A multicomponent reaction between α-substituted acroleins, nitroalkanes and paraformaldehyde: Efficient construction of nitro δ-lactol

Article abstract of DOI:10.1055/s-0030-1260194

A base-catalyzed multicomponent cascade reaction between α-substituted acroleins, nitroalkanes, and paraformaldehyde that proceeded smoothly to give high yields of functionalized δ-lactols under mild conditions, is described. This methodology is useful in

Full text of DOI:10.1055/s-0030-1260194

PAPER
3439
A Multicomponent Reaction between a-Substituted Acroleins, Nitroalkanes
and Paraformaldehyde: Efficient Construction of Nitro d-Lactol
Guoxi Xiong,a,b Mohui Wei,a Yirong Zhou,a Yungui Li,a Fanglin Zhang,*a Yuefa Gong*a
a
Department of Chemistry, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, P. R. of China
Fax +86(27)87543632; E-mail: hyvzfl@gmail.com; E-mail: gongyf@mail.hust.edu.cn
b
Research and Development Center, China Tobacco Hubei Industrial Co. Ltd., Wuhan 430040, P. R. of China
Received 5 July 2011; revised 27 July 2011
We are interested in the rational design of new multicom-
Abstract: A base-catalyzed multicomponent cascade reaction be-
ponent approaches to reach this goal. Retrosynthetic anal-
tween a-substituted acroleins, nitroalkanes, and paraformaldehyde
ysis of manzacidin A and C leads to the identification of
that proceeded smoothly to give high yields of functionalized d-lac-
the key motif d-lactone 14a and then to d-lactols 2
tols under mild conditions, is described. This methodology is useful
in the development of a concise synthetic route to natural products (Scheme 1). In this paper, we report one highly chemo-
( )-manzacidin A and C.
and regioselective synthetic method that enables access to
d-lactol 2 through a three-component cascade reaction be-
tween a-substituted acrolein, nitroalkane, and paraformal-
dehyde. From the synthetic point of view, this kind of d-
lactol core is not only a very important precursor in the
synthesis of natural products4a,5 and biologically active
compounds6 such as dysibetaine5a and NK1 antagonists,6e
but also, as a versatile synthetic platform, can be easily
converted into useful products such as tetrahydropyran, g-
lactam, and prolinol, among others.7
Key words: multicomponent reaction, a-substituted acroleins, 1,8-
diazabicyclo[5.4.0]undec-7-ene, d-lactols
Organocatalytic multicomponent reactions are powerful
tools in natural products synthesis and drug discovery that
have attracted much attention because they typically pro-
ceed in a highly efficient and atom-economical manner
through the formation of multiple new bonds in a one-pot
system, which saves time and energy by avoiding purifi-
cation of intermediates and the protection/deprotection of
functional groups.1 Bromopyrrole alkaloids, such as man-
zacidin A and C,2 have shown potent bioactivities as a-
adrenoceptor blockers, antagonists of serotonergic recep-
tors, and actomyosin ATPase activators.3 The biological
profiles of these molecules, combined with the synthetic
interest in constructing unusual structures, have resulted
in a number of successful total syntheses of manzacidin
A4 and C.5 Nevertheless, the development of facile and ef-
ficient strategies to access these molecules is still an un-
met challenge.
The desired d-lactol 2 would be generated when a-substi-
tuted acroleins 3, nitroalkanes 4 and paraformaldehyde
were mixed together in the presence of an appropriate cat-
alyst through the pathways outlined in Scheme 2. For
Path a, nitroalkane 4 first reacts with paraformaldehyde to
give b-nitro alcohol A, which then undergoes a Michael-
hemiacetalization with a-substituted acrolein 3 to afford
d-lactol 2. Alternatively, with the aid of base, nitroalkane
4 could also react with a-substituted acrolein 3 to give
Michael adduct B.8 The generated intermediate B further
reacts with paraformaldehyde through hydroxymethyla-
tion and subsequent intramolecular hemiacetalization to
produce d-lactol 2. Thus, the chemo- and regioselectivity
Br
H2N
HN
N
HN
N
NH2
O
HO
N
CO2H
CO2H
O
O
H
O
1
manzacidin A
manzacidin C (C6 epimer)
R2
R2
R1
R1
+
NO2
O
NO2
HO
O
(HCHO)n
2
Scheme 1 Retrosynthetic analysis of manzacidin A and C
SYNTHESIS 2011, No. 21, pp 3439–3446
x
x.
x
x
.
2
0
1
1
Advanced online publication: 01.09.2011
DOI: 10.1055/s-0030-1260194; Art ID: H67611SS
© Georg Thieme Verlag Stuttgart · New York

3440
G. Xiong et al.
PAPER
(HCHO)n
Table 1 Optimization of the Three-Component Cascade Reaction
of Nitroethane, 2-Benzylacrolein, and Paraformaldehydea
NO2
NO2
Bn
path a
Bn
catalyst
R2
NO2
NO2
R2
OH
(10 mol%)
+
+
(HCHO)n
R1
4
solvent, r.t.
HO
O
O
A
3a
4a
2a
R1
O
path b
O
drc
3
Entry
Catalyst
Solvent
Time
(h)
Yield
(%)b
3
1
2
DABCO
DMA
Et3N
toluene
toluene
toluene
toluene
toluene
CHCl3
CH2Cl2
n-hexane
EtOAc
THF
24
24
24
48
12
12
12
36
12
12
12
12
12
12
12
28
37
21
<10
82
73
80
78
89
87
75
90
94
96
96
70:30
72:28
63:37
–
O2N
R1
R2
R1
R2
O
NO2
3
HO
O
B
4
Imidazole
DBU
(HCHO)n
2
5
75:25
71:29
66:34
80:20
71:29
63:37
74:26
73:27
78:22
78:22
78:22
Scheme 2 Possible pathways of the three-component cascade reac-
tion
6
DBU
7
DBU
was the first issue to address for the development of this
cascade reaction.
