A bio-inspired cascade and a late-stage directed sp3 C–H lithiation enables a concise total synthesis of (?)-virosaine A

Article abstract of DOI:10.1016/j.tet.2017.12.026

The asymmetric total synthesis of (?)-virosaine A was achieved in 9% overall yield from commercially/readily available starting materials. Inspired by an intriguing biosynthetic proposal, a novel cascade reaction sequence was developed to efficiently cons

Full text of DOI:10.1016/j.tet.2017.12.026

Accepted Manuscript
3
A bio-inspired cascade and a late-stage directed sp C-H lithiation enables a concise
total synthesis of (−)-virosaine A
Jonathan M.E. Hughes, James L. Gleason
PII:
S0040-4020(17)31286-3
10.1016/j.tet.2017.12.026
TET 29182
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 September 2017
Revised Date: 7 December 2017
Accepted Date: 12 December 2017
Please cite this article as: Hughes JME, Gleason JL, A bio-inspired cascade and a late-stage directed
3
sp C-H lithiation enables a concise total synthesis of (−)-virosaine A, Tetrahedron (2018), doi: 10.1016/
j.tet.2017.12.026.
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A bio-inspired cascade and a late-stage
directed sp3 C-H lithiation enables a concise
total synthesis of (-)-virosaine A
Leave this area blank for abstract info.
Jonathan M. E. Hughes and James L. Gleason*
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montréal, Québec, H3A 0B8, Canada
O
CO2Me
Cl
Cl
Cl
O
O
O
O
SiEt3
O
O
N
O
O
O
N
O
N
O
O
O
HO
N
O
bio-inspired
cascade
O
selective
O
OH
TBSO
sp3 C-H lithiation
N
N
O
O
(-)-virosaine A
O
O
O
H
H
O
O
O
OAc
O
N
N
H
O
O
AcO
H
N
O
N
O

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ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A bio-inspired cascade and a late-stage directed sp3 C-H lithiation enables a concise
total synthesis of (-)-virosaine A
Jonathan M. E. Hughes, James L. Gleason
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montréal, Québec, H3A 0B8 Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The asymmetric total synthesis of (-)-virosaine A was achieved in 9% overall yield from
commercially/readily available starting materials. Inspired by an intriguing biosynthetic
proposal, a novel cascade reaction sequence was developed to efficiently construct the caged
polycyclic core of virosaine A. The pivotal cascade precursor was readily available in
enantiopure form via a robust route that featured an enantioselective one-pot Diels-Alder
cycloaddition/organolithium addition. Several contemporary methods of C-H functionalization
were applied to the cascade product and yielded a diverse set of novel complex polycycles.
Ultimately, a combination of NMR and computational analyses laid the groundwork for a
successful directed lithiation strategy to selectively functionalize the caged core and complete
the total synthesis of virosaine A.
Available online
Keywords:
Alkaloids
Cascade reactions
Total synthesis
Directed lithiation
Cycloaddition
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
in natural products and has intriguing biosynthetic origins (vide
infra).6 Interestingly, an isoxazolidine moiety is also present in
the related Securinega alkaloid flueggine A (5), uniting the two
monomeric fragments from which this dimer is constructed.7
The Securinega alkaloids are a fascinating class of secondary
plant metabolites found within the Euphorbiaceae family.1 The
structural characteristics of these natural products, typified by
their bridged tetracyclic scaffolds and an intriguing α,β,γ,δ-
unsaturated lactone moiety, have provided a continual source of
inspiration for synthetic chemists.2 Securinine (1), the parent
member of this family, was isolated more than 60 years ago and
has been the most extensively studied Securinega alkaloid
(Figure 1). It exhibits an extensive biological activity profile and
was for a time marketed as a drug for its stimulant and
antiplasmodic effects.1 Its intriguing profile and structure spurred
numerous synthetic efforts which have culminated in a number of
elegent total syntheses.3 As isolation efforts of this natural
product class progressed, several highly oxidized and/or
rearranged members emerged. Virosaine A (3) and B (4), isolated
in 2012 from the twigs and leaves of Flueggea virosa in China,
are two such examples that have undergone additional skeletal
oxidation and reorganization to yield unprecedented caged
polycycles.4 The virosaines (3 and 4) are arguably the most
complex monomeric members of this alkaloid family and,
interestingly, are pseudoenantiomers, inverted at all stereocenters
except C8.5 They contain several notable structural features that
make them particularly challenging synthetic targets. These
include the presence of multiple bridged bicycles, six congested
stereocenters and, perhaps most intriguingly, an isoxazolidine
ring embedded in the pentacyclic framework. The latter is
Figure 1. Securinega alkaloids.
