Cyclobutane Synthesis and Fragmentation. A Cascade Route to the Lycopodium Alkaloid (-)-Huperzine A

Article abstract of DOI:10.1021/acs.joc.5b01619

An asymmetric total synthesis of the nootropic alkaloid (-)-huperzine A was completed using a cascade sequence initiated by an intramolecular aza-Prins reaction and terminated by a stereoelectronically guided fragmentation of a cyclobutylcarbinyl cation as the key step in assembling the bicyclo[3.3.1]nonene core of the natural product. Intramolecular [2 + 2]-photocycloaddition of the crotyl ether of (S)-4-hydroxycyclohex-2-enone afforded a bicyclo[4.2.0]octanone containing an embedded tetrahydrofuran in which the cyclohexanone moiety was converted to a triisopropylsilyl enol ether and functionalized as an allylic azide. The derived primary amine was acylated with α-phenylselenylacrylic acid, and the resulting amide was reacted with trimethylaluminum to give a [2 + 2]-cycloadduct, which underwent retroaldol fission to produce a fused α-phenylselenyl δ-lactam. Periodate oxidation of this lactam led directly to an α-pyridone, which was converted to a fused 2-methoxypyridine. Reductive cleavage of the activated "pyridylic" C-O bond in this tetracycle and elaboration of the resultant hydroxy ketone to a diketone was followed by chemoselective conversion of the methyl ketone in this structure to an endo isopropenyl group. Condensation of the remaining ketone with methyl carbamate in the presence of acid initiated the programmed cascade sequence and furnished a known synthetic precursor to huperzine A. Subsequent demethylation of the carbamate and the methoxypyridine, accompanied by in situ decarboxylation of the intermediate carbamic acid, gave (-)-huperzine A.

Full text of DOI:10.1021/acs.joc.5b01619

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Article
Cyclobutane Synthesis and Fragmentation. A Cascade
Route to the Lycopodium Alkaloid (-)-Huperzine A
James D. White, Yang Li, Jungchul Kim, and Miroslav Terinek
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01619 • Publication Date (Web): 10 Sep 2015
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Cyclobutane Synthesis and Fragmentation. A Cascade Route to the
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Lycopodium Alkaloid (-)-Huperzine A
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James D, White,* Yang Li, Jungchul Kim and Miroslav Terinek
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States
Table of Contents / Abstract Graphic
O
H
H
H
1. H2NCO2Me
H
H
N
OMe
N
O
p-TsOH
NH2
Huperzine A
2. TMSI
O
O
ABSTRACT: An asymmetric total synthesis of the nootropic alkaloid (-)-huperzine A was
completed using a cascade sequence initiated by an intramolecular aza-Prins reaction and
terminated by a stereoelectronically guided fragmentation of a cyclobutylcarbinyl cation as the
key step in assembling the bicyclo[3.3.1]nonene core of the natural product. Intramolecular
[2+2]-photocycloaddition of the crotyl ether of (S)-4-hydroxycyclohex-2-enone afforded a
bicyclo[4.2.0]octanone containing an embedded tetrahydrofuran in which the cyclohexanone
moiety was converted to a triisopropylsilyl enol ether and functionalized as an allylic azide. The
derived primary amine was acylated with α-phenylselenylacrylic acid and the resulting amide
was reacted with trimethylaluminum to give a [2+2]-cycloadduct which underwent retroaldol
fission to produce a fused α-phenylselenyl δ-lactam. Periodate oxidation of this lactam led
directly to an α-pyridone which was converted to a fused 2-methoxypyridine. Reductive
cleavage of the activated “pyridylic” C-O bond in this tetracycle and elaboration of the resultant
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hydroxy ketone to a diketone was followed by chemoselective conversion of the methyl ketone
in this structure to an endo isopropenyl group. Condensation of the remaining ketone with
methyl carbamate in the presence of acid initiated the programmed cascade sequence and
furnished a known synthetic precursor to huperzine A. Subsequent demethylation of the
carbamate and the methoxypyridine, accompanied by in situ decarboxylation of the intermediate
carbamic acid, gave (-)-huperzine A.
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INTRODUCTION
The seminal publications by Woodward and Hoffmann five decades ago that set forth “rules”
governing, among other reactions, the addition of one alkene unit to another1 has spawned a vast
body of research on both the theoretical and synthetic implications of the [2+2]-cycloaddition
process.2 A rationale based on “orbital symmetry”, or more precisely upon orbital correlation
diagrams that consider the relationship of HOMO and LUMO electronic states of reactants,
explained that while cycloaddition of two alkenes in their ground electronic states was thermally
“forbidden”, the corresponding cycloaddition with one of the alkenes in an electronically excited
state would be “allowed”. In the latter case, a cyclobutane would result, initially in an
electronically excited state but relaxation to ground state would follow.3 Deciding what
“forbidden” actually means in energy terms is not always straightforward4 but a practical
consequence of the Woodward-Hoffmann paradigm is that extensive use has been made of
photochemistry to excite an alkene in the presence of a second ground state alkene to prepare
cyclobutanes.5 An early application of this principle to the synthesis of a natural product (and one
inspired by the insight brought to cycloaddition processes by Woodward himself during his
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legendary research group meetings of the 1960’s) was our synthesis of the bourbonene
sesquiterpenoids, where photocycloaddition of cyclopentenone to a substituted cyclopentene
installed the central cyclobutane in these tricyclic structures.6
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The ease with which cyclobutanes can be synthesized photochemically taken with the fact that
the four-membered carbocycle contains ca. 26 kcal/mol of strain energy7 has led to a rich
portfolio of synthetic applications resulting from release of that ring strain.8 Examples include
cycloreversion of a cyclobutane to form two new alkene units, a process employed in our
synthesis of byssochlamic acid,9 ring expansion to a cyclopentane,10 and ring scission to generate
new cyclic or acyclic entities possessing diminished strain relative to the starting
cyclobutane.11,12 A cyclobutane cleavage pathway that can be characterized as a “downhill”
progression in energy terms is the conceptual basis for our synthesis of the Lycopodium alkaloid
huperzine A (1).13 Huperzine A, a constituent of the club moss Huperzia serrata (Thunb.), has
attracted attention as a result of claims that the compound has restorative properties for cognitive
impairment and has the ability to improve memory function. Historically, H. serrata has been
used in China under the name Chien Tseng Ta to treat a variety of illnesses including
Alzheimer’s dementia.14 Although huperzine A is easily accessible from its natural source and is
often sold as a component of herbal remedies, the compound continues to be a target of
opportunity among synthetic organic chemists.
