Concise stereoselective synthesis of cis-3-alkoxy-2-carbomethoxy medium-ring oxacycles from (R)-3-(3-butenyl)-4-propynoyloxazolidin-2-one

Article abstract of DOI:10.1016/j.tetlet.2007.12.111

A concise process for the stereoselective synthesis of chiral cis-3-alkoxy-2-carbomethoxy medium-ring oxacycles from (R)-3-(3-butenyl)-4-propynoyloxazolidin-2-one (1) was developed. The process includes five major steps: (i) hetero-Michael reaction betwee

Full text of DOI:10.1016/j.tetlet.2007.12.111

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1514–1517
Concise stereoselective synthesis of cis-3-alkoxy-2-
carbomethoxy medium-ring oxacycles from
(R)-3-(3-butenyl)-4-propynoyloxazolidin-2-one
a
a,
*
Daisuke Sato , Kenshu Fujiwara , Hidetoshi Kawai a,b, Takanori Suzuki a
a Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
b PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
Received 21 November 2007; revised 13 December 2007; accepted 20 December 2007
Available online 25 December 2007
Abstract
A concise process for the stereoselective synthesis of chiral cis-3-alkoxy-2-carbomethoxy medium-ring oxacycles from (R)-3-(3-
butenyl)-4-propynoyloxazolidin-2-one (1) was developed. The process includes five major steps: (i) hetero-Michael reaction between
an alcohol and 1, (ii) stereoselective reduction of the resulting ketone, featuring stereochemical assistance of the neighboring oxazoli-
din-2-one group, (iii) esterification with an alkoxy acetic acid, (iv) chirality-transferring Ireland–Claisen rearrangement of the resulting
3-alkoxyallyl glycolate ester to provide a syn-2,3-dialkoxy carboxylate ester, and (v) relay ring-closing olefin metathesis to form a
medium-ring ether along with the simultaneous removal of the oxazolidin-2-one moiety.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Stereoselective synthesis; Cyclic ethers; Ireland–Claisen rearrangement; Relay ring-closing olefin metathesis
Medium-ring ethers, often occurring in potent bioactive
natural products,1 have attracted much attention among
synthetic chemists due to the challenges in the stereoselective
construction of the medium-rings and ether systems with
adjacent oxygen-functionalities. To date, various synthetic
methodologies have been reported by numerous research
groups,2 including our diastereoselective synthesis of race-
mic cis- and trans-3-alkoxy-2-carbomethoxy eight-mem-
bered oxacycles from 3-alkoxyallyl glycolates via Ireland–
Claisen rearrangement3 and ring-closing olefin metathesis
(RCM).4,5 As an extension of our methodology toward
the construction of optically active cyclic ethers, the concise
stereoselective synthesis of (2S,3R)-cis-3-alkoxy-2-carbo-
methoxy medium-ring oxacycles (2) from (R)-3-(3-butenyl)-
4-propynoyloxazolidin-2-one (1) is described herein.
Our asymmetric synthesis of medium-ring ethers 2 from
chiral E-3-alkoxyallyl alcohol 5 is shown in Scheme 1.
Based on our previously reported synthetic methodology,
5 was transformed into glycolate ester 4, which was
subjected to a chirality-transferring Ireland–Claisen rear-
rangement to 3, then cyclized to 2 via RCM. Because the
preparation of 5 requires the stereoselective construction
of an E-alkoxy alkene with a hydroxymethyne group, dia-
stereoselective reduction of 6 to 5 was carried out with the
assistance of a 3-(3-butenyl)oxazolidin-2-one-4-yl moiety
(R1) (as a chiral auxiliary),6 following the E-selective
hetero-Michael reaction of an alcohol to 1, which was
prepared from L-serine. Furthermore, the chiral auxiliary
can be removed, as bicyclic 8, during the final cyclization
of 3 to 2 by a relay ring-closing olefin metathesis (RRCM)
process7 via intermediates 7 and 9.
