Application of a stereoselective rhodium(II)-catalyzed oxonium ylide formation-[2,3]-sigmatropic rearrangement of an α-diazo-β-keto ester to the synthesis of 2-epi-cinatrin C1 dimethyl ester

Article abstract of DOI:10.1055/s-0032-1317694

The Rh₂(OAc)₄-catalyzed oxonium ylide formation-[2,3]-sigmatropic rearrangement of a highly functionalized α-diazo-β-keto ester derived from d-glucose proceeded stereoselectively to give the corresponding tetrahydrofuran-3-one as a single diastereomer in high yield. This reaction was applied to the synthesis of 2-epi-cinatrin C₁ dimethyl ester as a key step. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317694

LETTER
▌65
lAettper plication of a Stereoselective Rhodium(II)-Catalyzed Oxonium Ylide
Formation–[2,3]-Sigmatropic Rearrangement of an α-Diazo-β-keto Ester to
the Synthesis of 2-epi-Cinatrin C1 Dimethyl Ester
Synthesis of 2-epi-Cinatrin C1 Dimethyl Ester
Takayuki Yakura,*a Ayaka Ozono,a Katsuaki Matsui,a Masayuki Yamashita,b Tomoya Fujiwaraa
a
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
Fax +81(76)4345053; E-mail: yakura@pha.u-toyama.ac.jp
b
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
Received: 17.10.2012; Accepted after revision: 05.11.2012
The outline of our synthesis of cinatrins is illustrated in
Abstract: The Rh2(OAc)4-catalyzed oxonium ylide formation–
Scheme 1. Cinatrins are generated from a key intermedi-
[2,3]-sigmatropic rearrangement of a highly functionalized α-diazo-
ate, a substituted tetrahydrofuran-3-one 3, by (a) oxida-
tion to a lactone, (b) introduction of the C1 unit, and (c)
β-keto ester derived from D-glucose proceeded stereoselectively to
give the corresponding tetrahydrofuran-3-one as a single diastereo-
mer in high yield. This reaction was applied to the synthesis of extension of the side chain. Furanone 3 is stereoselective-
2-epi-cinatrin C1 dimethyl ester as a key step.
ly synthesized from α-diazo-β-keto ester 4 by using the
rhodium(II)-catalyzed oxonium ylide formation–[2,3]-
sigmatropic rearrangement. The diazoketo ester 4 is easily
prepared from D-glucose.
Key words: diazoketo ester, rhodium(II) catalyst, oxonium ylide,
[2,3]-sigmatropic rearrangement, cinatrin
HO
Metal carbenes derived from α-diazocarbonyl compounds
are highly electrophilic and react with an available Lewis
base to form an ylide. When the resulting ylide has an al-
lylic substituent at the proper position, a subsequent [2,3]-
sigmatropic rearrangement takes place. Such metal-cata-
lyzed carbenoid reactions have become a powerful tool
for the synthesis of functionalized cyclic compounds in-
cluding oxacycles.1 We recently reported a stereoselective
copper-catalyzed oxonium ylide formation–[2,3]-sigma-
tropic rearrangement reaction of an α-diazo ketone to give
2,6-trans-dihydropyran-3-one2 and a rhodium(II)-cata-
lyzed reaction of α-diazo-β-keto esters leading to 3-oxo-
tetrahydrofurans.3
HO
CO2H
O
O
H
H
O
cinatrin A
cinatrin B
O
HO
HO
CO2H
O
O
O
O
HO
HO
CO2H
O
O
CO2H
cinatrin C1 (1)
A family of cinatrins, which were isolated from the fer-
mentation broth of the microorganism Circinotrichum fal-
catisporum RF-641 by Itazaki and co-workers, possess
phospholipase A2 inhibitory activity.4 Among them, the
cinatrins A and B have a unique spirolactone skeleton as
a key structural component, whereas cinatrin C1 (1) con-
tains a highly substituted γ-lactone framework that ap-
pears to be a ring-opened derivative of cinatrin B (Figure
1). The stereoselective construction of substituted γ-lac-
tones with three continuous stereocenters is one of the
most important issues for the synthesis of these attractive
bioactive compounds.5
HO
HO
CO2Me
2
O
O
CO2Me
2-epi-cinatrin C1 dimethyl ester (2)
Figure 1 Cinatrin family
We started our synthesis from D-glucose (Scheme 2). Ac-
cording to the reported procedure,6 diol 5 was prepared
from D-glucose in two steps. The selective protection of
the primary alcohol by a pivaloyl (Piv) group followed by
allylation of the remaining secondary alcohol gave 6. The
benzylidene diol protecting group was changed to a tert-
butyldimethylsilyl (TBS) group, leading to bis-TBS ether
7. The removal of the Piv group by diisobutylaluminum
hydride (DIBAL-H) reduction, oxidation to the aldehyde,
and subsequent β-keto ester formation with methyl diazo-
acetate in the presence of tin(II) chloride gave keto ester
8. Subsequently, a diazo transfer reaction converted 8 to
α-diazo-β-keto ester 4.
