New approach toward the total synthesis of (+)-batzellaside B

Article abstract of DOI:10.3762/bjoc.8.210

A new synthetic approach to (+)-batzellaside B from naturally abundant L-pyroglutamic acid is presented in this article. The key synthetic step involves Sharpless asymmetric dihydroxylation of an olefinic substrate functionalized with an acetoxy group to

Full text of DOI:10.3762/bjoc.8.210

A new approach toward the total synthesis
of (+)-batzellaside B
Jolanta Wierzejska, Shin-ichi Motogoe, Yuto Makino, Tetsuya Sengoku,
Masaki Takahashi and Hidemi Yoda*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1831–1838.
Department of Materials Science, Faculty of Engineering, Shizuoka
University, 3-5-1 Johoku, Naka-ku, Hamamatsu, Shizuoka 432-8561,
Japan
doi:10.3762/bjoc.8.210
Received: 04 August 2012
Accepted: 24 September 2012
Published: 25 October 2012
Email:
Hidemi Yoda* - tchyoda@ipc.shizuoka.ac.jp
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
* Corresponding author
Keywords:
Guest Editor: T. K. Lindhorst
asymmetric dihydroxylation; (+)-batzellaside B; iminosugar;
L-pyroglutamic acid; total synthesis
© 2012 Wierzejska et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A new synthetic approach to (+)-batzellaside B from naturally abundant L-pyroglutamic acid is presented in this article. The key
synthetic step involves Sharpless asymmetric dihydroxylation of an olefinic substrate functionalized with an acetoxy group to intro-
duce two chiral centres diastereoselectively into the structure. Heterocyclic hemiaminal 4, which could be converted from the
resulting product, was found to provide stereospecific access to enantiomerically enriched allylated intermediate, offering better
prospects for the total synthesis of this natural product.
Introduction
Iminosugars, monosaccharide analogues in which the endo- ment of type II diabetes and Gaucher disease, respectively, has
cyclic oxygen has been replaced by nitrogen, display beneficial imparted therapeutic applications of this class of natural prod-
therapeutic activity as sugar-mimicking glycosidase inhibitors ucts.
[1-4]. Since the discovery of nojirimycin (Figure 1), which was
isolated from Streptomyces roseochromogenes R-468 and In this context, (+)-batzellasides A–C (1a–c) (Figure 2),
S. lavendulae SF-425 in the 1960s [5], this class of compounds C-alkylated azasugars isolated in 2004 from a sponge Batzella
has attracted a great deal of interest in the medical community sp. collected off the west coast of Madagascar, represent the
due to their promising pharmaceutical potential as antidiabetic first example of iminosugars from a marine organism [11].
[6], antitumor [7] and antiviral [8] agents. Undoubtedly, These naturally occurring products have been demonstrated to
approval of Glyset [9] and Miglustat [10] (Figure 1) for treat- retain a remarkably high degree of potency against Staphylo-
1831

Beilstein J. Org. Chem. 2012, 8, 1831–1838.
coccus epidermidis with MICs of ≤6.3 μg/mL, thus serving as
new potent antibacterial agents [11]. As a part of our research
program on the synthesis and investigation of biologically
active natural products [12-18], we have pursued the synthetic
elaboration of (+)-batzellaside B (1b) as a represent member of
this new class of iminosugar alkaloids.
In a previous publication, we communicated the first total syn-
thesis of (+)-batzellaside B (1b) by the use of L-arabinose,
wherein the absolute stereochemistry of this natural product was
completely established by the modified Mosher analysis of a
synthetic intermediate prepared through a separate route
(Scheme 1) [19]. In this approach involving nucleophilic
cyclization of acyclic aldehyde in situ generated from olefin 2
for constructing the piperidine ring system, proper synthetic
manipulation of the three inherent stereocenters contained in the
chiral source was a key strategy for ensuring effective stereo-
control to achieve completion of the target-directed synthesis.
The overall yield in 22 steps from 2,3,5-tri-O-benzyl-L-arabi-
nose (3) was 3.9%. Although 1b and its related analogues are
now accessible through the pathway established above,
Figure 1: Examples of naturally occurring iminosugars.
Figure 2: The chemical structures of (+)-batzellasides A–C (1a–c).
Scheme 1: Our previous approach to (+)-batzellaside B and retrosynthetic analysis for the new synthetic strategy.
1832

