A concise and divergent approach to hydroxylated piperidine alkaloids and Azasugar Lactams

Article abstract of DOI:10.1002/ejoc.201201618

The vinylogous Mannich reaction (VMR) between 2-(tertbutyldimethylsilyloxy) furan (TBSOF) and (R_S)-t-BS-imine 12a and the application of the VMR adduct butenolide 13a as a versatile chiral building block for the synthesis of hydroxylated piperidine alkaloids and azasugars were investigated. Firstly, both the anti diastereoselectivity and the chemical yield of the asymmetric VMR between TBSOF and (R_S)-t-BS-imine 12a were improved by the use of Sm(OTf)₃/ H₂O (1.5 equiv.) as the promoter. Similar diastereoselectivities were also obtained with Yb(OTf)₃/H₂O, Cu(OTf)₂/H₂O, Zn(OTf)₂/H₂O, or the Br?nsted acids TfOH or MsOH as the promotors. Secondly, an efficient four-step procedure for the elaboration of butenolide 13a into piperidine alkaloid (–)-deoxoprosophylline (2) was established. Thirdly, by taking advantage of the olefin functionality in the butenolide 13a, polyhydroxylated δ-lactams 23 and 21, which are ready precursors of azasugars L-deoxyallonojirimycin (ent-7) and L-3- epi-fagomine (ent-6), were obtained in two and three steps, respectively, via dihydroxylated lactone 17. The easily available synthetic intermediate 17 can also serve as a key intermediate for the synthesis of the glycosyl nucleoside amino acid cores of polyoxins and nikkomycins.

Full text of DOI:10.1002/ejoc.201201618

FULL PAPER
DOI: 10.1002/ejoc.201201618
A Concise and Divergent Approach to Hydroxylated Piperidine Alkaloids and
Azasugar Lactams
Lian-Dong Guo,[a] Pan Liang,[a] Jian-Feng Zheng,[a] and Pei-Qiang Huang*[a]
Keywords: Stereoselective synthesis / Medicinal chemistry / Lactones / Lactams / Azasugars
The vinylogous Mannich reaction (VMR) between 2-(tert-
butyldimethylsilyloxy)furan (TBSOF) and (RS)-t-BS-imine
12a and the application of the VMR adduct butenolide 13a
as a versatile chiral building block for the synthesis of hy-
droxylated piperidine alkaloids and azasugars were investi-
gated. Firstly, both the anti diastereoselectivity and the
chemical yield of the asymmetric VMR between TBSOF and
(RS)-t-BS-imine 12a were improved by the use of Sm(OTf)3/
H2O (1.5 equiv.) as the promoter. Similar diastereoselectivi-
ties were also obtained with Yb(OTf)3/H2O, Cu(OTf)2/H2O,
Zn(OTf)2/H2O, or the Brønsted acids TfOH or MsOH as the
promotors. Secondly, an efficient four-step procedure for the
elaboration of butenolide 13a into piperidine alkaloid (–)-de-
oxoprosophylline (2) was established. Thirdly, by taking ad-
vantage of the olefin functionality in the butenolide 13a,
polyhydroxylated δ-lactams 23 and 21, which are ready pre-
cursors of azasugars L-deoxyallonojirimycin (ent-7) and L-3-
epi-fagomine (ent-6), were obtained in two and three steps,
respectively, via dihydroxylated lactone 17. The easily avail-
able synthetic intermediate 17 can also serve as a key inter-
mediate for the synthesis of the glycosyl nucleoside amino
acid cores of polyoxins and nikkomycins.
nojirimycin (α-homoallonojirimycin, α-allo-HNJ, 8) are
iminosugars isolated from the Thai medicinal plants Con-
narus ferrugineus.[9] Prior to its isolation, allo-DNJ (7),[10]
as well as its antipode,[11] had been synthesized several
times.[10–12] Biological studies[13] showed that allo-DNJ
showed a potent inhibitory activity against rat intestinal
lactase and bovine liver cytosolic β-galactosidase,[10]
Introduction
6-Substituted 2-methyl- or 2-(hydroxymethyl)piperidin-3-
ols are common structural features of many alkaloids[1] and
azasugars.[2] Several alkaloids such as (–)-prosophylline (1,
Figure 1), for example, were isolated from the leaves of the
West African savanna tree Prosopis africana Taub[3] and
from Microcos philippinensis (Perk.) Burret (Tiliaceae).[4]
These alkaloids and their deoxygenated derivatives, such as
(–)-deoxoprosophylline (2, also known as desoxoprosophyl-
line), exhibited diverse biological properties including anal-
gesic, antibiotic, anesthetic, and CNS stimulant activities.[5]
The development of new selective acetylcholinesterase in-
hibitors from such an alkaloid has been reported recently.[6]
Several hydroxylated piperidine alkaloids such as morus-
imic acids D (3) and E (4) have recently been isolated from
the fruits of white mulberry Morus alba Linne (Moraceae),
a tree native to China and Korea, growing in Turkey.[7]
Interestingly, several polyhydroxylated piperidine alkaloids,
known as azasugars or iminosugars, such as 1-deoxynojiri-
mycin (DNJ, 5) and 3-epi-fagomine (6) have been isolated
from the roots, leaves, and fruits of white mulberry.[8] d-1-
Deoxy-4-epi-nojirimycin (allo-DNJ, 7) and α-4-epi-homo-
[a] Department of Chemistry and Fujian Provincial Key
Laboratory of Chemical Biology, College of Chemistry and
Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, P. R. China
Fax: +86-592-2186400
E-mail: pqhuang@xmu.edu.cn
Homepage: http://210.34.14.15/kydw_ktz/pqhuang/index.html
http://www.xmu.edu.cn/english/index.asp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201618.
