The total synthesis of D-chalcose and its C-3 epimer

Article abstract of DOI:10.3762/bjoc.9.296

We completed a new and efficient synthesis of D-chalcose (I) and the first synthesis of its C-3 epimer (I') in nine steps with overall yields of 23% and 24%, respectively. The key steps in the sequence were the formation of the stereocenter on C3 via Grignard reaction, the introduction of the stereogenic center on C2 by Sharpless asymmetric dihydroxylation, the protection of the C1 and C2 hydroxy groups with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), and the selective cleavage of the primary OTBS ether using catalytic DL-10-camphorsulfonic acid (CSA) in MeOH.

Full text of DOI:10.3762/bjoc.9.296

The total synthesis of D-chalcose and its C-3 epimer
Jun Sun1, Song Fan1, Zhan Wang1, Guoning Zhang1, Kai Bao*2
and Weige Zhang*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2620–2624.
1Key Laboratory of Structure-Based Drug Design & Discovery,
Ministry of Education, Shenyang Pharmaceutical University,
Shenyang 110016, China and 2Center for Molecular Imaging, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston,
MA 02215, United States
doi:10.3762/bjoc.9.296
Received: 24 August 2013
Accepted: 07 November 2013
Published: 22 November 2013
Email:
Associate Editor: S. Flitsch
Jun Sun - Jun_84@163.com; Kai Bao* - kbao@bidmc.harvard.edu;
Weige Zhang* - zhangweige2000@sina.com
© 2013 Sun et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
asymmetric dihydroxylation; chalcose; epimer; total synthesis
Abstract
We completed a new and efficient synthesis of D-chalcose (I) and the first synthesis of its C-3 epimer (I′) in nine steps with overall
yields of 23% and 24%, respectively. The key steps in the sequence were the formation of the stereocenter on C3 via Grignard reac-
tion, the introduction of the stereogenic center on C2 by Sharpless asymmetric dihydroxylation, the protection of the C1 and C2
hydroxy groups with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), and the selective cleavage of the primary OTBS
ether using catalytic DL-10-camphorsulfonic acid (CSA) in MeOH.
Introduction
Chalcose (4,6-dideoxy-3-O-methyl-D-xylo-hexose, I [1,2]) is a ities. Acrolein dimer [12], methyl 2-cis-5-hexadienoate [13],
structural component of many macrolide antibiotics, such as and trans-1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene [14]
chalcomycin [3], neutramycin [4], and lankamycin [5] have been utilized as non-carbohydrate precursors during the
(Scheme 1). After its structure was determined using chemical synthesis of DL-chalcose, but no attempt was made to resolve
degradation and spectroscopic analyses, several syntheses of the racemate. D- and L-chalcose were prepared from racemic or
chalcose were reported. The conversion of desosamine into meso-divinylglycols by Schmidt et al. [15,16], however, this
D-chalcose was described by Westwood’s group [6]. A small method had drawbacks, such as non-commercially sourced ma-
number of stereospecific syntheses beginning from carbohy- terial and unsatisfactory overall yield. As part of our study
drate precursors have been reported [7-10], but the route devel- concerning the structure–activity relationships and chemistry of
oped by Usov et al. [11] was especially significant because it new antibiotics, we sought to develop a reliable and efficient
demonstrated a facile method to introduce the deoxy functional- synthetic route starting from inexpensive, commercial sources
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to provide access to chalcose. We describe a new and efficient generated alcohol 4 and 4′ as a 4:5 mixture of diastereomers
9-step synthesis of D-chalcose (I) with a 23% overall yield. In [19]. This mixture was separated using silica gel chromatog-
addition its efficiency, the route enabled facile preparation of raphy to achieve a 78% overall yield over three steps. The
chalcose’s C-3 epimer (4,6-dideoxy-3-O-methyl-D-ribo-hexose, unwanted syn-diastereomer 4' was converted into the required
I′); the C-3 epimer has not been synthesized previously.
anti-diastereomer 4 via Mitsunobu inversion followed by
removal of the benzoate group under basic conditions [20].
Similarly, alcohol 4 could be converted to 4′.
Results and Discussion
The retrosynthetic analysis of I and I′ is presented in Scheme 1.
Diol II and II′ arose from a Sharpless asymmetric dihydroxyla- Alcohol 4 was methylated using MeI and t-BuOK to produce 5
tion that form the C2 stereogenic center. The installation of the in nearly quantitative yield (Scheme 3). Sharpless asymmetric
C3 stereocenter on vinyl ether III was proposed to utilize a dihydroxylation [21] of olefin 5 using AD-mix-β in a 1:1 mix-
Grignard reaction followed by chromatographic separation. ture of t-BuOH/H2O at 0 °C over four days afforded diol 6 with
Aldehyde IV would be generated from commercial ethyl (R)-3- S configuration in 80% yield.
hydroxybutyrate (1) via reduction.
