A Concise Enantioselective Total Synthesis of (?)-Virosaine A

Article abstract of DOI:10.1002/anie.201706273

The total synthesis of (?)-virosaine A (1) was achieved in ten steps starting from furan and 2-bromoacrolein. A one-pot Diels–Alder cycloaddition/organolithium addition initiated an efficient sequence to access a key oxime/epoxide intermediate. Heating this intermediate in acetic acid resulted in an intramolecular epoxide opening/nitrone [3+2] cycloaddition cascade to construct the caged core of 1 in a single step. Several methods of C?H functionalization were assessed on the cascade product, and ultimately, a directed lithiation/bromination effected selective C14 functionalization, enabling the synthesis of 1.

Full text of DOI:10.1002/anie.201706273

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: A Concise, Enantioselective Total Synthesis of (-)-Virosaine A
Authors: James L. Gleason and Jonathan M. E. Hughes
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706273
Angew. Chem. 10.1002/ange.201706273
Link to VoR: http://dx.doi.org/10.1002/anie.201706273
http://dx.doi.org/10.1002/ange.201706273

10.1002/anie.201706273
Angewandte Chemie International Edition
COMMUNICATION
A Concise, Enantioselective Total Synthesis of (–)-Virosaine A
Jonathan M. E. Hughes and James L. Gleason*
butanolide in
3 impossible. Thus, the success of the nitrone
Abstract: The total synthesis of (–)-virosaine A (1) was achieved in 10
steps starting from furan and 2-bromoacrolein. A one-pot Diels-Alder
cycloaddition/organolithium addition initiated an efficient sequence to
access a key oxime/epoxide intermediate. Heating this intermediate in
acetic acid resulted in an intramolecular epoxide opening/nitrone
[3+2] cycloaddition cascade to construct the caged core of 1 in a
single step. Several methods of C-H functionalization were assessed on
the cascade product and, ultimately, a directed lithiation/bromination
effected selective C14 functionalization to enable the synthesis of 1.
formation/cycloaddition cascade strategy ultimately hinged on the ability
to selectively functionalize 4 at C14. Late-stage C-H functionalization is
an increasingly powerful tool for the synthesis of complex natural
products and recent progress in the areas of carbene and nitrene insertion
and C-H oxidation chemistry, in particular, have provided powerful new
additions
to
the
arsenal
of
potential
strategic
transformations.[
While their application in complex
,
,
,
,
,
]
10 11 12 13 14 15
molecule settings is often challenging, it can enable more efficient
overall strategies. In the present context, while late stage regio- and
chemoselective manipulation of the unactivated C14-H14 bond in 4
might be difficult due to the presence of 11 other C-H bonds and the
basic isoxazolidine, it would enable the epoxide opening/nitrone
cycloaddition cascade as a viable, concise route to the natural product.
A
The Securinega alkaloids are a broad class of natural products that are
distributed among plants of the Euphorbiaceae family and, owing to their
fascinating structural features and biological activities, have been the
target of many successful and elegant total synthesis efforts.[1] Recently,
some of the most structurally complex Securinega alkaloids were
isolated from Flueggea virosa, a large shrub widely distributed in
southern China and known for its use in the treatment of eczema, allergic
dermatitis and scald.[2] Among these new alkaloids, virosaine A (1) and
B (2) were noted for containing the most highly caged structures of the
Securinega class (Figure 1A).[ 3 ] The proposed biosynthesis of the
polycyclic virosaine core is particularly noteworthy, as it is believed to
involve a [3+2] nitrone cycloaddition, a transformation that is rare in
alkaloid biosynthesis.[4,5,6,7,8] The caged pentacyclic frameworks of 1 and
2 have made them attractive yet challenging targets for total synthesis.
To date, there has been only one reported synthesis of 1 and 2, in 18 and
10 steps respectively.[5a,5b] In both cases, the strategies relied on N-
oxidation of another Securinega alkaloid (O-silylated bubbialidine and
allonorsecurinine, respectively) to furnish a nitrone that engaged in the
putative biosynthetic [3+2] cycloaddition as the final step. Here, we
describe a highly concise approach to 1 that exploits a selective late-
stage modification of an unactivated C(sp3)-H bond of a polycyclic core
that is rapidly assembled via a cascade epoxide opening/nitrone
cycloaddition.