Figure 1. Structures of some hydroxylated piperidine alkaloids,
azasugars, and azasugar lactams.
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Hydroxylated Piperidine Alkaloids and Azasugar Lactams
whereas l-allo-DNJ was a better inhibitor of α-mannosid- sulfinimine 12a.[22] In view of the potential use of the ad-
ase than d-manno-DNJ, and so might become a key com- duct 13a in the asymmetric synthesis of piperidine alkaloids
pound for the drug design.[11] The compound d-allono-δ- and azasugars,[16l,23] a further investigation into the VMR
lactam (9) has been synthesized for conformational analysis of (RS)-t-BS-imine 12a was undertaken with the goal of im-
and evaluation as a glycosidase inhibitor.[14] These mo- proving the diastereoselectivity. In the light of the beneficial
lecules have consequently become attractive synthetic tar- effects of metal triflates (especially rare-earth metal tri-
gets for the development both of new synthetic methodolo- flates) in organic synthesis,[24,25] several M(OTf)n species
gies and of new pharmaceuticals.[1,2,10–18]
were evaluated as promoters in the VMR between (RS)-t-
The intensive studies on azasugars have led to the devel- BS-imine 12a and TBSOF.
opment of several pharmaceuticals.[2c] Miglitol (10), for ex-
As can be seen from Table 1, when (RS)-t-BS-imine 12a
ample, is an oral antidiabetic drug currently used to treat was treated with 2.5 equiv. of TBSOF in the presence of
type 2 diabetes, whereas Miglustat (11), marketed under the 0.2 equiv. of Sm(OTf)3, in CH2Cl2 for 16 h, the desired but-
trade name Zavesca, is a drug developed by Actelion used enolide 13a was produced as a 51:49 mixture of dia-
to treat Type 1 Gaucher disease (GD1).
stereomers in 55% yield (Table 1, Entry 1). Favorable effects
We recently developed a flexible approach to 5-amino- of water have been reported both in M(OTf)n-mediated re-
alkylbutenolides and 6-substituted 5-hydroxypiperidin-2- actions[24a,26] and in VMRs,[27] so water was examined as
ones 14 (Scheme 1) based on the asymmetric vinylogous an additive. When water (1.5 equiv.) was added to the above
Mannich reactions (VMRs)[19,20] between 2-(tert-butyldi- Sm(OTf)3-promoted VMR, the reaction proceeded
methylsilyloxy)furan (TBSOF)[20] and (RS)- or (SS)-tert- smoothly to give the adduct 13a in excellent yield (93%)
butanesulfinimines (t-BS-imines)[21] 12.[22] The efficiency and with an improved 86:14 anti/syn diastereoselectivity
and versatility of the methodology prompted us to investi- (Entry 2). When the amount of water was increased to
gate its application to the asymmetric synthesis of alkaloids 10.0 equiv., only a slight decrease in diastereoselectivity
and azasugars. Here we report the results, including an im- (from 84:16 to 82:18) was observed and almost the same
proved anti-diastereoselective VMR between sulfinimine yield was maintained (Entry 3). A favorable effect of water
12a and TBSOF, together with concise and divergent elabo-
ration of the adduct 13a both to (–)-deoxoprosophylline (2)
and to azasugar δ-lactams 23 and 21, as well as to potential
Table 1. The VMR between (RS)-t-BS-imine 12a and TBSOF.[a]
key intermediate 17 for the synthesis of the glycosyl nucleo-
side amino acid cores of polyoxins and nikkomycins.
