A direct and general method for the reductive alkylation of tertiary lactams/amides: Application to the step economical synthesis of alkaloid (-)-morusimic acid D

Article abstract of DOI:10.1021/jo4007656

Full details of the direct and general method for the reductive alkylation of tertiary lactams and amides to give tertiary sec-alkylamines are presented. This one-pot method consists of in situ activation of a lactam or an amide with Tf₂O/DTBMP, addition of a Grignard reagent, and reduction of the resulting iminium intermediates. Alkyl, benzyl, and aryl Grignard reagents and several reductants or reducing conditions (LiAlH₄, NaBH₄, Hantzsch ester, Bu₃SnH, Pd(OH)₂/C, H₂) could be used effectively. Reductive alkylations of substituted lactams demonstrated good to excellent 1,3-asymmetric induction to provide the corresponding di- or trisubstituted pyrrolidine/piperidine in 6:1 (LiAlH₄), 11:1 (Et ₃SiH), and 20:1 (catalytic hydrogenation) cis/trans diastereoselectivity, respectively. The versatility of this methodology was demonstrated by its application in the concise stereoselective synthesis of piperidine alkaloid (-)-morusimic acid.

Full text of DOI:10.1021/jo4007656

Article
pubs.acs.org/joc
A Direct and General Method for the Reductive Alkylation of Tertiary
Lactams/Amides: Application to the Step Economical Synthesis of
Alkaloid (−)-Morusimic Acid D
Kai-Jiong Xiao,† Yu Wang,† Ying-Hong Huang,† Xiao-Gang Wang,† and Pei-Qiang Huang*,†,‡
†Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, People’s
Republic of China
‡The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: Full details of the direct and general method for
the reductive alkylation of tertiary lactams and amides to give
tertiary sec-alkylamines are presented. This one-pot method
consists of in situ activation of a lactam or an amide with
Tf2O/DTBMP, addition of a Grignard reagent, and reduction
of the resulting iminium intermediates. Alkyl, benzyl, and aryl
Grignard reagents and several reductants or reducing conditions (LiAlH4, NaBH4, Hantzsch ester, Bu3SnH, Pd(OH)2/C, H2)
could be used effectively. Reductive alkylations of substituted lactams demonstrated good to excellent 1,3-asymmetric induction
to provide the corresponding di- or trisubstituted pyrrolidine/piperidine in 6:1 (LiAlH4), 11:1 (Et3SiH), and 20:1 (catalytic
hydrogenation) cis/trans diastereoselectivity, respectively. The versatility of this methodology was demonstrated by its application
in the concise stereoselective synthesis of piperidine alkaloid (−)-morusimic acid.
Scheme 1. Transformation of Amides/Lactams into the
Corresponding sec-Alkylamines
INTRODUCTION
■
sec-Alkylamines, especially α-substituted pyrrolidines, piper-
idines, pyrrolizidines, indolizidines, and quinolizidines, are key
structural features found in many bioactive alkaloids and
pharmaceutically relevant molecules.1 Some representative
pyrrolidine and piperidine alkaloids are shown in Figure 1,
philes.10−13 Among the widely used multistep methods14−18
were those via thioamide derivatives;14 by N-deprotection−
activation via N-carbamoylation/sulfonylation (8 to B via A),
followed by stepwise reductive alkylation on N-acyl/N-
carbamoyl derivatives B (via D)15 or N-α-amidoalkylation of
F,16 or N-t-butyl formamidines,17 and via enol triflates C.18
Our continuing interest in bioactive alkaloids8e,19 has led us
to focus our attention on the development of step-economical
synthetic methods.19−22 One of the methods developed
involves the first general one-pot transformation of tertiary
lactams and amides into the corresponding tert-alkylamines by
Figure 1. Selected pyrrolidine and piperidine alkaloids containing the
sec-alkylamine motif.
which include (−)-irniine (2),2 (−)-bgugaine (3),3 (+)-pre-
ussin (4),4 coniine (5),5 (−)-cassine (6),6 and (−)-morusimic
acid D (7).7 The broad spectrum of bioactivities exhibited by
pyrrolidine and piperidine alkaloids render them attractive
synthetic targets, and a number of synthetic methodologies
have been developed.8,9 Many of these converge on a common
transformation of lactams (8, Scheme 1) to the corresponding
α-substituted pyrrolidines or piperidines 1.8b,d−f,i The direct
reductive alkylation of 8 to 1, although highly desirable, has
been limited to some special substrates or specific nucleo-
Received: April 10, 2013
© XXXX American Chemical Society
A
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Scheme 2. One-Pot Reductive Alkylation of Lactams/Amides and Its Application to the Syntheses of Alkaloids ( )-Bgugaine,
( )-Coniine, and (−)-Cassine
bis-reductive alkylation with organometallic reagents.20a Our
Table 1. Results of the One-Pot Reductive Alkylation of 2-
recent interest was expanded to the development of a direct
and general reductive alkylation method for the one-pot
transformation of tertiary amides/lactams into tertiary sec-
alkylamines, and the preliminary results have been communi-
cated.21 We now report the full account of this study, which
includes optimizing reaction conditions to achieve a highly
diastereoselective one-pot reductive alkylation of lactams and
applying the methodology to the improved synthesis of
(−)-morusimic acid D (7).