8
DBU
The three-component cascade reaction between 2-benzyl-
acrolein (3a), nitroethane (4a), and paraformaldehyde was
first performed in toluene using various bases, such as
1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-dimethyl-
4-aminopyridine (DMAP), triethylamine, imidazole, or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the catalyst
at room temperature (Table 1, entries 1–5). It was found
that DBU showed the best catalytic activity among these
bases, although d-lactol 2a was generated in all the other
cases. Thus, DBU was chosen for further examination of
reaction media (Table 1, entries 6–13). In the presence of
10 mol% DBU, ethanol was found to be the best solvent,
and the desired product d-lactol 2a was isolated in excel-
lent yield (Table 1, entry 13). In fact, under the optimized
reaction conditions, the respective reactions of preformed
2-nitropropan-1-ol with 2-benzylacrolein (3a) or of pre-
formed 2-benzyl-4-nitropentanal with paraformaldehyde
proceeded smoothly to afford d-lactol 2a with excellent
yields (Table 1, entries 14 and 15). Based on these obser-
vations, we believe that the d-lactol 2 can be generated
through both of the pathways shown in Scheme 2. Diaste-
reoselectivity for the above reaction was moderate in all
the cases, which was determined by 1H NMR spectrosco-
py after 2a was reduced into the corresponding tetrahy-
dropyran by the action of Et3SiH/BF3·Et2O in order to
differentiate the chemical shifts.
9
DBU
10
11
12
13
14d
15e
DBU
DBU
MeCN
MeOH
EtOH
DBU
DBU
DBU
EtOH
DBU
EtOH
a Reaction conditions: nitroethane (0.55 mmol), 2-benzylacrolein (0.5
mmol), paraformaldehyde (0.6 mmol), catalyst (10 mol%), solvent
(1 mL), r.t.
b Isolated yield of 2a.
c Diastereoselectivity determined by 1H NMR analysis of crude tet-
rahydropyran.
d Reactions performed with 2-nitropropan-1-ol (0.55 mmol) and 2-
benzylacrolein (0.5 mmol).
e Reactions performed with 2-benzyl-4-nitropentanal (0.5 mmol) and
paraformaldehyde (0.6 mmol).
lectivities. For a-substituted acroleins, which were pre-
pared by application of the Pihko methylenation,9 to our
delight, the cascade reaction accommodated a range of
alkyl groups at the a-position of the substituted acroleins
(R1 = Bn, n-pentyl, n-Pr, and i-Pr). Most importantly, a
number of functionalized groups (R1 = PhthNCH2, BnO,
and BocNH) were well-tolerated (products 5m, 5n, and
5o, respectively).
With the optimized reaction conditions in hand, the sub-
strate scope of this cascade reaction was investigated. Be-
cause it was difficult to purify and analyze d-lactols 2,
they were first converted into tetrahydropyrans
(Method A) or d-lactones (Method B), respectively, and
then isolated and characterized; the results are summa-
rized in Table 2. With respect to the nitroalkanes, not only
were simple aliphatic and aromatic nitroethanes accepted
in the reaction, but also functionalized nitroalkanes 4h–i
were well-tolerated, and the corresponding products 5a–i
were obtained in good yields with moderate diastereose-
As a synthetic application of this cascade procedure, the
semisynthesis of ( )-manzacidin A and C was then under-
taken. The major diastereoisomer of 5o was first separated
by silica gel column chromatography and then reduced to
d-lactone 6 with hydrogen over Pd/C. The d-lactone 6
could be readily converted into the g-lactam 7 in excellent
yields at 40 °C in methanol (Scheme 3). Nuclear Over-
hauser effect (NOE) experiments with 7 clearly showed
Synthesis 2011, No. 21, 3439–3446 © Thieme Stuttgart · New York

PAPER
Multicomponent Cascade Synthesis of Nitro d-Lactol
3441
that the methyl group at the 5-position and the proton at tively, in three steps, as reported by Ohfune previously.4a
the 3-position are located on the same side of the ring and, The catalytic ability of DBU to tolerate the structural
thus, can be assigned as cis-7. The major diastereoisomer change of nitroalkanes, enables the analogues of ( )-
of 5o should therefore be trans-5o. In fact, trans-6 and cis- manzacidin A and C to be successfully prepared by this
6 can be converted into ( )-manzacidin A and C, respec- route.
