Synthetic studies on nemorosone via enantioselective intramolecular cyclopropanation

Article abstract of DOI:10.1016/j.tetlet.2009.12.147

This Letter describes synthetic studies of nemorosone via enantioselective intramolecular cyclopropanation. For the total synthesis of nemorosone, three potential intermediates were evaluated through the efficiency of three sequential reactions, namely, their intramolecular cyclopropanation, dimethylation of the resultant cyclopropanes, and ring-opening reaction of the alkylated cyclopropanes. As a result, α-diazomethyl ketone 10c was found to be the most suitable. The enantioselective intramolecular cyclopropanation to construct the bicyclo[3.3.1]nonane core and preparation of the compound with all the correct stereogenic centers of nemorosone are also described.

Full text of DOI:10.1016/j.tetlet.2009.12.147

Tetrahedron Letters 51 (2010) 1298–1302
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Tetrahedron Letters
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Synthetic studies on nemorosone via enantioselective intramolecular
cyclopropanation
*
Masahito Abe, Aya Saito, Masahisa Nakada
Departments of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes synthetic studies of nemorosone via enantioselective intramolecular cyclopropana-
tion. For the total synthesis of nemorosone, three potential intermediates were evaluated through the
efficiency of three sequential reactions, namely, their intramolecular cyclopropanation, dimethylation
of the resultant cyclopropanes, and ring-opening reaction of the alkylated cyclopropanes. As a result,
Received 7 December 2009
Revised 22 December 2009
Accepted 24 December 2009
Available online 7 January 2010
a
-diazomethyl ketone 10c was found to be the most suitable. The enantioselective intramolecular cyclo-
propanation to construct the bicyclo[3.3.1]nonane core and preparation of the compound with all the
correct stereogenic centers of nemorosone are also described.
Ó 2010 Elsevier Ltd. All rights reserved.
Polycyclic polyprenylated acylphloroglucinols (PPAPs) have di-
verse and complex structures with intriguing biological activities
including cytotoxicity against several human cancer cell lines.
PPAPs feature a highly oxygenated and densely substituted bicy-
clo[3.3.1]nonane-2,4,9-trione or bicyclo[3.2.1]octane-2,4,8-trione
core incorporating C5H9 or C10H17 (prenyl, geranyl, etc.) side
chains.1 PPAPs have been divided into type-A, B, and C. Typical
type-A PPAPs include hyperforin,2 adhyperforin,3 and nemorosone4
(Fig. 1). Such PPAPs might suffer from further cyclizations involv-
ing the -diketone and the alkene in side-chain alkenes to afford fur-
ano-fused compounds such as garsubellin,5 furohyperforin,6 and
hyperibone G.7 The fascinating and wide-ranging biological activi-
ties of PPAPs have made them attractive synthetic targets, and
many synthetic studies8 including total syntheses9 have been re-
ported thus far. We report herein synthetic studies on nemorosone
via enantioselective intramolecular cyclopropanation that could
also be utilized to synthesize other type-A PPAPs.
esis with 2-methyl-2-butene in a late stage.12 Therefore, com-
pound 5 (Scheme 2) would be a potential substrate for the
cross-metathesis. Compound 5 was expected to be obtained by
the oxidation of compound 6. Compound 6 could be prepared from
compound 7, which was thought to be obtained from the ring-
opening reaction of compound 8. Hence, we decided to prepare
three
a
-diazo-b-keto compounds 10a–c (R4 = CO2Et, SO2Ph, H) to
examine their IMCP, subsequent alkylation of the cyclopropanes
9, and ring-opening reaction of the alkylated cyclopropanes 8.
Then, we intended to select one among 10a–c on the basis of the
overall yield from 10 to 7 to pursue the enantioselective prepara-
tion of 7 and further transformation toward enantioselective total
synthesis of nemorosone.
