Total synthesis of newbouldine via reductive N-N bond formation

Article abstract of DOI:10.1016/j.tet.2010.05.085

The first total synthesis of newbouldine has been achieved employing a new, reductive N-N bond forming reaction. The asymmetric synthesis confirms that the natural product is a racemate.

Full text of DOI:10.1016/j.tet.2010.05.085

Tetrahedron 66 (2010) 6626e6631
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of newbouldine via reductive NeN bond formation
*
Michael Pangerl, Chambers C. Hughes, Dirk Trauner
€
Department of Chemistry, Ludwig-Maximilians-Universitat München, Butenandtstrasse 5-13, 81377 Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of newbouldine has been achieved employing a new, reductive NeN bond
forming reaction. The asymmetric synthesis confirms that the natural product is a racemate.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 March 2010
Received in revised form
11 May 2010
Accepted 21 May 2010
Available online 26 May 2010
Keywords:
Newbouldine
Natural product synthesis
NeN bond
Hydrazone
Amathaspiramide F
1. Introduction
migraine, earache, conjunctivitis, and various forms of orchitis.13
A crude extract of these alkaloids has been shown to exhibit
Natural products that contain an NeN bond are relatively
scarce.1 An intriguing representative of this class is keramamine B
(1, Fig. 1), which contains three contiguous nitrogen atoms as part
of a six-membered ring.2 Elaiomycin (2) belongs to a small family of
natural products containing the unusual azoxy functionality,3e5
whereas himastatin (3) is a striking example of a natural product
featuring the more common piperazic acid moiety.6 Very recently,
dentigerumycin (4), a bacterial mediator of ant-fungus symbiosis
containing three piperazic acid units, was disclosed by Clardy et al.7
Naturally occurring hydrazones are even less common and few
examples have to date been described. These include the optically
active tricyclichydrazone cinachyramine(5), whichwasisolatedfrom
the Okinawan sponge Cinachyrella sp. Its absolute stereochemistry
has not yet been defined.8 The unusual antibiotic NG-067 (6) features
the hydrazone functionality as part of a quinone imine system.9
Another family of alkaloids containing the hydrazone moiety
is represented by the molecule newbouldine (7), originally iso-
lated from the West African tree Newbouldia laevis together with
its 40-hydroxy- and 40-methoxy derivatives 8 and 9, as well as
withasomnine (10), 40-hydroxywithasomnine (11) and 40-
methoxywithasomnine (12).10,11 The root bark of N. leavis is used
for a wide variety of ethnomedicinal purposes,12 such as the
treatment of enlarged spleen, dysentery, worm infestations,
potent neurological effects.14
In terms of their structure, the newbouldines (7e9) and the
withasomnines (10e12) differ in the extent of saturation of the
five-membered heterocyclic ring. The latter contain a pyrazole
unit as part of a bicyclic system, whereas the former feature a non-
aromatic pyrazoline, thus giving rise to two stereogenic centers.
Remarkably, none of the pyrazoline natural products are opti-
cally active, suggesting the racemic nature of their biosynthesis.
This is all the more remarkable as the newbouldines (7e9) are
presumably derived from the amino acids proline, phenylalanine,
and tyrosine, respectively. It can also be assumed that the NeN
bonds in these natural products are formed via oxidative processes,
which have been suggested in other biosynthetic pathways.15e18
Although a number of chemical syntheses of withasomnine (10)
havebeen reported,19e27 onlyone of them has exploited an oxidative
NeN bond formation methodology.27 In contrast, no total syntheses
of newbouldines (7e9) have thus far been disclosed. We now report
a short and efficient synthesis of 7, which was fashioned by a re-
ductive hydrazone formation, previously developed in our
laboratories.
Our new method was discovered during a total synthesis of
amathaspiramide F (20), shown in Scheme 1.28 Its key step was
a highly stereoselective alkylation of oxazolidinone 13 with nitro-
olefin 14 to yield nitroalkane 15. This was followed by hydrolysis of
the aminal function in 15 to yield secondary amine 16 and then by
protection to afford trifluoroacetimidate 17. Subsequent formation
* Corresponding author. Fax: þ49 89218077972; e-mail address: dirk.trauner@
cup.uni-muenchen.de (D. Trauner).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.085

M. Pangerl et al. / Tetrahedron 66 (2010) 6626e6631
6627
N
OH
H
O
N
H
N
H
N
HN
HO
HN
H
N
N
H
O
O
HO
O
O
HO
OMe
OH
HO
O
O
O
O
N
O
O
O
O
N
n-C6H13
N
N
N
OH
OH
N
H
O
N
N
H
H
NH
N
N
NH
N
H
1
O
N
3
OH
2
R
HO
Me
O
N
OH
O
H
N
N
N
N
NH HN
N
R
N
N
N
5
O
withasomnine: R = H, 10
7
newbouldine (
)
HO
Me
O
O
O
O
O
O
11
4'-hydroxywithasomnine: R = OH (
4'-methoxywithasomnine: R = OMe (
)
12
N
Me
H
)
MeO
H
O
NH
N
N
N
N
N
HN
N
HN
O
8
4'-hydroxynewbouldine: R = OH (
)
Me
4'-methoxynewbouldine: R = OMe (9)
4
6
Figure 1. A selection of NeN bond containing natural products.
of oxime 18 under mildly reductive conditions and an unusual
hydrolysis in the presence of IBX then gave spiroheterobicyclic
intermediate 19. In the final step, reductive cleavage of the amide
provided the natural product 20. Full details of this total synthesis
are reported in the Experimental section.
chloride. Instead of the desired process, however, an
unprecedented reductive NeN bond formation took place, affording
bicyclic pyrazoline 21 in modest yield (Scheme 2).28 The X-ray
structure of 21 is shown in Figure 2. It did not escape our notice that
compound 21 contained the core 3-phenyl-tetrahydro-3H-pyrrolo-
pyrazole framework of the newbouldines, albeit with the wrong
relative configuration of the aryl ring-bearing stereocenter.
