Total Synthesis of (-)-Chromodorolide B by a Computationally-Guided Radical Addition/Cyclization/Fragmentation Cascade

Article abstract of DOI:10.1021/jacs.7b13799

The first total synthesis of a chromodorolide marine diterpenoid is described. The core of the diterpenoid is constructed by a bimolecular radical addition/cyclization/fragmentation cascade that unites two complex fragments and forms two C-C bonds and four contiguous stereogenic centers of (-)-chromodorolide B in a single step. This coupling step is initiated by visible-light photocatalytic fragmentation of a redox-active ester, which can be accomplished in the presence of an iridium or a less-precious electron-rich dicyanobenzene photocatalyst, and employs equimolar amounts of the two addends. Computational studies guided the development of this central step of the synthesis and provide insight into the origin of the observed stereoselectivity.

Full text of DOI:10.1021/jacs.7b13799

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Article
Total Synthesis of (–)-Chromodorolide B By a Computationally-
Guided Radical Addition/Cyclization/Fragmentation Cascade
Daniel Tao, Yuriy Slutskyy, Mikko Muuronen, Alexander Le, Philipp Kohler, and Larry E. Overman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13799 • Publication Date (Web): 07 Feb 2018
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Journal of the American Chemical Society
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Total Synthesis of ( )-Chromodorolide B By a Computationally-
Guided Radical Addition/Cyclization/Fragmentation Cascade
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Daniel J. Tao, Yuriy Slutskyy, Mikko Muuronen, Alexander Le, Philipp Kohler, and Larry E. Overman*
†Department of Chemistry, University of California, Irvine, California 92697-2025
ABSTRACT:
The first total synthesis of a chromodorolide marine diterpenoid is described. The core of the diterpenoid is constructed by a
bimolecular radical addition/cyclization/fragmentation cascade that unites two complex fragments and forms two C-C bonds and four con-
tiguous stereogenic centers of (-)-chromodorolide B in a single step. This coupling step is initiated by visible-light photocatalytic fragmentation
of a redox-active ester, which can be accomplished in the presence of an iridium or a less-precious electron-rich dicyanobenzene photocatalyst,
and employs equimolar amounts of the two addends. Computational studies guided the development of this central step of the synthesis and
provide insight into the origin of the observed stereoselectivity.
10
nudibranchs potentially feed. Chromodorolide A ( ) was first re-
INTRODUCTION
ported in 1989 by Anderson and Clardy, with its novel structure be-
ing revealed by X-ray crystallography.17a Two years later these work-
ers described a second diterpenoid found in skin extracts of the trop-
ical dorid nudibranch Chromodoris cavae, which showed a high fre-
quency carbonyl stretching band at 1812 cm–1 in its IR spectrum.17b
Detailed analyses of H and C NMR spectra indicated that this
11
diterpenoid, chromodorolide B ( ), had the same chromodorane
carbon skeleton as chromodorolide A, but the bridging lactone ring
Convergent strategies where advanced fragments of a target
molecule are prepared in parallel and joined together at the latest
possible stage in a synthesis are nearly always more efficient than lin-
ear strategies.1 A corollary of this fact is the importance of reactions
that are capable of combining complex molecules efficiently with
high regio- and stereoselectivity. Recent investigations have shown
that bimolecular-coupling reactions of tertiary carbon radicals can
unite advanced synthetic fragments of structurally complex natural
products in an efficient fashion.2,3 Cascade reactions in which an in-
termediate produced in a bond-forming reaction propagates to con-
struct additional bonds of a target molecule also typically increase
efficiency in a chemical synthesis.4 Radical cascade reactions, in par-
