Synthetic efforts toward the Lycopodium alkaloids inspires a hydrogen iodide mediated method for the hydroamination and hydroetherification of olefins

Article abstract of DOI:10.1002/chem.201406242

Progress toward the total syntheses of a diverse set of fawcettimine-type Lycopodium alkaloids via a "Heathcock-type" 6-5-9 tricycle is disclosed. This route features an intermolecular Diels-Alder cycloaddition to rapidly furnish the 6-5-fused bicycle and a highly chemoselective directed hydrogenation to build the azonane fragment. While conducting these synthetic studies, trimethylsilyl iodide was found to effect a hydroamination reaction to furnish the tetracyclic core of serratine and related natural products. This observation has been expanded into a general method for the room temperature hydroamination of unactivated olefins with tosylamides utilizing catalytic "anhydrous" HI (generated in situ from trimethylsilyl iodide and water). The presence of the iodide anion is critical to the success of this Bronsted acid catalyzed protocol, possibly due to its function as a weakly coordinating anion. These conditions also effect the analogous hydroetherification reaction of alcohols with unactivated olefins.

Full text of DOI:10.1002/chem.201406242

DOI: 10.1002/chem.201406242
Full Paper
&
Hydroamination |Hot Paper|
Synthetic Efforts toward the Lycopodium Alkaloids Inspires
a Hydrogen Iodide Mediated Method for the Hydroamination and
Hydroetherification of Olefins
Paul R. Leger, Rebecca A. Murphy, Eugenia Pushkarskaya, and Richmond Sarpong*[a]
Abstract: Progress toward the total syntheses of a diverse
set of fawcettimine-type Lycopodium alkaloids via a “Heath-
cock-type” 6–5–9 tricycle is disclosed. This route features an
intermolecular Diels–Alder cycloaddition to rapidly furnish
the 6–5-fused bicycle and a highly chemoselective directed
hydrogenation to build the azonane fragment. While
conducting these synthetic studies, trimethylsilyl iodide was
found to effect a hydroamination reaction to furnish the
tetracyclic core of serratine and related natural products.
This observation has been expanded into a general method
for the room temperature hydroamination of unactivated
olefins with tosylamides utilizing catalytic “anhydrous” HI
(generated in situ from trimethylsilyl iodide and water). The
presence of the iodide anion is critical to the success of this
Brønsted acid catalyzed protocol, possibly due to its function
as a weakly coordinating anion. These conditions also effect
the analogous hydroetherification reaction of alcohols with
unactivated olefins.
Introduction
Natural products are selected as targets for synthesis for a
variety of reasons. For example, many natural products display
fascinating biological activity that can be more deeply investi-
gated with ready access to the natural compound as well as
unnatural derivatives. Structurally complex natural products
offer opportunities to test and extend the scope of new meth-
ods and explore novel strategies for synthesis. Finally, the high
density of functional groupings in natural products offer
unique scenarios that often yield surprising transformations
that may then be extended to other systems.
Our group has maintained an interest in the total synthesis
of members of the Lycopodium alkaloid class of natural prod-
ucts over the last decade.[1] These alkaloids possess interesting
biological activity as well as challenging structural complexity,
which makes them attractive synthetic targets.[2] In our
approach to a variety of architecturally unique fawcettimine-
type Lycopodium alkaloids, we became drawn to a divergent
strategy that would employ 6–5–9 “Heathcock-type” tricycle
1 (Scheme 1).[3] This synthetic plan has the potential to provide
access to natural products including lycopladine D (2),
lycopladine B (3), serratine (4), lycoposerramine S (5), and
palhinine A (6).
Scheme 1. A divergent approach to a variety of Lycopodium alkaloids.