Br
Br
NO2
O
O
1) t-BuLi, HMPA,
H
N
MeO
then TBSCl
Br
MeO
NMe
NMe
Br
Br
N
14
2)
→ MgBr2•OEt2
NO2
O
O
NaOMe
→TiCl3, H2O
(72 %)
MeHN
MeO
Br
MeO
Br
NO2
13
15
(40 %)
NHMe
N
NH
16
N
Br
Br
14
21
Br
Br
Scheme 2. Discovery of a reductive NeN bond formation method.
NO2
O
Br
NO2
O
TFAA MeO
(quant.)
1) 4 M H2SO4
MeO
NHMe
O
2) MeOH
(73 %)
N
NHMe
NH
16
F3C
17
Br
Br
Br
OH
Br
N
OH
MeO
IBX
O
MeO
NMe
SnCl2, PhSH, Et3N
(84 %)
NHMe
O
N
N
(65 %)
O
O
18
19
F3C
F3C
Br
MeO
Br
OH
NMe
LiBH4
(80 %)
NH
O
20
amathaspiramide F (
)
Scheme 1. Total synthesis of amathaspiramide F (20).
As part of this work, we investigated ways to convert nitroalkane
intermediate 16 directly to the natural product 29 via Nef reaction.
More specifically, it wasanticipated thatthedesired product couldbe
obtained upon treatment with sodium methoxide and titanium(III)
Figure 2. X-ray crystal structure of tetrahydro-3H-pyrrolo-pyrazole 21.

6628
M. Pangerl et al. / Tetrahedron 66 (2010) 6626e6631
Table 1
2. Results and discussion
NMR data of natural and synthetic 7
4'
2
3'
3
Having made the keydiscovery that the TiCl3-mediated reductive
reaction process can provide quick access to the newbouldine skel-
eton, we decided to launch a synthesis of the natural product. To
confirm the racemic nature of 7, which had only been indicated by
the lack of a detectable optical rotation, we chose to carry out this
synthesis in an asymmetric fashion (Scheme 3). It started from
known N-Boc-(S)-prolinal (22),29 which was converted into nitro-
olefin 24 using an established procedure.30 Nucleophilic attack of
deprotonated nitromethane onto aldehyde 22 gave nitroalcohol 23,
and subsequent elimination provided the desired nitroolefin 24 in
high yield. The phenyl ring was installed using a cuprate conjugate
addition, which gave the desired 3-amino nitroalkane 25a together
with 25b as a 2:1 mixture of diastereoisomers. Although careful
optimization of the reaction conditions resulted in a good yield
(81%), the stereoselectivity of the conjugate addition could not be
further improved.
5'
6'
2'
1'
H
4
3a
5
N
N
6
1
Position
Natural 7
Synthetic 7
1H
13C
1H
13C
2
3
3a
4
6.82 br s
4.05 br s
3.68 m
147.0
61.1
71.4
31.4
6.84 br s
4.00 br s
3.72e3.64 m
147.0
61.0
71.2
31.2
a
b
2.00 m
1.56 m
a
b
2.03e1.95 m
1.59e1.55 m
5
6
1.70 m
3.69 m
3.17 m
23.9
53.6
1.74e1.67 m
3.72e3.64 m
3.23e3.16 m
23.7
53.5
10
140.5
127.3
129.0
127.4
140.3
127.1
128.9
127.3
20, 60
30, 50
40
H
O
H
H
OH
NO2
7.34e7.26 m
7.36e7.21 m
KOH, MeNO2
(90 %)
N
N
Boc
Boc
22
23
It is also interesting to speculate on the mechanism of the key
NeN bond formation (Scheme 4). According to McMurry, reduction
of the nitro group in 25a would initially lead to a nitroso compound
(27).32 Instead of the usual hydrolysis, however, intermediate 27
coordinates to a Lewis-acidic titanium(IV) species generated in the
previous step (/28) and thus gets activated toward intramolecular
nucleophilic attack of the nearby secondary amine. This would
result in NeN bond formation to afford intermediate 29, which
then undergoes elimination of a Ti(IV) oxo species under the
strongly basic reaction conditions to yield the final product 7.
H
MeSO2Cl, Et3N
(95 %)
N
NO2
Boc
24
PhBr, n-BuLi,
Cu(CN)•LiCl (2.5 mol%)
H
H
+
(81%)
N
NO2
N
NO2
Boc
Boc
25a
(2:1)
25b
NaOMe
→ TiCl3, H2O
H
H
TFA, PhSMe
MeOH, NaOMe
TiCl3, H2O
H
H
25a
N
(30 %)
(quant.)
O
N
H
N
NO2
N
H
N
O
N
H
N
26
(–)-newbouldine (7)
O
25a
27
Scheme 3. Total synthesis of newbouldine (7).
Cl
HO
Cl
Ti
Cl
Deprotection of the secondary amine by treatment with TFA in
the presence of thioanisole then provided pyrrolidine 26 in quan-
titative yield, thus setting the stage for the key NeN bond formation
and the completion of the synthesis. We envisaged that the NeN
bond would be formed under the same reductive conditions as those
discovered in the amathaspiramide F synthesis. Indeed, upon
treatment with sodium methoxide and aqueous titanium(III) chlo-
ride, this reaction occurred, albeit in very low yield. Further
investigations revealed that significant amounts of material were
lost during the workup procedure, probably as a result of complex-
ation to titanium salts. Also, we found that crude product mixtures
would rapidly decompose on silica, thus making purification diffi-
cult. Finally, improved workup conditions allowed access to a single
enantiomer of the natural product (7) in modest but reproducible
yields (30%).
