Enantioselective Total Synthesis of Chondrosterins I and J by Catalytic Asymmetric Intramolecular Aldol Reaction Using Chiral Diamine Catalyst

Article abstract of DOI:10.1002/ejoc.202000579

The first enantioselective total synthesis of chondrosterins I and J was accomplished. The synthetic method focuses on an intramolecular aldol reaction through catalytic asymmetric desymmetrization using chiral diamine catalyst. An intensive investigation of this reaction improved the enantiomeric excess up to 92 percent ee. In addition, stereoselective reduction of the ketone moiety efficiently converted chondrosterin I to chondrosterin J.

Full text of DOI:10.1002/ejoc.202000579

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Enantioselective total synthesis of chondrosterins I and J via
catalytic asymmetric intramolecular aldol reaction using chiral
diamine catalyst
Authors: Yuichiro Kawamoto, Daiki Ozone, Toyoharu Kobayashi, and
Hisanaka Ito
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000579
Link to VoR: https://doi.org/10.1002/ejoc.202000579
01/2020

10.1002/ejoc.202000579
European Journal of Organic Chemistry
FULL PAPER
Enantioselective total synthesis of chondrosterins I and J via
catalytic asymmetric intramolecular aldol reaction using chiral
diamine catalyst
Yuichiro Kawamoto, [a] Daiki Ozone, [a] Toyoharu Kobayashi, [a] and Hisanaka Ito *[a]
[a]
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: itohisa@toyaku.ac.jp http://www.ls.toyaku.ac.jp/~lbc-11/
Y. Kawamoto Dr., D. Ozone Mr., T. Kobayashi Dr., H. Ito Prof.
Abstract: The first enantioselective total synthesis of chondrosterins
ctivities against human nasopharyngeal cancer cell lines CNE-1
and CNE-2 with IC50 values of 1.32 and 0.56 uM, respectively. In
contrast, 1 shows no activity (IC50 values >200 uM) (Figure 1).
During the course of our synthetic investigations of the
chondrosterin skeleton, we reported a stereoselective synthesis
of racemic 1 using a desymmetric intramolecular aldol reaction.5
In an effort to develop an enantioselective synthesis of the linear
triquinane framework, we focused on an asymmetric
desymmetrization. Here we report in detail an enantioselective
total synthesis of chondrosterin I (1) and J (2) via a catalytic
asymmetric intramolecular aldol reaction, which is different from
that of the racemic synthesis of 1.
I and J was accomplished. The synthetic method focuses on an
intramolecular
aldol
reaction
via
catalytic
asymmetric
desymmetrization using chiral diamine catalyst. An intensive
investigation of this reaction improved the enantiomeric excess up to
92% ee. In addition, stereoselective reduction of the ketone moiety
efficiently converted chondrosterin I to chondrosterin J.
Introduction
A marine fungus, Chondrostereum sp., isolated from a soft
coral Sarcophyton tortuosum yielded chondrosterins I and J as
hirsutane framework sesquiterpenoids in 2014.1-4 The structures
were elucidated through intensive spectroscopic analysis of MS,
NMR and X-ray single-crystal diffraction data. These compounds
possess linear triquinane sesquiterpenes featuring three five-
membered rings fused together in an extended fashion. They
have 3 or 4 stereo-genic centers and an a,b-unsaturated
carboxylic acid. In addition, compound 1 also contains a ketone
moiety while compound 2 is in the reduced form. It should be
noted that these metabolites, chondrosterins I and J, were
obtained from a culture medium containing glycerol as the carbon
source instead of glucose, creating their unique structural
outcome. It is also reported that compound 2 displays cytotoxic a-
Results and Discussion
Tricyclopentanoids have been attracting much attention
because of biological activities and unique appearance.6 Many
examples of their total synthesis have been reported to date.7-10
O
H
O
H
COOH
H
1
2
OH
H
H
CHO
O
OH
9
H
H
H
COOH
H
H
COOH
COOH
chiral
diamine catalyst
chondrosterin I (1)
chondrosterin J (2)
O
H
OH
OH
O
OHC
asymmetric
desymmetrization
O
O
O
O
H
OH
OH
H
10
chondrosterin A (3)
hirsutanol A (4)
incarnal (5)
OH
H
H
O
H
O
O
MeO2C
H
O
O
CO2H
complicatic acid (6)
H
H
H
H
O
OH
O
H
coriolin (7)
capnellane (8)
11
12
Figure 1. Chemical structures of compounds 1, 2 and related natural products.
Scheme 1. Retrosynthetic analysis of 1 and 2.
1
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10.1002/ejoc.202000579
European Journal of Organic Chemistry
FULL PAPER
However, there have been few reports in which the triquinane
skeleton is built by taking advantage of the potential symmetry of
the architecture.11 The summary of our synthetic plan is illustrated
in Scheme 1. The target molecules would be derived from
ketoaldehyde 9 in a 1 or 2-step operation. It was envisioned that
the optically active tricyclic skeleton 9 could be constructed
through an intramolecular aldol reaction of meso diketoaldehyde
10 by means of asymmetric desymmetrization utilizing a chiral
diamine catalyst.12,13 Compound 10 would in turn be synthesized
from compound 11, which could be retrodisconnected to known
a,b-unsaturated ester 12.
duct 18 as a diastereomixture in excellent yield. The resultant
product bearing the nitro group was subjected to oxidative Nef
reaction conditions. Conversion to the a-nitrocarbanion with
NaOMe followed by ozonolysis proceeded smoothly to furnish g-
ketoester 19 in 86% yield as a single diastereomer although
combination of t-BuOK with Oxone® failed to dissatisfactory yield
(Table 2). Cyclization of g-ketoester 19 to diketone 11 was
successful by employing t-BuOK under reflux conditions.
Moreover, addition of 1 equivalent of t-BuOH as a proton source
improved the yield up to 95% (Table 3).
Table 2. Investigation of Nef reaction.
p-ABSA
Et3N
O
O
MeO2C
MeO2C
hv
N2
O
Table
CH3CN
−15 ℃ to rt, 5min
THF/MeOH
rt, 36 h
O
O2N
O
13
14
18
19
62% (2 steps)
entry
reagents
solvents
temp.
rt
time
result
MeO2C
MeO2C
SOCl2
NaBH4
t-BuOK (1.1 eq.)
Oxone® (1.2 eq.)
CH2Cl2/H2O
MeOH
1
2
2 h
5 h
19: 45%
pyridine
rt to 65 ℃, 5 h
MeOH
0 ℃, 30 min
O
HO
NaOMe (1.5 eq.)
O3
19: 86% (dr >95:5)
−78 ℃
15
16
89%
Table 3. Establishment of bicyclic diketone 11.