Strategies that employ a common intermediate related to
1 for the synthesis of Lycopodium alkaloids have been docu-
mented for almost 30 years.[2b] We were interested in extend-
ing this Heathcock-inspired strategy to the synthesis of a more
diverse group of Lycopodium alkaloids in which additional
carbon–carbon or carbon–heteroatom bonds exist. For exam-
ple, lycopladine B (3) and lycopladine D (2) are further oxidized
at C16. Serratine (4) and lycoposerramine S (5) both possess
rare CÀN bonds at C4 and C5, respectively. Finally, palhinine A
(6) contains an additional CÀC bond between C16 and C4 that
results in a very congested 2.2.2 bicyclic core. We envisioned
all of these natural products arising from the functionalization
of a common, tricyclic intermediate (1). Tricycle 1 could be
[a] P. R. Leger,+ R. A. Murphy,+ E. Pushkarskaya, Prof. R. Sarpong
Department of Chemistry, University of California, Berkeley
Latimer Hall, Berkeley, CA 94720 (USA)
Fax: (+1) 510-642-9675
E-mail: rsarpong@berkeley.edu
[+] These authors contributed equally to this work.
prepared from the elaboration of bicycle
7 (Scheme 2),
which, in turn, could arise from diene 8 and dienophile 9
using a Diels–Alder reaction.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406242.
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ed; presumed to be endo relative to the ketone group). Bicyclic
ketone 7 was converted to the corresponding vinyl triflate (not
shown) using hard enolization conditions. The ester group was
then reduced to the primary alcohol, which was oxidized with
Dess–Martin periodinane to provide aldehyde 11 in 49% yield
over three steps.
From aldehyde 11, Wittig reaction gave enoate 12
(Scheme 4), which upon Suzuki cross-coupling with the borane
Scheme 2. Retrosynthesis of tricycle 1.
In this paper, we describe the realization of this synthetic
plan for the preparation of tricycle 1 and the advancement of
this intermediate to the synthesis of the skeleton of serratine
(4) using a late-stage transannular alkene hydroamination. This
transformation has led to the development of more general
alkene hydroamination and hydroalkoxylation protocols, the
studies of which are also described.
Scheme 4. Elaboration to amine 13.
generated from N-Boc allylamine yielded N-Boc amine 13.
These cross-coupling conditions, based on precedent by Trost
and Toste,[6] are uniquely effective for the Suzuki coupling of
the sterically congested vinyl triflate. The introduction of the
saturated three-carbon chain now installs all of the carbon
atoms necessary for the targeted natural products. The
synthesis of key intermediate 13 is achieved in 29% yield
over seven steps from TBS-protected propargyl alcohol 10.
Toward the synthesis of 6–5–9 tricycle 1, ester 13 was
reduced to provide allylic alcohol 14 (Scheme 5), which then
Results and Discussion
Synthesis of “Heathcock-type” tricycle 1
The synthesis of 1 commenced with the preparation of diene
8 and dienophile 9. Given the established efficiency of an
enyne metathesis approach for the synthesis of substituted
dienes related to 8,[4] we utilized this approach to rapidly syn-
thesize large quantities of this requisite diene (Scheme 3). Ethyl
Scheme 3. Forward synthesis to aldehyde 11.
vinyl ether was selected as the alkene partner in the enyne
metathesis because of its low boiling point, which facilitates
the removal of the excess olefin that is often required for good
conversions. The enyne metathesis of ethyl vinyl ether and
tert-butyldimethylsilyl (TBS)-protected propargyl alcohol (10)
was most efficient under the conditions developed by the Lip-
shutz group (2 mol% Grubbs II, 3 mol% CuI),[5] which provided
the desired diene (8) in 80% yield as a 3:1 mixture of E/Z
isomers. Diene 8 was then used in a Diels–Alder reaction with
readily available dienophile 9 to provide 6–5 bicycle 7 as
a 2.9:1 mixture of diastereomers (major diastereomer illustrat-
Scheme 5. Accessing 6–5–9 tricycle 1.
served as a substrate in a directed hydrogenation with Wilkin-
son’s catalyst to furnish 15.[7] This hydrogenation was sensitive
to both reaction time and the order of reagent addition, but
typically proceeded in about 79% yield. Notably, it provided an
avenue for chemo-differentiation of the three carbon–carbon
double bonds in 14. This is especially important
because we were unable to effect a 1,4-reduction of enoate 13.