Pyrrolidinone 8b
a
entry
reductant or [H]
yield (%)
1
2
3
4
5
6
7
8
LiAlH4 (3.0 equiv), 1 h
82
71
70
75
68
15
19
0
NaBH4 (3.0 equiv), 1 h
Hantzsch ester (3.0 equiv), 1 h
Bu3SnH (3.0 equiv), 1 h
20% Pd(OH)2/C, H2, 2 h
Et3SiH (10.0 equiv), 8 h
(EtO)3SiH (10.0 equiv), 8 h
Ph3SiH (10.0 equiv), 8 h
RESULTS AND DISCUSSION
■
In our preliminary communication,21 reductive alkylation of
both lactams and amides was achieved by successive treatment
of lactams/amides 8 with Tf2O/DTBMP23 (−78 to 0 °C),
RMgX, and LiAlH4 (or NaBH4). The corresponding sec-
alkylamines 1a−1j were obtained in yields ranging from 58% to
82%, along with 7−26% of the side products 9 (Scheme 2).
The synthetic utility of this one-pot transformation was
demonstrated by the concise syntheses of alkaloids ( )-bgu-
gaine, ( )-coniine, and (−)-cassine.
a
Isolated yield.
chemo- and stereoselective reduction. However, silane
reductants gave poor results even with a prolonged reaction
time (8 h) (entries 6−8).
Perhaps not surprisingly, we were able to apply this one-pot
reductive alkylation method to the case of amides as well
(Scheme 3). Thus, successive treatment of amide 8c with
Tf2O/DTBMP, phenylmagnesium bromide, and LiAlH4 gave
the desired amine 1l in 60% yield.
To explore the generality of reducing agents needed for this
method, we set out to screen other milder reductants or
reducing conditions. The reductive ethylation of N-benzyl-2-
pyrrolidinone 8b was selected as the model reaction for this
purpose. Successive treatment of 2-pyrrolidinone 8b (1.0
equiv) and DTBMP (1.2 equiv) with 1.0 mol equiv each of
Tf2O (−78 to 0 °C) and ethylmagnesium bromide (−78 °C to
rt) gave the presumed intermediate G, which was trapped with
different reductants to give pyrrolidine 1a (Table 1). LiAlH4
was found to give the best yield of pyrrolidine 1a (82%, entry
l). Other reductants, such as NaBH4, Hantzsch ester (HEH),
and Bu3SnH, also gave pyrrolidine 1a in ≥70% yield (entries
2−4). Notably, catalytic hydrogenation [20% Pd(OH)2/C, H2,
rt, 2 h] also furnished the desired product in 68% yield (entry
5). These results are promising because of their potentials for
With the optimized reaction conditions defined, we next
studied the stereoselectivity of the reductive alkylation. Thus,
Scheme 3. One-Pot Reductive Arylation of Amides 8c
B
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(S)-pyroglutaminol derivative 1024 was subjected to the
reductive ethylation conditions (Scheme 4), which produced
diastereoselectivity of 20:1 (entry 5). The 2,6-cis stereo-
chemistry of compound 14a was confirmed by NOESY
experiments.
Scheme 4. 1,3-Asymmetric Induction in the One-Pot
Reductive Ethylation of Lactam 10
A plausible rationale for the stereochemical outcomes in
Table 2 is depicted in Scheme 6. After Tf2O-activated Grignard
reagent addition, an iminium ion intermediate is generated,
which may exist as conformer M1 or M2. Because of the
stereoelectronic effects, the down-face attack of a hydride on
conformer M1 will lead to the formation of the chair conformer
M3, which is favored over the up-face attack, leading to an
unfavorable twisted boat conformer. For the same reason, up-
face attack of a hydride on conformer M2 is favored over the
down-face attack. The relative stability of the transition states
leading to M3 and M4 depends on the competing A1,2-
interaction (between the Me and PMB groups) in conformer
M1 and A1,3-interaction (between Me and the approaching
hydride) in conformer M2. For reactive hydride donors LiAlH4,
NaBH4, and Bu3SnH, the A1,3-interaction between a neat
hydride (a small nucleophile) and the methyl group is less
important compared to the A1,2-interaction in conformer M1,
resulting in the formation of 2,6-trans-diastereomer 14b as the
major diastereomer. In contrast, for the less-polarized reductant
Et3SiH, a severe A1,3-interaction exists between Me and the
incoming Et3SiH in conformer M2. This favors the
predominant down-face hydride attack on conformer M1,
resulting in diastereomer 14a. Under the Pd(OH)2/C-catalyzed
conditions, the adsorbed H2 on the Pd(OH)2/C surface
becomes even more hindered, and attacks exclusively on
conformer M1. This results in the formation of 2,6-cis-
diastereomer 14a in excellent diastereoselectivity.
