DIBAL-mediated reductive transformation of trans-dimethyl tartrate acetonide into ε-hydroxy α,β-unsaturated ester and its derivatives

Article abstract of DOI:10.1021/jo200019j

Stepwise, selective DIBAL reduction of the acetonide diester derived from tartaric acid followed by the Horner- Emmons reaction effectively provided desymmetrized hydroxy mono-olefination products in a one-pot operation.

Full text of DOI:10.1021/jo200019j

NOTE
pubs.acs.org/joc
DIBAL-Mediated Reductive Transformation of trans-Dimethyl Tartrate
Acetonide into ε-Hydroxy r,β-Unsaturated Ester and Its Derivatives
Takashi Tomioka,* Yuki Yabe, Tohru Takahashi, and Tracy K. Simmons
Department of Chemistry and Biochemistry, University of Mississippi, University, Mississippi 38677, United States
S Supporting Information
b
ABSTRACT: Stepwise, selective DIBAL reduction of the acet-
onide diester derived from tartaric acid followed by the Hornerꢀ
Emmons reaction effectively provided desymmetrized hydroxy
mono-olefination products in a one-pot operation.
he D-(ꢀ)- and L-(þ)-tartaric acids are well-known chiral
Scheme 1. Short Synthetic Approach to 3 and 4
T
molecules possessing two useful stereogenic centers. Both
the natural (L) and unnatural (D) isomers are relatively inexpen-
sive and widely available even on a bulk scale. Therefore, these
molecules have continually been utilized as an important chiral
starting material in various natural product synthesis.
Among a number of the derivatives, the acetonide protected
diester 2, easily prepared from the acid 1 by simple one- or two-
step reactions (Scheme 1),1 is often employed to lead to further
symmetrical or unsymmetrical acetonides. In particular, a series
of acetonide esters 4 including but not limited to 4aꢀe
(Figure 1) are frequently seen as chiral building blocks for the
construction of a variety of synthetic intermediates in total
synthesis.2ꢀ8 However, there is no general, efficient path to
access these compounds. Indeed, many of the literature routes
require a long reaction sequence that includes redundant pro-
tectionꢀdeprotection and/or oxidationꢀreduction processes
and often results in low overall yields (e.g., 4a, five steps from
dimethyl L-tartrate;2 4b, seven steps from cis-2-butene-1,4-diol;3
4c, six steps from L-tartaric acid;4 4d, seven steps from L-tartaric
acid;5 4e, seven steps from L-arabitol,6 etc.7,8). However, since all
these acetonides 4 should technically be accessible from the
common acetonide derivative 3 by means of a standard
one-step chemical transformation currently available, compound
3 seems to be a highly versatile and potentially useful molecule
(Scheme 1). Nonetheless, the synthesis of 3 has been rarely
studied, and to the best of our knowledge, no practical route to 3
is yet available,9 even though efficient approaches for cis-acet-
onide isomers of 3 have been well-established.10 Thus, we
envisioned that exploring a facile, single-pot transformation of
acetonide diester 2 into 3 would be highly desirable, and
furthermore, enable rapid access to 4 as well as to other useful
analogues in just a few steps from tartaric acid 1 or, more
conveniently, from a commercially available acetonide diester 2.
A recent literature report11 describes eight-step approach to 3
(3a) via a chiral diol 5 (Scheme 2). Although the starting
D-mannitol is a very cheap material, the overall yield is disap-
pointingly low (17%) (39% for the first four steps12 and 44% for
Figure 1. Series of acetonide esters 4aꢀe
Scheme 2. Synthesis of 3a
the second four steps11). Naturally, the diol intermediate 5 can be
prepared from D-tartaric acid by two steps,13 but the overall
reaction efficiency (a total of six steps to 3a) is still not
satisfactory for this class of simple molecules.14
Meanwhile, Seebach et al. employed a short-step approach to
3 (3b) starting from an acetonide diester 2 (2a) (Scheme 3).15
Treatment of 2a with 3 equiv of DIBAL reagent at ꢀ78 °C
Received: January 7, 2011
Published: April 29, 2011
r
2011 American Chemical Society
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The Journal of Organic Chemistry
NOTE
followed by a Soxhlet extraction and further distillation afforded
the corresponding lactol/hydroxyaldehyde 6 in 45% yield. Sub-
sequently, Wittig olefination of 6 provided 3b in 80%. While the
overall yield was fair (36%)16 and the obtained 3b was a mixture
of E/Z isomers with a partial epimerization at C4, this protocol
still implies a potential feasibility for one-pot reductive transfor-
mation of diester 2 into 3 as described in Scheme 1.