Beilstein J. Org. Chem. 2012, 8, 1831–1838.
pursuing a new synthetic approach strongly appealed to us, The present publication describes the results of our continuing
because the existing route is still rather unsatisfactory mainly in challenges associated with this targeted natural product on the
terms of the insufficient supply and the time-consuming basis of the above synthetic strategy. As a result, and in addition
preparation of the tribenzyl ether 3, which is not commercially to improvement of the inefficient stereoselectivity observed in
available [20]. We thus decided to explore new alternative allylation process from 4 to 7, we established the new alter-
strategies allowing for a more efficient and convenient access to native synthetic route to (+)-batzellaside B from L-pyroglu-
this natural product and its derivatives. From a retrosynthetic tamic acid, which offers the advantages of convenience and
point of view, L-pyroglutamic acid, whose rich natural simplicity of total synthesis.
abundance makes it a commercially and economically viable
substrate [21], can be envisaged as a potentially practical Results and Discussion
starting material for this purpose (Scheme 1). Furthermore, it The synthesis began with the preparation of N-Boc-protected
can be considered that the heterocyclic hemiaminal 4, a γ-lactam 8 by stepwise functionalization of L-pyroglutamic
common precursor of the target molecule for both synthetic acid, using literature procedures (Scheme 2) [22]. As indicated
strategies, would be derived by an analogous cyclization of the previously, this compound underwent efficient ring opening
acyclic aldehyde generated in situ from cyanide 5. In this upon treatment with sodium methoxide in methanol to provide
proposed strategy, the key transformation will involve Sharp- acyclic ester 9 in 98% yield [23]. In the next step, the TBS
less asymmetric dihydroxylation to install stereoselectively the protecting group in 9 was removed by exposure to methanolic
hydroxy groups at C3 and C4 positions of the olefinic substrate p-TsOH to give the corresponding alcohol, which was then
6, and an intramolecular cyclization of aldehyde generated in subjected to reaction with 2,2-dimethoxypropane (2,2-DMP) in
situ from 5 to construct the piperidine ring system.
the presence of BF3·Et2O [24] to produce N,O-acetonide 10 in
Scheme 2: Reagents and conditions: (a) see [22]; (b) MeONa, MeOH, rt; 98%; (c) (i) p-TsOH, MeOH, rt; (ii) BF3·Et2O, 2,2-DMP, acetone, rt; 93%
(two steps); (d) (i) LDA, HMPA, PhSeBr, THF, −78 °C; (ii) m-CPBA, CH2Cl2, −40 °C; 90% (two steps); (e) DIBAL-H, THF, 0 °C; 95%; (f) OsO4, NMO,
t-BuOH/H2O (1/1), rt; 30%, 12a-A/12a-B = 24/76; (g) (i) TBSCl, Et3N, CH2Cl2, rt; (ii) BnBr, NaH, Bu4NI, THF, rt; (h) (i) p-TsOH, MeOH, rt; (ii) TFA,
CH2Cl2, rt; (i) (i) NaIO4, Et2O/H2O (1/1), rt; (ii) PCC, MS 4 Å, CH2Cl2, rt; 17% (six steps); (j) TBSCl, imidazole, DMF; 77% (6b); or MOMCl, NaH, THF;
68% (6c); or Ac2O, DMAP, Et3N, CH2Cl2; 99% (6d).
1833

