Unified total syntheses of fawcettimine class alkaloids: Fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B

Article abstract of DOI:10.1021/jo3006045

The total syntheses of the lycopodium alkaloids fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy that relies on a Diels-Alder reaction to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary center. Access to the enantioselective syntheses of both antipodes of those alkaloids can be achieved by kinetic resolution of the earliest intermediate via a Sharpless asymmetric dihydroxylation (Sharpless AD). Compared to existing approaches to these alkaloids, our synthetic route possesses superior stereocontrol over the C-4 and C-15 stereogenic centers as well as allowing for more functional variation on the 6-membered ring.

Full text of DOI:10.1021/jo3006045

Article
pubs.acs.org/joc
Unified Total Syntheses of Fawcettimine Class Alkaloids:
Fawcettimine, Fawcettidine, Lycoflexine, and Lycoposerramine B
,
†
Guojun Pan and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
†The University of Colorado Cancer Center, Aurora, Colorado 80045, United States
*
S Supporting Information
ABSTRACT: The total syntheses of the lycopodium alkaloids
fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B have
been accomplished through an efficient, unified, and stereo-
controlled strategy that relies on a Diels−Alder reaction to
construct the cis-fused 6,5-carbocycles with one all-carbon
quaternary center. Access to the enantioselective syntheses of
both antipodes of those alkaloids can be achieved by kinetic
resolution of the earliest intermediate via a Sharpless asymmetric
dihydroxylation (Sharpless AD). Compared to existing approaches
to these alkaloids, our synthetic route possesses superior stereocontrol over the C-4 and C-15 stereogenic centers as well as
allowing for more functional variation on the 6-membered ring.
INTRODUCTION
(1) to fawcettidine (2) seems to have been overlooked by the
■
10
laboratories who have studied the total synthesis of these
alkaloids as interrogation of this transformation has not been
heretofore reported. Lycoflexine (3) was isolated in 1973 by
The Lycopodium alkaloids continue to attract attention within
the chemical community due to their fascinating structures,
biogenesis, and range of interesting biological activities,
especially the demonstrated capacity of these substances to
inhibit acetylcholinesterase. The fawcettimine subclass, with
more than 80 members isolated thus far, features a cis-fused 6,5-
carbocyclic ring core connected to an azonine ring containing
an all-carbon quaternary center (Figure 1). The first member of
3c
Ayer and co-workers from Lycopodium clavatum var. inflexum.
1
,2
This alkaloid contains two adjacent all-carbon quaternary
centers. A biomimetic conversion of 1 to 3 via a Mannich
reaction was also reported by Ayer, which serves as the key step
6
b,11
in two recently reported total syntheses of (+)-3.
Lycoposerramine B (4), the first lycopodium alkaloid known
to contain an oxime functionality, was isolated in 2005 by
12a
Takayama and co-workers from Lycopodium serratum. The
biosynthesis of 4 from 1 was proposed, which requires the
inversion of the C-4 stereogenic center. However, this inversion
12a
was found to be difficult,
which is consistent with the
observation made by Heathcock’s group in their landmark
fawcettimine synthesis that the S-configuration at C-4 was
5
thermodynamically more stable than its epimer. A 10:1
mixture in favor of the S-epimer was also observed by Toste’s
6a
group in their (+)-fawcettimine synthesis. The difficulty in
controlling the formation of the uncommon R-configuration at
C-4 may, in part, account for the single reported total synthesis
7
of (+)-4.
Lobscurinol (5) and epilobscurinol (6) were isolated in 1989
Figure 1. Structures of representative fawcettimine class alkaloids.
3d
by Ayer and Kasitu from Lycopodium obscurum. They are two
isomeric alkaloids, and both contain an enone moiety.
Lycopoclavamine A (7) was isolated in 2011 by Takayama
and co-workers from Lycopodium clavatum. This alkaloid
contains a β-oriented methyl group at C-15, which differs
this class, fawcettimine (1), was isolated in 1959 by Burnell
from Lycopodium fawcetti, collected in the Blue Mountain
3
a
Range of Jamaica. This alkaloid has inspired significant
interest from the synthetic community, resulting in five total
12b
4
,5
6,7
from other fawcettimine class members. To date, no total
syntheses (two racemic, three enantioselective ) and two
8
formal syntheses. From the same plant, these workers also
3
b
isolated fawcettidine (2). Plausibly, 2 is biosynthesized from 1
Received: April 5, 2012
9
by dehydration. The biogenetic dehydration of fawcettimine
©
XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Article
synthesis or synthetic approach to alkaloids 5−7 has been
reported.
Scheme 2. Our Synthetic Plan for 1−4
Inspired by the fascinating and challenging structural
diversities demonstrated by the fawcettimine class alkaloids,
we embarked on their total syntheses, with the aim that a
general strategy could be developed to address many of the
family members. Herein we report our syntheses of 1−4 via an
efficient, unified, and stereocontrolled strategy.
RESULTS AND DISCUSSION
■
Retrosynthetic Analysis. From a strategic vantage, the
critical challenge in contemplating the synthesis of this class
alkaloids and many other members is the formation of the cis-
fused 6,5-carbocyclic core with one all-carbon quaternary
center. To date, the most frequently employed strategy has
relied upon exploiting the existing methyl group of 5-
methylcyclohex-2-enones to control the trans-addition of
4
16
reagents (diene for Inubushi’s synthesis and nucleophiles for
12. Enone 11 can be obtained from ketal 13, which is a
5
,6,8,10a,11
17
others
) in setting the C-7 stereogenic center (Scheme
known compound. It is worthy of note that by employing the
1
3
1
, A). Starting with enantiomerically pure 5-methylcyclohex-
enantiomerically pure form of 13, the enantiospecific syntheses
of 1−4 can also be achieved (vide infra).
Synthesis of 9. Our racemic syntheses of 1−4 commenced
with the known ketal 13, which could be synthesized in one
step from commercially available isoprene (14) and cyclo-
pentenone ethylene ketal (15) via an ionic Diels−Alder
Scheme 1. (A) Strategies Employed by Inubushi, Heathcock,
Toste, Liu and Chau, Jung, Yang, Dake, and Ramharter; (B)
Strategy Employed by Mukai
17
reaction (D−A) (Scheme 3). Oxidative cleavage of the
a
Scheme 3. Synthesis of Enone 11
a
Reagents and conditions: (a) 1.0 mol % of RuCl ·H O, NaIO ,
3
2
4
ClCH CH Cl/H O (v/v 5:4), rt, 3 h, 75%; (b) KOH, H O, reflux, 15
h, 79%.
6
,8,10a,11
2
2
2
2
2
-enones, enantiospecific syntheses have been realized.
Apparently, this strategy will not be suitable for the synthesis of
−)-lycopoclavamine A (7), which contains an unusual β-
(
18
oriented methyl group at C-15. Very recently, the Mukai group
reported an alternative strategy, which utilized a Pauson−
Khand reaction to set the C-7 stereogenic center (Scheme 1,
B). These workers also utilized the additional stereocontrol
garnered at C-4 to construct lycoposerramine B, although their
synthesis is quite lengthy, requiring more than 26 steps from
alkene moiety on 13 was effected under Yang’s conditions
and afforded keto-aldehyde 16 in 75% yield. In comparison, the
1
9
Lemieux−Johnson reagent (OsO and NaIO ) or ozonolysis
4
4
gave very low yield of the desired product. From 16, the
selective intramolecular aldol condensation/dehydration
2
0
process was achieved by treatment of 16 with KOH in
7
commercially available materials.
refluxing H O for 15 h. Enone 11 was thus obtained in 79%
2
Given the fact that most of the fawcettimine class alkaloids
yield, which set the stage for the key Diels−Alder reaction.
However, it is well-documented that enones like 11, which
lack a second activating group, are poor dienophiles for
intermolecular Diels−Alder reactions. In particular, this
potential hurdle was exacerbated in our case by the fact that
(1) enone 11 can be sensitive to Lewis or Brønsted acid
catalyzed conditions because of the labile ketal moiety and (2)
enone 11 is deactivated by β-alkyl substitution, both electroni-
cally and sterically.
14
are structurally related, a unified synthetic strategy with
inherent flexibility to access several members of this family
constitutes the current state-of-art in natural products synthesis.
In light of the common variations encountered on the 6-
membered carbocycles (hexanone or hexenone, etc.), we
envisioned that a highly stereoselective Diels−Alder reaction
could be utilized to construct this ring. Scheme 2 summarizes
our synthetic plan. Fawcettimine (1), fawcettidine (2), and
lycoflexine (3) can be derived from the same intermediate
21
Despite the fact that there was no literature precedent for a
D−A reaction between a β-alkyl-substituted enone and a 1-
siloxy-substituted diene, the reaction of enone 11 with diene 17
was chosen as a model to investigate the planned Diels−Alder
1
5
diketo amine 8, which in turn can be obtained from nosylate
with the inversion of the C-4 stereogenic center. With the
9
azonine cis-fused to the 5-membered ring, 9 was also envisioned
to serve as the synthetic progenitor for lycoposerramine B (4).
By disconnecting the azonine ring of 9 and reconnecting to
form a 5-membered ring, 9 was envisioned to be derived from
0, in which the ladder-like cis-fused 6,5,6 rings suggest a
Diels−Alder reaction (D−A) between enone 11 and diene
reaction (Table 1). As anticipated, Lewis acids such as ZnCl or
2
EtAlCl failed to yield any desired product. Both 11 and 17
2
were found to be unstable under these conditions (entries 1
and 2). We then focused our attention on thermal conditions.
Although no reaction took place in toluene at 110 °C, a 15%
1
B
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Table 1. Diels−Alder Reaction between Enone 11 and
Dienes
skeletons, was converted to enone 24 in 95% yield by
successive treatment of 10 with TBAF and Dess−Martin
24
periodinane (Scheme 4). This one-pot enone formation
a
Scheme 4. Synthesis of Diol 31
a,b
diene
T
yield
(%)
entry
(equiv)
solvent
CH Cl
(°C)
time product
c
1
17 (6.0)
17 (2.0)
17 (2.4)
17 (10.0)
17 (10.0)
17 (10.0)
17 (10.0)
17 (10.0)
12 (10.0)
12 (6.0)
12 (2.5)
12 (2.0)
18 (6.0)
19 (6.0)
20 (6.0)
0
3 h
1 h
10 h
4 d
3 d
10 h
9 h
16 h
6 h
9 h
9 h
10 h
4 h
4 h
4 h
21
21
21
21
21
21
21
21
10
10
10
10
22
23
24
0
0
2
2
d
2
CH Cl
−78
110
170
190
240
190
200
195
185
180
180
190
190
190
2
2
3
PhMe
xylene
n.r.
e
4
15 (75)
30 (67)
9
e
5
e
6
e,
e,
e,
f
f
f
7
8
9
48 (69)
37 (55)
35 (76)
56 (65)
74 (92)
58 (89)
0
e,f
1
0
a
e
,
,
f
,
,
g
Reagents and conditions: (a) TBAF, CH Cl , rt, 12 h; then NaHCO ,
2 2 3
1
1
2
Dess−Martin periodinane, rt, 6 h, 95% for one pot; (b) LiHMDS,
e
f
g
1
NCCO Me, Et O, −78 °C to rt, overnight, 60% (94% brsm); (c)
e
,
,
f
f
2
2
1
3
4
NaBH , MeOH/CH Cl (v/v 1:1), −42 °C, 5 h; then acetone, 1 M
4
2
2
e
1
0
HCl, 5 h, 80% for one pot; (d) m-CPBA, NaHCO , CH Cl , rt, 24 h,
3
2
2
e,f,h
1
5
22
92%; (e) MsCl, pyridine, rt, overnight, 97%; (f) 5 mol % of Pd/C, 5
mol % of Rh/Al O , H , 80 psi, 24 h; then DBU, H , 80 psi, 12 h, 93%
a
b
Yield of isolated product. Yield in parentheses is based on recovered
2
3
2
2
c
d
for one pot; (g) LiAlH , THF, reflux, overnight; (h) Ac O, cat. DMAP,
1
1. 25 mol % of ZnCl was added. 2.5 equiv of EtAlCl was added.