Entry Promoter
Equiv. of H2O 13a/syn diastereomer[b]
(% yield)[c]
1
2
3
4
5
6
7
8
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
Yb(OTf)3
Yb(OTf)3
Eu(OTf)3
Cu(OTf)2
Zn(OTf)2
TfOH[d]
MsOH[d]
–
–
1.5
10
51:49 (55)
86:14 (93)
82:18 (92)
59:41 (64)
85:15 (90)
75:25 (36)
85:15 (85)
84:16 (88)
82:18 (79)
84:16 (87)
NR[e]
–
1.5
1.5
1.5
1.5
–
9
10
11
12
13
14
–
1.5
1.5[f]
1.5[g]
TfOH[f]
trace[f]
TfOH[g]
Sm(OTf)3
84:16 (75)
84:16 (83)
Scheme 1. Our synthetic plan for the development of vinylogous
Mannich reaction adduct 13a as a versatile building block for the
synthesis of heterocycles.
[h]
–
[a] General experimental conditions: M(OTf)x (0.1 mmol) in
CH2Cl2 (4 mL), H2O (0.75 mmol), compound 12a (0.5 mmol), and
TBSOF (1.25 mmol) under N21, at room temp. for 16 h. [b] Ratios
determined by analysis of the H NMR spectra of the crude mix-
tures. [c] Combined and isolated yields. [d] 0.8 equiv. of TfOH or
MsOH were used, and the reactions were conducted at –78 °C for
2 h. [e] No reaction. [f] 0.01 m TfOH-containing water was used,
and the reaction was conducted at room temp. for 16 h; a trace of
product was observed, but the ratio was not determined.
[g] 0.2 equiv. of TfOH was used, and the reaction was conducted
at room temp. for 0.5 h. [h] 1.5 equiv. of MeOH was used instead
Results and Discussion
In our previous TMSOTf-promoted VMRs between the
Ellman sulfinimines 12 and TBSOF, good to excellent dia-
stereoselectivities were obtained in most cases (Scheme 1).
However, only a modest anti diastereoselectivity (dr =
75:25) was obtained with the benzyloxyethanal-derived of H2O.
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L.-D. Guo, P. Liang, J.-F. Zheng, P.-Q. Huang
FULL PAPER
was also observed with the Yb(OTf)3-catalyzed VMR (En-
With access to butenolide 13a secured, we next investi-
tries 4, 5). Screening of other metal triflates in the presence gated its application to the synthesis of hydroxylated piper-
of 1.5 equiv. of water was then performed. When Eu(OTf)3 idine alkaloids.[1,15] (–)-Deoxoprosophylline (2)[16] was se-
was used, a lower diastereoselectivity and a poor yield (En- lected as our target molecule. Although we had already
try 6) were obtained. With Cu(OTf)2 or Zn(OTf)2 as the demonstrated that butenolide 13 could be converted into 2-
catalyst, diastereoselectivities similar to those achieved with piperidinone derivative 14 by a three-step procedure,[22] and
Sm(OTf)3 and Yb(OTf)3 were observed, but lower yields had also developed a versatile method for direct transfor-
were obtained (Entries 7, 8). The results are surprising be- mation of lactams to piperidines by reductive alkylation,[29]
cause both Cu(OTf)2 and Zn(OTf)2 are sensitive to water, additional protection/deprotection steps were still required
whereas Sm(OTf)3 and Yb(OTf)3 are water-tolerant Lewis to complete the total synthesis of piperidine alkaloids as
acids. It seemed that the roles in these reactions were played shown in Scheme 1.
by other forms of Cu2+ and Zn2+ catalysts generated in situ
We envisaged that the synthetic route could be greatly
(vide infra). However, triflic acid[28] had already been shown simplified if we firstly undertake the ring-opening alkyl-
to be an effective promoter for the VMR. Indeed, when ation of lactone 13a, instead of ring-expansion to 2-piperid-
the VMR between 12a and TBSOF was carried out in the inone 14 (cf. Scheme 2). The anti-butenolide 13a was thus
presence of TfOH or MsOH as the catalyst, similar dia- subjected to catalytic hydrogenation (H2, 1 atm, 10% Pd/C,
stereoselectivities and yields were obtained (Entries 9, 10).
EtOAc, room temp., 16 h) to give lactone 15 (90% yield).
To provide insight into the possible role of water in the This was treated with 2.0 equiv. of the alkynyltrifluorobor-
M(OTf)n/H2O-mediated VMR, a control experiment in the ate[30] generated in situ from dodec-1-ynyllithium and
presence solely of 1.5 equiv. of water was undertaken. No BF3·OEt2, to give the desired ynone 16 in 85% yield. Cleav-
formation of the desired product was observed (Table 1, En- age of the chiral auxiliary in compound 16 with 4 m HCl in
try 11). This result implies that water is not a direct pro- MeOH (r.t., 6 h), followed by catalytic hydrogenation under
moter for the reaction. To investigate the effect of trace acidic conditions [H2, 80 psi, 20% Pd(OH)2/C, EtOH, HCl,
amounts of TfOH that might be formed in situ from the room temp., 24 h], produced (–)-deoxoprosophilline (2) in
reaction between Sm(OTf)3 and water,[24a] the reaction was 81% yield over two steps. The physical and spectroscopic
run in the presence of 1.5 equiv. of a 0.01 m aqueous solu- data for our synthetic product are in agreement with those
tion of TfOH, and only a trace of product was detected by reported [m.p. 88–89 °C; lit.[16a] 90–91 °C. [α]D23 = –16.4
TLC monitoring (Entry 12). This result demonstrated that (c = 1.0, CHCl3); lit.[16r] [α]D25 = –15.9 (c = 0.62, CHCl3)].