O
O
O
O
H
H
H
OH
8
H
H
H
O
H
O
N
HO
N
H
H
virosaine A (1)
selective C14 functionalization
key intermediate
caged pentacycle
virosaine B (2)
B
O
O
13
H
14
HO
O
[3+2]
HO
H
10
O
O
multiple bridged bicycles
12 distinct C-H bonds
basic tertiary nitrogen
isoxazolidine (N-O bond)
2
O
9
N
N
N
O
O
3
4
5
N-alkylation/
epoxide opening
O
O
[4+2]
Br
CHO
OHC
O
+
O
HO
N
Br
ref. 9
9
8
7
6
In examining 1, we envisaged that the alcohol and enoate functional
groups might be mutually masked via an ether bridge, leading to caged
hexacycle 3 (Figure 1B). Further, cleavage of the C13-C14 bond (vide
infra) results in key intermediate 4, the caged core of 3, which might
arise by a bio-inspired [3+2] cycloaddition of nitrone 5. We envisioned
that 5 could be generated in a stereo- and regiocontrolled fashion by
opening of an epoxide with a pendant oxime, a process that might be
incorporated in tandem with the nitrone cycloaddition (6→5→4).
Finally, cascade precursor 6 might be produced efficiently beginning
with Corey’s asymmetric Diels-Alder cycloaddition of 2-bromoacrolein
(9) with furan (8).[9] Importantly, cycloaddition of 9 is limited to furan
itself, with substituted furans leading only to Michael addition products,
making early stage introduction of functionality necessary for the
Figure 1. (a) Virosaine A (1) and B (2) and (b) retrosynthetic analysis of 1.
Oxabicycle 7 was readily generated by oxazaborolidinone-catalyzed
cycloaddition of 2-bromoacrolein (9) with furan (8).[9,16] In our hands,
and those of others,[16] 7 proved insufficiently stable to isolate. However,
we found that 7 could be trapped in situ by a variety of organolithium
and Grignard reagents to give stable bromohydrin products. In particular,
addition of organolithium 11 afforded 12 in 62% yield, 2.7:1 d.r. and
]
83% ee.[17 Screening of alternative conditions (nucleophile, additive,
solvent, etc.) did not improve diastereoselectivity further. Although the
diasteromers of 12 could not be separated chromatographically,
recrystallization gratifyingly provided alcohol 12 in >20:1 d.r. and >99%
]
ee.[18 This one-pot process served to install all but two carbons of the
final natural product. Subsequent acid-promoted dioxolane cleavage to
give lactol 13 was followed by condensation with TBSONH2 to provide
O-silyl oxime 14 in 92% yield over two steps. Epoxide formation then
proceeded smoothly upon treatment with NaH to afford 15 in near
quantitative yield.
[*]
J. M. E. Hughes, Prof. Dr. J. L. Gleason
Department of Chemistry, McGill University
801 Sherbrooke W., Montreal, QC, H3A 0B8 (Canada)
E-mail: jim.gleason@mcgill.ca
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706273
Angewandte Chemie International Edition
COMMUNICATION
8[d]
AcOH
-
120
40 min
82
O
Me
O
Br
CHO
B
N
[b]
[c]
[a] Isolated yields of 4. Oxime 6 used as starting material. Microwave
n-Bu
Li
Ts
O
N
O
O
10
heating. [d] 5 mmol scale.