4
2
2
2
e
f
pyridine, rt, 24 h; (i) 5 mol % [t-Bu Sn(OH)Cl] , MeOH/THF (v/v
Reaction was performed in a sealed tube. Reaction was performed in
2
2
g
1
:1), rt, 30 h, 85% for three steps (≥95% brsm).
a microwave reactor. Reaction was performed with >1.0 g of 11.
h
Excess K CO in MeOH was added to quench the reaction.
2
3
together with the preceding highly selective Diels−Alder
reaction should be very useful for the syntheses of lobscurinol
(5), epilobscurinol (6) (Figure 1, vide supra), and other enone-
(
75% brsm) yield of D−A adduct 21 was isolated by heating
diene 17 and enone 11 in xylene at 170 °C for 4 days (entries 3
and 4). The yield could be improved to 30% (67% brsm) by
heating 11 and 17 in the absence of solvent at 190 °C for 3
days (entry 5). To our delight, the reaction time could be
dramatically shortened and the yield could be further improved
25a
containing alkaloids such as magellanine and magellanino-
25b
ne.
From enone 24, homologation and selective reduction of
26
27
the newly formed β-keto ester 25 under Ward’s conditions
gave, after acid workup, the β-hydroxy ester 26. Although 26 is
22
by performing the reaction in a microwave reactor (entry 7).
28
However, higher temperature or longer reaction time resulted
in lower yield of 21, presumably due to the decomposition of
starting materials or D−A adduct (entries 6 and 8).
a keto enone, the Baeyer−Villiger oxidation was found to be
highly selective, and only the desired lactone 27 was isolated in
92% yield.
Under these microwave-assisted conditions, diene 12 and
enone 11 gave the desired adduct 10, which held its key
position in our synthetic route (entries 9−12). Further
optimization showed that on gram-scale, the amount of 12
could be reduced to 2.5 equiv, which provided adduct 10 in
Installation of the correct relative stereochemistry at C-15
(fawcettimine numbering) was tackled next. We envisioned that
by increasing the steric hindrance of the convex face of the cis-
fused 6,5-carbocycles, hydrogenation could only take place
from the more accessible concave face and set the required
stereogenic center at C-15 for the syntheses of 1−4. To this
end, the hydroxyl group of 27 was mesylated to increase its
steric bulk and facilitate its later removal. Pleasingly, the
sequence of hydrogenation of the enone group on 28,
elimination of the mesylate and hydrogenation of the incipient
α,β-unsaturated ester could be conducted in one-pot to afford
the desired lactone 29 as a single diastereomer in 93% yield.
The correct stereochemistry at C-15 was confirmed by NOESY
data.
It is worth noting that direct hydrogenation of β-keto ester
25 afforded the corresponding reduction product with a dr 1:1
at C-15. Apparently, devoid of the steric hindrance exerted by
the mesylate on 28, the facial selectivity of the enone reduction
was significantly eroded. However, this nonselective reduction
7
4% yield (92% brsm, dr = 1.0 (endo):0.4 (exo)) (entry 11).
Compared to 1-siloxybutadiene 17 and 12, 1-acetoxybuta-
diene 18 gave no desired adduct 22 (entry 13). The
polymerization of 18 was found to be a significant problem.
23
23
1
,1-Disubstituted butadienes, such as 19 and 20, were also
tested under these microwave-assisted D−A conditions.
Although no adduct 23 was formed when diene 20 was
employed, it was interesting to find that diene 20 did furnish
the desired enone 24 (with basic workup after D−A), albeit the
yield was low (22%). To the best of our knowledge, this
represents the first example of a Diels−Alder reaction between
a 1,1-disiloxybutadiene and a β-alkyl-substituted enone.
29
The Diels−Alder adduct 10, containing all but one carbon
atom of the fawcettimine, fawcettidine, and lycoposerramine B
C
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has an inherent advantage over existing fawcettimine class
alkaloids syntheses in that the unusual β-oriented methyl group
at C-15 can now be accessed and is potentially applicable to the
synthesis of (−)-lycopoclavamine A (7) (Figure 1, vide supra).
Efforts to control the facial selectivity of this reduction to give
diastereomer are worthy of further pursuit.
equiv of Ph P, and 6 equiv of 40% DEAD was optimal (entries
6 and 14−18).
3
Although pyridine (py) was not identified as a suitable
solvent from the above solvent screening, it was noticed that
fewer byproducts were formed in this solvent (entry 5). We
were thus intrigued by the possible beneficial effect of pyridine
as a cosolvent and conducted another survey for solvent
combinations (Table 3). It is also worthy of note that because
Lactone 29 obtained above was fully reduced to the
corresponding tetraol and then peracylated to give tetraacetate
3
0. Selective removal of the two primary acetyl groups on 30
30
was accomplished by using Otera’s catalyst, with diol 31
isolated in 85% yield over this three-step sequence. The
byproduct of this highly selective deacetylation could be readily
recovered and recycled, which increased the yield of
deacetylation product to ≥95% (brsm).
With diol 31 in hand, the hurdle remaining for the synthesis
of fawcettimine (1) was the formation of the 9-membered
azonine ring. Guided by the elegant synthesis of (−)-strych-
nine by the Fukuyama group as well as our own experience
with the synthesis of FR900482, we decided to employ a
double (inter- then intramolecular) Fukuyama−Mitsunobu
reaction to construct the medium-ring N-heterocycle. To this
end, diol 31 was subjected to extensive screening of reaction
parameters (Table 2). The effect of solvent was first examined,
Table 3. One-Pot Synthesis of 9 from 31
3
1
a
entry
solvent (v/v)
DMSO
yield (%)
32
1
2
3
4
5
6
7
8
38
30
35
25
27
48
50
47
33
DMSO/py (1:1)
DMSO/py (3:1)
DMSO/py (6:1)
CH CN/py (1:1)
3
CH CN/py (3:1)
3
CH CN/py (5:1)
3
Table 2. Double Fukuyama−Mitsunobu Reaction To Form
Azonine 32
CH CN/py (6:1)
3
a
Yield of isolated product.
azonine 32 coeluted with NsNH upon column chromatog-
2
raphy, an in situ deacylation procedure was conducted after the
double Fukuyama−Mitsunobu reaction to obviate isolation and
purification problems. Even though a favorable effect was not
observed when pyridine was added to DMSO (entries 1−4),
we were pleased to find that addition of pyridine to acetonitrile
as the cosolvent improved the yield of azonine significantly
a
yield
entry
reagent (equiv)
solvent
(%)
1
2
3
4
NsNH (4), Ph P (6), 40% DEAD (6)
THF
24
20
36
33
25
38
16
28
19
nr
2
3
NsNH (4), Ph P (6), 40% DEAD (6)
CH Cl
2
2
3
2
NsNH (4), Ph P (6), 40% DEAD (6)
CH CN
2
3
3
(
entries 5−8). The best result was achieved when a 5:1 (v/v)
NsNH (4), Ph P (6), 40% DEAD (6)
DMF
py
2
3
combination of acetonitrile and pyridine was used as the
solvent, with azonine 9 isolated in 50% yield for this one-pot
procedure (entry 7).
b
5
NsNH (4), Ph P (6), 40% DEAD (6)
2 3
6
7
8
9
NsNH (4), Ph P (6), 40% DEAD (6)
DMSO
DMSO
DMSO
2
3
NsNH (4), Ph P (6), DEAD (6)
2
3
Synthesis of Fawcettimine, Fawcettidine, Lycoflexine,
and Lycoposerramine B. Azonine 9 served as the common
intermediate for our syntheses of 1−4 (Scheme 5). From 9, the
synthesis of fawcettimine (1) proved to be straightforward.
Dess−Martin oxidation of 9 provided diketone 33, which upon
treatment with PhSH under basic conditions followed by acidic
workup afforded (±)-fawcettimine (1) as its HBr salt. The
inversion of the C-4 stereogenic center apparently occurs when
the free amine resulting from nosyl group removal is treated
with HBr rendering the HBr salt of the natural alkaloid. In this
way, we were able to realize complete stereocontrol over the C-
NsNH (4), Ph P (6), DIAD (6)
2
3
NsNH (4), Ph P (6), DIAD (6)
CH CN
2
3
3
10
11
12
13
14
15
16
17
18
NsNH (4), (n-Bu) P (6), 40% DEAD (6)
DMSO
2
3
NsNH (4), (Me N) P (6), 40% DEAD (6) DMSO
nr
2
2
3
c
NsNH (4), Diphos (6), 40% DEAD (6)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
nr
2
d
NsNH (4), (n-Bu) P (6), ADDP (6)
nr
2
3
NsNH (4), Ph P (10), 40% DEAD (10)
26
23
26
20
16
2
3
NsNH (6), Ph P (6), 40% DEAD (6)
2
3
NsNH (4), Ph P (5), 40% DEAD (5)
2
3
NsNH (3), Ph P (6), 40% DEAD (6)
2
3
NsNH (2), Ph P (4), 40% DEAD (4)
2
3
4
stereogenic center.
Next, the biomimetic dehydration of (±)-fawcettimine (1) to
a
1
b
Yield was determined by H NMR. Diol 31 was partially recovered.
Diphos = ethylenebis(diphenylphosphine). ADDP = 1,1′-
c
d
(
±)-fawcettidine (2) was investigated. Although this trans-
(
azodicarbonyl)dipiperidine.
formation was reported to be realized through the agency of
34
POCl −pyridine, the yield and experimental details for this
3
and it was found that the reaction performed best in a dipolar
aprotic solvent, such as DMSO or acetonitrile (entries 1−6).
Compared to 40% DEAD solution, pure DEAD or DIAD gave
lower yields of 32 (entries 7−9). No reaction took place when
other phosphines were used instead of the Ph P (entry 10−13).
Finally, the relative ratio of each reagent to diol 31 was adjusted
transformation were not reported, and we decided to
investigate alternative conditions. To our delight, we found
that this dehydration took place when (±)-1 was treated with
35
excess oxalic acid in AcOH at 160 °C for 12 h, which afforded
(±)-fawcettidine (2) in 80% yield. From diketone 33, a one-pot
nosyl group deprotection/Mannich reaction afforded (±)-lyco-
flexine (3) in 91% yield.
3
and it was found that the combination of 4 equiv of NsNH , 6
2
D
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a
Scheme 5. Synthesis of (± )-1−4
olfactory properties and are widely used by the fragrance
17
industry, the asymmetric synthesis of enantiomerically pure
3 has not been reported. After a considerable amount of
1
experimentation, we were pleased to find that (+)-13 in high
enantiomeric purity could be obtained through kinetic
resolution of racemic 13. Thus, when (±)-13 was subjected
to Sharpless asymmetric dihydroxylation (Sharpless AD)
37
conditions, a very effective kinetic resolution took place and
provided (+)-13 in 36% yield and greater than 99.8% ee, from
which the naturally configured (+)-alkaloids can be synthe-
38
sized. On the other hand, the diol (−)-36 obtained was
cleaved to afford keto aldehyde (−)-16 in 52% ee, which can be
deployed for the synthesis of the corresponding (−)-antipodes.
