Total synthesis of lepadiformine alkaloids using N-Boc α-amino nitriles as trianion synthons

Article abstract of DOI:10.1021/jo300161x

Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent reductive lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski-Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.

Full text of DOI:10.1021/jo300161x

Article
pubs.acs.org/joc
Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino
Nitriles as Trianion Synthons
Matthew A. Perry, Matthew D. Morin, Brian W. Slafer, and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, Irvine, California 92697, United States
S
* Supporting Information
ABSTRACT: Lepadiformine A, B, and C were synthesized in an
enantiomerically pure form using a reductive cyclization strategy.
N-Boc α-amino nitriles were deprotonated and alkylated with
enantiomerically pure dibromides to afford the first ring. The
products were manipulated to introduce phosphate leaving groups,
and subsequent reductive lithiation followed by intramolecular
alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a
mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This
appendage was introduced in a sequence using a Polonovski−Potier reaction as the key step. The synthetic strategy is
stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.
Reduction of nitrile moieties for the stereoselective removal
of nitrile groups is well documented in the literature.7 These
decyanation reactions presumably proceed through reactive
alkyl metal species that are directly protonated under the
reaction conditions. More recently, the formation of alkyl metal
species by reductive metalation has been developed.8 Reductive
decyanation and cyclization of the resulting organometallic
intermediate was first described in Grierson’s synthesis of
gephyrotoxin-16B (7) (eq 3).9 These two transformations, the
alkylation of nitrile-stabilized anions and a reductive decyana-
tion followed by cyclization, can be combined to assemble
complex structures rapidly and often stereoselectively. In this
report, we provide a full account of the synthesis of lepadi-
formine alkaloids based on a sequential alkylation and reductive
cyclization of α-aminonitriles.10
INTRODUCTION
■
The use of stabilized carbanions to effect carbon−carbon bond
formation is a long established strategy in organic synthesis.1
Nitrile-stabilized anions (ketene iminates) have been applied to
the construction of complex molecules by way of inter-
molecular alkylation and subsequent cyclization.2 Stork used
aminonitriles and cyanohydrin anions as aldehyde anion equiva-
lents.3,4 In a seminal report, Husson employed a double alkylation
method to construct cyclohexyl aminonitriles from
α,ω-alkyl bromides and di-N-benzyl cyanomethylamine 2 (eq 1).5
We have studied the reductive cyclization of α-heteronitriles
for stereoselective syntheses of spirocyclic frameworks exten-
sively.11 Recent studies aimed toward expanding the synthetic
scope of this methodology have shown that spiropyrrolidine
moieties can be accessed from exo-cyclic α-aminonitriles in
good yield and high diastereoselectivity (eq 4).10,12 The
structural similarity of spirocycle 9 to the core of fasicularin,
cylindricine, and lepadiformine alkaloids captured our interest,
and the fully substituted spiropyrrolidine core of these
compounds arises naturally using this approach. We decided
to develop the alkylation and reductive cyclization strategy with
a synthetic approach to the lepadiformine alkaloids.10
We reported a sequential nitrile alkylation sequence to assemble
tertiary α-aminonitriles as reductive carbolithiation precursors
(eq 2).6 Each of these strategies takes advantage of the high
nucleophilicity of nitrile-stabilized anions.
Received: January 26, 2012
Published: March 13, 2012
© 2012 American Chemical Society
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Lepadiformine A (Figure 1, 11) was isolated by Biard and co-
workers from the marine tunicate Clavelina lepadiformis off the
coast of Tunisia.13 Initial biological studies found moderate
spiropyrrolidine motif (Figure 2). Formation of the cyclo-
hexane ring would be accomplished by double alkylation of
chiral acyclic dibromides 15a,b with α-aminonitrile 16. The
Figure 1. Lepadiformine alkaloids.
Figure 2. Retrosynthetic analysis of the lepadiformine alkaloids.
cytotoxic activity against various cell lines: nasopharnyx carcinoma
(KB, IC50 = 9.20 μg/mL), human colon adenocarcinoma cells
(HT29, IC50 = 0.75 μg/mL), and nonsmall-cell carcinoma
(NSCLC-N6, IC50 = 6.10 μg/mL). Unequivocal assignment of
the carbon skeleton was determined by 13C NMR INAD-
EQUATE experiments with the placement of the heteroatoms
established from mass spectrometry fragmentation patterns. Clear
assignment of the relative configuration was complicated by the
integral dibromide fragments would arise from alkyne
reduction, TBS deprotection, and Appel-type26 halogenation
of alkynyl diol intermediates, whose stereochemical config-
urations would be installed by sequential Noyori-Ikariya
transfer hydrogenations. The requisite precursors would
originate from acetylide addition of a fragment derived from
17a,b27,28 and aldehyde 18. The syntheses of lepadiformine
A−C arising from this synthetic plan are presented below.10
1
poor resolution of the H NMR signals leading to the incorrect
cis-fused assignment of the A and B rings. Support for the
controversial proposal of a zwitterionic species was provided by
the low field singlet (∼10 ppm) corresponding to a proton bound
to one of the heteroatoms, the low chemical shifts of the carbons
directly bonded to the nitrogen and the lack of chemical reactivity
of the primary alcohol.
Inspired by the intriguing structure of lepadiformine, several
groups attempted to prepare lepadiformine including Weinreb,14
Kibayashi,15 Pearson,16 Oppolzer,17 Funk,18 Kim,19 Hsung,20 and
Renaud21 among others.22 Synthetic work by Weinreb14 and
Pearson16 determined the original zwitterionic structure 10 to be
incorrect, and unambiguous assignment of the relative
configuration (11) was accomplished by total synthesis of the
racemate and X-ray crystallographic studies by the Kibayashi
group.15 Further work by Weinreb established the absolute
configuration.23 The synthetic challenge represented by this
class of alkaloids has inspired several groups to complete total
syntheses.22,10
In 2006, lepadiformines B (12) and C (13a), which contain a
truncated four-carbon side chain, were isolated from the marine
tunicate Clavelina moluccensis off the coast of Djibouti by the
Sauviat group.24 Biological studies showed moderate inhibition
of cardiac inward rectifying K+ channel for analogues 11 and
12, and diminished activity for 13a, which was attributed to the
absence of the C-2 hydroxymethyl moiety. The absolute con-
figuration of lepadiformine B and C were assumed to
correspond to the absolute configuration of lepadiformine A.
Lepadiformine C has attracted the attention of the synthetic
community.25
We envisioned syntheses of lepadiformines A, B, and C from
similar intermediates in a strategy that rapidly introduces all
three rings from acyclic precursors. The retrosynthetic analysis
involved an N-alkylation to form the tricyclic core with
reductive cyclization providing the synthetically challenging
RESULTS
■
The enantiomerically pure acyclic dibromide was prepared via
the corresponding diol as outlined in Scheme 1. Synthesis of
the dibromides 15a,b began with the addition of lithium TMS-
acetylide to aldehyde 19a,b with subsequent oxidation to ynone
20a,b. Reduction using the Noyori-Ikariya hydrogen-transfer
catalyst Ru-(p-cymene)-TsDPEN (21), followed by removal of
the trimethylsilyl group produced enantioenriched alcohols
22a,b. Elaboration of the side chain proceeded by protection of
the propargylic alcohol and addition of the lithiated alkyne to
aldehyde 18 to give 23a,b. Oxidation of the propargylic alcohols
under Dondoni’s modified Swern conditions,29 followed by a
second Noyori-Ikariya reduction gave (5S,8S)-24a,b as a single
diastereomer. Conversion of propargylic alcohol 24a,b to
dibromide 15a,b was initiated with alkyne reduction using Pt/C
pretreated under H2 atmosphere prior to addition of the alkyne,
a procedure that proved unreliable on scale. Deleterious
formation of ketone byproduct 26 was circumvented by use
of platinum oxide and increasing the hydrogen pressure to
200 psi.30 Subsequent removal of the TBS ether by treatment
with PPTS in methanol afforded diols 27a,b. Bromination of the
diols to afford the double alkylation precursors 15a,b was
previously accomplished using NBS and triphenylphosphine in
moderate yields, in part due to a difficult purification. Optimized
conditions26a using bromine, triphenylphosphine, and triethyl-
amine provided higher yields with greater consistency, improved
purification, and eliminated the formation of a tetrahydropyran
byproduct 28. To examine whether an increase in the electro-
philicity of the secondary bromide center would be beneficial in
the double alkylation, dibromide 25 was also prepared in a similar
fashion. Subsequent double alkylation studies with dibromide 25
were unsuccessful and were not explored further.
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Scheme 1. Synthesis of the Dibromide Fragments
Synthesis of the α-aminonitrile 16 proceeded by protection
of 3-amino-1-propanol as the TBS ether followed by
cyanomethylation and protection of the amine as the Boc-
carbamate.10 With the coupling components in hand, a one-pot
double nitrile anion alkylation with diastereomerically pure
dibromide 15a and α-aminonitrile 16 was conducted (Table 1).
Treatment of 16 with base generates a nitrile anion that
displaces the primary bromide of 15a; a second equivalent of
base forms another nitrile anion that then cyclizes via 6-exo-tet
displacement of the secondary bromide. Initial studies were
plagued by low yields and formation of elimination byproduct
29. Procedural optimization did provide more consistent yields,
albeit in the range of thirty percent. Alkylation with the more
reactive propargyl bromide 25 was attempted, but none of the
desired product was isolated. Apparently the strongly basic
that aggregation may be inhibiting complete reaction (entry 4).
Addition of base at decreased temperature with warming to
0 °C favors formation of product and monoalkylated inter-
mediate as well as suppresses the formation of eliminated byproduct
(entry 8). After an exhaustive screen of reaction conditions,
consistent 80% yields of 14a were obtained with the use of
freshly distilled DMPU in THF, addition of LDA (3.5 equiv)
and slow increase in temperature from −78 − 0 °C (entry 8).
The concentration of the reaction was not examined in
depth, but lower yields were observed with a concentration
less than 0.06 M.
The synthesis of lepadiformine A and B by an alkylation
sequence with an elaborated chiral α-aminonitrile (30) con-
taining the C2 side chain was also investigated (Figure 3).31
Table 1. Nitrile Anion Double Alkylation for 14a
Figure 3. Alkylation and reductive cyclization of chiral aminonitrile.
Unfortunately, the double alkylation and reductive cyclization
steps were problematic, affording the respective products, 31
and 32, in an unoptimized 20 and 27% yield. These findings
suggest that the presence of α-substitution to nitrogen in the
nitrile results in increased steric hindrance and/or reduced
nucleophilicity of the nitrile anion. These findings solidified the
decision to use the simple α-aminonitrile 16 for the formation
of the spiropyrrolidine framework with incorporation of the C2
side chain at a later stage.
