Stereospecific benzyne-induced olefination from β-amino alcohols and its application to the total synthesis of (-)-1-deoxy-D-fructose

Article abstract of DOI:10.1002/chem.201001735

'Ole in one! Treatment of β-amino alcohols with CS₂ under alkaline conditions gave 1,3-thiazolidine-2-thiones, which were then treated with benzyne generated in situ. The reaction underwent an unprecedented addition-elimination process to give the desired olefins in 60-87 yields (see scheme; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene). Copyright

Full text of DOI:10.1002/chem.201001735

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DOI: 10.1002/chem.201001735
Stereospecific Benzyne-Induced Olefination from b-Amino Alcohols and
Its Application to the Total Synthesis of (À)-1-Deoxy-d-fructose
Jih Ru Hwu*[a, b] and Yung Chang Hsu[a]
Chemists endeavor to develop efficient methods for the
generation of carbon–carbon double bonds in organic and
biomolecules with stereospecificity.[1] The outcomes benefit
synthetic and natural product chemistry to a great extent.
Herein, we contribute a new method to form the C=C bond
that is complementary to existing methods. Some of the
prominent methods include the coupling of aldehydes with
organic phosphonium halides in the Wittig reaction,[2] the
coupling of two aldehydes in the McMurry reaction,[3] the
decomposition of cyclic thionocarbonates in the Corey–
Winter reaction,[4,5] the decomposition of cyclic 2-alkoxy-
1,3-dioxolanes in the Eastwood olefination,[5] the deoxyge-
nation of epoxides,[1] and so forth. Alternatively, the C=C
bond can be generated by 1,2-elimination reactions of sub-
strates containing various functional groups. These sub-
strates could be b-silyl alcohols in the Peterson olefination,[6]
bisdithiocarbonates in the Barton deoxygenation,[5] 1,2-diha-
lides with zinc in DMSO,[1] or 1,2-diols and their derivatives
under reductive conditions.[1]
To test the feasibility of a new olefination method, we
first tried to find the conditions for the conversion of (2S)-3-
(1-methylindol-3-yl)propanol 1a to the corresponding ally-
lindole 4a. Thus, compound 1a was treated with 1,8-
diazabicycloACTHUNTGRNEUNG[5.4.0]undec-7-ene (DBU) and carbon disul-
fide[10] in acetonitrile to produce 1,3-thiazolidine-2-thione 2a
in 94% yield (Scheme 1).[11] Compound 2a was then added
Scheme 1. Conditions used for the conversion of b-amino alcohols to ole-
fins. DBU=1,8-diazabicycloACTHUNTGRNEUNG[5.4.0]undec-7-ene.
However, disadvantages and limitations exist in some of
these methods,[1,3,5] such as demands on toxic reagents, in-
compatibility of other reducible functional groups with the
applied strong reducing reagents, the lack of stereospecific
control when forming the C=C bond, and so forth.
Herein, we report our success in the development of a
novel benzyne-induced method for the generation of a C=C
bond from b-amino alcohols. To the best of our knowledge,
this method has never been reported. The use of b-amino al-
cohol as the starting material offers great advantages: some
are commercially available, many come from natural sour-
ces,[7,8] and a number of them can be derived from natural
a-amino acids.[9] In addition, we report our application of
this new method as the key step in an efficient total synthe-
sis of (À)-1-deoxy-d-fructose, which possesses biological and
optical activities.
to a solution of 2-silylphenyl triflate (3) and CsF in acetoni-
trile at room temperature for 4.5 h to give allylindole 4a in
81% yield. By using the same procedures, (2S)-3-(1H-indol-
3-yl)propanol 1b was also successfully converted to allylin-
dole 4b from 2b (Scheme 1). However, the yield for the ole-
fination step of 2b to 4b was lower than that for 2a to 4a
(61 vs. 81%, respectively). The diversity is caused as a result
of the presence of an acidic proton in the substrate 2b.