OMe
H
O
H
H
Cl
Ti
O
N
N
N
O
N
Cl
Ti OH
Cl
Cl
H
Cl–
29
28
H
N
N
7
newbouldine ( )
Scheme 4. Suggested mechanism for the formation of newbouldine (7).
While the NMR data of our synthetic material matched the
published data in all respects (Table 1),10 our enantiomerically pure
18
newbouldine (7) showed significant optical activity ([
(c 0.5, MeOH)) in contrast to the natural material ([
a
]
ꢀ93
3. Conclusion
D
a]
0 (c 0.7,
D
CHCl3)), thus confirming that naturally occurring newbouldine (7)
is indeed a racemate. It would certainly be worthwhile to further
investigate the biosynthetic origin of this unusual alkaloid and to
establish how the newbouldines relate to their achiral congeners,
the withasomnines.
In summary, we have described the first total synthesis of
(ꢀ)-newbouldine (7), which features an unusual key step and
proceeds in 14% overall yield. Our asymmetric synthesis confirms
that the natural product is a racemate, belying its proposed bio-
synthetic origin from presumably enantiopure amino acids (i.e.,

M. Pangerl et al. / Tetrahedron 66 (2010) 6626e6631
6629
proline and phenylalanine). Our synthetic material is currently
being tested for biological activity, the results of which will soon be
disclosed.
(5ꢁ100 mL). The combined extracts were washed with brine
(100 mL), dried over MgSO4, filtered, and concentrated. The prod-
uct was purified by column chromatography (EtOAc/hex 6:4) to
yield 16 as a white solid (290 mg, 73%): [
a]
20 ꢀ36.5 (c 1.00, CHCl3);
D
4. Experimental section
mp 146e147 ꢂC; IR (KBr): 1650, 1549, 1474, 1248; 1H NMR:
d¼7.78
(br s,1H), 7.71 (s,1H), 6.82 (s,1H), 5.36 (dd, J¼14.0,11.2 Hz,1H), 5.00
(dd, J¼14.0, 2.8 Hz, 1H), 4.23 (dd, J¼11.2, 2.8 Hz, 1H), 3.79 (s, 3H),
3.17e3.08 (m, 1H), 3.01e2.94 (m, 1H), 2.70 (d, J¼5.2 Hz, 3H),
2.34e2.24 (m, 1H), 2.00e1.85 (m, 2H), 1.81e1.61 (m, 2H); 13C NMR:
4.1. (E)-1,5-Dibromo-2-methoxy-4-(2-nitrovinyl)benzene
(14)28,34
A solution of 2,4-dibromo-5-methoxybenzaldehyde33 (5.71 g,
19.4 mmol) and ammonium acetate (6.0 g, 78 mmol) in nitro-
methane (6.1 mL) and acetic acid (19.4 mL) was heated at reflux for
0.5 h. The mixture was allowed to cool, diluted with water (300 mL)
and extracted with CH2Cl2 (3ꢁ150 mL). The combined extracts
were washed with a satd aq NaHCO3 solution (100 mL) and brine
(100 mL), dried over MgSO4, and filtered. Silica gel (150 mL) was
added and the resulting mixture was concentrated to dryness. The
product was purified by column chromatography (EtOAc/hex
1:9/1:6) to afford 14 as a yellow solid (4.22 g, 65%): mp
d
¼175.3, 156.0, 136.9, 136.7, 116.7, 112.6, 111.1, 78.6, 71.3, 56.6, 50.3,
46.9, 37.7, 26.0, 25.8; HRMS (FABþ): m/z (MþH)þ calculated for
C15H2079Br81BrN3O4: 465.9800; found: 465.9795.
4.4. (S)-2-((R)-1-(2,4-Dibromo-5-methoxyphenyl)-3-
nitropropyl)-N-methyl-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-
carboxamide (17)
To a solution of amine 16 (400 mg, 0.860 mmol) and pyridine
(0.35 mL 4.3 mmol) in CH2Cl2 (8.6 mL) at 0 ꢂC was added tri-
fluoroacetic anhydride (0.24 mL, 1.7 mmol) dropwise via syringe.
After 1 h at 0 ꢂC, the reaction was quenched with methanol
(5 mL). After an additional 2 h at room temperature, the solution
was diluted with water (100 mL) and extracted with CH2Cl2
(3ꢁ80 mL). The combined extracts were washed with water
(2ꢁ50 mL) and brine (50 mL), dried over MgSO4, filtered, and
concentrated. The product was purified by column chromatog-
168e172 ꢂC; IR (KBr): 2360, 1629, 1514, 1338; 1H NMR:
(d, J¼13.6 Hz, 1H), 7.87 (s, 1H), 7.57 (d, J¼13.6 Hz, 1H), 7.00 (s, 1H),
d¼8.30
3.94 (s, 3H); 13C NMR:
d
¼156.0, 139.2, 137.9, 137.3, 130.3, 117.4, 117.2,
110.5, 56.9; HRMS (EIþ): m/z (M)þ calculated for C9H781Br2NO3:
338.8752; found: 338.8747.