H
(10 mol %)
OH
O
9
11
OHC
O
+
CH2Cl2, -78 o
C
Et2O, -78 o
C
With an efficient route to the virosaine core in hand, the final obstacle
was to selectively functionalize C14 of bridged pentacycle 4 to install
the butanolide ring. Owing to the significant challenges of regio- and
chemoselectivity, we opted to use the C10 hydroxyl as a tether for
intramolecular functionalization to limit the potential sites of reactivity
to C2, C9 and (the desired) C14 (see 4, Figure 1B). The most attractive
possibility for tethered functionalization was an intramolecular carbene
C-H insertion of an α-diazoacetate to directly deliver 3. Given that
there are very few reports of related carbene insertions into bridgehead
positions, we were cognizant of the potential difficulties associated
with this strategy.[11e,20] Nonetheless, we felt that such a direct approach
Br
O
Br
7
12
62%, 2.7:1 dr, 83% ee
O
30%, >20:1 dr, >99% ee
(recryst.)
8
5% aq. HCl
THF, rt
OTBS
N
HO
O
O
O
NH2OTBS,
4Å MS
O
OH
NaH, THF
O
TBSO
0 oC to rt
99%
N
CH2Cl2, rt
Br
Br
14
92%
(2 steps)
15
13
Scheme 1. Enantioselective synthesis of cascade precursor 15.
to access virosaine
A
warranted investigation. Accordingly,
diazoacetate 16 was prepared from 4 in one pot via sequential diketene
addition, diazo transfer, and deacetylation (Scheme 2). However, under
a range of carbene generating conditions (Rh2+, Cu2+, hν), we observed
only formation of complex mixtures from which no clean products
could be isolated. Since α-silyl diazoacetates have been shown to
attenuate C-H insertion reactivity, we prepared triethylsilyl
diazoacetate 17 by silylation of 16.[20c] Carbene insertion reactions of
17 were cleaner than those of the parent 16 and we were able to effect
With epoxide 15 in hand, we turned our attention to the key epoxide
opening/nitrone cycloaddition cascade reaction sequence (Table 1).
There is limited literature precedent for this type of cascade and, to the
best of our knowledge, application to access a bridged polycyclic ring
system is unprecedented.[19] Initially, we observed that oxime addition
to the epoxide in 15 required prolonged heating at high temperatures
under neutral conditions. Advantageously, the use of mild protic acids,
such as pyridinium p-toluenesulfonate (PPTS), promoted rapid epoxide
opening to form nitrone 5. Furthermore, when the reaction was
conducted in xylenes at 140 °C, nitrone 5 underwent the desired [3+2]
cycloaddition directly to give 4 in 26% overall yield (entry 1).
Encouraged by these results, we screened a variety of solvents for the
transformation and found that THF and MeCN improved the yield
significantly in combination with microwave heating (entries 3 and 5).
Gratifyingly, further screening revealed that, while acetic acid was not
an efficient promoter when employed in acetonitrile (entry 6), the
reaction conducted in acetic acid as solvent afforded 4 in a remarkable
92% yield in one pot from 15 (entry 7). Overall, this novel cascade
process allowed us to access the complex core of virosaine A (1) in
only 5 steps from commercially available materials.
a
C-H insertion using
a
variety of metal catalysts, with
Rh2(NHC(O)CF3)4 providing the product in the highest isolated yield.
Unfortunately, structural analysis revealed that the carbene insertion
had occurred at the C9 methylene instead of the desired C14 methine,
affording α-silyllactone 18.
R
O
O
N2
SiEt3
H
diketene, DMAP,
CH2Cl2, -20 oC to rt;
14
O
O
HO
N
14
Rh2(NHC(O)CF3)4
O
O
O
nOe
9
PhMe, 120 oC
47%
MsN3, Et3N, MeCN, rt;
then LiOH-H2O, rt
9
H
N
N
O
O
O
98%
4
18
16 (R = H)
17 (R = SiEt3)
Et3SiOTf, Et3N
CH2Cl2, rt
88%
Table 1. Cascade reaction sequence optimization.
Scheme 2. Carbene C-H insertion reaction of diazoacetate 17.
O
HO
Given the undesirable site-selectivity of the carbene insertion, we
explored the potential of a nitrene C-H insertion to functionalize C14.
Although this would not install the lactone directly, the resulting aminal
might be hydrolyzed to a ketone suitable for subsequent manipulation.
Furthermore, we were encouraged by several reports of nitrene
insertions into bridgehead C-H bonds in complex molecule
settings.[11a,11f,21] To this end, carbamate 19 was prepared by treating
alcohol 4 with Cl3CC(O)NCO followed by NaHCO3/MeOH (Scheme 3).