room temperature and the second step at ꢀ78 °C) was also
investigated (Figure 2). The results indicate that the route B
conditions, adding 2 equiv of DIBAL at rt (step 1) and another 1
equiv at ꢀ78 °C (step 2), are strictly required to maximize the
yield of 3c.
All of the entries and reactions discussed/shown so far were
operated on a 1 mmol scale. The scalability was therefore
examined. First, the reaction was run on a 10 mmol scale, and
3c was successfully obtained in 44% yield. However, since the
first-step DIBAL reduction was a slightly exothermic process that
was not preferred for a large-scale operation, the addition
temperature was lowered to 0 °C to be safe (Scheme 5).
Interestingly, this modified condition somewhat improved the
yield of 3c (46% f 49% on a 1 mmol scale). More excitedly, even
a 40 times larger scale reaction still afforded 3c in 51% yield,
which is essentially the same as the one obtained at 1 mmol
reaction scale. Thus, the reaction proved to be scalable.
To explore the scope and limitations of this route B approach,
other HWE-type reagents were accordingly employed
(Scheme 6). All the cases worked well with similar efficiency
and afforded corresponding olefins (3d, 3e, and 3f) in 46ꢀ52%
yield, even though the R-cyano phosphonate reagent was not
To begin, the Seebach’s protocol under various “single-pot”
conditions, that is, without isolation of 6, was initially examined.
Even though the desired product 3b was somewhat observed, the
E/Z selectivity was, as expected, marginal (E/Z = ∼6:4). In order
to avoid this stereochemical drawback, the Wittig reagent was
exchanged for a HornerꢀWadsworthꢀEmmons (HWE) re-
agent, which is compatible with the use of DIBAL.17 The use
of [(EtO)2P(O)CHCOOEt]ꢀNaþ exclusively gave the desired
E-isomer (E/Z = >25:1);18 however, the yield of 3c was
disappointingly low (13%) (route A in Scheme 4), although,
on the basis of the original Seebach protocol, the entire DIBAL
addition temperature was initially maintained at ꢀ78 °C to
prepare the lactol 6 via an organoaluminum intermediate 7.
Because of the poor reaction efficiency of route A, an alternative
approach through a presumed hydroxy ester 8 was then explored
by adding the first 2 equiv of DIBAL at rt (route B in Scheme 4).19
Surprisingly, the applied route B conditions greatly improved the
overall product yield of 3c to 46%.
Table 1. Screening of Conditions for Routes A and Ba
As summarized in Table 1, both route A and B conditions were
further examined. Although the reaction yield was variable under
different conditions, the route B (entries 4ꢀ10) still proved to be
superior to route A (entries 1ꢀ3). Route B was highly solvent/
temperature-dependent (entries 4ꢀ7), but much less subject to
the ester substituent group (entries 6, 9, and 10). A faster DIBAL
addition still gave the same results (entry 8). [Note: Not
surprisingly, in the crude reaction mixture, two side products,
(1) over-reduced diol acetonide 5 and (2) C2-symmetrical R,β-
unsaturated diester,20 were always observed (the composition
ratio of these depends on the reaction conditions). These were
easily separated from product 3c by column chromatography.]