The biosynthetic proposals for the virosaines (3 and 4) and
flueggine A (5) all involve a union of cyclic imine 6 with
arylpyruvic acid 7 to produce one of three diastereomeric
tricyclic intermediates 8a, 8b, or 8c (Scheme 1).4,7,8 Direct
oxidation of 8a and 8b is suggested to generate nitrones 9 and 10,
respectively, which are proposed to undergo subsequent
intramolecular [3+2] cycloaddition to produce virosaine A (3)
and B (4). Of note, synthetic studies suggest that the
biosyntheses of 3 and 4 may involve the intermediacy of other
Securinega alkaloids. Gademann demonstrated that the
bubbialidine core could be oxidized/rearranged to access nitrone
9 and Yang and Li showed that nitrone 10 could be accessed
from allonorsecurinine in a similar fashion.9 In the case of
flueggine A (5), intramolecular dehydration of 8c generates
norsecurinine (2), which is then proposed to undergo
oxidation/rearrangement to generate nitrone 12. However, 12
particularly noteworthy, as it is an extremely rare structural motif
———
Corresponding author. Tel.: +1-514-398-5596; fax: +1-514-398-3797; e-mail: jim.gleason@mcgill.ca

2
Tetrahedron
ACCEPTED MANUSCRIPT
interestingly does not undergo an intramolecular [3+2] nitrone
Retrosynthetically, we identified lactone 13 as precursor of 3
cycloaddition, presumably due to increased non-bonding
interactions incurred in the alternative caged framework that
would be formed with this diastereomer.10 Instead, 12 reacts with
norsecurinine (2) in an intermolecular sense to produce the dimer
flueggine A (5). Evidence to support the feasibility of these rare
biosynthetic nitrone cycloadditions have mounted in recent years
via both biomimetic syntheses and computational studies, the
latter of which suggest that the energy barriers required for these
cycloadditions are low enough such that enzymatic intervention
is not required.11,12,13
that effectively masks both the butenolide and C8 hydroxyl
groups (Scheme 2). Hexacycle 13 could be simplified to
pentacycle 14, with an unspecified R group at C14 that could
eventually be elaborated into the butanolide in 13. Drawing
inspiration from the proposed biosynthesis, we traced pentacycle
14 back to the corresponding nitrone 15 via a [3+2] nitrone
cycloaddition. In order to install the requisite nitrone, we planned
to open a trisubstituted epoxide with a pendant oxime, leading
back to 16. The advantage of this method is that it would build
the nitrone in a stereospecific fashion and would eliminate any
concerns of chemo- or regioselectivity compared to oxidative
methods of nitrone formation. Furthermore, our goal was to
implement this epoxide-opening step in tandem with the
subsequent
nitrone
cycloaddition
(16ꢀ15ꢀ14).
The
development of such a cascade reaction sequence would enable
an efficient entry into the complex polycyclic virosaine core.
Finally, we traced the cascade precursor 16 back to aldehyde 17,
the [4+2] cycloadduct of 2-bromoacrolein (18) and substituted
furan 19.15
Scheme 2. Original retrosynthetic analysis of 1.
3. Results and Discussion
3.1 Model cascade reaction sequence.
Given that the proposed bio-inspired cascade reaction
sequence to access the caged pentacycle 14 was a focal point of
the synthetic plan, we initially pursued a model study to assess
the feasibility of this approach. Cascade reactions involving
tandem nitrone formation/[3+2] cycloaddition have provided a
platform for rapid complexity generation in several total
syntheses.16 However, there is limited literature precedent for
cascades that specifically involve an intramolecular epoxide
opening/intramolecular nitrone cycloaddition, with only one
reported example prior to our work. Specifically, Grigg and
coworkers demonstrated that heating an acyclic substrate
containing an oxime, epoxide, and olefin resulted in N-alkylative
epoxide opening to generate a nitrone that underwent a
subsequenct [3+2] cycloaddition to yield an angularly fused
tricycle.17 To the best of our knowledge, there were no examples
of such a cascade to access bridged systems similar to that found
in the virosaine core.
Scheme 1. Proposed biosyntheses of the virosaines (3 and 4)
and flueggine A (5).
The synthetically challenging characteristics and unique
biosynthetic origin of 3 motivated us to pursue its total synthesis.
In particular, at the time we began our studies, the putative [3+2]
dipolar cycloaddition had not been investigated synthetically.