Here we report the stereoselective rhodium(II)-catalyzed
oxonium ylide formation–[2,3]-sigmatropic rearrange-
ment of α-diazo-β-keto ester 4 derived from D-glucose
and its application to the synthesis of 2-epi-cinatrin C1 di-
methyl ester 2.
SYNLETT 2013, 24, 0065–0068
Advanced online publication: 27.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317694; Art ID: ST-2012-U0898-L
© Georg Thieme Verlag Stuttgart · New York

66
T. Yakura et al.
LETTER
groups and showed the 3,4-cis stereochemistry. This indi-
cated that the rhodium(II)-catalyzed reaction proceeds via
oxonium ylide A, which is apparently a more stable inter-
mediate than B, and that the subsequent [2,3]-sigmatropic
rearrangement of the allyl group from oxygen to carbon
formed 3, consistent with our previously reported stere-
oselectivity for the reaction of 5-allyloxy-2-diazo-3-ke-
toesters (Scheme 4). In the subsequent reduction, the
hydride should attack the carbonyl group from the α-side
to avoid the adjacent bulky α-TBDMSO group of ketone
to give β-hydroxy compound 9.
b) introduction of
C1 unit
a) oxidation
TBSO
O
cinatrins
TBSO
O
CO2Me
3
c) extension of
side chain
Rh(II)-catalyzed
oxonium ylide formation
[2,3]-sigmatropic rearrangement
TBSO
O
CO2Me
D-glucose
TBSO
O
N2
4
Scheme 1 Retrosynthetic analysis of cinatrins
Ph
O
Ph
O
O
ref. 6 (2 steps)
a, b
O
O
D-glucose
OPiv
OH OH
5
6
OTBS
OPiv
c, d
e–g
TBSO
OTBS
O
7
h
4
TBSO
CO2Me
O
O
Scheme 3 Reagents and conditions: (a) NaBH4, CH2Cl2–MeOH,
–80 °C, 10 min, 92%; (b) 4-nitrobenzoyl chloride, Et3N, DMAP,
CH2Cl2, r.t., 1.5 h, 88%.
8
Scheme 2 Reagents and conditions: (a) t-BuCOCl, pyridine, DMAP,
CH2Cl2, r.t., 1.5 h, 97%; (b) allyl bromide, Ag2O, CaSO4, benzene,
r.t., 39 h, 90%; (c) CSA, MeOH, r.t., 18.5 h, 89%; (d) TBSOTf, i-
Pr2NEt, CH2Cl2, 0 °C, 20 min, 99%; (e) DIBAL-H, CH2Cl2, –80 °C,
30 min, 89%; (f) Dess–Martin periodinane, CH2Cl2, r.t., 1.5 h, 92%;
(g) N2CHCO2Me, SnCl2, CH2Cl2, r.t., 5.5 h, 75%; (h) TsN3, Et3N,
MeCN, r.t., 4 h, 96%.