the desired pyrrolidine 11 and its diastereomer with a dr = 6:1
(determined by 1H NMR analysis of the crude reaction
mixture) in a combined yield of 73%. NOESY experiments (cf.
the Supporting Information) established a 2,5-cis-stereo-
chemistry for the major diastereomer 11. This demonstrated
that reductive alkylation proceeds with a good 1,3-asymmetric
induction, with the hydride approaching the iminium
intermediate (cf. G in Table 1) from the opposite face of the
existing substituent on the pyrrolidine ring.
To demonstrate the power of this direct reductive alkylation
method, the synthesis of (−)-morusimic acid D (7)7 was
envisaged. Although this alkaloid has been synthesized from our
laboratory, the previous approach is lengthy, 10 steps required
for the transformation of lactam 12 to (−)-morusimic acid D
(7) (Scheme 5).25 A combination of the present direct
reductive alkylation method with Noyori catalytic asymmetric
hydrogenation26 allowed shortening the synthetic routes by five
steps.
Scheme 5. Previous Approach to (−)-Morusimic Acid D
To pursuing the synthesis of (−)-morusimic acid D, silyl
ether 14a was treated with the Br2/PPh3 complex,27 which gave
the bromide 15 in 82% yield (Scheme 7). Reacting 15 with the
dianion generated in situ from benzyl 3-oxobutanoate produced
16 in 73% yield. The Noyori catalytic asymmetric hydro-
genation26 of the HCl salt of 16 produced β-hydroxy ester 17
as the sole diastereomer in 73% yield. The stereochemistry of
the newly formed chiral center was confirmed by its conversion
into (−)-morusimic acid D. Pd(OH)2/C-catalyzed hydro-
genolysis of 17 under H2 (6 atm) at rt for 24 h afforded
(−)-morusimic acid D (7) {[α]2D0 = −13.9 (c 0.25, MeOH); lit.7
The synthesis of (−)-morusimic acid D (7) commenced with
the reductive alkylation of piperidin-2-one 12.25 Successive
treatment of 12 with Tf2O/DTBMP, Grignard reagent 13, and
LiAlH4, or NaBH4 or Bu3SnH, gave piperidine 14a in
disappointing diastereoselectivities (Table 2, entries 1−3).
The use of milder reductant Et3SiH led to an improved ratio of
11:1 but in only 32% yield (entry 4). To our delight, under the
catalytic hydrogenation conditions [20% Pd(OH)2/C, H2, rt, 2
h], the desired piperidine 14a was obtained in 60% yield with a
[α]2D0 = −14.6 (c 0.25, MeOH)} in 85% yield. The 1H and 13
C
NMR spectral data of our synthetic product are in good
agreement with those reported.7
Table 2. Influence of the Reductants on the Reductive Alkylation of Piperidin-2-one 12
a
b
entry
reductant [H]
product (% yield)
dr (14a/14b)
1
2
3
4
5
LiAlH4 (3.0 equiv), 0 °C, 1 h
NaBH4 (3.0 equiv), 0 °C, 1 h
Bu3SnH (3.0 equiv), 0 °C, 1 h
Et3SiH (10.0 equiv), rt, 24 h
20% Pd(OH)2/C, H2, rt, 2 h
75
71
67
32
60
1:1.4
1:1.5
1:2
11:1
20:1
a
b
1
Isolated yield. Determined by H NMR.
C
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Scheme 6. Plausible Stereochemical Courses of the Reductive Alkylation Reaction of Lactam 12
titrated before use.28 All other commercially available compounds were
used as received.