R1
O
O
O
9
O
R2
O
1
We have reported the construction of the bicyclo[3.3.1]nonane
derivative 4 (Scheme 1) including the common scaffold that can be
found in type-A PPAPs.10 The key reaction in our approach to 4 is
HO
3
2
8
7
6
5
4
O
O
H
H
the intramolecular cyclopropanation (IMCP) of a-diazo-b-keto es-
OH
ter 1 and subsequent regioselective ring-opening reaction of the
methoxycyclopropane 3. This approach could be enantioselective
when a chiral bisoxazoline ligand is used instead of 2, and enan-
tio-enriched 4 and its derivatives are expected to be obtained.11
Our retrosynthetic analysis of type-A PPAPs is shown in Scheme
2. To synthesize type-A PPAPs from 4, prenyl groups must be intro-
duced at C3, C5, and C7 of 4, and alkyl groups at C8. Allyl groups at
C3, C5, and C7 can be converted to prenyl groups via cross-metath-
hyperforin (R1 = Me)
adhyperforin (R1 = Et)
garsubellin A (R2 = H)
furohyperforin (R2 = prenyl)
Ph
O
Ph
O
O
O
HO
O
O
O
H
H
OH
hyperibone G
nemorosone
* Corresponding author. Tel.: +81 352863240.
E-mail address: mnakada@waseda.jp (M. Nakada).
Figure 1. Structures of some type-A PPAPs.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.147

M. Abe et al. / Tetrahedron Letters 51 (2010) 1298–1302
1299
We first prepared
easy two-step procedure from aldehyde 15. 2,6-Dihydroxybenzoic
a
-diazo-b-keto ester 10a (Scheme 3) by an
acid 11 were allylated with allylbromide and potassium carbonate
followed by Claisen rearrangement and O-methylation to afford al-
lyl ester 12. Compound 12 was hydrolyzed to the carboxylic acid,
followed by Birch reduction and methylation of the product to af-
ford methyl ester. The enolate generated by the treatment of 13
with LDA was subjected to reaction with bromoacetonitrile, fol-
lowed by the hydrolysis of the methyl ester, formation of the acid
chloride, and reduction to afford alcohol 14. Compound 14 was
converted to the corresponding TBDPS ether, followed by reduction
with DIBAL to afford aldehyde 15. Compound 15 was subjected to
MeO
OTBDPS
[CuOTf]2 C6H6 (5 mol%)
ligand 2 (15 mol%)
O
N2
CO2Et
toluene, 80 °C, 1.5 h
MeO
O
O
1
N
N
13
reaction with ethyl diazoacetate and SnCl2 to afford the b-keto
2
ester, and this in turn was successfully converted to a-diazo-b-keto
ester 10a via a diazotransfer reaction.
MeO
OTBDPS
O
OTBDPS
8
1
ZnCl2, rt
3.5 h, 70%
MeO
3
Other substrates for the IMCP, 10b and 10c, were prepared as
shown in Scheme 4. The former was prepared by the reaction of
a dianion of methyl phenyl sulfone with the methyl ester, which
was prepared from 15 via Pinnick oxidation and methylation. The
latter was prepared by a modified Danheiser’s protocol using the
methyl ketone,14 which was obtained by the addition of methyl-
lithium to 15 and subsequent Swern oxidation.15
O
OH
7
MeO
H
CO2Et
CO2Et
3
4
Scheme 1. Intramolecular cyclopropanation (IMCP) of
the subsequent ring-opening reaction.
a-diazo-b-keto ester 1 and
With 10a–c in hand, we applied their IMCP, subsequent dime-
thylation in C8, and the ring-opening reaction, respectively. The re-
sults of the three reactions are summarized in Table 1. The IMCP of
10a afforded 9a in 40% yield and dimethylation of 9a proceeded
with 43% yield, and the ring-opening reaction of 8a afforded 7a
in 55% yield. Extensive optimization did not improve the yields
of the three reactions. In the case of 10b, the yields of IMCP and
dimethylation were 57% and 69%, respectively, which were better
than those of 10a. Interestingly, the ring-opening reaction of 8b re-
sulted in no reactions or decomposition of 8b under any acidic con-
ditions. The reactions attempted using nucleophiles under basic
and neutral conditions (Li2S, LiI, NaCl) gave the same results.