Activation of the primary alcohol (15) as the tosylate and dis-
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placement with sodium iodide gave alkyl iodide 16 in 67%
yield over the two steps. Alternatively, alcohol 15 could be con-
verted to iodide 16 in one step using the Appel reaction, al-
though this proceeded in lower yield as compared to the two-
step procedure. Exposure of 16 to potassium hydride
promoted the displacement of the iodide by the carbamate
nitrogen to furnish the desired Heathcock-type 6–5–9 tricycle 1.
tecting groups is known to be mediated by TMSI as well as
strong acids,[9] so it is unsurprising that the secondary amine
of 1 would be deprotected under these conditions. What was
unanticipated is the efficient hydroamination under such mild
conditions given the general difficulty of effecting these trans-
formations. In our case, it is likely that the proximity of the sec-
ondary amine to the alkene group played a role in facilitating
this reaction. Our hypothesis is that the azonane ring resides
underneath the 6–5 bicycle in 1, positioning the amine group
very close to the carbon–carbon double bond.
Unexpected reactivity of tricycle 1
With tricycle 1 in hand, we began to investigate routes to di-
verge this versatile intermediate toward various fawcettimine-
type Lycopodium alkaloids. Over the course of these studies,
we observed the unexpected generation of enal 17 (Scheme 6)
Hydroamination studies
Even though the hydroamination of 1 to give 20 might be fa-
vored by virtue of proximity, it served as inspiration for further
investigations into the scope and limitations for this type of
hydroamination.[10] While acid-mediated hydration and hydro-
etherification of unactivated alkenes has been known for over
a century,[11] the analogous acid-mediated reaction with nitro-
gen nucleophiles has been much more elusive. This is because
hydroaminations are often thermoneutral or slightly exother-
mic and usually have associated negative reaction entropies.[12]
Moreover, acid catalysis of hydroamination has the associated
hurdle in that acidic conditions will protonate the amine, ren-
dering it non-nucleophilic. It wasn’t until 2002 that Hartwig
et al. disclosed the first acid-catalyzed hydroamination of
unactivated olefins in which they utilized triflic acid (TfOH) at
elevated temperatures (1008C) to effectively catalyze a CÀN
bond-forming process.[13] The nitrogen basicity problem was
overcome in this case by employing tosylamides as nucleo-
philes. Tosylamides are basic enough to be protonated by trifl-
ic acid, yet the resulting tosylamidium ion is acidic enough to
transfer its proton to the alkene group, thus allowing for pro-
ductive CÀN bond formation. A few other examples of acid-
catalyzed hydroaminations have been reported since Hartwig’s
seminal report; however, most protocols require elevated tem-
peratures to achieve good conversion.[14] We sought to build
upon these previous studies and our observations (en route to
syntheses of Lycopodium alkaloids) by exploring the role of
TMSI in other hydroamination reactions.
Scheme 6. Unexpected reactivity to furnish enal 17.
when tricycle 1 was exposed to in situ generated trimethylsilyl
iodide (TMSI). Enal 17 could potentially arise from trimethylsilyl
or hydrogen iodide assisted loss of ethanol (to form 18),
followed by hydrolysis (to give 19) and isomerization to the
more thermodynamically favored enal (17).
To our delight, increasing the amount of TMSI from two to
ten equivalents promoted the transformation of 1 to 20
(Scheme 7), which is the tetracyclic core of the natural prod-
We commenced our studies with alkenyl tosylamide 22a
(Table 1) as a test substrate. Using the same reagents (TMSCl/
NaI) that had been employed in the conversion of 1 to 20, al-
Table 1. Effect of various TMS-X species.
Scheme 7. Unexpected reactivity to furnish tetracycle 20.