The second stage was to explore the possible stereospeci-
ficity associated with the new olefination method shown in
Scheme 2 by the formation of cis- or trans-stilbene exclu-
sively as the model. Accordingly, various erythro- and threo-
b-amino alcohols 5a–5d were treated with DBU and carbon
disulfide to generate the 1,3-thiazolidine-2-thiones of type 6
[a] Prof. J. R. Hwu, Dr. Y. Chang Hsu
Department of Chemistry, National Tsing Hua University
Hsinchu, Taiwan 30013 (R.O.C.)
Fax : (+886)35-721594
E-mail: jrhwu@mx.nthu.edu.tw
[b] Prof. J. R. Hwu
Department of Chemistry, National Central University
Jhongli, Taiwan 32001 (R.O.C.)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001735.
Scheme 2. A stereospecific method for the synthesis of olefins from
b-amino alcohols via 1,3-thiazolidine-2-thiones.
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Table 1. Stereospecific synthesis of olefins from acyclic b-amino alcohols by
the method shown in Scheme 2.
These results clearly indicate the trans relationship of the
two phenyl groups that are attached directly to the 1,3-
thiazolidine-2-thione nucleus. Furthermore, trans-stilbene
(7b) was produced as the exclusive product from 6b, 6c,
b-Amino alcohol
thiazolidine-2-thione Yield Olefin prod-
Yield
[%]
[%]
uct
1
and 6d’, as determined by H NMR and 13C NMR spec-
5a
ACHTUNGTRENNUNG(threo)
troscopy, which gave peaks at d=7.11 and 128.7 ppm, re-
spectively (vs. d=6.59 and 130.2 ppm, respectively, for
cis-stilbene), corresponding to the vinylic protons and the
sp2 carbons, respectively. These spectroscopic results con-
firm the stereospecificity for the conversions of erythro-
5b to trans-stilbene (7b) and threo-5a to cis-stilbene
(7a).
In addition to the acyclic substrates 5a–5d, we at-
tempted to broaden the scope of the new olefination
method to cyclic compounds. Consequently, b-amino al-
cohols with the nitrogen atoms incorporated in a pyrroli-
dine or piperidine moiety were used as the starting mate-
rials (see Table 2). Treatment of b-amino alcohols 8a–8e
with carbon disulfide and DBU or aqueous sodium hy-
droxide[12] produced the corresponding heterobicyclic 1,3-
thiazo-2-thiones 9a–9e (see Scheme 3). By following the
6a
6b
94
7a 75
5b
ACHTUNGTRENNUNG(erythro)
96
7b 77
7c 78
7d 87
5c
ACHTUNGTRENNUNG(erythro)
6c
6d
99
5d
(erythro)
60[a]
G
6d’[b] 98
[a] For the conversions of 5d to 6d: i) CS2, NEt3 and ii) SOCl2. [b] Acetamide
6d’ was prepared by treating 6d with Ac2O and pyridine.
(Table 1). The reaction mixture containing 6, 3, and CsF in
acetonitrile was stirred at room temperature to generate the
desired cis- or trans-stilbene (7a or 7b, respectively).
Table 2. Formation of alkenyl 2-imino-1,3-benzothioles from cyclic b-amino alco-
hols by the method shown in Scheme 3 except stated otherwise.
b-Amino alcohol
Thiazolidine-2-
thione
Yield Olefin product
[%]
Yield
[%]
To prove that the transformations proceed with stereospe-
cificity, we confirmed the molecular framework of one of
the starting materials (6c) by using single crystal X-ray dif-
fraction analysis. The monoclinic crystals of 6c, as shown in
Figure 1, possessed the space group P21/c with a=7.0769(7),
b=16.2587(17), c=16.7757(17) ꢁ, a=908, b=97.076(4)8,
and g=908. A dihedral angle of 129.868 was found for the
8a
8b
8c
9a 72
10a 66
3
Ph-CH-CH-Ph moiety, as well as a J coupling of 4.6 Hz for
9b 81[a]
10b 60
the C4 and C5 protons in the 1H NMR spectrum of 6c.
9c 85[a]
10c 62
10d 65
8d
9d 86
11[b] 12
8e
9e 93
10e 61
[a] For the conversions of 8b and 8c to 9b and 9c, respectively: i) 8b or 8c with
Figure 1. ORTEP diagram of molecular framework 6c obtained by X-ray CF3COOH; ii) CS2, DBU. [b] 1,3-Benzothiazol-2-one 11 was formed as a byprod-
diffraction analysis. Ellipsoids at 50% probability.[21]
uct in the reaction.