Table 2 Scope of the DBU-Catalyzed Three-Component Cascade Reactiona
R2
NO2
R2
NO2
R1
R3
method
A or B
R1
O
R1
(HCHO)n
DBU
+
EtOH
O
R3
HO
O
NO2
R2
3
5
2
4
3a: R1 = Bn
R3 = H, O
3b: R1 = n-pentyl
3c: R1 = n-Pr
4a: R2 = H
4b: R2 = Me
4c: R2 = Ph
3d: R1 = i-Pr
4f: R2 = 2,4-Cl2C6H3
3e: R1 = PhthNCH2
3f: R1 = BnO
4g: R2 = 3,4-(OCH2O)C6H3
4h: R2 = CH2CH2CO2Me
4d: R2 = 4-FC6H4
3g: R1 = BocNH
4e: R2 = 4-MeOC6H4 4i: R2 = OH
Entry
1
Products
Yield (%)b
84
drc
Bn
NO2
78:22
O
O
5a
Bn
NO2
2
3
82
85
75:25
84:16
5b
Bn
NO2
Bn
O
O
O
5c
F
Bn
4
5
83
80
85:15
84:16
NO2
5d
OMe
Bn
NO2
Cl
5e
Cl
Bn
6
7
79
86
84:16
84:16
NO2
O
O
5f
Bn
O
NO2
O
5g
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3442
G. Xiong et al.
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Table 2 Scope of the DBU-Catalyzed Three-Component Cascade Reactiona (continued)
R2
R2
NO2
R1
R3
method
A or B
R1
O
R1
(HCHO)n
DBU
NO2
+
EtOH
O
R3
HO
O
NO2
R2
3
5
2
4
3a: R1 = Bn
R3 = H, O
3b: R1 = n-pentyl
3c: R1 = n-Pr
4a: R2 = H
4b: R2 = Me
4c: R2 = Ph
3d: R1 = i-Pr
4f: R2 = 2,4-Cl2C6H3
3e: R1 = PhthNCH2
3f: R1 = BnO
4g: R2 = 3,4-(OCH2O)C6H3
4h: R2 = CH2CH2CO2Me
4d: R2 = 4-FC6H4
3g: R1 = BocNH
4e: R2 = 4-MeOC6H4 4i: R2 = OH
Entry
8
Products
Yield (%)b
drc
NO2
Bn
O
75
64:36
O
OMe
5h
OH
Bn
9
10
11
84
80
76
78:22
77:23
78:22
NO2
O
5i
Bn
4
NO2
O
5j
Bn
NO2
O
O
5k
Bn
NO2
12
84
82:18
5l
PhthN
NO2
13
14
15
79
74
71
77:23
78:22
80:20
O
5m
BnO
NO2
O
5n
O
BocHN
NO2
O
O
5o
a Reaction conditions: acrolein (0.5 mmol), nitroalkane (0.55 mmol), paraformaldehyde (0.6 mmol), DBU (0.05 mmol), EtOH (1 mL) at r.t.
b Isolated yield of 5.
c Diastereoselectivities determined by 1H NMR analysis of crude 5.
In summary, we have developed a novel organocatalytic, ficient domino reaction affords functionalized d-lactols
multicomponent cascade reaction between various ni- and their derivatives such as d-lactones and tetrahydropy-
troalkanes, a-substituted acroleins, and paraformaldehyde rans in good yields. Furthermore, this method provides a
by employing DBU as the catalyst. This versatile and ef- facile approach to the natural products ( )-manzacidin A
Synthesis 2011, No. 21, 3439–3446 © Thieme Stuttgart · New York

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Multicomponent Cascade Synthesis of Nitro d-Lactol
3443
Br
BocHN
O
trans-5o
cis-5o
Pd/C, H2
MeOH
3 steps
NH2
HN
N
O
O
N
CO2H
ref. 4a
H
trans-6, 82% yield
cis-6, 86% yield
O
( )-manzacidin A and C
BocHN
MeOH
40 °C
OH
cis-7, 95% yield
N
trans-7, 96% yield
O
H
Scheme 3 Formal semisynthesis of ( )-manzacidin A and C
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 138.2, 128.8, 128.6,
and C from easily accessible reagents under mild condi-
tions.
126.5, 86.1, 73.1, 72.6, 38.7, 38.4, 33.6, 24.3.
HRMS (ESI): m/z [M + Na]+ calcd for C13H17NNaO3: 258.11006;
found: 258.11009.
Solvents were purified by standard procedures and distilled before
use. Reagents and starting materials obtained from commercial sup-
pliers were used without further purification unless otherwise noted.
For thin-layer chromatography (TLC), silica gel plates GF254 were
used and compounds were visualized by irradiation with UV light,
I2, or by treatment with basic KMnO4. NMR spectra were obtained
with a Bruker AV-400 NMR spectrometer with TMS as the internal
standard. Chemical shifts were reported in parts per million (ppm),
and the residual solvent peak was used as an internal reference: 1H
(d = 7.26 ppm), 13C (d = 77.0 ppm). Multiplicity is indicated as fol-
lows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of doublet), br s (broad singlet). Coupling constants are re-
ported in hertz (Hz). High-resolution mass spectra were obtained on
a Bruker Apex IV FTMS using electrospray ionization (ESI). Flash
chromatography was carried out on silica gel 60 A (10–40 mm, pur-
chased from Qingdao Haiyang).
5-Benzyl-3-ethyltetrahydro-3-nitro-2H-pyran (5b)
Yield: 82%; diastereomeric ratio: 75:25 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.31–7.28 (m, 2 H),
7.22–7.20 (m, 1 H), 7.14–7.13 (m, 2 H), 4.63 (dd, J = 12.8, 2.8 Hz,
1 H), 4.11 (dd, J = 11.2, 2.4 Hz, 1 H, minor isomer), 3.87 (ddd,
J = 11.2, 4.4, 2.0 Hz, 1 H), 3.28 (d, J = 12.8 Hz, 1 H), 3.03 (d,
J = 11.2 Hz, 1 H), 2.79–2.73 (m, 1 H), 2.56–2.45 (m, 2 H), 2.19–
2.10 (m, 1 H), 1.86–1.76 (m, 1 H), 1.68–1.59 (m, 1 H), 1.25 (dd,
J = 14.4, 12.0 Hz, 1 H), 0.85 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 138.3, 128.8, 128.6,
126.4, 89.7, 72.9, 72.6, 38.5, 36.6, 33.5, 30.8, 7.3.
