Total synthesis of verruculogen and fumitremorgin a enabled by ligand-controlled C-H borylation

Article abstract of DOI:10.1021/jacs.5b07154

Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C-H borylation/Chan-Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3-disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals.

Full text of DOI:10.1021/jacs.5b07154

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Total Synthesis of Verruculogen and Fumitremorgin A Enabled by
Ligand-controlled C–H Borylation
Yu Feng,‡ Dane Holte,‡ Jochen Zoller, Shigenobu Umemiya, Leah R. Simke,
and Phil S. Baran*
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Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Supporting Information Placeholder
ester (3), which would ideally be derived from a chiral
and inexpensive starting material, L-tryptophan methyl
ABSTRACT: Verruculogen and fumitremorgin A are
bioactive alkaloids that contain unique eight-
a
O
membered endoperoxide. Although related natural prod-
ucts such as fumitremorgins B and C have been previ-
ously synthesized, we report the first synthesis of the
more complex, endoperoxide-containing members of
this family. A concise route to verruculogen and fu-
mitremorgin A relied not only on a hydroperoxide/indole
hemiaminal cyclization, but also on the ability to access
RO
HO
CO2Me
NH2
N
N
MeO
MeO
H
N
N
H
3
O
Me
Me
O
literature gap:
regioselective
transformation
H
O
Me
Me
fumitremorgin A (1): R = prenyl
: R = H
CO2Me
the
seemingly
simple
starting
material,
6-
verruculogen (2)
methoxytryptophan. An iridium-catalyzed C–H boryla-
tion/Chan–Lam procedure guided by an N-TIPS group
enabled the conversion of a tryptophan derivative into a
6-methoxytryptophan derivative, proving to be a general
way to functionalize the C6 position of an N,C3-
disubstituted indole for the synthesis of indole-
containing natural products and pharmaceuticals.
• Juxtaposition of oxidizing peroxide
and oxidizable π bonds
NH2
H
• Direct route to 6-substituted
tryptophan is unsolved
L-tryptophan
methyl ester
N
H
Figure 1. Retrosynthetic analysis of fumitremorgin A (1)
and verruculogen (2).
ester (Figure 1). To our surprise, a short, scalable, regio-
controlled route to 3 had not been reported. Given the
sheer number of tryptamine-based alkaloids with C6
substitution, this is not such an esoteric problem.7 The
only direct route to 3 from a tryptophan derivative in-
volves a lead tetraacetate oxidation to afford a complex
mixture of 5-, 6- and 7-oxytryptophans.6,8 Known routes
to 3 or its derivatives either involve ring synthesis9 or
C3-functionalization of 6-methoxyindole,10,11 which in
turn is formed by ring synthesis11a,11c,12 (see summary of
literature routes in the Supporting Information). To fill
this gap in methodology, C–H functionalization logic13
was applied to the C6 problem.
Fumitremorgin A (1, Figure 1)1 and verruculogen (2)2
stand alone as the only family of alkaloids that harbor an
eight-membered endoperoxide.3 Indeed, of the five-, six-
and eight-membered rings embedded in these hexacyclic
alkaloids, the peroxide bridge is perhaps their most
astounding feature. The juxtaposition of this classic oxi-
dant with two nearby prenyl groups and a readily oxi-
dizable 6-methoxyindole residue add to the allure of this
40-year-old unanswered synthetic puzzle. Aside from
their exotic structure, these polycyclic tryptophan-based
natural products were first identified due to their tremor-
inducing activity in mice,1,2 and the fumitremorgins dis-
play potent activity against multi-drug resistant (MDR)
cancer cell lines4 and also against HIV by a similar
mechanism.5 Although family members such as fu-
mitremorgins B and C as well as verruculogen-TR2 have
been previously synthesized,6 the more complex, en-
doperoxide-containing compounds 1 and 2 have not yet
been made. In this Communication, we present concise
total syntheses of 1 and 2 that hinge upon a scalable so-
lution to the synthesis of 6-substituted tryptophan and a
diastereoselective peroxide-forming ring closure.