First, as shown in Scheme 2, chiral acetylene ketone 18
was prepared from known oxazolidinone 109,10 (available
from L-serine) via Swern oxidation,11 followed by the
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706 4924.
E-mail address: fjwkn@sci.hokudai.ac.jp (K. Fujiwara).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.111

D. Sato et al. / Tetrahedron Letters 49 (2008) 1514–1517
1515
Chirality-Transferring
R1-Assisted
Stereoselective
Reduction
Ireland-Claisen Rearrangement
Esterification
O
O
O
O
O
O
O
O
MeO
R2O
MeO
R2O
MeO
R1
O
HO
R1
n
n
n
n
OR2
R1
OR2
OR2
R
R
R
R1
2
3
3
4
5
n = 1-3
O
O
Relay
Ring-Closing
Olefin Metathesis
MeO
O
n
Hetero-Michael
Reaction
O
R1
O
R2O
[Ru]
MeO
R2O
n
HOR2
O
R
N
N2
R1
OR2
L-Serine
O
O
O
R
[Ru]
N
O
O
O
9
8
7
1
6
Scheme 1.
1) Swern oxid.
2)
1) KHMDS
HO2CCH2OR (12a-c)
O
MgBr
78 °C
(75%, 2 steps)
TMSCl, THF
EDCI•HCl
RO
HO
THF,
—
O
O
O
DMAP, CH2Cl2
25 °C, 1 h
—78
0 °C
Ref. 9
N
14 —19 h
L-serine
1
11
BnO
3) IBX, EtOAc
reflux, 16 h (80%)
O
2) TMSCHN2
MeOH
N
10
a: R=-(E)-CH2CH=CHPr
13a-c
O
Scheme 2.
b: R=-(Z)-CH2CH2CH=CHEt
c: R=-(Z)-CH2CH2CH2CH=CHMe
addition of ethynylmagnesium bromide and IBX oxida-
tion12 (overall 60%).
O
MesN
Cl
NMes
Ru
OR
MeO
BnO
Next, to establish the geometry and stereocenter for the
subsequent Ireland–Claisen rearrangement step, the
hetero-Michael reaction between acetylene ketone 1 and
an alcohol, followed by diastereoselective reduction was
investigated (Scheme 3). In the presence of a catalytic
amount of DMAP, the reaction between 1 and benzyl alco-
hol proceeded smoothly to selectively give an E-alkenyl
ketone (75%),13 which was reduced with L-Selectride to
afford alcohol 11 as a single stereoisomer (82%).6
O
H
O
Cl
Ph
PCy3
MeO
2
n
+
8
3
(CH2Cl)2 (5 mM)
80 °C
3 h (for 14a,c) or
4 h (for 14b)
O
BnO
N
H
(100%)
(100%)
(72%)
14a (55%)*
O
15a (n=1; 89%)
15b (n=2; 57%)
15c (n=3; 58%)
14b (56%)
*
14c (60%)*
*yeild from 11
Scheme 4.
The second half of our synthetic route is shown in
Scheme 4. Using EDCI/DMAP, alcohol 11 was esterified
with alkenyloxyacetic acids 12a–c to give corresponding
esters 13a–c, which are unstable under typical purification
conditions but easily separable from impurities by simple
extractive work up, and therefore, used without further
purification. Upon deprotonation of esters 13a–c using
KHMDS in THF at ꢀ78 °C in the presence of TMSCl,
the resulting ketene silyl acetals stereoselectively rearranged
to the corresponding carboxylic acids while warming to
ambient temperature. Treatment of each carboxylic acid
with TMSCHN2 produced a stereochemically homo-
geneous methyl (E)-syn-2,3-dialkoxy-4-pentenoate (14a:
55%, 14b: 56%, 14c: 60%, from 11). Trienes 14a–c were then
subjected to RRCM using a second-generation Grubbs’
catalyst14 to give the corresponding six-, seven-, and
eight-membered cyclic ethers 15a–c15 (89%, 57%, and
58%, respectively) along with 8 (72–100%). The relative
stereochemistry of 15a–c was confirmed by the relatively
small JH2–H3 values (15a: 2.8 Hz, 15b: 1.8 Hz, 15c: 3.3 Hz)
and the presence of NOE between H2 and H3 in NMR
analysis. To prove the efficiency of the chirality-transfer
process from 1 to the oxocycle products, the absolute
stereochemistry of 15a was investigated as a representative
example and determined to be a 2S,3R-configuration16 with
the same optical purity (>93% ee)17 as that of 10.18
OH
1) BnOH, DMAP (0.05 eq)
CH2Cl2, 25 °C, 1 h (75%)
BnO
O
O
N
1
2) L-Selectride,THF
—78 °C, 15 min (82%)
11
Scheme 3.

