Studies toward the total synthesis of armatol F: Stereoselective construction of the C6 and C7 stereocenters and formation of the A-ring skeleton

Article abstract of DOI:10.1016/j.tetlet.2010.06.026

Armatol F, isolated from the red alga Chondria armata as a polyether triterpene, has a solitary oxepane (A-ring) and a fused tricyclic ether moiety (BCD-ring). The A-ring features a rare cis-relationship between the hydroxy group at the quaternary carbon C6 and the carbon chain at C7. As part of our program toward the total synthesis of armatol F, a new stereoselective method for the construction of the C6 and C7 stereocenters has been developed based on chirality-transferring Ireland-Claisen rearrangement. The A-ring skeleton has also been synthesized from the rearrangement product by a process including ring-closing olefin metathesis.

Full text of DOI:10.1016/j.tetlet.2010.06.026

Tetrahedron Letters 51 (2010) 4263–4266
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Tetrahedron Letters
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Studies toward the total synthesis of armatol F: stereoselective construction
of the C6 and C7 stereocenters and formation of the A-ring skeleton
a
a
Kenshu Fujiwara a, , Yuta Hirose , Daisuke Sato , 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
a r t i c l e i n f o
a b s t r a c t
Article history:
Armatol F, isolated from the red alga Chondria armata as a polyether triterpene, has a solitary oxepane
(A-ring) and a fused tricyclic ether moiety (BCD-ring). The A-ring features a rare cis-relationship between
the hydroxy group at the quaternary carbon C6 and the carbon chain at C7. As part of our program toward
the total synthesis of armatol F, a new stereoselective method for the construction of the C6 and C7 ste-
reocenters has been developed based on chirality-transferring Ireland-Claisen rearrangement. The A-ring
skeleton has also been synthesized from the rearrangement product by a process including ring-closing
olefin metathesis.
Received 28 May 2010
Accepted 7 June 2010
Available online 11 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Armatol F (1, Fig. 1) was isolated from the red alga Chondria ar-
mata by Ciavatta et al. as a polyether triterpene.1 It has a solitary
oxepane (A-ring), a fused tricyclic ether moiety (BCD-ring), and
bromo substituents at both ends of the molecule. Partial relative
configurations of the A-ring and the BCD-ring have been deter-
mined by NMR analysis, though the relative relationship between
the A and the BCD-rings and the configuration at C10 is unclear.
The partial absolute stereochemistry of the A-ring can be deduced
as shown in Figure 1 by analogy with that of armatol A, a congener
of 1.1
It is remarkable that the hydroxy group at the C6 quaternary
carbon in the A-ring of 1 is in a cis-relationship to the carbon chain
at C7, because the cis-configuration is unusual among the natural
oxepanes possessing similar substituents.2 The cis-fusion between
the C and D rings of 1 is also unusual for natural fused polycyclic
ethers.3,4
The remarkable structural characteristics of 1 prompted us to
initiate a program toward the total synthesis and determination
of full absolute configuration of 1. As part of the program, the syn-
thesis of the A-ring has been studied. We describe herein the ster-
eoselective construction of the C6 and C7 stereocenters based on
chirality-transferring Ireland-Claisen rearrangement and the for-
mation of the A-ring skeleton.
The outline of the synthesis of the A-ring skeleton (2), an impor-
tant synthetic intermediate for the full functionalized A-ring, is
shown in Scheme 1 retrosynthetically. The synthesis included the
following challenges: (i) formation of the seven-membered ring
of 2 and (ii) stereoselective construction of a congested tert-alkoxy
b0-methyl-b0-alkoxyalkyl ether, corresponding to the C2–O–C7–C6
27
28
25 1 Me
Me OH
8
Me
24
7
11
O
O
B
Me
H
26
10
Me
Me30
O
C
6
Me
A
Br
3
D
O
OH
H
Me
Br
22
29
Armatol F (1)
Figure 1.