Scheme 7. Improved Stereoselective Synthesis of
(−)-Morusimic Acid D
1-Benzyl-2-ethylpyrrolidine (1a). Tf2O (101 μL, 0.60 mmol)
was added dropwise to a cooled (−78 °C) solution of lactam 8b (88
mg, 0.50 mmol) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 123
mg, 0.60 mmol) in CH2Cl2 (5 mL). The resultant mixture was allowed
to warm to 0 °C over 1 h. After being cooled to −78 °C, a solution of
ethylmagnesium bromide (0.44 M, 1.14 mL, 0.50 mmol) in Et2O was
added dropwise. The mixture was allowed to warm slowly to rt and
stirred for 1 h. LiAlH4 (57 mg, 1.50 mmol) was then added in one
portion at 0 °C. After being stirred for 1 h, the reaction was quenched
by careful addition of a 20% NaOH solution. The mixture was filtered,
and the solid was washed with CH2Cl2. The filtrate was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (eluent:
EtOAc/n-hexane = 1/20) to afford pyrrolidine 1a (106 mg, yield:
82%) as a colorless oil. IR (KBr) 3062, 3028, 2961, 2926, 2854, 1495,
1
1455, 1380, 1029, 747, 670 cm−1; H NMR (400 MHz, CDCl3) δ =
0.93 (dd, J = 7.5, 7.5 Hz, 3H), 1.35 (ddq, J = 13.3, 9.0, 7.5 Hz, 1H),
1.45−1.56 (m, 1H), 1.58−1.84 (m, 2H), 1.78 (dqd, J = 13.3, 7.5, 2.9
Hz, 1H), 1.87−1.98 (m, 1H), 2.12 (dd, J = 16.8, 9.2 Hz, 1H), 2.29
(ddd, J = 16.8, 8.2, 3.3 Hz, 1H), 2.92 (ddd, J = 9.0, 7.8, 2.9 Hz, 1H),
3.18 (d, J = 12.9 Hz, 1H), 4.04 (d, J = 12.9 Hz, 1H), 7.21−7.35 (m,
5H) ppm; 13C NMR (100 MHz, CDCl3) δ = 10.4, 21.8, 26.5, 29.8,
54.2, 58.5, 65.8, 126.8, 128.1 (2C), 129.0 (2C), 139.5 ppm; MS (ESI)
m/z 190 (M + H+, 100%); Anal. Calcd for C13H19N: C, 82.48; H,
10.12; N, 7.40. Found: C, 82.57; H, 10.17; N, 7.37.
N,N-Dibenzyl-1-phenylpentan-1-amine (1l). Following the
procedure described for the synthesis of compound 1a, the reductive
alkylation of amide 8c (281 mg, 1.00 mmol) with phenylmagnesium
bromide and LiAlH4 gave, after flash chromatography on silica gel
(eluent: EtOAc/n-hexane = 1/100), amine 1l (343 mg, yield: 60%) as
a colorless oil. IR (KBr) 3061, 3026, 2954, 2929, 2858, 1493, 1453,
1028, 744, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ = 0.85 (t, J = 7.2
Hz, 3H), 1.18−1.43 (m, 2H), 1.72−1.84 (m, 1H), 1.98−2.09 (m, 1H),
3.15 (d, J = 13.8 Hz, 2H), 3.66 (dd, J = 7.4, 7.4 Hz, 1H), 3.81 (d, J =
13.8 Hz, 2H), 7.18−7.41 (m, 15H) ppm; 13C NMR (100 MHz,
CDCl3) δ = 14.0, 22.7, 29.1, 30.2, 30.9, 53.7 (2C), 61.8, 126.7 (2C),
126.9, 127.9 (2C), 128.2 (4C), 128.7 (4C), 129.0 (2C), 139.3, 140.5
(2C) ppm; MS (ESI) m/z 344 (M + H+, 100%); HRESIMS calcd for
[C25H30N]+ (M + H+) 344.2373, found 344.2376.
CONCLUSION
■
In summary, we have developed a general method for the direct
reductive alkylation of lactams/amides to give sec-alkylamines.
A number of Grignard reagents and several reductants or
reducing conditions can be used for this one-pot reductive
alkylation reaction, which displayed good to excellent 1,3-
asymmetric induction in cyclic systems. By combining this
method with Noyori catalytic asymmetric hydrogenation, we
achieved a highly efficient five-step stereoselective synthesis of
(−)-morusimic acid D from lactam 12. The use of Et3SiH as a
mild and highly diastereoselective reductant, and that of
catalytic hydrogenation conditions, found a basis for expanding
this method to a catalytic enantioselective methodology.
EXPERIMENTAL SECTION
■
Unless otherwise stated, reactions were performed in oven-dried
glassware under a nitrogen atmosphere. Dichloromethane was distilled
over calcium hydride under a nitrogen atmosphere. THF was distilled
over sodium benzophenone ketyl under a nitrogen atmosphere. Silica
gel (300−400 mesh) was used for flash column chromatography,
eluting with ethyl acetate (EtOAc)/n-hexane. Melting points were
uncorrected. Infrared spectra were measured using film KBr pellet
(2S,5S)-1-Benzyl-2-ethyl-5-(methoxymethyl)pyrrolidine (11).
