Stereoselective synthesis of (-)-jimenezin

Article abstract of DOI:10.1016/j.tetlet.2005.07.148

Total synthesis of jimenezin was achieved via radical cyclization of β-alkoxyacrylate and β-alkoxyvinyl sulfoxide intermediates and intramolecular olefin metathesis reaction.

Full text of DOI:10.1016/j.tetlet.2005.07.148

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6621–6623
Stereoselective synthesis of (ꢀ)-jimenezin
Cheol Hee Hwang, Gyochang Keum, Kyoung Il Sohn, Dong Hoon Lee and Eun Lee*
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea
Received 28 June 2005; revised 28 July 2005; accepted 29 July 2005
Available online 15 August 2005
Abstract—Total synthesis of jimenezin was achieved via radical cyclization of b-alkoxyacrylate and b-alkoxyvinyl sulfoxide inter-
mediates and intramolecular olefin metathesis reaction.
Ó 2005 Published by Elsevier Ltd.
Jimenezin (1) is an Annonaceous acetogenin isolated
from the seeds of Rollinia mucosa (Jacquin) Baillon.1
It is quite active in the brine shrimp lethality test (IC50
5.7 ng/mL) and exhibits potent cytotoxic activity against
six human solid tumor lines. The original structure pro-
posed was corrected by Takahashi and co-workers via
total synthesis, which was achieved by using carbo-
hydrates as chiral building blocks.2 Jimenezin (1) is a
rare example of acetogenins possessing a hydroxylated
cis-2,6-disubstituted oxane ring along with an adjacent
cis-2,5-disubstituted oxolane ring and one flanking
hydroxyl group on the oxolane side (Scheme 1). Radical
cyclization reactions of b-alkoxyacrylates and related
vinyl ethers are now well known to produce cis-2,5-
disubstituted oxolane and cis-2,6-disubstituted oxane
rings,3 and we intended to examine the efficacy of these
reactions in a stereocontrolled synthesis of jimenezin (1).
O
O
OH
HO
O
1 (-)-Jimenezin
Cytotoxic Annonaceous acetogenin
from Rollinia mucosa seeds
O
OH
OR'
OR'
O
O
O
PhS
PhS
O
O
H
O
O
O
In retrosynthetic analysis, hydroxy oxane F was to be
prepared from a b-alkoxyacrylate aldehyde precursor
G via samarium(II) iodide-mediated cyclization. Oxo-
lane derivative D was envisaged to arise via radical cycli-
zation of b-alkoxyvinyl sulfoxide E. The homoallylic
alcohol prepared from aldehyde C was to be converted
into carboxylate ester B, which may serve as a precursor
for macrolactone A via ring-forming olefin metathesis.
Incorporation of (S)-propylene oxide unit into A and
further manipulations should generate jimenezin (1)
(Scheme 1).
O
O
O
C10H21
C10H21
C10H21
OR
OR
OR
C
B
A
O
O
S
S
Ar
Ar
O
Ph
O
Ph
X
O
O
O
O
O
O
O
O
C10H21
C10H21
O
CO2Et
OH CO2Et
OR
Keywords: Jimenezin; b-Alkoxyacrylate; b-Alkoxyvinyl sulfoxide;
OR
Radical cyclization; Intramolecular olefin metathesis.
G
F
E
D
*
Corresponding author. Tel.: +82 28806646; fax: +82 28891568;
e-mail: eunlee@snu.ac.kr
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.148

6622
C. H. Hwang et al. / Tetrahedron Letters 46 (2005) 6621–6623
Dibenzoate 3 was prepared from trans-3-hexenedioic
acid (2) and transformed into diol 4 (96% ee)4 via Sharp-
less asymmetric dihydroxylation.5 The PMB acetal pre-
pared from 4 was reduced in the presence of titanium
chloride and sodium cyanoborohydride6 and triol 5
was prepared via subsequent removal of benzoate
groups via LAH reduction.