The first synthesis of huperzine A as its racemate was completed by Kozikowski who used a
tandem Michael-aldol sequence to fabricate the bicyclo[3.3.1]nonene portion of the molecule.15
The route was subsequently improved by the Kozikowski group16 and then adapted to an
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asymmetric synthesis of natural (-)-huperzine A.17 A synthesis of racemic 1 almost identical to
that of Kozikowski has been published by Ji.18 Kozikowski later developed a second route to 1
using a palladium-catalyzed bicycloannulation to construct the bicyclo[3.3.1]nonene core19 and
this strategy has been utilized by both Terashima in a synthesis of (-)-120 and by Langlois in a
formal synthesis of (+)-1.21 Two recent syntheses of huperzine A using novel approaches, one
by Fukuyama22 and the other by Lin,23 have been reported.
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H
N
OMe
H
N
a
aza-Prins
N
OMe
O
N
H
NH2
H
N
H
EWG
EWG
H
Huperzine A (1)
3
2
Pyridine
Annulation
H
H
R
R
[2+2]-photoaddition
+
O
O
4
Scheme 1. Proposed Route to Huperzine A Using an Aza-Prins-cyclobutylcarbinyl Cation
Fragmentation Cascade
RESULTS AND DISCUSSION
Our approach to 1 was based on the proposition that release of strain in a cyclobutane embedded
within a structure such as 2 could be used to generate the less strained bicyclo[3.3.1]nonene
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framework of 1 (Scheme 1).24 The event designed to release that strain would be fragmentation
of bond “a” in cyclobutylcarbinyl cation 3, the cation being formed via an intramolecular aza-
Prins reaction25 of 2. While alternative fragmentation modes of the cyclobutane in 3 are
certainly conceivable, the orbital alignment suggested by the arrows in Scheme 1 implies that a
stereoelectronic bias should favor the fragmentation pathway we desire. The retrosynthetic
direction from 2 envisioned construction of a bicyclo[4.2.0]octane precursor 4 via [2+2]-
photocycloaddition of a cyclohexenone to a suitably functionalized alkene,26 with the
methoxypyridine unit in 2 being fused to this template in a subsequent operation. As it
happened, a [2+2]-cycloaddition and fragmentation of the resultant cyclobutane also featured in
the methoxypyridine annulation en route to 2.
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Our goal from the outset was an asymmetric synthesis of huperzine A in its natural absolute
configuration and it was recognized that a plausible way to achieve this would be to incorporate
a stereogenic center in one of the photo partners leading to 4. Maximum stereocontrol would be
assured if the photocycloaddition were intramolecular27 and a decision was made to link the two
photo addends through a functional group in the cyclohexenone partner. An attractive starting
point based on this precept was (S)-(-)-4-hydroxycyclohex-2-enone (5), prepared from (-)-quinic
acid by the method of Danishefsky.28 However, our first approach to the bicyclooctane core of
4 via photocycloaddition of an unsaturated ester derived from 5 proved to be flawed since neither
crotonate 6, prepared from 5 and crotonyl chloride, nor ester 7, obtained from 5 with (E)-2-
methyl-3-pentenoic acid, afforded any trace of cycloadducts 8 and 9 upon irradiation (Scheme
2). Instead, complex mixtures were produced in each case.
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O
O
O
OH
O
O
Cl
hν
H
AgCN
7
8
9
77%
O
H
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O
O
5
6
8
CO2H
81%
DCC, DMAP
O
O
H
O
O
O
O
hν
H
7
9
Scheme 2. Attempted Photocycloaddition of Unsaturated Esters of 4-Hydroxycyclohex-2-
enone
While these failed sequences were disappointing, we were aware that previous studies by
others29 had shown that unsaturated ethers tethered to a photoreactive cyclic enone readily
undergo intramolecular [2+2]-cycloaddition. For example, Garibaldi et al. reported that
irradiation of 3-allylyoxycyclopent-2-enone (10) gave tricyclic adduct 11 in high yield (Scheme
3).30
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O
O
H
hν
(ref 30)
6
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95%
H
O
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O
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Scheme 3. Intramolecular Photocycloaddition of 3-Allyloxycylopent-2-enone
Based on this precedent, we used Martin’s method31 to prepare crotyl ether 12 as a prospective
photo substrate by treatment of 5 with trans crotyl bromide and silver(I) oxide. After exploratory
studies to determine optimal reaction conditions, intramolecular [2+2]-adduct 13 was obtained in
a consistent 55-60% yield upon irradiation of 12 through Pyrex glass with a 450W medium
pressure mercury lamp (Scheme 4). It was important to use degassed dichloromethane as solvent
for this reaction which was carried out at 0 °C and was generally complete within two hours.
Since four new stereocenters were generated in 13 from the single stereogenic carbon in 12,
verification of the configuration of 13 was undertaken using nOe experiments. The proton
correlations shown in Figure 1 confirmed that cycloaddition of 12 had occurred in a syn sense at
the cyclohexenone double bond and with preservation of the trans relationship originating in the
crotyl appendage.
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O
Br
OH
H
H
O
Ag2O
hν
58%
59%
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O
O
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5
1. PhSeCl,
EtOAc
81%
2. NaIO4
OH
HO
O
Dess-Martin
periodinane
H
H
H
H
H
H
Zn, EtOH
53%
H
67%
H
O
O
O
16
15
14
Scheme 4. Intramolecular Photocycloaddition of (4S)-4-Crotyloxycyclohex-2-enone and
Reductive C-O Cleavage of the Product
2%
5%
O
H
H
H
H
3%
Me
O
1%
Figure 1. Nuclear Overhauser Enhancement of Irradiated Proton Signals in 13
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With 13 in hand, our next goal was fusion of a methoxypyridine unit to this bicyclic substrate.