The implicit challenge of a strategy seeking to modify
only the C6–H bond is evident given the known propen-
sity of indole to react preferentially at C2,14 C3,14 and
C7.15 In fact, it could be argued that the C6 position is
the most difficult position to directly functionalize on an
indole, even when considering electrophilic aromatic
substitution and directed ortho-metalation strategies.16
C–H borylation was selected as the method of choice to
solve this problem given its demonstrated utility on tryp-
tophan systems14b,15d and recent reports showing ligand
control of regioselectivity.17 Additionally, we postulated
that a large blocking group on the indole nitrogen such
as a TIPS group would be necessary to obtain the de-
sired regioselectivity. Thus, Boc-L-Trp(TIPS)-OMe (4;
Figure 2) was chosen as our starting point in order to
A suitable retrosynthetic precursor to fumitremorgin A
(1) and verruculogen (2) is 6-methoxytryptophan methyl
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shield the C2 and C7 positions from reacting.14a Initially,
reaction of 4 with B2Pin2 under catalytic [Ir(cod)Cl]2 and
1
A. Optimization of ligand-controlled borylation of indoles, demonstrated on tryptophan ester derivative B. Substrate scope: indoles and carbazolesf
PinB
2
3
4
5
6
7
8
9
Dimeric [Ir],
ligand,
HBPin, B2Pin2
CO2Me
CO2Me
CO2Me
5
5
CO2Me
5
Me
6
6
NHBoc
NHBoc PinB
NHBoc
6
N
TIPS
4a
solvent,
temperature, time
N
TIPS
5
N
TIPS
6
N
TIPS
N
TIPS
7
8
L1: 77%, 3:1 C6:C5
L2: 80%, 4:1 C6:C5
L3: 84%, 14:1 C6:C5
L1: 69%, 2:1 C6:C5
L2: 73%, 3:1 C6:C5
L3: 75%, 9:1 C6:C5
Yield
(%)c
[Ir]
[Ir]
Ligand HBPin B2Pin2
(mol%) (equiv.) (equiv.)
Temp. Time
(°C) (h)
Recovered
4 (%)
Solventb
6 : 5d
Entry
Ligand
catalyst (mol%)
OTBS
5
5
1
2
3
4
5
6
7
8
9
[Ir(cod)Cl]2 1.5
L1
L1
L1
L1
L1
L1
L2
L2
L2
L2
L2
L3
L4
L5
L3
3
6
3
6
6
10
10
10
10
10
10
10
10
10
4
0
0.5
0
0
1.0
octane
MTBE
octane
MTBE
80
23
80
23
23
60
60
60
60
60
16
16
16
16
16
24
24
24
24
48
24
24
24
24
5
0
0
2.0 : 1
---
---
78
~100
~100
~100
52
25
7
13
[Ir(cod)OMe]2
3
3.5
1.0
0
6
6
[Ir(cod)Cl]2 1.5
N
TIPS
N
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
3
3
5
5
5
5
5
5
5
5
5
2
0
---
9
TIPS 10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0
1.0 hexanes
4.0 hexanes
4.0 hexanes
4.0 hexanes
hexanes
4.0 hexanes
23
47
64
55
0
66
74
77
0
2.0 : 1
2.7 : 1
3.8 : 1
3.2 : 1
---
3.9 : 1
3.8 : 1
8.0 : 1
---
L1: 65%, 3:2 C6:C5
L2: 79%, 3:1 C6:C5
L3: 81%, 8:1 C6:C5
L1: 66%, 3:2 C6:C5
L2: 74%, 2:1 C6:C5
L3: 76%, 6:1 C6:C5
0.25
0.25
0
2.0
0.25
0.25
0.25
0.25
0.25
0.25
5
CN
0
~100
6
0
6
Br
10 [Ir(cod)OMe]2
11 [Ir(cod)OMe]2
12 [Ir(cod)OMe]2
13 [Ir(cod)OMe]2
14 [Ir(cod)OMe]2
15 [Ir(cod)OMe]2
4.0 hexanes 80e
4.0 hexanes 80e
4.0 hexanes 80e
4.0 hexanes 80e
N
N
TIPS 11g
L1: 49%, 2:1 C6:C5
L2: 51%, 3:1 C6:C5
L3: 54%, 8:1 C6:C5
TIPS 12
No reaction
0
~100
0
0
69
72
6.2 : 1
7.5 : 1
4.0 hexanes 80e 18
Me
6
3
6
3
a All reactions were performed on 0.1 mmol scale. b Dry solvents were used. c Isolated yields represent the sum
of C5- and C6-borylated indole products. d Regioselectivity was determined by crude 1H NMR. e Sealed tube.