We thus embarked on a bio-inspired approach that would feature
the nitrone cycloaddition as an integral step. However, in
contrast to the subsequently reported syntheses that generated the
nitrone via oxidative cleavage of a tertiary amine, our route
employed an epoxide opening to generate the nitrone followed in
tandem by the dipolar cycloaddition. Moreover, the route was
enabled by the selective late-stage manipulation of an unactivated
C(sp3)-H bond in a pentacyclic intermediate, resulting in a short,
efficient synthesis. Herein, the evolution and full details of these
efforts are reported.14
We identified acyclic epoxy oxime 20 as a simplified model
substrate for our proposed cascade transformation (Scheme 3).
The synthesis of oxime 20 commenced with sequential silyl
protection and allylation of alkynol 23 to provide enyne 24 in
excellent yield over two steps (Scheme 4). Stereoselective
reduction of 24 to the corresponding cis skipped diene was
2. Synthetic Plan
achieved
using
nickel
boride/H2.18,19,20
Subsequent
2.1 Retrosynthetic analysis.
chemoselective oxidation of the internal olefin was achieved
using m-CPBA to yield epoxide 25 in 52% yield over two steps.

3
Protecting group removal and oxidation to aldehyde 26
proceeded without incident and then oxime 20 was prepared
through condensation of 26 with NH2OH.
Scheme 5. Cascade reaction sequence of model oxime 20 to
access the truncated virosaine core 22.
ACCEPTED MANUSCRIPT
3.2 Attempted Diels-Alder reaction of 2-bromoacrolein (18) and
ethyl 2-(furan-2-yl)acetate (19, R = CH2CO2Et).
With the feasibility of the bio-inspired cascade reaction
sequence established, we turned our attention to the Diels-Alder
reaction required to construct oxabicyclo[2.2.1]heptene 17.22 The
enantioselective Diels-Alder reaction of furan (19, R = H) with 2-
bromoacrolein (18) was previously reported by Corey and
appeared well suited to our needs.23 To this end, we attempted the
cycloaddition of ethyl 2-(furan-2-yl)acetate (19, R = CH2CO2Et)
with 2-bromoacrolein (18) by allowing them to react in the
presence of oxazaborolidinone catalyst 30 (Scheme 6). However,
to our dismay, the only products generated in the reaction were
furans 31 and 32, resulting from a Friedel-Crafts conjugate
addition. Disappointingly, modifying the reaction conditions
(reaction time, temperature, catalyst, quenching method, etc.) did
not alter the course of the reaction and either generated 31 and
32, in varying amounts, or resulted in polymerization of 18.24
Several other substituted furans (19, R = OMe, Me, TMS)
yielded similarly disappointing results.
Scheme 3. Proposed cascade reaction sequence to access a
truncated virosaine core 22.
Scheme 4. Synthesis of model cascade precursor 20.
With the model oxime 20 in hand, we investigated the
epoxide-opening/nitrone cycloaddition cascade reaction sequence
to access the bridged tricycle 22 (Scheme 5). Following the
report by Grigg and coworkers, we initially heated 20 in xylenes
o
at 140 C and were pleased to find that the desired product 22
was generated. However, the yield of the overall process suffered
due to the sluggish nature of the initial epoxide-opening step. As
a result, extended reaction times were required to drive the
reaction to completion and led to significant decomposition. This
observation led us to the use of additives to promote the epoxide
opening step. Ultimately we found that the use of protic acids,
such as para-toluenesulfonic acid (p-TSA), promoted N-
alkylation at room temperature to generate nitrone 21 in 81%
yield. Gratifyingly, heating 21 in xylenes effected the [3+2]
cycloaddition to produce 22 in 78% yield as a 7:1 mixture
alongside the regioisomeric cycloadduct 27. Furthermore, we
were pleased to find that the use of catalytic protic acid at
elevated temperatures (5 mol % PPTS, xylenes, 140 oC)
generated 22 in 48% yield in a single pot process from oxime 20,
thereby establishing the feasibility of this cascade approach to
access a simplified bridged virosaine core. Interestingly, during
these studies, we found that significantly different outcomes
resulted depending upon the additive employed. For example,
adding LiCl produced oxazine 28 as the major product, via O-
alkylation of the oxime to open the epoxide. In contrast, using
K2CO3 generated nitrile 29 in 65% yield, presumably via initial
O-alkylation to give oxazine 28 followed by subsequent base-
mediated Kemp elimination.21 Evidence to support this proposal
was gained by subjecting 28 to the same reaction conditions,
which resulted in clean conversion to nitrile 29 in 84% yield.
Scheme 6. Reaction of 2-bromoacrolein (18) with ethyl 2-
(furan-2-yl)acetate (19, R = CH2CO2Et).