Our initial route envisioned introduction of a 2,3-double bond into 13, then using the derived
cyclohexenone 14 as a dienophile in a [4+2]-cycloaddition with a 1-azadiene.32 The
transformation of 13 to cyclohexenone 14 was straightforward and involved α-selenylation with
phenylselenyl chloride followed by in situ oxidation with sodium periodate.33 Before testing 14
as a dienophile in an aza-Diels-Alder reaction, we took advantage of an opportunity to
investigate reductive cleavage of the allylic C-O bond of the tetrahydrofuran since the resulting
primary alcohol would be a logical platform for advance toward the endo isopropenyl group of 2.
An extensive search for a suitable method to effect this reductive scission revealed that only
Yadav’s protocol34 using zinc in refluxing ethanol was successful in producing 15, other
reductants generally returning saturated ketone 13 as the major product. Oxidation of 15 to an
aldehyde which would precede completion of a path to the isopropenyl substituent of 2
surprisingly afforded the intramolecular aldol product 16, a result that in retrospect could have
been foreseen given the endo disposition of the transient aldehyde and its proximity to the β,γ-
unsaturated ketone. Attempts to reverse the formation of 16 were unsuccessful and installation
of the isopropenyl group of 2 was therefore deferred to a later step.
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It was evident that formation 16 upon oxidation of 15 could have been avoided if a pyridine ring
were fused to 13 so that enolization of the ketone was blocked. Attention therefore returned to
enone 14 as a prospective dienophile partner for an aza-Diels-Alder reaction that would create a
δ-lactam for eventual aromatization to a pyridine. In this scenario, the C-O bond for reductive
cleavage would become pseudo-benzylic, i.e. “pyridylic”, and consequently should be more
susceptible towards fission than the corresponding C-O bond in 14. Unfortunately, 14 failed to
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react with any of a variety of 1-azadienes including those bearing methoxy substituents at C-2
and C-4 as well those carrying an activating N-dimethylamino substituent,35 and it became
apparent from these experiments that the combination of a weak dienophile with a 1-azadiene
was an incompatible pairing for cycloaddition. This approach to annulation of the pyridine
moiety of 2 was therefore abandoned in favor of a stepwise plan.
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The first step in our new route to 2 envisioned conjugate addition of azide to enone 14 but this
reaction encountered the twin difficulties of facile reversibility and clean separation of an
unstable product from starting material. As a result, we were unable to force the reaction to
completion. A timely solution to this problem appeared in a publication from the Magnus
laboratory which reported that treatment of a triisopropylsilyl enol ether with trimethylsilyl azide
and iodosobenzene gave an allylic azide in good yield.36 Application of the Magnus protocol to
13 first required preparation of silyl enol ether 17 which, after brief chromatographic
purification, was exposed to iodosobenzene and trimethylsilyl azide at low temperature (Scheme
5). The reaction afforded an excellent yield of azide 18 as a single stereoisomer whose exo
configuration was proven by proton-proton coupling constants in its NMR spectrum (Figure 2).
Reduction of 18 with lithium aluminum hydride furnished primary amine 19 which was reacted
in situ with acryloyl chloride to yield amide 20.
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O
O
O
H
H
H
PhIO
H
H
KHMDS
TIPSCl
N3
TMSN3
CH2Cl2 , -19 °C
86% (2 steps)
THF, 0 °C
H
O
OTIPS
OTIPS
18
17
13
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LiAlH4
Et2O, 0 °C
94%
O
O
H
O
O
Cl
Et3N
H
N
H
H
N
H
H
NH2
O
O
O
Et2O, 0 °C
82%
H
H
H
OTIPS
OTIPS
20
21
19
Scheme 5. Synthesis of Acrylamide 20 from Photoadduct 13
6Hz
3Hz
O
H
H
H
H
6Hz
N3
H
OTIPS
Figure 2. Proton-proton Coupling Constants in Azide 18
It was hoped that silyl enol ether 20 would undergo Lewis acid-catalyzed intramolecular
Mukaiyama-Narasaka conjugate addition37 to generate δ-lactam 21 but hydrolysis of the silyl
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enol ether and subsequent β elimination of the acrylamide moiety intervened to regenerate 14.
5
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9
On the supposition that an α-bromo amide would provide a more compliant acceptor for ring
closure, amine 19 was acylated with α-bromoacryloyl chloride to afford 22 but this bromo
amide suffered the same fate as 20 when Narasaka cyclization was attempted. At this point, a
second publication from the Magnus lab came to our attention in the form of a report describing
intramolecular trimethylaluminum-catalyzed [2+2]-cycloaddition of acrylamide 23 to give 24
(Scheme 6).38
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H
N
H
DCE
AlMe3,
O
NH
80 °C
(ref 38)
O
43%
OTIPS
23
TIPSO
24
Scheme 6. Magnus’ Trimethylaluminum-mediated [2+2]-Cycloaddition of Acrylamide 23
The Magnus reaction conditions applied to 22 led smoothly to crystalline pentacyclic adduct 25
(Scheme 7). It is noteworthy that the configuration of the nine stereogenic carbons in the
congested framework of 25 emanate from the single stereocenter in 5 and that 25 is quite stable
despite the presence of ring strain associated with two embedded cyclobutanes. Although
formally a [2+2]-cycloaddition, the transformation of 22 to 25 falls outside the scope of the
Woodward-Hoffmann rules and is most likely a stepwise process involving zwitterionic
intermediate 26.
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O
1.LiAlH4
O
O
H
N
AlMe
3, DCE
H
H
H
H
H
H
N
OAlMe2
Br
O
N3
Et2O, 0 °C
70 °C
Br
Et3N
2.
76%
Br
COCl
OTIPS
OTIPS
OTIPS
18
Et2O, 0 °C
59%
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22
O
H
H
H
O
H
H
H
H
N
OAlMe2
Br
NH
O
H
TIPSO
Br
25
OTIPS
26
Scheme 7. Trimethylaluminum-mediated [2+2]-Cycloaddition of Bromoacrylamide 22
The β-silyloxy carbonyl motif contained within the δ-lactam portion of 25 set the stage for
retroaldol fission of the new cyclobutane ring and exposure of 25 to aqueous HF in nitromethane
gave α-bromo lactams 27 and 28 in high yield as a 3:1 epimeric mixture (Scheme 8). In
principle, base-mediated elimination of HBr from either of these δ-lactams should yield a
dihydropyridone from which the methoxypyridine system of 2 could be obtained after
aromatization. However, we had not foreseen that basic reaction conditions could also generate
a ketone enolate from these keto lactams and that internal alkylation resulting in 1,3-elimination
could occur.39 In fact, exposure of the major bromo lactam 27 to DBU gave fused cyclopropane
29 as the only detectable product and minor isomer 28 suffered the same fate.