With (+)-13 of high enantiomeric purity in hand, the
enantiospecific syntheses of epijasmonate and its analogues can
17
also be realized. Compared to AD-mix-β, kinetic resolution of
(
±)-13 by AD-mix-α should provide the corresponding
enantiomer, (−)-13. Thus, this kinetic resolution is readily
adaptable to applications in the enantiospecific syntheses of the
jasmonoid fragrances.
39
a
Reagents and conditions: (a) Dess−Martin periodinane, NaHCO ,
3
CH Cl , rt, 6 h, 90%; (b) PhSH, 1 M KOH, CH CN, reflux, 8 h, 92%;
CONCLUSIONS
2
2
3
■
(
c) (CO H) , AcOH, 160 °C, 12 h, 80%; (d) PhSH, 1 M KOH,
2 2
The efficient total syntheses of fawcettimine, lycoflexine,
fawcettidine, and lycoposerramine B have been accomplished
through an efficient, unified, and stereocontrolled strategy that
required 16, 16, 17, and 17 steps, respectively, from
commercially available materials. The key transformations
involve (1) a Diels−Alder reaction between enone 11 and 1-
siloxy diene 12 to construct the cis-fused 6,5-carbocycles 10
with one all-carbon quaternary center and (2) a double
Fukuyama−Mitsunobu reaction to form the azonine ring.
Access to the enantiospecific syntheses of these alkaloids can be
achieved by kinetic resolution of the earliest intermediate (13)
via Sharpless asymmetric dihydroxylation technology which can
be conducted on a multigram scale. We have further
demonstrated that the putative biomimetic conversion of
fawcettimine to fawcettidine can be realized and significantly,
we have accomplished the most concise synthesis of
lycoposerramine B thus far recorded. Compared to existing
approaches to these alkaloids, our unified synthetic route
possesses better stereocontrol over the C-4 and C-15
stereogenic centers as well as allowing for more variation in
the 6-membered ring. The application of this strategic approach
to the stereocontrolled synthesis of other Lycopodium alkaloid
family members is currently under investigation.
CH CN, reflux, 8 h; then HCO H, 37% HCHO (aq), reflux,
3
2
overnight, 91% for one pot; (e) PhSH, 1 M KOH, CH CN, reflux,
3
8
h; then MeOH, 37% HCHO (aq), NaBH CN, rt, overnight, 90% for
3
one pot; (f) (COCl) , DMSO, CH Cl , −78 °C, 1 h; then Et N, −78
2
2
2
3
°
C to rt, 2 h; (g) Et NH, NH OH·HCl, EtOH, rt, 24 h, 40% for two
2 2
steps.
Azonine 9, with the nine-membered N-heterocycle cis-fused
to the 5-membered ring, was readily converted to (±)-lycopo-
serramine B (4). Removal of the nosyl group of 9 followed by
in situ reductive amination generated tertiary amine 34 in 90%
36
yield. Subsequent Swern oxidation and selective oxime
12a
formation under Takayama’s conditions afforded (±)-lyco-
poserramine B (4) in 40% overall yield from 34. All of the
spectral data obtained for the synthetic natural alkaloids were
5
−7,10a,11,12a
fully consistent with those reported.
Enantiospecific Syntheses. While the protocols just
detailed provided the racemic natural products, we recognized
that the enantiospecific syntheses of these substances could be
achieved by employing enantiomerically pure (+)-13 (Scheme
6). Despite the fact that 13 is the intermediate for the synthesis
of epijasmonate and some analogues, which possess pleasant
a
Scheme 6. Kinetic Resolution of (± )-13
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were performed in
single-neck round-bottom flasks fitted with rubber septa under positive
pressure of argon with magnetic stirring, unless otherwise noted.
Solvents were dried by passage through columns of activated alumina.
LiClO (ACS grade) was heated in oven (120 °C) for 3 days before
4
use. All other reagents were prepared by known literature procedures
or used as obtained from commercial sources without further
purification, unless otherwise indicated. Reaction progress was
monitored by thin-layer chromatography (TLC) carried out on 0.25
mm coated commercial silica gel plates impregnated with a fluorescent
indicator (254 nm) visualized by UV light and/or submersion in
standard TLC stains (KMnO , vanillin, anisaldehyde, etc.) followed by
4
heating on a hot plate (∼200 °C, 15 s). Flash column chromatography
was performed on silica gel (230−400 mesh), unless otherwise
a
1
13
Reagents and conditions: (a) AD-mix-β, MeSO NH , K CO , t-
indicated. H and C NMR spectra were obtained from 300 or 400
MHz spectrometers. The chemical shifts are given in parts per million
2
2
2
3
BuOH/H O (v/v 1:1), 0−4 °C, 7 h; (b) NaIO , THF/H O (v/v 4:3),
rt, 3 h, 90%.
2
4
2
(ppm) relative to TMS at δ 0.00 ppm or to residual CDCl δ 7.27 ppm
3
E
dx.doi.org/10.1021/jo3006045 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
for proton spectra and relative to CDCl at δ 77.23 ppm for carbon
+12.4 (c 16.23, CHCl ), >99.8% ee. After eluting (+)-13, crude
3
3
spectra, unless otherwise noted. IR spectra were recorded on a FT-IR
spectrophotometer using NaCl plates. High-resolution mass spectra
were obtained using a TOF spectrometer using simultaneous
electrospray (ESI) and atmospheric pressure chemical ionization
(−)-36 was loaded to the same column and chromatographed (THF/
hexanes/EtOAc 1:1:1) to yield (−)-36 (1.104 g, 60%) as a colorless
oil. Analytical data for (−)-36. IR (film): 3424, 2940, 1438, 1329,
−1 1
1208, 1153, 1120, 1044, 1014 cm . H NMR (300 MHz, CDCl ): δ
3
(
APCI). Excess (ee) values were measured on a GC or HPLC device.
Optical rotations were recorded on a polarimeter at a wavelength of
89 nm. Melting points were measured on a capillary melting point
3.73−4.04 (m, 5H), 2.19−2.39 (m, 2H), 1.54−1.96 (m, 8H), 1.32−
1.46 (m, 2H), 1.24 (s, 3H). 13C NMR (75 MHz, CDCl ): δ 118.7,
3
5
72.3, 71.7, 65.2, 64.2, 46.0, 40.1, 35.7, 32.7, 28.0, 27.6, 27.3. HRMS
+
apparatus and are uncorrected. Unless otherwise noted, all compounds
are racemates although they are drawn as a single enantiomers in the
natural series.
(ESI): calcd for C H NaO [M + Na] 251.1254, found 251.1250.
12
20
4
The absolute stereochemistry of (+)-13 was determined by
converting (+)-13 to 5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-
one and comparing its optical rotation with the product obtained from
Corey’s CBS-catalyzed Diels−Alder reaction.
(
3a′R,7a′S)-5′-Methyl-2′,3′,3a′,4′,7′,7a′-hexahydrospiro-
17
[
[1,3]dioxolane-2,1′-indene] (13).
Following the procedure
17
described by Hailes, to an oven-dried 500 mL round-bottomed
(3aR,7aS)-5-Methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-
1
flask with reflux condenser were added LiClO (136.18 g, 1.28 mol)
one from (+)-13. Following the procedure described by Hailes, in a
4
and Et O (320 mL). After the mxiture was stirred at room temperature
for 1.5 h, isoprene (14) (32 mL, 320 mmol, 4.0 equiv), 2-cyclopenten-
25-mL round-bottomed flask, (+)-13 (95.0% ee, 0.157 g, 0.81 mmol,
1.0 equiv) was dissolved in MeOH (ACS grade, 4 mL) at 0 °C.
Aqueous HCl solution (2.7 M, 0.25 mL) was added drop by drop. The
2
1
-one ethylene ketal (15) (9.46 mL, 80 mmol, 1.0 equiv), and
camphorsulfonic acid solution (0.5 M in THF, 0.37 mL, 0.23 mol %)
were added. The resulting solution was stirred for an additional 50 min
resulting mixture was stirred at 0 °C for 2 h before satd NaHCO (8
3
mL) was added. The mixture was extracted with hexanes (3 × 15 mL).
The combined organic layer was dried over anhydrous MgSO4,
filtered, and concentrated at reduced pressure (∼15 mmHg, rotavap
water bath temperature 0−5 °C). The crude obtained was purified by
before NEt (0.40 mL) was added. Cold water (200 mL) was then
3
added cautiously, and the organic layer was separated. The aqueous
layer was extracted with Et O (2 × 200 mL). The combined organic
2
layer was dried over anhydrous MgSO , filtered and concentrated at
flash column chromatography (hexanes/Et O, 15:1) to afford the title
4
2
reduced pressure (∼15 mmHg, rotavap water bath temperature 0−5
compound (0.092 g, 76%, 92.3% ee) as a colorless oil. [α] = +21.5 (c
D
1
°
C). The crude obtained was purified by flash column chromatography
3.57, CHCl ). H NMR (300 MHz, CDCl ): δ 5.31 (br s, 1H), 2.44−
3
3
(
hexanes/EtOAc 50:1) to afford the title compound (14.76 g, 95%) as
2.55 (m, 1H), 1.93−2.39 (m, 8H), 1.72−1.81 (m, 1H), 1.61 (s, 3H).
1
13
a colorless oil (R = 0.57, hexanes/EtOAc 10:1). H NMR (300 MHz,
C NMR (75 MHz, CDCl ): δ 220.0, 132.5, 118.9, 46.8, 34.4, 33.0,
f
3
CDCl ): δ 5.36−5.40 (m, 1H), 3.80−3.96 (m, 4H), 2.26−2.37 (m,
31.0, 26.7, 24.1, 21.9. [α] = +12.4 (c 16.23, CHCl ), >99.8% ee. GC
3
D
3
13
1
H), 1.66−2.18 (m, 8H), 1.64 (S, 3H), 1.39−1.52 (m, 1H). C NMR
conditions: column: Chiraldex B-DM (cat. no. 77023), Adv.
Separation Technologies, Inc., oven: 130 °c; carrier: helium, head
pressure 15 psi; detection: FID 250 °C
(
75 MHz, CDCl ): δ 132.2, 119.8, 119.2, 64.9, 64.0, 41.4, 35.0, 34.0,
3
3
1.9, 27.1, 24.1, 22.3.
-((6S,7R)-7-(2-Oxopropyl)-1,4-dioxaspiro[4.4]nonan-6-yl)-
2
(3aR,7aS)-5-Methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-
one from Corey’s CBS-Catalyzed Diels−Alder Reaction. To a
25-mL flame-dried round-bottomed flask were added toluene (1.0
mL) and (S)-(−)-O-tolyl-CBS-oxazaborolidine solution (0.5 M in
toluene, 0.80 mL, 0.4 mmol, 20 mol %), and the solution was stirred
and cooled to −25 °C. (CF SO ) NH (0.20 M in CH Cl , freshly
acetaldehyde (16). In a 2000-mL three-neck round-bottomed flask
equipped with mechanical stirrer were dissolved 13 (5.06 g, 26.05
mmol, 1.0 equiv), and RuCl ·xH O (0.054 g, 0.26 mmol, 1.0 mol %)
3
2
in ClCH CH Cl (130 mL) and H O (104 mL). The resulting mixture
2
2
2
was stirred vigorously at room temperature. NaIO (11.142 g, 52.09
4
3
2
2
2
2
mmol, 2.0 equiv) was then added in portions over 5 min. After 3 h at
prepared, 1.80 mL, 0.36 mmol, 18 mol %) was then added dropwise.