4
9
Rh(II)
O
NaBH4
TBSO
H
TBSO
H
Next, we examined the rhodium(II)-catalyzed reaction of
4, a key step of our cinatrin synthetic plan (Scheme 3). We
recently reported that the rhodium(II)-catalyzed reaction
of 5-allyloxy-2-diazo-3-ketoesters gave methyl 5-substi-
tuted 2-allyl-3-oxotetrahydrofuran-2-carboxylates in high
yields with excellent stereoselectivities.3 According to the
reported procedure,3 4 was treated with 3 mol% of dirho-
dium(II) tetraacetate [Rh2(OAc)4] in dichloromethane un-
der reflux for eight hours. The reaction smoothly
proceeded to give tetrahydrofuran-3-one 3 as a single dia-
stereomer in 79% yield.7 The reduction of 3 with sodium
borohydride produced alcohol 9, which was esterified
with 4-nitrobenzoyl chloride to give a crystalline product,
ester 10.8 The X-ray analysis of 10 confirmed the trans re-
lationship between the 5-silyloxymethyl and 2-allyl
O
– CO2Me
O
O
+
CO2Me
H–
TBSO
TBSO
oxonium ylide A
3
TBSO
O
TBSO
TBSO
H
O
CO2Me
– CO2Me
O
+
O
TBSO
oxonium ylide B
Scheme 4 Stereochemical preferences for rhodium(II)-catalyzed re-
action of 4 and the following reduction
Synlett 2013, 24, 65–68
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-epi-Cinatrin C1 Dimethyl Ester
67
The excellent stereoselectivity of the NaBH4 reduction of In conclusion, the Rh2(OAc)4-catalyzed oxonium ylide
3 encouraged us to synthesize 2-epi-cinatrin C1 in order to formation–[2,3]-sigmatropic rearrangement reaction of α-
prove the utility of our strategy for the synthesis of cina- diazo-β-keto ester 4 derived from D-glucose stereoselec-
trin derivatives (Scheme 5). The chain extension of the al- tively proceeded to give tetrahydrofuran-3-one 3 as a sin-
lyl group using olefin metathesis with Grubbs’ second gle diastereomer in high yield. The resulting 3 was
generation catalyst and 1-undecene gave (E)-alkene 119 converted into 2-epi-cinatrin C1 dimethyl ester 2. As our
that was reduced to an alkyl group to give 12 in 91% yield results have demonstrated the utility of our strategy for the
in two steps. The nucleophilic addition of a vinyl group to construction of the core structure of cinatrin derivatives,
12 by using vinylmagnesium bromide exclusively pro- the stereoselective introduction of the C1 unit at the 2-
duced α-vinyl adduct 13. This addition displayed the same positon from the β-side and the total synthesis of cinatrin
stereoselectivity as that observed in the reduction of 3. C1 and its derivatives are now in progress.
The stereochemistry of 13 was confirmed by the subse-
quent formation of the acetonide of 15. The vinyl group
was next converted to a methoxycarbonyl moiety by the
References
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds; John Wiley & Sons: New York, 1998. (b) For
a review, see: Merlic, C. A.; Zechman, A. L. Synthesis 2003,
1137.
(2) Yakura, T.; Muramatsu, W.; Uenishi, J. Chem. Pharm. Bull.
2005, 53, 989.
(3) Yakura, T.; Matsui, K.; Matsuzaka, K.; Yamashita, M.
Heterocycles 2009, 79, 353.
(4) (a) Itazaki, H.; Nagashima, K.; Kawamura, Y.; Matsumoto,
K.; Nakai, H.; Terui, Y. J. Antibiot. 1992, 45, 38. (b) Tanaka,
K.; Itazaki, H.; Yoshida, T. J. Antibiot. 1992, 45, 50.
(5) (a) Evans, D. A.; Trotter, B. W.; Barrow, J. C. Tetrahedron
1997, 53, 8779. (b) Cuzzupe, A. N.; Florio, R. D.; Rizzacasa,
M. A. J. Org. Chem. 2002, 67, 4392. (c) Cuzzupe, A. N.;
Florio, R. D.; White, J. M.; Rizzacasa, M. A. Org. Biomol.