4.2. (3S,7aS)-3-tert-Butyl-7a-((R)-1-(2,4-dibromo-5-
methoxyphenyl)-3-nitropropyl)-2-methylhexahydro-1H-
pyrrolo[1,2-c]imidazol-1-one (15)
raphy (EtOAc/hex 6:4) to give 17 as a white solid (480 mg,
20
quant.): [
a]
ꢀ38.9 (c 1.00, CHCl3); mp 72e73 ꢂC; IR (film): 3019,
D
1695, 1682; 1H NMR:
d
¼7.77 (s, 1H), 6.66 (s, 1H), 6.25 (s, br, 1H)
To a solution of (3R,7aS)-3-tert-butyl-2-methylhexahydro-1H-
pyrrolo[1,2-c]imidazol-1-one (13) (235 mg, 1.19 mmol) in THF
(4.0 mL) at ꢀ78 ꢂC was added a solution of t-BuLi in pentane
(0.88 mL, 1.5 M, 1.3 mmol) dropwise using a syringe. After 10 min
5.26 (dd, J¼10.4, 3.2 Hz, 1H), 5.08 (dd, J¼14.0, 3.2 Hz, 1H), 4.87
(dd, J¼14.0, 10.4 Hz, 1H), 3.91e3.81 (m, 1H), 3.82 (s, 3H), 3.36 (m,
1H), 2.83 (d, J¼4.8 Hz, 3H), 2.53e2.42 (m, 1H), 2.32e2.21 (m, 1H),
1.90e1.76 (m, 1H), 1.62e1.50 (m, 1H); 13C NMR:
d
¼169.5, 157.6 (q,
at ꢀ78 ꢂC, HMPA (250
mL, 1.44 mmol) was added and the solu-
J¼37 Hz), 156.1, 137.4, 135.6, 117.9, 116.2 (q, J¼286 Hz), 113.5, 111.9,
79.1, 75.8, 56.3, 50.0 (q, J¼4.0 Hz), 46.4, 36.3, 27.3, 23.3; HRMS
(FABþ): m/z (MþH)þ calculated for C17H1979Br2F3N3O5: 559.9644;
found: 559.9632.
tion was allowed to warm to room temperature over 1 h. The
mixture was then cooled to 0 ꢂC and a solution of tert-butyldi-
methylsilyl chloride (TBSCl, 218 mg, 1.44 mmol) in THF (1.0 mL)
was added dropwise using a cannula. Immediately, magnesium
bromide diethyl etherate (MgBr2$OEt2, 372 mg, 1.44 mmol) was
added in one portion. After 2 h at ꢀ78 ꢂC, the mixture was
allowed to warm to room temperature over 10 h, poured into
a satd aq NaHCO3 solution (200 mL) and extracted with CH2Cl2
(5ꢁ100 mL). The combined extracts were washed with brine
(100 mL), dried over MgSO4, filtered, and concentrated. The
product was purified by column chromatography (EtOAc/hex
4:6) to furnish 15 (7:1 mixture of diastereomers) as a white
4.5. (S)-2-(R)-2(Z)-1-((2,4-Dibromo-5-methoxyphenyl)-3-
(hydroxyimino)propyl)-N-methyl-1-(2,2,2-trifluoroacetyl)
pyrrolidine-2-carboxamide (18)
To a solution of tin(II) chloride (198 mg, 1.04 mmol) in CH3CN
(10 mL) were added thiophenol (0.32 mL, 3.1 mmol) and Et3N
(0.48 mL, 3.4 mmol) successively via syringe. The mixture turned
distinctly yellow. After 0.5 h, a solution of amide 17 in CH3CN
(6.5 mL) was added dropwise via cannula and the flask containing
the amide was rinsed with an additional CH3CN (0.5 mL). After 10 h
at room temperature, the mixture was concentrated. The product
solid (459 mg, 72%). The major isomer could be purified by
20
recrystallisation from CH2Cl2/hexanes:
[
a
]
D
ꢀ21.7 (c 1.00,
CHCl3); mp 198e200 ꢂC; IR (KBr): 2966, 1694, 1549, 1476; 1H
NMR:
d
¼7.73 (s, 1H), 6.78 (s, 1H), 4.97 (dd, J¼13.5, 5.5 Hz, 1H),
was purified by column chromatography (EtOAc/hex 6:4) to yield
20
4.82 (dd, J¼13.5, 9.5 Hz, 1H), 4.53 (dd, J¼9.5, 5.5 Hz, 1H), 3.88 (s,
3H), 3.78 (s, 1H), 3.07 (m, 1H), 2.88 (s, 3H), 2.78 (m, 1H),
2.12e1.99 (m, 2H), 1.84e1.65 (m, 2H), 1.12 (s, 9H); 13C NMR:
18 as a white solid (317 mg, 84%): [
a]
þ59.6 (c 1.00, CHCl3); mp
D
72e73 ꢂC; IR (film): 3342, 3017, 1679; 1H NMR:
d
¼8.05 (br s, 1H),
7.73 (s, 1H), 7.70 (br s, 1H) 7.52 (d, J¼6.8 Hz,1H), 6.83 (s, 1H), 5.76 (d,
J¼6.8 Hz, 1H), 3.91 (m, 1H), 3.86 (s, 3H), 3.59 (m, 1H), 2.95 (m, 1H),
2.70 (d, J¼4.8 Hz, 3H), 2.19 (m, 1H), 1.98e1.73 (m, 2H); 13C NMR:
d
¼177.5, 155.6, 136.9, 135.8, 117.7, 112.4, 111.0, 83.6, 76.7, 75.4,
56.7, 49.5, 44.6, 33.4, 30.8, 30.6, 28.7 (br), 25.3; HRMS (FABþ):
m/z (MþH)þ calculated for C20H2879Br81BrN3O4: 534.0426;
found: 534.0417.
d
¼169.4, 158.2 (q, J¼37 Hz), 155.6, 149.2, 137.0, 135.0, 116.8, 116.4 (q,
J¼287 Hz),113.6,112.9, 77.5, 56.6, 50.1 (q, J¼4.0 Hz), 44.8, 32.4, 26.9,
23.8; HRMS (FABþ): m/z (MþH)þ calculated for C17H1979Br2F3N3O4:
543.9694; found: 543.9657.