With 19 in hand, we surveyed several sets of conditions and found that
He’s conditions (PhI(OAc)2, AgOTf, bathophenanthroline, MeCN, 82
oC) provided a single product, which was identified as oxazolidinone
20.[11f,21,22] In contrast to the selectivity observed in the carbene insertion,
oxidative functionalization of carbamate 19 occurred at C2, a result that
highlights the sensitivity of the system to the nature of the reactive
intermediate (carbenoid vs. nitrenoid). All attempts to deactivate C2 by
protonation or BF3 coordination of the isoxazolidine nitrogen did not
alter the selectivity of the insertion process.[23] Interestingly, we found
that the same reaction, conducted in CH2Cl2 instead of MeCN,
HO
N
O
O
HO
H
O
Table 1
O
N
O
TBSO
O
N
N
O
15
5
4
Entry Solvent Acid (equiv.)
T (oC)
140
70
Time
8 h
Yield (%)[a]
1[b]
2
xylenes PPTS (0.2)
26
40
45
28
50
<10
92
THF
PPTS (1)
PPTS (1)
PPTS (1)
PPTS (1)
AcOH (5)
-
12 h
1 h
3[c]
4[c]
5[c]
6[c]
7[c]
THF
100
120
120
120
120
MeOH
MeCN
MeCN
AcOH
1 h
1 h
1 h
30 min
This article is protected by copyright. All rights reserved.

10.1002/anie.201706273
Angewandte Chemie International Edition
COMMUNICATION
exclusively generated ketone 21, whose formation is the result of both immediately oxidized to lactone 3. Exposure of 3 to activated neutral
C2 oxidation and C10-C14 bond cleavage. Al2O3 delivered (-)-virosaine A (1) in 77% yield (one pot) from 25.
O
O
PhI(OAc)2, AgOTf
bathophenanthroline
14
O
N
O
NH2
2
H
MeCN, 82 o
C
N
O
HO
N
O
20
14
Cl3CC(O)NCO
CH2Cl2, rt;
sealed tube
80%
O
O
2
O
O
then NaHCO3,
MeOH, rt
O
n-BuHN
N
PhI(OAc)2, AgOTf
bathophenanthroline
Br
H
OAc
14
10
O
O
CDI, KOH
PhMe, 60 oC;
HO
N
n-BuHN
O
O
s-BuLi,
THF, -78 oC;
14
14
AcO
99%
2
O
O
O
4
19
CH2Cl2, 50 o
C
O
N
then n-BuNH2
CH2Cl2, rt
then Br2, -78 o
C
sealed tube
20%
O
N
N
O
4
O
O
21
70% + 20% rsm
23
22
99%
Scheme 3. Oxidative transformations of carbamate 19.
O
AIBN
SnBu3
HO
N
n-BuHN
O
LiAlH4, THF
O
O
The lack of reactivity at C14 in both the carbene and nitrene chemistry
is likely due to combination of unfavourable sterics and
C6H6, 85 o
C
0 oC to 70 o
C
a
N
O
O
94%
71% + 27% 22
stereoelectronics. In particular, the inability of the lone pair from the
bridging oxygen to donate into the C14-H14 σ* orbital presumably
results in only inductive deactivation by the electronegative oxygen.[11e]
Indeed, assessing the three potential sites of reactivity by both DFT and
NMR chemical shift analysis, methods which have been used
previously to predict site-selectivity for radical and oxidative
functionalizations,[11c,11g,24,25] provide support for low reactivity of C14.
NMR analysis revealed that both H14 and C14 are the most downfield
signals in 4, suggesting that the position is electron poor. Also
consistent with this notion, NPA charge analysis indicated that C14 has
a relatively high positive charge and NBO analysis indicated that the
C14-H14 bond has the lowest energy HOMO of all the C-H bonds in
4.[26]
25
24
O
O
O
O3, CH2Cl2, -78 oC;
Me2S, -78 oC to rt;
Al2O3
EtOAc, rt
O
O
OH
77%
[one pot]
then DMP, pyr
CH2Cl2, rt
N
N
O
O
(-)-virosaine A (1)
3
Scheme 4. Synthesis of (-)-virosaine A (1).