ucts serratine (4) and 8-deoxyserratine (21), in 50% yield. The
structure of 20 was confirmed by X-ray crystallographic analy-
sis of a single crystal.[8] In the remarkable conversion of 1 to
20, not only was the bis allylic ether moiety on the six-mem-
bered ring converted to the enal motif (see Scheme 6), but
also, the Boc-protecting group was cleaved and the resulting
amine underwent transannular hydroamination with the
carbon–carbon double bond in the five-membered ring to
form a new CÀN bond to the C4 position. Cleavage of Boc-pro-
Entry
Reagent (equiv)
t [h]
Conversion [%]
1
2
3
4
5
6
7
8
TMSCl/NaI (2)
TMSCl (2)
TMSOTf (2)
TMSI (2)
1
20
2
1
4
4
4
20
100
0
47
100
97
21
30
33
TMSI (0.2)
TMSOTf (0.2)
TMSBr (0.2)
57% HI (2)
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kenyl tosylamide 22a was fully converted to afford pyrrolidine
23a (entry 1, Table 1). In the absence of NaI (i.e., with TMSCl
alone; entry 2), the starting material was recovered and none
of the hydroamination product was observed. When a stronger
silylating reagent (TMSOTf) was employed (entry 3), 47% con-
version to the hydroamination product was achieved after 2 h
at room temperature. We were pleased to find that using TMSI
gave complete conversion to the hydroamination product
after only 1 h (entry 4). Furthermore, a catalytic amount of
TMSI (0.2 equiv) could be used, which led to 97% conversion
of 22a in 4 h (entry 5). In contrast, TMSOTf and TMSBr were
sub-optimal when sub-stoichiometric amounts of these
reagents were employed, leading only to 21% and 30% con-
version, respectively, after 4 h (entries 6 and 7). Unfortunately,
the hydroamination conditions using 20 mol% of TMSI were
only specific for sulfonamides and not efficient for other amine
substrates.
Table 2. Effect of added water on conversion.
Entry
Water [equiv]
Conversion [%]
1
2
3
4
5
0
76
96
88
89
78
0.05
0.10
0.25
0.50
fact that “anhydrous” HI could catalyze this reaction under
milder conditions as compared to triflic acid. This difference is
not explained by relative acid strength, since triflic acid (pKa =
À12) is more acidic as compared to HI (pKa =À10). Moreover,
both triflic acid and HI are strong enough to fully protonate
the tosylamide (pKa of an alkyl tosylamidium ca. À6).[15] This
leveling effect should render both acid-catalyzed reactions
identical in rate, since the active acid in both cases is the
tosylamidium. However, this is not what was observed.
With the initially established conditions for the hydroamina-
tion of 22a in hand, we next turned to investigating the mech-
anism of this transformation. The addition of base either shut
down the reaction (0.2 equivalents triethylamine) or severely
retarded the rate (15% conversion after 20 h with 0.2 equiv
2,6-di-tert-butylpyridine). This suggested that the generation of
acid was vital to the success of this reaction. When HI (57% so-
lution in water) was used instead of TMSI, the reaction pro-
ceeded at a sluggish rate, indicating that in situ generation of
HI might not be the sole promoting factor (see Table 1,
entry 8). From these observations, we hypothesized that a
silylated amine intermediate could be responsible for the
milder reaction temperatures enjoyed by the TMSI-promoted
hydroamination relative to the triflic acid mediated conditions
identified by Hartwig.[13] TMSI could silylate the tosylamide,
thus generating an active ion pair that can participate in
a facile protonation of the alkene group. However, we did not
observe any silylated intermediates in the reaction mixture
when the reaction was conducted in CD2Cl2 and monitored by
1H NMR spectroscopy. We have also observed that for a mixture
of N-methyl tosylamide and TMSI, the equilibrium lies towards
the free tosylamide and TMSI as opposed to the silylated
tosylamide.
To further elucidate the differences between the triflic acid
and HI-mediated hydroaminations, we compared conversion at
room temperature in the presence of various additives. As
shown in Table 3, the conversion after 4 h was the same
Table 3. Additive effects.
Entry
Reagent
Additive (equiv)
Conversion [%]
1
2
3
TfOH
–
–
20
21
19
97
94
97
76
83
22
13
TMSOTf[a]
TfOH
HMDSO (0.2)
–
4
5
6
7
8
9
10
TMSI[a]
TMSCl[a]
TMSI[a]
TMSOTf[a]
TfOH
NaI (0.2)
NaOTf (0.2)
NaI (0.2)
NaI (0.2)
NaBF4 (0.2)
Notably, the TMSI promoted conversion of 22a to 23a pro-
ceeded in a modest 76% conversion after 4 h when conducted
on gram scale. This decreased reaction rate upon scale-up sug-
gested that adventitious water could be playing an important
role. To test this hypothesis, a series of experiments was carried
out in which varying amounts of water were introduced. The
results are summarized in Table 2 and show that the addition
of 0.05 equivalents of water (entry 2) is optimal. It therefore
seems unlikely that TMSI is the active catalyst in this reaction;
rather, TMSI may serve as a precursor to generate HI and
hexamethyldisiloxane (HMDSO) in the presence of trace water.