After 10 min at −25 °C, 2-cyclopenten-1-one (168 μL, 2 mmol, 1.0
equiv) and isoprene (1.0 mL, 10 mmol, 5 equiv) were added. The
room temperature, satd Na S O (50 mL) was added. The organic
2
2
3
layer was separated, and the aqueous layer was extracted with EtOAc
(
3 × 100 mL). The combined organic layer was dried over anhydrous
reaction mixture was stirred for 3 days at −25 °C before NEt (56 μL)
3
MgSO . After filtration and concentration, the crude obtained was
was added to quench. The mixture was then warmed to room
temperature and concentrated at reduced pressure (∼15 mmHg,
rotavap water bath temperature 0−10 °C). The crude obtained was
purified by flash column chromatography (hexanes/EtOAc, 10:1) to
afford the title compound (0.157 g, 52%) as a colorless oil. The
4
purified by flash column chromatography (hexanes/EtOAc, 2:1) to
afford the title compound (4.42 g, 75%) as a colorless oil (R = 0.23,
f
hexanes/EtOAc 2:1). IR (thin film): 3413, 2956, 2888, 1716, 1413,
−
1 1
1
2
(
1
6
358, 1289, 1121 cm . H NMR (300 MHz, CDCl ): δ 9.70 (dd, J =
3
.7, 1.5 Hz, 1H), 3.73−3.91 (m, 4H), 2.60−2.74 (m, 2H), 2.30−2.48
absolute stereochemistry of title compound was assigned as shown
2
m, 3H), 2.16−2.24 (m, 1H), 2.10 (s, 3H), 1.71−2.02 (m, 3H), 1.23−
according to the model proposed by Corey’s group. [α] = +9.8 (c
D
.36 (m, 1H). 13C NMR (75 MHz, CDCl ): δ 208.1, 202.2, 117.7,
3
8.32, CHCl ), 73.5% ee. GC conditions: column: Chiraldex B-DM
3
5.0, 64.5, 45.4, 43.7, 39.7, 34.6, 34.2, 30.4, 27.7. HRMS (ESI): calcd
for C H O [M + H] 227.1278, found 227.1276.
(cat. no. 77023), Adv. Separation Technologies, Inc., oven: 130 °c;
carrier: helium, head pressure 15 psi; detection: FID 250 °C.
Compound (−)-16 from (−)-36. In a 25-mL round-bottomed
flask was dissolved (−)-36 (0.129 g, 0.70 mmol, 1.0 equiv) in THF
+
12
19
4
Kinetic Resolution of (± )-13. In a 500-mL round-bottomed flask
were dissolved (±)-13 (1.94 g, 10 mmol, 1.0 equiv), methanesulfo-
namide (0.951 g, 10 mmol, 1.0 equiv), and K CO (4.146 g, 30 mmol,
2
3
(ACS grade, 4 mL) and H O (3 mL). The mixture was stirred
2
3
equiv) in t-BuOH/H O (v/v 1:1, 100 mL). The mixture was stirred
vigorously at room temperature, and then NaIO (0.225 g, 1.05 mmol,
2
4
at 0 °C, and then AD-mix-β (1.41 g/mmol, 14.1 g) was added in one
1.5 equiv) was added in one portion. After 2 h, satd Na S O (5 mL)
2
2
3
portion. After the mxiture was stirred at 0−4 °C for 7 h, satd Na S O
was added to quench the reaction. The mixture was extracted with
2
2
3
(
50 mL) was added. The mixture was extracted with hexanes (2 × 100
EtOAc (3 × 15 mL). The combined organic layer was washed with
mL). The combined hexanes extract layer was washed successively
brine (5 mL) and dried over anhydrous MgSO . After filtration and
4
with H O (4 × 50 mL) and brine (40 mL) and dried over anhydrous
concentration, the residue was purified by flash column chromatog-
raphy (hexanes/EtOAc, 2:1) to afford the title compound (0.144 g,
90%) as a colorless oil. [α] = −11.3 (c 3.38, CHCl ), 52% ee.
2
Na SO . After filtration and concentration at reduced pressure (∼15
2
4
mmHg, rotavap water bath temperature 0−5 °C), the crude (+)-13
was obtained, which also contains a small amount of (−)-36. All of the
aqueous layers were combined, and NaCl was added until saturation.
D
3
1-((3a′S,6a′S)-3′,3a′,6′,6a′-Tetrahydro-2′H-spiro[[1,3]-
dioxolane-2,1′-pentalen]-4′-yl)ethanone (11). To a 1000-mL
round-bottomed flask equipped with reflux condenser were added keto
The aqueous layer was then extracted with CHCl (3 × 50 mL). The
3
combined CHCl extract layer was dried over anhydrous Na SO .
aldehyde 16 (3.30 g, 58.86 mmol, 1.0 equiv) and H O (740 mL). The
3
2
4
2
After filtration and concentration, the crude (−)-36 was obtained. The
mixture was stirred at room temperature, and oxygen was carefully
removed under reduced pressure (∼15 mmHg) for 20 min. The flask
was refilled with Ar, and the vacuo-Ar cycle was repeated for three
crude (+)-13 was purified by flash column chromatography (hexanes/
EtOAc, 50:1) to afford (+)-13 (0.67 g, 36%) as a colorless oil. [α] =
D
F
dx.doi.org/10.1021/jo3006045 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
times. Solid KOH (3.30 g, 51.2 mmol, 3.5 equiv) was quickly added,
and the vacuo-Ar cycle was repeated twice. The resulting pale yellow
solution was gently refluxed for 15 h, cooled to room temperature, and
extracted with EtOAc (3 × 100 mL). The combined organic layer was
washed with brine (50 mL) and dried over anhydrous Na SO . After
temperature, the pale yellow solution was transferred to a 25-mL
round-bottomed flask by pipet. A short-path distillation head was
attached, and the volatiles were removed (∼100 °C/4 mmHg for 0.5
h). The residue was purified by flash column chromatography
(hexanes/EtOAc, 7:1 to 2:1) to afford recovered 11 (0.21 g, 19%)
and title compound (1.44 g, dr 1:0.4, 74%, 92% brsm) as inseparable
diastereomers. IR (thin film): 2957, 1696, 1350, 1251, 1096, 1065
2
4
filtration and concentration, the crude obtained was purified by flash
column chromatography (hexanes/EtOAc, 4:1) to afford the title
−1 1
compound (2.44 g, 79%) as a yellow oil (R = 0.17, hexanes/EtOAc
cm . H NMR (300 MHz, CDCl , major diastereomer): δ 5.07 (s,
f
3
4
:1). IR (thin film): 2960, 2883, 1708, 1666, 1619, 1435, 1373, 1107
1H), 4.09 (t, J = 1.8 Hz, 1H), 3.75−3.91(m, 4H), 2.92 (td, J = 8.4, 8.0
−1 1
cm . H NMR (300 MHz, CDCl ): δ 6.61−6.62 (m, 1H), 3.77−4.00
Hz, 1H), 2.23−2.52 (m, 3H), 2.06(s, 3H), 1.72−1.88 (m, 2H), 1.60−
3
(
2
1
m, 4H), 3.45−3.55 (m, 1H), 2.48−2.78 (m, 3H), 2.28 (s, 3H), 1.90−
1.70 (m, 3H), 1.56 (app d, J = 1.8 Hz, 3H), 1.26−1.38 (m, 1H), 0.96−
13
13
.11 (m, 1H), 1.51−1.70 (m, 3H). C NMR (75 MHz, CDCl ): δ
1.10 (m, 1H), 0.12(s, 9H). C NMR (75 MHz, CDCl , major
3
3
96.6, 147.5, 144.1, 118.5, 65.1, 64.2, 47.2, 47.1, 35.2, 33.6, 28.4, 27.3.
diastereomer): δ 211.3, 135.6, 123.1, 118.3, 70.9, 67.5, 65.1, 64.8, 64.3,
+
HRMS (ESI): calcd for C H O [M + H] 209.1172, found
46.77, 46.75, 36.8, 35.4, 32.4, 31.8, 26.1, 23.2, 0.4. HRMS (ESI): calcd
12
17
3
+
2
09.1176.
for C H NaO Si [M + Na] 387.1962, found 387.1963.
20
32
4
1
- ( ( 3 a S , 3 b R , 7 a S , 8 a S ) - 4 - ( ( T r i m e t h y l s i l y l ) o x y ) -
(3aS,3bS,7aR,8aS)-3b-Acetyl-6-methyl-3,3a,7,7a,8,8a-hexa-
hydro-2H-spiro[cyclopenta[a]indene-1,2′-[1,3]dioxolan]-4-
(3bH)-one 24. To a solution of 10 (1.556 g, 4.27 mmol, 1.0 equiv) in
CH Cl (ACS grade, 43 mL) was added TBAF (1.228 g, 4.70 mmol,
3
1
,3a,3b,4,7,7a,8,8a-octahydro-2H-spiro[cyclopenta[a]indene-
,2′-[1,3]dioxolane]-3b-yl)ethanone (21). To a 10-mL CEM
Discover reaction vessel with magnetic stirring bar were added
enone 11 (0.208 g, 1.0 mmol, 1.0 equiv) and diene 17 (1.423 g, 10.0
mmol, 10.0 equiv). The vessel was flushed with Ar, capped, and put in
the microwave reactor. The mixture was heated to 190 °C and kept at
this temperature with high-speed stirring for 9 h. After being cooled to
room temperature, the pale yellow solution was transferred to a 25-mL
round-bottomed flask by pipet. A short-path distillation head was
attached and the volatiles (contain diene 17 and crotonaldehyde) were
removed (∼100 °C/4 mmHg for 0.5 h). The residue was purified by
flash column chromatography (hexanes/EtOAc, 7:1 to 2:1) to afford
recovered 11 (0.062 g, 30%) and title compound (0.168 g, 48%, 69%
2
2
1.1 equiv). The reaction was stirred at room temperature for 12 h, and
NaHCO (1.434 g, 17.07 mmol, 4.0 equiv) was added. Dess−Martin
3
periodinane (2.534 g, 5.98 mmol, 1.4 equiv) was then added in
portions over 5 min. The suspension was stirred for 6 h then quenched
with satd Na S O (10 mL) and satd NaHCO (20 mL). After being
2
2
3
3
stirred for another 6 h, the organic layer was separated and the
aqueous layer was extracted with EtOAc (2 × 20 mL). The combined
organic layer was washed with brine (20 mL), dried over anhydrous
Na SO , filtered, and concentrated. The residue was purified by flash
2
4
column chromatography (hexanes/EtOAc, 4:1) to afford the title
brsm) as a pale yellow oil (inseparable diastereomers, dr 1:0.6; R =
compound (1.18 g, 95%, R = 0.28, hexanes/EtOAc 4:1) as a white
f
f
0
1
5
4
6
2
0
1
.21, hexanes/EtOAc 6:1). IR (thin film): 3029, 2957, 2883, 1697,
solid. Mp = 111−113 °C. IR (thin film): 2959, 2888, 1702, 1658,
−1
1
−1 1
426, 1350, 1251, 1222, 1093 cm . H NMR (300 MHz, CDCl ): δ
1355, 1197, 1094 cm . H NMR (300 MHz, CDCl ): δ 5.81−5.83
3
3
.70−5.77 (m, 0.67H), 5.58−5.68 (m, 1.5H), 5.39−5.45 (m, 0.94H),
.34 (app d, J = 5.1 Hz, 0.57H), 4.13−4.19 (m, 1H), 3.84−3.98 (m,
H), 3.01 (dt, J = 8.7, 6.9 Hz, 0.97H), 2.82 (q, J = 8.7 Hz, 0.6H),
.35−2.61 (m, 4.7H), 2.14 (s, 2.6H), 2.11 (s, 1.6H), 1.98−2.08 (m,
.74H), 1.59−1.96 (m, 8H), 1.41 (td, J = 13.2, 10.8 Hz, 1.2H), 1.01−
.19 (m, 1.7H), 0.18 (s, 7.5H), 0.16 (s, 4.8H). 13C NMR (75 MHz,
(m, 1H), 3.80−3.91 (m, 4H), 3.64 (q, J = 8.7 Hz, 1H), 2.73−2.92 (m,
2H), 2.39 (t, J = 9.9 Hz, 1H), 2.15 (d, J = 19.2 Hz, 1H), 2.03 (s, 3H),
1.87 (s, 3H), 1.81 (td, J = 6.0, 1.5 Hz, 1H), 1.67−1.76 (m, 2H), 1.53−
1.65 (m, 1H), 1.38 (td, J = 13.2, 10.5 Hz, 1H), 0.99−1.11 (m, 1H).