MeO2C
MeO2C
DBU
O
MeO2C
H
CH2Cl2
rt, 12 h
Table
Cl
17
12
83% (2 steps)
THF
O
O
H
19
11
Scheme 2. Preparation of 12.
entry
reagents
temp.
time
result
To realize our goal, the investigation to synthesize chiral
chondrosterin I and J commenced with the preparation of 12
according to the reported procedure14 as shown in Scheme 2.
After diazotransfer, Wolff rearrangement of 14 took place to afford
b-ketoester 15. The successive 3-step sequence involving typical
hydride reduction, chlorination and dehydrochlorination with a
slight modification of the original produced 12. Next task is to
establish bicyclic diketone 11 with nitro Michael addition15 and
oxidative Nef reaction16 as described in Tables 1, 2 and 3. Table
1 provides the result of investigation of nitro Michael addition. It
shows that amine bases and LHMDS led to recovery of starting
material or decomposition. However, treatment of Michael
acceptor 12 with 1-nitropropane and TBAF as a base afforded ad-
t-BuOK (3 eq.)
1
2
reflux
12 h
2 h
11: 74%
11: 95%
t-BuOK (3 eq.)
t-BuOH (1 eq.)
60 ℃
Scheme 3 illustrates racemic synthesis of compound 1 from
compound 11.5 Installation of the a-chain was executed by a 3-
step procedure. Treatment of 11 with allyl bromide and potassium
fluoride promoted allylation of the diketone to give a mixture of the
O-allylated product 20 in 32% yield and the desired C-allylated
product 21 in 61% yield. The undesired O-allylated 20 was
converted to 21 in 94% yield by Claisen rearrangement upon
heating.17 Cross metathesis of 21 with t-butyl acrylate was
performed by utilizing the second generation Grubbs catalyst18 to
afford unsaturated ester 22 in 82% yield. Compound 22 was
transformed into 23 by hydrogenation. Exposure of 23 to condition
of t-BuOK in THF at −78 ºC gave a satisfactory outcome with the
isolation of the preferable aldol adduct 24 in 75% yield. The
resultant alcohol 24 was subjected to general dehydration
conditions and the subsequent deprotection by TFA easily
proceeded to furnish racemic chondrosterin I (1).
Table 1. Investigation of nitro Michael reaction.
MeO2C
MeO2C
NO2
Table
O2N
12
18
entry
temp.
base
solvent
time
result
DBU (1 eq.)
TMG (1 eq.)
1
2
THF
40 ℃
50 ℃
2 d
3 d
no reaction
Scheme 4 shows the efficient route to prepare catalytic
asymmetric desymmetrization precursor 10. Elongation of the a-
chain of compound 21 was accomplished by a 2-step sequence.
Cross metathesis of 21 with acrolein was performed with the
Grubbs second generation catalyst18 to give unsaturated aldehy-
−
comlex mixture.
LHMDS (1.8 eq.)
TBAF (1 eq.)
3
4
THF
THF
−78 to 0 ℃
40 ℃
24 h
24 h
no reaction
18: 92%
(diastereomer mixture)
2
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10.1002/ejoc.202000579
European Journal of Organic Chemistry
FULL PAPER
O
Table 4. First screening for catalyst.
H
O
O
H
H
O
H
Table
Br
O
20 (32%)
H
KF
CH3CN, 70 ℃, 2 h
DMF, 110 ℃
O
H
CHO
H
+
O
48 h
CHO
10
9
94%
O
H
H
O
11
NaClO2, NaH2PO4
2-methyl-2-butene
H
O
H
t-BuOH/H2O, rt, 2 h
21 (61%)
H
COOH
97%
O
CO2t-Bu
1
H
H2, Pd/C (5 mol %)
Grubbs II (5 mol %)
Me
N
N
N
t-Bu
NH
27
CH2Cl2, reflux, 14 h
82%
EtOH, rt, 2 h
98%
O
H
N
N
O
t-BuO2C
N
H
NH
22
NH
Ph
26
28
O
O
H
H
entry
reagents
temp.
yield
trace
65%
optical puritya
n.d.
solvent
time
3 d
t-BuOK
L-proline
(0.1 eq.)
1
2
DMF
rt to 60 ℃
rt to 60 ℃
THF, −78 ℃, 2 h
O
H
H
OH
t-BuO2C
CO2t-Bu
26 (0.1 eq.)
H2O (5 eq.)
75% (dr = 3:1)
CH3CN
3 d
8% ee
24
23
27 (0.3 eq.)
TFA (0.3 eq.)
3
4
DMSO
NMP
0 to 60 ℃
0 ℃
60 h
3 d
trace
54%
n.d.
O
28 (0.3 eq.)
TFA (0.3 eq.)
H
48% eeb
TFA
SOCl2
chondrosterin I
a Optical yield was determined by HPLC on a chiral phase (AD-H).
b Optical purity in entry 4 was determined by derivatization to carboxylic acid 1.
(1: racemic)
pyridine, rt, 16 h
81%
CH2Cl2, rt, 3 h
92%
H
CO2H
by Hayashi et al that the TFA salt of (S)-2-(pyrrolidinylmethyl)-
pyrrolidine 28 in NMP at 0 ºC was the most effective to construct
a bicyclo[4.3.0]nonene framework by asymmetric intramolecular
aldol reaction of similar meso tricarbonyl compounds.19 This
literature encouraged us to apply the aforementioned condition to
our substrate and the desired aldol reaction proceeded followed
by dehydration to afford 9 in 54% yield. The dehydrated product
9 was oxidized to carboxylic acid 1, chondrosterins I, utilizing
NaClO2.22 In entry 4, optical purity of 9 was determined by
derivatization to carboxylic acid 1, which indicated that it was
constructed in 48% ee.
Having found the TFA salt of diamine containing a pyrrolidine
core favorable, a second screening of the effect of altering the
“right hand” of the diamine was examined as summarized in Table
5. Entries 1 and 2 show that the dibenzylamino and didecylamino
groups,23 which are bulky and flexible, exhibited moderate yields
and optical purities with similar results to that of catalyst 28. In
entry 3, compound 9 was obtained in 42% yield in 50% ee by
utilizing diamine 32 with a planar right hand. Fortunately, catalyst
33 bearing an azepane ring that is slightly bulkier than the
pyrrolidine ring was successful for improvement of the
enantiomeric excess of 1. Treatment of compound 10 with 33
furnished dehydrated product 9 in 42% yield in 73% ee (entry 4).
