A New and Versatile Allylic Alcohol Anion and Acyl β-Anion Equivalent for Three-Carbon Homologations

Full text of DOI:10.1021/jo9714627

J . Org. Chem. 1997, 62, 9369 9371
9369
Sch em e 1
A New a n d Ver sa tile Allylic Alcoh ol An ion
a n d Acyl â-An ion Equ iva len t for
Th r ee-Ca r bon Hom ologa tion s
Romualdo Caputo, Annalisa Guaragna,
Giovanni Palumbo,* and Silvana Pedatella
Dipartimento di Chimica Organica e Biologica,
Universita` di Napoli Federico II, Via Mezzocannone,
16 I-80134 Napoli, Italy
Received August 5, 1997
There are many reagents useful for the extension of
organic molecules by three carbons with some functional-
ity at the new terminus.1 However, to the best of our
knowledge, the possibility of introducing an allylic alcohol
residue is restricted to only a few examples2 despite its
potential utility in the synthesis of complex organic
molecules, like saccharides and related polyhydroxylated
natural products, e.g., via asymmetric epoxidation3 or
dihydroxylation.4 Therefore, we report herein the design,
synthesis, and some examples of the synthetic versatility
of 3-C-lithiated (5,6-dihydro-1,4-dithiin-2-yl)[(4-methoxy-
benzyl)oxy]methane (1) which can be utilized as an allylic
alcohol anion equivalent and leads to elongations of
various electrophiles by introduction of a fully protected
hydroxypropenyl moiety. The latter contains a double
bond, which can be unravelled with the cis configuration
by diastereoselective removal of the dimethylene disul-
fur bridge, as well as a protected primary hydroxyl group
that, depending on the deprotection conditions used
(DDQ/NaBH4 or DDQ), may lead either to the free allylic
alcohol or to an ,â-unsaturated aldehyde.
The parent compound of 1, 2-[[O-(p-methoxybenzyl)-
oxy]methyl]-5,6-dihydro-1,4-dithiin (2), can be easily
prepared in four steps (overall yield 83%) from com-
mercial methyl pyruvate via its 1,3-dithiolane and ring
enlargement5 of the latter. The choice of 4-methoxyben-
zyl ether (MPM)6 as the hydroxyl-protecting group was
crucial to the utilization of 2 as the intended allylic
alcohol anion equivalent via its lithiation (Scheme 1). In
addition, 4-methoxybenzyl ethers have the advantage of
being selectively removed when in the presence of other
common protecting groups including non-ring-substituted
benzyl ethers.7 The use of protecting groups such as tert-
butyldimethylsilyl ethers (TBDMS) and tetrahydropyra-
nyls (THP) was rather unsatisfactory and resulted in poor
reactivity of the entire molecule under the C C bond-
forming reaction conditions.
electrophilessnamely, methyl iodide, benzyl bromide,
(R)- and (S)-benzyl glycidyl ether, (R)-O-isopropyli-
deneglyceral8saccording to a standard procedure we
already reported9 for other 5,6-dihydro-1,4-dithiins. The
results are shown in Table 1. The synthetic relevance
of these coupling reactions resides on the fact that the
products can be either deprotected, keeping the double
bond tied up by the dimethylene disulfur bridge (Table
2), or stereoselectively desulfurized affording a cis-
configurated 4-methoxybenzyl propenyl ether (Scheme 2).
The cleavage of the 4-methoxybenzyl ether function
was performed by treatment of the coupling products
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in
CH2Cl2/H2O and then sodium borohydride in ethanol. The
results are shown in Table 2. Sodium cyanoborohydride,
reported10 to be effective in the reductive cleavage of
MPM ethers, led instead to only poor results. It is
noteworthy that, if the above MPM ethers are cleaved
by treatment with an equivalent amount of DDQ, a
formyl function is quantitatively obtained rather than the
expected7 primary alcohol (Table 2) in the final product.
