Diastereoselective construction of substituted tetrahydropyrans using an intramolecular oxy-Michael strategy

Article abstract of DOI:10.1016/j.tetlet.2009.01.084

The highly diastereoselective construction of substituted tetrahydropyrans, a common core segment (C3-C10) of the thiomarinols and the pseudomonic acid antibiotics, has been accomplished using the intramolecular oxy-Michael reaction under both basic and h

Full text of DOI:10.1016/j.tetlet.2009.01.084

Tetrahedron Letters 50 (2009) 1504–1506
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective construction of substituted tetrahydropyrans using
an intramolecular oxy-Michael strategy
Fumika Yakushiji a, Jacques Maddaluno b, Masahiro Yoshida a, Kozo Shishido a,
*
a Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
b Laboratoire des Fonctions Azotées & Oxygènées Complexes de l’IRCOF, CNRS UMR 6014 & FR 3038, Université de Rouen, 76821 Mont St. Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The highly diastereoselective construction of substituted tetrahydropyrans, a common core segment (C3–
C10) of the thiomarinols and the pseudomonic acid antibiotics, has been accomplished using the intra-
molecular oxy-Michael reaction under both basic and high-pressure conditions followed by regio- and
stereoselective epoxide opening with acetylide.
Received 16 December 2008
Revised 14 January 2009
Accepted 15 January 2009
Available online 20 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Thiomarinols,1 hybrid antibiotics composed of a pseudomonic
acid analogue and a pyrrothine core,2 and pseudomonic acids3 be-
long to the family of C-glycopyranoside antibiotics. Produced by
Alteromonas rava sp. nov. SANK 73390 and Pseudomonas fluores-
cens, respectively, these compounds possess potent antibiotic
activities, in particular thiomarinol B, which showed excellent
in vitro antimicrobial activity against Gram-positive and Gram-
negative bacteria.1c Because of their intriguing structural features
and interesting biological profiles, they represent attractive targets
for total synthesis. Although many fascinating routes to pseudo-
monic acids3 have been reported, so far only one successful, and
elegant, total synthesis of thiomarinol antibiotic has been reported
by Gao and Hall.4
stituted tetrahydropyran 1 with the requisite stereochemistry
(Scheme 1).
In this Letter, we report the stereochemical outcome of the
IMOM reaction of 2 under anionic and unprecedented high-pres-
sure conditions8 and the subsequent transformation of the cyc-
loadducts 3 to the C3–C10 segment 1 of the antibiotics. Although
many examples of carbon–carbon9 and carbon–nitrogen bonds10
forming intermolecular Michael reaction under high-pressure con-
ditions have been reported, there are very few examples in the lit-
erature on the intramolecular version.11
The substrates for the IMOM reaction were synthesized as
shown in Scheme 2. To determine the stereochemical outcome of
During the course of our studies directed toward the total syn-
thesis of thiomarinols A and B, we sought to develop an efficient
methodology for the diastereoselective construction of the C3–
C10 segment 1 containing the tetrahydropyran ring,5 which is a
common core structure of the thiomarinols and pseudomonic acids
(Fig. 1).
The key feature of our strategy is the use of an intramolecular
oxy-Michael (IMOM) reaction6 of the hydroxy enoate 2 bearing a
cis-epoxide for the construction of the tetrasubstituted tetrahydro-
pyran 3a. We anticipated that the presence of the cis-epoxide6c
would promote the kinetic formation of the pyran ring by the
Thorpe-Ingold-like effect.7 The diastereoselectivity at the future
C5 can be deduced by comparing the possible transition states T1
and T2, in which the sterically less demanding transition state T1
might be predominant, and the pyran 3a with the 5S configuration
would be generated as the major product. The epoxide could then
be opened by an acetylide anion at the future C8 in a regio- and
stereoselective fashion resulting in the formation of the tetrasub-
OH
OH
HO
O
O
8
H
10
11
5
N
O
O
3
5
HN
O
OH
S
Thiomarinol A: X=S
X
Thiomarinol B: X=SO2
OH
OH
O
HO
O
10
HO
O
O
6
O
Pseudomonic acid A
Pseudomonic acid C: C10/C11 E-alkene
10
OR2
R1O
O
3
RO
1
* Corresponding author. Tel.: +81 88 6337287; fax: +81 88 6339575.