The dependence of the reaction yield of 3c on variations in the
amount of DIBAL at two different temperatures (the first step at
entry
2
reaction solvent
3c (%)
route A conditions
1
2
3
R = Me
R = Me
R = Me
THF
19b
13
THF
toluene
13
route B conditions
4
5
R = Me
R = Me
R = Me
R = Me
R = Me
R = Et
THF
21
25c
hexane
toluene
toluene
toluene
toluene
toluene
Scheme 3. Synthesis of 3b
6
46
7
29b
46d
46
8
9
10
R = i-Pr
48
a Reaction conditions: 2 (1.0 mmol), DIBAL (1.0 M in toluene), DIBAL
addition rate (1.0 mmol/h), solvent (4.0 mL), HWE reagent (1.5
mmol). b HWE reagent was added at r.t. c Used DIBAL (1.0 M in
hexane). d DIBAL addition rate (2.0 mmol/h).
a Ph3PdCHCO2Me.
Scheme 4. One-Pot Transformation of 2a into 3c
a [(EtO)2P(O)CHCOOEt]ꢀNaþ.
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NOTE
Scheme 7. Transformation of 3 into 4
a 2-Benzyloxy-1-methylpyridinium triflate. b tert-Butylchlorodiphenylsi-
lane. c DessꢀMartin periodinane.
was also cleanly introduced on the hydroxyl group of 3c in 97%.
Pd/C-catalyzed hydrogenation quantitatively converted 3c into
the reduced ester 4d. One-pot transformation of 3c into 4e was
also attempted; however, the yield of 4e was consistently low
(<20%). Therefore, following DMP oxidation of 3c, the aldehyde
was isolated as a crude product and then used for the next Wittig
olefination. This stepwise approach improved the yield to 38%,
which is comparable to the reported ones.23 These results
strongly support that the now more readily available 3 can play
an important role as a versatile intermediate for organic synthesis.
In addition, the number of reaction steps to access 4 through our
newly established approach are less than half those of literature
protocols. Thus, even though the reaction yield from 2 to 3 is fair
(up to 52%), these new routes to 4 are still highly competitive
and useful from the aspect of overall synthetic efficiency.
In summary, applying a unique, stepwise DIBAL addition
sequence to trans-dimethyl tartrate acetonide 2a most effectively
gave the corresponding lactol intermediate 6 that was subse-
quently exposed to various HornerꢀWadsworthꢀEmmons re-
agents to provide γ-hydroxy mono-olefination products. This
simple protocol now enables a rapid access to a number of useful
chiral acetonide derivatives such as 3 and 4 starting from readily
available tartaric acid.
Figure 2. Dependence of the yield of 3c on the amounts of DIBAL at
the first and second steps.
Scheme 5. Testing Scalability (1 mmol vs 40 mmol)
Scheme 6. Different Phosphonate Reagents
’ EXPERIMENTAL SECTION
Materials and Methods. All experiments were performed in
flame-dried glassware fitted with rubber septa under argon atmosphere.
Toluene was dried by passing through activated alumina. Tetrahydro-
furan (THF) was distilled over sodium/benzophenone ketyl. Unless
otherwise noted, all other reagents were obtained from commercial
a Yields in parentheses were obtained when the first-step DIBAL
addition was operated at room temperature.
1
sources and used as received. H nuclear magnetic resonance (NMR)
spectra were recorded at 300 or 500 MHz. Data are presented as follows:
chemical shift (in ppm on the δ scale relative to δH 7.26 for the residual
protons in CDCl3), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad), coupling constant (J/Hz), integra-
tion. Coupling constants were taken directly from the spectra and are
uncorrected. 13C NMR spectra were recorded at 75 or 125 MHz, and all
chemical shift values are reported in ppm on the δ scale, with an internal
reference of δC 77.0 for CDCl3. Infrared spectral data are reported in
units of cmꢀ1. Analytical TLC was performed on silica gel plates using
UV light and/or potassium permanganate stain followed by heating.
Flash column chromatography was performed on silica gel 60A
(32ꢀ63D).
very E stereoselective (E/Z = 63:37). Again, the first-step DIBAL
addition temperatures (0 °C vs rt) affected the product yields.