13
C NMR (75 MHz, CDCl ): δ 204.4, 196.1, 161.5, 124.7, 118.0, 73.9,
3
65.2, 64.5, 46.7, 46.6, 37.2, 35.7, 32.0, 30.2, 27.7, 25.2, 24.7. HRMS
+
CDCl ): δ 211.3, 210.0, 129.6, 128.6, 127.9, 125.9, 118.4, 118.2, 70.2,
(ESI): calcd for C H O [M + H] 291.1591, found 291.1595.
3
17 23
4
6
3
6.5, 65.2, 65.1, 64.9, 64.40, 64.35, 49.2, 48.5, 46.84, 46.78, 36.4, 36.0,
5.5, 33.9, 32.4, 31.85, 31.81, 28.2, 27.1, 26.2, 26.0, 0.6, 0.4. HRMS
Compound 24 from Diels−Alder Reaction between 20 and
11. To a 10-mL CEM Discover reaction vessel with magnetic stirring
+
23
(
ESI): calcd for C H NaO Si [M + Na] 373.1806, found 373.1803.
bar were added diene 20 (0.733 g, 3.0 mmol, 6.0 equiv) and enone
19
30
4
1
6
(
E)-Trimethyl((3-methylbuta-1,3-dien-1-yl)oxy)silane (12).
11 (0.104 g, 0.5 mmol, 1.0 equiv). The vessel was flushed with Ar,
sealed, and put in a microwave reactor. The mixture was heated to 190
°C and kept at this temperature with high speed stirring for 4 h. After
cooling to room temperature, the brown solution was transferred to
round-bottomed flask by pipet with the aid of MeOH (10 mL). K CO
16
Following the procedure described by Duhamel, to a 500-mL 2
necked round-bottomed flask equipped with reflux condenser and
glass stopper was added ZnCl (0.30 g, 2.2 mmol, 0.8 mol %). The
condenser was connected to vacuum, and the flask was heated by
2
2
3
flame until all the solid ZnCl melted. After being cooled to room
(0.70 g) was added, and the mixture was stirred at room temperature
overnight. EtOAc (20 mL) was added, and the mixture was washed
with brine (2 × 10 mL). The organic layer was dried over anhydrous
Na SO , filtered and concentrated. The residue was purified by flash
2
temperature, the flask was charged with Ar. Et O (60 mL), 3-
2
methylcrotonaldehyde (24 mL, 250 mmol, 1.0 equiv), NEt (40 mL,
3
2
87.5 mmol, 1.15 equiv), and TMSCl (34.9 mL, 275 mmol, 1.10
2
4
equiv) were added. The suspension was stirred at gentle reflux for 25
h. After the solution was cooled to room temperature, hexanes (200
mL) were added, and the triethylamine hydrochloride precipitate was
removed by filtering over sintered glass funnel under reduced pressure
and washed with hexanes (50 mL). The filtrate was concentrated by
rotavap and the residue was distilled under reduced pressure (55−65
column chromatography (hexanes/EtOAc, 4:1) to afford the title
compound (0.032 g, 22%).
Methyl 3-((3aS, 3bS, 7aR, 8aS)-6-Methyl-4-oxo-
3,3a,3b,4,7,7a,8,8a-octahydro-2H-spiro[cyclopenta[a]indene-
1
,2′-[1,3]dioxolan]-3b-yl)-3-oxopropanoate (25). To a stirred
solution of 24 (0.6663 g, 2.295 mmol, 1.0 equiv) in Et O (23 mL) at
2
−
78 °C (dry ice/acetone bath) was added solid LiHMDS (0.4608 g,
°
C/20 mmHg) to give title compound (30.96 g, 79%, E:Z = 1.0:0.11)
1
2.754 mmol, 1.2 equiv). The solution was stirred at −78 °C for 40 min
before the cooling bath was removed. The flask was allowed to warm
to room temperature over 20 min and then cooled to −78 °C. Methyl
cyanoformate (0.22 mL, 2.754 mmol, 1.2 equiv) was added, and the
solution was allowed to warm to room temperature on its own
as a colorless oil. H NMR (300 MHz, CDCl , E isomer): δ 6.53 (dt, J
3
=
2
12.3, 0.6 Hz, 1H), 5.79 (dd, J = 12.3, 0.6 Hz, 1H), 4.66−4.76 (m,
H), 1.81 (dd, J = 1.2, 0.6 Hz, 3H), 0.22 (s, 9H). 13C NMR (75 MHz,
CDCl , E isomer): δ 142.0, 140.2, 116.3, 111.7, 18.2, 0.6.
3
1
-((3aS,3bR,7aR,8aS)-6-Methyl-4-((trimethylsilyl)oxy)-
3
1
,3a,3b,4,7,7a,8,8a-octahydro-2H-spiro[cyclopenta[a]indene-
,2′-[1,3]dioxolan]-3b-yl)ethanone (10). To a 10-mL CEM
overnight. Saturated NaHCO (12 mL) was then added to quench the
3
reaction. The organic layer was separated, and the aqueous layer was
extracted with EtOAc (2 × 15 mL). The combined organic layer was
washed with brine (15 mL), dried over anhydrous Na SO , filtered,
Discover reaction vessel with magnetic stirring bar were added diene
1
2 (2.08 g, 13.28 mmol, 2.5 equiv) and enone 11 (1.11 g, 5.31 mmol,
2
4
1
.0 equiv). The vessel was flushed with Ar, sealed, and put in
and concentrated. The residue was purified by flash column
chromatography (hexanes/EtOAc, 7:1 to give 24 then 1:1 to give
25) to afford recovered 24 (0.2392 g, 36%) and title compound
microwave reactor. The mixture was heated to 180 °C and kept at this
temperature with high speed stirring for 9 h. After cooling to room
G
dx.doi.org/10.1021/jo3006045 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
0.4814 g, 60%, 94% brsm) as a colorless oil (contains ∼8% enol ester
anhydrous Na SO . After filtration and concentration, the residue
obtained was purified by flash column chromatography (hexanes/
EtOAc, 2:1) to afford the title compound (0.494 g, 97%) as a colorless
2
4
forms, R = 0.14, hexanes/EtOAc 4:1). IR (thin film): 2955, 2888,
1
f
−1 1
746, 1703, 1658, 1437, 1321, 1236, 1152, 1017 cm . H NMR (300
MHz, CDCl ): δ 12.37 (s, 0.08H), 5.84 (s, 1H), 5.05 (s, 0.08H),
oil (inseparable diastereomers, dr 1:0.18; R = 0.19, hexanes/EtOAc
3
f
3
2
0
.79−3.90 (m, 6.3H), 3.77 (s, 0.76H), 3.50−3.70 (m, 4.9), 3.44 (d, J =
.4 Hz, 2H), 2.64−3.02 (m, 3.1H), 2.06−2.55 (m, 3.5H), 2.04 (s,
.84H), 1.98 (s, 0.49H), 1.34−1.88 (m, 13H), 0.96−1.12 (m, 1.8H).
2:1). IR (thin film): 2954, 1738, 1654, 1437, 1339, 1249, 1172, 1131,
−1 1
1021 cm . H NMR (300 MHz, CDCl , major diastereomer): δ 5.81
3
(s, 1H), 5.27 (dd, J = 8.4, 3.0 Hz, 1H), 4.54 (td, J = 8.4, 3.3 Hz, 1H),
3.61 (s, 3H), 3.19 (dt, J = 13.2, 6.6 Hz, 1H), 3.01 (s, 3H), 2.94−2.96
1
3
C NMR (75 MHz, CDCl , β-keto ester form): δ 198.9, 195.4, 167.7,
3
1
3
3
62.1, 124.8, 117.7, 73.7, 65.1, 64.5, 52.4, 47.3, 46.8, 46.3, 37.1, 35.8,
1.8, 30.1, 25.1, 24.8. HRMS (ESI): calcd for C H O [M + H]
49.1646, found 349.1644.
R)-Methyl 3-Hydroxy-3-((3aS,3bS,7aR,8aS)-6-methyl-1,4-
dioxo-1,2,3,3a,3b,4,7,7a,8,8a-decahydrocyclopenta[a]inden-
b-yl)propanoate (26). To a stirred solution of β-keto ester 25
0.214 g, 0.613 mmol, 1.0 equiv) in CH Cl (4 mL) and MeOH (4
(m, 1H), 2.80−2.88 (m, 1H), 2.63−2.72 (m, 1H), 2.55 (dt, J = 16.8, 3
+
13
Hz, 1H), 1.97−2.29 (m, 4H), 1.93 (s, 3H), 1.67−1.88 (m, 3H).
C
19
25
6
NMR (75 MHz, CDCl
, major diastereomer): δ 197.8, 171.8, 170.8,
3
(
161.8, 124.2, 79.0, 76.6, 60.5, 52.5, 41.2, 39.3, 37.0, 36.8, 35.3, 30.5,
30.4, 24.8, 20.5. HRMS (ESI): calcd for C18
423.1084, found 423.1076.
H24NaO
S [M + Na]+
8
3
(
Methyl 3-((4aR, 4bS, 7R,8aS, 9aS)-7-Methyl-2, 5-
dioxododecahydroindeno[2,1-b]pyran-4b-yl)propanoate (29).
In a 100-mL hydrogenation vessel was dissolved 28 (0.494 g, 1.23
mmol, 1.0 equiv) in EtOAc (ACS grade, 13 mL). Five wt % Pd/C
2
2
mL) at −42 °C (dry ice/CH CN bath) was added NaBH (0.214 g,
3
4
5
.66 mmol, 9.2 equiv). The solution was stirred at −42 °C for 4.5 h.