E-mail address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
Figure 1. Thiomarinols and pseudomonic acids and the C3–C10 core segment.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.084

F. Yakushiji et al. / Tetrahedron Letters 50 (2009) 1504–1506
1505
Table 1
O
R1O
EtO2C
IMOM reaction under basic conditions
O
O
O
R1O
R1O
R1O
OH
2
base
+
5
H
conditions
O
OR2
9, 10, 15-17
O
H
H
O
OR1
EtO2C
EtO2C
EtO2C
18 (5S)
19 (5R)
O
O
EtO2C
O
OR1
H
EtO2C
T1
O
T2
Entry
Enoate (config.)
Base
Conditions
Yield (%)
18:19
1
2
3
4
5
9 (E)
10 (E)
16 (Z)
17 (Z/E = 6:1)
15 (Z/E = 6:1)
NaH
NaH
NaH
NaH
TBAF
CH2Cl2,0 °C, 2 h
CH2Cl2, 0 °C, 2 h
CH2Cl2, 0 °C, 2 h
CH2Cl2, 0 °C, 2 h
THF, rt, 1 h
89
97
90
99
92
5.7:1
12:1
>99:1
>99:1
>99:1
O
R1O
R1O
5
O
O
3a
3b
EtO2C
EtO2C
1
undesired 4R-isomer 6 to the desired 4S-isomer 5 could be carried
out by the Mitsunobu reaction followed by hydrolysis. The allyl
alcohol 5 was subjected to cross metathesis12 with ethyl acrylate
and the Hoveyda catalyst 713 to provide the E-enoates 8, which fur-
nished 9 and 10 via silylation or methoxymethylation followed by
selective desilylation.14 The Z-enoates 16 and 17 were prepared
starting from the aldehydes 11 and 12, which were obtained by
sequential protection of the hydroxyl function in 5 and by ozonol-
ysis. Exposure of 11 and 12 to Ando olefination conditions15 with
13 resulted in the exclusive formation of the Z-enoate 14 and a
Z/E = 6:1 inseparable mixture of 15, respectively. They were then
converted to 16 (Z only) and 17 (Z/E = 6:1) by desilylation in good
overall yields from 5 (Scheme 2).
Scheme 1. Synthetic strategy.
the cyclization, we prepared the hydroxy E-enoates 9 and 10 and
the Z-enoates 16 and 17. Starting with the optically active epoxy
alcohol 4, oxidation and vinylation provided a chromatographically
separable 1:1 mixture of the alcohols 5 and 6. Conversion of the
O
HO
O
1. Dess-Martin periodinane
CH2Cl2, rt, 0.5 h
4
HO
With the hydroxy enoates in hand, we initially examined the
key IMOM reaction under basic conditions.20 Treatment of the E-
enoates 9 and 10 with NaH in dichloromethane (DCM) at 0 °C for
2 h provided a separable mixture of the diastereoisomers 18 (5S)
and 19 (5R) in 89% yield (dr = 5.7:1; R1 = TBS) and 97% yield
(dr = 12:1; R1 = MOM), respectively (Table 1, entries 1 and 2). It
was demonstrated that the yield and diastereoselectivity were af-
fected by changing the C4-hydroxy protective group (TBS?MOM)
in the E-enoates 9 and 10. When the reaction was conducted for
the Z- and Z-rich (Z/E = 6:1) enoates 16 and 17 under the same
reaction conditions, the desired pyran 18 was obtained as a single
diastereomer in 90% (R1 = TBS) and 99% yields (R1 = MOM), respec-
tively (Entries 3 and 4). One-pot conversion of 15 to 18 (a mixture
of Z/E = 6:1) via a desilylation/cyclization sequence was carried out
by treatment of 15 with TBAF in THF providing 18 (R1 = MOM) in
92% yield (Table 1, entry 5).
OR
5: 4S (40%)
6: 4R (40%)
2. CH2=CHMgCl
THF, 0 °C, 15 min
4
OR
R=TBDPS
1. p-nitrobenzoic acid
Ph3P, DIAD, CH2Cl2
rt, 15 h
NMes
Ru
MesN
Cl
5
6
Cl
2. LiOH•H2O, THF, H2O
O
rt, 15 h
(54%, 2 steps)
7
1) TBSCl, 4-DMAP
imidazole, rt, 0.5 h
or MOMCl, iPr2NEt
40 °C, 15h
O
HO
CH2=CHCO2Et
CH2Cl2, rt, 3.5 h
5
OR
2) TBAF, AcOH
NaHCO3, THF
0 °C~rt, 1h
or TBAF, NH4Cl
THF, 0 °C, 6 h
7 (5 mol%)
EtO2C
8
(60%)
O
RO
Next, we examined the conversions under high-pressure condi-
tions.21 After considerable experimentation, it was found that the
presence of Hünig’s base (iPr2NEt) as an additive16 was necessary.