This limitation of the furan Diels-Alder reaction presented a
significant problem as our proposed route relied on the [4+2]
cycloaddition to install requisite functionality in 14 to ultimately
generate the butenolide in 3 (vide supra). Faced with this
unanticipated obstacle, we considered the use of known
oxabicycle 33, resulting from cycloaddition with furan rather
than its substituted congeners, within our proposed route to
access pentacycle 34 (Scheme 7).23 However, this subtle change
had a significant consequence in that it would require the
implementation of a selective late-stage functionalization at C14
of 34 to construct butanolide 13. While late-stage C-H
functionalization strategies have proven enabling in total
synthesis, their successful implementation can be challenging
within complex molecular frameworks.25,26 In this particular case,
the presence of the isoxazolidine and 12 distinct C-H bonds make
selective functionalization of 34 an ambitious task. Nevertheless,
we were greatly motivated to pursue this strategy as it not only
would enable our proposed cascade reaction sequence but also,
together, these key transformations would allow us to prepare 3
in a highly efficient manner.
Scheme 7. Late-stage C14 functionalization strategy to access
3 via oxabicycle 33.
3.3 Synthesis of cascade precursor 44.

4
Tetrahedron
ACCEPTED MANUSCRIPT
We prepared Corey’s oxabicycle 33 by combining 2-
converted to O-silylated oxime 43 by treatment with TBSONH2
bromoacrolein (18) with furan (35) in the presence of
oxazaborolidinone 30 at –78 °C in CH2Cl2 (Scheme 8).23 In our
hands, 33 was difficult to isolate in high yield or purity and
readily underwent cycloreversion to return starting materials.
Similar observations with bicycle 33 were made by Carreira, who
opted to trap the aldehyde in situ by addition of either an enolate,
silyl ketene acetal, or NaBH4.27 We examined a similar approach
to trap 33 in situ with a Grignard or equivalent nucleophile to
access a bromohydrin product that was expected to be more
stable. Initially, we found that allyl and 3-butenylmagnesium
bromide could be added to the unstable aldehyde to provide
bromohydrins 36 and 37, respectively. In both cases, the products
were generated with negligible diastereoselectivity. Moreover,
the terminal olefins in 36 and 37 could not be selectively
manipulated in the presence of the strained internal olefin and
prompted us to examine other nucleophiles. Ultimately, thorough
screening led us to identify organolithium 38 as the most
selective nucleophile, providing the desired bromohydrin product
39 in 62% yield and in a favorable, albeit modest, 2.7:1 d.r. and
83% ee.28 Interestingly, in studying this reaction, we found that
the yield and ee of bromohydrin 39 was highly dependent on the
method used to generate the oxazaborolidinone Diels-Alder
catalyst 30. Specifically, we found that the best yield and ee
values were obtained when 30 was generated using neat n-
butyldichloroborane,27c while using either n-butylboronic acid or
a toluene solution of n-butyldichloroborane provided inferior
results. Furthermore, while the two bromohydrin diastereomers
were inseparable by chromatography, we were gratified to find
that recrystallization delivered the desired diastereomer 39 in
>20:1 d.r. and >99% ee. Overall, this one-pot process efficiently
installed 10 of the 12 carbon atoms and 3 of the 6 stereocenters
of the natural product.
in the presence of molecular sieves. Finally, treatment of 43 with
NaH effected smooth conversion to epoxide 44, a protected
analogue of our cascade precursor. Importantly, we found that the
silyl protecting group was critical to the success of this epoxide
formation. In contrast, the corresponding unprotected oxime
failed to undergo bromide displacement and, instead, produced
cyclic aminal 45, which could not be converted to epoxide 16.
Scheme 9. Synthesis of cascade precursor 44.
3.4 Cascade reaction sequence optimization to access the
virosaine core 34.
The development of a robust route to access the oxime
epoxide set the stage for the study of the key cascade reaction
sequence to prepare the pentacyclic virosaine core 34 (Table 1).
Initial cascade studies were conducted on the free oxime 16 (R =
H, see Supporting Information for preparation) and, gratifyingly,
submission to the reaction conditions that were developed during
the initial model studies afforded 34 as the sole product in a
promising 26% yield (entry 1).29 Encouraged by these results, we
examined direct cascade reactions using silyl oxime 44. The
amount of PPTS was increased to 1 equivalent in order to
facilitate silyl group cleavage and we examined more polar
solvents due to the low solubility of PPTS in xylenes. We found
that the cyclization occurred in both THF and MeCN with
significantly improved yields (entries 3 and 4), while MeOH did
not lead to any significant improvement (entry 5). Additionally,
we found that using microwave heating in place of conventional
heating led to a significant decrease in reaction time (entry 2 vs.