OTHP
Me
OTHP
1 Me
Me
RCM
7
7
O
O
O
Me
Me
Me
2 A
6
6
2
Me
OH
Me
Me
Br
3
OPMP
OPMP
1
2
3
OTMS
Z
O
O
4
7
Me
6
Me
7
CO2Me
E
O
O
Me
Me
Br
O
Me
PMPO
5
7
O
Me
6
Me
Me
4
O
O
OPMP
4
Me
6
Me
Me
O
Br
E
6
Me
Me
PMPO
O
4
Chirality-Transferring
Ireland-Claisen Rearrangement
Esterification
Me OH
O
Me
O
PMPO
6
4
O
Me
+
OH
O
Me
Me
Me
Br
8
7
* Corresponding author. Tel.: +81 (0)11 706 2701; fax: +81 (0)11 706 4924.
E-mail address: fjwkn@sci.hokudai.ac.jp (K. Fujiwara).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.026

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K. Fujiwara et al. / Tetrahedron Letters 51 (2010) 4263–4266
part of 2. The seven-membered ring was formed by employing the
ring-closing olefin metathesis of diene 3. Applying the Ireland-
Claisen rearrangement to ester 6 provided the congested ether 4
in a chirality transferring fashion via a presumed chair-shaped
transition state derived from a Z-ketene silyl acetal intermediate
(5).5,6 The success of the stereoselective rearrangement strongly
relied on the stereoselective construction of the substrate’s
trisubstituted E-enol ether group and the adjacent chiral center
C4, which originated from alcohol 7. The counterpart carboxylic
acid 8 included a 2-methyl-3-bromo-2-butyl group as a masked
2-methyl-3-buten-2-yl group.
2,2-dimethyl-1,3-dioxolan-4-yl group,12 produced 7 in 92% yield
under Luche conditions.13,14
The enantiomer of 7 (ent-7) was also prepared from 1,2:5,6-
di-O-isopropylidene-D a similar manner
-mannitol (16)15 in
(Scheme 4).
The stereoselective construction of the quaternary and tertiary
centers at C6 and C7, respectively, was first examined with ent-7
and 8 (Scheme 5). Esterification of ent-7 with 8, mediated by ED-
CIꢀHCl and DMAP, smoothly produced ester ent-6, which was sub-
jected to the next reaction immediately after purification because
of its instability. The ester was then treated with LDA followed
by TMSCl at ꢁ78 °C, and the resulting ketene silyl acetal was rear-
ranged by warming to ambient temperature to produce carboxylic
acids, which were converted to ent-4 and 17 by methylation with
The carboxylic acid 8 was prepared as a racemate by NBS-
mediated bromoetherification of 2-methyl-2-butene with methyl
glycolate (9) without using a solvent and subsequent basic hydro-
lysis in 54% overall yield based on 9 (Scheme 2).7
Synthesis of alcohol 7 from 5,6-O-isopropylidene-
L-gulonic acid
Me
O
-lactone (11) is shown in Scheme 3.8 Oxidative cleavage of 119
NaIO4
Me
c
OH
O
pH 7 buffer
followed by the addition of propynyl lithium derived from 1-bro-
mo-1-propene gave alcohol 13 as a mixture of diastereomers in
33% overall yield. The alcohol was oxidized with Dess–Martin peri-
odinane to afford acetylene ketone 14 in 94% yield.10 The hetero-
Michael reaction of 14 with an excess amount of 4-methoxyphenol
in the presence of PBu3 and N,N-dimethylbenzylamine furnished E-
enol ether ketone 15 as a single geometrical isomer in 46% yield.11
The absence of PBu3 or N,N-dimethylbenzylamine resulted in a
poor yield of 15. The mechanistic details are unknown at present.