Although it has been reported that the steric repulsion between
the cis-substituents on a cyclopropane accelerates its ring-opening
reaction,16 we speculate that this is not the case and rather, a bulky
phenylsulfonyl group could prevent the cyclopropane in 8b from
reacting with the reagent.
R1
O
OTBDPS
O
O
R2
R2
R3
type-A
PPAPs
MeO
MeO
R3
O
5
H
H
6
OTBDPS
O
OTBDPS
MeO
R2
R3
O
R2
R3
R5
MeO
R4
OMe
8
O
R5
7
MeO
R5
OTBDPS
MeO
OTBDPS
R4
R5
10a (R4 = CO2Et)
10b (R4 = SO2Ph)
10c (R4 = H)
O
N2
O
OMe
R4
OMe
R5
R5
9
IMCP of a-diazomethyl ketone 10c proceeded at room temper-
ature to afford 9c in 97% yield. This result suggests that the slow
reaction rate and low yield of the IMCPs of 10a and 10b can be
attributed to the steric hindrance around the metal–carbene cen-
ter. Dimethylation of 9c with iodomethane afforded 8c in 74%
yield, and the ring-opening reaction of 8c under the conditions
listed in Table 1 successfully afforded 7c in 95% yield. On the basis
of the results described above, we decided to examine the enantio-
selective intramolecular cyclopropanation of 10c and further
transformation from 7c.
Scheme 2. Retrosynthetic analysis of type-A PPAPs (R5 = allyl).
1) CH2=CHCH2Br, K2CO3
acetone, reflux, 84%
MeO
HO
R5
CO2R5
OMe
CO2H
OH
2) o-dichlorobenzene
reflux, 91%
R5
3) MeOTs, K2CO3, DMF
50 °C, 90%
11
12
1) BrCH2CN, LDA
THF, 0 °C, 81%
2) KOH, MeOH
H2O, THF, reflux
1) KOH, MeOH
H2O, THF, reflux
MeO
The enantioselective IMCPs of 10c are summarized in Table 2.
CO2Me
2) Li, liq.NH3, MeOH
THF, –78 °C
R5
17
The catalytic asymmetric IMCP (CAIMCP) using Rh2(5R-MEPY)4
afforded the desired product 9c in 74% yield; however, interest-
ingly, it was formed as a racemic mixture. CAIMCP with bisoxazo-
line ligand A18a (Fig. 2) and CuOTf proceeded quite smoothly at
OMe
R5 13
3) CCl4, PPh3
(CH2Cl)2, 50 °C
4) NaBH4, MeOH
THF, –30 °C
3) MeI, K2CO3, acetone
50 °C, 51% (3 steps)
90% (3 steps)
MeO
OTBDPS
MeO
OH
CN
1) TBDPSCl, imidazole
DMAP, DMF, 80 °C
R5
R5
1) NaClO2, NaH2PO4, t-BuOH, H2O, THF
2-methyl-2-butene, rt
CHO
2) MeI, K2CO3, acetone, rt, 91% (2 steps)
2) DIBAL-H, Et2O, 0 °C
76% (2 steps)
OMe
OMe
14
10b
R5
15
15
R5
OTBDPS
CO2Et
R5
15
3) LiCH2SO2Ph, THF, 0 °C, 91%
4) TsN3, Et3N, rt, CH3CN, 91%
MeO
OTBDPS
R4
MeO
1) N2=CHCO2Et, CH2Cl2
rt, SnCl2
R5
1) MeLi, Et2O, 0 °C
2) Swern oxidation, 90% (2 steps)
N2
O
N2
OMe
O
10c
2) TsN3, Et3N, CH3CN
rt, 85% (2 steps)
R5
OMe
10a
3) LHMDS, CF3CO2CH2CF3, THF, –78
4) p-NO2PhSO2N3, Et3N, CH3CN
78 % (2 steps)
°C
R5
10b (R4 = SO2Ph)
10c (R4 = H)
Scheme 3. Preparation of
11 (R5 = allyl).
a-diazo-b-keto ester 10a from 2,6-dihydroxybenzoic acid
Scheme 4. Preparation of 10b and 10c (R5 = allyl).