In entry 4, aldol product 29 was also produced in 45% yield as a
mixture of diastereomers at C3 and Burgess’ reagent dehydrated
29 to compound 9 in 65% yield.24 Compound 9 derived from 29
was also oxidized to carboxylic acid 1 in the same fashion and the
optical purity of 1 was found to be 68% ee. Furthermore, the
enantiomeric excess was improved up to 92% ee through a
refinement of the experimental procedure (entry 5). Thus, the
reagents were added dropwise at −10 ºC to generate an excellent
Scheme 3. Racemic synthesis of compound 1.
de 25 in 85% yield. The double bond of 25 was in turn reduced to
10, the asymmetric aldol reaction precursor, by hydrogenation.
With access to precursor 10 achieved, the next challenge was
to build the tricyclic skeleton in an optically active form. The
organocatalyst-mediated enantioselective intramolecular aldol
reaction was examined in detail (Tables 4, 5 and 6). This reaction
features the rare combination of the aldehyde as nucleophile and
the ketone as electrophile.19 Table 4 describes our first screening
efforts to search for an appropriate catalyst type for the reaction.
Conditions employing a conventional proline catalyst provided a
trace amount of desired compound 9 (entry 1), whereas catalyst
26 containing a tetrazole as a carboxylic acid equivalent20 gave a
moderate yield but with very low ee (entry 2). Although MacMillan
catalyst 2721 also resulted in failure, diamine catalyst 28 seemed
to be suitable for this cyclization (entries 3 and 4). It was reported
CHO
O
O
H
H
Grubbs II (25 mol %)
CH2Cl2, reflux, 36 h
85%
O
H
O
H
OHC
21
25
O
H
H2, Pd/C (10 mol %)
EtOH, rt, 1 h
98%
O
H
CHO
10
Scheme 4. Synthesis of catalytic asymmetric desymmetrization precursor 10.
3
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10.1002/ejoc.202000579
European Journal of Organic Chemistry
FULL PAPER
Table 5. Second screening for catalyst.
The effect of altering an acid was also tested with catalyst 33 in
Table 6. Exposure to AcOH salt of 33 instead of TFA led to
recovery of starting molecule and ClCH2COOH with a slightly
increased acidity gave 10% ee, implying that strong acid may be
essential for desired cyclization. These failures prompted us to
attempt 2,4-dinitrobenzenesulfonic acid and TfOH. Thus, upon
treatment of 10 with these strong acids enantioselective
cyclization took place to provide 9 in 70% ee and 72% ee,
respectively. However, substantial improvement in both yield and
enantiomeric excess was not observed.
O
H
C3
H
OH
CHO
29
Burgess
reagent
(1:1 mixture of
diastereomers at C3)
O
catalyst (0.3 eq.)
TFA (0.3 eq.)
H
THF, 60 ℃
16 h
+
O
65%
NMP, 0 ℃, 3 d
O
H
H
The proposed reaction mechanism is as follows. Enamine 35 is
formed through the reaction of the TFA salt of catalyst 33 with the
aldehyde moiety of diketoaldehyde 10 (Scheme 5). Subsequent
intramolecular attack to one of the carbonyl groups generates 36.
Hydrolysis of the iminium ion 36 yields the aldol product 29 and
regenerates catalyst 33. The aldol product 29 undergoes
dehydration to give a,b-unsaturated aldehyde 9 under the
reaction conditions or upon treatment with the Burgess’ reagent,
without diminishing the enantioselectivity. Transition states A and
B depict a possible explanation for the selectivity. In A and B, a
proton on the nitrogen atom activates one of the carbonyl oxygens.
This activation enables the enamine moiety to intramolecularly
attack the ketone carbonyl group. There is little steric bias in the
case of state A, while significant steric hindrance between the
azepane ring and the bicyclic skeleton cannot be avoided in the
case of B. Thus, the cyclization enantioselectively occurs via A.
Having succeeded in the asymmetric desymmetrization, we
turned our attention to the final conversion to another natural
product. The resultant material 1 was allowed to typical reductive
conditions to give the secondary alcohol, chondrosterin J (2), in a
stereoselective manner (Scheme 6).
CHO
10
H
CHO
9
n-C10H21
N
Ph
N
N
NH
NH
NH n-C10H21
Ph
30
31
32
N
N
NH
NH
33
34
optical purity of 1c
(derived from 9)
optical purity of 1c
(derived from 29)
entry
catalyst yield of 9
yield of 29
28
30
54%
42%
45%
42%
42%
55%
45%
48% ee
33% ee
56% ee
50% ee
73% ee
92% ee
69% ee
1a
2a
3a
4a
5b
6a
31
32
33
33
34
45%
68% ee
n.d.
30% (10 + 29)
O
HN
H
N
+H
O
a Reaction was performed on a 0.04 mmol scale.
H
b Reaction was performed on a 0.40 mmol scale. Reagents were added dropwise at −10 ℃
and then warm to 0 ℃. Inseparable 10 + 29 was also produced in 30% yield.
c Optical yield was determined by HPLC on a chiral phase (AD-H).
-
33
CF3CO2
O
H
O
−H2O
H
N
-
CF3CO2
CHO
N
+H
35
Table 6. Effect of altering an acid.
10
N
O
O
NH
H
H
O
O
H
33 (0.3 eq.)
H
acid (0.3 eq.)
H
OH
N+
O
N
H
H+
N
NMP, 0 ℃, 3 d
H
O
H
CHO
N
CHO
-
9
10
CF3CO2
A
36
optical purity of 1b
(derived from 9)
entry
yield of 9
acid
O
O
H
H
dehydration
TFA
AcOH
42%
73% ee
n.d.
1a
2a
H
trace
H
OH
CHO
CHO
ClCH2COOH
2,4-dinitro
52%
37%
48%
10% ee
29
9
+H2O
3a
4a
70% ee
72% ee
+
benzenesulfonic acid
TfOH
HN
N
N
H+
+H
33
a Reaction was performed on a 0.04 mmol scale.
b Optical yield was determined by HPLC on a chiral phase (AD-H).
O
N
-
CF3CO2
H
outcome of 9 (55% yield, 92% ee), along with an inseparable
mixture of 10 and 29 in 30% yield. On the other hand, diamine 34
possessing a bulkier octahydroazocin ring only afforded 45%
yield and 69% ee (entry 6).
O
H
B
Scheme 5. Proposed reaction mechanism.
4
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10.1002/ejoc.202000579
European Journal of Organic Chemistry
FULL PAPER
Both the 1H and 13C NMR data of synthetic chondrosterin J were
identical to those reported in the literature. However, there are
considerable discrepancies of the absolute values of optical
rotation between natural and synthetic compounds 1 and 2. In
addition, compound 1 also exhibits the opposite sign of specific
optical rotation. The absolute steric configuration of the synthetic
product has been definitely confirmed by X-ray crystallographic
analysis (Scheme 7), suggesting that the isolated chondrosterin I
and J are racemic mixture or included impurities.