Apparently, the aldehyde formation is not the result of
the known oxidation11 of the free allylic hydroxyl group
by DDQ. As a matter of fact the MPM ether 4, when
treated with only 50% of the equivalent amount of DDQ,
afforded aldehyde 14 and anisole (from the 4-methoxy-
benzyl ether moiety) in an approximately 1:1 ratio and
50% yield, in addition to a relevant amount (ca. 40%) of
unreacted starting product. No traces of the hydroxyl-
bearing compound 13 were detected. This is likely due
to the preferential abstraction of a hydrogen atom from
the vinylic rather than from the benzylic12 methylene
group and the consequent formation of a sulfur-stabilized
carbocation.
The subsequent coupling reactions were effected by
treatment of 2 with BuLi and then with miscellaneous
Desulfurization of the above MPM ethers with Raney-
Ni (W2) in glacial acetic acid at 0 °C led, as expected,13
only to cis isomer formation (Scheme 2). Deprotection
of the allyllic hydroxyl group and desulfurization of the
double bond can be carried out independently, leading
either to allylic alcohols or to their corresponding MPM
ethers having a cis-configurated double bond. Two
* To whom correspondence should be addressed. Tel: 39 81 704
1279. Fax: 39 81 704 1283. E-mail: ctsgroup@cds.unina.it.
(1) Stowell, J . C. Chem. Rev. (Washington, D.C.) 1984, 84, 409.
(2) (a) Nishiyama, H.; Narimatsu, S.; Itoh, K. Tetrahedron Lett.
1981, 22, 5289. (b) Miller, R. B.; Al-Hassan, M. I. J . Org. Chem. 1983,
48, 4113. (c) Patterson, J . W. Synthesis 1985, 337.
(3) Schweiter, M. J .; Sharpless, K. B. Tetrahedron Lett. 1985, 26,
2543.
(4) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. (Washington, D.C.) 1994, 94, 2483. (b) VanNieuwenhze, M. S.;
Sharpless, K. B. Tetrahedron Lett. 1994, 35, 843. (c) Park, C. Y.;
Sharpless, K. B. Tetrahedron Lett. 1994, 35, 2495.
(5) Caputo, R.; Ferreri, C.; Palumbo, G. Synthesis 1991, 223.
(6) Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis;
J ohn Wiley & Sons: New York, 1995; pp 3326 3329.
(7) (a) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetrahedron 1986, 42, 3021. (b) Oikawa, Y.; Tanaka, T.; Horita,
K.; Yonemitsu, O. Tetrahedron Lett. 1984, 25, 5397. (c) Oikawa, Y.;
Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
(8) Schimdt, C. R.; Bryant, J . D. Org. Synth. 1993, 72, 6.
(9) Caputo, R.; Longobardo, L.; Palumbo, G.; Pedatella, S.; Giordano,
F. Tetrahedron 1996, 52, 11857 and literature cited therein.
(10) Srikrishna, A.; Viswajanani, R.; Sattiggeri, J . A.; Vijaykumar,
D. J . Org. Chem. 1995, 60, 5961.
(11) (a) Braude, E. A.; Linstead, R. P.; Woolridge, K. R. J . Chem.
Soc. 1956, 3070. (b) Burn, D.; Petrow, V.; Weston, G. O. Tetrahedron
Lett. 1960, 9, 14.
(12) Walker, D.; Hiebert, J . D. Chem. Rev. 1967, 67, 153.
(13) Caputo, R.; Palumbo, G.; Pedatella, S. Tetrahedron 1994, 50,
7265.
S0022-3263(97)01462-X CCC: $14.00 © 1997 American Chemical Society

9370 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
Ta ble 1. Cou p lin g Rea ction s of 2 w ith Miscella n eou s
Electr op h iles
rotations were measured on CHCl3 solutions (1.0-dm cell). Thin-
layer chromatography (TLC) analyses were performed on silica
gel Merck 60 F254 plates (0.2-mm layer tickness). Column
chromatography was carried out with Merck Kieselgel 60 (70
230 mesh). Dry solvents were distilled immediately before use
(CH2Cl2 and CHCl3 from P2O5; Et2O from LiAlH4).