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O
O
H
O
H
H
H
H
H
H
HF (48%)
MeNO2
H
H
H
H
H
N
O
R1
N
DBU, tol
NH
O
86%
Δ, 43%
R2
O
H
O
TIPSO
O
Br
27, R1=H, R2=Br
28, R1=Br, R2=H
25
10
11
12
13
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15
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25
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27
28
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36
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39
40
41
42
43
44
45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
29
Scheme 8. Retroaldol Fission of 25 and Elimination to Cyclopropane 29
The intramolecular alkylation that produced 29 was avoided by replacing the bromine atom in 22
with a selenium substituent so that formation of an α,β-unsaturated δ-lactam could be
accomplished oxidatively rather than by treatment with base. This revision necessitated a return
to azide 18. Coupling of the primary amine from reduction of 18 with α-phenylselenylacrylic
acid40 in the presence of 3,5-dinitrobenzoyl chloride gave amide 30 which upon treatment with
trimethylaluminum afforded the expected [2+2]-cycloadduct 31 (Scheme 9). The latter
underwent retroaldol fission with aqueous HF in nitromethane to give separable epimeric α-
selenyl lactams 32 and 33 in an approximately 1:1 ratio. Exposure of 32 and 33 to sodium
periodate revealed that the two α-selenyl lactams behaved differently. Whereas both 32 and 33
formed their respective selenoxides, only that from 33 underwent elimination. The failure of the
selenoxide from 32 to give an unsaturated lactam is attributed to an unfavorable steric interaction
of the endo phenylselenyloxy substituent in this structure with the ketone carbonyl which
prevents correct alignment for a 1,2-syn elimination. Fortunately, a potential loss of material at
this late stage was averted when the mixture of α-selenyl lactams was found to equilibrate in
favor of 33 (10:1) with excess aqueous HF. A second fortuitous discovery was that reaction of
33 with excess sodium periodate led to fully unsaturated α-pyridone 34. The dehydrogenation
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that occurs after elimination of the selenoxide from 33 to form a transient α,β-unsaturated δ-
lactam is probably initiated by oxidation at the activated ring junction but the precise mechanism
of this transformation remains unknown. In any event, the foregoing results provided an
efficient pathway from 31 to 34 involving exposure of 31 to four equivalents of aqueous HF in
nitromethane followed directly by addition of excess sodium periodate to afford 34 in 83%
overall yield. Pyridone 34 was converted uneventfully to methoxypyridine 35 with methyl
iodide in the presence of silver(I) carbonate.
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O
O
H
N
H
H
H
H
1. LiAlH4, Et2O
N3
O
SePh
2.
SePh
CO2H
OTIPS
18
OTIPS
30
3, 5-(O2N)2C6H3COCl
Et3N, 69%
AlMe3
69%
DCE, 80 °C
O
H
H
O
H
N
H
H
H
H
HF (48%)
MeNO2
O
R1
NH
O
R2
89%
TIPSO
SePh
O
32, R1=H, R2=SePh
31
33, R1=SePh, R2=H
NaIO4
83%
MeOH-H2O
O
H
O
H
N
MeI
Ag2CO3
H
H
N
OMe
O
CHCl3
91%
H
O
O
35
34
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Scheme 9. Trimethylaluminum-mediated [2+2]-Cycloaddition of α-
8
9
Phenylselenylacrylamide 30, Retroaldol Cleavage of 31 and Oxidation to Pyridone 34
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Reductive scission of the activated “pyridylic” C-O bond in 35 was expected to be more facile
than cleavage of the analogous C-O bond in 14 but this hypothesis proved to be unfounded.
Although hydrogenolysis of 35 using various palladium catalysts including Pearlman’s catalyst41
did produce a primary alcohol under forcing conditions, the reaction was always accompanied by
reduction of the keto group. As with 14, the only satisfactory reagent for effecting reductive
cleavage of the C-O bond in 35 proved to be zinc.34 Activation of zinc using Newman’s
method42 and exposure of 35 to an excess of the metal in MeOH containing 0.2M NaOH at
reflux gave hydroxy ketone 36 in excellent yield with no detectable reduction of the carbonyl
group (Scheme 10). Alcohol 36 was advanced to keto aldehyde 37 upon oxidation with Dess-
Martin periodinane43 and a chemoselective Grignard reaction44 at the aldehyde of 37 with
methylmagnesium bromide produced an inconsequential 1:1 mixture of epimeric hydroxy
ketones 38. Oxidation of the mixture, again with Dess-Martin periodinane,43 yielded a single
diketone 39.
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OH
O
H
H
H
Zn, NaOH
MeOH-H2O
N
OMe
N
OMe
80 °C, 94%
H
O
O
35
36
10
11
12
13
14
15
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21
22
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DMP
CH2Cl2
93%
OH
O
H
H
H
N
OMe
MeMgI
Et2O, -78 °C
N
OMe
H
76%
H
O
O
37
38
DMP
CH2Cl2
92%
O
H
H
N
OMe
O
39
Scheme 10. Reductive Cleavage of 35 and Oxidation to Diketone 39
At this point, our blueprint called for differentiating the two ketones of 39 by converting the
methyl ketone to the isopropenyl group of 2 whilst leaving the cyclohexanone carbonyl intact for
later derivatization as an activated imine. It was reasoned that the cyclohexanone carbonyl of 39
should be relatively unreactive towards methylenating reagents by virtue of its “through
conjugation” to the methoxy substituent on the pyridine ring. On the other hand, the endo
orientation of the methyl ketone in 39 presents a “hidden” carbonyl to an external reagent that
could also render this functional group unreactive. Predictably, attempts to effect selective
methylenation of the methyl ketone of 39 using Peterson olefination,45 Petasis-Tebbe
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methylenation46 or a Wittig reaction47 met with little success and confirmed that
chemoselectivity was difficult to achieve in this structural setting (Scheme 11). Wittig
olefination of 39 with methylenetriphenylphosphorane did give a modest yield of 40 along with
41 and the bis methylenated product 42, and a small bonus accrued from the finding that 41
could be ozonized efficiently to 39 which could then be recycled. Nevertheless, acquisition of
40 from 39 using this late-stage strategy was an impractical means for advancing the synthesis
toward 1.