Chem. 2003, 1, 3572.
usual three-step protocol to afford 14. The removal of the
two silyl groups gave triol 15, and the subsequent forma-
tion of the acetonide of the cis-diol produced 16. Oxida-
tion of 16 to lactone 17 was achieved by Taber’s
procedure,10 whereby the treatment of 16 with pyridinium
dichromate (PDC) and acetic anhydride in CH2Cl2–N,N-
dimethylformamide (DMF) under reflux resulted in 17.
The final deprotection of the acetonide to diol was trou-
blesome because the typical acidic conditions were not
suitable for this transformation. However, the deprotec-
tion was achieved by the treatment of 17 with iodine in
methanol11 under reflux to give 2-epi-cinatrin C1 dimethyl
ester 212,13 in 84% yield.
TBSO
O
TBSO
O
(6) Tanabe, G.; Yoshikai, K.; Hatanaka, T.; Yamamoto, M.;
Shao, Y.; Minematsu, T.; Muraoka, O.; Wang, T.; Matsuda,
H.; Yoshikawa, M. Bioorg. Med. Chem. 2007, 15, 3926.
(7) Rhodium(II)-Catalyzed Reaction of α-Diazo-β-keto
Ester 4: To a solution of Rh2(OAc)4 (17 mg, 0.038 mmol) in
CH2Cl2 (40 mL) was added a solution of 4 (618 mg, 1.27
mmol) in CH2Cl2 (24 mL). The resulting solution was
refluxed for 8 h. After concentration of the reaction, the
residue was purified by column chromatography on SiO2
(5% EtOAc in hexane) to give 3 (459 mg, 79%) as a
colorless oil; [α]D26 +12.9 (c = 0.750, CHCl3). IR (neat):
1781, 1753 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.09 (s,
6 H), 0.11 (s, 3 H), 0.18 (s, 3 H), 0.90 (s, 9 H), 0.91 (s, 9 H),
2.61–2.81 (m, 2 H), 3.72 (s, 3 H), 3.82 (dd, J = 11.8, 3.0 Hz,
1 H), 3.91 (ddd, J = 8.9, 3.0, 2.1 Hz, 1 H), 4.00 (dd, J = 11.8,
2.1 Hz, 1 H), 4.57 (d, J = 8.8 Hz, 1 H), 5.11–5.21 (m, 2 H),
5.67–5.81 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = –5.5,
–5.4, –5.3, –4.4, 18.2, 18.3, 25.6 (3), 25.8 (3), 38.4, 52.8,
61.3, 72.3, 80.2, 84.8, 120.2, 130.7, 167.6, 208.6. MS: m/z =
459 [M+ + H]. HRMS (EI): m/z calcd for C22H43O6Si2:
459.2598; found: 459.2578.
(8) Spectroscopic data for 10: colorless crystals; mp 86–88 °C
(from 5% EtOAc in hexane); [α]D21 −30.8° (c = 0.5, CHCl3).
IR (neat): 1740, 1531 cm–1. 1H NMR (300 MHz, CDCl3): δ
= −0.04 (s, 3 H), 0.06 (s, 3 H), 0.09 (s, 3 H), 0.10 (s, 3 H),
0.74 (s, 9 H), 0.91 (s, 9 H), 2.74 (dd, J = 14.0, 7.4 Hz, 1 H),
2.89 (dd, J = 13.6, 7.4 Hz, 1 H), 3.70 (dd, J = 11.8, 4.0 Hz, 1
H), 3.73 (s, 3 H), 3.81 (dd, J = 11.3, 3.3 Hz, 1 H), 4.08 (dt, J
= 5.2, 3.3 Hz, 1 H), 4.52 (t, J = 4.9 Hz, 1 H), 5.01–5.06 (m,
1 H), 5.08 (br s, 1 H), 5.64–5.79 (m, 1 H), 5.75 (d, J = 4.9
Hz, 1 H), 8.25 (d, J = 8.8 Hz, 2 H), 8.32 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = −5.53, −5.46, −5.1, −5.0,
17.7, 18.4, 25.5 (3), 25.9 (3), 38.4, 52.4, 62.4, 71.4, 84.9,
86.2, 119.0, 123.7, 130.8, 131.6, 135.2, 160.7, 163.5, 171.7.