HRMS (ESI): m/z [M + Na]+ calcd for C14H19NNaO3: 272.12571;
found: 272.12564.
3,5-Dibenzyltetrahydro-3-nitro-2H-pyran (5c)
Multicomponent Cascade Reaction; General Procedure
To a mixture of a-substituted acrolein (0.5 mmol), nitroalkane (0.55
mmol), and paraformaldehyde (0.6 mmol) in EtOH (800 mL), was
added a solution of DBU in EtOH (0.25 M, 200 mL). The reaction
mixture was stirred at r.t. until complete consumption of the a-sub-
stituted acrolein was observed. The reaction mixture was filtered
through a silica gel pad, washed with 5% MeOH–CH2Cl2, and con-
centrated in vacuo.
Yield: 85%; diastereomeric ratio: 84:16 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.29–7.24 (m, 5 H),
7.21–7.17 (m, 1 H), 7.09–7.07 (m, 2 H), 7.02–7.00 (m, 2 H), 4.63
(dd, J = 12.8, 2.8 Hz, 1 H), 4.18 (dd, J = 11.2, 1.6 Hz, 1 H, minor
isomer), 3.87 (ddd, J = 11.2, 4.4, 2.0 Hz, 1 H), 3.38 (d, J = 12.4 Hz,
1 H), 3.07–2.90 (m, 3 H), 2.65–2.60 (m, 1 H), 2.53 (dd, J = 13.6,
6.4 Hz, 1 H), 2.40 (dd, J = 14.0, 8.0 Hz, 1 H), 2.13–2.07 (m, 1 H),
1.43–1.36 (m, 1 H).
Method A
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 138.3, 132.9, 129.7,
128.8, 128.7, 128.5, 127.9, 126.5, 89.8, 72.7, 72.4, 43.9, 38.6, 37.0,
33.6.
HRMS (ESI): m/z [M + Na]+ calcd for C19H21NNaO3: 334.14136;
found: 334.14142.
The resulting crude d-lactol 2a–m was dissolved in CH2Cl2 (10.0
mL), and triethylsilane (5.0 mmol) and TFA (5.0 mmol) were added
at –78 °C. After stirring at –78 °C for 1 h, the temperature of reac-
tion mixture was gradually raised to r.t. The reaction was quenched
with aq NaHCO3 (10.0 mL) and extracted with CH2Cl2 (3 × 30 mL).
The organic phase was combined, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The diastereoisomeric ratio
was determined by 1H NMR analysis of crude product 5 (based on
the different chemical shift of OCHaHbCNO2). The residue was pu-
rified by flash chromatography (CH2Cl2) to give the corresponding
tetrahydropyran 5a–m (major).
3-(4-Fluorobenzyl)-5-benzyltetrahydro-3-nitro-2H-pyran (5d)
Yield: 83%; diastereomeric ratio: 85:15 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.29–7.25 (m, 2 H),
7.22–7.18 (m, 1 H), 7.09 (d, J = 7.2 Hz, 2 H), 7.00–6.97 (m, 4 H),
4.62 (dd, J = 12.4, 2.8 Hz, 1 H), 4.09 (dd, J = 11.6, 2.0 Hz, 1 H,
minor isomer), 3.83 (ddd, J = 11.2, 4.4, 1.6 Hz, 1 H), 3.37 (d,
J = 12.4 Hz, 1 H), 3.06–2.98 (m, 2 H), 2.88 (d, J = 14.4 Hz, 1 H),
2.62–2.58 (m, 1 H), 2.54 (dd, J = 14.0, 6.4 Hz, 1 H), 2.42 (dd,
J = 14.0, 8.0 Hz, 1 H), 2.15–2.06 (m, 1 H), 1.44–1.34 (m, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 162.5 (d,
J = 245.3 Hz), 138.1, 131.2 (d, J = 8.0 Hz), 128.8, 128.6 (d,
J = 2.6 Hz), 128.5, 126.5, 115.7 (d, J = 21.4 Hz), 89.7, 72.7, 72.4,
43.0, 38.6, 37.0, 33.6.
5-Benzyltetrahydro-3-methyl-3-nitro-2H-pyran (5a)
Yield: 84%; diastereomeric ratio: 78:22 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.31–7.27 (m, 2 H),
7.23–7.19 (m, 1 H), 7.14–7.11 (m, 2 H), 4.61 (dd, J = 12.4, 2.8 Hz,
1 H), 3.97 (dd, J = 11.2, 2.4 Hz, 1 H, minor isomer), 3.87 (ddd,
J = 11.2, 4.3, 1.8 Hz, 1 H), 3.26 (d, J = 12.8 Hz, 1 H), 3.03 (d,
J = 11.2 Hz, 1 H), 2.75–2.69 (m, 1 H), 2.50–2.48 (m, 2 H), 2.22–
2.12 (m, 1 H), 1.41 (s, 3 H), 1.30 (dd, J = 14.8, 12.4 Hz, 1 H).
Synthesis 2011, No. 21, 3439–3446 © Thieme Stuttgart · New York

3444
G. Xiong et al.
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HRMS (ESI): m/z [M + Na]+ calcd for C19H20FNNaO3: 352.13194;
found: 352.13199.
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d (major) = 172.2,
138.1, 128.8, 128.6, 126.5, 88.5, 72.8, 72.5, 52.0, 38.4, 36.6, 33.4,
32.1, 27.6.