Following the procedure described for the synthesis of compound 1a,
the reductive alkylation of lactam 1024 (219 mg, 1.00 mmol) with
ethylmagnesium bromide and LAH gave, after flash chromatography
on silica gel (eluent: EtOAc/n-hexane = 1/100), pyrrolidine 11 and its
diastereomer (dr = 6/1, determined by 1H NMR of the crude
product) in a combined yield of 73%. 11: colorless oil; [α]2D0 +4.6 (c
1.0, CHCl3); IR (KBr) 3062, 3027, 2959, 2925, 2873, 2854, 1494,
1
techniques. H and 13C NMR spectra were recorded at 400 and 100
MHz, respectively. Mass spectra were obtained using electrospray
ionization and an FT-ICR analyzer (ESI-MS) for high-resolution mass
spectra (HRMS). Tf2O was distilled over phosphorus pentoxide and
was stored for use within a week. All the Grignard reagents were
1
1454, 1115, 746, 699 cm−1; H NMR (400 MHz, CDCl3) δ = 0.83
(dd, J = 7.4, 7.4 Hz, 3H), 1.14−1.89 (m, 4H), 2.53−2.62 (m, 1H),
D
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2.86−2.95 (m, 1H), 3.02−3.14 (m, 2H), 3.20 (s, 3H), 3.71 (d, J = 14.0
Hz, 1H), 3.88 (d, J = 14.0 Hz, 1H), 7.19−7.35 (m, 5H) ppm; 13C
NMR (100 MHz, CDCl3) δ = 10.5, 27.4, 27.7, 29.1, 29.7, 57.9, 58.9,
64.0, 67.0, 65.8, 126.6, 128.0 (2C), 129.0 (2C), 140.5 ppm; MS (ESI)
m/z 234 (M + H+, 100%); HRESIMS calcd for [C15H24NO]+ (M +
H+) 234.1852, found 234.1853.
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
EtOAc/n-hexane = 1/2) to afford compound 16 (69 mg, yield: 73%)
as a colorless oil. [α]2D0 −24.2 (c 1.0, CHCl3); IR (KBr) 2927, 2854,
1
2854, 1744, 1716, 1510, 1454, 1243, 1096, 737, 697 cm−1; H NMR
(2S,3R,6R)-3-(Benzyloxy)-6-[8-(tert-butyldimethylsilyloxy)-
octyl]-1-(4-methoxybenzyl)-2-methylpiperidine (14a). Tf2O
(101 μL, 0.60 mmol) was added dropwise to a cooled (−78 °C)
solution of the known lactam 1225 (170 mg, 0.50 mmol) and 2,6-di-
tert-butyl-4-methylpyridine (123 mg, 0.60 mmol) in CH2Cl2 (5 mL),
and the resultant mixture was allowed to warm to 0 °C over 1 h. After
being cooled to −78 °C, a solution of freshly prepared Grignard
reagent 13 (0.30 M in THF, 1.67 mL, 0.50 mmol) was added dropwise
to the resultant mixture. The mixture was allowed to warm slowly to
room temperature and stirred for 1 h. The resulting mixture was
concentrated under reduced pressure to give a residue, which, without
further purification, was dissolved in EtOAc (1 mL) and hydro-
genolyzed in the presence of 20% Pd(OH)2/C (80 mg) under a
hydrogen atmosphere (1 atm, balloon) at room temperature for 2 h.
The mixture was concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (eluent: EtOAc/n-
hexane = 1/10) to afford compound 14a (170 mg, yield: 60%) (dr =
(400 MHz, CDCl3) δ 1.21 (d, J = 6.2 Hz, 3H), 1.16−1.81 (m, 19H),
2.12−2.21 (m, 1H), 2.40−2.48 (m, 1H), 2.48 (t, J = 7.3 Hz, 2H), 2.62
(dq, J = 8.6, 6.2 Hz, 1H), 3.13 (ddd, J = 8.7, 8.6, 4.4 Hz, 1H), 3.46 (s,
2H), 3.71 (d, J = 16.4 Hz, 1H), 3.75 (d, J = 16.4 Hz, 1H), 3.77 (s, 3H),
4.45 (d, J = 11.5 Hz, 1H), 4.61 (d, J = 11.5 Hz, 1H), 5.16 (s, 2H), 6.81
(d, J = 8.6 Hz, 2H), 7.23−7.35 (m, 12H) ppm; 13C NMR (100 MHz,
CDCl3) δ 17.7, 23.4, 26.4, 27.4, 28.9 (2C), 29.2, 29.3, 29.4, 29.8, 34.3,
43.0, 49.2, 51.5, 52.2, 61.3, 61.6, 70.7, 79.0, 113.3 (2C), 127.4, 127.6
(2C), 128.1, 128.2 (2C), 128.3 (2C), 128.4, 128.5 (2C), 128.8 (2C),
135.3, 138.9, 158.0, 167.0, 202.6 ppm; MS (ESI) m/z 628 (M + H+,
100%); HRESIMS calcd for [C40H54NO5]+ (M + H+) 628.3997, found
628.4001.