traces of TfOH also did not play a role in the reaction. The previously documented[16i] 2,6-cis diastereoselectivity
These results allowed us to assume that an active SmIII spe- in the last catalytic hydrogenation was thus confirmed.
cies was formed due to the presence of water. A six-mem-
bered reactive transition state containing both a Sm–O che-
lation and an H–N hydrogen bond (A or B) is suggested
(Figure 2); this on one hand activates the sulfinimine and
on the other hand improves the diastereoselectivity of the
reaction. It could also explain why use of more water has
little effect either on yields or on diastereoselectivities. This
model can also be used to explain the results of the
Cu(OTf)2/H2O- or Zn(OTf)2/H2O-mediated VMR (En-
tries 7 and 8). Conversely, the results of the Cu(OTf)2/H2O-
or Zn(OTf)2/H2O-mediated reaction also support the pro-
posed mechanism. To judge on the more plausible transi-
tion state out of A and B, the Sm(OTf)3/MeOH-mediated
reaction was conducted, and gave the desired adduct 13a in
Scheme 2. Concise synthesis of (–)-deoxoprosophylline (2).
a yield of 83% and in a dr of 84:16 (Entry 14). This result
To demonstrate the applicability of the butenolide 13a in
(via transition state C) supports the transition state B. Fi- the synthesis of azasugars, the syntheses of azasugar lact-
nally, when the reaction was conducted in the presence of ams 21 and 23 (Scheme 1) were carried out. The most
0.2 equiv. of TfOH and 1.5 equiv. of water (Entry 13), the straightforward approach could only be achieved by taking
result obtained was almost the same as that in the absence advantage of the olefin functionality in butenolide 13a.
of water (Entry 9).
Epoxidation of 13a was first attempted. Unfortunately, un-
der a variety of conditions, the starting butenolide were re-
covered. Dihydroxylation of butenolide 13a was then inves-
tigated. The use of the K2Os2O2(OH)4/NMO oxidation sys-
tem failed to produce the desired product,[31] but the utiliza-
tion of KMnO4 in combination with crown ether[32] turned
out to be fruitful. Treatment of 13a with KMnO4 and 18-
crown-6 at –40 °C for 6 h produced the desired dihydrox-
ylated product 17 as the sole observable diastereomer[33] in
Figure 2. Plausible reactive species in the M(OTf)n/H2O-mediated
VMR.
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Hydroxylated Piperidine Alkaloids and Azasugar Lactams
68% yield (Scheme 3). Lower yields were obtained when the ence of HMPA and ethylene glycol, treatment of lactone 17
reaction was run at a higher or lower temperature. No over- with a 0.1 m solution of SmI2 (4 equiv.) in THF at room
oxidation of sulfinamide was observed. The stereochemistry temp. for 12 h produced the α-dehydroxylated product 22
of the hydroxylated lactone 17 was assigned according to smoothly in 82% yield. Lactone 22 was converted into lac-
the literature precedents.[31–33]
tam 23 in 80% yield by the same procedure as described for
the transformation of 17 to 21 (Scheme 4).
Lactam 21 could be converted into l-1-deoxyallonojiri-
mycin (ent-7),[12a] an inhibitor of α-mannosidase.[11] Simi-
larly, lactam 23 is a ready precursor of l-3-epi-fagomine
(ent-6),[18b,36] a moderate inhibitor both of α-glucosidase
and of β-galactosidase.[18e]
Conclusions
In summary, an improved diastereoselective synthesis of
butenolide 13a through the VMR between TBSOF and
(RS)-t-BS-imine 12a is reported. Thanks to the multiple
functionalities of butenolide 13a, an efficient and divergent
approach for the total synthesis of piperidine alkaloids and
azasugar lactams has been developed. (–)-Deoxoprosophil-
line (2) was synthesized in five steps starting from (RS)-t-
BS-imine 12a in an overall yield of 49%. This represents
the most efficient total synthesis of (–)-deoxoprosophilline
(2) from commercially available starting materials (six
steps). From butenolide 13a, polyhydroxylated δ-lactams 23
and 21, key intermediates for the synthesis of azasugars,
were synthesized in two and three steps, respectively, via
dihydroxylated lactone intermediate 17. In addition, the
easy access to lactone 17 paved the way for the concise and
diastereoselective synthesis of the glycosyl nucleoside amino
acid cores of the polyoxins and nikkomycins.