3). Among the additives assessed, both BF3ꢁOEt2 and HF were
found to be detrimental to reaction, producing only trace amounts
of 34, at best (entries 6 and 7). Importantly, while acetic acid was
not an efficient promoter when employed as an additive in
acetonitrile (entry 8), the reaction conducted in acetic acid as
solvent afforded 34 in 78% yield (entry 9). Furthermore, we were
pleased to find that by reducing the reaction time to 30 minutes,
34 could be isolated in an excellent 92% yield (entry 10).
Moreover, the reaction could also be conducted on gram scale
(5.2 mmol) using conventional heating, to produce the virosaine
core in only a slightly diminished 82% yield (entry 11). Overall,
this novel cascade process allowed us to access the complex core
of virosaine A (3) in only 5 steps from commercially available
materials.
Scheme 8. Enantioselective synthesis of bromohydrin 39.
With an efficient process established for the generation of 39,
we focused on its elaboration to the key cascade precursor.
Initially, we found that bromohydrin 39 could be cleanly
converted to the corresponding epoxide 40 by treatment with
K2CO3 in MeOH (Scheme 9). The stereochemical assignment of
39 was unambiguously confirmed by an observed nuclear
Overhauser effect (nOe) between the epoxide proton and the
axial proton of the bridged bicycle in 40. Unfortunately,
attempted acid-mediated dioxolane removal failed to reveal the
latent aldehyde 41 and led to decomposition of material and/or
complex mixtures in every case. Alternatively, we found that the
dioxolane protecting group could be removed directly from
bromohydrin 39 under mildly acidic conditions to provide the
corresponding lactol 42 in near quantitative yield. All attempts at
base-mediated conversion of 42 to aldehyde 41 were met with
failure. However, we found that lactol 42 could be directly

5
Accordingly, diazoacetate 46 was prepared from 34 in a high-
ACCEPTED MANUSCRIPT
yielding one-pot procedure involving sequential diketene
addition, diazo transfer, and deacetylation (Scheme 10). With 46
in hand, we surveyed several common Rh2+ and Cu2+ catalysts
but were disappointed to find that complex, inseparable mixtures
of products were generated in every case. As a result, we turned
our attention to the corresponding silyl diazoacetate 47, which
was prepared by treating 46 with Et3SiOTf. Silyl diazoacetates
have previously been shown to attenuate C-H insertion reactivity
and, consistent with this observation, metal-catalyzed reactions
of 47 resulted in fewer undesired byproducts than reactions of the
parent diazoacetate 46.31d Moreover, several Rh2+ catalysts
produced a single C-H insertion product, with Rh2(NHC(O)CF3)4
providing the highest isolated yield. Unfortunately, structural
analysis revealed this product to be silyllactone 48, resulting
from C-H insertion into the C9 methylene. Interestingly, in
addition to the lactone product 48, butyrate 49 was consistently
generated in minor amounts, presumably via a silyl carbene
rearrangement.32
Table 1. Cascade reaction sequence optimization.
Entry Solvent Acid
(equiv.)
xylenes PPTS (0.2)
Temp
(oC)
140
70
Time Yield
(%)a
1b
2
8 h
12 h
1 h
1 h
1 h
26
THF
THF
PPTS (1)
PPTS (1)
40
3c
4c
5c
6
100
120
120
45
MeCN PPTS (1)
MeOH PPTS (1)
50
28
CH2Cl2 BF3ꢁOEt2 (2) 0 ꢀ 45 17 h
MeCN HF in H2O (5) 22 ꢀ 70 15 h
0
7
trace
<10d
78
8c
9c
10c
11e
MeCN AcOH (5)
120
120
120
120
1 h
1 h
AcOH
AcOH
AcOH
-
-
-
30 min 92
40 min 82
b
aIsolated yields of 34. Oxime 16 (R = H) used as starting
material. cMicrowave heating. dRecovered 89% starting
material. e5.2 mmol scale.
Scheme 10. Carbene insertion of silyl diazoacetate 47.
3.5 Carbene C-H insertion strategies to functionalize C14 of the
virosaine core.
To study the consequence of modifying the substrate
electronics on the carbene insertion process, we prepared
diazomalonate 51 by acylation of 34 with methyl malonyl
chloride followed by diazo transfer on the intermediate malonate
50 (Scheme 11). Intriguingly, when diazomalonate 51 was
treated with catalytic amounts of either Rh2(OAc)4 or
Rh2(NHC(O)CF3)4, the major product was ether 53. The
mechanism for the formation of 53 likely involves trapping of the
highly electrophilic rhodium carbenoid by an oxygen lone pair to
generate oxonium ylide 52. An elimination/protonation process
would then deliver the observed product 53.33
With an efficient route in place to access the polycyclic
virosaine core, the final obstacle was selective C14
functionalization to install the butanolide ring. Direct selective
functionalization of 34 would likely be a challenging task due to
potential difficulties associated with controlling regioselectivity
in the presence of 12 distinct C-H bonds and chemoselectivity in
the presence of the basic isoxazolidine. However, the presence of
the C10 hydroxy as a tethering point opened the possibility to
carry out an intramolecular functionalization, effectively limiting
the potential sites of reactivity to the C2 methine, the C9
methylene and the (desired) C14 methine (Figure 2).