3-(4-Methoxybenzyl)-5-benzyltetrahydro-3-nitro-2H-pyran
(5e)
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d (minor) = 7.32–7.28
(m, 2 H), 7.26–7.21 (m, 1 H), 7.13–7.11 (m, 2 H), 4.07 (dd,
J = 11.2, 2.4 Hz, 1 H), 3.89–3.85 (m, 1 H), 3.64 (s, 3 H), 3.61 (d,
J = 11.2 Hz, 1 H), 3.04 (dd, J = 11.6, 11.2 Hz, 1 H), 2.55–2.45 (m,
2 H), 2.42–2.38 (m, 1 H), 2.36–2.27 (m, 2 H), 2.24–2.07 (m, 3 H),
1.77 (dd, J = 12.8, 12.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d (minor) = 172.3,
138.2, 128.8, 128.7, 126.6, 86.2, 72.8, 70.9, 52.0, 38.4, 37.7, 32.1,
29.1, 28.1.
Yield: 80%; diastereomeric ratio: 84:16 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.29–7.25 (m, 2 H),
7.21–7.18 (m, 1 H), 7.10–7.08 (m, 2 H), 6.94–6.91 (m, 2 H), 6.84–
6.81 (m, 2 H), 4.62 (dd, J = 12.4, 2.8 Hz, 1 H), 4.12 (dd, J = 11.2,
2.0 Hz, 1 H, minor isomer), 3.81 (ddd, J = 11.2, 4.4, 1.6 Hz, 1 H),
3.78 (s, 3 H), 3.36 (d, J = 12.4 Hz, 1 H), 3.01–2.96 (m, 2 H), 2.86
(d, J = 14.0 Hz, 1 H), 2.64–2.60 (m, 1 H), 2.54 (dd, J = 14.0,
6.4 Hz, 1 H), 2.41 (dd, J = 14.0, 8.0 Hz, 1 H), 2.13–2.06 (m, 1 H),
1.37 (dd, J = 14.4, 12.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 159.3, 138.3, 130.8,
128.8, 128.5, 126.5, 124.8, 114.1, 89.9, 72.6, 72.3, 55.3, 43.1, 38.6,
37.0, 33.6.
HRMS (ESI): m/z [M + Na]+ calcd for C20H23NNaO4: 364.15193;
found: 364.15185.
HRMS (ESI): m/z [M + Na]+ calcd for C16H21NNaO5: 330.13119;
found: 330.13112.
(5-Benzyltetrahydro-3-nitro-2H-pyran-3-yl)methanol (5i)
Yield: 84%; diastereomeric ratio: 78:22 (determined by 1H NMR).
1H NMR (400 MHz, DMSO-d6, 25 °C, TMS): d = 7.20–7.16 (m,
2 H), 7.10–7.04 (m, 3 H), 5.42 (t, J = 6.0 Hz, 1 H), 4.43 (dd,
J = 12.4, 2.8 Hz, 1 H), 4.13 (dd, J = 11.2, 1.6 Hz, 1 H, minor iso-
mer), 3.75 (dd, J = 11.2, 2.8 Hz, 1 H), 3.62 (dd, J = 11.6, 6.0 Hz,
1 H), 3.53 (dd, J = 11.6, 6.0 Hz, 1 H), 3.44 (d, J = 12.4 Hz, 1 H),
3.07 (t, J = 11.2 Hz, 1 H), 2.54 (dd, J = 13.6, 6.4 Hz, 1 H), 2.44 (dd,
J = 14.4, 2.0 Hz, 1 H), 2.36 (dd, J = 13.6, 8.0 Hz, 1 H), 1.88–1.86
(m, 1 H), 1.46 (dd, J = 14.4, 12.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6, 25 °C, TMS): d = 139.3, 129.3,
128.8, 126.6, 91.2, 72.2, 69.7, 66.1, 33.9, 33.6.
HRMS (ESI): m/z [M + Na]+ calcd for C13H17NNaO4: 274.10498;
found: 274.10491.
3-(2,4-Dichlorobenzyl)-5-benzyltetrahydro-3-nitro-2H-pyran
(5f)
Yield: 79%; diastereomeric ratio: 82:18 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.40 (d, J = 2.0 Hz,
1 H), 7.29–7.25 (m, 2 H), 7.22–7.20 (m, 1 H), 7.17 (dd, J = 8.4,
2.0 Hz, 1 H), 7.10–7.08 (m, 2 H), 6.90 (d, J = 8.4 Hz, 1 H), 4.61
(dd, J = 12.8, 2.8 Hz, 1 H), 4.18 (dd, J = 11.6, 2.0 Hz, 1 H, minor
isomer), 3.83 (ddd, J = 11.2, 4.4, 1.6 Hz, 1 H), 3.45 (d, J = 12.4 Hz,
1 H), 3.20–3.12 (m, 2 H), 3.02 (d, J = 8.4 Hz, 1 H), 2.62–2.57 (m,
1 H), 2.52 (dd, J = 14.0, 6.8 Hz, 1 H), 2.44 (dd, J = 14.0, 8.0 Hz,
1 H), 2.11–2.05 (m, 1 H), 1.52 (dd, J = 14.4, 12.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 138.1, 135.4, 134.6,
132.2, 129.9, 129.7, 128.8, 128.6, 127.7, 126.5, 90.3, 72.6, 72.1,
39.3, 38.5, 36.8, 33.7.
HRMS (ESI): m/z [M + Na]+ calcd for C19H19Cl2NNaO3:
402.06342; found: 402.06348.