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O
H
N
OMe
H
O
39
A. (1) TMSCH2MgCl, THF; (2) HF
B. Cp2TiMe2, tol
C. Ph3PCH3Br, n-BuLi, THF
O
H
H
H
H
N
OMe
N
OMe
N
OMe
+
+
H
H
O
40
41
42
0%
0%
4%
A
B
C
8%
6%
21%
32%
14%
13%
Scheme 11. Attempted Methylenation of Diketone 39
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Selective methylenation at the sterically hindered methyl ketone of 39 was solved when it was
recognized that this ketone, in contrast to the cyclohexanone carbonyl, was enolizable and that it
cleanly formed enol triflate 43 in the presence of base and Comins’ reagent48 (Scheme 12).
Subsequent reaction of 43 with hexamethyldistannane and
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tetrakis(triphenylphosphine)palladium(0) resulted in Stille cross-coupling49 that replaced the
triflate by a methyl group and gave 40 as a crystalline solid in an overall yield of 56% from 39.
Cl
OTf
O
KHMDS
H
H
H
H
N
OMe
N
OMe
N
N(SO2CF3)2
THF, 74%
O
O
39
43
(Ph3P)4Pd
(SnMe3)2
76%
N
H
H
H2NOH, HCl
N
OMe
OMe
NaOAc, MeOH
68%
H
H
O
N
OH
44 (4.5:1)
40
Scheme 12. Conversion of Diketone 39 to Isopropenyl Ketone 40 and its Oxime 44
In contrast to its reluctant engagement with methylenating agents, the cyclohexanone carbonyl of
40 readily condensed with benzylamine and with hydroxylamine hydrochloride, in the latter case
forming a mixture of syn and anti oximes 44 (Scheme 13). The possibility that activation of the
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mixture of oximes through exposure to a Lewis acid such as TiCl4 could trigger aza-Prins
cyclization25 followed by the cyclobutane fragmentation envisioned in Scheme 1 was
investigated briefly but Beckmann rearrangement50 of 44 to an expanded ε-lactam appeared to be
the only outcome from these experiments.
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H
H2NCO2Me
p-TsOH
H
H
N
OMe
N
OMe
C6H6, Δ
H
N
37%
O
CO2Me
45
40
TMSI
N
H
OMe
N
O
1. ClCO2Me, K2CO3
MeOH
NH
NH2
2. MeI, Ag2CO3
CHCl3
35%, 2 steps
CO2Me
1
46
Scheme 13. Conversion of Isopropenyl Ketone 40 to (-)-Huperzine A
A more attractive derivative of 40 for initiating the cascade sequence projected in Scheme 1
appeared to be imino ester 45 since Beckmann rearrangement would be avoided and the reaction
cascade, if successful, would lead directly to known compound 46, the penultimate intermediate
in Kozikowski’s synthesis of huperzine A.15 Ketone 40 was therefore condensed with methyl
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carbamate in the presence of anhydrous p-toluenesulfonic acid in hot benzene, and although
carbamate 45 could not isolated its formation was signalled by a color change of the reaction
medium to yellow. The color dissipated over several hours and chromatographic purification of
the resulting mixture of products afforded 46 whose spectral data matched those published by
Kozikowski.15 Although a mixture of (E) and (Z) isomers at the exo-ethylidene substituent of 46
could have been anticipated from 45, Kozikowski showed in the course of his synthetic work that
the mixture equilibrates under acidic conditions to yield the thermodynamically favored (E)
isomer.
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Completion of our synthesis of (-)-1 followed Kozikowski’s route15 and involved treatment of 46
with trimethylsilyl iodide in chloroform (Scheme 13). This reagent caused demethylation of
both the methoxypyridine and the methyl carbamate along with concomitant decarboxylation of
the intermediate carbamic acid and furnished material identical with natural (-)-huperzine A.
Further confirmation that the structure of 46 from 40 had been correctly assigned was obtained
by reacting a sample of natural (-)-huperzine A with methyl chloroformate in the presence of
potassium carbonate and then treating the resulting urethane with methyl iodide and silver(I)
carbonate to yield methoxypyridine 46.
CONCLUSION
Although shorter pathways to huperzine A than the synthesis described here have appeared,15-23
our route demonstrates that ring strain inherent in a cyclobutane can be used to advantage in a
molecular environment where that strain can be released in a controlled fashion. The exercise of
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predicting which of two or more ring cleavage modes will prevail in a particular structural
setting is not always easy but, as illustrated in the present work, stereoelectronic factors can
guide ring scission toward a preferred reaction pathway. Taken with other ring opening
reactions of cyclobutanes such as cycloreversion (“[2-2]”),9 de Mayo-type retroaldol fission11
and retro-Mannich fragmentation,12 it is clear that the four-membered carbocycle offers a
valuable resource for the synthesis of natural and non-natural products.
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EXPERIMENTAL SECTION
General Techniques
All reactions requiring anhydrous conditions were conducted in flame-dried glass apparatus
under an atmosphere of argon. THF, Et2O, CH2Cl2, DMF, benzene and acetonitrile were dried by
passage through an activated alumina column under argon. DMSO was distilled from CaH2 at 15
mm Hg and stored over activated 4Å molecular sieves. Anhydrous MeOH was freshly distilled
from CaH2. Preparative chromatographic separations were performed on silica gel (35-75 µm);
reactions were followed by TLC analysis using silica plates with fluorescent indicator (254 nm)
and visualized with a UV lamp or phosphomolybdic acid. Reactions were performed at various
scales depending upon availability of the starting material and reflect the practical limitation that
reactions in a lengthy synthetic sequence must be carried out many times, often by different
individuals. Melting points were measured on a capillary melting point apparatus. Optical
rotations were measured with a polarimeter at ambient temperature using a 1 mL capacity cell
with 1 dm path length. Infrared (IR) spectra were recorded using a thin film supported on KBr
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discs or dispersed in a KBr pellet. 1H and 13C NMR spectra were recorded in Fourier transform
mode at the field strength specified on a 300, 400 or 700 MHz spectrometer. Spectra were
obtained on CDCl3 solutions in 5 mm diameter tubes, and chemical shifts in ppm (part per
million) are quoted relative to the residual signals of chloroform (δH 7.26 ppm, or δC 77.0 ppm).