The diastereoselective reduction of 15, assisted by the neighboring
O
H
O
O
CH2Cl2
23 °C, 1 h
O
O
OH
16
Me
Me
Me
Me
ent-12
MgBr
Me
1) DMPI (86%)
2) PMPOH
PBu3
73%
(2 steps)
Me OH
OH
BnNMe2 (66%)
PMPO
O
O
O
O
Me
3) NaBH4
CeCl3•7H2O
(93%)
Me
Me
Me
Me
Me
Me
O
ent-7
ent-13
Me
Me
O
O
Me (2 eq)
OR
50% aq. NaOH
MeOH, 23 °C, 3 h
54% (2 steps)
HO
Scheme 4.
OMe
NBS (2 eq)
23 °C, 10 h
(without solvent)
Me
Br
9
10: R=Me
8: R=H
O
Me OH
8, DMAP
Me
O
EDCI•HCl
Me
Me
O
PMPO
O
Me
Me
Scheme 2.
O
Me
O
Me
CH2Cl2
23 °C
Me
O
Br
PMPO
ent-6
ent-7
Me
O
Me
O
R1
R2
KIO4
O
Me
1) LDA (3.0 eq), Solvent
–78 °C, Time
then TMSCl (3.0 eq)
–78 °C, 30 min
O
O
O
KHCO3
H
O
Me
Me
7
O
Me
OPMP
6
Me
CH2Cl2-H2O
(10:1)
23 °C, 10 h
Me
HO
11
OH
Br
O
Br
12
then 23 °C, 1 h
Me
Me
O
(1.6 eq)
Me
2) TMSCHN2
PhH-MeOH (3:1)
O
BuLi (3 eq), THF
–78 °C, 20 min
then 12
–78 °C, 30 min
33% (2 steps)
ent-4: R1=H, R2=CO2Me
17: R1=CO2Me, R2=H
O
O
Me
Me
DMPI, NaHCO3
CH2Cl2
Me
Yield
(3 steps)
Entry
Solventa
THF
Et2O-THF (14:1)
Time
ent-4 : 17
94%
OH
(8 eq)
14
23 °C, 2 h
OH
1
20 min
20 min
52%
36%
78%
39%
66%
1.4 : 1
1.3 : 1
5 : 1
O
MeO
2
O
Me
Me
Me
PBu3 (0.4 eq)
3
toluene-THF (14:1) 20 min
NMe2
(0.4 eq)
13
4
toluene
toluene
toluene
20 min
5 min
5 min
≥20 : 1
13 : 1
CH2Cl2
0 °C → 23 °C, 18 h
46%
5
NaBH4
CeCl3•7H2O
MeOH
6b
52% 4 : ent-17 =
≥20 : 1
Me
O
PMPO
7
O
a A small amount of hexane (~10%, from BuLi soln.) was contained.
–78 °C, 10 min
92%
O
Me
b Alcohol 7 was used instead of ent-7.
15
Me
Scheme 3.
Scheme 5.

K. Fujiwara et al. / Tetrahedron Letters 51 (2010) 4263–4266
4265
TMS-diazomethane. During optimization of reaction conditions to
THPO
Me
THPO
Me
THPO
O
1) OsO4
NMO
Me
obtain the desired ent-4 exclusively, we observed a significant sol-
vent effect on the selectivity of ent-4 and 17, shown in the inset ta-
ble in Scheme 5.16 When THF or Et2O was used as solvent, the ratio
of ent-4 to 17 was low (1.3–1.4:1) (entries 1 and 2). Treatment of a
solution of ester ent-6 in toluene with a solution of LDA in THF en-
hanced the combined yield (78% over three steps) and the ratio of
ent-4 (5:1) (entry 3). Exclusion of THF from the reaction media by
use of a solution of LDA in toluene produced ent-4 predominantly
(P20:1), but in moderate yield (39% over three steps) (entry 4).
Since the decreased yield was attributable to the instability of an
enolate intermediate from ent-6 in toluene, the time period for
deprotonation from the substrate was shortened to avoid decom-
position of the enolate. As a result, a 5-min treatment of ent-6 with
LDA effectively furnished ent-4 in good yield (66% over three steps)
with high selectivity (13:1) (entry 5).19 The optimized conditions
were applied to natural enantiomer 7, and the desired 420 was ob-
tained exclusively in 52% yield over three steps. Thus, the stereose-
lective construction of the quaternary and tertiary stereocenters at
C6 and C7, respectively, of the A-ring of 1 was achieved.