Figure 2. Tethering strategy for intramolecular
functionalization of the virosaine core.
The most direct route to access 3 via a C-H modification was
through an intramolecular C-H insertion reaction of diazoacetate
46 to prepare lactone 13.30 There are only a few successful
examples of carbene C-H insertions at bridgehead positions
reported in the literature and challenges associated with their
implementation have been noted in several cases.31 Nevertheless,
the potential directness of this route merited investigation.
Scheme 11. Reactions of diazomalonate 51 to form cyclic
ether 53.
We considered whether the undesired reactivity observed in
the attempted metal-catalyzed carbene insertions might be due to
the sterics associated with the large rhodium carbenoid. This
prompted us to explore the possibility of using a free carbene to

6
Tetrahedron
insert into the C14-H14 bond. Accordingly, solutions of
3.6 Nitrene C-H insertion strategy to functionalize C14 of the
ACCEPTED MANUSCRIPT
diazoacetates 46 and 47 in CCl4 were exposed to ultraviolet light
(254 nm). However, under these conditions, the only products
generated in the reaction were perchlorinated esters 54 and 55
resulting from exclusive reaction with the solvent itself.
Changing the reaction medium to the less reactive PhCF3 did not
prove beneficial and, in the case of both diazoacetate substrates,
complex mixtures of products were generated. In the case of silyl
diazoacetate 47, several products could be assigned from the
crude reaction mixture. These included three previously known
compounds (alcohol 34, silyllactone 48, and butyrate 49) as well
virosaine core.
The inability of the carbenes to insert into the bridgehead
position can potentially be attributed to several factors, such as
the steric environment around C14 and/or the silyl rhodium
carbenoid as well as the presence of other reactive functional
groups in the system. As an alternative to this approach, we
considered the corresponding nitrene C-H insertion reactions,
which have seen considerable development throughout the past
two decades and have enjoyed widespread utility in the synthesis
of natural products.35,36 Furthermore, there are several reports of
the use of intramolecular nitrene C-H insertions to functionalize
bridgehead positions in complex molecular settings.26a,26f,36e-g
Although a nitrene insertion at C14 in a carbamate such as 60
would not introduce the butanolide directly, hydrolysis of the
resulting oxazolidinone would reveal a ketone (e.g. 62) which
might be amenable to further manipulation to ultimately produce
3 (Scheme 14).
as oxygen trapping
/ elimination product 56 (tentative
assignment). These results indicated that a free carbene was far
from selective and was unlikely to deliver the desired C-H
insertion product in high yield, if at all.
Scheme 14. Proposed nitrene C-H insertion route to
functionalize C14 and access virosaine A (3).
Scheme 12. Photolytic carbene generation from
diazoacetates 46 and 47.
Carbamate 60 was prepared in near quantitative yield from
alcohol 34 through sequential reaction with Cl3CC(O)NCO and
NaHCO3/MeOH (Scheme 15). With 60 in hand, we screened
various nitrene generating conditions and quickly identified He’s
conditions [PhI(OAc)2, AgOTf, bathophenanthroline, MeCN, 82
oC, sealed tube] as optimal, providing a single reaction product in
80% yield. However, structural elucidation revealed that, in
contrast to the carbene insertion reaction of silyldiazoacetate 47
(vide supra), nitrene insertion of 60 had occurred at C2 to
provide oxazolidinone 63. Interestingly, we found that the same
reaction conducted in CH2Cl2, instead of MeCN, provided a
completely different product. Extensive 2D NMR analysis
revealed this new product to be diacetoxy ketone 64, whose
formation is the result of both C2 oxidation and C10-C14 bond
cleavage. Our preliminary mechanistic hypothesis for the
formation of 64 is that oxazolidinone 63 is initially generated and
that, under the slightly more acidic conditions (CH2Cl2 vs.
MeCN), C2-aminal exchange takes place followed by a second
oxidation that results in the C10-C14 bond cleavage.37 Evidence
to support the potential intermediacy of 63 was gained by
converting it to 64 upon submission to the same reaction
conditions.