(5,6-Dih yd r o-1,4-d it h iin -2-yl)[(4-m et h oxyb en zyl)oxy]-
m eth a n e (2): prepared in four steps (a d) from commercial
methyl pyruvate in a 83% overall yield as follows.
(a )Meth yl 2-Meth yl-1,3-d ith iola n e-2-ca r boxyla te. Methyl
pyruvate (4.0 g, 39.2 mmol), freshly prepared PPh3 I2 complex14
(39.2 mmol), and 1,2-ethanedithiol (3.2 mL, 39.2 mmol) dissolved
in dry CH2Cl2 (60 mL) were stirred under N2 atmosphere for 3
h (TLC monitoring). Usual workup14 afforded the title compound
(6.3 g, 90%). 1H NMR (250 MHz): δ 1.95 (s, 3H), 3.38 3.48 (m,
2H), 3.49 3.60 (m, 2H), 3.75 (s, 3H). IR: 1735 cm 1. MS: m/z
178 (M ). Anal. Calcd for C6H10O2S2: C, 40.42; H, 5.65.
Found: C, 40.55; H, 5.58.
(b)Meth yl 5,6-Dih yd r o-1,4-d ith iin e-2-ca r boxyla te. A so-
lution of methyl 2-methyl-1,3-dithiolane-2-carboxylate (1.2 g, 6.6
mmol) and NBS (2.4 g, 13.2 mmol) in dry CHCl3 (100 mL) was
stirred at room temperature in the dark for 16 h. Workup5 led
to the title compound (1.1 g, 98%). 1H NMR (200 MHz): δ 3.13
1
3.22 (m, 4H), 3.77 (s, 3H), 7.58 (s, 1H). IR: 1700 cm
. MS:
m/z 176 (M ). Anal. Calcd for C6H8O2S2: C, 40.89; H, 4.57.
Found: C, 40.65; H, 4.66.
(c)(5,6-Dih yd r o-1,4-d ith iin -2-yl)m eth a n ol (9). To a stirred
solution of methyl 5,6-dihydro-1,4-dithiine-2-carboxylate (1.0 g,
5.7 mmol) in dry Et2O (20 mL), at 0 °C and under N2 atmosphere,
was added a suspension of LiAlH4 (0.8 g, 17.0 mmol) in the same
solvent in small portions. After 30 min, AcOEt (a few drops)
and aq 2 N HCl (10 mL) were added to the reaction mixture.
The organic phase was washed with brine until neutral, then
dried (Na2SO4), and evaporated under reduced pressure. Chro-
matography of the crude residue on silica gel (light petroleum
AcOEt, 8:2) afforded pure 9 (0.8 g, 98%). 1H NMR (200 MHz):
1
δ 3.05 3.18 (m, 4H), 4.12 (s, 2H), 6.15 (s, 1H). IR: 3445 cm
.
MS: m/z 148 (M ). Anal. Calcd for C5H8OS2: C, 40.51; H, 5.44.
Found: C, 40.79; H, 5.38.
(d ) 4-Methoxybenzyl chloride (1.3 g, 8.0 mmol) dissolved in
dry DMF (20 mL) was added dropwise to a solution of pure 9
(1.0 g, 6.7 mmol) and NaH (0.2 g, 8.3 mmol) in the same solvent
(20 mL) that had been kept under magnetic stirring and N2
atmosphere for 30 min at room temperature. The stirring was
continued for 15 h, and the reaction mixture was diluted with
brine and extracted with Et2O. The combined organic layers,
after drying (Na2SO4) and evaporating under reduced pressure,
gave a crude product which chromatography on silica gel (light
petroleum Et2O, 9:1) and afforded the pure oily 2 (6.4 g, 96%).