The construction of the seven-membered ring from 4 is illus-
trated in Scheme 6. The 2,2-dimethyl-1,3-dioxolan-4-yl group of
4 was transformed to a hydroxymethyl group via acidic hydrolysis,
oxidative diol cleavage, and Luche reduction (97% over three
steps). The protection of the resulting 17 as a TIPS ether followed
by reduction of the ester group afforded alcohol 18 (90% over
two steps). After THP protection of 18, the resulting THP ether
was treated with t-BuOK in a 3:1 DMSO–THF solution to give a
mixture of a dehydrobrominated product and its desilylated alco-
hol (19).7 Complete desilylation of the mixture with TBAF provided
19 in good overall yield (73% over three steps). The allyl alcohol
group of 19 was then converted to a terminal alkenyl group accord-
ing to Movassaghi’s procedure.21 Substitution of the hydroxyl
group of 19 with N-isopropylidene-N0-(2-nitrophenylsulfo-
nyl)hydrazide (IPNBSH) under Mitsunobu conditions22 in the pres-
ence of an excess amount of 1-hexene as a scavenger of free
diimide,6c followed by in situ hydrolysis of the hydrazone group,
induced spontaneous elimination of a sulfinate and reductive ole-
fin migration to produce diene 3 quantitatively. Ring-closing olefin
O
O
LiEt3BH
Me
HO
Me
HO
Me
Br
3
2
A
Me
Me
Me
2) TsCl
45%
81%
ds = 2.3:1
PMPO
PMPO
PMPO
TsO
20
21
22
Scheme 7.
metathesis of 3 in the presence of second-generation Grubbs’ cat-
alyst23 smoothly furnished 224,20 in excellent yield (96%), thereby
completing the stereoselective construction of the A-ring skeleton
of 1. Similarly, the enantiomer of 2 (ent-2) was synthesized from
ent-4 (overall 54%). Both 2 and ent-2 would be available for the
synthesis of 1 and its stereoisomers aiming at determination of full
absolute stereochemistry.
In conclusion, the A-ring skeleton (2) of armatol F (1), which has
unique configurations at C6 and C7 among natural oxepanes, has
been constructed based on chirality-transferring Ireland-Claisen
rearrangement and ring-closing olefin metathesis. Transformation
of 2 to the full functionalized A-ring (22) is currently underway via
a route including dihydroxylation, selective tosylation, reduction
by Robins’ procedure,25 and installation of a bromo group (Scheme
7). At present, alcohol 21 was obtained stereoselectively as a pre-
liminary result.26 Further studies toward the total synthesis of
armatol F are in progress in this laboratory, specifically the stereo-
selective installation of a bromo group at C3 in the A-ring and the
construction of the BCD-ring.
Acknowledgments
We thank Dr. Eri Fukushi (GC–MS & NMR Laboratory, Graduate
School of Agriculture, 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 Educa-
tion, Culture, Sports, Science, and Technology of Japanese
Government.
References and notes
1) 1 M HCl-THF (1:1)
23 °C, 14 h
2) NaIO4, pH 7 buffer
THF, 23 °C, 1 h
1) TIPSOTf
2,6-lutidine
CH2Cl2
1. Ciavatta, M. L.; Wahidulla, S.; D’Souza, L.; Scognamiglio, G.; Cimino, G.
Tetrahedron 2001, 57, 617.
Me
CO2Me
O
2. Examples
of
natural
r-2-alkyl-t-3-hydroxy-c-3-methyloxepanes.
Me
Me
Hemibrevetoxin B: (a) Prasad, A. V. K.; Shimizu, Y. J. Am. Chem. Soc. 1989,
111, 6476; Gambierol: (b) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc.
1993, 115, 361; (c) Morohashi, A.; Satake, M.; Yasumoto, T. Tetrahedron Lett.