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Stereospecific Benzyne-Induced Olefination from b-Amino Alcohols
COMMUNICATION
zyne-induced method as the key step on the intermediate 15
gave enol acetate 16 in 75% yield. Finally, saponification
followed by cyclization in situ produced the desired target
17. This total synthesis involved five steps and proceeded in
51% overall yield.
Our design of the new olefination strategy is illustrated in
Scheme 5, in which we use the conversion of 5c to 7b and
byproduct 20 as an example. The amino and the hydroxyl
Scheme 3. Synthesis of alkenyl 2-imino-1,3-benzodithioles from b-amino
alcohols of pyrrolidines or piperidines.
same procedure described before, we converted 9a–9e into
2-imino-1,3-benzodithioles 10a–10e as the major products in
60–66% yields. This benzyne-induced tandem ring-opening/
olefination step with cyclic amino alcohol substrates may
also lead to trace amounts of byproduct. For example, the
byproduct 1,3-benzothiazol-2-one 11 was isolated in 12%
yield during the conversion of 9d to 10d. Generally, high
stereospecificity was achieved, not only during the forma-
tion of aryl olefins shown in Table 1, but also in the success-
ful conversions of 9b and 9c to alkyl olefins 10b and 10c,
respectively.
Next, we wanted to demonstrate the efficiency and applic-
ability of this olefination method in the synthesis of an opti-
cally active target. Consequently, we utilized the olefination
as the key step in a total synthesis of (À)-1-deoxy-d-fructose
(17, Scheme 4), which inhibits erythrocyte glycolysis by 42
Scheme 5. A plausible mechanism for the benzyne-induced olefination.
groups in 5c with an erythro configuration react with DBU
and then carbon disulfide to generate the dithiocarbamate
intermediate 18. Then an intramolecular SN2 reaction occurs
to give the diphenyl-2-thione 6c in the trans form. Com-
pound 6c would then add onto benzyne, generated in situ
from 3 and CsF, through a [3+2] cycloaddition[16] to give the
tricyclic intermediate 19. Subsequently, it undergoes a retro
[3+2] pathway to produce the desired trans-olefin 7b and
the byproduct 20. Lakshmikantham and Cava[17] also report-
ed a similar type of reaction between a benzyne and ethyl-
ene trithiocarbonate. Alternatively, the possibility exists for
a concerted process to take place between 6c and benzyne,
which involves a simultaneous addition and ring opening of
1,3-thiazolidine-2-thione moiety. Accordingly, the same
products are generated directly.
Scheme 4. Total synthesis of (À)-1-deoxy-d-fructose from d-(+)-glucose
by using the benzyne-induced olefination method as the key step.
[a] Based on recovered starting material (14%).
During our validation of the reaction mechanism, we
identified a byproduct 11 in the conversion of 9d to 10d
(Scheme 6). The byproduct is likely to come from the attack
and 56% at concentrations of 25 and 50 mm, respectively.[13]
The total synthesis of 17 has been reported by several
groups.[14] We started our total synthesis with the cost-effec-
tive d-(+)-glucose (12). Reaction of 12 with n-butylamine in
a mixture of methanol and ethanol produced the b-amino
alcohol intermediate 13, which was converted to 1,3-thiazoli-
dine-2-thione 14 with carbon disulfide.[15] The five free hy-
droxyl groups therein were then protected with acetyl
groups by using acetic anhydride. Application of the ben-
of the 1,3-thiazolidine-2-thione nucleus in 9d (N C=S) on
À
À
benzyne (i.e., pathway a), instead of initial attack of the S
C=S on benzyne (i.e., pathway b, leading to 10d) as shown
in Scheme 6. Hydrolysis of the resulting 1,3-benzothiazole-2-
thione 21 gave 1,3-benzothiazol-2-one 11 as the byproduct.
Various methods have been developed for the generation
of benzyne;[18] however, we found that the use of 3 and CsF,
for its generation and application in situ, fitted our needs
and provided the best yields of the desired olefins. These
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J. R. Hwu and Y. Chang Hsu
Scheme 6. 1,3-Thiazo-2-thiones react with benzyne by two accessible
pathways.