1300
M. Abe et al. / Tetrahedron Letters 51 (2010) 1298–1302
Table 1
Transformation from 10a–c to 7a–c (R5 = allyl)
OTBDPS
O
MeO
OTBDPS
MeO
MeO
OTBDPS
R4
R5
R5
OTBDPS
O
R5
Ring-opening
reaction
MeO
R5
IMCP
Dimethylation
O
O
N2
O
OMe
R4
R4
OMe
R5 R4
OMe
R5
R5
R5
10a (R4 = CO2Et)
10b (R4 = SO2Ph)
10c (R4 = H)
9a (R4 = CO2Et)
9b (R4 = SO2Ph)
9c (R4 = H)
8a (R4 = CO2Et)
8b (R4 = SO2Ph)
8c (R4 = H)
7a (R4 = CO2Et)a
7b (R4 = SO2Ph)
7c (R4 = H)
Entry
10
IMCP
Conditions
Yieldb (%)
Dimethylation
Conditions
Yieldb (%)
Ring-opening
reaction
Yieldb (%)
Conditions
1
2
3
10a
10b
10c
CuOTf (20 mol %), ligand 2 (30 mol %)
toluene, 60 °C, 17 h
CuOTf (20 mol %), ligand 2 (30 mol %)
toluene, 50 °C, 10 h
CuOTf (10 mol %), ligand 2 (15 mol %)
toluene, rt, 12 h
40 (9a)
57 (9b)
97 (9c)
MeI, KH, THF, 0 °C, 12 h
43 (8a)
69 (8b)
74 (8c)
PPTS, (CH2Cl)2, 50 °C,
12 h
See text
55 (7a)
0 (7b)
MeI, KH, THF, À20 °C, 2 days
MeI, tBuOK, THF/HMPA = 6:1,
À78 °C, 6 h
2 N HCl, THF, rt, 12 h
95 (7c)
a
Compound 7a exists as the enol form.
Isolated yields.
b
Table 2
R1 R1
Enantioselective preparation of 10c (R5 = allyl)
O
O
O
O
O
N
MeO
OTBDPS
O
MeO
OTBDPS
O
N
O
N
N
R5
R5
N
N
N
N2
R2
R2
Conditions
toluene
i-Pr
i-Pr
O
A: R1 = Me, R2 = i-Pr
B: R1 = Et, R2 = i-Pr
C: R1 = Bn, R2 = i-Pr
D: R1 = Me, R2 = t-Bu
i-Pr
i-Pr
E
F
OMe
H
OMe
R5
R5
Entry Catalysta
10c
9c
Temp
(°C)
Time (h)
1 min
Yieldc (%)
74
eed (%)
0
Figure 2. Structures of ligands A–F.