1516
D. Sato et al. / Tetrahedron Letters 49 (2008) 1514–1517
293; (c) Scheuer, P. J. Tetrahedron 1994, 50, 3; (d) Shimizu, Y. Chem.
MesN
NMes
Ru
Rev. 1993, 93, 1658; (e) Yasumoto, T.; Murata, M. Chem. Rev. 1993,
93, 1895. See also: (f) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.;
Northcore, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2001, 18, 1.
2. Recent reviews for the synthesis of medium-ring ethers see: (a)
Fujiwara, K. In Topics in Heterocyclic Chemistry; Springer: Berlin,
2006; Vol. 5, p 97; (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004,
104, 2127; (c) Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301;
(d) Elliot, M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 1 2001,
2303; (e) Yet, L. Chem. Rev. 2000, 100, 2963; (f) Hoberg, J. O.
Tetrahedron 1998, 54, 12631; (g) Alverz, E.; Candenas, M.-L.; Perez,
R.; Ravelo, J. L.; Martin, J. D. Chem. Rev. 1995, 95, 1953.
3. Recent reviews: (a) Castro, A. M. M. Chem. Rev. 2004, 104, 2939; (b)
Nubbemeyer, U. Synthesis 2003, 961; (c) Chai, Y.; Hong, S.-P.;
Lindsay, H. A.; McFarland, C.; MxIntosh, M. C. Tetrahedron 2002,
58, 2905.
4. (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinhem, 2003. For the tandem use of Ireland–Claisen rearran-
gement and ring closing olefin metathesis; see: (b) Barrett, A. G. M.;
Ahmed, M.; Baker, S. P.; Baugh, S. P. D.; Braddock, D. C.;
Procopiou, P. A.; White, A. J. P.; William, D. J. J. Org. Chem. 2000,
65, 3716; (c) Miller, J. F.; Termin, A.; Koch, K.; Piscopio, A. D. J.
Org. Chem. 1998, 63, 3158; (d) Burke, S. D.; Ng, R. A.; Morrison, J.
A.; Alberti, M. J. J. Org. Chem. 1998, 63, 3160.
MeO2C
BnO
O
Cl
Cl
Ph
MeO2C
BnO
O
PCy3
Pr
(CH2Cl)2 (5 mM)
80 °C, 3 h
O
N
Bu
(~17%)
O
16
15a
Scheme 5.
Then, we examined RCM of 3-butyloxazolidin-2-on-4-yl
derivative 16 instead of 14a as a control experiment to clar-
ify the efficiency of the N-(3-butenyl) group in RRCM pro-
cess. As a result, a significant decrease in the yield of 15a
(ꢁ17%) was observed under identical cyclization condi-
tions (Scheme 5).19 This indicates that, during the initial
step of RRCM, the metathesis of the N-(3-butenyl) group
is required for high yields of the cyclic ethers.