TLC showed complete consumption of 25. Acetone (4 mL) was
added to quench the additional NaBH . The reaction was allowed to
(0.494 g) and 5 wt % Rh/Al
was sealed. H (80 psi) was filled and then released. This process was
repeated twice, and the vessel was refilled with H (80 psi). After the
mixture was stirred at room temperature for 1 day, H was released
2 3
O (0.494 g) were added, and the vessel
4
warm to room temperature over 3 h, and 1 M HCl (6 mL) was added
to adjust the pH to 1.0 (pH paper). The mixture was stirred at room
temperature overnight and then extracted with EtOAc (3 × 15 mL).
The combined organic layer was washed with satd NaHCO (10 mL)
and brine (10 mL) and dried over anhydrous Na SO . After filtration
2
2
2
and TLC showed complete consumption of 28. DBU (0.28 mL, 1.85
mmol, 1.5 equiv) was then added, and the vessel was resealed and
3
2
4
and concentration, the residue obtained was purified by flash column
chromatography (hexanes/EtOAc, 2:1) to afford the title compound
refilled with H
2
(80 psi). The reaction was stirred at room temperature
for another 12 h and then filtered over a Bu
pressure and washed with EtOAc. The filtrate was concentrated and
the residue obtained was purified by flash column chromatography
̈
chner funnel at reduced
(
0.150 g, 80%) as a colorless oil (inseparable diastereomers, dr 1:0.14;
R = 0.28, hexanes/EtOAc 1:1). IR (thin film): 3470, 2953, 1735, 1653,
f
−
1
1
(hexanes/EtOAc, 2:1) to afford the title compound (0.353 g, 93%) as
1
437, 1173, 1116 cm . H NMR (300 MHz, CDCl , major
3
a white solid (R = 0.16, hexanes/EtOAc 2:1). Mp = 78−80 °C. IR
diastereomer): δ 5.79 (s, 1H), 4.12 (br d, J = 10.8 Hz, 1H), 3.62 (s,
f
−1 1
(
thin film): 2955, 1737, 1699, 1437, 1248, 1191, 1132, 1033 cm . H
3
2
1
H), 3.37−3.46 (m, 2H), 2.71−2.79 (m, 1H), 2.51−2.62 (m, 2H),
NMR (300 MHz, CDCl ): δ 4.65 (td, J = 7.8, 3.0 Hz, 1H), 3.63 (s,
.33−2.46 (m, 2H), 2.15−2.24 (m, 3H), 2.03−2.14 (m, 1H), 1.87−
3
13
3
2
1
H), 3.20 (dt, J = 13.2, 6.9 Hz, 1H), 2.60 (dt, J = 16.5, 3.0 Hz, 1H),
.43−2.53 (m, 1H), 2.24−2.35 (m, 4H), 1.99−2.19 (m, 2H), 1.67−
.96 (m, 7H), 1.49 (qd, J = 13.3, 3.3 Hz, 1H), 1.02 (d, J = 6.3 Hz, 3H).
.99 (m, 5H), 1.63−1.77 (m, 1H). C NMR (75 MHz, CDCl , major
3
diastereomer): δ 221.5, 201.1, 173.4, 159.9, 125.2, 68.3, 61.4, 52.1,
4
7.9, 45.1, 40.0, 38.2, 36.4, 32.9, 31.5, 24.7, 23.4. HRMS (ESI): calcd
1
3
+
C NMR (75 MHz, CDCl ): δ 213.6, 173.1, 172.6, 80.0, 60.2, 52.1,
for C H O [M + H] 307.1540, found 307.1542.
3
17
23
5
(
R)-Methyl 3-Hydroxy-3-((4aR,4bS,8aS,9aS)-7-methyl-2,5-
dioxo-2,3,4,4a,4b,5,8,8a,9,9a-decahydroindeno[2,1-b]pyran-
b-yl)propanoate (27). (Note: open flask reaction.) In a 100-mL
47.0, 43.6, 38.9, 36.5, 31.9, 30.4, 30.1, 29.9, 27.5, 22.4, 19.6. HRMS
+
(ESI): calcd for C H O [M + H] 309.1697, found 309.1698.
17
25
5
4
(2S,3R,3aS,6R,7aS)-3,3a-Bis(3-acetoxypropyl)-6-methylocta-
hydro-1H-indene-2,4-diyl Diacetate (30). In a 50-mL oven-dried
round-bottomed flask equipped with reflux condenser was dissolved
29 (0.204 g, 0.66 mmol, 1.0 equiv) in THF (14 mL) and the mixture
round-bottomed flask equipped with reflux condenser was dissolved β-
hydroxy ester 26 (0.595 g, 1.94 mmol, 1.0 equiv) in CH Cl (ACS
grade, 20 mL). NaHCO (0.978 g, 11.64 mmol, 6 equiv) was added,
2
2
3
and the reaction was cooled to 0 °C (ice−water bath). m-CPBA (77%,
stirred at room temperature. LiAlH (0.075 g, 1.98 mmol, 3 equiv) was
added in one portion, and the mixture was heated at reflux overnight.
4
0
.739 g, 3.30 mmol, 1.7 equiv) was then added in portions over 5 min,
and the reaction was allowed to warm to room temperature on its
own. After 24 h, satd Na S O (6 mL) was added to quench the
After being cooled to room temperature, the reaction was quenched by
successive addition of H
(225 μL). The resulting slurry was stirred for another 4 h and then
filtered over a Buchner funnel at reduced pressure and washed with
O (75 μL), 15% NaOH (75 μL), and H O
2
2
3
2
2
reaction. Saturated Na CO (14 mL) was added, and the mixture was
2
3
extracted EtOAc (3 × 20 mL). The combined organic layer was
̈
washed with brine (20 mL), dried over anhydrous Na SO , filtered,
EtOAc. After concentration, the crude tetraol obtained was used in the
2
4
and concentrated. The residue was purified by flash column
chromatography (hexanes/EtOAc, 1:1 to 1:2) to afford the title
compound (0.575 g, 92%) as a colorless oil (inseparable
next step without further purification.
To a stirred solution of the tetraol obtained from above (0.66
mmol, theoretical, 1.0 equiv) in pyridine (7 mL) were added one
diastereomers, dr 1:0.14; R = 0.12, hexanes/EtOAc 1:1). IR (thin
crystal of DMAP and Ac
reaction was stirred at room temperature for 1 day and then quenched
with satd NaHCO (10 mL). The mixture was extracted with EtOAc
(3 × 10 mL), washed with brine (10 mL), and dried over anhydrous
Na SO . After filtration and concentration, the crude obtained was
2
O (0.50 mL, 5.30 mmol, 8 equiv). The
f
−1
1
film): 3383, 1736, 1648, 1437, 1071 cm . H NMR (300 MHz,
CDCl , major diastereomer): δ 5.82 (s, 1H), 4.78−4.51 (m, 1H), 4.11
3
3
(
9
2
br d, J = 10.8 Hz, 1H), 3.58 (s, 3H), 2.99−3.08 (m, 1H), 2.92 (td, J =
.6, 5.4 Hz, 1H), 2.01−2.60 (m, 9H), 1.89 (s, 3H), 1.78−1.87 (m,
2
4
H). 13C NMR (75 MHz, CDCl , major diastereomer): δ 201.0, 172.8,
used in the next step directly without further purification. An analytic
sample was purified by flash column chromatography (hexanes/
EtOAc, 2:1) to afford the title compound as a colorless oil (inseparable
3
1
2
72.4, 160.9, 125.7, 80.0, 68.5, 59.8, 52.1, 42.5, 38.0, 34.9, 31.8, 30.4,
+
4.8, 20.0. HRMS (ESI): calcd for C H O [M + H] 323.1489,
17
23
6
found 323.1488.
diastereomers, dr 9:1; R = 0.14, hexanes/EtOAc 4:1). IR (thin film):
f
−1
1
2
956, 1737, 1458, 1370, 1239, 1024 cm . H NMR (300 MHz,
(
R)-Methyl 3-((4aR,4bS,8aS,9aS)-7-Methyl-2,5-dioxo-
,3,4,4a,4b,5,8,8a,9,9a-decahydroindeno[2,1-b]pyran-4b-yl)-3-
(methylsulfonyl)oxy)propanoate (28). To a stirred solution of 27
2
(
CDCl , major diastereomer): δ 5.17 (app t, J = 4.2 Hz, 1H), 4.63 (dd,
3
J = 11.4, 3.9 Hz, 1H), 3.86−4.05 (m, 4H), 2.24−2.32 (m, 1H), 1.982
(s, 3H), 1.961 (s, 3H), 1.957 (s, 3H), 1.948 (s, 3H), 1.79−1.87 (m,
1H), 1.22−1.76 (m, 13H), 1.04−1.16 (m, 2H), 0.84 (d, J = 6.3 Hz,
(
0.410 g, 1.27 mmol, 1.0 equiv) in pyridine (13 mL) at 0 °C (ice−
water bath) was added MsCl (0.40 mL, 5.09 mmol, 4 equiv). The
solution was allowed to warm to room temperature on its own
3H). 13C NMR (75 MHz, CDCl , major diastereomer): δ 171.2, 171.1,
3
overnight. Saturated NaHCO (15 mL) was then added carefully, and
170.9, 170.4, 81.5, 75.7, 65.3, 64.6, 53.3, 46.5, 39.9, 36.4, 36.3, 33.2,
3
the mixture was extracted with EtOAc (3 × 15 mL). The combined
organic layer was washed with brine (15 mL) and dried over
28.1, 27.0, 24.8, 24.2, 22.7, 22.0, 21.40, 21.36, 21.2, 21.1. HRMS (ESI):
+
calcd for C H NO [M + NH ] 472.2905, found 472.2900.
24
42
8
4
H
dx.doi.org/10.1021/jo3006045 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
2S,3R,3aS,6R,7aS)-3,3a-Bis(3-hydroxypropyl)-6-methylocta-
hydro-1H-indene-2,4-diyl Diacetate (31). To a stirred solution of
0 (0.66 mmol, theoretical, 1.0 equiv) obtained above in MeOH (ACS
grade, 3.3 mL) and THF (ACS grade, 3.3 mL) was added Otera’s
7.96 (m, 1H), 7.64−7.72 (m, 2H), 7.56−7.62 (m, 1H), 4.62 (dt, J =
8.4, 6.0 Hz, 1H), 3.67−3.78 (m, 1H), 3.47−3.55 (m, 2H), 3.13 (ddd, J
= 14.8, 9.6, 4.8 Hz, 1H), 2.95 (dt, J = 13.2, 4.0 Hz, 1H), 1.51−2.31 (m,
3
16H), 1.22−1.31 (m, 2H), 1.06−1.14 (m, 1H), 0.92 (d, J = 6.4, 3H).
30
13
catalyst ([t-Bu Sn(OH)Cl] ) (0.019 g, 33 μmol, 5 mol %). The
reaction was stirred at room temperature for 30 h, and NEt (50 μL)
was added to quench the reaction. After concentration, the residue was
purified by flash column chromatography (hexanes/EtOAc/THF,
:2:0.5) to afford recovered materials (0.052 g, contains mono- or
triacetate, which could be recycled by reacetylation to 30) and 31
0.208 g, 85% for three steps, ≥95% brsm) as a colorless oil
inseparable diasteromers, dr 9:1; R = 0.07, hexanes/EtOAc 1:2). IR
C NMR (100 MHz, CDCl ): δ 133.5, 132.1, 131.4, 130.9, 124.1,
2
2
3
3
74.1, 73.0, 51.8, 50.8, 48.0, 46.4, 42.5, 40.4, 36.9, 32.8, 29.5, 27.4, 24.6,
+
24.5, 22.3, 16.5. HRMS (ESI): calcd for C H N O S [M + H]
22
33
2
5
453.2059, found 453.2061.