Thus, a solution of 9 in a mixture of iPr2NEt and DCM (1/9) was ex-
posed to the high-pressure conditions (12.6 kbar), and the diaste-
reomeric pyrans 18 and 19 were obtained in 62% yield in a ratio
of 4.6:1 (Table 2, entry 1). It should be noted that in the case of
the E-enoate 9, the addition of ethanol17 to the reaction media in-
creased the yield up to 96% with higher diastereoselectivity (16:1)
(entry 2). As in the case under basic conditions, the Z-enoates 16
and 17 provided excellent yields and diastereoselectivity of the de-
sired pyran 18 (entries 3 and 4). When the reaction was carried out
at an atmospheric pressure, the starting hydroxy enoate was recov-
ered completely (Table 2, entry 5).
iPr
OH
9: R=TBS (75%, 2 steps)
EtO2C
O POCH2CO2Et
2
10: R=MOM (66%, 2 steps)
13
1. TBSCl, 4-DMAP
imidazole, rt, 0.5 h
or MOMCl, iPr2NEt
40 °C, 15 h
O
RO
OHC
13, DBU
NaI, THF
5
OTBDPS
–78 °C, 2 h
O
2. O3 then Me2S
–78 °C~rt, 8 h
11: R=TBS
12: R=MOM
O
TBAF, AcOH
RO
EtO2C
RO
EtO2C
Since attempted treatment of the epoxy pyran 1818 (R1 = MOM)
with trimethylsilylacetylene in the presence of nBuLi and boron tri-
fluoride etherate19 produced the acetylenic alcohol 2018 only in
40% yield, 18 (R1 = MOM) was hydrolyzed and the resulting
carboxylic acid was reduced via a mixed anhydride to give the
expected alcohol which was immediately protected as the
NaHCO3, THF
0 °C~rt, 1 h
OTBDPS
OH
or TBAF, NH4Cl
THF, 0 °C, 6 h
16: R=TBS (47%, 4 steps)
17: R=MOM (59%, 4 steps)
14: R=TBS (Z only)
15: R=MOM (Z/E=6/1)
Scheme 2. Synthesis of the substrates.

1506
F. Yakushiji et al. / Tetrahedron Letters 50 (2009) 1504–1506
Table 2
IMOM reaction under high-pressure conditions
Entry
Enoate (config.)
Pressure (kbar)
Conditions
Yield (%)
18:19
1
2
3
4
5
9 (E)
9 (E)
16 (Z)
17 (Z/E = 6:1)
16 (Z)
12.6
10.9
13.3
12.9
—
iPr2NEt/CH2Cl2 = 1/9, rt, 15 h
iPr2NEt/CH2Cl2/EtOH = 1/4.5/4.5, rt, 19 h
iPr2NEt/CH2Cl2 = 1/9, rt, 19 h
iPr2NEt/CH2Cl2 = 1/9 rt, 18 h
62
96
96
99
4.6:1
16:1
>99:1
>99:1
iPr2NEt/CH2Cl2 = 1/9, rt, 7 days
Recovered
6. For a review, see: (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545; (b) Masaki,
H.; Maeyama, J.; Kamada, K.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. J. Am.
Chem. Soc. 2000, 122, 5216; (c) Harvey, J. E.; Raw, S. A.; Taylor, R. J. K. Org. Lett.
2004, 6, 2611; (d) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008, 130,
46. and references cited therein.
7. (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New
York, 1994; (b) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.
8. (a) Isaacs, N. S. In Liquid-Phase High Pressure Chemistry; John Wiley and Sons:
Chichester, New York, Brisbane, Tronto, 1984; pp 182–201; (b) VanEldik, R.;
Asano, T.; Le Noble, W. J. Chem. Rev. 1989, 89, 549; (c) Klärner, F. G.; Ruster, V.;
Zimny, B.; Hochstrate, D. High-Pressure Res. 1991, 7, 133; (d) Matsumoto, K.;
Hamana, H.; Iida, H. Helv. Chim. Acta 2005, 88, 2033.