Substrate generality besides diester 2 was also explored. Un-
fortunately, when dimethyl succinate and dimethyl glutarate
were tested, the route B conditions did not give desired olefins
in an effective manner (only 15% and 26% yield, respectively).
Thus, the presence of the conformational constraint imparted by
the acetonide group seems to be important.
Finally, one-step transformation of compound 3 into 4 was
investigated (Scheme 7). Benzylation of 3c by employing
Dudley’s reagent (2-benzyloxy-1-methylpyridinium triflate)21
successfully afforded 4a in 75% yield.22 A silyl protecting group
General Procedure for the Synthesis of 3 (3c) on a 1.0
mmol Scale. Into a solution of 2a (183 μL, 1.0 mmol) in dry toluene
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NOTE
(4.0 mL) under argon atmosphere was added DIBAL reagent (2.0 mL,
1.0 M solution in toluene, 2.0 mmol) slowly over a period of 2 h at 0 °C
by using a syringe pump. After being stirred for 1 h at 0 °C, the resulting
solution was placed in a dry ice/acetone cooling bath (ꢀ78 °C) and
another 1 equiv of DIBAL reagent (1.0 mL, 1.0 M solution in toluene,
1.0 mmol) was slowly added over a period of 1 h. Following the addition
of HornerꢀEmmons reagent that was separately prepared from triethyl
phosphonoacetate (300 μL, 1.5 mmol) and NaH (60 mg, 60% in mineral
oil, 1.5 mmol) in dry toluene (2 mL), the reaction mixture was stirred
overnight (ꢀ78 °C to r.t.) and quenched with saturated Rochelle’s salt
solution (2 mL). The resulting mixture was vigorously stirred for 2 h and
diluted with H2O (2 mL). After the phase separation, the aqueous layer
was extracted with Et2O (2 ꢁ 15 mL). The combined organics were then
dried over MgSO4 and concentrated under reduced pressure. The crude
product was purified by SiO2 column chromatography (Hex/EtOAc =
3/1) to afford 3c (113 mg, 49%) as a colorless oil.
(E)-Ethyl 3-[(4S,5S)-5-hydroxymethyl-2,2-dimethyl-1,3-di-
oxolan-4-yl]prop-2-enoate (3c): [R]20D ꢀ8.67 (c 1.43, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 6.91 (dd, J = 5.8, 15.6 Hz, 1H), 6.14 (d, J =
15.6 Hz, 1H), 4.53 (m, 1H), 4.21 (q, J = 6.0 Hz, 2H), 3.87 (m, J = 7.8 Hz,
2H), 3.68 (m, J = 6.9 Hz, 1H), 2.70 (brs, 1H), 1.46 (s, 3H), 1.45 (s, 3H),
1.30 (t, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.9, 143.8,
122.8, 110.0, 80.7, 76.0, 60.7, 60.6, 26.9, 26.7, 14.1; IR spectra (neat) 1727,
3480; HRMS (EI) calcd for C10H15O5 215.0919 [M ꢀ CH3]þ, found
215.0924.
(E)-tert-Butyl 3-[(4S,5S)-5-Hydroxymethyl-2,2-dimethyl-
1,3-dioxolan-4-yl]prop-2-enoate (3d). The title compound was pre-
pared according to the general procedure. Column chromatography (Hex/
EtOAc = 3/1) yielded 3d (125 mg, 48%) as a colorless oil: [R]20D ꢀ6.69
(c 1.27, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.76 (dd, J = 6.2, 15.8 Hz,
1H), 6.07 (dd, J = 1.2, 15.8 Hz, 1H), 4.46 (m, 1H), 3.84 (m, 2H), 3.64 (m,
1H), 2.34 (brs, 1H), 1.46 (s, 9H), 1.43 (s, 3H), 1.42 (s, 3H); 13C NMR (75
MHz, CDCl3) δ165.1, 142.4, 124.8, 109.9, 80.74, 80.73, 76.0, 60.6, 27.9, 26.8,
26.7; IR spectra (neat) 1710, 3469; HRMS (EI) calcd for C12H19O5
243.1232 [M ꢀ CH3]þ, found 243.1231.