1H NMR (400 MHz): δ 3.13 3.23 (m, 4H), 3.83 (s, 3H), 4.00 (s,
2H), 4.43 (s, 2H), 6.20 (s, 1H), 6.88 (d, 2H, J
8.0). MS: m/z 268 (M ). Anal. Calcd for C13H16O2S2: C,
58.18; H, 6.00. Found: C, 57.97; H, 6.08.
Cou p lin g R ea ct ion of w it h E lect r op h iles. (2S)-1-
8.5), 7.26 (d, 2H,
J
2
(Ben zyloxy)-3-(3-{[(4-m et h oxyb en zyl)oxy]m et h yl}-5,6-d i-
h yd r o-1,4-d ith iin -2-yl)p r op a n -2-ol (5). Typ ica l P r oced u r e.
To a stirred solution of dithiin 2 (1.0 g, 3.7 mmol) in anhydrous
THF (5 mL), at 78 °C and under argon atmosphere, was added
1.6 M BuLi in hexane (2.7 mL, 4.4 mmol) via cannula, dropwise
over 10 min, followed by benzyl (S)-( )-glycidyl ether (0.7 mL,
4.4 mmol) and Ti(OPri)4 (0.2 mL, 0.9 mmol) dissolved in the same
solvent (2 mL). The reaction mixture was kept for 1 h at 78
°C and for 3 h at 40 °C and then the reaction quenched
carefully with 10% aq NH4Cl (5 mL). Usual workup9 and
chromatography on silica gel (light petroleum acetone, 8:2) of
the crude residue finally afforded pure 5 (1.4 g, 90%). 1H NMR
examples reported in Scheme 2 illustrate the synthesis
of polyhydroxylated substrates (17, 18) with different
protections of the hydroxyl groups.
In conclusion, we have disclosed the synthesis of 2 and
its application in the three-carbon elongation, introducing
in one step different functionalities such as a protected
cis double bond with either a protected allylic primary
hydroxyl group or a formyl group. Considering that the
double bond can be further functionalized, even in a
stereocontrolled manner, the utilization of 2 in the
elongation of chiral substrates as (R)- and (S)-benzyl
glycidyl ether and (R)-O-isopropylideneglyceral may rep-
resent an unprecedented and powerful tool for designing
new synthetic strategies in the area of biologically
relevant polyhydroxylated products.
(250 MHz): δ 2.39 (dd, 1H, J
15.0), 3.19 (s, 4H), 3.44 (dd, 1H, J
4.6, 10.0), 3.80 (s, 3H), 3.93 (d, 1H, J
4.5, 15.0), 2.65 (dd, 1H, J
8.4,
5.5, 10.0), 3.48 (dd, 1H, J
11.5), 3.95 4.05 (m,
1H), 4.14 (d, 1H, J
2H, J
11.5), 4.48 (s, 2H), 4.55 (s, 2H), 6.87 (d,
8.0), 7.22 (d, 2H, J
8.0), 7.28 7.40 (m, 5H). [ ]25
D
8.0 (c 2.0). IR: 3430 cm 1. Anal. Calcd for C23H28O4S2: C,
63.86; H, 6.52. Found: C, 63.75; H, 6.55.
Exp er im en ta l Section
Red u ctive Clea va ge of MP M Eth er Der iva tives. (3-
Ben zyl-5,6-d ih yd r o-1,4-d ith iin -2-yl)m eth a n ol (13). Typ ica l
Gen er a l. 1H NMR spectra were recorded on CDCl3 solutions;
chemical shifts are reported in ppm (δ) downfield from internal
tetramethylsilane (TMS), and J values are given in Hz. Optical
(14) Caputo, R.; Ferreri, C.; Palumbo, G. Synthesis 1987, 386.