Pummerer rearrangement. Reaction of 12 with the
Roush boronate 139 provided a 3.8:1 mixture favoring
(R)-homoallylic alcohol 14.10 Yamaguchi esterification
of 14 with carboxylic acid 15 proceeded smoothly to
yield the ester diene 16 (Scheme 3).
Epoxide 18 was obtained from (R)-glycidyl tosylate
(17)11 via reaction with octenyl Grignard reagent and
DBU treatment, and a three-step sequence provided car-
boxylic acid 15 (Scheme 4).
Selective benzylidene acetal protection of the 1,3-diol
moiety in 5, iodide substitution of the primary hydroxyl
group, and subsequent substitution with lithiated 1,3-
dithiane produced the dithiane intermediate 6. PMB ether
deprotection of 6, reaction with ethyl propiolate in the
presence of NMM, and dithiane deprotection yielded b-
alkoxyacrylate aldehyde 7. Samarium iodide-mediated
radical cyclization7 of 7 proceeded smoothly, and the
oxane derivative 8 was obtained in high yield (Scheme 2).
The crucial ring-closing olefin metathesis reaction of 16
proceeded efficiently to give the olefin mixture 19.12
O
S
O
S
Tol
I
Tol
O
Ph
O
O
O
O
1)~4)
82%
5)~9)
58%
Conversion of 8 into olefin 9 required MOM protection
of the hydroxyl group, and Wittig reaction of the corre-
sponding aldehyde. DIBAL reduction of 9 produced a
benzyl ether intermediate, from which (E)-b-alkoxyvinyl
(S)-sulfoxide 10 was obtained via hydrogenation/
hydrogenolysis, tosylation of the primary hydroxyl
group, reaction with ethynyl p-tolyl (S)-sulfoxide, and
iodide substitution. The key radical cyclization
(matched case)8 of 10 in the presence of tributylstannane
and triethylborane at low temperature furnished a single
oxolane product 11, and aldehyde 12 was prepared via
10)
93%
8
O
O
C7H15
C10H21
C10H21
OMOM
9
OMOM
10
OMOM
11
CO2iPr
CO2iPr
OTBS
O
B
11)
82%
O
O
13
PhS
HO
O
H
O
O
OH
OBz
OBz
O
O
HO2C
12)
13)
1)~3)
5)~7)
82%
4)
HO
HO
78%
93%
O
O
O
OPMB
OH
95%
99%
C10H21
OMOM
12
C10H21
C10H21
CO2H
OMOM
OMOM
16
HO
BzO
BzO
14
5
3
2
4
(R:S = 3.8:1 favored)
8)~10)
79%
Scheme 3. Reagents and conditions: (1) 5.0 equiv MOMCl, 8.0 equiv
DIPEA, DCM, 0 °C–rt; (2) 1.0 equiv LAH, ether, 0 °C–rt; (3)
2.0 equiv Dess–Martin periodinane, DCM, rt, 2 h; (4) 2.6 equiv n-
BuLi, 2.6 equiv n-C8H17PPh3+Iꢀ, THF, ꢀ78 °C–rt; (5) 2.2 equiv
DIBAL, DCM, 0 °C; (6) H2, Pd–C, MeOH, rt; (7) 1.0 equiv p-TsCl,
0.02 equiv n-Bu2SnO, 1.0 equiv TEA, rt, 10 h; (8) 3.0 equiv (S)-p-
TolS(O)CCH, 1.0 equiv NMM, DCM, 0 °C–rt, 1 d; (9) 4.0 equiv NaI,
acetone, reflux, 16 h; (10) 1.5 equiv n-Bu3SnH, 0.5 equiv Et3B, toluene,
ꢀ30 °C; (11) 2.0 equiv TFAA, 5.0 equiv 2,4,6-collidine, 0 °C, 10 min;
5.0 equiv K2CO3, 0.2 M NaH2PO4–Na2HPO4 buffer (pH 7.0), 0 °C,
O
Ph
O
Ph
O
Ph
O
O
O
O
O
14)
11)~13)
82%
93%
OPMB
S
OH CO2Et
O
CO2Et
S
8
˚
6
7
30 min; (12) 13, 4 A MS, toluene, ꢀ78 °C, 3 h; (13) 1.5 equiv 2,4,6-
Cl3PhCOCl, 1.7 equiv TEA, 1.2 equiv 15, THF; 2.0 equiv DMAP,
benzene, 14.