Unless otherwise noted, all solvents and reagents were obtained from
commercial suppliers and used without further purification. Routine
monitoring of reactions was carried out Merck silica gel 60 F254 TLC
plates. Column chromatography was performed on Kanto Chemical Silica
Gel 60N (spherical, neutral 60–230 μm) with the solvents indicated.
Melting points were taken on a Yanako MP-S3 micro melting point
1
apparatus and are uncorrected. H and 13C NMR spectra were measured
with a JASCO ECZ 400S (400 MHz) spectrometer. Chemical shifts were
expressed in ppm using CHCl3 (7.26 ppm for 1H NMR, 77.0 ppm for 13C
NMR) in CDCl3 as internal standard. Infrared spectral measurements were
carried out with a JASCO FT/IR-4700 and only noteworthy absorptions
were listed. HRMS spectra measured on a Micromass LCT spectrometer.
X-ray crystallographic analysis was taken with Burker APEX2 Ultra TXS.
O
OH
H
H
NaBH4
MeOH, 0 ℃, 20 min
Methyl 4,4-dimethyl-2-oxocyclopentane-1-carboxylate (15): To
a
H
H
COOH
COOH
suspension of 13 (2.00 g, 13.0 mmol) and p-acetoamidobenzene
sulfonylazide (p-ABSA) (3.21g, 14.3 mmol) in CH3CN (30 ml) were added
dropwise Et3N (13.0 ml, 13.0 mmol) at –15 ºC, the reaction mixture was
stirred at the same temperature for 5 min. The mixture was allowed to
warm to rt, the insoluble material was removed by filtration, and
concentrated in vacuo to afford the crude 14. A stirred solution of the crude
14 in THF (100 ml) and MeOH (2 ml) was stirred under visible-light
irradiation for 36 h. After concentration in vacuo, the resultant residue was
purified by silica gel column chromatography (hexane-AcOEt, 5:1) to afford
15 (1.51 g, 62%) as a colorless oil. The spectroscopic data were consistent
with those reported previously.14
95%, dr > 95:5
chondrosterin J (2)
1
[α]D25 +87.17 (c 0.65 MeOH)
lit. [α]D20 −17.73 (c 0.015 MeOH)
[α]D25 −114.17 (c 0.50 MeOH)
lit. [α]D20 −9.11 (c 0.006 MeOH)
Scheme 6. Completion of enantioselective total synthesis.
The absolute configuration was determined by X-ray
analysis25 of compound 37, the p-bromophenylester of 1. The X-
ray single-crystal diffraction data suggests that our asymmetric
aldol reaction made progress via the same reaction mechanism
as Hayashi’s aldol reaction19 to provide the same absolute
stereochemistry.
Methyl 2-hydroxy-4,4-dimethylcyclopentane-1-carboxylate (16): To a
stirred solution of 15 (500 mg, 2.93 mmol) in MeOH (10 ml) was added
NaBH4 (55.6 mg, 1,47 mmol) at 0 ºC, and the mixture was stirred at the
same temperature for 30 min. The reaction mixture was quenched with sat.
NH4Cl aqueous solution, and extracted with AcOEt three times. The
combined organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The resultant residue was purified by silica gel
column chromatography (hexane-AcOEt, 3:1) to afford 16 (450 mg, 89%)
as a mixture of diastereomers (3:1). The spectroscopic data were
consistent with those reported previously.14
O
H
O
EDCI, DMAP
H
p-bromophenol
H
O
O
CH2Cl2, rt, 15 h
51%
H
COOH
1
37
Br
Methyl 4,4-dimethylcyclopent-1-ene-1-carboxylate (12): To a stirred
solution of 16 (2.00 g, 11.6 mmol) in pyridine (2 ml) was added dropwise
SOCl2 (0.99 ml, 13.6 mmol) at 0 ºC under Ar atmosphere, and the mixture
was stirred at room temperature for 3 h. After the mixture was stirred at 65
ºC for 2 h, was quenched with 1 M HCl, and extracted with ether five times.
The combined organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo to afford the crude 17. To a stirred solution of
the crude 17 in CH2Cl2 (50 ml) was added DBU (2.65 ml, 17.7 mmol) at 0
ºC, and the mixture was stirred at room temperature for 12 h. The reaction
mixture was quenched with sat. NH4Cl aqueous solution, and extracted
with AcOEt three times. The combined organic layer was washed with
brine, dried over MgSO4, and concentrated in vacuo. The resultant residue
was purified by silica gel column chromatography (hexane-AcOEt, 7:1) to
afford 12 (1.49 g, 83%) as a yellow oil. The spectroscopic data were
consistent with those reported previously.14
37
Scheme 7. Determination of the absolute configuration.
Conclusion
In conclusion, the first enantioselective total synthesis of
chondrosterins I and J was efficiently accomplished in 8 and 9
steps from known 12, 20.4% and 19.4% overall yield, respectively.
The synthetic strategy concentrated on an intramolecular aldol
reaction by means of catalytic asymmetric desymmetrization of
tricarbonyl compound 10. The optical purity went up to 92% ee
with catalyst 33. In the final step, stereoselective reduction of the
ketone moiety of 1 produced another target molecule 2 in
enantiomerically rich form.
Methyl
4,4-dimethyl-2-(1-nitropropyl)cyclopentane-1-carboxylate
(18): To a stirred solution of 12 (2.00 g, 13.0 mmol) in 1-nitropropane (1.20
ml, 13.4 mmol) were added dropwise TBAF (1.0 M in THF, 13.0 ml, 13.0
mmol) at room temperature under Ar atmosphere, and the reaction mixture
was stirred at 40 ºC for 24 h. After cooling to room temperature the reaction
mixture was quenched with 1 M HCl, and extracted with ether. The
combined organic layers were washed with brine, dried over MgSO4 and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane-AcOEt, 5:1) to afford 18 (2.90 g, 92%) as a
colorless oil and a mixture of 2 diastereomers. IR (neat) 2955, 2871, 1737,
1550, 1463, 1437, 1370, 1314, 1261, 1245, 1199, 1171, 808 cm-1; 1H NMR
(400 MHz, CDCl3) d 0.88-0.96 (3H, m), 0.99-1.05 (6H, m), 1.21-1.42 (1H,
m), 1.62-2.04 (5H, m), 2.61-3.05 (2H, m), 3.66, 3.71 (3H, s) 4.29-4.41 (1H,
m); 13C NMR (400 MHz, CDCl3) d 10.4, 10.5, 25.3, 25.4, 28.6, 29.0, 29.5
Experimental Section
General Remarks: All reactions involving air- and moisture-sensitive
reagents were carried out using standard syringe-septum cap techniques.