With aminonitrile 14a,b available in good yield, construction
of the spiropyrrolidine system proceeded by deprotection of
the TBS ether followed by phosphorylation to give reductive
cyclization precursor 33a,b (Scheme 2). Treatment of the
phosphates 33a,b with Freeman’s reagent (lithium di-tert-butyl-
biphenylide, LiDBB)32 afforded spiropyrrolidines 35a,b as
single diastereomers. Mechanistic studies to determine the
origin of diastereoselectivity under reductive cyclization
conditions indicate cyclization proceeds via a double inversion
sequence with overall retention of configuration with respect to
the nitrile starting material.10
entry
base
temp. (°C)
solvent
yield
1
2
LDA (4 equiv)
−40
−40
DMPU/THF (1:4) 3−35%
DMPU/THF (1:2) elim. (29)
LDA (2 equiv),
LiNEt2 (2 equiv)
3
LDA (3 equiv),
KHMDS(2equiv)
−40
DMPU/THF (1:2) 49%
4
5
6
7
8
LDA (4 equiv)
−40
−20
−40
−78 to 0
−78 to 0
DMPU
THF
49%
LiNEt2 (3 equiv)
LiNEt2 (3 equiv)
LDA (4.5 equiv)
LDA (3.5 equiv)
decomp.
decomp.
22%
THF
LiCl/THF
DMPU/THF (1:1) 80−82%
conditions of the reaction led to decomposition of the sensitive
dibromide. Further optimization of the dialkylation with 15a
led to better results. Subsequent studies revealed that the use of
less hindered bases, such as LiNEt2 (entries 2 and 6), and
elevated reaction temperature (entries 1 and 5) only promotes
the formation of elimination byproduct 29. An increase in yield
was observed with the use of DMPU as the solvent, indicating
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spectroscopic data identical to those reported for the natural
product with the exception of the optical rotation (vide infra).
Based on the established lithiation chemistry of N-Boc-
pyrrolidines, a synthetic strategy using spiropyrrolidine 35a to
construct lepadiformine B (12) was initiated. Following a
procedure developed by Beak,33 spiropyrrolidine 35a was
lithiated and trapped with DMF to afford spiroprolinal 37 in
31% yield as a 4:1 mixture of chromatographically inseparable
diastereomers (Table 2, entry 1).34 The configuration of the
major isomer was (S)-37, as demonstrated by the subsequent
conversion to lepadiformine B (Scheme 4).35 In an effort to
improve the yield and diastereoselectivity of the reaction a
number of conditions were examined. An increase in the
temperature was found to moderately improve the yield with a
concomitant reversal in diastereoselectivity (entry 2). Reaction
times of greater than one hour at increased temperature also
decreased yield (entry 3). Product formation was also highly
electrophile-dependent. Of the electrophiles screened, DMF (38)
and Weinreb amide 39 provided the highest yields (entries 1, 2, 9)
with morpholine-4-carbaldehyde (40), methyl formate (42),
and benzotriazole-1-methanol (41) proving unsatisfactory
(entries 4, 5, 6). Unfortunately, neither the yields nor the
selectivity for this transformation were satisfactory.
Scheme 2. Reductive Cyclization
The synthesis of lepadiformine C (13a) and demethoxy-
lepadiformine A (13b) proceeded with formation of the final
ring via a mesylate intermediate as previously demonstrated by
Kibayashi in the synthesis of (+)-cylindricine C.22f In this case,
activation of the alcohol to mesylate 36a,b was chosen to allow
for facile Boc deprotection and N-alkylation/cyclization
(Scheme 3). A previous attempt to effect cyclization using
Scheme 3. Synthesis of Lepadiformine C
In an attempt to induce greater diastereoselectivity, the use
of a chiral diamine ligand was explored. The desired stereo-
chemistry of the lithiation/carbonylation required the use of a
(+)-sparteine surrogate. O’Brien et al. reported on the use of
chiral cyclohexyl diamine 43 on N-Boc-pyrrolidines in good
yield and higher (Figure 4).36 Formylation of spiropyrrolidine
CCl4 and PPh3 resulted in the formation of the trifluoro-
acetamide, which arose from the dehydration of residual TFA
in the reaction mixture. Removal of the Boc group from 36a,b
with TFA followed by addition of saturated NaHCO3 resulted
in isolation of natural product 13a and tricycle 13b as a free
amine. In order to compare the spectral data of synthetic
lepadiformine C to that reported in the literature, 13a was con-
verted to the hydrochloride salt by treatment with anhydrous
HCl/CHCl3. The resultant synthetic material displayed
Table 2. N-Boc-pyrrolidine Formylation
Figure 4. Examined electrophiles and diamine ligands.
35a using diamine 43 provided similar yields but lower dia-
stereoselectivity (entry 7). A recent report by O’Brien on
diamine-free lithiation/trapping of N-Boc-heterocycles pro-
vided a new avenue to improve the yield and, potentially,
diastereoselectivity.37 Use of the more coordinating solvent
THF (or Me-THF) results in an s-BuLi/THF complex, which
promoted lithiation similar to that of s-BuLi/TMEDA. At low
temperatures the use of THF resulted in low yields (entry 8).
Higher reaction temperatures gave higher yields but the
undesired (R)-isomer was favored (entry 9). Due to the lack
of complexation of (−)-sparteine to s-BuLi in THF or the faster
rate of lithiation by s-BuLi/THF, the use of a chelating diamine
in THF was not attempted. To determine the identity of the
diastereomeric mixtures, a control reaction with (−)-sparteine
(44) was conducted (entry 10). A deuterium incorporation study
was conducted to examine whether deprotonation or trapping of
the electrophile was insufficient. The deuterium incorporation of
a
entry
T (°C)
solvent
time
E
additive yield (dr S:R)
1
−78 Et2O
−60 to −30 Et2O
−60 Et2O
3 h
1 h
3 h
38
39
45
31% (4:1)
54% (1:7.4)
20%
2
45
3
38 or 39
45
4
−30 THF
−30 THF
−78 Et2O
−78 Et2O
5 min 40
5 min 42
n/a
n/a
45
9%
5
21%
6
3 h
3 h
41
38
38
3%
7
43
34% (2:1)
10%
8
−78 Me-THF 1 h
n/a
n/a
44
9
−30 THF
−78 Et2O
−78 Et2O
−60 Et2O
5 min 38 or 39
43% (1:13.8)
11% (1:2)
31% D incorp
10
11
12
3 h
2 h
4 h
38
CD3OD
45
bc
,
38 or 39
45
60%
a
b
The dr was determined by GC/MS. 4.4 equiv of s-BuLi or
sequential addition of s-BuLi (5 × 1.3 equiv) and electrophile (5 × 1.3
c
equiv). No recovered starting material.
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31% is congruent with the observed yields, suggesting that
deprotonation is problematic (entry 11). With conditions capable
of providing moderate yields and good diastereoselectivity for the
undesired (R)-configuration (entries 2 and 12), an equilibration
of the aldehyde to the (S)-configuration was attempted.
Inspection of the spirocycle 37 suggests the possibility of
equilibrating the aldehyde (R)-37 to a thermodynamically more
stable (S)-37 based on relief of steric strain. To test the
hypothesis, spiropyrrolidine 37, as a mixture of diastereomers,
was subjected to a variety of conditions (Table 3). Initial attempts
reduced with sodium borohydride, and the resultant alcohol was
protected as the acetyl ester to afford 46 (4:1 diastereomeric
mixture). Fluoride-mediated removal of the silyl protecting group,
followed by activation of the alcohol as the mesylate provided
N-alkylation precursor 47 as a mixture of diastereomers. Removal
of the Boc group by TFA followed by neutralization provided
O-acetyl-lepadiformine B (48) as a single stereoisomer. The stereo-
selectivity of the reaction may be attributed to the difference in the
rates of cyclization for the two diastereomers: the less hindered (S)-
isomer reacts faster compared to the undesired (R)-isomer. The
moderate yield may be attributed to the formation of a number
of byproducts. Products of an elimination pathway include the
O-acetyl, N-acetyl (derived from an O- to N-acyl migration) and
Boc-protected starting material. Unreacted free amine as well as
acetate hydrolysis of the cyclized product (lepadiformine B) was
also observed. Basic hydrolysis of the acetyl ester and acidification
provided synthetic lepadiformine B (12) as the hydrochloride salt.
In an effort to install the C2 side chain in a more efficient and
stereoselective fashion, a new route to convert lepadiformine C
to lepadiformine B was proposed. Lepadiformine B would arise
from a 3-step procedure involving oxidative cyanation,
hydrolysis of the nitrile and reduction to the alcohol. Initial
attempts at oxidative cyanation following the work of
Murahashi were unsuccessful, with no perceptible formation
of product (Table 4, entry 1).38 Subsequent efforts using
Table 3. Attempted Equilibration of Spiropyrrolidine 37
dri
a
entry
1
base
solvent
temp (°C) time (S:R) drf (S:R)
Et3N, SiO2 Hexanes/
EtOAc
22
48 h 1:7.4
1:3.5
2
Et3N, SiO2 Hexanes/
EtOAc
22−90
4 d 4:1
2:1
3
4
5
6
7
DBU
DMF
22
22
22
22
22
48 h 4:1
48 h 4:1
48 h 1:7.4
19 h 4:1
19 h 1:7.4
3.4:1
b
pyrrolidine DMF
pyrrolidine DMF
97:3
b
b
3:97
b
K2CO3
K2CO3
MeOH
MeOH
97:3
3:97
a
b
The dr was determined by GC/MS. Formation of byproduct(s)
resulted in supposed equilibration selectivity.
show convergence toward a 1:1 ratio of diastereomers, indicating
no significant preference for either the R or S configuration
(entries 1−3). The use of pyrrolidine and potassium carbonate
were promising: a sample enriched in the (S)-isomer showed com-
plete conversion to the desired diastereomer (entries 4 and 6).
These results were then obfuscated by the conversion of an
enriched (R)-isomer sample to the undesired (R)-isomer
(entries 5 and 7). Analysis of the equilibrium reactions con-
ducted by MS showed formation of an aldol byproduct,
indicating that the observed increase in diastereomeric ratio was
the result of an aldol addition reaction between the aldehyde
reactants. This side reaction effectively removed the minor iso-
mer to provide an increase in diastereomeric ratio; the outcome
may be rationalized by postulating a diastereoselective aldol reaction
between the (R)-aldehyde and the (S)-aldehyde that would pre-
ferentially remove racemic aldehyde from the mixture. Unfortu-
nately, the increase in diastereomeric ratio was an impractical
solution because it was accompanied by a reduction in yield.
The synthesis of lepadiformine B was completed from aldehyde
37 as outlined in Scheme 4. A mixture of diastereomeric
aldehydes 37 (4:1 (S)-37 to (R)-37, Table 2, entry 1) was
Table 4. Oxidative α-Cyanation
entry
solvent
temp (°C)
reagents
yield (%)
1
2
3
4
CH2Cl2
CH3CN
CH3CN
CH2Cl2
22
RuCl3, H2O2, AcOH, NaCN
0
0
+
23−100
23−120
0−22
C7H7 BF4−, KCN
a
+
−
C7H7 BF4
m-CPBA, TFAA, KCN
0
85
a
Iminium ion formation control experiment.
aromatic cation tropylium tetrafluoroborate as reported by
Lambert and Allen also showed no conversion (entry 2).39
A
control reaction was attempted to determine if iminium
formation was possible under various reaction temperatures.
The iminium salt was not observed upon treatment with
tropylium salt in the absence of a nucleophile even at tem-
peratures up to 120 °C (entry 3). The search for a more robust
method led to the use of a Polonovski-Potier reaction (entry
4).40 Formation of the N-oxide with peroxide followed by
TFAA mediated rearrangement achieved iminium ion for-
mation. Subsequent cyanide trapping provided aminonitrile 49a
as a 6:1 (S:R) ratio of diastereomers. Conversion of the nitrile
to the aldehyde by DIBAL-H reduction was problematic,
providing a 1:1 mixture of aldehyde and lepadiformine C.