4.3. (S)-2-((R)-1-(2,4-Dibromo-5-methoxyphenyl)-3-
nitropropyl)-N-methylpyrrolidine-2-carboxamide (16)
4.6. 1-((5S,8S,9R)-9-(2,4-Dibromo-5-methoxyphenyl)-8-
hydroxy-7-methyl-1,7-diazaspiro[4.4]nonan-1-yl)-2,2,2-
trifluoroethanone (19)
To a solution of amide 15 (459 mg, 0.861 mmol) in THF (8.8 mL)
was added 4 M aq H2SO4 (8.8 mL) dropwise via syringe. After 24 h,
the solution was cooled to 0 ꢂC and 1 M aq NaOH (35 mL) was
added dropwise via cannula. The mixture was diluted with a satd
aq NaHCO3 (200 mL) solution and extracted with CH2Cl2
To a solution of oxime 18 (240 mg, 0.440 mmol) in DMSO
(1.1 mL) and THF (3.3 mL) was added IBX (148 mg, 0.529 mmol).

6630
M. Pangerl et al. / Tetrahedron 66 (2010) 6626e6631
After 18 h at room temperature, the reaction was quenched with
water. The solution was diluted with additional water (100 mL) and
extracted with CH2Cl2 (3ꢁ50 mL). The combined extracts were
washed with water (2ꢁ50 mL) and brine (50 mL), dried over
MgSO4, filtered and, concentrated. The product was purified by
(CHCl3/MeOH 100:1). Nitroalcohol 23 was obtained as a 1:1
mixture of diastereomers and crystallized as colorless needles
18
(15.2 g, 90%): Rf: 0.05 (CHCl3); [
a]
ꢀ51 (c 1.2, MeOH); IR (film):
D
3405, 2975, 1663, 1552, 1366, 1254, 1162; 1H NMR (mixture of
diastereomers and rotamers):
d
¼4.90 (br s, 0.55H), 4.75 (br s,
column chromatography (EtOAc/hex 6:4) to give 19 as a white solid
0.45H), 4.53e4.35 (m, 2H), 4.09e3.89 (m, 2H), 3.60e3.13 (m, 2H),
20
(152 mg, 65%): [
a]
ꢀ217.0 (c 0.50, THF); mp 226 ꢂC; IR (film):
2.44e1.76 (m, 4H), 1.45 (s, 5H), 1.46 (s, 4H); 13C NMR (mixture of
D
3385, 3244, 1680; 1H NMR (THF-d8):
d
¼7.85 (s, 1H), 6.84 (s, 1H),
diastereomers and rotamers):
d
¼154.9, 81.1, 81.0, 79.6, 78.4, 78.3,
5.48 (d, J¼7.6 Hz, 1H), 5.21 (apparent t, J¼6.8 Hz, 1H), 3.91 (d,
J¼6.8 Hz, 1H), 3.77 (s, 3H), 3.67e3.59 (m, 1H), 3.32 (m, 1H), 2.87 (s,
3H), 2.58e2.50 (m, 1H), 2.42e2.34 (m, 1H), 2.07e1.97 (m, 1H),
73.4, 71.6, 71.5, 61.2, 59.9, 59.8, 47.9, 47.5, 28.6, 28.4, 24.3, 24.2,
23.9, 23.8; HRMS (ESIþ): m/z (MþH)þ calculated for C11H21N2O5:
261.1451; found: 261.1438.
1.86e1.75 (m, 1H); 13C NMR (THF-d8):
d
¼171.8, 159.3 (q, J¼36 Hz),
159.2, 139.9, 120.1, 119.7 (q, J¼286 Hz), 116.4, 114.8, 91.8, 76.3, 62.1,
58.8, 52.1 (q, J¼4.0 Hz), 41.4, 33.3, 29.9, 27.4; HRMS (FABþ): m/z
(MþH)þ calculated for C17H1879Br2F3N2O4: 528.9585; found:
528.9556.
4.10. (S)-(E)-tert-Butyl 2-(2-nitrovinyl)pyrrolidine-1-
carboxylate (24)
To a solution of nitroalcohol 23 (14.7 g, 56.5 mmol, 1.0 equiv) in
CH2Cl2 (30 mL) at 0 ꢂC was added methane sulfonylchloride
(6.6 mL, 84.8 mmol, 1.5 equiv) dropwise over 30 min. After 1.5 h at
0 ꢂC, triethylamine (14.1 mL, 102 mmol, 1.8 equiv) was added
dropwise over 30 min. After 30 min at 0 ꢂC, the viscous suspension
was directly subjected to column chromatography without any
previous workup (CHCl3). After removal of solvent, vinyl-
4.7. (5S,8S,9R)-9-(2,4-Dibromo-5-methoxyphenyl)-7-methyl-
1,7-diazaspiro[4.4]nonan-8-ol (amathaspiramide F, 20)
To a solution of acetal 19 (96.2 mg, 0.181 mmol) in THF
(1.8 mL) at 0 ꢂC was added a solution of lithium borohydride in
THF (0.20 mL, 2.0 M, 0.40 mmol) dropwise via syringe. The solu-
tion was allowed to warm to room temperature over 12 h and the
reaction was then quenched with a satd aq NH4Cl solution. The
mixture was diluted with a satd aq NaHCO3 solution (50 mL) and
extracted with CH2Cl2 (3ꢁ30 mL). The combined extracts were
dried over MgSO4, filtered, and concentrated. The product was
purified by column chromatography (EtOAc/acetone 5:1) to afford
nitrocompound 24 crystallized as yellow crystals (13.1 g, 95%): Rf:
18
0.17 (CHCl3); [
a
]
ꢀ51 (c 1.2, MeOH); IR (film): 2976, 2877, 1692,
D
1521, 1388, 1350, 1160; 1H NMR:
d
¼7.08 (dd, 1H, J¼13.3 Hz, 6.3 Hz,
1H), 6.94 (d, 1H, J¼13.3 Hz, 1H), 4.57e4.45 (m, 1H), 3.44 (br s, 2H),
2.19e2.09 (m, 1H), 1.94e1.85 (m, 3H), 1.41 (s, 9H); 13C NMR:
d
¼154.0, 142.0, 139.7, 80.2, 54.9, 46.5, 31.5, 28.3, 23.4; HRMS (ESI-):
20 as a white solid (62.5 mg, 80%). The product was further pu-
m/z (M-H)ꢀ calculated for C11H17N2O4: 241.1188; found: 241.1222.