In conclusion, we have achieved the shortest enantioselective total
synthesis of (-)-virosaine A (1) in 9% overall yield. The route features an
efficient epoxide opening/nitrone cycloaddition cascade reaction
sequence to rapidly construct the core of 1.
implementation of this strategy hinged on the ability to selectively
manipulate the C14-H14 bond. Several methods of C-H
functionalization were investigated and highlighted the significant effect
that method choice has on regioselectivity in a complex molecule
setting. Selective functionalization was ultimately achieved via a
directed lithiation/bromination sequence, which enabled the completion
of the total synthesis in an efficient manner.
The successful
NPA partial
atomic charge
on carbon
1H
( , ppm) ( , ppm)
13C
C-H HOMO
Energy (eV)
2
10
Site
δ
δ
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
4: “top-down” perspective
Figure 2. Evaluation of the potential sites of reactivity in 4 using NMR
chemical shift assessment and natural population analysis (NPA)/natural
bond orbital (NBO) analysis of the energy minimized structure
determined at B3LYP/6-311++G** theory level.
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.
Given the electron deficient nature of C14, we reasoned that it might be
possible to carry out a site-directed deprotonation to functionalize this
position.[ 27 ] Indeed, we were delighted to find that carbamate 22,
prepared via sequential treatment of 4 with carbonyl diimidazole and n-
BuNH2, could be lithiated selectively at C14 using 2.2 equivalents of s-
BuLi (Scheme 4). Subsequent quenching of this lithiated species with
Br2 led exclusively to alkyl bromide 23 in good yield.[28 ] With a
functional handle at C14 in place, butanolide ring construction and the
completion of the total synthesis was within reach. Radical allylation
employing Keck’s conditions smoothly delivered allylated carbamate 24
in 71% yield.[29 ] The remaining mass balance of the reaction was
reduction product 22, which was conveniently recycled. Removal of the
carbamate using LiAlH4 then provided alcohol 25 in excellent yield
without any concurrent N-O bond cleavage, setting the stage for the final
annulation event. Ozonolysis of 25 produced a lactol, which was
Keywords: virosaine A • total synthesis • alkaloids • directed lithiation
• domino reactions
[1] For reviews on synthesis of Securinega alkaloids, see: a) E.
Chirkin, W. Atkatlian, F.-H. Porée, in The Alkaloids, Vol. 74 (Ed.: H.-
J. Knölker), Academic Press, New York, 2015, pp 1-120; b) S. M.
Weinreb, Nat. Prod. Rep. 2009, 26, 758.
[2] L. Bingtao, M. G. Gilbert, in Flora of China, Vol. 11 (Eds.: An
Editorial Committee) Science Press, Beijing, 2008, pp 177-179.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706273
Angewandte Chemie International Edition
COMMUNICATION
[3] B.-X. Zhao, Y. Wang, D.-M. Zhang, X.-J. Huang, L.-L. Bai, Y.
Yan, J.-M. Chen, T.-B. Lu, Y.-T. Wang, Q.-W. Zhang, W.-C. Ye, Org.
Lett. 2012, 14, 3096.
[4] For the occurrence of the isoxazolidine moiety in natural
products, see: a) M. Berthet, T. Cheviet, G. Dujardin, I. Parrot, J.
Martinez, Chem. Rev. 2016, 116, 15235 and references therein; b) C.-
E. Nge, K.-S. Sim, S.-H. Lim, N. F. Thomas, Y.-Y. Low, T.-S. Kam, J.
Nat. Prod. 2016, 79, 2709.
[5] For recent total syntheses employing biomimetic [3+2] nitrone
cycloadditions, see: a) H. Miyatake-Ondozabal, L. M. Bannwart, K.
Gademann, Chem. Commun. 2013, 49, 1921; b) H. Wei, C. Qiao, G.