A revised route was explored to avoid the modest recovery
observed in this step.
Scheme 4. Synthesis of Lepadiformine B
An improved synthesis of lepadiformine A and B was realized
by forgoing purification until hydrolysis of the aminonitrile to
the methyl ester was complete. Following the procedure
established above (Scheme 3), spiropyrrolidines 35a,b were
converted to the mesylates 36a,b and cyclized to the lepadi-
formine skeleton. Without purification, the tertiary amines
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13a,b were subjected to a three-step sequence to provide the
methyl esters 50a,b in 28 and 43% overall yield as single
diastereomers. The minor isomers from the aminonitriles 49a,b
did not lead to the corresponding methyl ester, perhaps due to
inefficient hydrolysis of this more sterically encumbered nitrile.
The sequence involved N-alkylation followed by formation of
the N-oxide and modified Polonovski reaction to afford the
aminonitriles 49a,b. Hydrolysis of the nitrile to the methyl ester
followed by reduction to the alcohol provided lepadiformine A
(11). Lepadiformine B was prepared by an analogous sequence
of transformations. Each natural product was isolated as a
single stereoisomer (Scheme 5). The hydrochloride salts of
Scheme 6. Proposed Mechanism for the Reductive
Cyclization
optical rotation of −11. Further investigation revealed that the
free base of synthetic 13a gave the sign and magnitude (+11)
reported by Sauviat. This data comparison indicated that either
the reported rotation was of the free base and not the HCl salt or
that the enantiomer of natural lepadiformine C was made. The
latter seems unreasonable based on multiple factors. First, com-
parison of the first two Noyori-Ikariya reduction products to
those reported in the literature confirms the stereochemistry and
enantioselectivity as described herein.23,42 Second, the stereo-
selective reduction of the alkynyl ketone with (S,S)-TsDPEN
ruthenium catalyst gave the correct (S)-enantiomer and the
second alkynyl ketone reduction with the same catalyst would
give selectively the desired (S,S)-intermediate 24a. This con-
figuration was confirmed by Mosher’s ester analysis. Third, with
the stereochemistry of the alcoholic carbon used for the final
bond formation clearly defined, formation of any other stereo-
center than those described herein would produce a molecule that
is inconsistent with the spectral data and not just the optical
rotation. Most importantly, the optical rotation of synthetic
lepadiformine B hydrochloride obtained from lepadiformine C is
in agreement with the reported value. These results prove that
synthesis of the desired enantiomer was achieved. Our current
data indicate that natural lepadiformine A and B have the same
absolute configuration. We propose that the configuration of
lepadiformine C is the same as lepadiformine B, and that the
discrepancy in optical rotation reported for the natural product
should be discounted.
Scheme 5. Synthesis of Lepadiformine A and B
lepadiformine A and B matched the reported spectral data for
the corresponding natural product. The optical rotation for
lepadiformine A was +1.8 (lit. [α]22 = +4.0) and that for
D
lepadiformine B was +3.2 (lit. [α]22 = +3.0).24
D
DISCUSSION
■
The key reductive cyclization reaction (e.g., 33a to 35a, Scheme 2)
proved to be an efficient, stereoselective process. The mechanistic
origin of selectivity was of interest and prompted an investiga-
tion aimed at identifying the configuration of the intermediate
organolithium. Reductive lithiation of control substrate 14a
followed by protonation of the resultant organolithium gave
cis-disubstituted cyclohexane 52 (eq 5). Assuming protonation
CONCLUSION
■
Lepadiformine A, B and C were synthesized enantioselectively
using a double alkylation and subsequent reductive cyclization
of an exo-cyclic α-aminonitrile. The syntheses described herein
highlight the use of α-aminonitriles as trianion synthons that
are capable of constructing fully substituted carbon centers in a
stereoselective fashion. Furthermore, the reductive lithiation
and cyclization transformation provides an innovative approach
for constructing spiropyrrolidine frameworks and one that will
be applicable to other synthetic problems.
proceeded with retention of configuration,41 the mechanism of
the reductive cyclization may proceed as proposed in Scheme 6.
The radical intermediate 53, stabilized by interaction with the
nitrogen electrons, creates a sterically encumbered environment
between the equatorial R′ group and the nitrogen R group (or
N-Boc group) resulting in a conformational isomerization to
produce radical 54. Further reduction of radical 54 to
alkyllithium 34a allows for cyclization via a SEinv pathway and
leads to spiropyrrolidine 35a. The overall stereochemical outcome
of the event is cyclization with retention of configuration.
With any enantioselective natural product synthesis,
unambiguous assignment of the absolute configuration is
essential. Sauviat and co-workers reported an optical rotation of
+11 for the hydrochloride salt of lepadiformine C. The synthetic
hydrochloride salt of lepadiformine C described herein has an
EXPERIMENTAL SECTION
■
General Experimental Details. All moisture sensitive reactions
were performed under a positive pressure of argon in flame- or oven-
dried glassware using standard septa/syringe techniques. Dichloro-
methane (CH2Cl2), diethyl ether (Et2O), toluene (PhMe) were
degassed and dried by filtration through alumina according to the
procedure by Grubbs.43 Chloroform (CHCl3), ethyl acetate (EtOAc),
nitromethane (MeNO2), hexanes and acetonitrile (MeCN) were
distilled over CaH2 under nitrogen or argon at atmospheric pressure
prior to use. All commercially available reagents were used as received,
unless otherwise stated. Thin layer chromatography (TLC) was
performed on Whatman K6F (250 μm) silica gel plates and visualized
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Article
using p-anisaldehyde stain. 1H NMR and 13C NMR spectra were
recorded at 500 and 125 MHz, respectively. 1H NMR spectra are
reported in ppm on the δ scale and referenced to the residual solvent
peaks. The data are presented as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad, app = apparent), coupling constant(s) in Hertz (Hz), and
integration. 13C NMR spectra are reported in ppm relative to CDCl3
(77.07 ppm). Unnumbered intermediates were assigned compound
numbers sequentially as S1, S2, S3, etc.
Experimental Procedures. (S)-Non-1-yn-3-ol (22b). To a
solution of (S)-1-(trimethylsilyl)non-1-yn-3-ol44 (25.6 g, 121 mmol)
in MeOH (500 mL) at 0 °C was added K2CO3 (20.0 g, 145 mmol).
After 1 h the suspension was passed through a pad of Celite
(2 cm) and concentrated to a yellow oil. Purification by column
chromatography (6:1 pentane/Et2O) gave the alcohol (16.3 g,
96%) as a clear oil. The spectral data matched those previously
reported in the literature.
column chromatography (96:4 pentane/Et2O) gave the ynone (4.19 g,
80%) as a clear oil: Rf = 0.70 (4:1 hexanes/EtOAc); IR (thin film)
1
2944, 2865, 2208, 1682, 1464 cm−1; H NMR (500 MHz, CDCl3) δ
4.62 (t, J = 6.3 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 2.58 (t, J = 7.2 Hz,
2H), 1.80−1.70 (m, 4H), 1.56−1.52 (m, 2H), 1.50−1.40 (m, 2H),
1.32−1.27 (m, 6H), 1.20−1.09 (m, 21H), 0.89 (s, 12H), 0.04 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 187.7, 93.6, 83.2, 63.0, 62.7, 45.2,
38.2, 32.0, 31.9, 29.0, 25.9, 24.8, 22.6, 20.5, 18.3, 18.0, 14.1, 12.2, −5.3;
HRMS (ESI) m/z Calcd for C29H58NaO3Si2 [M + Na]+ 533.3822,
found 533.3831.
(5S,8S)-Triisopropylsilyloxy-1-(tert-butyldimethylsiloxy)tetradec-
6-yn-5-ol (24b). To a solution of ynone S2 (4.19 g, 8.20 mmol) in
OmniSolv i-PrOH (100 mL) was added Ru[(S,S)-TsDPEN](η-p-
cymene) 21 (172 mg, 0.287 mmol, 3.5 mol %) producing a deep
purple solution. After 24 h, the red solution was concentrated in vacuo
to a dark red oil. Purification by column chromatography (95:5
pentane/Et2O) gave 24b (3.77 g, 90%) as a clear oil: Rf = 0.58 (4:1
22
hexanes/EtOAc); [α]D = −14.5 (c = 1.0, CHCl3); IR (thin film)
(S)-(Non-1-yn-3-yloxy)triisopropylsilyl (S1). To a solution of
alcohol 22b (5.00 g, 35.7 mmol) in CH2Cl2 (70.0 mL) at −78 °C
was added 2,6-lutidine (8.31 mL, 71.3 mmol, 2.0 equiv) and TIPSOTf
(11.5 mL, 42.8 mmol, 1.2 equiv). The mixture was allowed to warm to rt
over 18 h and the reaction was quenched with saturated aq. NaHCO3
(10 mL) and water (50 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were washed with brine, dried over MgSO4, and con-
centrated in vacuo to give a clear oil. Purification by column chromato-
graphy (98:2 pentane/Et2O) gave S1 (10.2 g, 97%) as a clear oil: Rf =
3350, 2935, 2866, 1464 cm−1; 1H NMR (500 MHz, CDCl3) δ 4.49 (t,
J = 6.3 Hz, 1H), 4.38 (q, J = 6.0 Hz, 1H), 3.62 (t, J = 6.5 Hz, 1H), 1.78
(d, J = 4.7 Hz, 1H), 1.74−1.66 (m, 4H), 1.58−1.53 (m, 2H), 1.52−
1.47 (m, 2H), 1.46−1.40 (m, 2H), 1.35−1.25 (m, 7H), 1.15−1.03 (m,
21H), 0.89 (s, 12H), 0.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
86.9, 84.8, 63.1, 63.0, 62.6, 38.9, 37.6, 32.5,31.8, 29.1, 26.0, 25.1, 22.7,
21.6, 18.4, 18.1, 14.1, 12.3, −5.3; HRMS (ESI) m/z Calcd for
C29H60NaO3Si2 [M + Na]+ 535.3979, found 535.3970.
(5S,8S)-Triisopropylsilyloxy-1-(tert-butyldimethylsiloxy)-
tetradecan-5-ol (S3). A Parr bomb with PtO2 (0.050 g) and alkyne
24b (9.45 g, 18.4 mmol) in EtOAc (35 mL) was charged to 200 psi
with H2 gas. After 10 h the suspension was filtered through a pad of
22
0.77 (3:1 pentane/Et2O); [α]D = −32.6 (c = 1.0, CHCl3); IR (thin
film) 3313, 2943, 2868, 1464, 1097 cm−1; 1H NMR (500 MHz, CDCl3)
δ 4.47 (td, J = 6.3, 6.3, 2.1 Hz, 1H), 2.38 (d, J = 2.0 Hz, 1H), 1.73−1.68
(m, 2H), 1.48 (m, 2H), 1.34−1.29 (m, 6H), 1.18−1.07 (m, 21H), 0.91
(t, J = 6.9 Hz, 3H); 13C NMR (125 MHz CDCl3) δ 85.9, 71.9, 63.0,
38.9, 31.8, 29.1, 24.9, 22.7, 18.1, 14.1, 12.3; HRMS (ESI) m/z Calcd for
C18H37OSi [M + H]+ 297.2614, found 297.2613.