Scheme 3. Synthesis of compound 17, a potential intermediate of
the glycosyl nucleoside amino acid cores of the polyoxins and
nikkomycins.
It is worth noting that differently protected analogues of
dihydroxylated lactone 17 (antipode) have served as the key
intermediates for the synthesis of the glycosyl nucleoside
amino acid cores of polyoxins and nikkomycins.[31,33] The
polyoxins and nikkomycins constitute a small group of
complex peptidyl nucleoside antibiotics, which are very
promising leads for the development of non-toxic antifun-
gal therapeutics.[31,33] Our easy access to lactone 17 thus
paved the way for the concise and diastereoselective synthe-
sis of those natural products (Scheme 3).
With the hydroxylated lactone 17 in hand, the syntheses
of azasugar lactams 21 and 23 were undertaken (Scheme 4).
Compound 17 was subjected to acidic hydrolysis (HCl,
12 m, 1,4-dioxane, room temp., 6 h) to remove the chiral
auxiliary. The resulting aminolactone was then treated with
K2CO3 in MeOH at room temp. for 23 h to give the ring-
expanded δ-lactam 21[34] in 75% yield over two steps.
Experimental Section
Typical Procedure for the Synthesis of (RS,4R,5S)-5-[(Benzyloxy-
methyl)(tert-butylsulfinylamino)methyl]furan-2(5H)-one (13a): H2O
(0.014 mL, 0.75 mmol, 1.5 equiv.), (R,E)-N-benzyloxyethylidene-
tert-butanesulfinamide[21f] (12a, 127 mg, 0.50 mmol, 1.0 equiv.),
and
2-(tert-butyldimethylsilyloxy)furan
(TBSOF,
247 mg,
1.25 mmol, 2.5 equiv.) were sequentially added under N2 to a sus-
pension of Sm(OTf)3 (60 mg, 0.10 mmol, 0.20 equiv.) in CH2Cl2
(4.0 mL). After the mixture had been stirred for 16 h at room tem-
perature, H2O (5.0 mL) was added. The mixture was extracted with
CH2Cl2 (10 mLϫ3). The combined organic layers were dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
EtOAc/hexane 1:1, v/v) to give butenolide 13a (134 mg, 80%) and
butenolide 13b (22 mg, 13%). The physical and spectroscopic data
for butenolide 13a and 13b are identical with those we reported
previously.[22]
(RS,4R,5S)-5-[(Benzyloxymethyl)(tert-butylsulfinylamino)methyl]-
furan-2(4H)-one (15): The hydrogenation of 13a was performed by
the protocol we described previously,[22] to give lactone 15 in 90%
yield. Its physical and spectroscopic data are identical to those we
reported previously.[22]
Scheme 4. Asymmetric synthesis of azasugar lactams 21 and 23.
HMPA
= hexamethylphosphoric triamide (hexamethylphos-
phoramide).
For the synthesis of lactam 23, the α-hydroxy group in
lactone 17 had to be reductively eliminated. SmI2-based
(RS)-N-[(2S,3R)-1-Benzyloxy-3-hydroxy-6-oxooctadec-7-yn-2-yl-
chemistry appeared to be suitable.[35] Indeed, in the pres- 2-methylpropan-2-yl]sulfinamide (16): nBuLi (0.38 mL, 2.4 m,
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L.-D. Guo, P. Liang, J.-F. Zheng, P.-Q. Huang
FULL PAPER
0.92 mmol, 2.0 equiv.) was added slowly at –78 °C under argon to
a solution of dodec-1-yne (160 mg, 0.96 mmol, 2.1 equiv.) in dry
THF (4.0 mL). The reaction mixture was stirred for 45 min at the
same temperature, after which BF3·Et2O (0.11 mL, 0.92 mmol,
2.0 equiv.) was added dropwise. Stirring was continued for 10 min,
and then lactone 15 (156 mg, 0.46 mmol, 1.0 equiv.) in THF
(2.5 mL) was added. The resulting mixture was stirred for 2 h at
the same temperature, after which a solution of saturated NH4Cl/
(RS,2S,3R,4S,5S)-5-[(Benzyloxymethyl)(tert-butylsulfinylamino)-
methyl]-3,4-dihydroxyfuran-2(4H)-one (17): KMnO4 (350 mg,
2.21 mmol) was added in small portions at –40 °C to a vigorously
stirred solution of compound 13a (610 mg, 1.81 mmol) and 18-