Liu, Z. Yang, C.-C. Li, Angew. Chem. Int. Ed. 2013, 52, 620; c) N. Ma,
Y. Yao, B.-X. Zhao, Y. Wang, W.-C. Ye, S. Jiang, Chem. Commun.
2014, 50, 9284; d) A. Y. Hong, C. D. Vanderwal J. Am. Chem. Soc.
2015, 137, 7306; e) A. Y. Hong, C. D. Vanderwal Tetrahedron, 2016,
in press; doi: 10.1016/j.tet.2016.11.004.
[6] For synthetic studies towards pyridomacrolidin employing a
biomimetic [3+2] nitrone cycloaddition, see: a) N. R. Irlapati, J. E.
Baldwin, R. M. Adlington, G. J. Pritchard, Org. Lett. 2003, 5, 2351; b)
N. R. Irlapati, J. E. Baldwin, R. M. Adlington, G. J. Pritchard, A. R.
Cowley, Tetrahedron, 2006, 62, 4603.
[13] For select reviews on carbene C-H insertion, see: a) H. M. L.
Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103, 286; b) M. P. Doyle,
R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110, 704; c) M. P.
Doyle, M. Ratnikov, Y. Liu, Org. Biomol. Chem. 2011, 9, 4007; d) F.
J. Lombard, M. J. Coster, Org. Biomol. Chem. 2015, 13, 6419; e) A.
Ford, H. Miel, A. Ring, C. N. Slattery, A. R. Maguire, M. A.
McKervey, Chem. Rev., 2015, 115, 9981.
[14] For select reviews on C-H oxidation, see: a) Z. Li, C. He, Eur.
J. Org. Chem. 2006, 4313; b) D. N. Zalatan, J. Du Bois, Top. Curr.
Chem. 2010, 292, 347; c) T. Newhouse, P. S. Baran, Angew. Chem. Int.
Ed. 2011, 50, 3362; d) F. Collet, C. Lescot, P. Dauben, Chem. Soc.
Rev. 2011, 40, 1926; e) M. C. White, Science 2012, 335, 807; f) J. L.
Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res. 2012, 45, 911; g) S.
Chiba, H. Chen, Org. Biomol. Chem. 2014, 12, 4051.
[15] For an example of late-stage C-H functionalization of a
Securinega alkaloid, see: J. He, L. G. Hamann, H. M. L. Davies, R. E.
J. Beckwith, Nature Commun. 2015, 6, 5943.
[16] a) C. S. Schindler, C. R. J. Stephenson, E. M. Carreira, Angew.
Chem. Int. Ed. 2008, 47, 8852; b) S. Diethelm, C. S. Schindler, E. M.
Carreira, Org. Lett. 2010, 12, 3950; c) H. F. Zipfel, E. M. Carreira,
Org. Lett. 2014, 16, 2854.
[ 7 ] For computational studies of biosynthetic [3+2] nitrone
cycloadditions, see: a) E. H. Krenske, A. Patel, K. N. Houk, J. Am.
Chem. Soc. 2013, 135, 17638-17642; b) P. P. Painter, R. P. Pemberton,
B. M. Wong, K. C. Ho, D. J. Tantillo, J. Org. Chem. 2014, 79, 432-
435.
[ 17 ] Optimum yields and ee’s were achieved when
oxazaborolidinone 10 was prepared using neat n-butyldichloroborane,
which was prepared according to: Brown, H. C.; Levy, A. B. J.
Organomet. Chem. 1972, 44, 233. Alternative methods to prepare 10,
either using a toluene solution of n-butyldichloroborane or from n-
butylboronic acid, provided inferior results.
[18] The relative stereochemistry of 12 was assigned based on nOe
correlations in the corresponding epoxide (see SI for details).
[19] R. Grigg, J. Markandu, Tetrahedron Lett. 1989, 30, 5489.
[20] a) E. Osawa, Y. Tahara, A. Togashi, T. Iizuka, N. Tanaka, T.
Kan, J. Org. Chem. 1982, 47, 1923; b) H. R. Sonawane, N. S. Bellur, J.