Beilstein J. Org. Chem. 2012, 8, 1831–1838.
93% yield over two steps. For the preparation of the E-isomer p-TsOH and TFA to give a dihydroxyamine intermediate,
of α,β-unsaturated ester 11, Wittig–Horner reaction employing which underwent spontaneous cyclization upon treatment with
Garner’s aldehyde has been well known [25,26]; however, we NaIO4 [36] followed by PCC oxidation to form the corres-
selected stereoselective olefination through deprotonation of 10 ponding trans-1,2-dibenzyloxy-substituted γ-lactone 14B in
with LDA followed by the addition of phenylselenyl bromide 17% yield over six steps. For comparison, optical rotation
[27] and subsequent oxidative elimination of the resulting measurement was performed on a solution of 14B in CHCl3 at
phenylseleno group with m-CPBA according to our previous c 0.36. Indeed, this compound exhibited optical activity with an
report [28], which gave E-isomer 11 in quantitative geometric [α]D24 value of −51.6, indicative of an opposite sense of
purity and 90% yield over two steps. Then, the ester moiety of absolute configuration in comparison to the literature data given
this compound was reduced with DIBAL-H to the corres- for (1S,2S)-dibenzyloxy γ-lactone ([α]D25 +60.1, c 1.0, CHCl3)
ponding hydroxymethyl functionality to afford 6a in 95% yield [34]. From this, we can conclude, as seen in Scheme 2, that the
[29].
more polar triol 12a-A obtained as a minor component of this
dihydroxylation process could be identified as the (1S,2S)-
With this olefinic compound in hand, we examined the dihy- isomer that should be supplied to advance our ongoing syn-
droxylation of 6a, which was carried out with OsO4 and NMO thetic strategy, albeit with low yield for its preparation.
in 50% aqueous t-BuOH at room temperature [30-33]. Under
these conditions, 6a provided an approximately 1:3 ratio of the In an effort to improve selectivity of stereogenesis for the dihy-
more- and less-polar diastereomeric triols 12a-A and 12a-B, droxylation step, we prepared three other olefinic substrates, in
respectively, in 30% yield. These diastereomers were separated which the hydroxy group in 6a was replaced by tert-butyl-
by silica-gel column chromatography and then derivatized to dimethylsilyloxy (TBSO), methoxymethyloxy (MOMO) and
trans-1,2-dibenzyloxy-substituted γ-lactone, which allows a acetoxy (AcO) groups, according to standard procedures
precise assignment of the absolute configuration by comparison [37,38], to give moderate to high yields (68–99%) of 6b–d, res-
with the specific optical rotation value [34]. Accordingly, the pectively. Having the four different olefinic compounds 6a–d
primary hydroxy group of 12a-B was chemoselectively available, we turned to an asymmetric technique of dihy-
protected as the TBS ether [35] and the remaining diol moiety droxylation to synthesize the (1S,2S)-constituent in preference
was then etherified with NaH and benzyl bromide, affording to another (Table 1). Indeed, the Sharpless methodology was
13B in a crude form. Deprotection of the acetal and TBS groups initially applied to 6a, by carrying out the reactions at room
of this product was carried out by stepwise reactions with temperature under a standard set of the asymmetric hy-
Table 1: Asymmetric dihydroxylation of 6a–d.
Entry
6
R
Reagent (amount [mol %])
T
Yield [%]a (12-A/12-B)b
1
a
a
b
b
c
c
d
d
d
d
d
H
AD-mix-α (0.5), MeSO2NH2 (100)
AD-mix-β (0.5), MeSO2NH2 (100)
AD-mix-α (0.5), MeSO2NH2 (100)
AD-mix-β (0.5), MeSO2NH2 (100)
AD-mix-α (0.5), MeSO2NH2 (100)
AD-mix-β (0.5), MeSO2NH2 (100)
AD-mix-α (0.5), MeSO2NH2 (100)
AD-mix-β (0.5), MeSO2NH2 (100)
AD-mix-α (0.5), MeSO2NH2 (100)
AD-mix-α (0.5)
rt
32 (45/55)
77 (13/87)
33 (14/86)
35 (40/60)
52 (50/50)
88 (0/100)
48 (69/31)
51 (9/91)
2
H
rt
3
TBS
TBS
MOM
MOM
Ac
rt
4
rt
5
rt
6
rt
7
rt
8
Ac
rt
9
Ac
0 °C
0 °C
0 °C
54 (78/22)
52 (84/16)
53 (83/17)
10
11
Ac
Ac
AD-mix-α (0.5), (DHQ)2PHAL (10)
aIsolated yield. bDiastereomeric ratios were determined by 1H NMR (300 MHz).
1834