Experimental Procedure for the Synthesis of 3c on a 40.0
mmol Scale. Into a solution of 2a (7.33 mL, 40.0 mmol) in dry toluene
(160 mL) under argon atmosphere was added DIBAL reagent (80.0 mL,
1.0 M solution in toluene, 80.0 mmol) slowly over a period of 2 h at 0 °C
by using a syringe pump. After being stirred for 1 h at the same
temperature, the resulting solution was placed in a dry ice/acetone
cooling bath (ꢀ78 °C), and another 1 equiv of DIBAL reagent (40.0 mL,
1.0 M solution in toluene, 40.0 mmol) was slowly added over a period of
1 h. Following the addition of HornerꢀEmmons reagent (over 20 min)
that was separately prepared from triethyl phosphonoacetate (12.0 mL,
60.0 mmol) and NaH (2.40 g, 60% in mineral oil, 60.0 mmol) in dry toluene
(80 mL), the reaction mixture was stirred for ∼12 h (ꢀ78 °C to rt).
The mixture was then quenched with saturated Rochelle’s salt solution
(80 mL) at 0 °C and vigorously stirred for 2 h at rt. After dilution with H2O
(80 mL), the biphasic mixture was separated. The separated aqueous layer
was extracted with Et2O (2 ꢁ 100 mL). The combined organics were dried
over MgSO4 and concentrated under reduced pressure. The crude product
was purified by SiO2 column chromatography (Hex/EtOAc = 3/1) to
afford 3c (4.68 g, 51%) as a colorless oil. [Note: Two side products, diol 5
(∼5% yield by NMR) and C2-symmetrical R,β-unsaturated diester (7%
yield, 780 mg), in the crude mixture were easily separated due to the large
differences in polarity [Rf (Hex/EtOAc = 3/1) 0.43 for the diester, 0.14 for
3c, and ∼0 for diol 5].]
One-Step Transformation of 3 into 4. Benzylation of 3c into
4a. Into a solution of 3c (103 μL, 0.5 mmol) in benzotrifluoride (2 mL)
were added 2-benzyloxy-1-methylpyridinium triflate21 (349 mg, 1
mmol) and MgO (40 mg, 1 mmol). The reaction mixture was stirred
at 83 °C. After being stirred for 66 h, the resulting reaction mixture was
then filtered through Celite with EtOAc and concentrated under
reduced pressure. The crude product was purified by SiO2 column
chromatography (Hex/EtOAc = 10/1) to give the compound 4a as a
colorless oil (120 mg, 75%). This product spectroscopically matched
that of the known compound:24 [R]20D = ꢀ23.2 (c 1.00, CHCl3) [lit.24
1
[R]20 = ꢀ23.4 (c 1.0, CHCl3)]; H NMR (300 MHz, CDCl3) δ
D
7.38ꢀ7.27 (m, 5 H), 6.90 (dd, J = 5.4, 15.8 Hz, 1H), 6.09 (dd, J = 1.5, 15.8
Hz, 1H), 4.60 (s, 2H), 4.43 (ddd, J = 1.5, 5.4, 8.4 Hz, 1H), 4.20 (q, J =
7.2 Hz, 2H), 3.96 (dt, J = 4.8 8.4 Hz, 1H), 3.63 (d, J = 4.8 Hz, 2H),1.46 (s,
3H), 1.44 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (75MHz, CDCl3) δ
166.0, 144.0, 137.7, 128.4, 127.8, 127.7, 122.6, 110.2, 79.6, 77.4, 73.6, 69.3,
60.6, 26.9, 26.7, 14.2.