Multiplicities in the 1H NMR spectra are described as: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad; coupling constants (J) are reported in Hz. Low (MS) and high
(HRMS) resolution mass spectra were measured at 70 ev using a quadrupole analyzer and are
reported with ion mass/charge (m/z) ratios as values in atomic mass units.
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4-Oxocyclohex-2-en-1-yl (E)-But-2-enoate (6). To a solution of AgCN (35 mg, 0.27 mmol)
and 4-hydroxycyclohex-2-en-1-one (30 mg, 0.27 mmol) in benzene (2 mL) at room temperature
was added crotonyl chloride (31 mg, 0.29 mmol). The mixture was stirred for 2 h at room
temperature and was heated for 6 h at 80 °C. After cooling to room temperature, the mixture was
diluted with Et2O (20 mL), washed with 10% aqueous NaHCO3, and dried over anhydrous
MgSO4. The solvent was removed under vacuum and the residue was chromatographed on
silica, using 10% EtOAc in hexane as eluent, to give 37 mg (77%) of 6 as a colorless oil: IR
(neat) 2961, 1718, 1687, 1257, 1102 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.9 (dd, J = 1.2, 7.1
Hz, 3H), 2.0-2.2 (m, 1H), 2.3-2.5 (m, 2H), 2.6 (m, 1H), 5.6 (m, 1H), 5.8-5.9 (dq, J = 1.7, 15.4
Hz, 1H), 6.0-6.1 (m, 1H), 6.8-6.9 (ddd, J = 1.6, 2.7, 10.5 Hz, 1H), 6.9-7.1 (dq, J = 7.1, 15.4 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 18.0, 28.7, 34.9, 67.3, 122.0, 130.7, 146.0, 147.8, 165.5,
197.9.
4-Oxocyclohex-2-en-1-yl (E)-2-Methylpent-3-enoate (7). To a solution of 4-hydroxycyclohex-
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2-en-1-one (0.10 g, 0.85 mmol) in Et2O (2 mL) at room temperature was added sequentially
DCC (0.19 g, 0.93 mmol) and DMAP (0.01 g, 0.09 mmol). The mixture was stirred for 4 h at
room temperature and the precipitated N,N-dicyclohexylurea was filtered off. The filtrate was
washed with water (3 x 1 mL), aqueous 5% AcOH (3 x 1 mL) and water (3 x 1 mL), and was
dried over anhydrous MgSO4. The solvent was removed under vacuum and the residue was
chromatographed on silica, using 25% EtOAc in hexane as eluent, to give 0.14 g (81%) of 7 as a
mixture of two diastereomers: IR (neat) 2934, 1735, 1692, 1246, 1165, 1138 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.25 (d, J = 7.0 Hz, 3H), 1.69 (dd, J = 2.1, 7.1 Hz, 3H), 2.09 (m, 1H), 2.35
(m, 2H), 2.47 (m, 1H), 2.60 (m, 1H), 3.48 (m, 1H), 5.40 (m, 1H), 5.59 (m, 2H), 6.05 (m, 1H),
6.83 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 13.0, 17.5, 28.4, 28.5, 34.8, 37.7, 67.4, 67.5, 126.5,
128.9, 130.7, 130.8, 147.4, 147.5, 174.2, 197.8.
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(S,E)-4-(But-2-en-1-yloxy)cyclohex-2-en-1-one (12). To a solution of 4-hydroxycyclohex-2-en-
1-one (0.33 g, 2.94 mmol) in crotyl bromide (2.5 mL) at 0 °C was added silver(I) oxide (1.7 g,
7.36 mmol) in several portions. The mixture was stirred for 6 h at room temperature, after which
the excess silver(I) oxide was filtered off and excess crotyl bromide was removed under reduced
pressure. The residue was chromatographed on silica, using 15% EtOAc in hexane as eluent, to
23
give 0.81 g (59%) of 5 as a colorless oil: [α]D -122 (c 1.51, CHCl3); IR (neat) 2946, 2851,
1686, 1251, 1094, 968 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.74 (dd, J = 1.2, 6.8 Hz, 3H), 1.91-
2.05 (m, 1H), 2.28-2.40 (m, 2H), 2.53-2.65 (m, 1H), 3.98 (m, 2H), 4.20 (m, 1H), 5.53-5.65 (dtq,
J = 1.2, 6.7, 15.4 Hz, 1H), 5.67-5.85 (dtq, J = 1.3, 6.8, 15.3 Hz, 1H), 5.98 (m, 1H), 6.97 (ddd, J =
2.2, 3.2, 10.8 Hz, 1H), 5.21 (s, 2H), 5.27 (d, J = 13.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
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17.7, 29.1, 35.2, 72.0, 127.0, 129.5, 130.2, 150.7, 198.7; MS (CI) m/z 167 (M+H), 149, 141, 123,
113; HRMS (CI) m/z 167.1066 (calcd for C10H15O2: 167.1072).
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(2aR,2a1R,3R,3aS,6aS)-3-Methylhexahydro-2H-cyclobuta[cd]benzofuran-4(2aH)-one (13).