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000579
European Journal of Organic Chemistry
FULL PAPER
(overlapping of 2 diastereomers), 38.4, 38.6, 43.1, 44.2, 45.0, 45.2, 45.2,
45.3, 46.2, 46.4, 52.0, 52.1, 93.7, 93.9, 175.5, 175.6; HRMS (ESI-TOF)
Calcd for C12H21NO4Na [M+Na]+ 266.1368. Found 266.1361.
tert-Butyl (E)-4-((2r,3aR,6aS)-2,5,5-trimethyl-1,3-dioxooctahydropent
alen-2-yl)-but-2-enoate (22): To a stirred suspension of Grubbs II catalyst
(58.0 mg, 0.0680 mmol) in CH2Cl2 at reflux under Ar atmosphere was
added 21 (300 mg, 1.36 mmol) and tert-butyl acrylate (0.990 ml, 6.80
mmol), and the suspension was stirred at the same temperature for 14 h.
After cooling to room temperature the reaction mixture was quenched with
H2O, and extracted with CHCl3. The combined organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo. The resultant
residue was purified by silica gel column chromatography (hexane-AcOEt,
7:1) to afford 22 (356 mg, 82%) as a white crystal. Mp 90-93 ºC; IR (KBr)
2957, 2934, 1757, 1714, 1655, 1366, 1336, 1301, 1280, 1167, 1151, 1132,
1029, 981 cm-1; 1H NMR (400 MHz, CDCl3) d 0.75 (3H, s), 0.98 (3H, s),
1.13 (3H, s), 1.43 (9H, s), 1.74-1.90 (4H, m), 2.37 (2H, dd, J = 8.0, 1.6 Hz),
3.26-3.35 (2H, m), 5.71 (1H, dt, J = 15.2, 1.2 Hz), 6.50-6.59 (1H, m); 13C
NMR (400 MHz, CDCl3) d 17.8, 27.3, 27.8, 28.0, 39.7, 40.8, 44.7, 51.6,
58.5, 80.5, 127.6, 139.1, 164.7, 218.0; HRMS (ESI-TOF) Calcd for
C19H28O4Na [M+Na]+ 343.1885. Found 343.1878.
Methyl 4,4-dimethyl-2-propionylcyclopentane-1-carboxylate (19): To
a stirred solution of 18 (1.00 g, 4.11 mmol) in MeOH (20 ml) was added
dropwise NaOMe (28% in MeOH, 1.50 ml, 6.17 mmol) at room
temperature under Ar atmosphere, the reaction mixture was stirred at the
same temperature for 30 min, and then was bubbled ozone at −78 ℃ for 5
h. The reaction mixture was quenched with dimethyl sulfide and allowed
to room temperature for over night. The mixture was partitioned between
AcOEt and sat. NH4Cl aqueous solution, the combined organic layer was
washed with brine, dried over MgSO4, and concentrated in vacuo. The
resultant residue was purified by silica gel column chromatography
(hexane-AcOEt, 10:1) to afford 19 (750 mg, 86%) as a colorless oil. IR
(neat) 2954, 2870, 1734, 1714, 1462, 1437, 1369, 1350, 1248, 1200, 1175,
1117 cm-1; 1H NMR (400 MHz, CDCl3) d 0.94-1.08 (9H, m), 1.43-1.52 (1H,
m), 1.64-1.72 (1H, m), 1.77-1.88 (2H, m), 2.37-2.53 (2H, m), 3.30-3.44 (2H,
m), 3.63 (3H, s); 13C NMR (400 MHz, CDCl3) d 7.6, 28.8, 28.9, 35.3, 39.5,
44.2, 44.3, 44.8, 51.8, 53.4, 175.8, 211.8; HRMS (ESI-TOF) Calcd for
C12H20O3Na [M+Na]+ 235.1310. Found 235.1304.
tert-Butyl 4-((2r,3aR,6aS)-2,5,5-trimethyl-1,3-dioxooctahydropentalen
-2-yl)butanoate (23): A suspension of 22 (280 mg, 0.873 mmol) and 10%
Pd/C (47 mg, 0.0437 mmol) in EtOH was stirred at room temperature for 2
h under H2 atmosphere. The insoluble material was removed by filtration,
and concentrated in vacuo to afford 23 (280 mg, 98%) as a pink oil. IR
(neat) 2961, 2930, 2868, 1722, 1712, 1366, 1260, 1148, 1073 cm-1; 1H
NMR (400 MHz, CDCl3) d 0.70 (3H, s), 0.97 (3H, s), 1.09 (3H, s), 1.38 (9H,
s), 1.41-1.61 (4H, m), 1.73-1.91 (4H, m), 2.05-2.16 (2H, m), 3.32-3.45 (2H,
m); 13C NMR (400 MHz, CDCl3) d 16.4, 19.5, 27.4, 27.8, 28.0, 34.9, 36.8,
40.8, 44.5, 51.3, 58.9, 80.7, 171.9, 218.6; HRMS (ESI-TOF) Calcd for
C19H30O4Na [M+Na]+ 345.2042. Found 345.2036.
(3aR,6aS)-2,5,5-Trimethyltetrahydropentalene-1,3(2H,3aH)-dione
(11): To a stirred solution of 19 (2.00 g, 9.42 mmol) in THF (50 ml) and t-
BuOH (0.89 ml, 9.42 mmol) was added t-BuOK (1 M in THF, 28.3 ml, 28.3
mmol) at room temperature under Ar atmosphere, and the reaction mixture
was stirred at 60 ºC for 2 h. After cooling to room temperature, the mixture
was quenched with 1 M HCl and concentrated in vacuo. The resultant
residue was purified by recrystallization to afford 11 (1.70 g, 95%) as a
colorless crystal. Mp 156-159 ºC; IR (KBr) 2955, 2867, 1775, 1732, 1575,
1465, 1446, 1395, 1360, 1245, 1220, 1111, 1084, 983 cm-1; 1H NMR (400
MHz, CDCl3) d 0.99 (6H, s), 1.43 (2H, dd, J = 13.2, 6.0 Hz), 1.62 (3H, s),
1.80 (2H, dd, J = 13.2, 9.2 Hz), 3.20 (2H, ddd, J = 12.0, 6.2, 5.6 Hz), 10.68
(1H, br); 13C NMR (100 MHz, CDCl3) d 5.8, 28.1, 28.5, 42.1, 43.5, 48.1,
111.0, 201.2; HRMS (ESI-TOF) calcd for C11H17O2 [M+H]+ 181.1229,
found 181.1222.
tert-Butyl (3aS,3bR,6aS,7aS)-3a-hydroxy-5,5,7a-trimethyl-7-oxodeca
hydro-1H-cyclopenta[a]pentalene-3-carboxylate (24): To
a stirred
solution of 23 (80 mg, 0.248 mmol) in THF (4 ml) was added t-BuOK (1.0
M in THF, 0.750 ml, 0.750 mmol) at −78 ºC under Ar atmosphere, and the
mixture was stirred at the same temperature for 2 h. The reaction mixture
was quenched with sat. NH4Cl aqueous solution, and extracted with AcOEt.