Celite with EtOAc and concentrated in vacuo to give the alkane S3
22
(9.50 g, 99%) as a clear oil: Rf = 0.54 (4:1 hexanes/EtOAc); [α]D
=
2.9 (c = 1.0, CHCl3); IR (thin film) 3367, 2935, 2864, 1464 cm−1; 1H
NMR (500 MHz, CDCl3) δ 3.88−3.83 (m, 1H), 3.62 (t, J = 6.5 Hz,
3H), 1.69−1.66 (m, 1H), 1.65−1.34 (m, 12H), 1.34−1.23 (m, 8H),
1.07 (br s, 21H), 0.89 (br m, 11H), 0.05 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 72.3, 72.0, 63.2, 37.2, 36.4, 32.8, 32.1, 31.9, 31.8, 29.6,
26.0, 25.1, 22.7, 22.1, 18.3, 14.1, 12.7, −5.3; HRMS (ESI) m/z Calcd
for C29H64NaO3Si2 [M + Na]+ 539.4292, found 539.4279.
(8S)-Triisopropylsilyloxy-1-(tert-butyldimethylsiloxy)tetradec-6-
yn-5-ol (23b). To a solution of alkyne S1 (6.70 g, 22.5 mmol) in
THF/DMPU (85/15, 100 mL) at −78 °C was added n-BuLi (10.2 mL
of a 2.30 M solution in hexanes, 23.5 mmol) dropwise over 10 min.
The solution was then warmed to −20 °C over 20 min. After cooling
to −40 °C, aldehyde 18 (4.89 g, 22.6 mmol) was added over 1.2 h.
After 20 min, the reaction was quenched with saturated aq. NH4Cl
(25 mL) and H2O (25 mL), and the mixture was warmed to rt. After
dilution of the mixture with Et2O (50 mL) the organic layer was
separated and the aqueous layer was extracted with Et2O (3 × 50 mL).
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo to give a clear oil. Purification by
column chromatography (gradient 98:2 pentane/Et2O to 90:10
pentane/Et2O) gave 23b (9.99 g, 86%, 1:1 mixture of diastereomers)
as a clear oil: Rf = 0.63 (4:1 hexanes/EtOAc); [α]D22 = −15.9 (c = 1.0,
(5S,8S)-Triisopropylsilyloxy-tetradecan-1,5-diol (27b). To a solu-
tion of the alcohol S3 (3.61 g, 6.98 mmol) in MeOH (40 mL) was
added PPTS (1.93 g, 7.70 mmol, 1.1 equiv) and the mixture was
stirred for 2 h. The mixture was then concentrated in vacuo and
partitioned with EtOAc (50 mL) and H2O (50 mL). The organic layer
was separated and the aqueous layer was extracted with EtOAc (3 ×
30 mL). The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo to give a clear oil. Purification
by column chromatography (1:1 hexanes/EtOAc) gave 27b (2.80 g,
22
>99%) as a clear oil: Rf = 0.54 (1:1 hexanes/EtOAc); [α]D = 2.90
1
(c = 1.0, CHCl3); IR (thin film) 3369, 2942, 2866, 1464 cm−1; H
1
CHCl3); IR (thin film) 3338, 2939, 2866, 1464 cm−1; H NMR (500
NMR (500 MHz, CDCl3) δ 3.90−3.83 (m, 1H), 3.66 (t, J = 6.5 Hz,
2H), 3.63−3.58 (m, 1H), 1.88 (br s, 1H), 1.77 (br s, 1H), 1.65−1.40
(m, 12H), 1.36−1.22 (m, 8H), 1.07 (br s, 21H), 0.89 (t, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 72.2, 71.9, 62.8, 36.9, 36.4, 32.7,
32.1, 31.9, 31.8, 29.7, 25.2, 22.7, 21.9, 18.2, 14.1, 12.6; HRMS (ESI)
m/z Calcd for C23H50NaO3Si [M + Na]+ 425.3427, found 425.3427.
(5R,8S)-Triisopropylsilyloxy-1,5-dibromododecane (15b). To a
suspension of triphenylphosphine (0.419 g, 1.60 mmol) and bromine
(1.54 mL, 30.0 mmol) in toluene (125 mL) at 0 °C was added a solution
of 27b (5.50 g, 13.7 mmol) and triethylamine (4.81 mL, 34.3 mmol) in
toluene (25 mL). After 12 h, the reaction mixture was diluted with Et2O
(100 mL) and filtered to remove the resultant precipitate. The filtrate
was washed with 1N aq. Na2S2O3 (25 mL), the organic layer was
separated and the aqueous layer was extracted with Et2O (2 × 25 mL).
The combined organic layers were dried over MgSO4, and concentrated
in vacuo to give a yellow oil. Purification by column chromatography
(98:2 hexanes/Et2O) gave 15b (6.24 g, 86%) as a clear oil: Rf = 0.60
MHz, CDCl3) δ 4.50 (t, J = 6.3 Hz, 1H), 4.39 (q, J = 6.0, 1H), 3.62
(t, J = 6.5 Hz, 2H), 1.75 (dd, J = 5.5, 1.9 Hz, 1H), 1.72−1.66 (m, 4H),
1.57−1.40 (m, 6H), 1.38−1.26 (m, 6H), 1.18−1.05 (m, 20H), 0.90 (s,
9H), 0.89 (t, J = 7.4 Hz, 3H), 0.05 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 86.9, 84.8, 63.1, 63.1, 62.6, 38.9, 37.6, 32.4, 31.8, 29.1, 26.0,
25.1, 22.7, 21.6, 18.4, 18.1, 14.1, 12.3, −5.3; HRMS (ESI) m/z Calcd
for C29H60NaO3Si2 [M + Na]+ 535.3979, found 535.3985.
(8S)-Triisopropylsilyloxy-1-(tert-butyldimethylsiloxy)tetradec-6-
yn-5-one (S2). To a solution of oxalyl chloride (1.17 mL, 13.4 mmol)
in CH2Cl2 (67 mL) at −78 °C was added dimethyl sulfoxide (1.60 mL,
22.6 mmol) in CH2Cl2 (33 mL) dropwise via addition funnel. The
mixture was allowed to stir for 30 min before a solution of alcohol 23b
(5.27 g, 10.3 mmol) in CH2Cl2 (33 mL) was added via addition funnel
over 20 min. After 30 min, EtN(i-Pr)2 (6.3 mL, 40.0 mmol) was added
dropwise by addition funnel, and the mixture was allowed to stir at
−78 °C for 1 h. Upon warming for 30 min, the reaction mixture was
poured on saturated aq. NH4Cl (50 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo to give a clear oil. Purification by
22
(95:5 hexanes/EtOAc); [α]D = 3.6 (c = 1.0, CHCl3); IR (thin film)
2941, 2866, 1464 cm−1; 1H NMR (500 MHz, CDCl3) δ 4.01 (tt, J = 8.3,
8.3, 4.7, 4.7 Hz, 1H), 3.83 (quintet, J = 5.7 Hz, 1H), 3.42 (t, J = 6.8 Hz,
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Article
2H), 1.91−1.80 (m, 5H), 1.75−1.67 (m, 1H), 1.63−1.45 (m, 5H), 1.29
(s, 9H), 1.07 (br s, 21H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 71.8, 58.4, 38.3, 36.9, 34.5, 34.2, 33.4, 32.2, 29.7, 26.3,
24.9, 22.7, 18.3, 14.2, 12.7; HRMS (APCI) m/z Calcd for C23H49OSiBr2
[M + H]+ 527.1921, found 527.1917.
Spiropyrrolidine 35b. An oven-dried round−bottom flask equipped
with a glass stir bar was cooled under vacuum and backfilled with argon.
The flask was charged with 1,10-phenanthroline (1 crystal), and a
solution of phosphate 33b (159 mg, 0.222 mmol) in THF (5.5 mL).
The solution was cooled to −78 °C and n-BuLi (ca. 2 M solution in
hexane) was added until a dark brown color persisted (2 drops).
To that solution at −78 °C was added LiDBB (∼0.5 M, 0.98 mL,
0.488 mmol) via syringe in a steady stream over 30 s to produce a
solution that remained dark green for at least 20 s. The mixture was stirred
for 1.5 h, then diluted with MeOH (0.1 mL) and saturated aq. NH4Cl
(1 mL). The reaction mixture was diluted with Et2O (4 mL), the
aqueous layer was separated and extracted with Et2O (3 × 3 mL). The
combined organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo to give a light yellow viscous solid. Purifi-
cation by column chromatography (gradient 97:3 hexane/CH2Cl2
then 98:2 hexane/EtOAc to 95:5 hexane/EtOAc) gave 35b (108 mg,
Aminonitrile 14b. To a solution of α-aminonitrile 16 (2.24 g,
6.81 mmol) and dibromide 15b (0.938 g, 5.68 mmol) in THF (45 mL)
and DMPU (45 mL) at −78 °C was added LDA (14.2 mL of a 1.0 M
solution in THF, 14.2 mmol, 2.5 equiv) over 20 min. The reaction was
stirred for 1 h and slowly warmed to 0 °C over 1 h. The solution was
cooled to −78 °C and LDA (5.69 mL of a 1.0 M solution in THF,
5.69 mmol, 1.0 equiv) was added dropwise over 10 min. The mixture
was stirred for 10 min, warmed to 0 °C over 1 h, and the reaction was
quenched with saturated aq. NH4Cl (10 mL) and water (10 mL). The
organic layer was separated and the aqueous layer was extracted with
Et2O (4 × 25 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo to give a yellow
oil. Purification by column chromatography (97:3 hexane/EtOAc)
gave 14b (3.16 g, 80%) as a clear oil: Rf = 0.48 (9:1 hexanes/EtOAc);
[α]D22 = −2.2 (c = 1.5, CHCl3); IR (thin film) 2931, 2866, 1697, 1466,
22
91%) as a clear oil: Rf = 0.29 (95:5 hexanes/EtOAc); [α]D = −19.1
(c = 3.0, CHCl3); IR (thin film) 2935, 2866, 1693, 1462, 1381 cm−1;
1H NMR (500 MHz, Benzene-d6, minor rotamer peaks denoted by *)
δ 4.05−3.95 (m, 1H), 3.70* (app. quint, J = 5.8 Hz) 3.48−3.40
(m, 1H), 3.26* (dd, J = 8.2 Hz), 2.94 (t, J = 11.9 Hz, 1H), 2.70* (dt,
J = 3.6, 13.0 Hz), 1.95−1.85 (m, 1H), 1.85−1.75 (m, 1H), 1.75−1.62
(m, 3H), 1.54 (s, 9H), 1.50−1.43 (m, 3H), 1.43−1.29 (m, 9H), 1.29−
1.09 (m, 20H), 1.09−0.99 (m, 1H) 0.93 (t, J = 6.8 Hz, 3H); 13C NMR
(125 MHz, Benzene-d6, 343K, minor rotamer denoted by *) δ 154.9,
78.6, 73.9*, 73.6, 68.2, 49.4*, 49.1, 44.0, 39.6, 37.5, 37.3*, 37.2*, 35.5,
34.0*, 32.7*, 32.7, 30.8, 30.5, 29.3*, 29.1*, 27.2, 26.8, 26.2, 25.6*,
25.6, 25.2, 24.4, 24.3*, 23.4, 21.6*, 21.5, 19.0*, 18.9, 14.5, 13.7; HRMS
(ESI) m/z Calcd for C32H63NNaO3Si [M + Na]+ 560.4475, found
560.4461.