20
rified by recrystallisation from CDCl3: [
a
]
ꢀ41.0 (c 0.50, MeOH);
D
IR, 1H and 13C NMR data are consistent with literature.31 HRMS
(FABþ): m/z (MþH)þ calculated for C15H1979Br2N2O3: 432.9762;
found: 432.9757.
4.11. (S)-tert-Butyl 2-((R)-2-nitro-1-phenylethyl)pyrrolidine-
1-carboxylate (25a)
4.8. (3R,3aS)-3-(2,4-Dibromo-5-methoxyphenyl)-N-methyl-
3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazole-3a-
carboxamide (21)
A solution of CuCN·2LiCl complex in THF was prepared by
heating a mixture of LiCl (2.3 g, 54 mmol, 2.0 equiv) and CuCN
(2.42 g, 27 mmol, 1.0 equiv) under high vacuum at 100 ꢂC for 24 h.
The mixture was then allowed to cool to room temperature under
argon atmosphere. THF (20 mL) was added and stirred for 24 h at
room temperature until a green colored solution was obtained. To
a solution of bromobenzene (1.2 mL, 11.4 mmol, 1.1 equiv) in THF
(35 mL) at ꢀ110 ꢂC was added n-BuLi (2.0 M in cyclohexane, 6.0 mL,
12.0 mmol, 1.15 equiv) dropwise over 10 min. After 45 min at
ꢀ110 ꢂC, CuCN·2LiCl complex (1.35 M in THF, 0.2 mL, 2.5 mol %) was
added in one portion. This reaction mixture was subsequently
added to a stirring solution of vinylnitrocompound 24 (2.5 g,
10.4 mmol, 1.0 equiv) in THF (15 mL) at ꢀ110 ꢂC over 10 min, using
a cannula. After 1 h at ꢀ110 ꢂC, the solution was allowed to slowly
warm to ꢀ78 ꢂC over 3 h. The reaction was quenched with acetic
acid (1.0 mL) and allowed to warm to room temperature. The bulk
of the solvent was removed and the residue was poured into a satd
aq NaHCO3 solution (150 mL) and extracted with CH2Cl2
(3ꢁ100 mL). The combined extracts were washed with water
(120 mL) and brine (120 mL), dried over MgSO4, filtered, and con-
centrated to give a crude orange product. Purification by column
chromatography (hex/EtOAc 9:1/5:1) yielded 25a (1.8 g, 55%) as
a colorless film, and 25b (0.91 g, 26%) as a colorless solid.
To a solution of amine 16 (211 mg, 0.454 mmol) in methanol
(4.5 mL) was added sodium methoxide (73.6 mg, 1.36 mmol).
After 1 h at room temperature, a solution of titanium(III) chloride
(700 mg, 4.54 mmol) in water (2.8 mL) was added dropwise via
cannula. After 3 h, the mixture was poured into a 1:1 solution of
satd aq NaHCO3 and 10% aq K2CO3 (200 mL) and extracted with
CH2Cl2 (5ꢁ50 mL), dried over MgSO4, filtered, and concentrated.
The product was purified by column chromatography
(EtOAc/EtOAc/MeOH 19:1) to yield 21 as a white solid (81 mg,
40%): mp 149e151 ꢂC; IR (KBr): 3379, 1683, 1661, 1474; 1H NMR:
d
¼7.74 (s, 1H), 7.18, (br s, 1H), 6.68 (s, 1H), 6.53 (s, 1H), 4.78 (m,
1H), 3.83 (s, 3H), 3.48e3.39 (m, 1H), 3.32e3.23 (m, 1H), 2.84 (d,
J¼5.2 Hz, 3H), 1.97e1.87 (m, 1H), 1.71e1.60 (m, 2H), 1.58e1.48 (m,
1H); 13C NMR:
d¼174.3, 155.3, 145.5, 137.3, 135.5, 115.9, 114.3,
112.3, 81.4, 60.0, 56.6, 54.4, 29.4, 26.4, 25.0; HRMS (FABþ): m/z
(MþH)þ calculated for C15H1879Br2N3O4: 429.9766; found:
429.9757.