1
Rh2(5R-
rt
b
MEPY)4
ligands E18c and F18d were also attempted (entries 8 and 9); how-
ever, the reactions were slow and the ee of 9c was very low. Use of
CuBF4 accelerated the reaction (entries 10–16). Thus, the reaction
completed in 1 min at room temperature (69%, 62% ee, entry 10)
and in 0.4 h at 0 °C (99%, 71% ee, entry 11). The reaction using
CuBF4 at À20 °C, however, did not complete (48% at 66% conv.),
but afforded 9c with 79% ee (entry 12). The reaction at À50 °C
did not proceed (entry 13). The reaction with a stoichiometric
amount of catalyst at À20 °C completed in 1 h to afford 9c with
58% yield and 75% ee (entry 14). The reactions were carried out
at À30 °C and at À40 °C, too, affording 9c with 69% yield (at 84%
conv., 80% ee) (entry 15) and 15% yield (at 15% conv., 80% ee) (entry
16), respectively.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
A + CuOTf
A + CuOTf
A + CuOTfe
B + CuOTf
C + CuOTf
D + CuOTf
E + CuOTf
F + CuOTf
A + CuBF4
A + CuBF4
A + CuBF4
A + CuBF4
rt
0
0.2
3.5
48
1
1 min
1 min
0.5, 40
97
70
59
62
77
46
36
À37
6
À20
39 (29% conv.)f
rt
100
87
75
rt
rt
rt, 50
rt, 50, 70
rt
91
1.5, 1.5, 48 63 (26% conv.)f
0
1 min
0.4
18
12
1
69
99
62
71
79
—
75
80
80
0
À20
À50
À20
À30
À40
48 (66% conv.)f
0
58
e
A + CuBF4
A + CuBF4
16
18
69 (84% conv.)f
15 (15% conv.)f
e
e
A + CuBF4
a
As described above, CAIMCP of 10c has some characteristic fea-
tures. First, the results in Table 2 suggest that it is relatively fast.
This fact is well explained by the reactive electron-rich methox-
yalkene in 10c. Second, although we have found that a bulky bisox-
azoline ligand effectively improves enantioselectivity in the
A-F are chiral ligands in Figure 2. Ligand (15 mol %) and CuOTf (10 mol %) were
used unless otherwise noted.
b
10 mol % of Rh2(5R-MEPY)4 was used in CH2Cl2.
Isolated yields.
ee determined by HPLC. The absolute configuration has not been determined.
100 mol % of CuX (X = OTf or BF4) and 150 mol % of A were used.
c
d
e
a
-diazo-b-keto sulfones,11 in the case of 10c, the ee of
f
Yields based on the recovered starting materials.
CAIMCP of
entry 2 is higher than those of entries 5–7. The results in entries
2 and 5–7 indicate that less bulky ligand A is more effective for
the CAIMCP of 10c. In addition, it should be noted that the CAIMCP
with ligand D (entry 7) exhibited reversal enantioselectivity when
compared with the other entries. The CAIMCP with CuBF4 afforded
the product with almost the same ee as the one obtained with
using CuOTf, however, the reaction with CuBF4 proceeded faster
than with CuOTf. The above-mentioned characteristic features of
the CAIMCP of 10c would be beneficial for designing a new chiral
bisoxazoline ligand effective for the CAIMCP of 10c. Determination
of the absolute structure of the product and further optimization of
the enantioselectivity are now in progress.
room temperature to afford 9c in 97% yield with 59% ee (entry 2).
CAIMCP with ligand A at 0 °C reduced the yield to 70%; however, it
improved the ee slightly to 62% (entry 3). The ee was further in-
creased to 77% in the reaction with a stoichiometric amount of cat-
alyst at À20 °C; however, the reaction proceeded sluggishly and
the yield was 39% (at 29% conversion) (entry 4). CAIMCP with li-
gand B18b proceeded quantitatively (entry 5), and interestingly,
the CAIMCPs with more bulky ligands C11a and D18a completed
within 1 min (entries 6 and 7). Although the yields in entries 5–7
were good, the ee of 9c did not increase. CAIMCPs with tridentate

M. Abe et al. / Tetrahedron Letters 51 (2010) 1298–1302
1301
Further transformation of 7c is shown in Scheme 5. We success-
fully introduced an allyl group into the C7 position of ketone 7c.
Thus, ketone 7c was converted to alkenyl iodide 16 via a hydrazone
under Barton’s conditions,19 followed by stereoselective reduction
with LiAlH4 from the less hindered side,20 removal of a TBDPS
group, acetonide formation of the resultant diol, lithiation via hal-
ogen–metal exchange, and subsequent trapping with carbon diox-
ide to afford carboxylic acid 17. 1,4-Reduction of 17 or its ester
form hardly occurred under several reaction conditions; however,
it was finally realized by Birch reduction. Although the product
was a mixture of diastereomers, 18 and 19, we found that the
methyl ester of 18 was converted to the desired isomer by epimer-
ization under the basic conditions, and subsequent reduction gave
alcohol 20 with the correct C7 configuration. The desired isomer
19, the stereochemistry of which was confirmed by NOE correla-
tions, was converted to 20 by reduction with LiAlH4. Alcohol 20
was converted to the corresponding triflate, which was subjected
to a coupling reaction with a divinylcuprate21 to successfully afford
21. Further transformation of 21 was difficult; however, after sev-
eral attempts, we found that the reaction of 21 with NBS under the
conditions for allylic bromination22 afforded 22 and 23. As the
yield of 22 was only 17%, further efforts are being continued to im-
prove the yield.