ticular intramolecular radical cascades, have long played a significant
role in the efficient construction of complex molecules.4,5 Much less
developed are strategies in which a bimolecular radical coupling re-
action initiates a further bond-forming cascade sequence.6 The dis-
covery of such a stereoselective sequence, whose optimization was
guided by computational analysis, led to the first total synthesis of
the marine diterpenoid chromodorolide B and is the subject of this
article.7
1
13
10
11
and , chromo-
in this case was 5-membered. Analogues of
12 14
dorolides C–E ( ) that display different degrees of acetylation
–
of the vicinal hydroxyl substituents were isolated subsequently from
two different marine sponges.18,19 The chromodorolides are the most
structurally intricate of the spongian diterpenoids, with 10 contigu-
ous stereocenters arrayed upon their pentacyclic ring systems. Prior
to the investigations reported in this account, the absolute configu-
ration of the chromodorolides was proposed upon the basis of their
presumed biosynthesis from diterpenoids having the spongian ring
system.20
Modest in vitro antitumor, nematocidal and antimicrobial activities
have been reported for various chromodorolides.17b,18,19a Because of
2
their structural relationship with molecules such as norrisolide ( ),
21,22
3
6
cheloviolene A ( ) and macfarlandin E ( ),
which have pro-
BACKGROUND
nounced effects on the Golgi apparatus, the activity of the chromo-
dorolides on the structure and function of the Golgi apparatus is po-
tentially more significant. In our own investigations of analogues
harboring 2,7-dioxabicyclo[3.2.1]octan-3-one or cis-2,8-dioxabicy-
clo[3.3.0]octan-3-one fragments, we have identified conjugation of
these ring systems with lysine side chains of proteins to form pyrrole
adducts as potentially involved in the biological activities of diterpe-
noids such as those depicted in Figure 1.22 As a result of the little-
studied biological activity of the chromodorolides, and the challenge
apparent in assembling these densely functionalized diterpenoids,
we initiated studies to develop chemical syntheses of the chromo-
dorolides. In this account, we detail the investigations that led to a
concise, stereocontrolled total synthesis of (–)-chromodorolide B
The rearranged spongian diterpenoids are a large and structurally di-
verse family of natural products, which have been isolated largely
from marine sources (Figure 1).8 Distinct members of this group are
characterized by the presence of a hydrophobic unit connected by a
single bond to a highly oxygenated cis-2,8-dioxabicyclo[3.3.0]oc-
9
tan-3-one fragment, as exemplified by dermalactone ( ), norri-
1
10
11
12
2
3
4
solide ( ), cheloviolene A ( ), macfarladin C ( ), or a 2,7-diox-
13
5
abicyclo[3.2.1]octan-3-one fragment as found in aplyviolene ( ),
macfarlandin E ( ), shahamin F ( ), verrielactone ( ), and
12
14
15
6
7
8
16
norrlandin ( ). In chromodorolides A-E (
clic frameworks are appended to an additional oxygenated cyclopen-
-
),17–19 these bicy-
9
10 14
tane ring.
The chromodorolides have been isolated from nudibranchs in the
genus Chromodoris and from encrusting sponges on which these
11
(
).
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Page 2 of 13
Figure 1
1
A. Representative structurally diverse rearranged spongian diterpenes that harbor the cis-2,8-dioxabicyclo[3.3.0]octan-3-one (blue) ring system.
2
O
3
4
5
6
OAc
HO
O
R1O
R2O
AcO
H
O
AcO
H
H
H
O
H
H
H
O
H
O
H
H
O
H
O
O
O
H
H
O
H
H
H
O
O
OAc
O
H
H
7
H
O
H
8
9
H
chromodorolide B (11): R1, R2 = Ac
chromodorolide C (12): R1=H, R2 = Ac
chromodorolide E (14): R1, R2 = H
dermalactone (1)
norrisolide (2)
cheloviolene A (3)
macfarlandin C (4)
10
11
12
13
14
15
16
17
18
19
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21
22
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59
60
B. Representative structurally diverse rearranged spongian diterpenes that harbor the cis-2,7-dioxabicyclo[3.2.1]octan-3-one (red) ring system.