Scheme 2. Reagents and conditions: (1) EtOH, cat. H2SO4, benzene,
reflux (–H2O), 2 d; (2) 2.0 equiv LAH, ether, 0 °C–rt; (3) 2.2 equiv
BzCl, 2.5 equiv pyridine, DCM, 0 °C–rt, 10 h; (4) 0.4 mol % OsO4,
0.01 equiv DHQ2(PHAL), 3.0 equiv K3FeCN6, 3.0 equiv NaHCO3,
3.0 equiv K2CO3, 1.0 equiv MeSO2NH2, t-BuOH–H2O (1:1) (0.1 M),
0 °C, 12 h; (5) 1.5 equiv (p-MeO)PhCH(OMe)2, 0.02 equiv CSA,
DCM, rt; (6) 1.2 equiv TiCl4, 1.5 equiv NaBH3CN, 2.0 equiv TEA,
MeCN, 0 °C, 50 min; (7) 2.0 equiv LAH, ether, 0 °C–rt; (8) 2.2 equiv
PhCH(OMe)2, 0.01 equiv CSA, DCM, rt; (9) 1.5 equiv I2, 1.5
equiv Ph3P, 2.0 equiv imidazole, DCM, rt; (10) 2.2 equiv n-BuLi,
2.2 equiv 1,3-dithiane, 3.0 equiv HMPA, THF, ꢀ30 °C–rt; (11) 1.1
equiv DDQ, DCM–H2O (20:1), rt; (12) 2.5 equiv HCCCO2Et,
0.15 equiv NMM, MeCN–DCM (1:1), rt; (13) 5.0 equiv MeI, 7.0 equiv
NaHCO3, MeCN–H2O (3:1), rt; (14) 3.0 equiv SmI2, THF, 3.0 equiv
MeOH, 0 °C, 10 min.
OTBS
O
O
TsO
1)~2)
62%
3)~5)
65%
17
PhS
CO2H
18
15
Scheme 4. Reagents and conditions: (1) 1.5 equiv C8H15MgBr, THF,
ꢀ40 °C, 3 h; (2) 2.1 equiv DBU, DCM, rt, 2 h; (3) 3.0 equiv
PhSCH2CO2H, 3.0 equiv LDA, THF, ꢀ78 °C–rt, 16 h; (4) 3.0 equiv
TBSCl, 5.0 equiv DCM, rt, 12 h; (5) 3.0 equiv K2CO3, MeOH–H2O
(7:1), rt.

C. H. Hwang et al. / Tetrahedron Letters 46 (2005) 6621–6623
6623
OTBS
13C NMR spectra of 1. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.07.148.
OTBS
O
O
PhS
PhS
CO2H
HO
2)
80%
1)
94%
3)~7)
39%
References and notes
16
O
O
1
´
1. Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1998,
61, 419–421; For introduction on Annonaceous acetog-
enins in general, read the following reviews: Alali, F. Q.;
Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–
540; Rupprecht, J. K.; Hui, Y.-H.; McLaughlin, J. L.
O
O
C10H21
C10H21
OMOM
OMOM
19
20
`
J. Nat. Prod. 1990, 53, 237–278; Bermejo, A.; Figadere, B.;
Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes,
D. Nat. Prod. Rep. 2005, 22, 269–303.
2. Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org.
Lett. 1999, 1, 2025–2028.
3. For a recent example of stereoselective b-alkoxyacrylate
radical cyclization reaction in natural product synthesis,
see: Kang, E. J.; Cho, E. J.; Lee, Y. E.; Ji, M. K.; Shin, D.
M.; Chung, Y. K.; Lee, E. J. Am. Chem. Soc. 2004, 126,
2680–2681; For more examples on oxacycle synthesis via
radical cyclization, read the following review: Lee, E. In
Radicals in Organic Synthesis. Applications; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp
303–333.