Benzyl (R)-12-[(2R,5R,6S)-5-(Benzyloxy)-1-(4-methoxyben-
zyl)-6-methylpiperidin-2-yl]-3-hydroxydodecanoate (17). Prep-
aration of the HCl salt of compound 16: acetyl chloride (0.2 mL) was
added at 0 °C to MeOH (2 mL), and the mixture was stirred at 0 °C
for 5 min. Compound 16 (63 mg, 0.10 mmol) was added. After being
stirred at rt for 30 min, the solvent was evaporated. The crude oily
product was used in the next step.
20/1, determined by H NMR) as a colorless oil. [α]2D0 −13.8 (c 1.0,
1
CHCl3); IR (KBr) 2928, 2855, 1511, 1463, 1248, 1098, 835, 775
cm−1; 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.92 (s, 9H), 1.24
(d, J = 6.3 Hz, 3H), 1.15−1.83 (m, 17H), 2.14−2.23 (m, 1H), 2.43−
2.52 (m, 1H), 2.66 (dq, J = 8.4, 6.3 Hz, 1H), 3.10−3.21 (m, 1H), 3.61
(t, J = 6.5 Hz, 2H), 3.75 (d, J = 14.7 Hz, 1H), 3.79 (d, J = 14.7 Hz,
1H), 3.81 (s, 3H), 4.49 (d, J = 11.6 Hz, 1H), 4.65 (d, J = 11.6 Hz, 1H),
6.85 (d, J = 8.7 Hz, 2H), 7.26−7.39 (m, 7H) ppm; 13C NMR (100
MHz, CDCl3) δ 5.3 (2C), 17.7, 18.4, 25.8, 26.0 (3C), 26.5, 27.5, 29.0,
29.4, 29.6, 29.9, 32.9, 34.3, 51.6, 55.2, 61.3, 61.6, 63.3, 70.8, 79.1, 113.3
(2C), 127.4, 127.7 (2C), 128.3 (2C), 128.9 (2C), 134.0, 128.9, 158.0
ppm; MS (ESI) m/z 568 (M + H+, 100%); HRESIMS calcd for
[C35H58NO3Si]+ (M + H+) 568.4180, found 568.4187.
A vial containing the HCl salt of compound 16 (63 mg, 0.10 mmol)
and catalyst [(R)-BINAP]RuCl2 (4 mg, 0.005 mmol, 5 mol %) in
MeOH (2 mL) was placed in an autoclave. After being purged with
hydrogen for 5 min, the pressure of hydrogen was raised to 6 atm, and
the mixture was stirred at 65 °C for 4 h. The reaction was then
stopped, and the mixture was diluted with CH2Cl2 (5 mL). The
resulting mixture was passed through a pad of silica gel, and the
collected solution was concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
EtOAc/n-hexane = 1/1) to afford compound 17 (46 mg, yield: 73%)
as a colorless oil. [α]2D0 −24.8 (c 1.0, CHCl3); IR (KBr) 3436, 2927,
(2S,3R,6R)-3-(Benzyloxy)-6-(8-bromooctyl)-1-(4-methoxy-
benzyl)-2-methylpiperidine (15). Bromine (31 μL, 0.60 mmol)
was added to a cooled (0 °C) solution of Ph3P (157 mg, 0.60 mmol)
in CH2Cl2 (6 mL). After being stirred at rt for 20 min, a solution of
compound 14a (227 mg, 0.40 mmol) in CH2Cl2 (2 mL) was added,
and the resultant mixture was stirred at rt for 30 min. The reaction was
quenched with water (5 mL), and the mixture was extracted with
dichloromethane (3 × 5 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (eluent: EtOAc/n-hexane = 1/5) to afford bromide 15 (170 mg,
yield: 82%) as a colorless oil. [α]2D0 −22.1 (c 1.0, CHCl3); IR (KBr)
1
2853, 1736, 1511, 1455, 1245, 1096, 737, 697 cm−1; H NMR (400