1
1392 cm−1; H NMR (500 MHz, Benzene-d6, 343 K) δ 3.93 (app s,
1H), 3.75 (app d, J = 7.7 Hz, 2H), 3.66 (app s, 2H), 2.98 (brs, 1H),
2.64 (t, J = 13.2 Hz, 1H), 2.00 (brm, 2H), 1.95−1.83 (m, 3H), 1.82−
1.71 (m, 1H)1.71−1.65 (m, 1H), 1.65−1.59 (m, 2H), 1.58−1.49 (m,
4H), 1.45 (s, 9H), 1.49−1.41 (m, 4H), 1.41−1.28 (m, 8H), 1.20−1.14
(m, 24H), 0.98 (s, 10H), 0.93 (app s, 3H), 0.09 (s, 6H); 13C NMR
(125 MHz, Benzene−d6, 343 K) δ 153.4, 117.7, 79.8, 72.5, 67.5, 61.0,
47.2, 41.3, 36.6, 34.2, 33.8, 33.6, 31.7, 29.54, 29.5, 28.0, 26.4, 25.7,
24.7, 24.6, 23.7. 22.4, 18.1, 18.0, 13.6, 12.8, −5.5; HRMS (ESI) m/z
Calcd for C39H78N2NaO4Si2 [M + Na]+ 717.5398, found 717.5385.
Amino Alcohol S4. To a solution of 14b (3.16 g, 4.54 mmol) in
MeOH (130 mL) was added PPTS (1.26 g, 4.99 mmol). The mixture
was stirred at rt for 12 h then concentrated in vacuo and partitioned
with EtOAc (50 mL) and water (25 mL). The organic layer was
separated and the aqueous layer was extracted with EtOAc (3 × 20 mL).
The combined organic layers were dried over MgSO4, and concentrated
in vacuo to give a clear oil. Purification by column chromatography (4:1
hexane/EtOAc) gave the alcohol (2.04 mg, 77%) as a clear oil: Rf = 0.44
(2:1 hexanes/EtOAc); [α]D22 = −5.0 (c = 1.15, CHCl3); IR (thin film)
Prolinal 37. To a solution of spiropyrrolidine 35a (200 mg, 0.390
mmol) and TMEDA (76 μL, 0.51 mmol) in Et2O (3.5 mL) at −78 °C
was added s-BuLi (392 μL of a 1.3 M solution in cyclohexane, 0.51
mmol). After 3 h, DMF (46 μL, 0.59 mmol) was added followed by
saturated aq. NH4Cl (1.5 mL) and water (1 mL). The organic layer
was separated and the aqueous layer was extracted with Et2O (3 × 3 mL).
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo to give a clear oil. Purification by
column chromatography (98:2 hexanes/EtOAc) gave 37 (64 mg, 31%,
86% brsm, 4:1 dr) as a clear oil as well as recovered spiropyrrolidine
(126 mg): 1H NMR (500 MHz, CDCl3) δ 9.57−9.30 (rotameric
doublet, J = 3.4 Hz, 1H), 4.30−4.21 (m, 1H), 4.08 (dt, J = 7.5, 3.1 Hz,
1H), 3.80 (quintet, J = 5.3 Hz, 2H), 2.58−2.49 (m, 1H), 2.38 (dt, 1H),
2.34−2.12 (m, 1H), 2.10−1.61 (m, 12H), 1.58−1.44 (m, 11H), 1.42−
1.36 (diastereo and rotameric singlets, 11H), 1.36−1.20 (m, 13H), 1.05
(diasteriomeric singlets, 32H), 0.94−0.84 (m, 8H); 13C NMR (125
MHz, CDCl3) δ 200.4, 152.3, 80.4, 72.4, 69.9, 67.8, 66.4, 42.6, 40.7, 36.2,
35.5, 34.2, 29.4, 28.3, 27.0, 26.2, 25.7, 24.3, 23.5, 23.1, 18.3, 14.2, 12.7,
201.3, 154.5, 80.7, 72.0, 68.9, 67.1, 66.7, 41.2, 36.1, 35.7, 34.6, 29.7, 28.5,
26.9, 25.8, 25.1, 24.4, 23.1, 18.3, 14.2, 12.7; IR (thin film) 2931, 1739,
1712, 1674, 1462 cm−1; HRMS (ESI) m/z calcd for C31H59NNaO4Si
[M + Na]+ 560.4111, found 560.4105.
1
3471, 2935, 2866, 1697, 1466, 1392 cm−1; H NMR (500 MHz, C6D6,
343 K) δ 3.93 (quintet, J = 5.1 Hz, 1H), 3.75−3.62 (m, 2H), 3.50 (t, J =
6.0 Hz, 2H), 2.87 (brs, 1H), 2.51 (t, J = 11.5 Hz, 1H), 1.95−1.71 (m,
6H), 1.70−1.57 (m, 3H), 1.57−1.46 (m, 5H), 1.41 (s, 9H), 1.46−1.39
(m, 4H), 1.39−1.26 (m, 7H), 1.25−1.02 (m, 24H), 0.93 (brt, J = 6.6 Hz,
3H); 13C NMR (125 MHz, C6D6, 343 K) δ 153.9, 117.7, 80.4, 72.4, 67.0,
59.4, 46.3, 41.5, 36.5, 34.3, 33.8, 33.4, 31.7, 29.5, 29.48, 27.9, 26.3, 24.7,
24.6, 23.6, 22.4, 18.0, 13.6, 12.8; HRMS (ESI) m/z Calcd for
C33H64N2NaO4Si [M + Na]+ 603.4533, found 603.4531.
Diethylphosphate 33b. To a solution of the alcohol S4 (127 mg,
0.219 mmol) in THF (6 mL) at 0 °C was added N-methylimidazole
(841 μL, 0.876 mmol) followed by diethyl chlorophosphate (548 μL,
0.657 mmol). After 2.5 h, saturated aq. NaHCO3 (2.0 mL) and brine
(2.0 mL) were added and the mixture was diluted with EtOAc (5 mL).
The organic layer was separated and the aqueous layer was extracted
with EtOAc (5 × 5 mL). The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo to give a clear
oil. Purification by column chromatography (2:1 hexanes/EtOAc)
gave 33b (149 mg, 95%) as a clear oil: Rf = 0.27 (4:3 hexanes/EtOAc);
Alcohol S5. To a solution of prolinal 37 (34 mg, 0.063 mmol) in
EtOH (1 mL) at 0 °C was added sodium borohydride (3.1 mg,
0.082 mmol). The reaction mixture was heated to 70 °C for 45 min,
cooled to r.t., and partitioned between Et2O (2 mL) and brine (2 mL).
The organic layer was separated and the aqueous layer was extracted
with Et2O (3 × 3 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo to give a clear oil.
Purification by column chromatography (9:1 hexanes/EtOAc) gave S5
22
[α]D = −2.7 (c = 1.35, CHCl3); IR (thin film) 2935, 2866, 1697,
1
1466, 1392, 1369 cm−1; H NMR (500 MHz, C6D6) δ 4.08 (dd, J =
1
5.9 Hz, 2H), 4.00 (quint, J = 6.9 Hz, 4H), 3.91 (brm, 1H), 3.80−3.62
(m, 2H), 3.05 (brs, 1H), 2.61 (brs, 1H), 2.15−1.95 (m, 2H), 1.95−
1.80 (m, 2H), 1.80−1.70 (m, 2H), 1.70−1.57 (m, 3H), 1.50−1.45 (m,
5H), 1.43 (s, 9H), 1.45−1.38 (m, 2H), 1.35−1.27 (app s, 8H), 1.18
(s) and 1.02 (s, 19H), 1.15−1.03 (m, 9H), 0.92 (brt, J = 6.6 Hz, 3H);
(23 mg, 68%, 4:1 dr) as a clear oil: H NMR (500 MHz, CDCl3) δ
4.35 (brs, 1H), 4.20−4.11 (m, 1H), 4.08−3.98 (m, 1H), 3.88−3.82
(m, 1H), 3.82−3.75 (m, 1H), 3.72−3.58 (m, 2H), 2.38−2.13 (m, 2H),
2.10−1.95 (m, 2H), 1.94−1.77 (m, 3H), 1.77−1.55 (m, 8H), 1.48 (s,
8H), 1.47 (s, 8H), 1.46 (s, 4H), 1.40−1.20 (m, 14H), 1.06 (s, 8H),
1.05 (s, 24H), 1.00−0.80 (m, 8H); 13C NMR (125 MHz, CDCl3) δ
156.7, 80.4, 72.4, 72.0, 69.3, 68.6, 62.8, 42.2, 39.0, 36.7, 36.2, 35.6,
34.7, 31.5, 28.6, 26.8, 26.3, 25.2, 24.5, 23.1, 18.3, 12.7; IR (thin film)
3130, 2930, 1720 cm−1; HRMS (ESI) m/z calcd for C31H61NO4SiNa
[M + Na]+ 562.4268, found 562.4269.
13C NMR (125 MHz, C6D6) δ 153.1, 117.7, 80.2, 72.2, 64.8 (d, 2JPC
=
6.3 Hz), 63.1 (ddd, 2JPC = 2.8 Hz), 41.0, 36.5, 34.0, 33.6, 31.9, 31.2 (d,
2JPC = 6.3 Hz), 29.7, 29.4, 27.9, 26.2, 24.7, 24.6, 23.7, 22.6, 18.1 (d, 3JPC
=
2.5 Hz), 15.8 (d, 3JPC = 6.3 Hz), 13.9, 12.7; HRMS (ESI) m/z Calcd for
C37H73N2NaO7SiP [M + Na]+ 739.4822, found 739.4815.
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Article
Acetate 46. To a solution of alcohol S5 (23 mg, 0.046 mmol) in
CH2Cl2 (0.5 mL) was added acetyl chloride (15 μL, 0.21 mmol),
pyridine (14 μL, 0.17 mmol) and DMAP (0.6 mg, 0.005 mmol),
respectively. After 12 h, the mixture was diluted with CH2Cl2, and the
reaction was quenched with saturated aq. NH4Cl (2 mL). The organic
layer was separated and the aqueous layer was extracted with Et2O
(3 × 3 mL). The combined organic layers were dried over MgSO4, and
concentrated in vacuo to give a clear oil. Purification by column
chromatography (9:1 hexanes/EtOAc) gave 46 (24 mg, 95%, 4:1 dr)
column chromatography (gradient 200:9:1 CHCl3/MeOH/NH4OH)
gave the compound 48 (3.0 mg, 41%) as a clear oil: 1H NMR (500 MHz,
CDCl3) δ 4.15 (dd, J = 10.2, 4.0 Hz, 1H), 3.73 (t, J = 8.4 Hz, 1H), 3.42−
3.30 (brm, 1H), 3.20−3.07 (brm, 1H), 2.05 (s, 3H), 1.94−1.86 (m, 1H),
1.80−1.56 (m, 10H), 1.56−1.43 (m, 4H), 1.43−1.15 (m, 9H), 1.04 (dq,
J = 12.5, 3.5 Hz, 1H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 171.2, 70.56, 67.9, 56.5, 53.6, 41.2, 37.9, 34.1, 30.9, 30.0, 28.4,
28.0, 26.4, 24.5, 24.0, 23.1, 22.5, 21.2, 14.2; cm−1; HRMS (ESI) m/z calcd
for C19H33O2NH [M + H]+ 308.2589, found 308.2587.