4. Enantiomeric excess was calculated from two peaks at d
5.87 and 5.97 (98:2) in the 1H NMR spectra of the bis-(S)-
(O)-acetylmandelate derivative of the diol.
5. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547.
6. Seebach, D.; Adam, G. Synthesis 1988, 373–375.
7. Hori, N.; Matsukura, H.; Nakata, T. Org. Lett. 1999, 1,
1099–1101; For recent examples of this strategy in natural
product synthesis, see: Takahashi, S.; Kubota, A.; Nakata,
T. Angew. Chem., Int. Ed. 2002, 41, 4751–4754; Takah-
ashi, S.; Kubota, A.; Nakata, T. Org. Lett. 2003, 5, 1353–
1356.
Scheme
5. Reagents
and
conditions:
(1)
15 mol %
(Cy3P)2RuCl2(CHPh), DCM, rt, 16 h; (2) 6 N LiOH, 12-crown-4,
MeOH–THF (1:1), reflux; (3) 5.0 equiv TESCl, 6.0 equiv imidazole,
DCM, rt; 3.0 equiv K2CO3, MeOH–H2O (7:1), rt; (4) 3.0 equiv LDA,
5.0 equiv (S)-propylene oxide, THF; p-TsOH, benzene, rt; (5) 1.0 equiv
m-CPBA, DCM, 0 °C; toluene, reflux, 1 h; (6) H2, 10 mol %
(Ph3P)3RhCl, benzene, rt; (7) 10% HCl–MeOH, DCM, rt.
Enolates derived from 19 failed to react with (S)-propyl-
ene oxide,13 and it was instead converted into the corre-
sponding hydroxy acid 20 under basic hydrolytic
conditions. After selective TES-protection of the hydro-
xyl group, lithium enolate generated was reacted with
(S)-propylene oxide to form an a-phenylthio c-lactone,
which provided a butenolide intermediate via oxida-
tion–elimination protocol. (ꢀ)-Jimenezin (1)14 was final-
ly obtained via selective hydrogenation and acidic
deprotection of protecting groups (Scheme 5).
In this synthesis, the oxane and oxolane moieties were
introduced in high stereoselectivity via radical cycliza-
tion of b-alkoxyacrylate and b-alkoxyvinyl sulfoxide
intermediates. Ring-closing olefin metathesis reaction
was employed for butenolide side-chain elongation.
8. Keum, G.; Kang, S. B.; Kim, Y.; Lee, E. Org. Lett. 2004,
6, 1895–1897.
9. Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Park, J. C.
J. Org. Chem. 1990, 55, 4109–4117.
10. Use of allyltrimethylsilane and allyltributylstannane in
the presence of Lewis acids (titanium tetrachloride or
magnesium bromide etherate) gave inferior results in this
case. Configuration of the carbinol center was elucidated
by 1H NMR analysis of the (S)-(O)-acetylmandelate
derivative.
11. Klunder, J. M.; Onami, T.; Sharpless, K. B. J. Org. Chem.
1989, 54, 1295–1304.
12. The E/Z ratio (ꢁ1:1) was determined tentatively.
13. The failure probably indicates steric crowding in the
enolate structure.
Acknowledgements
The authors thank the Ministry of Science and Technol-
ogy, Republic of Korea, and KISTEP for a NRL grant
(1999) and Center for Bioactive Molecular Hybrids
(Yonsei University and KOSEF) for a research grant.
BK21 graduate fellowship grants to C. H. Hwang are
gratefully acknowledged.
Supplementary data
14. The sample exhibited identical spectroscopic characteris-
tics as those of the synthetic sample reported in Ref.
½29ꢂ
Supplementary Information available: experimental de-
tails for preparation of 8, 11, 19 and 1, and H and
2: ½aꢂD ꢀ9.1 (c 0.34, MeOH). (Data for the natural
1
D
sample: ½aꢂ26 ꢀ8.9 (c 0.05, MeOH).)2