4.9. (S)-tert-Butyl 2-(1-hydroxy-2-nitroethyl)pyrrolidine-1-
carboxylate (23)
21
4.11.1. Compound 25a. Rf: 0.45 (CHCl3); [
a
]
þ10.3 (c 1.0, MeOH);
D
To a solution of Boc-
L
-prolinal 22 (13.1 g, 65.7 mmol, 1.0 equiv)
IR (film): 3349, 2917, 1628, 1536, 1451, 1379, 1059; 1H NMR (mixture
of rotamers):
¼7.36e7.10 (m, 5H), 4.90e4.74 (m, 1H), 4.64, (dd, br,
J¼13.2, 9.0 Hz,1H), 4.26e4.05 (m, 1H), 3.65e3.14 (m, 3H), 2.01e1.35
(m, 13H); 13C NMR (mixture of rotamers):
in nitromethane (39.0 mL, 716 mmol, 11.2 equiv) was added 3 M
KOH in methanol (1.0 mL, 3.0 mmol). After 4 h at room temper-
ature, acetic acid (0.5 mL, 9.0 mmol) was added and the resulting
solution was stirred for 1 h. Subsequently, the reaction mixture
was subjected to column chromatography and directly purified
d
d¼156.2, 155.2, 138.1,
136.6, 129.6, 129.0, 128.2, 127.9, 127.7, 127.6, 81.5, 80.5, 78.7, 78.5,
62.3, 60.3, 49.2, 47.8, 46.8, 46.2, 28.8, 28.5, 28.4, 28.3, 23.2, 22.3;

M. Pangerl et al. / Tetrahedron 66 (2010) 6626e6631
6631
HRMS (EIþ): m/z (M)þ calculated for C17H24N2O4: 320.1736; found:
320.1726.
(ESIþ): m/z (MþH)þ calculated for C12H15N2: 187.1235; found:
187.1230.
4.11.2. Compound 25b. Rf: 0.42 (CHCl3); [
a]
21 ꢀ79 (c 1.0, MeOH); IR
D
Acknowledgements
(film): 3350, 2915, 1628, 1550, 1446, 1358, 1059; 1H NMR (mixture
of rotamers):
d
¼7.36e7.15 (m, 5H), 5.03e4.60 (m, 2H), 4.35e3.75
We thank Dr. Fred Hollander for the X-ray crystal structure of
compound 21 and the Center of Integrated Protein Science, Munich
(CIPSM) for the financial support.
(m, 2H), 3.62e3.17 (m, 1H), 3.17e2.78 (m, 1H), 2.06e1.81 (m, 1H),
1.80e1.68 (m, 1H), 1.50 (s, br, 9H), 1.40e0.82 (m, 2H); 13C NMR
(mixture of rotamers):
d¼155.7, 136.7, 129.5, 128.6 (br), 127.8, 80.9,
79.9, 78.2, 76.1, 60.4, 59.8, 49.0, 47.8, 46.0, 44.9, 29.4, 29.0, 28.5 (br),
23.5, 23.2; HRMS (ESIþ): m/z (MþNa)þ calculated for
C17H24N2O423Na: 342.1634; found: 343.1628.
Supplementary data
Crystallographic data for compound 21 have been deposited at
the Cambridge Crystallographic Data Center (CCDC 189001). Sup-
plementary data associated with this article can be found in the
online version at doi:10.1016/j.tet.2010.05.085.
4.12. (S)-2-((R)-2-Nitro-1-phenylethyl)pyrrolidine (26)
To a stirred solution of 25a (1.0 g, 3.1 mmol, 1.0 equiv) and
thioanisole (0.4 mL, 3.1 mmol, 1.0 equiv) in CH2Cl2 (4 mL) was
added trifluoroacetic acid (6.0 mL, 80 mmol, 25 equiv). After 4 h at
room temperature, the mixture was diluted with a satd aq
NaHCO3 solution (75 mL) and extracted with CH2Cl2 (5ꢁ50 mL).
The combined extracts were washed with brine (150 mL), dried
over Na2SO4, filtered, and concentrated to give a crude light yel-
low product. The product was purified by column chromatogra-
References and notes
1. LaRue, T. A. Lloydia 1977, 40, 307.
2. Nakamura, H.; Deng, S.; Kobayashi, J.; Ohizumi, Y. Tetrahedron Lett. 1987, 28, 621.
3. Gasco, A.; Serafino, A.; Mortarini, V.; Menziani, E. Tetrahedron Lett. 1964, 523.
4. (a) Langley, B. W.; Lythgoe, B. Cell. Mol. Life Sci. 1949, 2716; (b) Langley, B. W.;
Lythgoe, B.; Riggs, N. V. Cell. Mol. Life Sci. 1951, 2309; (c) Langley, B. W.; Lythgoe,
B.; Rayner, L. S. Cell. Mol. Life Sci. 1952, 4191.
5. Moss, R. A.; Matuso, M. Chem. Commun. Ed. 1976, 1643.
6. (a) Lam, K. S.; Hesler, G. A.; Mattei, J. M.; Mamber, S. W.; Forenza, S. J. Antibiot.1990,
43, 956; (b) Leet, J. E.; Schroeder, D. R.; Krishnan, B. S.; Matson, J. A. J. Antibiot.1989,
43, 961; (c) Leet, J. E.; Schroeder, D. R.; Golik, J.; Matson, J. A.; Doyle, T. W.; Lam, K.
S.; Hill, S. E.; Lee, M. S.; Whitney, J. L.; Krishnan, B. S. J. Antibiot. 1996, 94, 299; (d)
Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 2995.