R. Ahuja, D. G. Kulkarni, J. Org. Chem. 1991, 56, 1434; c) M.
Kawasumi, N. Kanoh, Y. Iwabuchi, Org. Lett. 2011, 13, 3620; d) S.
Jansone-Popova, J. A. May, Tetrahedron, 2016, 72, 3734.
[8] For selected total syntheses employing related biomimetic 1,3-
dipolar cycloadditions, see: a) B. B. Snider, J. F. Grabowski,
Tetrahedron Lett. 2005, 46, 823; b) B. B. Snider, J. F. Grabowski c) P.
A. Roethle, P. T. Hernandez, D. Trauner, Org. Lett. 2006, 8, 5901; d) B.
Tang, C. D. Bray, G. Pattenden, Tetrahedron Lett. 2006, 47, 6401; e) S.
Nakamura, Y. Sugano, F. Kikuchi, S. Hashimoto, Angew. Chem. Int.
Ed. 2006, 45, 6532; f) B. B. Snider, X. Wu, S. Nakamura, S.
Hashimoto, Org. Lett. 2007, 9, 873; g) Y. Sugano, F. Kikuchi, A. Toita,
S. Nakamura, S. Hashimoto, Chem. Eur. J. 2012, 18, 9682; h) D.
Stichnoth, P. Kölle, T. J. Kimbrough, E. Riedle, R. de Vivie-Riedle, D.
Trauner, Nat. Commun. 2014, 5, 5597; i) S. Strych, G. Journot, R. P.
Pemberton, S. C. Wang, D. J. Tantillo, D. Trauner, Angew. Chem. Int.
Ed. 2015, 54, 5079; j) P. Ellerbrock, N. Armanino, M. K. Ilg, R.
Webster, D. Trauner, Nat. Chem. 2015, 7, 879.
[21] a) K. W. Quasdorf, A. D. Huters, M. W. Lodewyk, D. J.
Tantillo, N. K. Garg, J. Am. Chem. Soc. 2012, 134, 1396; b) E. D.
Styduhar, A. D. Huters, N. A. Weires, N. K. Garg, Angew. Chem. Int.
Ed. 2013, 52, 12422; c) N. A. Weires, E. D. Styduhar, E. L. Baker, N.
K. Garg, J. Am. Chem. Soc. 2014, 136, 14710.
[9] E. J. Corey, T.-P. Loh, Tetrahedron Lett. 1993, 34, 3979.
[10] For select reviews on C-H functionalization, see: a) K. Godulal,
D. Sames, Science 2006, 312, 67; b) H. M. L. Davies, J. R. Manning,
Nature, 2008, 451, 417; c) W. R. Gutekunst, P. S. Baran, Chem. Soc.
Rev. 2011, 40, 1976; d) L. McMurray, F. O’Hara, M. J. Gaunt, Chem.
Soc. Rev. 2011, 40, 1885; e) J. Yamaguchi, A. D. Yamaguchi, K. Itami,
Angew. Chem. Int. Ed. 2012, 51, 8960; f) D. Y.-K. Chen, S. W. Youn,
Chem. Eur. J. 2012, 18, 9452; g) J. Egger, E. M. Carreira, Nat. Prod.
Rep. 2014, 31, 449; h) Y. Qiu, S. Gao, Nat. Prod. Rep. 2016, 33, 562;
i) H. M. L. Davies, D. Morton, J. Org. Chem. 2016, 81, 343.
[11] For selected recent total syntheses employing late-stage C(sp3)-
H functionalizations, see: a) A. Hinman, J. Du Bois, J. Am. Chem. Soc.
2003, 125, 11510; b) A. Bisai, S. P. West, R. Sarpong, J. Am. Chem.
Soc. 2008, 130, 7222; c) K. Chen, P. S. Baran, Nature, 2009, 459, 824;
d) E. M. Stang, M. C. White, Nature Chem. 2009, 1, 547; e) S. Y. Yun,
J.-C. Zheng, D. Lee, J. Am. Chem. Soc. 2009, 131, 8413; f) A. D.
Huters, K. W. Quasdorf, E. D. Styduhar, N. K. Garg, J. Am. Chem.