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9371
Ta ble 2. Clea va ge of th e MP M Eth er Der iva tives u n d er Red u ctive a n d Oxid a tive Con d ition s
(0.4 g, 1.8 mmol) in one portion at room temperature. After 1
h, the suspension was filtered and the solid washed with CH2-
Cl2. The organic layer was separated, dried (Na2SO4), and
evaporated under reduced pressure. Chromatography of the
crude product on silica gel (light petroleum AcOEt, 8:2) gave
the pure aldehyde 14 (0.25 g, 89%). Mp: 109 110 °C (benzene
hexane). 1H NMR (200 MHz): δ 3.46 3.58 (m, 2H), 3.61 3.71
(m, 2H), 4.49 (s, 2H), 7.60 7.71 (m, 5H), 10.33 (s, 1H). Anal.
Calcd for C12H12OS2: C, 60.98; H, 5.12. Found: C, 61.15; H,
5.05.
Sch em e 2
Dia ster eoselective Desu lfu r iza tion Rea ction s. (1S,3Z)-
1-[(Ben zyloxy)m eth yl]-5-h yd r oxy-3-p en ten yl Aceta te (17).
Typ ica l P r oced u r e. A solution of dithiin 15 (0.1 g, 0.28 mmol)
in glacial acetic acid (10 mL) was added in one portion to a
stirred suspension of Raney-Ni (W2) (1.0 g, wet) in the same
solvent (10 mL) at 0 °C and under dry argon (or nitrogen)
stream. The resulting suspension was stirred for 5 min (TLC
monitoring). Then the solid was filtered off and washed with
glacial acetic acid, water, and Et2O. The filtrate was neutralized
with saturated aq Na2CO3 and extracted with Et2O. The
combined organic layers were washed with water until neutral,
dried (Na2SO4), and evaporated under reduced pressure to afford
a crude residue. Chromatography of the latter on silica gel
(benzene Et2O, 9:1) gave the pure sulfur-free enyl acetate (17).
1H NMR (250 MHz): δ 2.08 (s, 3H), 2.42 2.52 (m, 2H), 3.50
3.58 (m, 2H), 4.19 (d, 2H), 4.52 4.60 (m, 2H), 4.98 5.10 (m, 1H),
5.45 5.60 (m, 1H), 5.70 5.85 (m, 1H), 7.27 7.43 (m, 5H). [ ]
P r oced u r e. To a stirred CH2Cl2 H2O (9:1) emulsion (50 mL)
containing MPM ether 4 (0.5 g, 1.4 mmol) was added DDQ (0.4
g, 1.8 mmol) in one portion at room temperature. After 1 h, most
of the solvent was evaporated under reduced pressure and
replaced by EtOH (10 mL). To the resulting solution was added
a suspension of NaBH4 (0.05 g, 4.0 equiv) in a little amount of
EtOH dropwise under stirring. After 10 min, the reaction
mixture was diluted with brine and extracted with AcOEt. The
combined organic layers were dried (Na2SO4) and evaporated
under reduced pressure. Chromatography of the crude product
on silica gel (light petroleum AcOEt, 8:2) gave the pure alcohol
25
7.6 (c
1.2). Anal. Calcd for C15H18O4: C, 68.68; H,
D
6.92. Found: C, 68.59; H, 6.95.
13 (0.25 g, 75%). 1H NMR (200 MHz): δ 3.18 (s, 4H), 3.68 (s,
1
2H), 4.23 (s, 2H), 7.20 7.32 (m, 5H). IR: 3430 cm
. Anal.
Ack n ow led gm en t. The authors thank Prof. S. Han-
essian for his advice and helpful discussions. Financial
support to R.C. from CNR and Murst are also gratefully
acknowledged.
Calcd for C12H14OS2: C, 60.46; H, 5.92. Found: C, 60.70; H,
5.99.
Oxid a tive Clea va ge of MP M Eth er Der iva tives. (3-
Ben zyl-5,6-d ih yd r o-1,4-d ith iin e-2-ca r ba ld eh yd e (14). Typ i-
ca l P r oced u r e. To a stirred CH2Cl2 H2O (9:1) emulsion (50
mL) containing MPM ether 4 (0.5 g, 1.4 mmol) was added DDQ
J O9714627