2
C12H25
CO2Me
a
b
3
C9H19
O
O
CO2Me
TBSO
TBSO
TBSO
11
12
HO
HO
TBSO
CO2Me
C12H25
C12H25
CO2Me
d–f
c
O
O
CO2Me
TBSO
TBSO
13
14
HO
O
O
O
HO
CO2Me
C12H25
CO2Me
C12H25
g
h
O
CO2Me
CO2Me
HO
HO
HO
15
16
HO
O
O
O
CO2Me
C12H25
CO2Me
C12H25
j
i
O
O
O
CO2Me
17
CO2Me
2
Scheme 5 Reagents and conditions: (a) 1-undecene, Grubbs’ sec-
ond-generation catalyst, CH2Cl2, reflux, 1 h, 96%; (b) 3 atm H2, Pd/C,
EtOH, r.t., 3 h, 95%; (c) vinylmagnesium bromide, THF, –80 °C, 20
min, 85%; (d) O3, Me2S, CH2Cl2–MeOH, –78 °C, 10 min; (e)
NaClO2, NaH2PO4·H2O, t-BuOH–2-methylbut-2-ene–H2O, r.t., 1 h;
(f) excess CH2N2, Et2O, r.t., 15 min, 82% for 3 steps; (g) concd HCl,
MeOH, r.t., 1.5 h, 92%; (h) 2,2-dimethoxypropane, TsOH, 60 °C,
1.5 h, 91%; (i) PDC, Ac2O, CH2Cl2–DMF, reflux, 1.5 h, 71%; (j) I2,
MeOH, reflux, 45 h, 84%.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 65–68

68
T. Yakura et al.
LETTER
MS: m/z = 610 [M+ + H]. HRMS (EI): m/z calcd for
C29H48O9NSi2: 610.2867; found: 610.2868. The X-ray data
are now being deposited with the CCDC. CCDC-908929
(for 10) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(300 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz, 3 H), 1.25 (br s,
20 H), 1.92 (ddd, J = 14.0, 11.8, 4.4 Hz, 1 H), 2.08 (ddd, J =
14.0, 11.8, 4.4 Hz, 1 H), 2.93 (d, J = 9.1 Hz, 1 H), 3.79 (s, 3
H), 3.86 (s, 3 H), 3.89 (br s, 1 H), 4.99 (d, J = 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.2, 29.3,
29.4, 29.56, 29.60, 30.7, 31.9, 53.3, 54.0, 71.3, 81.3, 89.2,
168.9, 169.1, 172.7. MS: m/z = 402 [M+]. HRMS (EI): m/z
calcd for C20H34O8: 402.2254; found: 402.2234.
(9) The coupling constant between the olefinic protons of 11
was observed to be 15.4 Hz.
(13) Unfortunately, the treatment of 2 with aqueous sodium
hydroxide according to Rizzacasa’s cinatrin syntheses (see
refs. 5a and 5b) gave a complex mixture. It is very interesting
that the stereochemistry of the C-2 position strongly
influenced its chemical stability.
(10) (a) Taber, D. F.; Song, Y. J. Org. Chem. 1996, 61, 7508.
(b) Kim, J. N.; Ryu, E. K. Tetrahedron Lett. 1992, 33, 3141.
(11) Szarek, W. A.; Zamojski, A.; Tiwari, K. N.; Ison, E. R.
Tetrahedron Lett. 1986, 27, 3827.
(12) Spectroscopic data for 2: a colorless oil; [α]D18 −35.1° (c =
0.750, CHCl3). IR (neat): 3462, 1806, 1748 cm–1. 1H NMR
Synlett 2013, 24, 65–68
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