1999, 40, 97; Brevenal: (d) Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.;
Bigwarfe, P. M., Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2; (e) Fuwa, H.; Ebine, M.;
Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 128, 16989.
3. Reviews for fused polycyclic ethers, see: (a) Yasumoto, T.; Murata, M. Chem.
Rev. 1993, 93, 1897; (b) Shimizu, Y. Chem. Rev. 1993, 93, 1685; (c) Murata, M.;
Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293; (d) Yasumoto, T. Chem. Rec. 2001, 1,
228; (e) Daranas, A. H.; Norte, M.; Fernández, J. J. Toxicon 2001, 39, 1101.
4. There are a few examples of natural polycyclic ethers possessing cis-fused
ether rings. Dactomelynes: (a) Gopichand, Y.; Schmitz, F. J.; Shelly, J.; Rahman,
A.; Van der Helm, D. J. Org. Chem. 1981, 46, 5192; Maitotoxin: (b) Satake, M.;
Ishida, S.; Yasumoto, T.; Murata, M.; Utsumi, H.; Hinomoto, T. J. Am. Chem. Soc.
1995, 117, 7019.
5. We expect the formation of intermediate Z-ketene silyl acetal 5 in the Ireland-
Claisen rearrangement of 6 from the stereochemistry of product 4 obtained.
The selective formation of Z-ketene silyl acetal intermediates in the Claisen
rearrangement reactions of allyl glycolate ester derivatives has been expected
from the stereochemistry of the major products by several research groups,
see: see also Ref. 17: (a) Sato, T.; Tajima, K.; Fujisawa, T. Tetrahedron Lett. 1983,
24, 729; (b) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J. J. Org. Chem. 1983, 48,
5221; (c) Gould, T. J.; Balestra, M.; Wittman, M. D.; Gary, J. A.; Rossano, L. T.;
Kallmerten, J. J. Org. Chem. 1987, 52, 3889.
23 °C, 1 h
Me
4
Br
HO
OPMP
3) NaBH4, CeCl3•7H2O
MeOH, –78 °C, 5 min
97% (3 steps)
2) LiAlH4
THF
0 °C
2 h
17
90%
(2 steps)
Me
Me
Me
1) DHP, CSA
CH2Cl2
23 °C, 13 h
OTHP
Me
OPMP
OH
O
O
Me
Me
Me
Br
OPMP
2) -BuOK
t
DMSO-THF (3:1)
23 °C, 3 h
3) TBAF, THF
0 °C, 0.5 h
OH
19
OTIPS
18
O
O
S
73% (3 steps)
HN N
O2N
(8 eq)
Me
Me
N
N
Mes
Mes
DEAD (8 eq)
THF-1-hexene (10:1)
0 °C, 1 h
Cl2Ru
Cy3P
Ph (0.1 eq)
2
3
then CF3CH2OH-H2O
23 °C, 2 h
6. For related approaches to b-alkoxyalkyl ethers using the Ireland-Claisen
rearrangement, see: (a) Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 3465; (b) Sato, D.; Fujiwara, K.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2008, 49, 1514; (c) Fujiwara, K.; Kawamura, N.; Kawai, H.;
Suzuki, T. Tetrahedron Lett. 2009, 50, 1236.
CH2Cl2, 23 °C, 17 h
[0.65 mM of 3]
96%
100%
Scheme 6.
7. Rodriguez, J.; Dulcere, J.-P.; Bertrand, M. Tetrahedron Lett. 1984, 25, 527.

4266
K. Fujiwara et al. / Tetrahedron Letters 51 (2010) 4263–4266
8. For a related approach to optically active E-3-alkoxyallyl alcohols, see: Goto, A.;
Fujiwara, K.; Kawai, A.; Kawai, H.; Suzuki, T. Org. Lett. 2007, 9, 5373.
9. Hubschwerlen, C.; Specklin, J.-L.; Higelin, J. Org. Synth. 1995, 72, 1.
10. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess, D. B.; Martin, J.