7
2
7
2
N
TIPS
N
Ligand structures:
tBu
13
TIPS
14
tBu
Me
Me
L1: 55%, regioisomeric mixture L1: 80%, 2:1 C7:C6
L2: 64%, regioisomeric mixture
L3: 67%, C2,C7-product major
L2: 87%, 2:1 C7:C6
L3: 89%, 5.5:1 C7:C6
Me
Me
Me
R
f Conditions: 5 mol% [Ir(cod)OMe]2, 10 mol% ligand, 0.25
equiv. HBPin, 4 equiv. B2Pin2, hexanes, 80 °C, 24 h; g 50 °C
N
N
N
N
N
N
N
N
L1: dtbpy
L2: Me4phen
L3: phen
L4 (R = H) and L5 (R = Me)
Figure 2. C–H borylation of indole derivatives for the synthesis of C6-substituted tryptophans. A. Optimization of the C–H
borylation reaction on tryptophan derivative 4 in order to preferentially achieve C6-borylation. B. Substrate scope involving
C3-substituted indoles as well as carbazoles.
dtbpy (L1) in octane14a led to low reactivity (5% isolated
yield) and low regioselectivity (2:1) of the desired C6-
borylated tryptophan product 6 (Figure 2A, entry 1).
Employing conditions developed for pyrrole-type het-
eroarenes,14b which involve HBPin under catalytic
[Ir(cod)OMe]2 and dtbpy (L1) in MTBE (specific sol-
vent for tryptophan substrates), none of the desired C6-
borylated product was obtained (entry 2). As such, opti-
mization of reaction conditions was needed. In order to
understand the effect of B2Pin2 versus HBPin, entry 1
was repeated using HBPin instead of B2Pin2 (entry 3),
and entry 3 was repeated using B2Pin2 instead of HBPin
(entry 4), but neither of these conditions provided prod-
uct. A solvent change from MTBE to a nonpolar solvent,
hexanes,14b gratifyingly resulted in 23% isolated yield of
a 2:1 mixture of 6 and 5, with 52% recovered 4 (entry
5). When both HBPin and B2Pin2 were added,18 this led
to an improved 47% isolated yield and 2.7:1 C6:C5 re-
gioselectivity (entry 6). Judging that dtbpy (L1) has
reached its limit in terms of regioselectivity, the ligand
was changed. An immediate effect was observed when
using tetramethylphenanthroline (Me4phen; L2),19
whereby 64% isolated yield of a 3.8:1 mixture of 6 and 5
was obtained (entry 7). Eliminating HBPin led to lower
yield (entry 8), whereas removing B2Pin2 was detri-
mental to the reaction (entry 9). Although a longer reac-
tion time did not improve the reaction (entry 10), slight-
ly higher temperatures led to 100% conversion (74%
isolated yield) for the first time (entry 11). Using these
optimized conditions of 5 mol% [Ir(cod)OMe]2, 10
mol% ligand, 0.25 equiv. HBPin, and 4.0 equiv. B2Pin2
in hexanes at 80 °C in a sealed tube for 24 h, a further
ligand screen was conducted (entries 12–14). Out of
these, phenanthroline (phen; L3) was the most effective,
resulting in 77% isolated yield and 8.0:1 C6:C5 regiose-
lectivity (entry 12). Since reduction of catalyst loading
to 2 mol% slightly decreased the yield (entry 15), the
conditions from entry 12 were retained.
Although this optimization was sufficient for the initial
goal of generating 6-substituted tryptophans, a substrate
screen was performed to examine the scope of N,C3-
disubstituted indole substrates that can undergo C6–H
borylation (Figure 2B). Re-screening ligands L1–L3 for
every substrate revealed that phen (L3) was indeed the
best ligand for this transformation. Both C3-substituted
and C2,C3-disubstituted indoles were viable substrates
(7–10), however, sensitive functional groups such as a
primary bromide (as in 12) were not tolerated. Of note,
reaction of desilylated 4 (i.e., Boc-L-Trp-OMe) only led
to small amounts of C2- and C7-borylated products (not
shown), indicating the importance of the TIPS
group.15c,15d As an extension of this indole reaction
methodology, N-TIPS-carbazole (13) was reacted to give
C2,C7-bis-borylated product, and C3-ethylated carba-
zole 14 provided C7-monoborylated product.
With this enabling method in hand, the total synthesis
of fumitremorgin A (1) and verruculogen (2) from inex-
pensive L-tryptophan became a more realistic endeavor
since decagram quantities of 3 were now accessible.