As a final attempt at using a carbene C-H insertion to
functionalize C14, we attempted an intermolecular carbene
insertion. Specifically, we exposed the TMS-protected virosaine
core 57 to ethyl diazoacetate in the presence of catalytic
Rh2(OAc)4 (Scheme 13). However, the only product generated in
the reaction was aminal 58 resulting from a formal N-O carbene
insertion. Perhaps unsurprisingly, the formation of 58 likely
occurs via trapping of a rhodium carbenoid intermediate by the
isoxazolidine nitrogen of 57. This would lead to aza ylide 59,
which can undergo subsequent Stevens rearrangement. While this
result was clearly undesired, to the best of our knowledge, this is
the first example of a carbene insertion into an isoxazolidine N-O
bond.34 In addition, this transformation clearly highlights the
difficulties of employing an intermolecular functionalization
strategy in the presence of the reactive isoxazolidine unit.
Scheme 13. Intermolecular carbene N-O insertion.

7
C10-C14 bond (Scheme 18). In contrast, we found that treating
ACCEPTED MANUSCRIPT
alcohol 34 with He’s nitrene insertion conditions, as above,
resulted in complementary selectivity to that observed for
carbamate 60. Specifically, the reaction produced tetracycles 69
and 70, each resulting from exclusive C2-C10 bond cleavage
followed by further oxidation to the N-alkoxylactam.39 As with
the nitrene chemistry above, attempts to deactivate C2 via
protonation or BF3-coordination of the isoxazolidine nitrogen
failed to alter the course of the reaction.38
Scheme 15. Oxidative transformations of carbamate 60.
Given the undesired regioselectivity observed in the oxidative
functionalization of carbamate 60, we wondered whether we
could electronically deactivate C2 and direct oxidation to another
site on the polycyclic core. Sanford and White have
independently demonstrated that C-H bonds proximal to basic
amines can be electronically deactivated through protonation or
Lewis acid coordination.38 Unfortunately, this strategy did not
translate successfully to our own system. Specifically, submitting
either the protonated or BF3-coordinated adduct 65 to oxidative
nitrene insertion conditions led only to decomposition of material
(Scheme 16).
Scheme 18. Oxidative C2-C10 bond cleavage of alcohol 34.
3.8 Directed lithiation approach to functionalize C14 of the
virosaine core.
The lack of reactivity at C14 suggested that a combination of
unfavourable steric and stereoelectronic properties were at play.
Indeed, Lee has elegantly demonstrated that bridgehead positions
vicinal to an oxygen atom are inductively deactivated towards C-
H insertion. Geometrical constraints prevent efficient n(O) ꢀ
σ*(C-H) electron delocalization and thus the main influence is
the electronegativity of the oxygen.26e Further assessment of the
potential sites of reactivity using both NMR and computational
analysis on alcohol 34 provided additional insight into this lack
of reactivity (Figure 3).26c,26g,40 Specifically, NMR analysis
revealed that both H14 and C14 were the most downfield signals
in their respective NMR spectra, suggesting that this position was
in fact more electron deficient than we had initially anticipated.
Consistent with this notion, the NPA partial charge of C14 was
calculated to be significantly more positive than both C2 or C9
and the C14-H14 bond was calculated to have the lowest energy
HOMO of all C-H bonds in 34. These observations were
consistent with the observed selectivity for carbene and nitrene
insertion at C9 and C2 over the desired position at C14.41
Scheme 16. Attempted nitrene C-H insertion of adduct 65.
3.7 Sequential C10-C14 oxidative cleavage/reductive pinacol
coupling strategy.
While the Ag-mediated oxidative transformations of
carbamate 60 failed to deliver the desired C-H insertion product
61, the formation of diacetoxy ketone 64 was intriguing.
Although not part of the initial strategy, the C14 position was
modified during the bond cleavage event to the aldehyde
oxidation state. This led us to consider whether it would be
possible to achieve this same bond cleavage while avoiding C2
oxidation to produce ketone 66 (Scheme 17). Further, 66 might
be oxidized to lactone 67 and a subsequent lactone-ketone
pinacol coupling could re-unite C10 and C14 to produce the
dihydroxylated virosaine core 68.
NPA partial
atomic charge
on carbon
1H
13C
C-H HOMO
Energy (eV)
2
Site
δ
δ
( , ppm) ( , ppm)
9
14
2
9
3.59
1.73
4.72
66.8
45.5
85.7
-0.037
-0.423
+0.095
-13.69
-13.71
-14.48
14
34: “top-down” perspective
Figure 3. Evaluation of the potential sites of reactivity in 34
by NMR chemical shift assessment and natural population
analysis (NPA)/natural bond orbital (NBO) analysis of the
energy-minimized structure determined at the B3LYP/6-
311++G** level of theory.