7. Oh, D.; Poulsen, M.; Currie, C. R.; Clardy, J. Nat. Chem. Biol. 2009, 5, 391.
8. Shimogawa, H.; Kuribayashi, S.; Teruya, T.; Suenaga, K.; Kigoshi, H. Tetrahedron
Lett. 2006, 47, 1409.
phy (CHCl3/MeOH/TEA 100:2:1) to yield amine 26 as a colorless
18
solid (0.69 g, quant.): Rf: 0.08 (CHCl3); [
a
d
]
þ36 (c 1.2, MeOH); IR
D
(film): 2987, 1658, 1552, 1174; 1H NMR:
¼7.34e7.16 (m, 5H), 4.99
(dd, J¼12.6, 5.0 Hz, 1H), 4.57 (dd, J¼12.6, 9.4 Hz, 1H), 3.36 (dt,
J¼9.7, 6.7 Hz, 1H), 3.28 (td, J¼9.6, 5.0 Hz, 1H) 3.00e2.89 (m, 2H),
2.73 (br s, 1H) 1.83e1.70 (m, 2H), 1.70e1.58 (m, 2H), 1.38e1.29 (m,
9. Mayumi, I.; Noriyoshi, S.; Kyoko, I.; Fumio, M.; Kazunori, H.; Kazutoshi, M. J.
Antibiot. 1999, 52, 224.
1H); 13C NMR:
d
¼138.9, 128.8, 127.9, 127.6, 79.6, 61.4, 50.6, 47.0,
31.0, 25.9; HRMS (EIþ): m/z (MþH)þ calculated for C12H17N2O2:
10. (a) Saburi, A. A.; Nia, R.; Fontaine, C.; Pays, M. Phytochemistry 1993, 35, 1053; (b)
Houghton, P. J.; Pandey, R.; Hawkest, J. E. Phytochemistry 1994, 35, 1602.
11. Aladesanmi, A. J.; Nia, R.; Nahrstedt, A. Planta Med. 1998, 64, 90.
12. F.R. Irvine. Woody Plants of Ghana; Oxford University: Oxford, p 738.
13. H.M. Burkill. The useful Plants of West tropical Africa; Royal Botanic Gardens,
Kew: London; Vol. 1.
14. (a) Correira, A.; Costa, A.; Paiva, M. Q. Ann. Fac. Farm. Porto 1965, 25, 35;
(b) Ferreira, M. A.; Correira, A.; Prista, L. N. Garcia Orta 1963, 11, 477.
15. Jolivet, S.; Mooibroek, H.; Wichers, H. J. FEMS Microbiol. Lett. 1998, 263.
16. Parry, R. J.; Li, Y.; Lii, F. L. J. Am. Chem. Soc. 1992, 114, 10062.
17. Tao, T.; Alemany, B. L.; Parry, R. J. Org. Lett. 2003, 5, 1213.
18. Parry, R. J.; Mueller, J. V. J. Am. Chem. Soc. 1984, 106, 5764.
19. Takano, S.; Seiichi, Y.; Ogasawara, K. Heterocycles 1982, 19, 1223.
20. Ranganathan, D.; Bamezai, S.; Sujata, S. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1991, 30, 169; Synth. Commun. 1985, 15, 259.
221.1291; found: 221.1278.
4.13. (3S)-3-Phenyl-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]
pyrazole (newbouldine, 7)
To a solution of amine 26 (50 mg, 0.23 mmol,1.0 equiv) in MeOH
(2.3 mL) was added sodium methoxide (37 mg, 0.69 mmol,
3.0 equiv). After 1 h at room temperature, titanium(III) chloride
(420 mg, 2.72 mmol, 12.0 equiv) in degassed water (1.8 mL) was
added dropwise over 5 min. After 3.5 h at room temperature, the
purple reaction mixture was poured into a 1:1:1:2 mixture of 10%
aq K2CO3/satd aq Na2CO3/satd aq Rochelle salt/CH2Cl2 (125 mL) and
stirred vigorously for 18 h under argon atmosphere. The organic
layer was separated, dried over MgSO4, filtered, and concentrated
to give a crude yellow product. The product was purified by column
21. Kunlikovich, O.; Nikolai, N.; Tyvorskii, V.; Kimpe, N.; Keppens, M. Tetrahedron
Lett. 1996, 37, 1095.
22. Ranganathan, D.; Bamezai, S.; Cun-Heng, H.; Clardy, J. Tetrahedron Lett.1985, 26, 5739.
23. Allin, S.; Barton, W. R. S.; Russel, R. W.; McInally, T. Tetrahedron Lett. 2002, 43, 4191.
24. Allin, S. M.; Barton, W. R. S.; Bowman, R.; Bridge, E.; Elsegood, M. R.; McInally,
T.; McKee, V. Tetrahedron 2008, 64, 7745.
€
25. Schroter, H. B.; Neumann, D.; Katritzky, A. R.; Swinbourne, F. J. Tetrahedron
1966, 22, 2895.
chromatography (CHCl3/MeOH 100:1) to yield 7 as a colorless oil
26. Guzman-Perez, A.; Maldonado, L. A. Synth. Commun. 1991, 21, 1667.
27. Onaka, T. Tetrahedron Lett. 1968, 54, 5711.
28. Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 4556.
29. Reed, P. E.; Katzenellenbogen, J. A. J. Org. Chem. 1991, 56, 2624.
30. Mahaboobi, S.; Popp, A.; Burgmeister, T.; Schollmeyer, D. Tetrahedron: Asym-
metry 1998, 9, 2369.
18
(13 mg, 30%): Rf: 0.11 (CHCl3); [
a
]
ꢀ93 (c 0.50, MeOH); IR (film):
D
3854, 3325, 2929, 1684, 1453; 1H NMR:
d
¼7.36e7.21 (m, 5H), 6.84
(br s, 1H), 4.00 (br s, 1H), 3.72e3.64 (m, 2H), 3.23e3.16 (m, 1H),
2.03e1.95 (m, 1H), 1.74e1.67 (m, 2H), 1.59e1.55 (m, 1H); 13C NMR:
d¼147.0, 140.3, 128.9, 127.3, 127.1, 71.2, 61.0, 53.5, 31.2, 23.7; HRMS
31. Morris, B. D.; Prinsep, M. R. J. Nat. Prod. 1999, 62, 688.