Soc. 2011, 133, 15797; g) S. Kawamura, H. Chu, J. Felding, P. S.
Baran, Nature, 2016, 532, 90; h) M. E. McCallum, C. M. Rasik, J. L.
Wood, M. K. Brown, J. Am. Chem. Soc. 2016, 138, 2437; i) K. Hung,
M. L. Condakes, T. Morikawa, T. J. Maimone, J. Am. Chem. Soc.
2016, 138, 16616; j) C. Liu, R. Chen, Y. Shen, Z. Liang, Y. Hua, Y.
Zhang, Angew. Chem. Int. Ed. DOI:10.1002/anie.201703803.
[12] For a recent review on late-stage C-H functionalization of drug-
like molecules, see: T. Cernak, K. D. Dykstra, S. Tyagarajan, P.
Vachal, S. W. Krska, Chem. Soc. Rev. 2016, 45, 546.
[22] a) Y. Cui, C. He, Angew. Chem. Int. Ed. 2004, 43, 4210; b) Z.
Li, D. A. Capretto, R. Rahaman, C. He, Angew. Chem. Int. Ed. 2007,
46, 5184.
[23] a) M. Lee, M. S. Sanford, J. Am. Chem. Soc. 2015, 137, 12796;
b) J. M. Howell, K. Feng, J. R. Clark, L. J. Trzepkowski, M. C. White,
J. Am. Chem. Soc. 2015, 137, 14590.
[24] a) Q. Michaudel, G. Journot, A. Regueiro-Ren, A. Goswami, Z.
Guo, T. P. Tully, L. Zou, R. O. Ramabhadran, K. N. Houk, P. S. Baran,
Angew. Chem. Int. Ed. 2014, 53, 12091; b) M. S. Chen, M. C. White,
Science 2007, 318, 783; c) M. A. Bigi, P. Liu, L. Zou, K. N. Houk, M.
C. White, Synlett 2012, 23, 2768; d) P. E. Gormisky, M. C. White, J.
Am. Chem. Soc. 2013, 135, 14052.
[25] For an alternative approach using IR, see: E. N. Bess, R. J.
DeLuca, D. J. Tindall, M. S. Oderinde, J. L. Roizen, J. Du Bois, M. S.
Sigman, J. Am. Chem. Soc. 2014, 136, 5783.
[26] See SI for details.
[27] For selected examples of directed lithiation at sp3 centers in
total synthesis, see Ref 11b and a) T. J. Wilkinson, N. W. Stehle, P.
Beak, Org. Lett. 2000, 2, 155; b) T. A. Johnson, M. D. Curtis, P. Beak,
J. Am. Chem. Soc. 2001, 123, 1004; c) V. H. Vu, F. Louafi, N. Girard,
R. Marion, T. Roisnel, V. Dorcet, J.-P. Hurvois, J. Org. Chem. 2014,
79, 3358; d) A. Varela, L. K. B. Garve, D. Leonori, V. K. Aggarwal,
Angew. Chem. Int. Ed. 2017, 56, 2127.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706273
Angewandte Chemie International Edition
COMMUNICATION
[28] Attempts to trap metallated species directly with carbon-
centered electrophiles (e.g. ethyl haloacetates) failed to deliver the
desired products.
[29] G. E. Keck, J. B. Yates, J. Am. Chem. Soc. 1982, 104, 5829.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706273
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
O
Jonathan M. E. Hughes and James L.
Gleason*
Br
CHO
H
O
HO
N
O
selective
late-stage
functionalization
O
O
5 steps
OH
O
> 99% ee
Page No. – Page No.
N
O
O
Li
key intermediate
(-)-virosaine A (1)
A Concise, Enantioselective Total
Synthesis of (–)-Virosaine A
The core of virosaine A is prepared in 5 short steps via a cycloaddition/organolithium
addition and a nitrone formation/cycloaddition cascade. Late-stage selective
functionalization of an unactivated C-H via directed lithiation enables conversion of the key
intermediate to the natural product.
This article is protected by copyright. All rights reserved.