This undertaking, however, was not without further chal-
lenges (Figure 3A).20 Thus, a variety of dihydro- and
tetrahydro-β-carbolines represented by the general struc-
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ize a late-stage oxidation that mimics the biosynthetic
ture 15 were subjected to oxidants in an attempt to real-
1
A. Failed attempts at the late-stage oxidation of indoles 15
B. Intermediates obtained when forging the eight-membered endoperoxide
O
O
[O]
2
3
4
5
6
7
8
H
H
H
R4
R4
N
O
N
late-stage
biomimetic oxidation
N
N
N
N
R1
R3
MeO
R1
R3
[O]
MeO
H
H
N
N
N
R2
15 Me
N
H
O
O
8 substrates
>70 reactions
Me
Me
Me
Me
Me
Me
O
Me
Me
O
H
O
R1 = H, OMe
R2 = H, prenyl
Me
O
Me
Me
Me
Me
R3 = CO2Me, diketopiperazine
EtO
16
17
18
R4 = H, Ac, Pro-Fmoc, diketopiperazine
C. Successful endoperoxide formation on model substrates
CO2Me
NAc
CO2Me
NAc
9
Me
CHO
Me 20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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59
60
R
R
N
H
N
O
BF3•OEt2, 4Å MS,
DCE, 15 min
Me
Me
Me
Me
HOO
O
H
For 19a: rt (42%)
For 19b: 0 °C (23%)
Me
Me
21a: R = H
21b: R = OMe
19a: R = H
19b: R = OMe
X-ray of 19a
X-ray of 21a
D. First total synthesis of verruculogen (2) and fumitremorgin A (1)a
O
b. [Ir],
B2Pin2;
c. HCl
d. TBAF
e. 24
OMe
CO2Me
CO2Me
CO2Me
then
[Cu], O2,
MeOH
5
a. TIPS-Cl
NH
NHBoc
NHBoc
MeO
NHBoc
MeO
6
N
N
TIPS
4
(65%,
8:1 C6:C5)
[one pot]
[gram scale]
N
(45 %
overall,
2:1 dr)
N
H
(89 %)
H
Commercially available
TIPS
23
Me
Me 25
Boc-L-Trp-OMe (22)
TBDPSOO
Me
f. Cl
R
N
TBDPSOO
CHO
CHO
(87%)
24
Me Me
Me 20
O
H
(26; R = Fmoc)
O
O
O
O
N
HO
RO
HO
HO
N
O
N
OMe
H
N
O
R
N
g. ZrCl4,
PhNO
h. HNEt2
j. TBAF
k. 20
N
N
N
MeO
MeO
MeO
MeO
i. OsO4
H
H
H
N
H
N
H
N
H
N
O
O
(30 %
overall)
(79 %)
(69 %
overall)
Me
Me
Me
Me
Me
Me
Me
O
H
TBDPSOO
TBDPSOO
TBDPSOO
O
[single
diastereomer]
Me
2: R = H
1: R = prenyl
Me
29
28
27
Me
l. prenyl bromide (95%)
aReagents and conditions: (a) LiHMDS, TIPS-Cl, THF, –78 °C (89%); (b) Ir[(cod)OMe]2 (5 mol %), phenanthroline (10 mol%), HBPin (0.25 equiv), B2Pin2 (4.0
equiv), hexanes, 80 °C, 24 h; then Cu(OAc)2, Et3N, MeOH, O2, 23 °C, 24 h (65%, 8:1 C6:C5); (c) 3 N HCl, MeOH, 60 °C; (d) 1 M TBAF, THF (91% over 2 steps);
(e) 24, 4Å MS, CHCl3, 0 °C, 1 h; then TFA (10 mol%), 0 °C, 24 h (49%, 2:1 dr desired:undesired); (f) 26, CH2Cl2, sat. aq. NaHCO3 (87%); (g) PhNO, ZrCl4, CH2Cl2,
0 °C (76%); (h) Et2NH, THF, 40 °C (91%); (i) OsO4 (2.5% in tBuOH), N-methylmorpholine N-oxide (50% in H2O), MeCN:acetone:H2O (2:2:1) (79%); (j) 1 M TBAF,
THF, AcOH, DMF, 0 °C; (k) 20, 4Å MS, BF3•OEt2, DCE, –20 °C (30% over 2 steps); (l) prenyl bromide, Bu2SnO, Bu4NI, DCE, 23 °C, 17 h (95%).