Beilstein J. Org. Chem. 2012, 8, 1831–1838.
droxylation conditions [39-41]. Using AD-mix-α and -β, we piperidine ring system. As shown in Scheme 3, the acetyl group
obtained mixtures of 12a-A and 12a-B in 45:55 and 13:87 ratios of the diastereomerically enriched mixture of 12d-A and 12d-B
with overall isolated yields of 32 and 77%, respectively was removed by exposure to K2CO3 in methanol to give the
(Table 1, entries 1 and 2). Analogously, the asymmetric dihy- separable mixture of alcohols 12a-A and 12a-B, respectively
droxylations of 6b and 6c produced predominantly the unde- [42]. After purification by silica-gel column chromatography,
sired less-polar diastereomers 12b-B and 12c-B, which could be 12a-A was subjected to the TBS protection–benzylation
converted by acidic deprotection to 12a-B (Table 1, entries 3,4 sequence, as illustrated for the preparation of 13B, to generate
and 6), while the reaction of 6c with AD-mix-α afforded a 13A in 50% yield over three steps. In the next step, deprotec-
50:50 mixture of diastereomers (Table 1, entry 5).
tion of the TBS group with TBAF [37] and subsequent tosyla-
tion of the resulting hydroxy group with TsCl in the presence of
A remarkable change in the product profile occurred when 6d pyridine was carried out to yield the corresponding tosylate,
was used for this reaction. By employing AD-mix-α under whose activated ester group could be displaced with NaCN in
the above reaction conditions, 6d gave rise to a 69:31 mixture DMSO to provide cyanide 15 in 80% yield over three steps
of 12d-A and 12d-B in 48% yield, leading to 12a-A and 12a-B [43]. Then, the N,O-acetonide group of 15 was cleaved upon
through hydrolysis under basic conditions, respectively, treatment with p-TsOH in methanol [44], and the released
whereas the use of AD-mix-β resulted in predominant primary hydroxy group was subsequently protected as the
formation of the undesired diastereomer (Table 1, entries 7 benzyl ether to produce the key intermediate 5 in 67% yield
and 8). The above observations led us to explore the over two steps. As expected, conversion of this compound into
AD-mix-α-mediated reaction of 6d at lower temperatures. the heterocyclic hemiaminal 4 was achieved in one pot with
When the reaction was performed at 0 °C with the same DIBAL-H by the formation of the aldehyde followed by
set of the reagents, the product selectivity for 12d-A was spontaneous intramolecular cyclization with a yield of 67%.
slightly improved (Table 1, entry 9). Remarkably, 6d under- The structural identity of this product was precisely confirmed
went slow reaction in the absence of MeSO2NH2 to give the by 1H NMR spectroscopic data, which proved to be in good
product mixture in 52% yield, and the diastereomeric ratio agreement with those on record for 4 [19]. Hence, we can
could be further enriched to 84:16 (Table 1, entry 10). Ad- conclude that a formal total synthesis of (+)-batzellasides B was
ditionally, a similar result was obtained by carrying out the accomplished, considering that the synthetic route from 4 to 1b
reaction using 0.1 equiv of (DHQ)2PHAL (53%, 83:17 in Ta- has been established previously.
ble 1, entry 11). The above observations clearly suggested a
possibility of improving the product selectivity by lowering the At this point, it was thus suggested that the remaining chal-
reaction temperature and/or introducing an additional catalytic lenge was to improve the stereoselectivity of the allylation of 4.
amount of chiral ligand.
In the first approach of our previous work [19], we demon-
strated that the heterocyclic hemiaminal 4 was allylated by
Having established the optimized conditions for the preparation following a protocol using allyltributylstannane (AllylSnBu3)
of 12d-A, our next objective was the construction of the and tert-butyldimethylsilyl triflate (TBSOTf) at −78 °C in
Scheme 3: Reagents and conditions: (a) (i) K2CO3, MeOH, rt; (ii) TBSCl, Et3N, CH2Cl2, rt; (iii) BnBr, NaH, Bu4NI, THF, rt; 50% (three steps); (b) (i)
TBAF, THF, rt; (ii) TsCl, pyridine, 0 °C to rt; (iii) NaCN, NaHCO3, DMSO, 60 °C; 80% (three steps); (c) (i) p-TsOH, MeOH, rt; (ii) BnBr, Ag2O, AcOEt,