O
O
O
O
O
O
OAc
RO
H
OAc
OH
O
O
O
O
O
O
O
H
H
H
H
O
O
OAc
O
OAc
O
OAc
O
H
OAc
H
OAc
OAc
H
H
H
chromodorolide A (10): R = Ac
chromodorolide D (13): R = H
aplyviolene (5)
macfarlandin E (6)
shahamin F (7)
verrielactone (8)
norrlandin (9)
would occur late in the synthesis, we examined this conversion ini-
tially in a model system harboring an isopropyl group in place of the
hydrindane fragment. cis-Oxabicyclo[3.3.0]octenone was read-
RESULTS AND DISCUSSION
General Synthetic Strategy.
disconnecting the lactone bonds in and to arrive at a common
Retrosynthetically, we envisioned
10 12
23
20
ily assembled from an allenoate precursor by a diastereoselective
phosphine-promoted (3+2) annulation.24 To our surprise, dihy-
15
tetracyclic acid intermediate (Scheme 1). We hypothesized that
both bridged and fused tricyclic frameworks could be prepared from
20
droxylation of took place with high stereoselectivity from the con-
21
cave face to give mainly diol . Other oxidants such as m-chloroper-
oxybenzoic acid or dimethyldioxirane behaved similarly, giving crys-
23
talline epoxide as the predominant product.
studies by the Houk group suggested that the contrasteric selectivity
15
acid
intramolecular lactonization. The cis-2,8-dioxabicyclo[3.3.0]octan-
12
by site-selective oxocarbenium ion formation, followed by
3-one fragment of chromodorolide C ( ) is likely to be accessed
17
25,26a
Computational
most readily, as kinetically favored 5-membered ring closure of
could dominate even if oxocarbenium ion formation were unselec-
tive yet reversible.22 In contrast, to construct the 2,7-dioxabicy-
23,27
20
for dihydroxylation of the enoate arose from torsional effects.
Torsional, electrostatic and steric effects can all influence stereose-
lection in dihydroxylations of cis-bicyclo[3.3.0]octenes, and a more
general discussion of this issue has been published.23
10
clo[3.2.1]octan-3-one fragment found in chromodorolide A ( ) re-
gioselective activation at C-15 would be required to permit less-ki-
16
netically favored lactonization of oxocarbenium ion . The success-
15
ful development of a strategy to form tetracyclic intermediate and
11
its conversion to (–)-chromodorolide B ( ) is detailed in this re-
port.7
RO2C
RO2C
H
Scheme 2
OAc
O
OAc
O
H
H
H
HO
HO
H
dihydroxylation?
H
OR
OR
O
Scheme 1
H
H
O
O
AcO
H
HO
AcO
H
OH
H
H
O
18
19
O
H
O
RO2C
OMe
O
MeO2C
HO
HO
OMe
O
MeO2C
HO
OMe
O
H
H
H
H
H
H
H
OAc
[R = Me]
OsO4, NMO
OAc
H
HO
+
H
t-BuOH/H2O
rt, 87%
Hydrindane (Hyd)
Hydrindane (Hyd)
H
H
i-Pr
O
O
i-Pr
O
i-Pr
O
chromodorolide A (10)
chromodorolide C (12)
92:8
20
21
22
O
[R = Bn]
BnO2C
OMe
H
H
O
O
acetone, rt
(dr> 10:1)
HO
O
H
HO
HO
O
O
OH
H
OAc
OAc
H
HO
HO
AcO
i-Pr
O
16
AcO
AcO
23 (66%)
O
O
O
15
C-16
oxocarbenium
formation
C-15
oxocarbenium
formation
H
H
H
H
H
OR
Hyd
H
Hyd
Hyd
OR
Revised Synthesis Plan: A Bimolecular Radical Addition/Cy-
clization/Fragmentation Cascade.
16
common intermediate
17
15
As installation of the cis-diol
functionality did not appear to be feasible from a cis-oxabicy-
clo[3.3.0]octenone precursor, we turned to a plan wherein the cis-
diol would be incorporated early in the synthetic sequence (Figure
2A). Disconnection of the lactone ring of chromodorolides A or B
Early Studies.
genated bicyclic motif found in envisaged late-stage dihydroxyla-
tion of an alkene precursor (Scheme 2). We expected that oxidation
18
of an intermediate such as would take place from the convex face
Our initial thoughts on accessing the highly oxy-
15
24
series leads to intermediate . Further simplification leads
19
opposite the bulky hydrindane fragment to generate . As this step
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A.