1
(7aR,9aS,11R,13aS)-11-Methyl-4-((2-nitrophenyl)sulfonyl)-
decahydro-1H-indeno[1,7a-e]azonine-8,13(2H,9H)-dione (33).
To a stirred solution of 9 (0.022 g, 49 μmol, 1.0 equiv) in CH Cl
(
(
(
2
2
(ACS grade, 2 mL) were added NaHCO (0.033 g, 0.39 mmol, 8.0
f
3
thin film): 3386, 2951, 2871, 1734, 1457, 1375, 1242, 1052, 1023
equiv) and Dess−Martin periodinane (0.084 g, 0.20 mmol, 4.0 equiv).
The suspension was stirred at room temperature for 6 h, and then satd
Na S O (3 mL) and satd NaHCO (3 mL) were added. After being
−
1 1
cm . H NMR (300 MHz, CDCl , major diastereomer): δ 5.24 (t, J =
3
4
2
1
.5 Hz, 1H), 4.70 (app dd, J = 12.0, 4.2 Hz, 1H), 3.47−3.74 (m, 4H),
.71 (br s, 2H), 2.31−2.40 (m, 1H), 2.007 (s, 3H), 2.004 (s, 3H),
.76−1.94 (m, 2H), 1.32−1.74 (m, 12H), 1.08−1.25 (m, 2H), 0.87 (d,
2
2
3
3
stirred for an additional 1 h, the mixture was extracted with CH Cl (3
2
2
× 5 mL). The combined organic layer was washed with brine (5 mL)
13
J = 6.3 Hz, 3H). C NMR (75 MHz, CDCl , major diastereomer): δ
and dried over anhydrous Na SO . After filtration and concentration,
2
4
3
1
3
71.4, 170.9, 81.7, 76.2, 63.6, 62.6, 53.3, 46.7, 40.1, 36.6, 36.2, 33.2,
the residue obtained was purified by flash column chromatography
(hexanes/EtOAc, 1:1) to afford the title compound (0.0195 g, 90%) as
a white solid. Mp = 232−235 °C dec. IR (thin film): 2924, 1737, 1700,
2.2, 28.8, 27.1, 24.1, 22.5, 22.1, 21.55, 21.52. HRMS (ESI): calcd for
+
C H NO [M + NH ] 388.2694 found 388.2696.
2
0
38
6
4
−1
1
(
7aR,8S,9aS,11R,13aS)-11-Methyl-4-((2-nitrophenyl)-
1544, 1439, 1373, 1347, 1168, 1128 cm . H NMR (400 MHz,
sulfonyl)tetradecahydro-1H-indeno[1,7a-e]azonine-8,13-diyl
Diacetate (32). To a stirred solution of 31 (0.0039 g, 10.5 μmol, 1.0
equiv), 2-nitrobenzenesulfonamide (0.0085 g, 42 μmol, 4.0 equiv), and
Ph P (0.0165 g, 63 μmol, 6.0 equiv) in DMSO (1.0 mL) at room
temperature was added DEAD (40 wt % in toluene, 29 μL, 63 μmol,
CDCl ): δ 7.92 (dd, J = 5.7, 2.0 Hz, 1H), 7.66−7.74 (m, 2H), 7.59
3
(dd, J = 5.4, 2.0 Hz, 1H), 3.63 (td, J = 12.8, 4.8 Hz, 1H), 3.52 (ddd, J =
15.2, 6.0, 4.0 Hz, 1H), 2.91−2.99 (m, 2H), 2.82 (dt, J = 13.6, 4.0 Hz,
1H), 2.60−2.66 (m, 1H), 1.60−2.41 (m, 13H), 1.48−1.54 (m, 1H),
3
13
1.23−1.34 (m, 1H), 1.09 (d, J = 6.0 Hz, 3H). C NMR (75 MHz,
6
.0 equiv). The reaction was stirred at room temperature for 1 day,
CDCl ): δ 218.7, 214.0, 148.9, 134.0, 131.6, 131.1, 130.9, 124.2, 60.3,
3
and then H O (8 mL) was added. The mixture was extracted with
EtOAc (3 × 3 mL). The combined organic layer was washed with
H O (3 mL) and brine (3 mL) and then dried over anhydrous
Na SO . After filtration and concentration, to the residue obtained was
added Et O (2 mL). The white precipitate was removed by filtering
through a filter funnel with a cotton plug and washed with Et O (3
50.1, 49.4, 46.8, 45.5, 42.4, 39.6, 31.2, 30.2, 29.7, 25.0, 22.5, 22.1, 20.9.
2
+
HRMS (ESI): calcd for C H N O S [M + H] 449.1741, found
22
29
2
6
2
449.1735.
2
4
(± )-Fawcettimine (1). In a 10-mL round-bottomed flask equipped
with reflux condenser was dissolved 33 (0.0127 g, 30 μmol, 1.0 equiv)
2
2
in CH CN (3 mL). KOH (1.0 M, 300 μmol, 0.30 mL, 10 equiv) and
3
mL). The filtrate was concentrated, and the crude obtained was
purified by preparative TLC (hexanes/EtOAc 1:1) to give the title
PhSH (15 μL, 150 μmol, 5 equiv) were added. The reaction was
stirred at gentle reflux for 6 h and then cooled to room temperature.
EtOAc (8 mL) was added, and the mixture was extracted with 1 M
HCl (3 × 4 mL). Solid Na CO was added to the combined aqueous
compound (0.0021 g, 38%; R = 0.24, hexanes/EtOAc 1:1) as a white
f
solid. IR (thin film): 2925, 2854, 1730, 1546, 1458, 1374, 1248, 1166,
2
3
−
1 1
1
7
4
2
1
4
2
5
028 cm . H NMR (300 MHz, CDCl ): δ 7.90−7.94 (m, 1H),
layer until saturation. The resulting mixture was extracted with 3%
3
.65−7.72 (m, 2H), 7.56−7.59 (m, 1H), 5.30−5.39 (m, 1H), 4.86−
MeOH in CHCl (3 × 5 mL). The combined organic layer was dried
3
.93 (m, 1H), 3.42−3.62 (m, 2H), 2.85−3.04 (m, 2H), 1.07−2.24 (m,
over anhydrous Na SO . After filtration and concentration, the residue
2
4
3H), 0.90 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl ): δ 171.0,
obtained was dissolved in CH Cl and HBr (0.1 M in H O, 0.30 mL,
3
2 2 2
70.6, 133.6, 131.8, 131.5, 130.8, 124.1, 75.9, 75.8, 50.7, 50.4, 46.04,
5.96, 42.5, 36.2, 33.6, 32.2, 30.0, 28.9, 26.9, 24.8, 24.1, 22.1, 21.7,
1.4, 17.0. HRMS (ESI): calcd for C H N NaO S [M + Na]
59.2085, found 559.2093.
7aR,8S,9aS,11R,13aS)-11-Methyl-4-((2-nitrophenyl)-
sulfonyl)tetradecahydro-1H-indeno[1,7a-e]azonine-8,13-diol
9). To a stirred solution of 31 (0.0876 g, 236 μmol, 1.0 equiv), 2-
nitrobenzenesulfonamide (0.191 g, 0.94 mmol, 4.0 equiv), and Ph3P
0.372 g, 1.42 mmol, 6.0 equiv) in CH CN (20 mL) and pyridine (4
30 μmol) added. After the solution was allowed to stand at room
temperature overnight, all of the volatiles were removed under
+
vacuum. To the solid obtained was added a minimum amount of Et O,
26
36
2
8
2
rinsed, and removed by pipet. The (±)-fawcettimine hydrobromide
(
salt remained was dissolved in CH Cl and dried over anhydrous
2 2
K CO overnight. After filtration and concentration, (±)-fawcettimine
2
3
(
(0.0073 g, 92%) was obtained as a pale yellow foam (R = 0.35, n-
f
BuOH/AcOH/H O 7:2:2). IR (thin film): 3287, 2923, 2856, 1735,
2
−1 1
(
1637, 1458, 1340, 1264, 1144, 1100, 1056 cm . H NMR (400 MHz,
3
mL) at room temperature was added DEAD (40 wt % in toluene, 0.65
mL, 1.42 mmol, 6.0 equiv) over 10 min. After 24 h at room
temperature, MeOH (24 mL) and K CO (0.326 g, 10.0 equiv) were
CDCl ): δ 3.76−3.85 (m, 1H), 3.58−3.70 (br, 1H), 3.40 (td, J = 14.2,
3
4.0 Hz, 1H), 3.03 (dd, J = 14.4, 4.8 Hz, 1H), 2.81−2.86 (m, 1H), 2.60
2
3
(dd, J = 18.0, 13.6 Hz, 1H), 1.82−2.35 (m, 11H), 1.37−1.76 (m, 5H),
1.00 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ 218.2, 59.9,
added. A reflux condenser was connected, and the suspension was
stirred with gentle reflux overnight. After cooling to room temperature,
the stirring bar was removed, and the solution was concentrated. The
residue was partitioned between EtOAc (15 mL) and brine (15 mL).
The organic layer was separated, and the aqueous layer was extracted
with EtOAc (2 × 15 mL). The combined organic layer was dried over
anhydrous Na SO , filtered, and concentrated. To the residue was
3
54.7, 50.6, 48.1, 43.4, 42.5, 41.6, 34.8, 31.8, 29.9, 27.6, 26.6, 23.9, 21.8,
+
20.9. HRMS (ESI) calcd. for C H NO [M + H] 264.1958, found
16
26
2
1
264.1962. Analytical Data for (±)-Fawcettimine Hydrobromide. H
NMR (400 MHz, CDCl ): δ 10.01 (br s, 1H), 5.80 (s, 1H), 4.18 (br s,
3
1H), 3.51−3.64 (m, 1H), 3.21 (br d, J = 11.2 Hz, 1H), 3.02 (br s, 1H),
2.81 (d, J = 12.4 Hz, 1H), 2.60 (dd, J = 16.8, 12.4 Hz, 1H), 1.82−2.46
(m, 12H), 1.75 (br d, J = 14.0 Hz, 1H), 1.64 (d, J = 12.8 Hz, 1H), 1.48
(td, J = 13.4, 4.8 Hz, 1H), 1.05 (d, J = 6.0 Hz, 3H). 13C NMR (75
2
4
added EtOH (3 mL), and the resulting NsNH2 precipitate was
removed by filtering over a filter funnel with a cotton plug and washed
with EtOH (3 × 3 mL). The filtrate was concentrated and the residue
obtained was purified by flash column chromatography (hexanes/
MHz, CDCl ): δ 216.2, 96.3, 59.2, 56.0, 51.6, 47.7, 43.3, 41.2, 40.3,
3
33.5, 31.4, 26.8, 24.2, 24.0, 21.6, 19.2.