rt; 67% (two steps); (d) DIBAL-H, toluene, −78 °C; 67%.
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Beilstein J. Org. Chem. 2012, 8, 1831–1838.
toluene to furnish the product 7 as a 69:31 mixture of diastereo- under precise stereochemical control as well as for circum-
meric isomers in 96% yield (Table 2, entry 1). Despite the venting the purification problems related to the diastereomeric
appealing performance observed in the above synthetic process, impurity in this product.
this reaction protocol has the major disadvantage of low stereo-
selectivity causing operational inconvenience associated with Conclusion
the laborious chromatographic separation of the two stereoiso- We have described a new synthetic approach to (+)-batzella-
mers. From the practical considerations, we next explored a side B from L-pyroglutamic acid. Starting from this chiral ma-
more efficient synthetic method for the stereoselective allylation terial, the formal total synthesis of the heterocyclic hemiaminal
of 4 using an appropriate combination of allylic reagent and 4, a key intermediate elaborated commonly in the first total syn-
Lewis acid to produce the desired diastereomer 7 preferentially. thesis, has been achieved in an efficient 21-step protocol in
Beginning with a reaction employing indium chloride (InCl3) 7.1% overall yield. Furthermore, the stereospecificity in the
instead of TBSOTf at 0 °C in dichloromethane, we observed no allylation of 4 has been exemplified by performing the pro-
substantial improvement in the stereoselectivity of the cedures with AllylTMS and two types of Lewis acids, which
allylation, affording a 44:56 mixture of 7 and 7’ in quantitative allows for simpler synthetic operation due to the ease of purifi-
yield (Table 2, entry 2). A much greater preference for the cation of the products. The present study clearly demonstrates
formation of 7 was observed in the cases where allyltrimethyl- that L-pyroglutamic acid can be used as a versatile chiral source
silane (AllylTMS) was used as an allylic reagent (Table 2, for synthesizing this class of biologically potent piperidine
entries 3–5). In fact, the reaction carried out with zinc chloride alkaloids and related analogues.
(ZnCl2) at room temperature in toluene led to exclusive stereo-
selectivity for 7 with 98% de, albeit in low yield (24%, Table 2,
Supporting Information
entry 3). Furthermore, the use of TBSOTf as a Lewis acid
resulted in significant enhancement of the reaction rate to give
Supporting Information File 1
almost the same stereochemical outcome (98 and 92% de) with
slightly and moderately higher yields (29 and 41%) for the
periods of 2 and 3 h (Table 2, entries 4 and 5), respectively. In
spite of its increased susceptibility, which should be discrimi-
nated from those of unsubstituted structural systems [45-50], it
became apparent that this multiply functionalized hemiaminal 4
is well tolerated to undergo direct allylation with the silyl
reagents. The results of the above investigations provide one
particularly successful route that has the potential to allow
direct asymmetric access to the advanced-stage intermediate 7
Full experimental details and characterization data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-210-S1.pdf]
Acknowledgements
We thank Ms. Manami Ohshima for partial support of this
research. This research was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Table 2: Diastereoselective allylation of 4.
Entry
Reagent (amount [equiv])
Solvent
T
Time
Yield [%]a (7/7’)b
1
2
3
4
5
AllylSnBu3 (3.0), TBSOTf (1.5)
AllylSnBu3 (3.0), InCl3 (1.5)
AllylTMS (4.0), ZnCl2 (4.0)
AllylTMS (4.0), TBSOTf (2.0)
AllylTMS (10.0), TBSOTf (1.5)
toluene
CH2Cl2
toluene
CH2Cl2
toluene
−78 °C
0 °C
9 h
96 (69/31)
quant. (44/56)
24 (99/1)
0.75 h
16 h
2 h
rt
−78 to −45 °C
−78 °C
29 (99/1)
3 h
41 (96/4)
aIsolated yield. bDiastereomeric ratios were determined by 1H NMR (300 MHz).
1836

Beilstein J. Org. Chem. 2012, 8, 1831–1838.
29.Spangenberg, T.; Schoenfelder, A.; Breit, B.; Mann, A.
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