crown-6 (100 mg, 0.36 mmol) in CH2Cl2 (10.0 mL). The reaction
mixture was then stirred for 6 h at the same temperature. The reac-
tion was quenched with Na2S2O3·5H2O (820 mg, 3.30 mmol), and
the mixture was carefully acidified with a solution of HCl (2 m). It
NH4OH (2:1, v/v, 2.0 mL) was added. The mixture was allowed to was then extracted with CH2Cl2 (10 mLϫ3), dried with anhydrous
warm to room temperature, poured into water (8 mL), and ex-
tracted with Et2O (10 mLϫ4). The combined organic layers were
dried with Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica
gel (eluent: EtOAc/hexane 1:2) to give compound 16 (198 mg, 85%)
as a pale yellow oil. [α]2D0 = –19.8 (c = 1.0, CHCl3). 1H NMR
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
EtOAc) to afford the starting material 13a (61 mg, 10%) and the
desired compound 17 (434 mg, 68%) as a white solid, m.p. 65–
66 °C. [α]2D0 = –25.1 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3,
25 °C, TMS): δ = 1.21 (s, 9 H, tBu), 1.87 (s, 2 H, OH), 3.47–3.55
3
3
(400 MHz, CDCl3, 25 °C, TMS): δ = 0.88 (t, JH,H = 6.9 Hz, 3 H,
18-CH3), 1.23–1.38 [m, 23 H, tBu, (11–17)-H], 1.52–1.59 (m, 2 H,
(m, 1 H, 5-H), 3.60–3.65 (m, 1 H, 4-H), 3.75 (dd, JH,H = 9.8,
3
4.1 Hz, 1 H, 6-H), 3.81 (dd, JH,H = 9.8, 3.0 Hz, 1 H, 6-H), 4.42–
3
10-H), 1.64–1.74 (m, 1 H, 4-H), 1.92–2.00 (m, 1 H, 4-H), 2.33 (t,
4.48 (m, 2 H, 2-H, 3-H), 4.50 (d, JH,H = 8.1 Hz, 1 H, NH), 4.52
3
3
3
3JH,H = 7.1 Hz, 2 H, 9-H), 2.64–2.80 (m, 2 H, 5-H), 3.12 (d, JH,H
(d, JH,H = 11.1 Hz, 1 H, CH2Ph), 4.57 (d, JH,H = 11.1 Hz, 1
H, CH2Ph), 7.29–7.37 (m, 5 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 22.5 (3 C), 56.3, 56.6, 68.4, 68.5, 69.4,
73.4, 84.4, 127.7 (2 C), 127.8, 128.4 (2 C), 137.3, 175.8 ppm. IR
= 6.5 Hz, 1 H, OH), 3.27–3.32 (m, 1 H, 2-H), 3.64–3.70 (m, 1 H,
3
3
3-H), 3.75 (dd, JH,H = 9.8, 3.8 Hz, 1 H, 1-H), 3.91 (dd, JH,H
=
3
9.8, 4.1 Hz, 1 H, 1-H), 3.98 (d, JH,H = 8.5 Hz, 1 H, NH), 4.48 (d,
3JH,H = 11.8 Hz, 1 H, CH2Ph), 4.57 (d, JH,H = 11.8 Hz, 1 H, (film): ν = 3303, 2963, 2925, 2868, 1781, 1449, 1379, 1130,
3
˜
CH2Ph), 7.25–7.35 (m, 5 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 13.9, 18.7, 22.4, 22.5 (3 C), 27.5, 27.6,
28.7, 28.8, 29.1, 29.2, 29.3, 31.7, 41.7, 55.9, 59.7, 70.1, 71.7, 73.3,
1047 cm–1. HRMS (ESI): calcd. for C17H25NO6S [M + Na]+
394.1300; found 394.1294.
(3S,4S,5S,6S)-6-Benzyloxymethyl-3,4,5-trihydroxypiperidin-2-one
(21): A solution of HCl (12 m, 0.67 mL, 8.0 mmol) was added to a
stirred solution of compound 17 (297 mg, 0.80 mmol) in 1,4-diox-
ane (4.0 mL). The reaction mixture was stirred at room tempera-
ture for 5 h and then concentrated under reduced pressure. The
residue was dissolved in dry MeOH (4.0 mL), and anhydrous
K2CO3 (552 mg, 4.0 mmol) was added at room temperature. After
having been stirred overnight, the mixture was concentrated under
reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel (eluent: CH2Cl2/MeOH 5:1) to give compound
80.7, 94.5, 127.7 (3 C), 128.3 (2 C), 137.4, 187.7 ppm. IR (film): ν
˜
= 3376, 2925, 2855, 2210, 1672, 1453, 1364, 1193, 1051, 784 cm–1.
HRMS (ESI): calcd. for C29H47NNaO4S [M + Na]+ 528.3118;
found 528.3123.
(–)-Deoxoprosophylline (2): A HCl/MeOH solution (4 m, 3.0 mL)
was added at room temperature under N2 to a solution of com-
pound 16 (90 mg, 0.18 mmol) in MeOH (3.0 mL). After having
been stirred for 4 h, the reaction mixture was concentrated and the
residue was dissolved in CH2Cl2 (20 mL). The resulting solution
was washed successively with a saturated aqueous solution of
Na2CO3 and brine, dried with Na2SO4, filtered, and concentrated.