9. (a) Uchida, T.; Matsumoto, K. Chem. Lett. 1981, 1673; (b) Bunce, A. R.; Schlecht,
F. M.; Dauben, G. W.; Heathcock, C. H. Tetrahedron Lett. 1983, 24, 4943; (c)
Dauben, G. W.; Gerdes, M. J. Tetrahedron Lett. 1983, 24, 3841; (d) Dauben, G. W.;
Bunce, A. R. J. Org. Chem. 1983, 48, 4642; (e) Kotsuki, H.; Arimura, K. Tetrahedron
Lett. 1997, 38, 7583; (f) Jenner, G. New J. Chem. 1999, 23, 525; (g) Camara, C.;
Joseph, O.; Dumas, F.; d’Angelo, J.; Chiaroni, A. Tetrahedron Lett. 2002, 43, 1445;
(h) Knappwost-Gieseke, C.; Nerenz, F.; Wartchow, R.; Winterfeldt, E. Chem. Eur.
J. 2003, 9, 3849.
10. (a) d’Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108, 8112; (b) Dumas, F.;
Fressigné, C.; Langlet, J.; Giessner-Prettre, C. J. Org. Chem. 1999, 64, 4725.
11. It has been reported that the enolate anion, generated in situ, added to the b-
carbon of butenolide intramolecularly under high-pressure conditions.9h
12. Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002, 74, 7.
13. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
OH
TMS
TMS
MOMO
R
18: R1=MOM
nBuLi
BF3•OEt2
–78 °C, 2 h
O
20: R=CO2Et (40%)
22: R=CH2OPMP
1. LiOH•H2O
THF, H2O, rt, 2 h
2. ClCO2Et, Et3N
then NaBH4
O
MOMO
PMPO
TMS
0 °C, 10 min
nBuLi
BF3•OEt2
–78 °C, 2 h
(98%)
O
3. p-MeOC6H4OH
DIAD, Ph3P
21
rt, 40 min
(88%, 3 steps)
PMP= p-MeOC6H4–
Scheme 3. Transformation of 18 to the C3–C10 segment 22.
p-methoxyphenyl (PMP) ether using the Mitsunobu protocol to
give 21 in 88% yield for the three steps. The latter was then treated
under the same reaction conditions as for 18 to provide the pyran
22 with the requisite four contiguous stereogenic centers in excel-
lent yield (Scheme 3).
14. Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shirahama, H.; Nakata,
M. Synlett 2000, 1306.
15. Ando, K. J. Org. Chem. 1998, 63, 8411.
In summary, an efficient protocol for the highly diastereoselec-
tive synthesis of the 2,3,4,5-tetrasubstituted tetrahydropyran core
structure of the thiomarinols and pseudomonic acid antibiotics
was devised with use of the IMOM reaction of the epoxy hydroxy
Z-enoate under both basic and high-pressure conditions. It should
be emphasized that this is the first time that the IMOM reaction for
assembling the substituted tetrahydropyrans under high-pressure
has been efficiently accomplished. Efforts aimed at completion of
the total synthesis of thiomarinols are ongoing and will be re-
ported in due course.
16. Reactions of 9 and 16 under high-pressure conditions in the presence of other
bases/solvents
(Et3N/CH2Cl2,
Et3N/THF,
(À)-quinine/CH2Cl2,
and
diphenylguanidine/trifluorotoluene) led to lower yields and poor
diastereoselectivities.
17. Al-Badri, H.; Maddaluno, J.; Masson, S.; Collignon, N. J. Chem. Soc., Perkin Trans.
1 1999, 2255.