Figure 3. Total synthesis of verruculogen (2) and fumitremorgin A (1). A. Failed attempts at directly oxidizing the indole
core 15. B. Isolated intermediates while attempting to forge the eight-membered endoperoxide. C. Successful eight-
membered endoperoxide formation. D. First total synthesis of verruculogen (2) and fumitremorgin A (1) enabled by indole
C6-borylation/oxidation and eight-membered endoperoxide closure.
pathway to 1 and 2.21 In spite of these efforts, none of
these reactions resulted in the endoperoxide 16. Some of
these reactions, however, encouragingly led to interme-
diates such as 17 and 18 that contain the required perox-
ide and cyclic motifs (Figure 3B). Studying these sys-
tems further, we eventually arrived at hydroperoxides
19a and 19b, whose NH and OOH groups can be cy-
clized onto 3-methyl-2-butenal (20) using BF3•OEt2
(Figure 3C). The presence of the eight-membered en-
doperoxide (as opposed to a seven-membered ether like
18) and the diastereoselectivity of the hemiaminal stere-
ocenter were confirmed by X-ray analysis of the starting
material 19a and the product 21a. Notably, 21a/21b con-
tain the requisite motifs of the oxidizing peroxide bond
and oxidizable π bonds present in alkaloids 1 and 2.
for the Ir-catalyzed borylation, Boc-L-Trp(TIPS)-OMe
(4). As described in Figure 2, 4 was borylated at the C6
position, then immediately subjected to Chan–Lam cou-
pling22 with methanol in one pot to give 23 in 65% yield
and with 8:1 C6:C5 selectivity. Deprotections with HCl
and TBAF led to 6-methoxytryptophan methyl ester (3;
not shown) in 91% yield from 23. Pictet–Spengler reac-
tion with TBDPS-protected peroxy-aldehyde 24 (see the
Supporting Information for its preparation from 20) led
to tricyclic peroxide 25 in 49% yield (2:1 d.r.). Coupling
with N-Fmoc-L-prolyl chloride (26) then gave 27 in 87%
yield. Late-stage dehydrogenation with ZrCl4/PhNO9d
proved essential as other oxidants such as DDQ failed in
this transformation. Fmoc removal gave pentacycle 28
(69% yield over 2 steps), followed by a chemoselective
dihydroxylation with OsO4 to give 29 (79% yield).6
Treatment with TBAF allowed the removal of the
TBDPS group, followed by the crucial endoperoxide-
forming cyclization with aldehyde 20 to give verrucu-
logen (2) in 30% yield over 2 steps. It is of note that this
This groundwork ultimately paved the way to the first
total synthesis of fumitremorgin A (1) and verruculogen
(2; Figure 3D). Commercially available Boc-L-Trp-OMe
(22) was protected with TIPS-Cl to give the precursor
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(3) Liu, D.-Z.; Liu, J.-K. Nat. Prod. Bioprospect. 2013, 3, 161.
final annulation reaction was achieved with complete
diastereoselectivity. Finally, prenylation of 2 using
prenyl bromide, much like the biosynthetic pathway
with prenyl pyrophosphate,21 led to fumitremorgin A (1)
in 95% yield.
(4) (a) Rabindran, S. K.; Ross, D. D.; Doyle, L. A.; Yang, W.;
Greenberger, L. M. Cancer Res. 2000, 60, 47; (b) Allen, J. D.;
van Loevezijn, A.; Lakhai, J. M.; van der Valk, M.; van
Tellingen, O.; Reid, G.; Schellens, J. H. M.; Koomen, G.-J.;
Schinkel, A. H. Mol. Cancer Ther. 2002, 1, 417.
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to, Y.; Akiyama, S.-I.; Baba, M. Mol. Pharm. 2003, 63, 65.
(6) For a review of the synthesis of fumitremorgins and verrucu-
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(7) (a) Williams, R. M.; Stocking, E. M.; Sanz-Cervera, J. F. Top.
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Ihara, M. Nat. Prod. Rep. 1998, 15, 327; (d) Ishikura, M.;
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Pharm. Bull. 1984, 32, 2544.
(9) (a) Gan, T.; Liu, R.; Yu, P.; Zhao, S.; Cook, J. M. J. Org.
Chem. 1997, 62, 9298; (b) Ma, C.; Liu, X.; Li, X.; Flippen-
Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66,
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(10) Although 6-methoxyindole is commercially available, it is
costly ($306/gram) and is significantly more expensive than
L-tryptophan methyl ester ($5.26/gram); 6-hydroxyindole is
not much cheaper ($240/gram). [Sigma-Aldrich 2015 prices]
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Bergmann, E. D.; Hoffmann, E. J. Chem. Soc. 1962, 2827; (c)
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(13) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40,
1976.