The combined organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo. The resultant residue was purified by silica gel
column chromatography (hexane-AcOEt, 8:1) to afford 24 (60 mg, 75%)
as a mixture of diastereomers (3:1). Data for less polar diastereomer (white
crystal): Mp 103-105 ºC; IR (KBr) 3568, 2932, 1712, 1455, 1383, 1316,
1255, 1130, 1074, 1030, 845 cm-1; 1H NMR (400 MHz, CDCl3) d 0.94 (3H,
s), 1.03 (3H, s), 1.10 (3H, s), 1.50 (9H, s), 1.41-1.73 (5H, m), 1.78-1.96
(3H, m), 2.72-2.80 (1H, m), 2.80 (1H, s), 2.90-3.03 (2H, m); 13C NMR (400
MHz, CDCl3) d 20.3, 27.2, 27.9, 28.2, 29.1, 36.8, 40.8, 43.0, 43.6, 48.8,
52.5, 56.7, 59.2, 81.9, 85.4, 173.4, 224.7; HRMS (ESI-TOF) Calcd for
C19H30O4Na [M+Na]+ 345.2042. Found 345.2032. Data for polar
diastereomer (white crystal): Mp 104-108 ºC; IR (KBr) 3478, 2955, 2868,
1732, 1706, 1454, 1380, 1302, 1258, 1219, 1157, 1101cm-1; 1H NMR (400
MHz, CDCl3) d 0.96 (3H, s), 1.07 (3H, s), 1.20 (3H, s), 1.48 (9H, s), 1.41-
1.74 (4H, m), 1.81-2.15 (4H, m), 2.47-2.53 (1H, m), 2.88-3.06 (2H, m), 3.64
(1H, s); 13C NMR (400 MHz, CDCl3) d 17.9, 23.8, 28.2, 28.7, 36.2, 41.0,
42.2, 42.3, 46.0, 52.6, 56.8, 60.2, 81.8, 86.0, 172.2, 222.6; HRMS (ESI-
TOF) Calcd for C19H30O4Na [M+Na]+ 345.2042. Found 345.2037.
(2r,3aR,6aS)-2-Allyl-2,5,5-trimethyltetrahydropentalene-1,3(2H,3aH)-
dione (21), (3aR,6aS)-3-(Allyloxy)-2,5,5-trimethyl-4,5,6,6a-tetrahydro
pentalen-1(3aH)-one (20): To a stirred solution of 11 (470 mg, 2.61 mmol)
in CH3CN (50 ml) was added allyl bromide (0.442 ml, 5.22 mmol) and
potassium fluoride (758 mg, 13.1 mmol) at room temperature under Ar
atmosphere, and the mixture was stirred at 70 ºC for 2 h. After cooling to
room temperature the reaction mixture was quenched with 1 M HCl, and
extracted with AcOEt. The combined organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. The resultant residue was
purified by silica gel column chromatography (hexane-AcOEt, 3:1) to afford
21 (350 mg, 61%) as a yellow oil and 22 (185 mg, 32%) as an orange oil.
A solution of 20 (50.0 mg, 0.227 mmol) in DMF (2 ml) was stirred at 110
ºC for 48 h under Ar atmosphere. After cooling to room temperature the
mixture was quenched with H2O, and extracted with diethyl ether. The
combined organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The resultant residue was purified by silica gel
column chromatography (hexane-AcOEt, 10:1) to afford 21 (47 mg, 94%)
as a yellow oil. Data for 21: IR (neat) 2956, 2932, 2868, 1760, 1719, 1464,
1450, 1370, 1209, 924 cm-1; 1H NMR (400 MHz, CDCl3) d 0.73 (3H, s),
0.98 (3H, s), 1.10 (3H, s), 1.74-1.88 (4H, m), 2.28 (2H, d, J = 7.2 Hz), 3.26-
3.35 (2H, m), 5.00-5.12 (2H, m), 5.51-5.63 (1H, m); 13C NMR (400 MHz,
CDCl3) d 17.2, 27.4, 27.8, 40.8, 42.4, 44.6, 51.6, 59.6, 120.0, 131.0, 218.6;
HRMS (ESI-TOF) Calcd for C14H19O2 [M-H]− 219.1385. Found 219.1390.
Data for 20: IR (neat) 2953, 2864, 1686, 1627, 1388, 1336, 1285, 1240,
1222, 1124, 977, 935 cm-1; 1H NMR (400 MHz, CDCl3) d 0.99 (3H, s), 1.00
(3H, s), 1.37 (1H, dd, J = 12.0, 8.0 Hz), 1.43 (1H, dd, J = 12.8, 8.0 Hz),
1.61 (3H, s), 1.72-1.89 (2H, m), 3.01-3.09 (1H, m), 3.30-3.38 (1H, m), 4.63-
4.73 (2H, m), 5.25-5.40 (2H, m), 5.90-6.01 (1H, m); 13C NMR (400 MHz,
CDCl3) d 6.3, 27.7, 28.5, 41.7, 43.3, 43.9, 43.9, 51.1, 70.1, 113.8, 117.8,
132.3, 185.5, 207.9; HRMS (ESI-TOF) Calcd for C14H20O2Na [M+Na]+
243.1361. Found 243.1352.
(E)-4-((2r,3aR,6aS)-2,5,5-trimethyl-1,3-dioxooctahydropentalen-2-yl)
but-2-enal (25): To a stirred suspension of Grubbs Ⅱ catalyst (105 mg,
0.124 mmol) in CH2Cl2 (2 ml) at reflux under Ar atmosphere was added 21
(110 mg, 0.499 mmol) and acrolein (0.17 ml, 2.496 mmol), and the
suspension was stirred at the same temperature for 36 h. After
concentration in vacuo, the resultant residue was purified by silica gel
column chromatography (hexane-AcOEt, 3:1) to afford 25 (105 mg, 85%)
as a colorless crystal. Mp 72-74 ºC; IR (KBr) 2949, 2864, 1719, 1678, 1464,
1317, 1252, 1199, 1068, 1028, 983 cm-1; 1H NMR (400 MHz, CDCl3) d 0.79
(3H, s), 1.02 (3H, s), 1.17 (3H, s), 1.79-1.94 (4H, m), 2.54 (2H, dd, J = 7.6,
1.2 Hz), 3.35-3.42 (2H, m), 6.10 (1H, ddt, J = 15.5, 7.8, 1.3 Hz), 6.56-6.65
(1H, m), 9.50 (1H, d, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) d 17.5, 27.4,
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000579
European Journal of Organic Chemistry
FULL PAPER
28.0, 39.3, 41.2, 44.9, 51.5, 58.1, 136.5, 149.1, 193.0, 217.5; HRMS (ESI-
TOF) calcd for C15H20O3Na [M+Na]+ 271.1310, found 271.1300.
room temperature under Ar atmosphere, and the mixture was stirred at 60
ºC for 16 h. The reaction mixture was quenched with H2O, and extracted
with AcOEt three times. The combined organic layer was washed with
brine, dried over MgSO4, and concentrated in vacuo. The resultant residue
was purified by silica gel column chromatography (hexane-AcOEt, 5:1) to
afford 9 (18 mg, 65%).