Lepadiformine B (12). To a solution of the tricyclic acetate 48
(3.0 mg, 0.010 mmol) in MeOH (0.2 mL) was added sodium
methoxide (5 mg, 0.10 mmol). After 1 h, EtOAc (1 mL) and saturated
aq. NH4Cl (1 mL) were added. The organic layer was separated and
the aqueous layer was extracted with EtOAc (3 × 1 mL). The com-
bined organic layers were dried over K2CO3 and concentrated in vacuo
to give a clear oil. Purification by column chromatography (gradient
200:9:1 CHCl3/MeOH/NH4OH) gave lepadiformine B (12) (2.6 mg,
>95%) as a clear oil. Lepadiformine B was converted to the HCl salt by
treatment with anhydrous HCl/CHCl3 (1.0 mL) followed by
concentration in vacuo. The spectral data matched those previously
reported in the literature.24
1
as a clear oil: H NMR (500 MHz, CDCl3) δ 4.29−4.07 (m, 2H),
4.07−3.92 (m, 1H), 3.90−3.75 (m, 1H), 2.56−2.46 (m, 1H), 2.35−
2.15 (m, 1H), 2.14−2.02 (m, 4H), 2.00−1.77 (m, 3H), 1.75−1.56 (m,
7H), 1.51−1.42 (m, 13H), 1.41−1.20 (m, 11H), 1.06 (s, 10H), 1.05
(s, 13H), 0.99−0.80 (m, 6H); 13C NMR (125 MHz, CDCl3) major
diastereomer: δ 170.9, 152.7, 79.2, 72.5, 68.9, 65.2, 58.1, 42.1, 40.0,
38.5, 36.2, 34.2, 31.1, 29.7, 28.5, 27.0, 26.3, 25.8, 24.2, 21.0, 18.2, 12.7;
minor diastereomer: 171.1, 153.9, 79.7, 72.4, 68.2, 64.6, 58.3, 41.3,
39.6, 36.1, 34.7, 31.7, 29.6, 28.6, 26.8, 26.2, 25.7, 25.3, 24.3, 21.1, 18.3,
12.6; cm−1; HRMS (ESI) m/z calcd for C33H63NO5SiNa [M + Na]+
604.4373, found 604.4368.
Alcohol S6. To a solution of 46 (23 mg, 0.040 mmol) in THF
(0.8 mL) at 0 °C was added TBAF (53 μL of a 1 N solution in THF,
0.053 mmol) and the mixture was stirred at rt. After 12 h, the solution
was diluted with Et2O (1 mL) followed by water (1 mL). The organic
layer was separated and the aqueous layer was extracted with Et2O (3 ×
3 mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo to give a clear oil. Purification by column
chromatography (2:1 hexane/EtOAc) gave S6 (15 mg, 91%, 4:1 dr) as
Alcohol S7. To a solution of TIPS ether 35b (380 mg, 0.706 mmol)
in THF (11 mL) at 0 °C was added TBAF (560 μL of a 1 N solution
in THF, 0.560 mmol). After 12 h at 0 °C, the solution was diluted with
Et2O (10 mL) and poured on water (5 mL). The organic layer was
separated and the aqueous layer was extracted with Et2O (3 × 5 mL).
The combined organic layers were dried over MgSO4 and concen-
trated in vacuo to give a clear oil. Purification by column chromato-
graphy (4:1 hexane/EtOAc) gave S7 (206 mg, 97%) as a clear oil: Rf =
1
a clear oil: Rf = 0.21 (4:1 hexanes/EtOAc): H NMR (500 MHz,
22
0.21 (4:1 hexanes/EtOAc); [α]D = −27.3 (c = 0.37, CHCl3); IR
CDCl3) δ 4.33−4.19 (m, 1H), 4.19−4.09 (m, 2H), 4.09−3.88 (m,
3H), 3.60−3.47 (m, 2H), 2.67−2. 57 (m, 1H), 2.50−2.42 (m, 1H),
2.37−2.09 (m, 3H), 2.10 (s, 4H), 2.05 (s, 2H), 2.00−1.77 (m, 6H),
1.76−1.51 (m, 14H), 1.48 (s, 4H), 1.45 (s, 14H), 1.44−1.10 (m,
23H), 0.90 (m, 7H); 13C NMR (125 MHz, CDCl3) major
diastereomer: δ 170.9, 153.0, 126.7, 79.4, 72.8, 68.9, 65.1, 58.2,
40.1, 38.4, 37.1, 35.4, 31.4, 29.8, 28.6, 27.8, 26.3, 25.8, 24.2, 22.8, 21.0,
14.1; minor distereomer: 171.1, 154.0, 125.7, 79.9, 72.5, 69.6, 64.6,
58.3, 39.5, 36.9, 36.0, 31.8, 30.8, 29.6, 28.6, 27.9, 26.2, 25.8, 24.3, 22.8,
21.1, 14.2; IR (thin film) 3243, 2934, 2893, 1710, 1695 cm−1; HRMS
(ESI) m/z calcd for C24H43NO5Na [M + Na]+ 448.3039, found
448.3022.
1
(thin film) 3464, 2927, 2858, 1693, 1682, 1454 cm−1; H NMR (500
MHz, CDCl3, minor rotamer denoted by *) δ 3.76−3.70* (m), 3.60−
3.50 (m, 1H), 3.50−3.39 (m, 1H), 3.23−3.15* (m, 1H), 3.08−3.00
(app. t, J = 10.0 Hz, 1H), 2.55 (dt, J = 13.7, 4.2 Hz, 1H), 2.40−
2.32* (m), 2.25−2.18* (m), 2.04 (app. s, 1H), 1.85 (app. d, J = 11.9
Hz, 1H), 1.71−1.64 (m, 9H), 1.51 (s, 9H), 1.43−1.25 (m, 11H),
1.24−1.11 (m, 1H), 1.11−0.95 (m, 1H), 0.82 (t, J = 6.6 Hz, 3H),
0.88−0.75 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 153.6, 78.5,
73.1, 72.1*, 68.2, 49.1*, 49.0, 43.4*, 41.0, 38.3, 38.0*, 36.7*, 35.7,
34.4, 32.4, 31.5*, 30.1, 29.9, 29.8, 28.7, 27.5, 26.8*, 26.3, 26.2,
26.1*, 24.9*, 24.7, 23.1, 22.5, 22.0*, 14.4; HRMS (ESI) m/z Calcd
for C23H43NNaO3 [M + Na]+ 404.3141, found 404.3134.
Mesylate 36b. To a solution of alcohol S7 (206 mg, 0.540 mmol) in
CH2Cl2 (10 mL) at 0 °C was added 2,6−lutidine (115 μL, 0.840 mmol)
followed by methanesulfonyl chloride (49 μL, 0.630 mmol).
After 12 h at 0 °C, the reaction mixture was poured on water
(3 mL), the organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (5 × 5 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo to give a clear oil.
Mesylate 47. To a solution of alcohol S6 (10 mg, 0.024 mmol) in
CH2Cl2 (0.5 mL) was added 2,6-lutidine (8.2 μL, 0.070 mmol)
followed by methanesulfonyl chloride (4.2 μL, 0.053 mmol). After
12 h, water (2 mL) and CH2Cl2 (2 mL) were added, the organic layer
was separated, and the aqueous layer was extracted with CH2Cl2 (4 ×
2 mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo to give a clear oil. Purification by column
chromatography (4:1 hexane/EtOAc) gave the product (12 mg, >95%,
1
Purification by column chromatography (4:1 hexane/EtOAc) gave 36b
4:1 dr) as a clear oil: H NMR (500 MHz, CDCl3) δ 4.75−4.61 (m,
22
(238 mg, 96%) as a clear oil: Rf = 0.45 (3:1 hexanes/EtOAc); [α]D
=
1H), 4.31−4.18 (m, 1H), 4.16−4.07 (m, 1H), 4.07−4.00 (m, 1H),
3.99−3.89 (m, 1H), 2.99 (three s, 3H), 2.60−2.45 (m, 1H), 2.30−2.13
(m, 1H), 2.07 (two s, 3H), 1.98−1.75 (m, 3H), 1.75−1.61 (m, 5H),
1.46 (two s, 10H), 1.40−1.28 (m, 5H), 1.28−1.09 (m, 2H), 1.08−0.95
(m, 1H), 0.95−0.85 (m, 4H); 13C NMR (125 MHz, CDCl3) major
diastereomer: δ 170.9, 152.8, 84.8, 79.4, 68.7, 65.1, 58.2, 39.7, 38.8,
38.6, 34.3, 33.3, 32.8, 29.7, 28.6, 27.1, 26.3, 25.7, 24.1, 22.5, 21.1,
19.8, 14.0; minor diastereomer: 171.1, 153.9, 83.8, 79.9, 68.1, 64.7,
58.4, 38.7, 38.6, 34.5, 33.4, 32.3, 29.5, 28.7, 27.2, 26.2, 26.1, 24.2, 22.6,
21.1, 19.9, 14.1; IR (thin film) 2934, 2865, 1710, 1695 cm−1; HRMS
(ESI) m/z calcd for C25H45NO7SNa [M + Na]+ 526.2814, found
526.2818.
−28.2 (c = 1.0, CHCl3); IR (thin film) 2931, 2862, 1693, 1454 cm−1;
1H NMR (500 MHz, CDCl3, minor rotamer denoted by *) δ 4.68
(m, 1H), 3.72−3.65* (m), 3.48−3.34 (m, 1H), 3.29−3.21 (m, 1H),
2.93−2.84 (m, 1H), 2.63 (dt, J = 13.3, 3.7 Hz, 1H), 2.47* (s, 1H), 2.35
(s, 2H), 2.30−2.23* (m), 2.23−2.13* (m), 1.77−1.69 (m, 1H), 1.69−
1.62 (m, 2H), 1.62−1.55 (m, 3H), 1.55 (s, 9H), 1.48−1.41 (m, 1H),
1.40−1.30 (m, 4H), 1.29−1.23 (m, 2H), 1.22−1.09 (m, 4H), 0.89
(t, J = 6.9 Hz, 3H), 0.81 (dq, J = 12.7, 3.1 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 153.7*, 152.9, 83.6, 82.4*, 78.6*, 77.9, 67.4, 66.8*,
49.1*, 48.7, 43.0*, 40.4, 37.9, 35.4*, 34.9*, 34.6, 34.2, 33.5*, 32.9, 31.7,
31.1*, 30.0, 29.6, 29.5*, 29.1, 28.4, 26.3*, 26.0, 25.7, 25.2*, 25.0, 24.4*,
24.3, 22.7, 22.3, 21.7*, 14.0; HRMS (ESI) m/z Calcd for
C24H45NNaO5S [M + Na]+ 482.2916, found 482.2902.
Tricycle 48. To a solution of mesylate 47 (12.0 mg, 0.024 mmol) in
CH2Cl2 (0.5 mL) at 0 °C was added TFA (73 μL, 0.95 mmol). After
stirring for 1.5 h, volatile materials were removed in vacuo and the
residue was dissolved in THF (0.5 mL), followed by addition of satu-
rated aq. NaHCO3 (0.5 mL). After 14 h, CHCl3 (2 mL) was added and
the organic layer was separated. The aqueous layer was extracted with
CHCl3 (3 × 1 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo to give a clear oil. Purification by
Tricycle 13b. To a solution of mesylate 36b (169 mg, 0.444 mmol)
in dry CH2Cl2 (4.4 mL) at 0 °C was added TFA (657 μL, 8.88 mmol).