The residue was dissolved in EtOH (2.0 mL). Concd. HCl
(0.10 mL) and 20% Pd(OH)2/C (50 mg) were added to the solution.
The mixture was stirred under hydrogen (80 psi) for 24 h. The cata-
lyst was filtered off through a Celite pad, and the pad was washed
with EtOH. The filtrates were concentrated, and the residue was
dissolved in water (5 mL) and extracted with diethyl ether (10 mL).
The aqueous layer was basified by addition of an aqueous solution
of NaOH (1 m) and extracted thoroughly with CHCl3 (10 mLϫ5).
The combined organic layers were dried with Na2SO4, filtered, and
concentrated. The residue was purified by chromatography on silica
21 (160 mg, 75%) as a colorless oil. [α]2D0 = –56.5 (c = 1.0, MeOH).
3
1H NMR (400 MHz, CD3OD, 25 °C, TMS): δ = 3.62 (dd, JH,H
=
3
9.2, 5.9 Hz, 1 H, 7-H), 3.67 (ddd, JH,H = 8.3, 5.9, 2.2 Hz, 1 H, 6-
H), 3.73 (dd, 3JH,H = 9.2, 2.2 Hz, 1 H, 7-H), 3.87 (dd, JH,H = 8.3,
3
3
2.0 Hz, 1 H, 5-H), 4.05 (d, JH,H = 2.6 Hz, 1 H, 3-H), 4.15 (dd,
3JH,H = 2.6, 2.0 Hz, 1 H, 4-H), 4.59 (br. s, 2 H, CH2Ph), 5.50 (s, 1
H, NH), 7.27–7.39 (m, 5 H, Ar-H) ppm. 13C NMR (100 MHz,
CD3OD, 25 °C, TMS): δ = 54.0, 65.8, 68.0, 69.1, 71.1, 72.3, 126.6
(2 C), 126.8, 127.3 (2 C), 137.3, 172.4 ppm. IR (film): ν = 3332,
˜
2913, 2859, 1661, 1453, 1300, 1105 cm–1. HRMS (ESI): calcd. for
C13H17NO5 [M + Na]+ 290.1004; found 290.1003.
(RS,3R,4S,5S)-5-[(Benzyloxymethyl)(tert-butylsulfinylamino)-
gel (CHCl3/MeOH/NH4OH 100:5:1) to afford (–)-deoxoprosophyl- methyl]-4-hydroxyfuran-2(4H)-one (22): A solution of freshly pre-
line (2) as a pale yellow solid (43 mg, 81%), which was recrys-
tallized from acetone to give a white solid, m.p. 88–89 °C (acetone)
pared SmI2 in THF (0.1 m, 30.0 mL, 3.0 mmol) was added slowly
to a degassed THF solution (10.0 mL) of compound 17 (278 mg,
0.75 mmol), ethylene glycol (0.57 mL, 9.0 mmol), and hexameth-
(lit.[16a] 90–91 °C). [α]2D0 = –16.4 (c = 1.0, CHCl3) [lit.[16r] [α]2D5
=
–15.9 (c = 0.62, CHCl3)]. 1H NMR (500 MHz, CDCl3, 25 °C, ylphosphoric triamide (HMPA, 1.2 mL, 6.9 mmol) in THF. The
3
TMS): δ = 0.87 (t, JH,H = 6.9 Hz, 3 H, 12Ј-CH3), 1.11–1.34 [m,
24 H, 3-H, 4-H, (1Ј-11Ј)-H], 1.72–1.75 (m, 1 H, 4-H), 1.99–2.04 (m,
mixture was stirred at room temperature for 10 h. The reaction was
quenched with a saturated aqueous solution of NaHCO3 (2 mL),
1 H, 3-H), 2.48–2.55 (m, 2 H, 1-H, 5-H), 3.13 (br. s, 3 H, all are and the mixture was diluted with diethyl ether (10 mL). The or-
3
exchangeable with D2O, OH, NH), 3.43 (ddd, JH,H = 10.8, 9.4,
ganic phase was separated, washed with a saturated aqueous solu-
4.6 Hz, 1 H, 2-H), 3.68 (dd, 3JH,H = 10.9, 5.6 Hz, 1 H, CH2O), 3.81 tion of Na2S2O3, dried with anhydrous Na2SO4, filtered, and con-
(dd, JH,H = 10.9, 4.5 Hz, 1 H, CH2O) ppm. 13C NMR (125 MHz, centrated under reduced pressure. The residue was purified by flash
3
CDCl3, 25 °C, TMS): δ = 14.1, 22.6, 26.2, 29.3, 29.6 (3 C), 29.7 (2
chromatography on silica gel (eluent: EtOAc/hexane 6:1) to give
C), 29.8, 30.8, 31.9, 33.6, 36.4, 55.9, 63.2, 63.6, 69.5 ppm. IR (film):
compound 22 (218 mg, 82%) as a colorless oil. [α]2D0 = –6.0 (c =
ν = 3266, 3176, 2920, 2850, 1467, 1454, 1193, 1056, 784 cm–1
.