4-((2r,3aR,6aS)-2,5,5-trimethyl-1,3-dioxooctahydropentalen-2-yl) buta
nal (10): A suspension of 25 (105 mg, 0.423 mmol) and 5% Pd/C (45 mg,
0.021 mmol) in EtOH (4 ml) was stirred at room temperature for 1 h under
H2 atmosphere. The insoluble material was removed by filtration, and
concentrated in vacuo to afford 10 (104 mg, 98%) as a colorless oil. IR
(neat) 2957, 2868, 2725, 1755, 1714, 1460, 1370, 1255, 1075 cm-1; 1H
NMR (400 MHz, CDCl3) d 0.74 (3H, s), 1.01 (3H, s), 1.13 (3H, s), 1.54-1.62
(4H, m), 1.78-1.94 (4H, m), 2.38-2.41 (2H, m), 3.38-3.46 (2H, m), 9.70 (1H,
t, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) d 16.6, 27.5, 27.9, 36.7, 41.0,
43.4, 44.7, 51.4, 59.3, 201.2, 218.7; HRMS (ESI-TOF) calcd for
C15H22O3Na [M+Na]+ 273.1467, found 273.1459.
(3bR,6aS,7aS)-5,5,7a-trimethyl-7-oxo-2,3b,4,5,6,6a,7,7a-octahydro-
1H-cyclopenta[a]pentalene-3-carboxylic acid (1: chiral): To a stirred
solution of 9 (20.0 mg, 0.086 mmol) in t-BuOH (0.1 ml) and H2O (0.1 ml)
and 2-methyl-2-butene (0.18 ml, 1.72 mmol) was added NaClO2 (23.3 mg,
0.258 mmol) and NaH2PO4 ･ 2H2O (67.8 mg, 0.430 mmol) at room
temperature, and the mixture was stirred at the same temperature for 2 h.
The reaction mixture was quenched with H2O, and extracted with AcOEt
three times. The combined organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The resultant residue was purified by
silica gel column chromatography (hexane-AcOEt, 3:1) to afford chiral 1
(3aS,3bR,6aS,7aS)-3a-hydroxy-5,5,7a-trimethyl-7-oxodecahydro-1H-
cyclopenta[a]pentalene-3-carbaldehyde (29), (3bR,6aS,7aS)-5,5,7a-
trimethyl-7-oxo-2,3b,4,5,6,6a,7,7a-octahydro-1H-cyclopenta[a]pental
ene-3-carbaldehyde (9): procedure for Table 5, entry 4; To a stirred
solution of 10 (10 mg, 0.040 mmol) in NMP (0.3 ml) was added dropwise
a solution of TFA and 33 (3.6 mg, 0.012 mmol) in NMP (0.1 ml) at 0 ºC,
and the mixture was stirred at the same temperature for 3 days. The
reaction mixture was quenched with H2O, and extracted with Et2O five
times. The combined organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The resultant residue was purified by
silica gel column chromatography (hexane-AcOEt, 5:1) to afford 29 (1:1
diastereomer mixture, 4.5 mg, 45%) as a colorless oil and 9 (3.9 mg, 42%)
25
(20.7 mg, 97%) as a colorless crystal. Mp 185-187 ºC; [α]D +87.17 (c
0.65, MeOH).
(3bR,6aS,7S,7aS)-7-hydroxy-5,5,7a-trimethyl-2,3b,4,5,6,6a,7,7a-octa
hydro-1H-cyclopenta[a]pentalene-3-carboxylic acid (2: chiral): To a
stirred solution of 1 (10.0 mg, 0.040 mmol) in MeOH (0.5 ml) was added
NaBH4 (1.5 mg, 0.040 mol) at 0 ºC, and the mixture was stirred at the same
temperature for 20 min. The reaction mixture was quenched with sat.
NH4Cl aqueous solution, and extracted with AcOEt three times. The
combined organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The resultant residue was purified by silica gel
column chromatography (hexane-AcOEt, 7:3) to afford chiral 2 (9.6 mg,
as
a white crystal. Enantiomeric excess of each compound was
determined after conversion into chondrosterin I (1) by HPLC with a
chiralpak AD-H column (20:1 = hexane: EtOH), flow speed 0.80 mL/min,
retention time of major enantiomer = 11.6 min, minor enantiomer = 14.3
min. Data for 29 (polar diastereomer): [α]D25 +140.45 (c 0.40, MeOH); IR
(neat) 2954, 2868, 1719, 1647, 1466, 1366, 1310, 1176, 1115, 1071, 944
cm-1; 1H NMR (400 MHz, CDCl3) d 0.93 (3H, s), 1.04 (3H, s), 1.13 (3H, s),
1.47-1.73 (5H, m), 1.87-2.01 (3H, m), 2.82 (1H, ddd, J = 8.4, 8.8, 9.6 Hz),
2.95-3.03 (2H, m), 3.47 (1H, s), 9.92 (1H, d, J = 1.2 Hz); 13C NMR (100
MHz, CDCl3) d 17.4, 21.6, 28.4, 28.9, 35.7, 41.2, 41.4, 42.6, 45.6, 52.2,
61.3, 63.0, 88.0, 203.5, 221.6; HRMS (ESI-TOF) calcd for C15H21O3 [M–
H]– 249.1491, found 249.1493. (less polar diastereomer): [α]D25 –3.43 (c
0.40, MeOH); IR (neat) 2953, 2870, 1718, 1636, 1541, 1507, 1457, 1121
cm-1; 1H NMR (400 MHz, CDCl3) d 0.96 (3H, s), 1.05 (3H, s), 1.17 (3H, s),
1.42 (1H, dd, J = 11.2, 11.2 Hz), 1.58-1.75 (3H, m), 1.80-1.95 (3H, m),
2.02-2.14 (1H, m), 2.15 (1H, s), 2.65 (1H, ddd, J = 1.2, 8.6, 8.6 Hz), 2.90-
2.97 (1H, m), 3.02-3.10 (1H, m), 9.81 (1H, s); 13C NMR (100 MHz, CDCl3)
d 19.8, 24.5, 28.0, 29.3, 37.3, 41.0, 42.7, 43.5, 49.6, 52.7, 59.7, 63.5, 87.3,
203.9, 223.8; HRMS (ESI-TOF) calcd for C15H21O3 [M–H]– 249.1491,
found 249.1494. Data for 9: Mp 75-77 ºC; [α]D25 +56.78 (c 0.60, MeOH);
IR (KBr) 3450, 2954, 2749, 1731, 1656, 1456, 1243, 1186, 1076, 898, 703
cm-1; 1H NMR (400 MHz, CDCl3) d 1.01 (3H, s), 1.15 (3H, s), 1.45 (3H, s),
1.65-1.76 (2H, m), 1.85-2.08 (4H, m), 2.67-2.80 (2H, m), 3.28 (1H, ddd, J
= 9.6, 9.6, 9.6 Hz), 3.91 (1H, ddd, J = 9.6, 9.6, 9.6 Hz), 9.94 (1H, s); 13C
NMR (100 MHz, CDCl3) d 24.0, 26.6, 28.3, 30.1, 35.8, 40.2, 43.9, 45.8,
47.2, 58.4, 63.8, 137.4, 172.8, 187.3, 219.5; HRMS (ESI-TOF) calcd for
C15H21O2 [M+H]+ 233.1542, found 233.1533.