(E)-4-[(4S,5S)-5-Hydroxymethyl-2,2-dimethyl-1,3-dioxolan-
4-yl]but-3-en-2-one(3e). Thetitlecompoundwaspreparedaccording
to the general procedure (note: the HWE reagent was prepared in dry THF
(2 mL) instead of dry toluene (2 mL) due to the poor solubility). Column
chromatography (Hex/EtOAc = 7/3 to 6/4) yielded 3e (105 mg, 52%) as a
colorless oil: [R]20D ꢀ9.23 (c 1.29, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 6.73 (dd, J = 6.2, 15.9 Hz, 1H), 6.36 (d, J = 15.9 Hz, 1H), 4.52 (m, 1H),
3.86 (m, 2H), 3.69 (brs, 1H), 2.78 (brs, 1H), 2.28 (s, 3H), 1.45 (s, 3H),
1.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.1, 142.5, 131.1, 110.0,
80.8, 76.2, 60.7, 27.4, 26.8, 26.6; IR spectra (neat): 1679, 3546; HRMS (EI)
calcd for C9H13O4 185.0814 [M ꢀ CH3]þ, found 185.0813.
Silyl Protection of 3c into 4c. Into a solution of 3c (103 μL,
0.5 mmol) in DMF (5 mL) were added tert-butylchlorodiphenylsilane
(133 μL, 0.51 mmol) and imidazole (68 mg, 1 mmol). The reaction
mixture was stirred at 0 °C for 10 h and then stirred overnight at room
temperature. After the phase separation, the aqueous layer was extracted
with Et2O (2 ꢁ 15 mL). The combined organics were then washed with
brine, dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by SiO2 column chromatography (Hex/
EtOAc = 20/1) to afford 4c (228 mg, 97%) as a colorless oil. This
product spectroscopically matched that of the known compound:4
[R]20D = ꢀ1.88 (c 3.41, CHCl3) [lit.4 [R]20D = ꢀ1.8 (c 3.4, CHCl3)];
1H NMR (300 MHz, CDCl3) δ 7.73ꢀ7.71 (m, 4 H), 7.43ꢀ7.41 (m,
6H), 6.97 (dd, J = 5.7, 15.8 Hz, 1H), 6.14 (d, J = 15.8 Hz, 1H), 4.62 (t, J =
5.7 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.88ꢀ3.85 (m, 3H), 1.47 (s, 3H),
1.45 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.10 (s, 9H) ; 13C NMR (75 MHz,
CDCl3) δ 166.0, 144.4, 135.60, 135.57, 132.9, 129.9, 129.8, 127.8, 127.7,
122.1, 109.9, 80.7, 77.5, 63.1, 60.5, 26.9, 26.8, 19.2, 14.2.
Hydrogenation of 3c into 4d. Into a solution of 3c (103 μL, 0.5
mmol) in MeOH (5 mL) was added 5% palladium on charcoal
anhydrous (12 mg, 10 wt %). The mixture was stirred under a hydrogen
atomosphere at room temperature for 4 h. The reaction mixture was
then filtered through Celite with EtOAc and concentrated under
reduced pressure. The crude product was purified by SiO2 column
chromatography (Hex/EtOAc = 3/1) to give the compound 4d as a
3-[(4S,5S)-5-Hydroxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]-
prop-2-enenitrile (3f). The title compound was prepared according to
the general procedure (note: the HWE reagent was prepared in dry
THF (2 mL) instead of dry toluene (2 mL) due to the poor solubility).
Column chromatography (Hex/EtOAc = 7/3 to 6/4) yielded 3f [53 mg
(E-isomer) þ 31 mg (Z-isomer) = 84 mg, 48%] as a colorless oil.