O
11
O
1
2
3
4
AcO
AcO
H
12
16
13
17
O
15
14
8
H
H
1
OAc
9
H
RO
O
OR1
O
CO2H
5
OR1
O
O
R'O2C
H
OR
H
H
OR1
O
5
6
7
8
12
H
O
H
O
O
H
13
14
chromodorolide B (11)
H
H
O
+
8
H
OR2
H
H
O
X
O
HO
O
AcO
H
H
O
9
24
25
26
27
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
H
OAc
H
chromodorolide A (10)
I
MeO2C
OHC
OR
MeO2C
OR
OR1
O
O
B. (X = Cl or SR)
+
H
HO
O
O
RO
H
OR1
O
O
O
H
OR
O
12
29
30
13
O
O
O
X
X
27
H
28
26
O
H
H
O
MeO2C
A
B
O
+
MeO2C
OR
O
OR1
RO
O
H
H
H
OR1
OR
O
31
32
H
O
OR1
H
O
H
H
O
H
A1,3
X
bond
rotation
O
O
O
5-exo
8
–X
X
H
25
O
O
H
O
A1,3 minimized
H
X
O
H
C
B
B'
Figure 2. A. B.
Plan for the proposed synthesis of chromodorolides B and A. Mechanistic analysis of the central radical addition/cycliza-
tion/fragmentation cascade to form pentacyclic intermediate
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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25
.
25
to hydrindene , with the expectation that late-stage hydrogenation
of its double bond would take place from the face opposite the angu-
lar methyl substituent to install the C-9 stereocenter. We were at-
the efficiency of the proposed cascade sequence (Figure 2B). First,
27
would have to correctly set the C-12 and C-13 stereocenters.33,34 Am-
ple precedent existed that this union would take place from the bu-
tenolide face opposite to the alkoxy group to correctly set the C-13
stereocenter.35 Less certain would be the facial selectivity of the re-
A
the Giese reaction to unite acetonide radical with butenolide
25
tracted to a carbon radical-based approach to construct , which we
expected to be compatible with pre-installed oxygen functionalities
at C-11, C-12 and C-17.28,29 The cyclopentane ring of key intermedi-
25
ate , we saw arising in one step from the union of tricyclic ace-
A
action of trisubstituted acetonide radical . To correctly form the C-
26
27 30
sioned the trans-hydrindane acetonide evolving from allylic alco-
tonide carboxylate
and (R)-5-alkoxybutenolide . We envi-
26
hol , which in turn would result from the addition of a vinylic nu-
12 stereocenter, this coupling would have to take place from the ac-
etonide radical face proximal to the vinylic b-substituent. As few C–
C bond-forming reactions of 2,2-dimethyl-1,3-dioxolane trisubsti-
tuted radicals had been described, with both syn- and anti-addition
being observed,36 it was uncertain at the outset from which face rad-
28
29 30
cleophile generated from vinyl iodide and aldehyde . As (S,S)-
3131
29
,
trimethylhydrindanone
and (R,R)-tartaric acid derived acetonide
plan outlined in Figure 2A projects assembling the chromodorolides
27 31
, and
is the obvious precursor of iodide
32
30 32
of aldehyde , the
A
ical intermediate would couple. We took some encouragement
from the report by Renaud that a bulky b-substituent (tert-butyl) fa-
vored bond formation cis to the substituent, although in these prec-
edents the alkene was unsubstituted at its bond-forming terminus.36a
The second step whose stereochemical outcome would be critical is
from three well known enantiopure starting materials:
32
,
.
In the projected cascade sequence,5 chiral acetonide (2,2-dime-
A
thyl-1,3-dioxolane) radical , formed from oxidative decarboxyla-
tion of precursor , would couple with butenolide to generate
B
alkoxyacyl radical which would undergo 5-exo cyclization with the
proximal alkene to generate intermediate (Figure 2B). The radical
B
the 5-exo cyclization of tetracyclic radical intermediate . We ex-
26 27
pected that this conversion would take place as depicted in Figure
2B by a conformation that minimizes destabilizing A1,3 interactions.