MHz, CDCl3) δ 1.21 (d, J = 6.3 Hz, 3H), 1.10−1.84 (m, 21H), 2.11−
2.21 (m, 1H), 2.40−2.48 (m, 1H), 2.45 (dd, J = 16.4, 9.0 Hz, 1H),
2.55 (dd, J = 16.4, 3.2 Hz, 1H), 2.62 (dq, J = 8.5, 6.3 Hz, 1H), 2.86 (br
s, 1H, D2O exchangeable), 3.13 (ddd, J = 8.7, 8.5, 4.3 Hz, 1H), 3.72 (d,
J = 13.4 Hz, 1H), 3.75 (d, J = 13.4 Hz, 1H), 3.78 (s, 3H), 3.97−4.05
(m, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 11.6 Hz, 1H), 5.15 (s,
2H), 6.81 (d, J = 8.7 Hz, 2H), 7.23−7.38 (m, 12H) ppm; 13C NMR
(100 MHz, CDCl3) δ 17.7, 25.4, 26.4, 27.4, 29.0, 29.4, 29.5, 29.5, 29.5,
29.9, 34.3, 36.5, 41.4, 51.6, 55.2, 61.3, 61.6, 66.4, 68.0, 70.8, 79.1, 113.3
(2C), 127.4, 127.7 (2C), 128.2 (2C), 128.3 (2C), 128.3, 128.6 (2C),
128.8 (2C), 134.0, 135.6, 138.9, 158.0, 172.8 ppm; MS (ESI) m/z 630
(M + H+, 100%); HRESIMS calcd for [C40H56NO5]+ (M + H+)
630.4153, found 630.4157.
(R)-3-Hydroxy-12-[(2R,5R,6S)-5-hydroxy-6-methylpiperidin-
2-yl]dodecanoic Acid, (−)-Morusimic Acid D (7). A suspension of
17 (35 mg, 0.06 mmol) and 20% Pd(OH)2/C (15 mg) in MeOH (2
mL) was stirred under a hydrogen atmosphere (6 atm) at room
temperature for 24 h. After the catalyst was filtered off, the filtrate was
concentrated under reduced pressure, affording compound 7 (14 mg,
yield: 85%) as a white solid. mp 230 °C (decomposed); [α]2D0 −13.9 (c
0.25, MeOH) {lit.7 [α]D20 −14.6 (c 0.25, MeOH)}; IR (KBr) 3381,
2924, 2851, 1566, 1415, 1342, 1066 cm−1; 1H NMR (400 MHz,
CD3OD) δ 1.37 (d, J = 6.3 Hz, 3H), 1.28−1.52 (m, 17H), 1.64−1.72
(m, 1H), 2.02 (d, J = 12.4 Hz, 1H), 2.08 (d, J = 12.4 Hz, 1H), 2.20−
2.41 (m, 2H), 2.80−2.90 (m, 1H), 2.92−3.02 (m, 1H), 3.36−3.42 (m,
1H), 3.84−3.96 (m, 1H) ppm; 13C NMR (100 MHz, CD3OD) δ 16.5,
26.5, 26.6, 29.1, 30.3, 30.3, 30.4, 30.4, 30.5, 33.4, 34.9, 38.1, 45.4, 58.1,
59.2, 70.4, 71.6, 180.5 ppm; MS m/z (ESI) 330 (M + H+, 100%);
HRESIMS calcd for [C18H36NO4]+ (M+H+) 330.2639, found
330.2633.
1
3064, 3025, 2929, 2854, 1510, 1454, 1243, 735, 698 cm−1; H NMR
(400 MHz, CDCl3) δ 1.21 (d, J = 6.3 Hz, 3H), 1.18−1.60 (m, 14H),
1.74−1.85 (m, 3H), 2.12−2.20 (m, 1H), 2.40−2.49 (m, 1H), 2.63 (dq,
J = 8.4, 6.3 Hz, 1H), 3.09−3.17 (m, 1H), 3.38 (t, J = 6.8 Hz, 2H), 3.71
(d, J = 14.8 Hz, 1H), 3.75 (d, J = 14.8 Hz, 1H), 3.78 (s, 3H), 4.45 (d, J
= 11.5 Hz, 1H), 4.61 (d, J = 11.5 Hz, 1H), 6.81 (d, J = 8.7 Hz, 2H),
7.26−7.36 (m, 7H) ppm; 13C NMR (100 MHz, CDCl3) δ 17.7, 26.3,
27.4, 28.0, 28.6, 28.9, 29.3, 29.7, 32.7, 33.9, 34.2, 51.6, 55.2, 61.3, 61.6,
70.7, 78.9, 113.3 (2C), 127.4, 127.6 (2C), 128.2 (2C), 128.8 (2C),
133.9, 138.8, 158.0 ppm; MS (ESI) m/z 516 (M + H+, 100%);
HRESIMS calcd for [C29H43BrNO2]+ (M + H+) 516.2472, found
516.2456.