E-Isomer: [R]20D ꢀ5.31 (c 1.28, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 6.73 (dd, J = 4.8, 16.2 Hz, 1H), 5.75 (dd, J = 1.5, 16.2 Hz, 1H), 4.51 (m,
1H), 3.84 (m, 2H), 3.68 (m, 1H), 2.39 (brs, 1H), 1.44 (s, 3H), 1.41
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 150.6, 116.7, 110.4, 100.7, 80.3,
76.2, 60.7, 26.8, 26.5; IR spectra (neat) 2230, 3475; HRMS (EI) calcd for
C8H10NO3 168.0661 [M ꢀ CH3]þ, found 168.0662. Z-Isomer: [R]20
D
7.50 (c 0.96, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.50 (dd, J = 8.3,
11.1 Hz, 1H), 5.53 (d, J = 11.1 Hz, 1H), 4.81 (m, 1H), 3.89 (m, 2H), 3.76
(m, 1H), 2.16 (brs, 1H), 1.47 (s, 3H), 1.46 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 150.5, 114.8, 111.0, 102.3, 80.8, 75.6, 61.1, 26.8, 26.6; IR
spectra (neat) 2227, 3485; HRMS (EI) calcd for C8H10NO3 168.0661
[M ꢀ CH3]þ, found 168.0659.
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NOTE
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Chen, A. Tetrahedron 2007, 63, 7053. (d) Totokotsopoulos, S. M.;
Anagnostaki, E. E.; Stathakis, C. I.; Yioti, E. G.; Hadjimichael, C. Z.;
Gallos, J. K. ARKIVOC 2009, 209. (e) Gopinath, P.; Debasree, C.;
Vidyarini, R. S.; Chandrasekaran, S. Tetrahedron 2010, 66, 7001.
(11) Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka, Y.; Tomioka,
K. J. Org. Chem. 2001, 66, 8199.
matched that of the known compound:25 [R]20 = ꢀ24.7 (c 2.60,
D
CHCl3) [lit.26 [R]23D = ꢀ24.1 (c 2.6, CHCl3)]; 1H NMR (300 MHz,
CDCl3) δ 4.10 (q, J = 7.2 Hz, 2H), 3.86 (dt =7.5, 3.6 Hz, 1H), 3.74 (m,
2H), 3.62 (m, 1H), 2.53ꢀ2.36 (m, 3H), 1.92 (m, 1H), 1.81 (m, 1H),
1.36 (s, 3H), 1.35 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 173.2, 108.8, 81.0, 76.1, 61.8, 60.5, 30.6, 27.9, 27.2, 26.9, 14.1.
DMP Oxidation/Wittig Olefination of 3c into 4e. DessꢀMartin
periodinane (467 mg, 1.1 mmol) was added to a solution of 3c (230 mg,
1.0 mmol) in CH2Cl2 (8 mL). After being stirred 2.5 h at rt, the reaction
mixture was quenched with satd NaHCO3 (5 mL) and satd Na2S2O3
(5 mL) and vigorously stirred for 10 min. After the phase separation, the
aqueous layer was extracted with CH2Cl2 (2 ꢁ 10 mL). The combined
organics were then dried over Mg2SO4 and concentrated in vacuo. The
crude aldehyde was immediately used for the next reaction. Into a
suspension of methyltriphenylphosphonium bromide (356 mg, 1.0
mmol) in dry THF (10 mL) at ꢀ78 °C (acetone/dry ice) was added
n-BuLi (360 μL, 2.5 M solution in hexane, 0.9 mmol) dropwise. After the
mixture was stirred for 30 min, a solution of the aldehyde in dry THF
(5 mL) was added slowly over 10 min. After the mixture was stirred for 1
h, the cooling bath was removed and the resulting mixture was stirred for
1 h at rt. After quenching with half-saturated NH4Cl (15 mL), the
separated aqueous layer was extracted with Et2O (2 ꢁ 15 mL). The
combined organics were washed with brine, dried over MgSO4, and
concentrated in vacuo. The crude oil was purified with silica gel column
chromatography (Hex/EtOAc = 95/5) to afford 85 mg colorless oil
(38%). This product spectroscopically matched that of the known
compound:6 [R]20 = þ9.48 (c 0.52, CHCl3) [lit. [R]20 = þ14.8
(12) Terashima, S.; Tamoto, K.; Sugimori, M. Tetrahedron Lett.
1982, 23, 4107.
D
D
(13) Wagner, S. H.; Lundt, I. J. Chem. Soc., Perkin Trans. 1 2001, 780.
