc/MeOH/HCO2H (100:10:1)] to obtain 8h formic acid
23
salt as a colorless oil; yield: 38 mg (96%); [α]D +58 (c 0.3, MeOH,
HCO2H salt).
(+)-Crambescin A Methyl Ester 8i (R = n-C12H25
)
Prepared from 7i and ammonium propionate according to the general
procedure; yield: 86 mg (60%); colorless oil; [α]D25 +48 (c 0.3, MeOH,
CF3CO2H salt).
1H NMR (600 MHz, CDCl3): δ = 10.32 (s, 1 H), 4.43 (dt, J = 10.8, 3.6 Hz,
1 H), 3.86 (td, J = 9.0, 2.4 Hz, 1 H), 3.74 (s, 3 H), 3.69 (dd, J = 17.4, 9.6
Hz, 1 H), 3.34 (ddd, J = 18.6, 8.4, 4.8 Hz, 1 H), 2.94 (dt, J = 18.6, 9.6 Hz,
1 H), 2.25–2.20 (m, 1 H), 2.13–2.04 (m, 1 H), 1.58–1.48 (m, 2 H), 1.37–
1.24 (m, 20 H), 0.87 (t, J = 7.2 Hz, 3 H).
(5) (a) Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.;
DeLeon, J.; Heurich, R.; Lichtblau, H.; Shaposhnik, Z.;
Daniewska, I.; Blackburn, T. P.; Branchek, T. A.; Gerald, C.;
Vaysse, P. J.; Forray, C. Nat. Med. 2002, 8, 825. (b) Basso, A. M.;
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M
Y. Guo et al.
Paper
Synthesis
Bratcher, N. A.; Gallagher, K. B.; Cowart, M. D.; Zhao, C.; Sun, M.;
Esbenshade, T. A.; Brune, M. E.; Fox, G. B.; Schmidt, M.; Collins,
C. A.; Souers, A. J.; Iyengar, R.; Vasudevan, A.; Kym, P. R.;
Hancock, A. A.; Rueter, L. E. Eur. J. Pharmacol. 2006, 540, 115.
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C.; Long, M. S. Tetrahedron Lett. 2002, 43, 9191. (c) Shimokawa,
J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew.
Chem. Int. Ed. 2004, 43, 1559. (d) Shimokawa, J.; Ishiwata, T.;
Shirai, K.; Koshino, H.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Chem. Eur. J. 2005, 11, 6878. (e) Arnold, M. A.; Day, K. A.; Durón,
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