After stirring for 1 h, CHCl3 (6.0 mL) and saturated aq. NaHCO3
(6.0 mL) were added, respectively. After 3.5 h, the organic layer was
separated and the aqueous layer was extracted with CHCl3 (3 × 5 mL).
The combined organic layers were dried over K2CO3 and concentrated
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Article
in vacuo to give a yellow oil. The crude material was carried on without
further purification. H NMR (500 MHz, CDCl3) δ 3.45−3.35 (brm,
product; Rf = 0.22 (4:1 hexanes/EtOAc); [α]22D −2.9 (c 2.75, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 3.71−3.65 (m, 1H), 3.68 (s, 3H), 3.20−3.12
1.24 (m, 6H), 1.24−1.11 (m, 6H), 1.11−1.04 (m, 1H), 0.99 (dq, J =
3.4, 12.7, 1H), 0.85 (t, J = 6.9, 3H); 13C NMR (125 MHz, CDCl3) δ
178.0, 77.4, 67.7, 61.5, 53.1, 52.0, 39.8, 38.6, 34.1, 31.9, 30.6, 29.5,
28.1, 27.4, 26.4, 24.6, 23.1, 22.7, 22.1, 14.2; IR (thin film) 2927, 2858,
2360, 2341, 1732, 1462 cm−1; HRMS (ESI) m/z calcd for C20H35NO2H
[M + H]+ 322.2746, found 322.2741.
General Procedure for Methyl Ester Reduction. To a 0.31 M
solution of methyl ester in Et2O at 0 °C was added lithium aluminum
hydride (1.5 equiv). After 30 min at r.t., the reaction was quenched by
sequential addition of water (x mL), 4 M NaOH (x mL), and water
(2x mL). The organic layer was separated, and the aqueous layer was
extracted with Et2O (3x). The combined organic layers were dried
over Na2SO4 and concentrated in vacuo to give the natural product as a
pale-yellow oil. The natural product was converted to the HCl salt by
treatment with anhydrous HCl/CHCl3 (1.0 mL) followed by
concentration in vacuo. The spectral data matched those previously
reported in the literature.13,24
1
2H), 2.75 (dt, J = 10.6, 7.3 Hz, 1H), 2.0−1.83 (m, 4H), 1.83−1.63
(m, 6H), 1.63−1.54 (m, 2H), 1.54−1.39 (m, 3H), 1.39−1.24 (m, 3H),
1.24−1.03 (m, 10H), 0.96 (dq, J = 12.9, 3.6 Hz, 1H), 0.76 (t, J = 6.7 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 77.4, 72.3, 54.3, 46.7, 38.1, 35.5,
32.0, 31.5, 29.8, 29.1, 27.8, 26.2, 25.4, 23.9, 22.6, 22.5, 20.3, 14.0; IR (thin
film) 3425, 2931, 2862, 1469 cm−1; HRMS (ESI) m/z calcd for
C18H33NH [M + H]− 264.2691, found 264.2693.
General Procedure for Oxidative Cyanation. To a 0.1 M
solution of 13a,b in CH2Cl2 at 0 °C was added a 0.67 M solution of
m−CPBA (1.1 equiv) in CH2Cl2 dropwise. After complete conversion
of the amine to the N−oxide, saturated aq. Na2CO3 was added and the
mixture was warmed to r.t. The aqueous layer was extracted with
CHCl3 (3×) and dried over Na2SO4 and concentrated to a yellow oil.
To a 0.1 M solution of the crude N-oxide in CH2Cl2 at 0 °C was added
TFAA (5.0 equiv) and potassium cyanide (5.0 equiv), respectively.
After stirring for 1.5 h, water was added and the pH adjusted to ∼5
with potassium acetate. After 30 min, saturated aq. Na2CO3 and
CHCl3 were added. The organic layer was separated, and the aqueous
layer was extracted with CHCl3 (3×). The combined organic layers
were dried over Na2SO4 and concentrated in vacuo to give a yellow oil.
The crude nitrile was carried on without further purification.
Lepadiformine B (Hydrochloride Salt) (51a). Starting from methyl
ester 50a (8 mg, 0.03 mmol), 7 mg (86%) of the HCl salt of the
1
natural product 12 was obtained; [α]22 = +3.2 (c 0.3, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 10.2 (brs, 1H), 5.24 (brs, 1H), 4.18 (d,
J = 13.0, 1H), 3.68 (t, J = 10.7, 1H), 3.62 (d, J = 12.8, 2H), 2.55−2.48
(brm, 1H), 2.40 (brdq, J = 8.3, 12.6, 1H), 2.17 (app s, 2H), 2.06 (dd,
J = 6.8, 12.8, 2H), 1.95 (app t, J = 12.9, 2H), 1.88−1.71 (m, 4H), 1.68
(app d, J = 9.2, 3H), 1.58−1.40 (m, 3H), 1.40−1.28 (m, 7H), 1.28−
1.15 (m, 3H), 1.10−0.98 (brm, 1H), 0.91 (t, J = 6.8, 3H); 13C NMR
(125 MHz, CDCl3) δ 77.4, 63.6, 60.1, 58.8, 36.3, 33.9, 30.9, 29.7, 28.6,
26.6, 25.1, 24.4, 23.4, 22.7, 22.6, 19.3, 14.1; cm−1; HRMS (ESI) m/z
calcd for C17H31NOH [M + H]+ 266.2484, found 266.2480.
1
C4 Tricyclic Aminonitrile 49a. H NMR (500 MHz, CDCl3) δ
3.93* (dd, J = 2.9, 4.3 Hz, 0.16H), 3.75 (dd, J = 6.8, 10.4, 1H), 3.19−
3.11 (m, 1H), 3.11−3.04* (m, 0.18H), 2.20 (quint, J = 6.5 Hz, 1H),
2.12−2.00 (m, 1H), 1.94−1.86* (m, 0.5H), 1.82 (dd, J = 6.8, 12.8 Hz,
1H), 1.80−1.68 (m, 2H), 1.68−1.62 (m, 4H), 1.62−1.49 (m, 5H),
1.49−1.38 (m, 5H), 1.38−1.17 (m, 11H), 0.97 (dq, J = 3.2, 12.6 Hz,
1H), 0.91 (t, J = 7.1 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 123.0,
77.2, 67.4, 52.5, 47.4, 39.7, 38.8, 33.9, 29.8, 29.5, 27.6, 26.2, 24.5, 22.7,
22.6, 22.3, 14.1; minor isomer: 49.9, 49.2, 42.1, 38.0, 33.8, 29.6, 29.5,
29.3, 28.1, 27.3, 26.4, 24.8, 22.9, 14.1; IR (thin film) 2931, 2862, 2237
cm−1; HRMS (ESI) m/z calcd for C17H28N2H [M + H]+ 261.2331,
found 261.2337; C16H28N [M − CN]+ 234.2222, found 234.2229.
C6 Tricyclic Aminonitrile 49b. 1H NMR (500 MHz, CDCl3, minor
isomer denoted by *) δ 3.93* (app. s, 0.18H), 3.75 (dd, J = 6.7, 10.4,
1H), 3.20−3.11 (m, 1H), 3.11−3.04* (app. dq, J = 7.2, 14.1 Hz,
0.18H), 2.20 (quint., J = 6.6, 1H), 2.13−2.00 (m, 2H), 1.94−1.86* (m,
1H), 1.82 (dd, J = 6.7, 12.7, 2H), 1.79−1.68 (m, 3H), 1.68−1.61 (m,
4H), 1.61−1.55 (m, 2H), 1.55−1.48 (m, 4H), 1.47−1.35 (m, 5H),
1.35−1.17 (m, 20H), 1.17−1.05* (m, 0.5H), 0.97 (dq, J = 3.2, 12.6,
1H), 0.91 (brm, 5H); 13C NMR (125 MHz, CDCl3) δ 123.0, 77.3,
67.5, 52.6, 47.4, 39.7, 38.8, 34.3, 30.2, 29.9, 29.8, 29.4, 27.6, 27.3, 24.5,
22.7, 22.6, 22.3, 14.1; minor isomer: 123.8, 49.9, 49.2, 42.1, 38.0, 34.1,
29.7, 29.6, 29.4, 28.1, 27.3, 27.1, 26.4, 24.8, 22.9, 14.0; IR (thin film)
2931, 2858, 2360, 2341, 1778 cm−1; HRMS (ESI) m/z calcd for
C19H32N2Na [M + Na]+ 311.2463, found 311.2454.
Lepadiformine A (hydrochloride salt)(51b). Starting from methyl
ester 50b (20 mg, 0.06 mmol) 19 mg (94%) of the HCl salt of the
1
natural product 11 was obtained; [α]22 = +1.8 (c 0.8, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 10.1 (brs, 1H), 4.15 (d, J = 12.4 Hz, 1H),
3.70−3.56 (m, 3H), 2.50−2.43 (brm, 1H), 2.37 (brdq, J = 7.2, 12.9
Hz, 1H), 2.15 (app s, 2H), 2.04 (dd, J = 7.0, 12.9 Hz, 2H), 1.99−1.89
(m, 2H), 1.86−1.71 (m, 4H), 1.66 (app d, J = 10.1 Hz, 3H), 1.56−
1.42 (m, 2H), 1.42−1.35 (m, 3H), 1.35−1.29 (m, 5H), 1.29−1.15
(brm, 10H), 1.02 (brdq, J = 3.1, 12.6 Hz, 1H), 0.86 (t, J = 6.6 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 77.3, 63.5, 60.0, 58.8, 36.2, 33.8,
31.7, 30.8, 29.9, 29.1, 26.5, 26.4, 25.0, 24.3, 23.3, 22.6, 22.5, 19.2, 14.1;
cm−1; HRMS (ESI) m/z calcd for C19H35NOH [M + H]+ 294.2797,
found 294.2798.
ASSOCIATED CONTENT
* Supporting Information
■
S
Proton and Carbon NMR spectra for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
General Procedure for Hydrolysis of Aminonitrile to Methyl
Ester. A 0.17 M solution of nitrile in MeOH/H2SO4 (20:1) was
heated to 110 °C in a sealed tube. After 3 days, the solution was cooled
to 0 °C and adjusted to pH 8 with saturated aq. NaHCO3. The organic
layer was separated, and the aqueous layer was extracted with CHCl3
(3×). The combined organic layers were dried over Na2SO4 and con-
centrated in vacuo to give a brown oil. Purification by column chroma-
tography (4:1 hexane/EtOAc) gave the methyl ester as a yellow oil.
C4 Methyl Ester 50a. Starting from mesylate 36a (63.0 mg,
AUTHOR INFORMATION
■
Corresponding Author
*srychnov@uci.edu
0.146 mmol) the sequence provided 12 mg (28% over 5 steps) of product;
Notes
1
Rf = 0.29 (4:1 hexanes/EtOAc); [α]22 −43.0 (c 0.4, CHCl3); H
D
The authors declare no competing financial interest.