3-Benzyltetrahydro-3-nitro-5-pentyl-2H-pyran (5j)
Yield: 80%; diastereomeric ratio: 77:23 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d (major) = 7.30–7.26
(m, 3 H), 7.07–7.01 (m, 2 H), 4.63 (dd, J = 12.8, 2.8 Hz, 1 H), 3.90
(ddd, J = 11.2, 4.4, 1.6 Hz, 1 H), 3.38 (d, J = 12.4 Hz, 1 H), 3.05 (d,
J = 14.0 Hz, 1 H), 2.97–2.88 (m, 2 H), 2.63–2.59 (m, 1 H), 1.75–
1.70 (m, 1 H), 1.32–1.23 (m, 7 H), 1.14–1.09 (m, 2 H), 0.86 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d (major) = 133.0,
129.7, 128.7, 127.8, 89.8, 73.1, 72.5, 43.9, 37.1, 32.2, 32.0, 31.9,
26.0, 22.5, 14.1.
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d (minor) = 7.30–7.26
(m, 3 H), 7.07–7.01 (m, 2 H), 4.12 (dd, J = 11.2, 2.4 Hz, 1 H), 3.98
(ddd, J = 11.2, 4.4, 0.8 Hz, 1 H), 3.49 (d, J = 11.2 Hz, 1 H), 3.44 (d,
J = 14.4 Hz, 1 H), 2.97–2.88 (m, 2 H), 2.39–2.35 (m, 1 H), 2.04–
1.96 (m, 1 H), 1.32–1.23 (m, 7 H), 1.14–1.09 (m, 2 H), 0.90 (t,
J = 6.8 Hz, 3 H).
5-[(5-Benzyltetrahydro-3-nitro-2H-pyran-3-yl)methyl]ben-
zo[d][1,3]dioxole (5g)
Yield: 86%; diastereomeric ratio: 84:16 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.29–7.25 (m, 2 H),
7.22–7.20 (m, 1 H), 7.10–7.09 (m, 2 H), 6.72 (d, J = 7.6 Hz, 1 H),
6.49–6.46 (m, 2 H), 5.94 (s, 2 H), 4.62 (dd, J = 12.8, 2.8 Hz, 1 H),
4.12 (dd, J = 11.2, 2.0 Hz, 1 H, minor isomer), 3.82 (ddd, J = 11.2,
4.4, 1.6 Hz, 1 H), 3.36 (d, J = 12.4 Hz, 1 H), 3.02–2.96 (m, 2 H),
2.83 (d, J = 14.4 Hz, 1 H), 2.66–2.61 (m, 1 H), 2.55 (dd, J = 13.6,
6.4 Hz, 1 H), 2.41 (dd, J = 14.0, 8.0 Hz, 1 H), 2.13–2.08 (m, 1 H),
1.37 (dd, J = 14.4, 12.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d (minor) = 134.2,
129.8, 128.7, 127.7, 87.4, 73.3, 70.5, 40.4, 37.9, 33.6, 32.0, 31.9,
26.2, 22.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C17H25NNaO3: 314.17266;
found: 314.17260.
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 147.9, 147.3, 138.2,
128.8, 128.5, 126.5, 126.3, 123.0, 109.9, 108.4, 101.2, 89.8, 72.6,
72.4, 43.6, 38.6, 37.0, 33.6.
HRMS (ESI): m/z [M + Na]+ calcd for C20H21NNaO5: 378.13119;
found: 378.13126.
3-Benzyltetrahydro-3-nitro-5-propyl-2H-pyran (5k)
Methyl 3-(5-Benzyltetrahydro-3-nitro-2H-pyran-3-yl)pro-
panoate (5h)
Yield: 76%; diastereomeric ratio: 78:22 (determined by 1H NMR).
Yield: 75%; diastereomeric ratio: 64:36 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.31–7.26 (m, 3 H),
7.04–7.02 (m, 2 H), 4.65 (dd, J = 12.8, 2.8 Hz, 1 H), 4.15 (dd,
J = 11.2, 2.4 Hz, 1 H, minor isomer), 3.92 (ddd, J = 11.2, 4.4,
1.6 Hz, 1 H), 3.39 (d, J = 12.8 Hz, 1 H), 3.08 (d, J = 14.0 Hz, 1 H),
2.96–2.90 (m, 2 H), 2.66–2.60 (m, 1 H), 1.80–1.73 (m, 1 H), 1.33–
1.23 (m, 3 H), 1.15–1.09 (m, 2 H), 0.87 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d (major) = 7.32–7.28
(m, 2 H), 7.26–7.21 (m, 1 H), 7.13–7.11 (m, 2 H), 4.60 (dd,
J = 12.4, 2.8 Hz, 1 H), 3.89–3.85 (m, 1 H), 3.64 (s, 3 H), 3.31 (d,
J = 12.8 Hz, 1 H), 3.04 (dd, J = 11.6, 11.2 Hz, 1 H), 2.70–2.66 (m,
1 H), 2.55–2.45 (m, 2 H), 2.42–2.38 (m, 1 H), 2.24–2.07 (m, 3 H),
2.00–1.92 (m, 1 H), 1.28 (dd, J = 14.4, 12.4 Hz, 1 H).
Synthesis 2011, No. 21, 3439–3446 © Thieme Stuttgart · New York

PAPER
Multicomponent Cascade Synthesis of Nitro d-Lactol
3445
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 133.0, 129.7, 128.7,
127.9, 89.7, 73.1, 72.5, 43.9, 37.1, 34.2, 31.8, 19.5, 14.2.
4.32 (dt, J = 11.6, 6.8 Hz, 1 H), 3.25 (dd, J = 14.4, 7.2 Hz, 1 H),
2.18 (t, J = 12.8 Hz, 1 H), 1.72 (s, 3 H), 1.45 (s, 9 H).