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4
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6
7
8
The longstanding challenge posed by the peroxide-
containing alkaloids,23 verruculogen (2) and fu-
mitremorgin A (1), has thus been put to rest in 11 and 12
steps, respectively, starting from a commercially availa-
ble tryptophan derivative. The enabling regioselective
C–H borylation of the remote C6 position of tryptophan
is a forceful reminder of the simplifying power of such
disconnections.24 One potential application of this work
is the synthesis of valuable unnatural amino acids
through C–H borylation and subsequent derivatiza-
tion.15d Lastly, this method was conducted on a variety
of related indole systems and, not surprisingly, has al-
ready been field-tested on decagram scale at Novartis for
incorporation into a medicinal chemistry program.25
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
analytical data (1H and 13C NMR, MS) for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
E-mail: pbaran@scripps.edu (P.S.B.).
Notes
The authors declare no competing financial interest.
Author Contributions
‡These authors contributed equally to this paper.
(14) (a) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura,
N. Tetrahedron Lett. 2002, 43, 5649; (b) Kallepalli, V. A.;
Shi, F.; Paul, S.; Onyeozili, E. N.; Maleczka, R. E.; Smith, M.
R. J. Org. Chem. 2009, 74, 9199; (c) Kawamorita, S.; Ohm-
iya, H.; Sawamura, M. J. Org. Chem. 2010, 75, 3855.
(15) (a) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.;
Maleczka, R. E.; Smith, M. R. J. Am. Chem. Soc. 2006, 128,
15552; (b) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J.
Am. Chem. Soc. 2010, 132, 4068; (c) Homer, J. A.; Sperry, J.
Tetrahedron Lett. 2014, 55, 5798; (d) Loach, R. P.; Fenton,
O. S.; Amaike, K.; Siegel, D. S.; Ozkal, E.; Movassaghi, M. J.
Org. Chem. 2014, 79, 11254.
(16) Ishihara, Y.; Montero, A.; Baran, P. S. The Portable Chem-
ist’s Consultant: A Survival Guide for Discovery, Process,
and Radiolabeling. Apple Publishing Group: Cupertino, 2015.
(17) Saito, Y.; Segawa, Y.; Itami, K. J. Am. Chem. Soc. 2015, 137,
5193.
(18) (a) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.;
Miyaura, N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
14263; (b) Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.;
Krska, S. W.; Maleczka, R. E.; Smith, M. R. J. Am. Chem.
Soc. 2013, 135, 7572.
(19) (a) Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2012,
134, 12422; (b) Larsen, M. A.; Hartwig, J. F. J. Am. Chem.
Soc. 2014, 136, 4287.
ACKNOWLEDGMENT
Financial support for this work was provided by
NIH/NIGMS (GM-073949), NSF (predoctoral fellowship
to D. H.), DAAD (predoctoral fellowship to J. Z.) and JSPS
(postdoctoral fellowship to S. U.). The authors thank Prof.
A. L. Rheingold and Dr. C. E. Moore for X-ray crystallo-
graphic analysis, Dr. W. Gutekunst for assistance in the
early phases of this project, and Dr. Y. Ishihara for assis-
tance in the preparation of this manuscript.
REFERENCES
(1) Isolation and/or structural determination of fumitremorgin A
(1): (a) Yamazaki, M.; Suzuki, S.; Miyaki, K. Chem. Pharm.
Bull. 1971, 19, 1739; (b) Yamazaki, M.; Fujimoto, H.; Kawa-
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(2) Isolation and/or structural determination of verruculogen (2):
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(20) Holte, D. Part I. Synthetic studies in sesquiterpenes; Part II.
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(21) Mundt, K.; Wollinsky, B.; Ruan, H.-L.; Zhu, T.; Li, S.-M.
(24) Fischer, D. F.; Sarpong, R. J. Am. Chem. Soc. 2010, 132,
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(22) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am.
Chem. Soc. 2010, 132, 1202.
(23) For recent syntheses of peroxide-containing terpenes, see: (a)
Cook, S. P. Synlett 2014, 25, 751; (b) Hu, X.; Maimone, T. J.
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5926.
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(25) Personal communication with Dr. Tetsuo Uno at the Ge-
nomics Institute of the Novartis Research Foundation.
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Graphical abstract
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Me
O
N
MeO2C
MeO2C
O
HO
NHBoc
NR
NH2
N
O
Me
MeO
H
NH
N
[8 steps]
Me
Me
O
H
6
6
O
Me
H
OMe
Me
fumitremorgin A
[40-year unanswered challenge]
[decagram-scale C–H activation @ C6]
[stereocontrolled peroxide synthesis]
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