Next, to selectively oxidize the primary alcohol into an alde-
The synthesis began by protecting the commercial ethyl (R)-3- hyde, we utilized TEMPO/NaClO [22] to oxidize diol 6.
hydroxybutyrate (1) using a nearly quantitative silylation of the However, the reaction failed to deliver aldehyde 7 (Scheme 3).
free hydroxy group under classical conditions (TBDPSCl, Therefore, we proposed that diol 6 should be protected and the
imidazole, DMF, rt) [17] to form the corresponding ester 2 primary OH group could then be selectively deprotected and
(Scheme 2). The reduction of 2 using DIBAL-H in anhydrous oxidized to yield the corresponding aldehyde. Our first step
CH2Cl2 at −78 °C was quenched with methanol at −30 °C to toward this goal was to select appropriate protective groups.
provide aldehyde 3 [18]. Subsequently, treating aldehyde 3 with Diol 6 was initially converted into benzylidene derivative 8
vinylmagnesium bromide in the presence of CuI at −78 °C (α,α-dimethoxytoluene/PPTS/CH2Cl2); 8 was subjected to a
Scheme 1: Retrosynthesis of I and I'. PG = protecting group; protecting groups may vary independently.
Scheme 2: Reagents and conditions: (a) TBDPSCl, DMAP, imidazole, CH2Cl2, rt, 99%; (b) DIBAL-H, CH2Cl2, −78 °C, 93%; (c) vinylmagnesium bro-
mide, CuI, Et2O, −78 °C, 85%; (d) 1) DIAD, PPh3, PhCOOH, THF, 40 °C; 2) 10% NaOH, THF, rt, 90% in two steps; (e) DEAD, PPh3, PhCOOH, THF,
40 °C; 2) 10% NaOH, THF, rt, 91% in two steps. TBDPS = t-butyldiphenylsilyl, DMAP = N,N-4-dimethylaminopyridine, DIBAL-H = diisobutylaluminum
hydride, DIAD = diisopropyl azodicarboxylate, DEAD = diethyl azodicarboxylate.
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Scheme 3: Reagents and conditions: (a) MeI, t-BuOK,THF, rt, 96%; (b) AD-mix-β, t-BuOH/H2O, 0 °C, 80%; (c) TEMPO, NaClO, CH2Cl2, −5 °C.
AD = asymmetric dihydroxylation, TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical.
regioselective reductive ring-opening reaction [23] with as the major product. In addition, we used HF·pyridine/THF
DIBAL-H in CH2Cl2 to afford a 1:1 mixture of free primary [26] (Table 1, entry 3 and 4) with similar effect. Treating 11
alcohol 9 and undesired secondary alcohol 10 (Scheme 4).
with AcOH/H2O/THF (13:7:3) [27] (Table 1, entry 5 and 6)
very slowly afforded alcohol 12 in low yield. Eventually, acid-
Consequently, we attempted to treat diol 6 with 2.5 equiv catalyzed deprotection conditions were examined using CSA
TBSOTf in anhydrous CH2Cl2 in the presence of 2,6-lutidine [28] (Table 1, entry 7–11) in various solvents. After several
for 12 h at room temperature, providing compound 11 in 90% attempts, we discovered that treating 11 with CSA (0.1 equiv)
yield [24]. Subsequently, we examined the deprotection of 11 in methanol at 0 °C for 45 min provided alcohol 12 in the
using the various conditions listed in Table 1. Compound 11 highest yield (Table 1, entry 10). Additionally, the combined
was initially treated with PPTS/MeOH [25] (Table 1, entry 1 yield increased with increasing reaction times, but, the amount
and 2) to form alcohol 12 as the major expected product. Unfor- of the desired alcohol 12 decreased (Table 1, entries 9 and 10).
tunately, this reaction was very low yielding and afforded diol 6 Moreover, using a protic solvent, such as methanol, was benefi-
Scheme 4: Reagents and conditions: (a) PhCH(OCH3)2, PPTS, CH2Cl2, rt; (b) DIBAL-H, CH2Cl2, 0 °C, 76% in two steps. PPTS = pyridinium
p-toluenesulfonate.
Table 1: Deprotection of 11.