HRMS (ESI): m/z [M + Na]+ calcd for C15H21NNaO3: 286.14136;
found: 286.14140.
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 169.5, 155.3, 84.3,
81.0, 71.7, 47.4, 37.0, 28.3, 24.7.
HRMS (ESI): m/z [M + Na]+ calcd for C11H18N2NaO6: 297.10571;
found: 297.10579.
3-Benzyltetrahydro-5-isopropyl-3-nitro-2H-pyran (5l)
Yield: 84%; diastereomeric ratio: 82:18 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.30–7.28 (m, 3 H),
7.04–7.02 (m, 2 H), 4.62 (dd, J = 12.4, 2.8 Hz, 1 H), 4.12 (dd,
J = 11.2, 2.0 Hz, 1 H, minor isomer), 3.97 (ddd, J = 11.2, 4.4,
2.0 Hz, 1 H), 3.36 (d, J = 12.4 Hz, 1 H), 3.07 (d, J = 13.6 Hz, 1 H),
3.02 (t, J = 14.4 Hz, 1 H), 2.94 (d, J = 13.6 Hz, 1 H), 2.68–2.63 (m,
1 H), 1.56–1.47 (m, 1 H), 1.41–1.33 (m, 2 H), 0.89 (d, J = 4.9 Hz,
3 H), 0.86 (d, J = 4.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 133.0, 129.7, 128.7,
127.9, 89.9, 72.2, 71.4, 44.1, 38.2, 24.7, 29.7, 19.8, 19.7.
HRMS (ESI): m/z [M + Na]+ calcd for C15H21NNaO3: 286.14136;
cis-5o (minor)
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 5.57 (d, J = 6.4 Hz,
1 H), 4.95 (d, J = 13.2 Hz, 1 H), 4.50 (dt, J = 10.4, 8.0 Hz, 1 H),
4.31 (d, J = 13.2 Hz, 1 H), 2.86–2.73 (m, 2 H), 1.75 (s, 3 H), 1.46
(s, 9 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 170.4, 155.2, 85.8,
80.9, 70.8, 46.9, 36.4, 28.3, 23.9.
HRMS (ESI): m/z [M + Na]+ calcd for C11H18N2NaO6: 297.10571;
found: 297.10576.
found: 286.14131.
Transformations of 5o; Typical Procedure
To a solution of trans-5o (0.3 mmol, 82 mg) in MeOH (5 mL), was
added Pd/C (20 mg, 10% w/w). The resulting suspension was
stirred under H2 (1 atm) at r.t. overnight. When the reaction was
complete, the reaction mixture was filtered through a pad of Celite
and washed with MeOH. The filtrate was concentrated under re-
duced pressure, and the residue was purified by column chromatog-
raphy (CH2Cl2 then CH2Cl2–MeOH, 100:1) to afford d-lactone
trans-6. A solution of trans-6 in MeOH (10 mL) was stirred over-
night at 40 °C and concentrated in vacuo to give the corresponding
g-lactam cis-7. Similar transformation was also applied to cis-5o,
which provided cis-6 and trans-7.
2-[(Tetrahydro-5-methyl-5-nitro-2H-pyran-3-yl)methyl]isoin-
doline-1,3-dione (5m)
Yield: 79%; diastereomeric ratio: 77:23 (determined by 1H NMR).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.86 (dd, J = 5.6,
3.2 Hz, 2 H), 7.75 (dd, J = 5.2, 2.8 Hz, 2 H), 4.61 (dd, J = 12.8,
2.8 Hz, 1 H), 4.01 (dd, J = 10.8, 2.0 Hz, 1 H, minor isomer), 3.97
(ddd, J = 11.2, 4.4, 2.0 Hz, 1 H), 3.57 (d, J = 6.8 Hz, 1 H), 3.29 (d,
J = 12.8 Hz, 1 H), 3.14 (dd, J = 11.6, 11.2 Hz, 1 H), 2.81–2.77 (m,
1 H), 2.34–2.28 (m, 1 H), 1.46 (s, 3 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 168.4, 134.3, 131.8,
123.5, 85.6, 73.0, 70.6, 39.2, 36.5, 32.7, 24.3.
HRMS (ESI): m/z [M + Na]+ calcd for C15H16N2NaO5: 327.09514;
found: 327.09508.
(trans)-tert-Butyl 5-Aminotetrahydro-5-methyl-2-oxo-2H-pyr-
an-3-ylcarbamate (trans-6)
Yield: 86%.
1H NMR (400 MHz, CD3OD, 25 °C, TMS): d = 4.35 (t, J = 8.0 Hz,
1 H), 3.70 (d, J = 11.2 Hz, 1 H), 3.32 (d, J = 11.2 Hz, 1 H), 2.21
(dd, J = 12.8, 10.0 Hz, 1 H), 1.99 (dd, J = 12.8, 6.4 Hz, 1 H), 1.46
(s, 9 H), 1.22 (s, 3 H).
13C NMR (100 MHz, CD3OD, 25 °C, TMS): d = 168.4, 156.4, 79.3,
63.8, 62.6, 34.0, 27.3, 18.8.
Method B
To a solution of the crude d-lactol 2n or 2o generated above in
CH2Cl2 (10.0 mL), 4 Å molecular sieves and pyridinium dichro-
mate (PDC; 376 mg, 1.0 mmol) were added at r.t. The reaction mix-
ture was stirred for 24 h, diluted with EtOAc (20.0 mL), filtered,
and concentrated under reduced pressure. The residue was purified
by flash chromatography (CH2Cl2 then CH2Cl2–MeOH, 100:1) to
give the corresponding d-lactone.