We believe that larger quantities of water retard the reaction
rate due to the Lewis basicity of the water oxygen atom (vide
infra). Thus, TMSI in the presence of small amounts of water
most likely serves as a source of ‘anhydrous’ HI.
TfOH
TfOH
NaBArF (0.2)
4
[a] Water (0.05 equiv) was also added to these reactions.
whether triflic acid or TMSOTf (in the presence of water; to
generate TfOH in situ) was used (entries 1 and 2). Similar ob-
servations were made for the reaction conducted in the pres-
ence of triflic acid and HMDSO (0.05 equiv, entry 3). These
comparisons indicate that HMDSO does not play a significant
role in the hydroamination.[16]
We next sought to ascertain the effect of the counter-anion
on the rate of the hydroamination reaction. The importance of
counter-anions is well documented in transition-metal-cata-
lyzed hydroaminations, with less coordinating anions (e.g., OTf,
OTs, and BAr4) generally increasing the catalytic activity of the
All evidence up to this stage pointed toward a Brønsted
acid catalyzed hydroamination, but we were intrigued by the
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metal.[17] However, the role of the counter-anion in Brønsted
acid catalyzed hydroaminations is not as well studied.[18] To ex-
plore the role of the counter-anion for the HI-mediated hydro-
amination, we tested the effect of several salt additives
(Table 3, entries 4–10). As noted previously, the use of in situ
generated TMSI (from TMSCl/NaI) results in 94% conversion
(entry 5). This conversion was retained when NaOTf was added
to the standard conditions (entry 6). Interestingly, the addition
of NaI to TMSOTf (entry 7) or to triflic acid (entry 8) increased
the reaction conversion substantially to 76 and 83%, respec-
tively, as compared to about 20% without added NaI (see en-
tries 1 and 2). These results indicate that the iodide anion is es-
sential to the success of the Brønsted acid catalyzed hydroami-
Table 4. Cyclizations of tosylamides with catalytic ‘anhydrous’ HI.
Reactant
Product
Yield[a] [%]
95
90
d.r.: 55:45
66
d.r.: 60:40
84[b]
87
nation at room temperature. Several other non-coordinating
À
anions such as BF4 and [B{3,5-(CF3)2C6H3}4] (BArF À; entries 9
4
and 10) were investigated with triflic acid; however, iodide was
the only anion that substantially accelerated the reaction rate.
The basis for this unique effect of iodide is still unclear, but we
hypothesize that the iodide anion likely forms a loose ion pair
with the tosylamidium (24, Scheme 8), which leads to an
78
47[b,c]
86
d.r.: 91:9
[a] Isolated yield. Reactions conducted using standard conditions: TMSI
(0.2 equiv), water (0.05 equiv), CH2Cl2 (0.2m), room temperature, 4 h.
[b] 2ꢁ0.2 equiv TMSI used over a reaction time of 12 h. [c] Isolated an ad-
ditional 14% unreacted starting material after 12 h.
tions.[13] Various substitution patterns on the olefin component
are also tolerated (22 f,g). Diene 22h also readily undergoes
HI-catalyzed hydroamination to afford the corresponding allylic
tosylamide (23h).
Scheme 8. Proposed catalytic cycle.
Although pyrolidine rings are easily accessible using this
methodology, the corresponding piperidine rings are not as ef-
ficiently accessed. Thus, when hexenyl tosylamide 27 was sub-
jected to the standard hydroamination conditions, a mixture of
products was observed (28, 29, 30; Scheme 9). The analogous
increase in the acidity of the tosylamidium relative to the
tosylamidium triflate ion pair.[19] It is known that ion-pair
acidities can differ substantially from standard ionic acidity.[20]
This acidification would serve to accelerate intramolecular
olefin protonation (24 to 25), which has been well established
as the rate-determining step in Brønsted acid catalyzed hydro-
amination reactions.[13]
Scope of the HI-catalyzed hydroamination reaction
Scheme 9. Reaction of hexenyl tosylamide.