18. Compound 18: Colorless oil. IR (neat) cmÀ1: 2901, 1735, 1446, 1257, 1148,
1045, 914, 728; a2D7 À34.27 (c 1.07, CHCl3); 1H NMR (400 MHz, CDCl3): d 4.83
(1H, d, J = 6.8 Hz), 4.76 (1H, d, J = 6.8 Hz), 4.20–4.10 (2H, m), 4.05 (1H, dd, J = 13
and 4.0 Hz), 3.88 (1H, d, J = 13 Hz), 3.81–3.74 (2H, m), 3.56 (1H, d, J = 4.8 Hz),
3.48 (1H, dd, J = 4.4 and 3.6 Hz), 3.45 (3H, s), 2.73 (1H, dd, J = 15 and 2.8 Hz),
2.39 (1H, dd, J = 15 and 7.2 Hz), 1.25 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3): d 170.87 (s), 96.43 (t), 75.15 (d), 69.95 (d), 64.71 (t), 60.49 (t), 55.67 (d),
52.40 (d), 55.05 (q), 37.35 (t), 14.10 (q); HRMS (ESI) m/z calcd for C11H18O6Na
[M+Na]+ 269.1001, found 269.1004. Compound 20: Colorless oil. IR (neat)
cmÀ1: 3576, 2960, 2255, 2171, 1730, 1250, 1107, 1027, 844; a2D7 +39.02 (c 0.56,
CHCl3); 1H NMR (400 MHz, CDCl3): d 4.75 (1H, d, J = 6.8 Hz), 4.69 (1H, d,
J = 6.8 Hz), 4.22–4.12 (3H, m), 4.07 (1H, dt, J = 8.8 and 3.6 Hz), 3.89 (1H, dd,
J = 11 and 2.8 Hz), 3.72 (2H, dd, J = 9.2 and 2.8 Hz), 3.43 (3H, s), 2.85 (1H, m),
2.71 (1H, dd, J = 15 and 4.0 Hz), 2.54 (1H, br s), 2.50 (1H, dd, J = 15 and 8.8 Hz),
1.27 (3H, t, J = 7.2 Hz), 0.15 (9H, s); 13C NMR (100 MHz, CDCl3): d 171.31 (s),
104.49 (d), 96.26 (t), 87.80 (d), 75.76 (d), 71.45 (d), 68.23 (d), 64.77 (t), 60.57
(t), 56.24 (q), 37.51 (t), 35.21 (d), 14.18 (q), 0.00 (t) Â 3; HRMS (ESI) m/z calcd
for C16H28O6NaSi [M+Na]+ 367.1553, found 367.1566.
Acknowledgments
We thank Dr. Isabelle Chataigner of the Université de Rouen for
technical assistance with high-pressure experiments and for help-
ful discussions. This work was supported financially in part by JSPS
Research Fellowship for Young Scientists (to F.Y.) (No. 19ꢀ6569)
and by a Grant-in-Aid for program for Promotion of Basic and Ap-
plied Researches for Innovations in Bio-oriented Industry.
19. (a) Yamaguchi, M.; Nobayashi, Y.; Hirao, I. Tetrahedron 1984, 45, 9265; (b)
Shindo, M.; Sugioka, T.; Shishido, K. Tetrahedron Lett. 2004, 49, 9265.
20. General procedure for the IMOM reaction under anionic conditions: To a solution
(0.05 M) of NaH (2.5 equiv) in CH2Cl2 was added the hydroxy enoate (1 equiv)
at 0 °C and was stirred at the same temperature for 2 h. The reaction mixture
was quenched with satd NaHCO3 (aq). The aqueous layer was extracted with
AcOEt, and the extract was washed with brine, dried over MgSO4, filtered, and
concentrated. The residue was purified through silica gel column
chromatography to give the cyclized product.
References and notes
1. (a) Shiozawa, H.; Kagasaki, T.; Kinoshita, T.; Haruyama, H.; Domon, H.; Utsui,
Y.; Kodama, K.; Takahashi, S. J. Antibiot. 1993, 46, 1834; (b) Shiozawa, H.;
Takahashi, S. J. Antibiot. 1994, 47, 851; (c) Shiozawa, H.; Kagasaki, T.; Torikawa,
A.; Tanaka, N.; Fujimoto, K.; Hata, T.; Furukawa, Y.; Takahashi, S. J. Antibiot.
1995, 48, 907.
2. (a) Ettinger, L.; Gäumann, E.; Hütter, R.; Keller-Schierlein, W.; Kardolfer, F.;
Neipp, L.; Prelog, V.; Zähner, H. Helv. Chim. Acta 1959, 42, 563; (b) Celmer, W.
D.; Solomons, I. A. J. Am. Chem. Soc. 1955, 77, 2861.
21. General procedure for the IMOM reaction under high-pressure conditions:
A
i
solution (0.05 M) of the hydroxy enoate (1 equiv) in a mixture of Pr2NEt and
the solvent (1:9) was allowed to stand under high pressure at room
temperature for 15–19 h. After reversion to atmospheric pressure, the
solvent was evaporated. The residue was purified through silica gel column
chromatography to give the cyclized product.
3. For a review, see: Class, Y. J.; DeShong, P. Chem. Rev. 1995, 95, 1843.
4. Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 1628.
5. For a review, see: Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045.