In summary, a concise process for the stereoselective
synthesis of chiral cis-3-alkoxy-2-carbomethoxy medium-
ring oxacycles from (R)-3-(3-butenyl)-4-propynoyloxazol-
idin-2-one (1) was developed. The process includes major
five steps: (i) hetero-Michael reaction between an alcohol
and 1, (ii) stereoselective reduction of the resulting ketone
6, featuring the stereochemical assistance of the neigh-
boring oxazolidin-2-one group, (iii) esterification with an
alkoxy acetic acid, (iv) chirality-transferring Ireland–Clais-
en rearrangement of the resulting 3-alkoxyallyl glycolate
ester 4 to provide syn-2,3-dialkoxy carboxylate ester 3,
and (v) relay ring-closing olefin metathesis to produce med-
ium-ring ether 2 along with the simultaneous removal of
the oxazolidin-2-one moiety. Further studies including
the reutilization of 8 and the application of the process to
natural product synthesis are currently underway in our
laboratories.
5. Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron
Lett. 2005, 46, 3465.
6. Katsumura, S.; Yamamoto, N.; Fukuda, E.; Iwama, S. Chem. Lett.
1995, 393.
7. (a) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210; See, also: (b) Boisvert, L.;
Beaumier, F.; Spino, C. Can. J. Chem. 2006, 84, 1290.
10
8. Selected spectral data of 1: ½aꢂD +1.1 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3) d 5.76 (1H, ddd, J = 16.9, 7.3, 6.9 Hz), 5.16–5.08
(2H, m), 4.50 (1H, t, J = 10.6 Hz), 4.42 (1H, dd, J = 10.6, 3.7 Hz),
4.39 (1H, dd, J = 10.6, 3.7 Hz), 3.75 (1H, dt, J = 14.3, 7.3 Hz), 3.52
(1H, s), 3.19 (1H, dt, J = 14.3, 6.6 Hz), 2.34 (2H, m); 13C NMR
(75.5 MHz, CDCl3) d 183.3 (C), 157.3 (C), 134.1 (CH), 117.4 (CH2),
84.7 (CH), 78.3 (C), 63.8 (CH), 63.1 (CH2), 42.4 (CH2), 31.4 (CH2);
IR (film) mmax 3250, 3080, 2979, 2919, 2091, 1753, 1691, 1450,
1443, 1415, 1217, 1113, 1047, 916, 757; LR-EIMS m/z 194 (10.9%,
[M++H]), 55 (bp); HR-EIMS calcd for C10H12O3N [M++H]: 194.08.
9. (a) Lin, C.-C.; Pan, Y.-s.; Patkar, L. N.; Lin, H.-M.; Tzou, D.-L. M.;
Subramanian, T. S.; Lin, C.-C. Bioorg. Med. Chem. 2004, 12, 3259;
(b) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418.
10. The optical purity of 10 was determined to be >93% ee by NMR
analysis of the derivative of 10 with (+)- or (ꢀ)-MTPA.
11. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2048.
Acknowledgments
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC–MS and NMR Laboratory, Graduate School of Agri-
culture, Hokkaido University) for the measurements of
mass spectra. This work was supported by a Global COE
Program (B01: Catalysis as the Basis for Innovation in
Materials Science) and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology of Japanese Government.
12. More, J. D.; Finney, N. S. Org. Lett. 2002, 17, 3001.
13. Ariza, X.; Costa, A. M.; Faja, M.; Pineda, O.; Vilarrasa, J. Org. Lett.
2000, 2, 2809.
14. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
23
15. Selected spectral data: 15a: ½aꢂD ꢀ239.4 (c 1.00, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.33–7.24 (5H, m), 5.86 (1H, dd, J = 10.8,
3.3 Hz), 5.98 (1H, ddd, J = 15.4, 2.6, 1.5 Hz), 4.66 (1H, d,
J = 11.8 Hz), 4.55 (1H, d, J = 11.8 Hz), 4.28 (1H, td, J = 14.1,
2.6 Hz), 4.25 (1H, d, J = 2.8 Hz), 4.19 (1H, dd, J = 14.1, 1.5 Hz), 4.15
(1H, dd J = 3.3, 2.8 Hz), 3.78 (3H, s); 13C NMR (75 MHz, CDCl3) d
169.4 (C), 138.2 (C), 131.2 (CH), 128.2 (CH ꢃ 2), 127.7 (CH ꢃ 2),
127.5 (CH), 122.8 (CH), 77.1 (CH), 70.5 (CH2), 68.7 (CH), 65.8
(CH2), 52.0 (CH3); IR (film) mmax 3032, 2950, 2869, 1764, 1735, 1496,
1454, 1437, 1393, 1352, 1322, 1292, 1260, 1209, 1189, 1096, 1068,
1041, 958, 938, 868, 739, 698; LR-EIMS; m/z 189 ([M+ꢀCO2CH3],
3.1%), 91 (bp); HR-EIMS calcd for C12H13O2 [M+ꢀCO2CH3]:
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.12.111.
References and notes
23
189.0916, found: 189.0879. 15b: ½aꢂD ꢀ145.5 (c 0.73, CHCl3); 1H
NMR (300 MHz, CDCl3) d 7.34–7.25 (5H, m), 6.09 (1H, ddd,
J = 11.3, 6.9, 3.6 Hz), 5.89 (1H, ddd, J = 11.3, 6.6, 2.5 Hz), 4.68 (1H,
1. Reviews for natural cyclic ethers, see: (a) Yasumoto, T. Chem. Rec.
2001, 3, 228; (b) Yasumoto, T.; Murata, M. Nat. Prod. Rep. 2000, 17,

D. Sato et al. / Tetrahedron Letters 49 (2008) 1514–1517
1517
d, J = 12.1 Hz), 4.45 (1H, d, J = 12.1 Hz), 4.37 (1H, dd, J = 6.6,
1.8 Hz), 4.32 (1H, dd, J = 9.5, 2.9 Hz), 4.26 (1H, d, J = 1.8 Hz), 3.74
with Pt/C, and the sign of the optical rotation of the derivative agreed
16
25
with that of the literature: ½aꢂD ꢀ51.5 (c 0.195, CHCl3) {lit.: ½aꢂD
(3H, s), 3.65 (1H, td, J = 9.5, 2.5 Hz), 2.71 (1H, m), 2.30 (1H, m); 13
C
ꢀ58.9 (c 2.1, CHCl3)}: Carrillo, R.; Martın, V. S.; Lopez, M.; Martın,
´
´
´
NMR (75 MHz, CDCl3) d 170.6 (C), 138.2 (C), 135.7 (CH), 128.2
(CH ꢃ 2), 127.9 (CH ꢃ 2), 127.6 (CH), 127.3 (CH), 81.7 (CH), 75.6
(CH), 70.3 (CH2), 69.7 (CH2), 52.2 (CH3), 31.9 (CH2); IR (film) mmax
3063, 3027, 2950, 2907, 1762, 1731, 1496, 1454, 1434, 1389, 1339,
1287, 1204, 1152, 1090, 1065, 1027, 921, 737, 698, 671; LR-FDMS m/z
262 ([M+], bp); HR-FDMS calcd for C15H18O4 [M+]: 262.1205,
T. Tetrahedron 2005, 61, 8177.
17. The precise optical purity of 15a was determined by NMR analysis
of the diastereomer ratio in the reaction mixture obtained from (R)-
or (S)-MTPA with an alcohol derived from 15a via LiAlH4-
reduction.
18. The absolute stereochemistry and optical purity of 15b,c have not yet
been determined due to the absence of appropriate literature for
authentic data. They are now under investigation.
23
found: 262.1205. 15c: ½aꢂD ꢀ58.7 (c 0.60, CHCl3); other spectral data
were identical with those reported in Ref. 5.
16. Ester 15a was converted to known (2R,3R)-3-benzyloxy-2-hydroxy-
methyloxane by reduction with LiAlH4 followed by hydrogenation
19. A significant amount of 16 was recovered (74%).