EtOAc, 1:1 to 1:2) to afford the title compound (0.054 g, 50%; R =
(± )-Fawcettidine (2). In a 10-mL round-bottomed flask equipped
with reflux condenser were dissolved fawcettimine (0.0054 g, 20 μmol,
1.0 equiv) and oxalic acid (0.0540 g, 0.6 mmol, 29.0 equiv) in AcOH
(2 mL). Oxygen was carefully removed through a freeze−pump−thaw
cycle 3 times. The flask was refilled with Ar, and the reaction was
f
0
.07, hexanes/EtOAc 1:2) as a white solid contaminated with trace
amount of Ph PO. An analytical sample was further purified by
3
preparative TLC (hexanes/EtOAc 1:2). IR (thin film): 3385, 2925,
−1 1
1
545, 1373, 1343, 1164 cm . H NMR (400 MHz, CDCl ): δ 7.91−
3
I
dx.doi.org/10.1021/jo3006045 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
stirred at 160 °C for 12 h. After the mixture was cooled to room
temperature, n-heptane was added, and all the volatiles were removed
under vacuum. To the residue was added aq 5% NH ·H O solution (5
round-bottomed flask was added CH Cl (1.0 mL), and the flask was
2
2
cooled to −78 °C (dry ice/acetone bath). (COCl) (13 μL, 152 μmol,
2
10.0 equiv) and DMSO (21.6 μL, 304 μmol, 20.0 equiv) were added.
The mixture was stirred at −78 °C for 30 min before 34 (4.3 mg, 15.2
μmol, 1.0 equiv) in 1.0 mL of CH Cl was added via syringe. The
3
2
mL), and the resulting mixture was extracted with 3% MeOH in
CHCl (4 × 4 mL). The combined organic layer was dried over
3
2
2
anhydrous Na SO . After filtration and concentration, the crude
resulting mixture was stirred at −78 °C for 1 h, and then NEt (85 μL,
3
2
4
obtained was purified by flash column chromatography (basic alumina,
608 μmol, 40.0 equiv) was added. After another 20 min, the reaction
was allowed to warm to room temperature and stirred at room
temperature for 2 h. Brine (4 mL) was added, and the resulting
hexanes/EtOAc, 2:1 then 3% MeOH in CHCl ) to afford the title
3
compound (0.0040 g, 80%) as a white foam (R = 0.24, MeOH/CHCl3
f
5
1
:95). IR (thin film): 2924, 2848, 1737, 1662, 1549, 1447, 1328, 1302,
253, 1216, 1193, 1169, 1149, 1105, 1030 cm . H NMR (400 MHz,
mixture was extracted with 3% MeOH in CHCl
combined organic layer was dried over anhydrous Na
3
(3 × 4 mL). The
−1 1
SO , filtered,
2
4
CDCl ): δ 5.69 (d, J = 4.8 Hz, 1H), 2.97−3.15 (m, 4H), 2.74 (ddd, J =
and concentrated to afford crude 35, which was used immediately in
next step without further purification. An analytical sample was
3
1
6.8, 7.6, 1.6 Hz, 1H), 2.22−2.36 (m, 2H), 2.05−2.20 (m, 3H), 1.82−
.00 (m, 2H), 1.54−1.79 (m, 3H), 1.21−1.41 (m, 4H), 1.06 (d, J = 6.8
2
purified by flash column chromatography (3% MeOH in CH
2
Cl
2
) to
): δ
13
1
Hz, 3H). C NMR (100 MHz, CDCl ): δ 219.1, 146.2, 127.4, 60.6,
give title compound as a colorless oil. H NMR (400 MHz, CDCl
3
3
5
6.5, 52.2, 46.4, 44.3, 39.4, 37.5, 34.4, 31.6, 29.4, 28.0, 24.1, 21.1.
2.90 (d, J = 5.2 Hz, 1H), 2.49−2.62 (m, 2H), 2.04−2.45 (m, 12H),
1.72−1.99 (m, 5H), 1.31−1.52 (m, 3H), 1.12−1.20 (m, 1H), 1.07 (d, J
+
HRMS (ESI): calcd for C H NO [M + H] 246.1852, found
16
24
= 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl
): δ 220.4, 214.4, 60.9,
2
46.1855.
3
(
± )-Lycoflexine (3). In a 10-mL round-bottomed flask equipped
55.0, 50.4, 49.0, 46.9, 44.5, 42.8, 39.6, 31.3, 30.4, 28.3, 25.5, 22.7, 22.6,
+
with reflux condenser was dissolved 33 (0.0024 g, 5.3 μmol, 1.0 equiv)
in CH CN (2 mL). KOH (1.0 M, 42 μmol, 42 μL, 8.0 equiv) and
PhSH (2.7 μL, 26 μmol, 5.0 equiv) were added. The reaction was
stirred at gentle reflux for 8 h and then cooled to room temperature.
H O (1 mL), HCO H (16 μL, 424 μmol, 80 equiv), and 37% HCHO
21.9. HRMS (ESI): calcd for C17
H28NO [M + H] 278.2115, found
2
278.2110.
3
(± )-Lycoposerramine B (4). Following the procedure described
12a
by Harayama and Takayama, to a solution of crude 35 (15.2 μmol,
theoretical) obtained above in EtOH (1.5 mL) was added Et NH (7.9
2
2
2
μL, 76 μmol, 5.0 equiv). The mixture was stirred at room temperature
(
aq, 34 μL, 424 μmol, 80 equiv) were added. The resulting mixture
for 3 h, and then NH OH·HCl (0.2 M in EtOH, 83.5 μL, 1.1 equiv)
was stirred at gentle reflux overnight before all of the volatiles were
removed at vacuum. The residue was dissolved in EtOAc (10 mL) and
extracted with 1 M HCl (3 × 4 mL). Solid Na CO was added to the
combined aqueous layer until saturation. The mixture was then
extracted with 3% MeOH in CHCl (3 × 4 mL), and the combined
organic layer was dried over anhydrous Na SO . After filtration and
concentration, the residue was purified by flash column chromatog-
raphy (basic alumina, hexanes/EtOAc, 1:2 then 3% MeOH in CHCl3)
to afford the title compound (0.0013 g, 91%) as a white solid (R =
2
was added dropwise via syringe. After the mixture was stirred at room
temperature for an additional 24 h, the reaction was quenched with
2
3
chilled satd NaHCO (3 mL) and extracted with 5% MeOH in CHCl
3
3
(
4 × 5 mL). The combined organic layer was dried over anhydrous
3
Na SO , filtered, and concentrated. The residue was chromatographed
2
4
2
4
(
10% MeOH in CHCl ) to afford crude titled compound. The crude
3
was rechromatographed (NH ·H O/MeOH/CHCl 0.05/5/95) to
afford the title compound (1.8 mg, 40%) as a colorless oil. IR (thin
film): 2918, 2849, 1702, 1451, 1369, 1268, 1210, 1139, 1076 cm . H
3
2
3
f
−1 1
0
1
.23, n-BuOH/AcOH/H O 7:2:2). IR (thin film): 2924, 2853, 1727,
2
−1
1
NMR (400 MHz, CDCl ): δ 3.18 (d, J = 3.2 Hz, 1H), 2.66 (app td, J =
699, 1456, 1352, 1208, 1174, 1127, 1063 cm . H NMR (400 MHz,
3
1
1
1
3.6, 3.6 Hz, 1H), 2.55 (ddd, J = 18.8, 9.2, 0.8 Hz, 1H), 2.38−2.45 (m,
CDCl ): δ 3.19 (ddd, J = 14.4, 2.8, 1.2 Hz, 1H), 3.13 (ddd, J = 13.6,
3
H), 2.18−2.36 (m, 8H), 1.96−2.16 (m, 4H), 1.55−1.80 (m, 5H),
8
.0, 4.0 Hz, 1H), 2.94−3.02 (m, 1H), 2.78−2.91 (m, 2H), 2.61−2.72
1
3
.43−1.50 (m, 1H), 1.15−1.40 (m, 3H), 1.04 (d, J = 6.4 Hz, 3H).
C
(
1
m, 2H), 2.19−2.42 (m, 6H), 2.06−2.17 (m, 2H), 1.91−2.01 (m, 2H),
NMR (100 MHz, CDCl ): δ 214.0, 169.8, 61.9, 55.2, 48.7, 47.0, 44.5,
.71−1.89 (m, 3H), 1.56−1.64 (m, 1H), 1.31−1.36 (m, 1H), 1.04 (d, J
3
6.0 Hz, 3H). 1 C NMR (100 MHz, CDCl ): δ 218.6, 214.1, 60.8,
3
43.1, 31.8, 30.1, 29.9, 28.9, 27.7, 25.7, 25.6, 22.6, 21.6. HRMS (ESI):
=
3
+
calcd for C H N O [M + H] 293.2224, found 293.2226.
5
1
2
8.7, 56.9, 53.8, 53.5, 46.9, 40.5, 40.3, 36.4, 31.5, 29.5, 28.2, 26.3, 22.6,
9.6. HRMS (ESI): calcd for C H NO [M + H] 276.1958, found
17 29
2
2
+
17
26
2
ASSOCIATED CONTENT
76.1962.
■
(
7aR,8S,9aS,11R,13aS)-4,11-Dimethyltetradecahydro-1H-
S
*
Supporting Information
indeno[1,7a-e]azonine-8,13-diol (34). In a 25-mL round-bot-
tomed flask equipped with reflux condenser was dissolved 9 (0.0310 g,
1
13
H and C NMR spectra for all compounds. Determination of
absolute configuration and GC chromatogram of (+)-13.
HPLC chromatogram of (−)-16 This material is available
free of charge via the Internet at http://pubs.acs.org.
6
9 μmol, 1.0 equiv) in CH CN (ACS grade, 4 mL). KOH (1.0 M, 0.55
3
mmol, 0.55 mL, 8 equiv) and PhSH (35 μL, 0.35 mmol, 5 equiv) were
added. The reaction was stirred at gentle reflux for 8 h and then cooled
to room temperature. MeOH (ACS grade, 4 mL), aq HCHO (37%,
AUTHOR INFORMATION
Corresponding Author
E-mail: rmw@lamar.colostate.edu.
1
54 μL, 2.07 mmol, 30 equiv), and NaBH CN (0.013 g, 0.21 mmol, 3
3
■
equiv) were added. After the solutionw as stirred at room temperature
overnight, aq HCl (1.0 M, 2.0 mL) was added, and the mixture was
extracted with 1 M HCl (3 × 3 mL). Solid Na CO was added to the
combined aqueous layer until saturation. The resulting mixture was
extracted with 5% MeOH in CHCl (4 × 4 mL), and the combined
organic layer was dried over anhydrous Na SO . After filtration and
concentration, the residue was purified by flash column chromatog-
raphy (basic alumina, 3% MeOH in CHCl ) to afford the title
compound (0.0175 g, 90%) as a white solid. IR (thin film): 3356,
*
2
3
Notes
The authors declare no competing financial interest.
3
2
4
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the National
Institutes of Health (Grant No. 2RO1 GM068011).
■
3
−1 1
2
925, 2869, 1721, 1660, 1455, 1376, 1273, 1107, 1066 cm . H NMR
(
2
1
7
300 MHz, CDCl ): δ 4.58−4.66 (m, 1H), 3.59−3.66 (m, 1H), 2.51−
3
REFERENCES
.76 (m, 3H), 2.17−2.47 (m, 6H), 1.81−2.14 (m, 5H), 1.11−1.74 (m,
■
2H), 0.93 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl ): δ 74.4,
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3.8, 55.8, 51.9, 48.0, 46.8, 43.3, 39.4, 37.6, 33.0, 28.4, 27.5, 26.7, 25.8,
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32
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(
7aR,9aS,11R,13aS)-4,11-Dimethyldecahydro-1H-indeno-
[1,7a-e]azonine-8,13(2H,9H)-dione (35). To a 15-mL flame-dried
J
dx.doi.org/10.1021/jo3006045 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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(
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(
6
(
7
(
(
1
K
dx.doi.org/10.1021/jo3006045 | J. Org. Chem. XXXX, XXX, XXX−XXX