ligand A effectively afforded the enantio-enriched compound 9c
with 48% yield (66% conv.) and 79% ee. Moreover, the reaction with
a stoichiometric amount of catalyst afforded the same product
with 69% yield (84% conv.) and 80% ee. Although the CAIMCP of
10c requires further optimization, some information about the
relationships between the structure of the chiral bisoxazoline li-
gand and the ee of the product were obtained through this study.
We have also succeeded in preparing the compound with all the
correct stereogenic centers of nemorosone. Further elaboration to-
ward the enantioselective total synthesis of nemorosone is now
underway and will be reported in due course.
Acknowledgments
This work was supported in part by a Waseda University Grant
for Special Research Projects, a Grant-in-Aid from JSPS and MEXT,
and the Global COE program ‘Center for Practical Chemical Wis-
dom’ by MEXT. The fellowship for young scientists to M.A. from
JSPS is also gratefully acknowledged.
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In summary, we prepared three
a-diazo-b-keto compounds
10a–c and evaluated their three sequential transformations,
namely, the IMCP of 10a–c, dimethylation at the C8 position of
the cyclopropanes 9a–c, and ring-opening reaction to afford two
bicycle[3.3.1]nonane compounds 7a and 7c. We found that a-dia-
zomethyl ketone 10c would be the most suitable intermediate for
the total synthesis of nemorosone. We also examined the enantio-
selective intramolecular cyclopropanation of 10c using some chiral
catalysts, and found that the CAIMCP with the chiral bisoxazoline
O
1) hydrazine, TEA, EtOH
1-octene, sealed tube
130 °C
O
OTBDPS
OTBDPS
I
MeO
R5
MeO
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O
7
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73% (2 steps)
R5
R5
7c
16
1) LiAlH4, Et2O, –78 °C
2) TBAF, THF, rt
96% (2 steps)
Na, t-BuOH, THF
NH3(l), –78 °C
O
H
O
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MeO
R5
3) CSA, acetone
rt, quant
4) nBuLi, CO2,
Et2O, –78 °C, 88%
CO2H
quant, 18/19 1/1.1
R5
17
O
H
O
H
O
O
LiAlH4, THF
MeO
R5
MeO
R5
+
H
20
CO2H
R5
CO2H
°
40 C, 86%
R5
H
18
19
1) TMSCHN2, benzene/MeOH, rt, 81%
2) K2CO3, MeOH, sealed tube, 120 °C, 98%
3) LiBHEt3, THF, rt, 100%
1) Tf2O, 2,6-lutidine
O
O
H
H
O
O
CH2Cl2, –78 °C
MeO
R5
MeO
R5
R5
2) nBu3SnCHCH2
nBuLi, CuCN, THF
0 °C, 92% (2 steps)
CH2OH
R5
20
H
R5
21
H
O
H
O
H
O
O
NBS, AIBN, CCl4
reflux, 1 h
O
Br
O
+
R5
R5
R5
R5
23 15%
H
H
22 17%
10. (a) Abe, M.; Nakada, M. Tetrahedron Lett. 2006, 47, 6347–6351; (b) Abe, M.;
Nakada, M. Tetrahedron Lett. 2007, 48, 4873–4877.
Scheme 5. Transformation from 7c to 22 (R5 = allyl).

1302
M. Abe et al. / Tetrahedron Letters 51 (2010) 1298–1302
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