1.0, CHCl3). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.22
1
˜
HRMS (ESI): calcd. for C18H38NO2 [M + H]+ 300.2897; found
300.2899.
(s, 9 H, tBu), 2.59 (dd, JH,H = 17.9, 6.3 Hz, 1 H, 2-H), 2.81 (dd,
3
3JH,H = 17.9, 7.8 Hz, 1 H, 2-H), 3.56 (br. s, 1 H, OH), 3.59–3.66
2234
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2230–2236

Hydroxylated Piperidine Alkaloids and Azasugar Lactams
3
[7]
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(m, 1 H, 5-H), 3.82 (dd, JH,H = 9.8, 3.8 Hz, 1 H, 6-H), 3.88 (dd,
3JH,H = 9.8, 2.9 Hz, 1 H, 6-H), 3.97 (d, JH,H = 8.3 Hz, 1 H, NH),
4.36 (dd, JH,H = 5.3, 5.1 Hz, 1 H, 4-H), 4.46–4.52 (m, 1 H, 3-H),
3
3
3
3
4.54 (d, JH,H = 11.5 Hz, 1 H, CH2Ph), 4.62 (d, JH,H = 11.5 Hz,
1 H, CH2Ph), 7.32–7.41 (m, 5 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 22.6 (3 C), 36.9, 56.5, 56.9, 67.9, 70.4,
74.0, 86.8, 128.0 (2 C), 128.3, 128.7 (2 C), 136.8, 173.9 ppm. IR
[9]
(film): ν = 3303, 2917, 2868, 1781, 1453, 1362, 1175, 1047 cm–1.
˜
HRMS (ESI): calcd. for C17H25NO5S [M + Na]+ 378.1351; found
378.1358.
(4R,5S,6S)-6-(Benzyloxymethyl)-4,5-dihydroxypiperidin-2-one (23):
A solution of HCl (12 m, 0.50 mL, 6.0 mmol) was added to a stirred
solution of compound 22 (213 mg, 0.60 mmol) in 1,4-dioxane
(4 mL). The reaction mixture was stirred at room temperature for
5 h and then concentrated under reduced pressure. The residue was
dissolved in dry MeOH (4 mL), and anhydrous K2CO3 (414 mg,
3.0 mmol) was added at room temperature. After having been
stirred overnight, the mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography on sil-
ica gel (eluent: CH2Cl2/MeOH 6:1) to give compound 23 (121 mg,
[10]
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Eur. J. Org. Chem. 2010, 2831–2844.
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Takao, Y. Nigawara, E. Nishino, I. Takagi, K. Maeda, S.
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4773; n) K.-i. Fuhshuku, K. Mori, Tetrahedron: Asymmetry
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Abraham, E. A. Brock, J. I. Candela-Lena, S. G. Davies, M.
Georgiou, R. L. Nicholson, J. H. Perkins, P. M. Roberts, A. J.
Russell, E. M. Sánchez-Fernández, P. M. Scott, A. D. Smith,
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80%) as a colorless oil. [α]2D0 = –33.5 (c = 1.0, CHCl3). H NMR
1
3
(400 MHz, D2O, 25 °C, TMS): δ = 2.40 (dd, JH,H = 18.1, 5.0 Hz,
1 H, 3-H), 2.58 (dd, 3JH,H = 18.1, 4.4 Hz, 1 H, 3-H), 3.55–3.64 (m,
3
2 H, 7-H), 3.65–3.70 (m, 1 H, 6-H), 3.87 (dd, JH,H = 7.1, 2.5 Hz,
3
1 H, 5-H), 4.10 (ddd, JH,H = 5.0, 4.4, 2.5 Hz, 1 H, 4-H), 4.56 (br.
s, 2 H, CH2Ph), 7.32–7.40 (m, 5 H, Ar-H) ppm. 13C NMR
(100 MHz, D2O, 25 °C, TMS): δ = 37.0, 53.5, 66.8, 68.3, 71.3, 73.4,
127.7 (2 C), 127.9, 128.5 (2 C), 137.4, 171.0 ppm. IR (film): ν =
˜
3299, 2917, 2868, 1640, 1449, 1399, 1317, 1068 cm–1. HRMS (ESI):
calcd. for C13H17NO4 [M + Na]+ 274.1055; found 274.1057.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of compounds 2, 16, 17, 21, 22, 23.
[13]
[14]
[15]
Acknowledgments
The authors are grateful for financial support from the National
Basic Research Program (973 Program) of China (grant number
2010CB833200) and the National Natural Science Foundation of
China (NSFC) (grant numbers 21072160 and 20832005).
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2235

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Published Online: February 20, 2013
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