Benzyl 12-[(2R,5R,6S)-5-(Benzyloxy)-1-(4-methoxybenzyl)-6-
methylpiperidin-2-yl]-3-oxododecanoate (16). To a cooled (0
°C) suspension of NaH (13 mg, 0.33 mmol) in THF (1 mL) under N2
was added a solution of benzyl acetoacetate (58 mg, 0.30 mmol) in
THF (1 mL). The resultant mixture was stirred at 0 °C for 30 min
before n-BuLi (0.12 mL, 0.30 mmol) was added dropwise. After being
stirred at 0 °C for 30 min, a solution of 15 (78 mg, 0.15 mmol) in
THF (1 mL) was added, and the mixture was warmed to rt and stirred
for 1 h. The reaction was then quenched with a saturated NH4Cl
solution (3 mL) and extracted with dichloromethane (3 × 3 mL). The
E
dx.doi.org/10.1021/jo4007656 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Matute, R. Heterocycles 2012, 84, 75−100. (j) Cochi, A.; Pardo, D. G.;
Cossy, J. Heterocycles 2012, 86, 89−116.
ASSOCIATED CONTENT
■
S
* Supporting Information
(9) For selected examples, see: (a) Randl, S.; Blechert, S. J. Org.
Chem. 2003, 68, 8879−8882. (b) Pu, X. T.; Ma, D. W. Angew. Chem.,
Int. Ed. 2004, 43, 4222−4225. (c) Leverett, C. A.; Cassidy, M. P.;
Padwa, A. J. Org. Chem. 2006, 71, 8591−8601. (d) Coombs, T. C.;
Lee, M. D.; Wong, H.; Armstrong, M.; Cheng, B.; Chen, W.; Moretto,
A. F.; Liebeskind, L. S. J. Org. Chem. 2008, 73, 882−888. (e) Shengule,
S. R.; Willis, A.; Pyne, S. G. Tetrahedron 2012, 68, 1207−1215.
(10) For selected examples of the direct reductive alkylation of
bicyclic lactams, see: (a) Liotta, D.; Saindane, M.; Sunay, U.; Jamison,
W. C. L.; Grossman, J.; Phillips, P. J. Org. Chem. 1985, 50, 3243−3245.
(b) Watanabe, Y.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989, 54,
4088−4097. (c) Comins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett.
2002, 4, 1611−1613.
1H and 13C NMR spectra of all new compounds and NOESY
spectra of compounds 11 and 14a. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pqhuang@xmu.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) An unsuccessful attempt for a reductive alkylation of a simple
monocyclic lactam (N-methyl-2-piperidinine) has been noted in ref
10b. Successful examples with N-, and O-containing substrates have
been reported: (a) Shibagaki, M.; Matsushita, H.; Kaneko, H.
Heterocycles 1986, 24, 2315−2319. (b) Micouin, L.; Quirion, J.-C.;
Husson, H.-P. Tetrahedron Lett. 1996, 37, 849−852. (c) Sancibrao, P.;
Karila, D.; Kouklovsky, C.; Vincent, G. J. Org. Chem. 2010, 75, 4333−
The authors are grateful for financial support from the National
Basic Research Program (973 Program) of China (Grant No.
2010CB833200), the NSF of China (21072160; 20832005),
and the Program for Changjiang Scholars and Innovative
Research Team in University (PCSIRT) of the Ministry of
Education, China. We are indebted to Professor Dr. Linfeng
Xie (University of Wisconsin Oshkosh/Xiamen University) for
his valuable contribution.
4336.
For the only known example of the direct reductive
methylation/arylation of unfunctionalized substrates, see: (d) Hwang,
Y. C.; Chu, M.; Fowler, F. W. J. Org. Chem. 1985, 50, 3885−3890.
For a one-pot reductive alkynylation using alkynyl boranes, see:
(e) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 1719−1722.
(12) For a direct transformation via partial reduction−vinylation, see:
(a) Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.; Koo, B.-
A.; Kim, H.-S. Angew. Chem., Int. Ed. 1999, 38, 3545−3547. For a
hydroxylated substrate, see: (b) Amat, M.; Llor, N.; Hidalgo, J.;
Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919−1928.
(13) For reductive alkylation and cyanation of N-alkoxyamides, see:
(a) Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew. Chem., Int.
Ed. 2010, 49, 6369−6372. (b) Vincent, G.; Guillot, R.; Kouklovsky, C.
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DEDICATION
■
Dedicated to Professor Guo-Qiang Lin on the occasion of his
70th Birthday.
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