C. J. Am. Chem. Soc. 1991, 113, 7277.
presence of a clear NOE between H7 and 6-CH3 of an alcohol derived from 2 via
removal of the THP group. For modified Mosher’s method, see: Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
21. (a) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838; (b) Movassaghi,
M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Angew. Chem., Int. Ed. 2006, 45, 5859; (c)
Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507.
22. Mitsunobu, O. Synthesis 1981, 1.
11. (a) Kuroda, H.; Tomita, I.; Endo, T. Polymer 1997, 38, 3655; (b) Inanaga, J.; Baba,
Y.; Hanamoto, T. Chem. Lett. 1993, 241.
12. (a) Pikul, S.; Kozlowska, M.; Jurczak, J. Tetrahedron Lett. 1987, 28, 2627; (b)
Yamanoi, T.; Akiyama, T.; Ishida, E.; Abe, H.; Amemiya, M.; Inazu, T. Chem. Lett.
1989, 335; (c) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J.
Org. Chem. 1989, 54, 702; (d) Chikashita, H.; Nikaya, T.; Uemura, H.; Itoh, H.
Bull. Chem. Soc. Jpn. 1989, 62, 2121.
23. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
24. Selected spectral data of 2: a 1:1 mixture of epimers at the acetal carbon of the
THP group; a colorless oil; ½a D26
ꢂ
ꢁ5.4 (c 0.37, CHCl3); IR (neat)
m 3020, 2971,
2936, 2866, 1504, 1216, 1121, 1096, 1031, 837 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) d 1.25 (3H, s), 1.27 (1/2 ꢃ 3H, s), 1.30 (1/2 ꢃ 3H, s), 1.41 (3H, s), 1.49–
1.89 (6H, m), 3.12–3.21 (1H, m), 3.48–3.56 (1H, m), 3.67 (1/2 ꢃ 1H, dd, J = 8.8,
11.3 Hz), 3.73–3.77 (1/2 ꢃ 1H, m), 3.76 (3H, s), 3.84–4.01 (1/2 ꢃ 1 + 2H, m),
4.11 (1/2 ꢃ 1H, dd, J = 2.0, 11.5 Hz), 4.67 (1/2 ꢃ 1H, br dd, J = 2.4, 4.6 Hz), 4.73
(1/2 ꢃ 1H, br t, J = 2.9 Hz), 5.36 (1H, br d, J = 10.8 Hz), 5.42–5.51 (1H, m), 6.76
(2H, br d, J = 9.2 Hz), 6.94 (2H, br d, J = 9.2 Hz); 13C NMR (75 MHz, CDCl3) d 18.8
(1/2 ꢃ CH2), 19.9 (1/2 ꢃ CH2), 22.8 (CH3), 25.5 (CH2), 26.1 (1/2 ꢃ CH3), 26.2 (1/
2 ꢃ CH3), 28.8 (CH3), 30.5 (1/2 ꢃ CH2), 30.7 (1/2 ꢃ CH2), 34.7 (1/2 ꢃ CH2), 34.8
(1/2 ꢃ CH2), 55.5 (CH3), 61.0 (1/2 ꢃ CH2), 62.6 (1/2 ꢃ CH2), 66.8 (1/2 ꢃ CH2),
67.8 (1/2 ꢃ CH2), 78.1 (1/2 ꢃ CH), 79.1 (C), 79.2 (1/2 ꢃ CH), 84.5 (C), 97.2 (1/
2 ꢃ CH), 100.0 (1/2 ꢃ CH), 113.8 (2 ꢃ CH), 122.39 (1/2 ꢃ CH), 122.44 (1/
2 ꢃ CH), 124.7 (2 ꢃ CH), 138.5 (CH), 148.3 (1/2 ꢃ C), 148.4 (1/2 ꢃ C), 155.5
(C); LR-EIMS m/z 376 (23.5%, [M+]), 124 (bp, [PMPOH+]); HR-EIMS calcd for
13. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
14. The configuration of the newly forming stereocenter (C4) of 7 was confirmed
by NMR analysis of
a
single diastereomeric 5-hydroxy-4-{2-(4-
methoxyphenoxy)propyl}-2-phenyl-1,3-dioxane obtained through a process
including conventional hydrogenation of 7, separation of epimers at C6,
hydrolysis of the acetonide, and benzylidene acetal formation.
15. Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6.
16. At present we can only speculate on the origins of the enhanced production of
ent-4 over 17 (or 4 over ent-17) in toluene. It is well known that the ability of
glycolate esters to support a cyclic chelate of the enolate counterion results in
the preferential formation of a Z-enolate,5,17 which reacts with TMSCl to
produce a ketene silyl acetal with retention of geometry.18 The Z-ketene silyl
acetal from ent-6 is thought to be rearranged to ent-4 stereospecifically.5 The
C
22H32O5 [M+]: 376.2250, found: 376.2245. Selected spectral data of an alcohol
reduced coordination ability of the
a-oxygen of ent-6 due to steric hindrance
derived from 2 via removal of the THP group: a colorless oil; ½a D25
ꢁ4.9 (c 0.19,
ꢂ
may interfere with the Z-enolate formation to result in the low ratio of ent-4 to
17 in polar solvents. However, in toluene, the low solvation ability of toluene
may destabilize the E-enolate rather than the Z-enolate, stabilized by the cyclic
chelate, to enhance the ratio of ent-4.
CHCl3); IR (neat) m 3468, 3020, 2971, 2928, 2854, 1505, 1464, 1374, 1214, 1182,
1135, 1093, 1036, 839 cmꢁ1 1H NMR (400 MHz, C6D6) d 1.09 (3H, s), 1.11 (3H,
;
s), 1.32 (1H, br s), 1.36 (3H, s), 1.59 (1H, dd, J = 8.8, 12.0 Hz), 3.24 (1H, br dd,
J = 5.2, 12.0 Hz), 3.30 (3H, s), 3.75 (1H, dd, J = 3.6, 8.4 Hz), 3.99 (1H, dd, J = 3.6,
12.0 Hz), 4.13 (1H, dd, J = 8.4, 12.0 Hz), 5.06 (1H, dd, J = 2.4, 10.8 Hz), 5.11 (1H,
ddd, J = 5.2, 8.8, 10.8 Hz), 6.70 (2H, br d, J = 9.2 Hz), 6.92 (2H, br d, J = 9.2 Hz);
13C NMR (75 MHz, CDCl3) d 23.0 (CH3), 26.5 (CH3), 28.8 (CH3), 34.7 (CH2), 55.5
(CH3), 62.5 (CH2), 79.3 (C), 79.6 (CH), 84.7 (C), 113.9 (2 ꢃ CH), 122.7 (CH), 124.7
(2 ꢃ CH), 137.9 (C), 148.0 (C), 155.8 (C); LR-EIMS m/z 292 (5.2%, [M+]), 124 (bp,
[PMPOH+]); HR-EIMS calcd for C17H24O4 [M+]: 292.1674, found: 292.1668.
25. Robins, M. J.; Nowak, I.; Wnuk, S. F.; Hansske, F.; Madej, D. J. Org. Chem. 2007,
72, 8216.
17. Denmark, S. E.; Chung, W. J. Org. Chem. 2008, 73, 4582.
18. Kanemasa, S.; Nomura, M.; Wada, E. Chem. Lett. 1991, 1735.
19. The time-dependent increase of the ratio of ent-4 might be attributable to the
different lifetimes of E- and Z-enolates.
20. The absolute configuration at C7 was determined by applying the modified
Mosher’s method to an alcohol derived from 18 via acetylation followed by
reductive elimination of the 3-bromo-2-methyl-2-butyl group with Zn/AcOH.
The absolute configuration at C6 was elucidated from the cis-relationship
between H7 and 6-CH3 of 2. The cis-relationship was confirmed by the
26. The details will be described elsewhere.