25
95%) as a white crystal and a single diastereomer. Mp 203-205 ºC; [α]D
–114.17 (c 0.50, MeOH); IR (KBr) 3387, 2952, 2865, 1679, 1597, 1419,
1279, 1198, 1117, 1060, 757 cm-1; 1H NMR (400 MHz, CDCl3) d 0.96 (3H,
s), 1.11 (3H, s), 1.25 (3H, s), 1.38 (1H, dd, J = 12.8, 9.6 Hz), 1.48 (1H, ddd,
J = 12.8, 9.6, 2.0 Hz), 1.75 (1H, m), 1.81 (1H, dd, J = 12.0, 6.8 Hz), 1.84
(1H, m), 2.00 (1H, ddd, J = 12.8, 9.6, 2.0 Hz), 2.71 (1H, dd, J = 15.6, 6.0
Hz), 2.86 (1H, ddd, J = 15.6, 9.6, 6.4 Hz), 3.21 (1H, dddd, J = 9.6, 9.6, 9.6,
6.8 Hz), 3.55 (1H, ddd, J = 9.6, 9.6, 9.6 Hz), 4.05 (1H, d, J = 9.6 Hz); 13
C
NMR (100 MHz, CDCl3) d 18.5, 26.6, 28.7, 33.8, 41.1, 42.0, 42.1, 42.1,
46.6, 51.9, 61.4, 79.0, 123.3, 170.5, 175.6; HRMS (ESI-TOF) calcd for
C15H21O3 [M–H]– 249.1491, found 249.1492.
4-bromophenyl-(3bR,6aS,7aS)-5,5,7a-trimethyl-7-oxo-2,3b,4,5, 6,6a,7,
7a-octahydro-1H-cyclopenta[a]pentalene-3-carboxylate (37): To
a
stirred solution of 1 (6.0 mg, 0.0242 mmol) in CH2Cl2 (0.3 ml) was added
EDCI (9.3 mg, 0.0484 mmol), DMAP (1.5 mg, 0.0121 mmol) and p-
bromophenol (8.4 mg, 0.484 mmol) at room temperature, and the mixture
was stirred at the same temperature for 15 h. The reaction mixture was
purified by silica gel column chromatography (hexane-AcOEt, 9:1) to afford
37 (5.0 mg, 51%) as a white crystal. Mp 111-115 ºC; [α]D25 +6.91 (c 0.28,
MeOH); IR (KBr) 2955, 2867, 1740, 1719, 1647, 1482, 1296, 1259, 1192,
1163, 1108, 1066, 1010 cm-1; 1H NMR (400 MHz, CDCl3) d 0.97 (3H, s),
1.13 (3H, s), 1.46 (3H, s), 1.59-1.72 (2H, m), 1.88 (1H, dd, J = 12.4, 5.6
Hz), 1.98-2.12 (3H, m), 2.82 (1H, dd, J = 16.0, 8.8 Hz), 2.93-3.02 (1H, m),
3.24 (1H, ddd, J = 10.0, 10.0, 10.0 Hz), 3.98 (1H, ddd, J = 9.6, 9.6, 9.6 Hz),
7.02 (2H, d, J = 8.8 Hz), 7.50 (2H, d, J = 8.8 Hz); 13C NMR (100 MHz,
CDCl3) d 23.9, 26.5, 28.3, 32.9, 35.7, 42.5, 43.6, 46.1, 46.3, 58.3, 63.8,
118.9, 123.5, 126.3, 132.6, 149.7, 162.9, 170.6, 220.0; HRMS (ESI-TOF)
calcd for C21H24BrO3 [M+H]+ 403.0909, found 403.0900.
procedure for Table 2, entry 5; To a stirred solution of 10 (100 mg, 0.40
mmol) in NMP (3 ml) was added dropwise a solution of TFA and 33 (36.0
mg, 0.12 mmol) in NMP (1 ml) at –10 ºC, and the mixture was stirred at 0
ºC for 3 days. The reaction mixture was quenched with H2O, and extracted
with Et2O five times. The combined organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. The resultant residue was
purified by silica gel column chromatography (hexane-AcOEt, 5:1) to afford
9 (51.0 mg, 55%, 92% ee) as a white crystal and inseparable mixture of
10 and 29 (28 mg, 30 %). Enantiomeric excess was determined after
conversion into chondrosterin I (1).
Keywords: Total synthesis • Natural products • Aldol reaction •
Asymmetric desymmetrization • Chiral diamine catalyst
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10.1002/ejoc.202000579
European Journal of Organic Chemistry
FULL PAPER
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8
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European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Key Topic : Total synthesis
N
NH
O
OH
O
O
H
H
H
H
(0.3 eq.)
TFA (0.3 eq.)
NMP, 0 ℃, 3 d
O
H
H
H
H
CHO
55%, 92% ee
COOH
COOH
CHO
chondrosterin I
chondrosterin J
asymmetric desymmetrization
with chiral diamine catalyst
The first enantioselective total synthesis of chondrosterins I and J was accomplished featuring a catalytic asymmetric intramolecular
aldol reaction with chiral diamine catalyst. The enantiomeric excess went up to 92% ee.
9
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