Scheme 7. Formation of a 1,3-oxazolidine-2-thione from b-amino alcohol.
conditions were also found to be mild enough and did not
cause migration of the terminal C=C bond to the conjugated
position during the conversions of 2a and 2b to 4a and 4b,
respectively.
produced in 78% yield. This 1,3-oxazolidine-2-thione did
not undergo a benzyne-induced elimination to give the cor-
responding olefin. Our findings on the isolation of 1,3-oxa-
zolidine-2-thione 27 as the product are consistent with those
reported by Le Corre and coworkers.[11]
Our reasoning for this outcome is that the tetrasubstituted
carbon center in the intermediate 24 is too hindered for an
SN2 reaction to take place. Alternatively, the oxide center in
the intermediate 26 could initiate an intramolecular cycliza-
tion. Due to the steric hindrance existing in some amino al-
cohol substrates, this method is limited to the generation of
tri- and tetrasubstituted olefins under the mild conditions
we applied. We are trying to find a solution to this problem
and will report our results.
In conclusion, an unprecedented benzyne-induced strat-
egy was developed for the conversion of b-amino alcohols
to olefins with good yields. Advantages associated with this
strategy include: the complete control of stereospecificity
and the position of unsaturation, the availability of the start-
ing material, and the mild conditions employed. Applica-
tions of this new method to the synthesis of complex imino-
sugars, such as polyhydroxylated piperidine and pyrrolidines,
with optical activity will be reported in due course.
Often benzynes react with nucleophiles,[16a,19] such as
amines, alcohols, carboxylic acids, electron-rich double
bonds, and so forth. The conditions applied in our olefina-
tion method tolerated an acidic proton present in the sub-
strate (e.g., compound 2b with a free NH group), although
the yield of product was slightly lower. To obtain higher
yields, we converted polyol 14 into the corresponding poly-
acetate 15, which underwent olefination to give 16 in 75%
yield (Scheme 4). A similar precaution was taken in the in-
direct conversion of 5d to 7b via the acetamide intermedi-
ate 6d’ (compare with 6d, Table 1). Moreover, our data pre-
sented in Tables 1 and 2 indicates that benzyl, n-butyl,
phenyl, and acetyl groups acted as ideal protecting groups
for the benzyne-induced olefination.
1,2-Diols are the starting materials used in the Corey–
Winter reaction.[4,5] Although the possible stereogenic
carbon centers attached to the hydroxyl groups are de-
stroyed after the double bond is formed, often the final
products (e.g., trichodermamides and valienamine) could
still possess optical activity.[20] The same logic is applicable
to our new olefination method by the use of b-amino alco-
hols as starting materials to produce asymmetric products. A
working example, shown in Scheme 4, demonstrates our suc-
cess in proving its feasibility.
Acknowledgements
As shown in Scheme 1 and Scheme 4, as well as Table 1
and Table 2, the new olefination method can be applied to
the synthesis of various 1,1- and 1,2-disubstituted olefins.
The successful examples include alkyl (e.g., 16), heteroalkyl
(e.g., 10b and 10c), arylalkyl (e.g., 10d), heteroarylalkyl
(e.g., 4a and 4b), and aryl (e.g., 7a and 7b) alkenes.
We are grateful to the National Science Council (Grant No. 99-2113-M-
007-008-MY3) of the Republic of China for support of this research.
Keywords: amino alcohols
·
benzyne
·
olefination
·
stereospecificity · total synthesis
To explore the limitations of this new method for the syn-
thesis of tri- and tetrasubstituted olefins, we applied b-
amino alcohols of type 22 as the starting material. Under
the same conversion conditions as described before, we did
not generate any 1,3-thiazolidine-2-thione 25 via the inter-
mediates 23 and 24 (see Scheme 7). Instead, a different het-
erocyclic compound 27[11] containing an oxygen atom was
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Stereospecific Benzyne-Induced Olefination from b-Amino Alcohols
COMMUNICATION
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Received: June 18, 2010
Revised: December 21, 2010
Published online: March 1, 2011
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