The apparent electron-deficient nature of C14 suggested an
alternative approach to C-H functionalization. Specifically, we
postulated that it might be possible to carry out a selective
directed deprotonation at C14 to produce
a metalated
intermediate that could be functionalized through the addition of
a suitable electrophile.42 We thus examined both tertiary and
secondary carbamates 71 and 72, easily prepared from 34 via
acylation with ClC(O)NEt2 or sequential addition of carbonyl
diimidazole and n-butylamine, respectively (Scheme 19). All
attempts at directed lithiation with tertiary carbamate 71 returned
only starting material. Gratifyingly, in contrast, we found that 72
Scheme 17. Sequential C10-C14 oxidative cleavage/reductive
pinacol coupling strategy to functionalize C14.
A series of oxidants were screened with both alcohol 34 and
carbamate 60 but all failed to induce selective cleavage of the

8
Tetrahedron
could be lithiated selectively at C14 upon treatment with 2.2
be efficiently carried out in a single pot and afforded virosaine A
ACCEPTED MANUSCRIPT
equiv. of s-BuLi, as judged by quenching of the organolithium
intermediate 73 with benzaldehyde to form alcohol 74 in 43%
yield. The stronger directing group ability of a metalated
secondary carbamate has been noted in other studies.43,44 With a
method in place for selective C14 functionalization, we attempted
to trap lithiated intermediate 73 with ethyl bromoacetate.
However, instead of generating the desired product 75,
brominated carbamate 76 was obtained in low yield resulting
from lithium-bromide exchange. Attempts at transmetalation
using CuCN, Li(2-thiophenyl)CuCN or MgBr2 failed to promote
(3) directly from alcohol 78 in an excellent 77% yield.
4. Conclusions
In summary, we have developed a concise enantioselective
route to access virosaine A (3) that proceeds in 10 steps and 9%
overall yield. Our synthetic strategy was built around a bio-
inspired cascade reaction sequence that allowed rapid
construction of the caged polycyclic core of the natural product.
Furthermore, after identifying a synthetic limitation of the
Scheme 19. Synthesis of (-)-virosaine A (3).
direct alkylation with ethyl iodooacetate. In addition, several
other carbon-based electrophiles also failed to produce the
desired products.45 While direct installation of the acetate unit
could not be accomplished, the bromide 76 was a potential
candidate for elaboration. Optimization revealed that 76 could be
obtained in 70% yield simply by quenching the dilithiated
intermediate 73 with Br2.
furan/2-bromoacrolein Diels-Alder reaction, we were required to
investigate several methods for late-stage C-H functionalization
to completely furnish the carbon framework of 3. Ultimately,
these C-H functionalization studies provided valuable
information on the differences in reactivity between several
positions on the virosaine core and reinforced the importance that
method selection holds when applying
a late-stage C-H
functionalization strategy on a complex molecule. Finally, a
combination of NMR and computational analyses provided a
foundation for the successful implementation of a directed
lithiation/bromination sequence to selectively functionalize C14
and complete the synthesis of 3.
With a bromide handle in place at C14, subsequent Keck
allylation delivered allylated carbamate 77 in 71% yield.46 Under
these conditions, a modest amount of debrominated carbamate 72
was also generated (27% yield) but could be conveniently
recycled through the sequence. Carbamate removal was then
smoothly carried out via reduction using LiAlH4 to deliver
alcohol 78 in 94% yield. In order to construct the final ring of the
natural product, we subjected 78 to ozone followed by workup
with dimethylsulfide and obtained lactol 79. The crude reaction
mixture also contained a minor amount of lactone 13. As a result,
we submitted the mixture directly to Dess-Martin oxidation to
exclusively provide lactone 13. Serendipitously, when we
attempted to purify 13 by silica gel flash chromatography, we
observed the formation of virosaine A (3). However, subsequent
attempts to replicate this silica gel-mediated rearrangement
(13ꢀ3) provided inconsistent results that led us to screen other
conditions for the transformation. Gratifyingly, we found that
simply submitting 13 to activated neutral alumina effected a
smooth and reproducible rearrangement to provide 3. This
sequence of ozonolysis, DMP oxidation and fragmentation could
5. Experimental
Detailed experimental procedures and characterization data
are provided in the Supporting Information associated with this
article.
Acknowledgements
This work was supported by the Natural Science and
Engineering Research Council of Canada (NSERC). J.M.E.H.
thanks NSERC and the Walter C. Sumner Foundation for
postgraduate fellowships. We thank Prof. Tristan Lambert
(Columbia University) for helpful discussions.
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Tetrahedron
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