A Pyrex photolysis apparatus was charged with a solution of 12 (0.91 g, 5.48 mmol) in CH2Cl2
(300 mL) and argon was passed through the solution for 2 h. The solution was cooled to 0 °C
and irradiated with a 450W medium-pressure mercury lamp for 2 h, after which the solvent was
evaporated under reduced pressure. The residue was chromatographed on silica, using 15%
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EtOAc in hexane as eluent, to give 0.52 g (58%) of 13: [α]D +238 (c 2.3, CHCl3); IR (neat)
2954, 2925, 2861, 1697, 1175, 1057, 1013 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.19 (d, J = 7.1
Hz, 3H), 1.91 (ddd, J = 2.3, 4.6, 14.2, 14.3 Hz, 1H), 2.08-2.28 (m, 2H), 2.39-2.50 (m, 2H), 2.58
(m, 1H), 2.85-2.95 (ddd, J = 8.6, 14.2, 15.8 Hz, 1H), 3.02 (q, J = 8.8 Hz, 1H), 3.57 (dd, J = 4.5,
9.0 Hz, 1H), 3.85 (d, J = 9.1 Hz, 1H), 3.98 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 21.5, 27.4,
32.7, 37.8, 39.2, 45.4, 47.8, 72.5, 74.0, 211.7; MS (CI) m/z 167 (M+H), 157, 149, 141, 137, 123,
113, 95; HRMS (CI) m/z 167.0992 (calcd for C10H15O2: 167.0994).
(2aR,2a1R,3R,3aS,6aS)-3-Methyl-2a1,3,3a,6a-tetrahydro-2H-cyclobuta[cd] benzofuran-
4(2aH)-one (14). To a solution of 13 (20 mg, 0.12 mmol) in EtOAc (4 mL) was added
phenylselenyl chloride (35 mg, 0.18 mmol) and the mixture was stirred for 1 h at room
temperature. The mixture was washed with saturated aqueous NaHCO3 (1 mL) and saturated
aqueous NaCl (1 mL), and was concentrated under reduced pressure. The residue was
dissolved in THF (4 mL) and water (2 mL) and the solution was treated with NaIO4 (77 mg,
0.36 mmol). The mixture was stirred for 3 h at room temperature and was poured into a mixture
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of Et2O (10 mL) and water (5 mL). The organic phase was separated, the aqueous phase was
extracted with EtOAc (3 x 10 mL), and the combined organic extract was washed with brine and
dried over anhydrous MgSO4. The solvent was removed under vacuum and the residue was
chromatographed on silica, using 15% EtOAc in hexane as eluent, to give 16 mg (81%) of 14 as
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a colorless oil: [α]D +175 (c 1.0, CHCl3); IR (neat) 2955, 2924, 2862, 1668, 1044 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.27 (d, J = 7.0 Hz, 3H), 2.31 (m, 1H), 2.58 (dd, J = 8.4, 8.5 Hz,
1H), 2.70 (m, 1H), 3.17 (ddd, J = 8.2, 8.2, 8.4 Hz, 1H), 3.59 (dd, J = 4.7, 9.8 Hz, 1H), 3.80 (d, J
= 9.7 Hz, 1H), 4.38 (dd, J = 5.1, 8.3 Hz, 1H), 6.15 (d, J = 10.0 Hz, 1H) 7.08 (dd, J = 5.2, 10.1
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 21.0, 37.4, 39.4, 44.2, 46.0, 70.4, 71.1, 131.6, 144.7,
198.0; MS (CI) m/z 165 (M+H), 147, 139, 135, 111, 95; HRMS (CI) m/z 165.0915 (calcd for
C10H13O2: 165.0916).
7-Hydroxymethyl-8-methylbicyclo[4.2.0]oct-4-en-2-one (15). To a solution of Zn-Cu dust (98
mg) in dry EtOH (3 mL) was added a solution of 13 (49 mg, 0.12 mmol) in dry EtOH (1 mL)
under argon and the mixture was refluxed for 10 h. The solution was cooled to room
temperature and filtered and the filtrate was concentrated under vacuum. The residue was
chromatographed on silica, using 30% EtOAc in hexane as eluent, to give 26 mg (52%) of 15 as
a colorless oil: IR (neat) 3419, 2920, 2862, 1699, 1257, 1020 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.19 (d, J = 6.7 Hz, 3H), 2.20-2.43 (m, 1H), 2.64 (m, 1H), 2.81-2.90 (m, 1H), 3.00-3.14 (m,
1H), 3.29-3.38 (m, 1H), 3.65-3.71 (m, 1H), 5.88 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 22.3,
36.9, 37.0, 37.4, 47.6, 49.7, 62.8, 124.6, 125.9, 208.2.
9-Hydroxy-8-methyltricyclo[3.3.1.02,7]non-3-en-6-one (16). To a solution of 15 (14 mg, 0.082
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mmol) in CH2Cl2 (3 mL) was added Dess-Martin periodinane (52 mg, 0.123 mmol) and the
mixture was stirred for 1.5 h at room temperature. The solution was diluted with Et2O (5 mL),
aqueous 10% Na2S2O3 (2 mL) was added and the mixture was stirred for 20 min. The solution
was washed with brine (5 mL) and was extracted with Et2O (2 x 20 mL). The extract was dried
over anhydrous MgSO4, the solvent was removed under vacuum and the residue was
chromatographed on silica, using 15% EtOAc in hexane as eluent, to give 9 mg (67%) of 16 as a
colorless oil: IR (neat) 3409, 2959, 1719, 1073 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.48 (d, J =
7.0 Hz, 3H), 2.42 (m, 2H), 2.57 (m, 1H), 3.25 (m, 1H), 3.62 (m, 1H), 4.04 (m, 1H), 6.19 (m,
1H), 6.32 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 17.5, 33.8, 38.3, 41.9, 51.3, 58.5, 73.8, 131.6,
132.6, 209.9.