Following our optimization of reaction conditions for the
HI-mediated tosylamide hydroamination of alkenes and investi-
gation of the roles of each reagent and additive, we sought to
examine the scope of the reaction (Table 4). We have found
that primary and secondary alkyl tosylamides 22a–c are effi-
cient substrates. Styrenyl compounds 22d,e also undergo
facile hydroamination. Notably, this substrate list includes the
p-anisole derivative 22e, which is known to be sensitive to
other, harsher, Brønsted acid mediated hydroamination condi-
cyclizations to form the five-membered rings are extremely
fast, whereas cyclization to form the corresponding six-
membered rings is somewhat slower. It would appear that the
lower rate of hydroamination in these last cases permits
undesired reaction pathways (e.g., hydride shifts or iodide
addition) to compete with the desired cyclization pathway.[21]
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Table 5. Cyclizations of oxygen nucleophiles
Reactant Product(s)
Yield[a] [%]
84[b,c]
61
d.r.: 85:15
98[b]
d.r.: 91:9
Scheme 10. Robustness screen additives.
58[b,d]
product yields, but significantly lower recoveries of the robust-
ness screen additives. The room temperature HI-mediated hy-
droamination conditions proved to be milder towards acid-
sensitive functional groups; however, these functional groups
also stalled the progress of the reaction. Thus, the functional
group robustness screen demonstrates the complementary
nature of HI and triflic acid in mediating the hydroamination
reactions.
23i=31
d.r.: 75:25
32e=56
d.r.: 66:33
[a] Isolated yield. Reactions conducted using standard conditions: TMSI
(0.2 equiv), water (0.05 equiv), CH2Cl2 (0.2m), room temperature, 4 h.
[b] NMR yield, CD2Cl2, mesitylene as internal standard. [c] Contained 13%
unreacted starting material after 4 h. [d] Contained 30% unreacted start-
ing material after 24 h, 2ꢁ0.2 equiv TMSI used.
The inhibition of hydroamination by these additives is likely
due to their mild Lewis basic character relative to the tosyla-
mide. To test this hypothesis, we conducted another screen of
additives, choosing additives that had conjugate acids with pKa
values ranging from À10 to 0 (Scheme 10b). We found that
indeed, additives with conjugate acids possessing a pKa above
À5 completely stopped the HI-mediated reaction, whereas less
basic additives were tolerated without any drop in product
yield.[23] Comparing these observations to the triflic acid medi-
ated conditions at 1008C, we found that more basic functional
groups are tolerated under this latter set of conditions. Only
additives possessing conjugate acids with pKa above À1
completely inhibited the reaction. These conditions likely work
in the presence of more basic additives due to the elevated
temperature at which these reactions are run. Overall, while
the HI-mediated reactions occur at a milder temperature, they
do not necessarily result in improved reaction yields over the
triflic acid mediated hydroamination reaction conditions. The
HI-promoted conditions do, however, provide a complementary
approach to hydroamination.
Gratifyingly, the hydroamination methodology can be ex-
tended to the hydroetherification of alkenyl alcohols to pro-
vide a range of cyclic ethers (Table 5). Primary and secondary
alcohols (31a–c) readily undergo cyclization to the correspond-
ing 2- and 2,5-functionalized tetrahydrofurans (32a–c). Addi-
tionally, carboxylic acid 31d serves as a suitable oxygen nucle-
ophile to provide lactone 32d, albeit at a lower reaction rate.
In an effort to estimate the relative cyclization rates of alcohols
and tosylamides, alkenyl hydroxyl tosylamide 31e was subject-
ed to the standard set of cyclization conditions. The pyrrolidine
product (23i) was obtained in 31% yield and the tetrahydro-
furan product (32e) was obtained in 56% yield, indicating that
hydroetherification occurs faster than the hydroamination of
the tosylamide group.