Entry
Conditions
Yield (%)a
Ratio (12:6)b
1
PPTS (0.1 equiv), MeOH, 0 °C, 2 h
PPTS (0.1 equiv), MeOH, 25 °C, 5 h
HF-pyridine, THF, 0 °C, 1 h
trace
11
2
0.5:1
3
trace
17
4
HF-pyridine, THF, 25 °C, 1 h
0.2:1
1.2:1
0.4:1
0.8:1
2.4:1
1.5:1
4.7:1
4.9:1
5
AcOH:H2O:THF (13:7:3), 25 °C, 2 d
AcOH:H2O:THF (13:7:3), 40 °C, 20 h
CSA (0.1 equiv), CH2Cl2:MeOH (1:1), 0 °C, 1 h
CSA (0.1 equiv), MeOH, 0 °C,1 h
CSA (0.1 equiv), MeOH, 0 °C,1.2 h
CSA (0.1 equiv), MeOH, 0 °C, 45 min
CSA (0.1 equiv), MeOH, 0 °C, 30 min
16
6
23
7
20
8
74
9
76
10
11
71
52
aCombined yields of 12 and 6. bThe ratios were determined after chromatographic separation.
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cial for the reaction (Table 1, entry 7). Consequently, control- 82% yield. Subsequently, treating 6′ with TBSOTf afforded 7′.
ling reaction time was crucial to avoid generating undesired diol Selectively deprotecting the primary hydroxy group using CSA
6. Fortunately, diol 6 could be recycled via TBSOTf to furnish in methanol at 0 °C for 45 min provided alcohol 8′ in 60%
11, and 11 could be converted into 12 (Scheme 5).
yield, as well as a 15% yield of diol 6′ that could be recycled to
form 7′ using TBSOTf. Alcohol 8′ was oxidized using
With requisite intermediate 12 in hand, our attention was Dess–Martin periodinane to give aldehyde 9′ in 86% yield.
directed toward preparing the final product, chalcose. Alcohol Finally, 9′ was efficiently deprotected with TBAF, leading to
12 was subjected to Dess–Martin periodinane [29] because it the C-3 epimer of chalcose (I′) in 83% yield. Epimer I′ was
afforded aldehyde 13 in 86% yield, making it superior to the acetylated using acetic anhydride in pyridine, furnishing diac-
Swern oxidation. Subsequently, aldehyde 13 was efficiently etate 10′ in 80% yield; in the major product, C1 was assigned a
deprotected using TBAF in THF at 0 °C for 1 h to form D-chal- β-configuration based on the NMR spectroscopy data.
cose (I) in 84% yield. Finally, D-chalcose (I) converted into
diacetate 14 via treatment with acetic anhydride to facilitate Conclusion
characterization (Scheme 6). The 1H NMR data for diacetate 14 In conclusion, we developed a new and efficient synthesis of
was identical to the data reported for the natural product- D-chalcose (I), requiring nine steps and demonstrating a 23%
derived D-chalcose diacetate [10].
overall yield. The first synthesis of its C-3 epimer (I′) was
achieved using a similar route in 24% overall yield. Key
A nearly identical synthetic procedure was used to transform 4′ epimeric intermediates 4 and 4′ could be interconverted via
into the C-3 epimer of chalcose (I′); this procedure began with a Mitsunobu reaction, and their absolute configurations were
methylation to form 5′ (Scheme 7). The stereoselective dihy- assigned after their transformation into D-chalcose (I) and its
droxylation of 5′ using AD-mix-β afforded desired diol 6′ in C-3 epimer (I′), respectively. Notably, the stereocenter on C3
Scheme 5: Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 90%; (b) CSA, MeOH, 0 °C, 59%. TBS = t-butyldimethylsilyl, Tf = trifluoro-
methanesulfonyl, CSA = DL-10-camphorsulfonic acid.
Scheme 6: Reagents and conditions: (a) Dess–Martin periodinane, CH2Cl2, rt, 86%; (b) TBAF, THF, 0 °C, 84%; (c) Py, AcO2, rt, 80%. TBAF = tetra-
n-butylammonium fluoride.
Scheme 7: Reagents and conditions: (a) MeI, t-BuOK,THF, rt, 96%; (b) AD-mix-β, t-BuOH/H2O, 0 °C, 82%; (c) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 91%;
(d) CSA, MeOH, 0 °C, 60%; (e) Dess–Martin periodinane, CH2Cl2, rt, 86%; (f) TBAF, THF, 0 °C, 83%; (g) Py, AcO2, rt, 80%.
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Acknowledgements
We gratefully acknowledge the National S&T Major Project
(2012ZX09103101-060), the National Natural Science Founda-
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