HRMS (ESI): m/z [M + Na]+ calcd for C11H20N2NaO4: 267.13153;
found: 267.13158.
3-(Benzyloxy)tetrahydro-5-methyl-5-nitropyran-2-one (5n)
(cis)-tert-Butyl 5-Aminotetrahydro-5-methyl-2-oxo-2H-pyran-
3-ylcarbamate (cis-6)
Yield: 74%; diastereomeric ratio: 78:22 (determined by 1H NMR).
Yield: 82%.
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 7.38–7.26 (m, 5 H),
4.94 (dd, J = 12.0, 11.6 Hz, 2 H), 4.82 (dd, J = 12.4, 1.6 Hz, 1 H,
minor isomer), 4.62 (d, J = 11.6 Hz, 1 H), 4.20 (d, J = 12.8 Hz,
1 H), 4.09 (dd, J = 9.2, 7.2 Hz, 1 H), 3.14 (dd, J = 15.6, 9.2 Hz,
1 H), 2.43 (dd, J = 15.6, 7.2 Hz, 1 H), 1.69 (s, 3 H).
1H NMR (400 MHz, CD3OD, 25 °C, TMS): d = 4.37 (t, J = 9.2 Hz,
1 H), 3.68 (d, J = 11.6 Hz, 1 H), 3.32 (d, J = 11.6 Hz, 1 H), 2.55
(dd, J = 12.4, 10.0 Hz, 1 H), 1.72 (dd, J = 11.6, 10.0 Hz, 1 H), 1.44
(s, 9 H), 1.23 (s, 3 H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): d = 169.3, 136.6, 128.7,
128.3, 128.0, 84.5, 72.6, 70.6, 69.7, 36.3, 25.0.
13C NMR (100 MHz, CD3OD, 25 °C, TMS): d = 169.0, 156.4, 79.1,
64.3, 62.7, 35.7, 27.3, 20.1.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NNaO5: 288.08424;
HRMS (ESI): m/z [M + Na]+ calcd for C11H20N2NaO4: 267.13153;
found: 288.08419.
found: 267.13147.
tert-Butyl Tetrahydro-5-methyl-5-nitro-2-oxo-2H-pyran-3-yl-
carbamate (5o)
(cis)-tert-Butyl 5-(Hydroxymethyl)-5-methyl-2-oxopyrrolidin-
3-ylcarbamate (cis-7)
Yield: 71%; trans-5o and cis-5o were isolated by flash chromatog-
Yield: 95%.
raphy.
1H NMR (400 MHz, DMSO-d6, 25 °C, TMS): d = 9.33 (s, 1 H),
6.85 (d, J = 9.2 Hz, 1 H), 4.85 (t, J = 5.6 Hz, 1 H), 4.11 (q,
J = 8.8 Hz, 1 H), 3.41 (dd, J = 10.8, 4.8 Hz, 1 H), 3.20 (dd,
J = 10.8, 5.6 Hz, 1 H), 2.00 (dd, J = 12.8, 9.6 Hz, 1 H), 1.85 (dd,
J = 12.8, 8.0 Hz, 1 H), 1.39 (s, 9 H), 1.07 (s, 3 H).
trans-5o (major)
1H NMR (400 MHz, CDCl3, 25 °C, TMS): d = 5.45 (d, J = 4.4 Hz,
1 H), 4.87 (dd, J = 12.4, 1.6 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H),
Synthesis 2011, No. 21, 3439–3446 © Thieme Stuttgart · New York

3446
G. Xiong et al.
PAPER
(2) Kobayashi, J.; Kanda, F.; Ishibashi, M.; Shigemori, H.
13C NMR (100 MHz, DMSO-d6, 25 °C, TMS): d = 167.3, 155.6,
78.6, 64.9, 61.6, 47.7, 34.2, 28.7, 19.9.
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HRMS (ESI): m/z [M + Na]+ calcd for C11H20N2NaO4: 267.13153;
found: 267.13160.
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Chem. Soc. 2000, 122, 10708. (b) Wehn, P. M.; Bois, J. D.
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(trans)-tert-Butyl 5-(Hydroxymethyl)-5-methyl-2-oxopyrroli-
din-3-ylcarbamate (trans-7)
Yield: 96%.
1H NMR (400 MHz, DMSO-d6, 25 °C, TMS): d = 9.34 (s, 1 H),
7.07 (d, J = 8.8 Hz, 1 H), 4.97 (t, J = 4.8 Hz, 1 H), 4.17 (t,
J = 9.6 Hz, 1 H), 3.43 (dd, J = 10.8, 5.6 Hz, 1 H), 3.15 (dd,
J = 10.8, 5.6 Hz, 1 H), 2.34 (dd, J = 12.0, 9.6 Hz, 1 H), 1.58 (dd,
J = 12.0, 10.0 Hz, 1 H), 1.38 (s, 9 H), 1.07 (s, 3 H).
13C NMR (100 MHz, DMSO-d6, 25 °C, TMS): d = 167.8, 155.6,
78.3, 64.4, 61.6, 48.4, 35.7, 28.7, 22.0.
HRMS (ESI): m/z [M + Na]+ calcd for C11H20N2NaO4: 267.13153;
(6) (a) Smith, A. B. III; Benowitz, A. B.; Guzman, M. C.;
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found: 267.13155.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (20902030; 20872041). The Center of Analysis and
Testing of Huazhong University of Science and Technology is
thanked for characterization of new compounds.
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Synthesis 2011, No. 21, 3439–3446 © Thieme Stuttgart · New York