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(((2aR,2a1R,3R,3aS,6R,6aR)-6-Azido-3-methyl-2a,2a1,3,3a,6,6a-hexahydro-2H-
cyclobuta[cd]benzofuran-4-yl)oxy)triisopropylsilane (18). To a solution of 13 (0.20 g, 1.20
mmol) and TIPSCI (0.31 mL, 1.44 mmol) in THF (5 mL) at 0 °C was added slowly KHMDS
(2.9 mL, 0.5M solution in toluene, 1.44 mmol) and the solution was stirred for 30 min at room
temperature. The solution was diluted with Et2O (20 mL), washed with water and brine, and
dried over MgSO4. The solvent was removed under vacuum and the residue was
chromatographed on silica, using 20% EtOAc in hexane as eluent, to give crude silyl enol ether
17. This material was dissolved in CH2Cl2 (10 mL) and iodosobenzene (0.32 g, 1.44 mmol)
was added to the solution. The resulting suspension was cooled to -19 °C, trimethylsilyl azide
(CAUTION! this compound can generate explosive hydrazoic acid, 0.38 mL, 2.89 mmol) was
added and the mixture was stirred at -19 °C for 45 min, at which point the suspension had
become a colorless solution. The mixture was allowed to warm to room temperature, the
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solvent was removed under vacuum, and the residue was filtered and washed with a 1:1 mixture
of Et2O (30 mL) and hexane (30 mL). The filtrate was concentrated under vacuum and the
residue was chromatographed on silica, using 4% EtOAc in hexane as eluent, to give 0.32 g
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(73%) of 18 as a colorless oil: [α]D -110 (c 1.2, CHCl3); IR (neat) 2946, 2866, 2099, 1649,
1377, 1228, 1199 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.05 (dd, J = 2.2, 7.1 Hz, 18H), 1.12-1.28
(m, 3H), 1,22 (d, J = 7.0 Hz, 3H), 1.90 (m, 1H), 2.29 (dd, J = 6.6, 8.3 Hz, 1H), 2.49 (ddd, J =
5.1, 5.2, 8.3 Hz, 1H), 3.08 (ddd, J = 6.7, 8.4, 8.7 Hz, 1H), 3.51 (dd, J = 5.0, 9.2 Hz, 1H), 3.75 (d,
J = 9.5 Hz, 1H), 3,79 (dd, J = 3.1, 6.6 Hz, 1H), 4.20 (dd, J = 2.2, 6.7 Hz, 1H), 4.83 (d, J = 6.7
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 12.5 (3C), 17.9 (7C), 21.8, 34.5, 38.6, 40.0, 44,4, 58.7,
72.6, 93.9, 157.8; MS (CI) m/z 364 (M+H), 321, 266, 165, 157, 131; HRMS (CI) m/z 364.2419
(calcd for C19H34N3O2Si: 364.2402).
N-(-3-Methyl-4-((triisopropylsilyl)oxy)-2a,2a1,3,3a,6,6a-hexahydro-2H-
cyclobuta[cd]benzofuran-6-yl)acrylamide (20). To a solution of 18 (0.26 g, 0.74 mmol) in
Et2O (6 mL) at 0 °C was added LiAlH4 (41 mg, 1.09 mmol) and the suspension was stirred for 1
h. The mixture was diluted with Et2O and the reaction was quenched with 15% aqueous NaOH
(0.078 mL). The mixture was stirred with MgSO4 (2.63 g) for 2 h, then was filtered and the
collected solid was washed with EtOAc. Removal of the solvent under vacuum left crude amine
19 (0.24 g). To a solution of the crude amine and Et3N (0.12 mL, 0.87 mmol) in Et2O (6 mL) at
0 °C was added acryloyl chloride (0.076 mL, 0.94 mmol) and the solution was stirred for 1h.
The mixture was diluted with Et2O (30 mL), washed with aqueous 0.1N HCI and brine, and
dried over MgSO4. The solvent was removed under vacuum and the residue was
chromatographed on silica, using 5% MeOH in CH2Cl2 as eluent, to give 0.24 g (84%) of 20 as
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a colorless oil: IR (neat) 3273 (br), 2944, 2865, 1655, 1532, 1223, 1196 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.08 (dd, J = 3.4, 7.0 Hz, 18H), 1.10-1.23 (m, 3H), 1.20 (d, J = 7.0 Hz, 3H),
1.92 (m, 1H), 2.20 (dd, J = 6.9, 9.2 Hz, 1H), 2.43 (m, 1H), 2.96 (m, 1H), 3.48 (dd, J = 5.2, 9.1
Hz, 1H), 3.78 (d, J = 9.1 Hz, 1H), 3.82 (dd, J = 2.2, 6.9 Hz, 1H), 4.79 (d, J = 6.2 Hz, 2H), 4.90
(m, 1H), 5.15 (m, 1H), 5.62 (dd, J = 1, 10 Hz, 1H), 6,01 (dd, J = 10, 17 Hz, 1H), 6,25 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 12.6 (3C), 17.9 (6C), 21.9, 33.9, 38.2, 40.0, 44,4, 47.2, 72.6, 76.3,
97.3, 126.4, 130.8, 155.7, 164.3; HRMS (CI) m/z 392.2622 (calcd for C22H38NO3Si: 392.2621).
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2-Bromo-N-((2aR,2a1R,3R,3aS,6R,6aR)-3-methyl-4-((triisopropylsilyl)oxy)-
2a,2a1,3,3a,6,6a-hexahydro-2H-cyclobuta[cd]benzofuran-6-yl)acrylamide (22). To a
solution of 18 (0.263 g, 0.742 mmol) in Et2O (7 mL) at 0 °C was added LiAlH4 (0.041 g, 1.09
mmol) and the suspension was stirred for 1 h. The mixture was diluted with Et2O and the
reaction was quenched with 15% aqueous NaOH (0.078 mL). The mixture was stirred with
MgSO4 (2.63 g) for 2 h, then was filtered and the collected solid was washed with EtOAc.
Removal of the solvent under vacuum left virtually pure 19 (0.24 g). In a separate flask, a
solution of 2-bromoacrylic acid (0.44 g, 2.90 mmol), oxalyl chloride (0.76 mL, 8.69 mmol) and
a catalytic amount of DMF in CH2Cl2 (5 mL) was stirred at room temperature for 12 h. The
solvent was removed in vacuo and the resulting α-bromoacryloyl chloride was added to a
solution of 19, prepared above, and Et3N (0.30 mL, 2.17 mmol) in Et2O (8 mL) at 0 °C. The
solution was stirred for 1 h at 0 °C and diluted with Et2O (30 mL). The solution was washed
with aqueous 0.1N HCI and brine, dried over MgSO4 and concentrated under vacuum to leave a
residue which was chromatographed on silica, using 13% EtOAc in hexane as eluent, to give
0.22 g (59%) of 22 as a colorless oil: IR (neat) 3325 (br), 2943, 2864, 1657, 1495, 1223, 1196
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