Comparative robustness screen
Many of the previously reported Brønsted acid catalyzed hy-
droaminations require temperatures at or above 1008C.[13]
Since our newly developed conditions do not require elevated
temperatures, we postulated that these conditions could pro-
vide better functional group tolerance, especially pertaining to
acid-sensitive groups. To test this hypothesis, we compared
our conditions to the standard triflic acid mediated hydroami-
nation conditions (at 1008C) in a “robustness screen” as recent-
ly popularized by Glorius and co-workers.[22] We began by test-
ing a range of acid-sensitive additives including silyl ethers,
silyl enol ethers, benzyl ethers, and acetals (Scheme 10a). We
found that our HI-mediated hydroamination conditions pro-
duced moderate product conversions and moderate additive
recovery, though the additive recovery varied depending on
the inherent stability of the additive.[23] In contrast, the triflic
acid hydroamination conditions usually produced excellent
Conclusions
We have prepared and investigated the transformation of an
advanced “Heathcock-type” 6–5–9 tricycle in our efforts to
access a range of Lycopodium alkaloids. Using this versatile
intermediate, we observed an unexpected HI-mediated trans-
annular hydroamination reaction to provide the tetracyclic
core of serratine and 8-deoxyserratine. The carbon skeleton of
these natural products was obtained in 12 steps from tert-bu-
tyldimethylsilyl-protected propargyl alcohol. This fortuitously
observed hydroamination reaction has led to further investiga-
tion of its limitations and scope. Through these studies, we
have demonstrated the critical importance of the iodide anion
in promoting this transformation. Due to the synthetic ease of
generating “anhydrous” HI from TMSI as well as the effective-
ness of this hydroamination method, we believe it will find
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Experimental Section
Representative hydroamination procedure: Tosylamide 22a
(200 mg, 0.84 mmol) was dissolved in dry CH2Cl2 (3.8 mL). CH2Cl2
pre-saturated with water (0.38 mL wet CH2Cl2, 0.042 mmol water,
0.05 equiv water) was then added, followed by TMSI (24 mL,
0.17 mmol, 0.2 equiv). The reaction mixture was allowed to stir at
room temperature. After 4 h, the mixture was quenched with satu-
rated sodium bicarbonate (2 mL) and sodium sulfite (1 mL) and ex-
tracted with CH2Cl2 (3ꢁ3 mL). The combined organic layers were
dried over magnesium sulfate, concentrated, and purified by
column chromatography (20% ethyl acetate in hexane) to yield
pyrrolidine 23a (189 mg, 95%).
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[16] Due to the difficult nature of dispensing exact amounts of pure, anhy-
drous HI, we were unable to conduct the analogous experiment with
TMSI and HI. However, the introduction of exogenous hexamethyldisi-
loxane to the TMSI-promoted hydroamination did not lead to an appre-
ciable increase the rate.
Acknowledgements
This work was funded by the NIH-NIGMS USA (R01 086374).
We acknowledge the National Science Foundation for a
Graduate Research Fellowship (P.R.L.) as well as the American
Chemical Society for
a Division of Organic Chemistry
Fellowship (R.A.M.). We would also like to thank the Hartwig
group (UC Berkeley) for the use of their GC instrumentation
and to thank Dr. Antonio DiPasquale (UC Berkeley) for solving
the crystal structure of compound 20 (supported by NIH
Shared Instrumentation Grant S10-RR027172).
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[19] Alternatively, it is possible that small quantities of iodine are being gen-
erated and that iodination serves to acidify the tosylamidium species.
However, addition of exogenous iodine to various reaction conditions
failed to accelerate the reaction rate. Attempts to sequester any in situ
formed iodine were met with inconclusive results as the basicity of the
sequestering additives could often account for the variations in conver-
sion.
[20] A. Streitwieser, Y.-J. Kim, J. Am. Chem. Soc. 2000, 122, 11783–11786.
[21] The alkyl iodide compound is a product and not an intermediate in this
reaction. Upon isolation and exposure to the reaction conditions, no
further reactivity was observed.
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[23] See the Supporting Information for more details.
Keywords: Brønsted acid catalysis
Lycopodium alkaloids · total synthesis · trimethylsilyl iodide
·
hydroamination
·
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Received: November 26, 2014
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
Harnessing the unexpected: The expe-
dient synthesis of a strategic synthetic
intermediate en route to structurally
diverse Lycopodium alkaloids has been
accomplished. During these studies, in
situ generated hydrogen iodide prom-
oted an unanticipated hydroamination.
This transformation has been
&
Hydroamination
P. R. Leger, R. A. Murphy, E. Pushkarskaya,
R. Sarpong*
&& – &&
Synthetic Efforts toward the
Lycopodium Alkaloids Inspires
a Hydrogen Iodide Mediated Method
for the Hydroamination and
Hydroetherification of Olefins
thoroughly investigated and expanded
into a general method for the hydro-
functionalization of unactivated olefins.
&
&
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
8
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!