NMR (500 MHz, CDCl3) δ 3.74−3.66 (m, 1H), 3.69 (s, 3H), 3.21−
3.13 (m, 1H), 2.06 (dt, J = 6.6, 10.5, 1H), 1.80 (quint, J = 6.7, 2H),
1.80−1.70 (m, 1H), 1.70−1.60 (m, 3H), 1.60−1.51 (m, 2H), 1.51−
1.38 (m, 5H), 1.38−1.14 (m, 7H), 1.14−1.04 (m, 1H), 1.00 (dq, J =
3.2, 12.6, 1H), 0.85 (t, J = 7.0, 3H); 13C NMR (125 MHz, CDCl3) δ
178.0, 77.3, 67.7, 61.5, 53.0, 52.0, 39.8, 38.6, 33.7, 30.6, 29.6, 29.4,
28.1, 26.4, 24.6, 23.1, 23.0, 22.1, 14.2; IR (thin film) 2931, 2862, 1732
cm−1; HRMS (ESI) m/z calcd for C18H31NO2H [M + H]+ 294.2433,
found 294.2433.
ACKNOWLEDGMENTS
■
This project was supported by a generous gift from the
Schering-Plough Research Institute. Initial studies were
supported by NIGMS GM-65338. M.A.P. acknowledges Vertex
Pharmaceuticals for a Vertex Scholar fellowship. We thank Prof.
Jean-Francois Biard for providing authentic spectra for
lepadiformine C.
C6 Methyl Ester 50b. Starting from mesylate 36b (204 mg,
0.444 mmol) the sequence provided 61 mg (43% over 5 steps) of
3399
dx.doi.org/10.1021/jo300161x | J. Org. Chem. 2012, 77, 3390−3400

The Journal of Organic Chemistry
Article
Ihara, M.; Tokuyama, H. Synlett 2010, 822−826. (d) Lygo, B.; Kirton,
H. M.; Lumley, C. Org. Biomol. Chem. 2008, 6, 3085−3090.
(e) Caldwell, J. J.; Craig, D. Angew. Chem., Int. Ed. 2007, 46, 2631−
2634. (f) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2005,
127, 1473−1480. (g) Liu, J.; Hsung, R. P.; Peters, S. D. Org. Lett. 2004,
6, 3989−3992. (h) Abe, H.; Aoyagi, S.; Kibayashi, C. Angew. Chem.,
Int. Ed. 2002, 41, 3017−3020. (i) Sun, P.; Sun, C.; Weinreb, S. M. Org.
Lett. 2001, 3, 3507−3510. (j) Aoyagi, S.; Kibayashi, C. Tetrahedron
Lett. 2000, 41, 1205−1208.
DEDICATION
■
Dedicated to Professor Gilbert Stork on the occasion of his
90th Birthday.
REFERENCES
■
(1) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React. 1984, 31, 1−364.
(2) A review: Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747−
789.
(3) Stork, G.; Ozorio, A. A.; Leong, Y. W. Tetrahedron Lett. 1978, 52,
5175−5178.
(23) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337−
4345.
(24) Sauviat, M.-P.; Vercauteren, J.; Grimaud, N.; Nabil, M.; Petit,
J.-Y.; Biard, J.-F. J. Nat. Prod. 2006, 69, 558−562.
(25) (a) Meyer, A. M.; Katz, C. E.; Li, S.-W.; Vander Velde, D.; Aube,
J. Org. Lett. 2010, 12, 1244−1247. Formal Synthesis: (b) Weidner,
K.; Giroult, A.; Panchaud, P.; Renaud, P. J. Am. Chem. Soc. 2010, 132,
17511−17515.
(26) (a) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801−811.
(b) Ponpipom, M. M.; Hanessian, S. Carbohydr. Res. 1971, 18, 342−
344.
(4) Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1971, 93, 5286−5287.
(5) (a) Guillaume, D.; Brum-Bousquet, M.; Aitken, D. J.; Husson,
H.-P. Bull. Soc. Chim. France 1994, 131, 391−396. (b) Ribeiro, C. M. R.;
Sebastiao, J. M.; Bonin, M.; Quirion, J.; Husson, H.-P. Tetrahedron Lett.
1994, 35, 7227−7230.
(6) Badhe, R. J.; Rychnovsky, S. D. Org. Lett. 2008, 10, 4017−4020.
(7) Review: (a) Mattalia, J.-M.; Marchi-Delapierre, C.; Hazimeh, H.;
Chanon, M. Arkivoc 2006, 4, 90−118. Review: (b) Husson, H.-P.;
Royer, J. Chem. Soc. Rev. 1999, 28, 383−394. (c) Arapakos, P. J. Am.
Chem. Soc. 1967, 89, 6794−6796. (d) Fabre, C.; Welvart, Z. C. R. Acad.
Sci. Paris, Ser. C 1970, 270, 1887−1889. (e) Rychnovsky, S. D.; Zeller,
S.; Skalitzky, D. J.; Griesgraber, G. J. Org. Chem. 1990, 55, 5550−5551.
(f) Rychnovsky, S. D.; Powers, J. P.; Lepage, T. J. J. Am. Chem. Soc.
1992, 114, 8375−8384. (g) Rychnovsky, S. D.; Swenson, S. S. J. Org.
Chem. 1997, 62, 1333−1340. (h) Rychnovsky, S. D.; Hata, T.; Kim, A. I.;
Buckmelter, A. J. Org. Lett. 2001, 3, 807−810.
(8) (a) Bonin, M.; Romero, J. R.; Grierson, D. S.; Husson, H.-P.
Tetrahedron Lett. 1982, 23, 3369−3372. (b) Buckmelter, A. J.; Powers,
J. P.; Rychnovsky, S. D. J. Am. Chem. Soc. 1998, 120, 5589−5590.
(c) Francois, D.; Poupon, E.; Kunesch, N.; Husson, H.-P. Eur. J. Org.
Chem. 2004, 23, 4823−4829.
(9) (a) Zeller, E.; Grierson, D. S. Heterocycles 1988, 27, 1575−1578.
(b) Zeller, E.; Sajus, H.; Grierson, D. S. Synlett 1991, 44−46.
(10) Preliminary communication: Perry, M. A.; Morin, M. D.; Slafer,
B. W.; Wolckenhauer, S. A.; Rychnovsky, S. D. J. Am. Chem. Soc. 2010,
132, 9591−9593.
(27) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738−8739.
(28) Yadav, J. S.; Maniyan, P. P. Synth. Commun. 1993, 23, 2731−
2741.
(29) Dondoni, A.; Perrone, D. Synthesis 1997, 527−529.
(30) Mori, K.; Ohtaki, T.; Ohrui, H.; Berkebile, D. R.; Carlson, D. A.
Eur. J. Org. Chem. 2004, 1089−1096.
(31) Slafer, B. W. Ph. D. Thesis, University of California, 2009.
(32) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924−1930.
(33) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109−1117.
(34) The aldehydes (S)-37 and (R)-37 show Boc rotamers in the
NMR spectra, in common with many of the compounds prepared in
this paper. High-temperature NMR studies lead to partial coalescence
of the rotamers, but do not facilitate the assignment of diastereomer
ratios. The diastereomeric ratios were determined by GC/MS for
these two compounds, and a sample GC/MS printout is included in
the Supporting Information.
(11) (a) Rychnovsky, S. D.; Hata, T.; Kim, A. I.; Buckmelter, A. Org.
Lett. 2001, 3, 807−810. (b) Rychnovsky, S. D.; Takaoka, L. R. Angew.
Chem., Int. Ed. 2003, 42, 818−820. (c) Wolckenhauer, S. A.;
Rychnovsky, S. D. Org. Lett. 2004, 6, 2745−2748. (d) Takaoka,
L. R.; Buckmelter, A. J.; LaCruz, T. E.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2005, 127, 528−529. (e) LaCruz, T. E.; Rychnovsky, S. D. J. Org.
Chem. 2006, 71, 1068−1073. (f) Morin, M.; Rychnovsky, S. D. Org.
Lett. 2005, 7, 2051−2053.
(35) The configuration assignments of (S)-37 and (R)-37 were
consistent with the enantioselective metalations using (−)-sparteine
(44) and O’Brien’s (+)-sparteine surrogate, diamine 43. Metalation
with (−)-sparteine (Table 2, entry 10) favors the (R) product, and
metalation with diamine 43 (Table 2, entry 7) favors the (S) product.
(36) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409−
1412.
(37) Graeme, B.; O’Brien, P.; Campos, K. R. Org. Lett. 2010, 12,
4176−4179.
(12) Wolckenhauer, S. A.; Rychnovsky, S. D. Tetrahedron 2005, 61,
3371−3381.
(38) (a) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am.
Chem. Soc. 2003, 125, 15312−15313. (b) Murahashi, S.-I.; Komiya, N.;
Terai, H. Angew. Chem., Int. Ed. 2005, 44, 6931−6933. (c) Murahashi,
S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008, 130,
11005−11012.
(13) Biard, J.-F.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.; Weber,
J. F.; Boufek, K. Tetrahedron Lett. 1994, 35, 2691−2694.
(14) (a) Werner, K. M.; De los Santos, J. M.; Weinreb, S. M.; Shang, M.
J. Org. Chem. 1999, 64, 686−687. (b) Werner, K. M.; De los Santos,
J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1999, 64, 4865−4873.
(15) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122,
4583−4592.
(16) (a) Pearson, W. H.; Barta, N. S.; Kampf, J. W. Tetrahedron Lett.
1997, 38, 3369−3372. (b) Pearson, W. H.; Ren, Y. J. Org. Chem. 1999,
64, 688−689.
(17) (a) Bagley, M. C.; Oppolzer, W. Tetrahedron: Asymmetry 2000,
11, 2625−2633. (b) Oppolzer, W.; Bochet, C. G. Tetrahedron:
Asymmetry 2000, 11, 4761−4770.
(39) Allen, J. M.; Lambert, T. H. J. Am. Chem. Soc. 2011, 133, 1260−
1262.
(40) (a) Grierson, D. S.; Harris, M.; Husson, H.-P. J. Am. Chem. Soc.
1980, 102, 1064−1082. (b) Cave, A.; Kan-Fan, C.; Potier, P.; Le Men, J.
Tetrahedron 1967, 23, 4681−4689.
(41) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am. Chem. Soc.
1997, 119, 11561−11570.
(42) Fenster, M. D. B.; Dake, G. R. Chem.Eur. J. 2005, 11, 639−
649.
(18) Greshock, J. T.; Funk, R. L. Org. Lett. 2001, 3, 3511−3514.
(19) Lee, M.; Lee, T.; Kim, E.-Y.; Ko, H.; Kim, D.; Kim, S. Org. Lett.
2006, 8, 745−748.
(20) Swidorski, J. J.; Wang, J.; Hsung, R. P. Org. Lett. 2006, 8, 777−
780.
(43) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518−1520.
(44) Nishizawa, M.; Yamada, M; Noyori, R. Tetrahedron Lett. 1981,
22, 247−250.
(21) Schar, P.; Renaud, P. Org. Lett. 2006, 8, 1569−1571.
̈
(22) Review: (a) Weinreb, S. M. Chem. Rev. 2006, 106, 2531−2549.
Lepdiformine A: (b) Mei, S.-L.; Zhao, G. Eur. J. Org. Chem. 2010,
1660−1668. (c) Fujitani, M.; Tsuchiya, M.; Okano, K.; Takasu, K.;
3400
dx.doi.org/10.1021/jo300161x | J. Org. Chem. 2012, 77, 3390−3400