(14) Although we attempted to explore two-step direct transforma-
tion of 5 into 3 by employing an oxidation of diol 5 followed by the
HornerꢀEmmons olefination via a lactol intermediate, the desired
product 3a was not observed. A major limitation of this route was the
first oxidation step. Even though several oxidation conditions were
carefully screened (e.g., DMP, TEMPO, and ParikhꢀDoering condi-
tions, etc.), the corresponding lactol intermediate was barely obtained.
(c 1.0, CHCl3)]; 1H NMR (300 MHz, CDCl3) δ 6.86 (dd, J = 5.4, 15.6
Hz, 1H), 6.12 (dd, J = 1.2, 15.6 Hz, 1H), 5.83 (ddd, J = 7.2, 10.2, 17.1 Hz,
1H), 5.40 (d, J = 17.1 Hz, 1H), 5.31 (d, J = 10.2 Hz, 1H), 4.28ꢀ4.10
(m, 4H), 1.47 (s, 3H), 1.45 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H) ; 13C NMR
(75 MHz, CDCl3) δ 166.2, 143.0, 133.8, 123.1, 120.1, 110.2, 82.3, 80.1,
60.8, 27.2, 27.0, 14.4.
’ ASSOCIATED CONTENT
1
Supporting Information. Copy of H and 13C NMR
S
b
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Schnurrenberger, P.; Hungerbuhler, E.; Seebach, D. Liebigs
Ann. Chem. 1987, 9, 733.
(16) Among the distilled fractions of 6, only the second one was used
for the next Wittig olefination (ref 15). Thus, the actual overall yield may
be lower than 36%.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tomioka@olemiss.edu.
(17) Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986,
27, 1257.
(18) Unlike the Takacs’s protocol (ref 17), the use of Liþ as a
countercation lowered the stereoselectivity (E/Z = 80:20).
(19) Ducry, L.; Roberge, D. M. Org. Process Res. Dev. 2008, 12, 163.
(20) This product spectroscopically matched that of the known
compound (Alexakis, A.; Tomassini, A.; Leconte, S. Tetrahedron 2004,
60, 9479):
’ ACKNOWLEDGMENT
The project described was supported by Grant No.
5P20RR021929 from the National Center for Research Re-
sources. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the
National Center for Research Resources or the National Insti-
tutes of Health. The University of Mississippi also supported this
research.
1H NMR (300 MHz, CDCl3) δ 6.87 (ddd, J = 1.8, 3.6, 15.9 Hz, 2H),
6.14 (d, J = 15.6 Hz, 2H), 4.28ꢀ4.30 (m, 2H), 4.22 (q, J = 7.2 Hz, 4H),
1.47 (s, 6H), 1.30 (t, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
165.9, 142.0, 123.9, 111.0, 79.9, 61.0, 27.0, 14.4.
(21) (a) Poon, K. W. C.; House, S. E.; Dudley, G. B. Synlett
2005, 3142. (b) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006,
71, 3923. (c) Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Org. Synth.
2007, 84, 295.
’ REFERENCES
(1) (a) Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S. B.
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dx.doi.org/10.1021/jo200019j |J. Org. Chem. 2011, 76, 4669–4674

The Journal of Organic Chemistry
NOTE
(22) Due to the presumed sensitivity of 3c to both acidic and basic
benzylation conditions, the neutral Dudley’s protocol was therefore
selected. Another neutral, silver oxide promoted benzylation condition
was not very effective for 3c.
(23) The overall yield of our three-step route from 2a to 4e is 19%
[51% (2a f 3c) and 38% (3c f 4e)]. Literature approaches: 21% over
seven steps from 2a (Sarabia, Francisco; Sanchez-Ruiz, A. J. Org. Chem.
2005, 70, 9514); 37% over seven steps from L-arabitol (ref 6); 20% over
six steps from D-mannitol (Chou, C.-Y.; Hou, D.-R. J. Org. Chem. 2006,
71, 9887).
(24) Lebar, M. D.; Baker, B. J. Tetrahedron 2010, 66, 1557.
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4674
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