As we had most concern about the facial selectivity in the bimo-
lecular radical coupling step, particularly with regard to facial selec-
tivity of the reaction of a trisubstituted acetonide radical, we chose
to examine this aspect of the ACF cascade in a model system having
C
cascade would then be terminated by b-fragmentation of the C–X
bond (X = Cl or SR) of this intermediate to yield pentacyclic product
25
. If successful, the proposed bimolecular radical addition/cycliza-
tion/fragmentation (ACF) cascade would form two C–C bonds and
four contiguous stereocenters of the chromodorolides in a single
step. The stereochemical outcome of two steps would be critical to
a terminal alkyne substituent at the b carbon of the acetonide radical
33
(Scheme 3). Starting with L-arabinose ( ), enantiopure N-acylox-
was prepared in 10 steps by way of the known
35
yphthalimide
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34 37,38
Using a slight modification39 of visible-light
photoredox conditions pioneered by Okada for generating radicals
acetonide alcohol
.
efficiency and enantioinduction. Unfortunately, further variation of
41
1
2
3
4
5
6
reaction temperatures and the use of unsubstituted BINOL ( , X =
40
35
from N-acyloxyphthalimides, the coupling of with 2.2 equiv of
H) led to no appreciable improvements in enantioselectivity or se-
42b
(entries 4–6). Unable to eliminate for-
36
enantiopure (R)-5-L-menthoxybutenolide (
)
line tricyclic lactone in 38% yield. X-ray analysis of confirmed
30b,c gave the crystal-
37
lectivity in forming
37
42a
mation of the trans-decalin product , we examined cyclization of
that the coupling step had taken place as desired.26b The other isola-
ble product, formed in 7% yield, was . H NMR NOE analysis con-
propargylic silane . However, reactions of this precursor gave
in low yield only (e.g., entry 7).47
40 46
43
1
38
firmed that this product formed from coupling of the trisubstituted
acetonide radical from the face opposite to the alkyne substituent,
resulting in the coupled radical being quenched rather than under-
going 5-exo cyclization with the trans-oriented alkyne substituent. In
subsequent studies published elsewhere, the coupling of a broad se-
7
8
9
X
Scheme 4
R
OH
OH
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
39: R = Me
40: R = CH2TMS
X
lection of trisubstituted acetonide radicals harboring b-substituents
was studied both experimentally and computationally.41 The origin
of the observed syn stereoselection for the addition of the trisubsti-
50 mol %
lewis acid
CH2Cl2
41
(50 mol %)
X = Cl or H
35
36
tuted radical formed from to butenolides such as is ascribed to
destabilizing non-covalent interactions between the alkynyl substit-
uent and silyl-protected hydroxymethyl substituent in the transition
Cl
or
Cl
+
state.36a,41 Since the b-substituent of the trisubstituted radical (Fig-
A
H
H
42b
H
42a
43
ure 2B) in the proposed ACF cascade is certainly larger than an al-
kyne, we were encouraged to proceed ahead to assemble the frag-
ments to examine this pivotal step in our synthesis plan.
yielda (ratio 42a:42b)b
35% (1.0:3.0)
<5% (ND)
31, %eec
entry
Lewis acid
SbCl5
TiCl4
R
X
T (ºC)
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Me
Cl
Cl
Cl
Cl
Cl
H
-78
-78
-78
-90
-50
-78
-78
0%
ND
SnCl4
SnCl4
SnCl4
SnCl4
55% (1.0:1.5)
53% (1.0:1.1)
12% (0:1.0)
18%
20%
ND
Scheme 3
TBSO
O
TBSO
O
HO
O
53% (1.1:1.0)
23% (0:1.0)
13%
ND
5 steps
5 steps
SnCl4
HO
O
CH2TMS
Cl
O
O
ONPhth
aIsolated combined yield of 42a and 42b. bDetermined by 1H NMR integration of the crude reaction
mixture. cHydrindanone 31 was obtained by ozonolysis of 42b or 43. Enantioselective HPLC
analysis of a hydrazone derivative was used to establish enantiopurity of 31.37
HO
OH
HO
L-arabinose (33)
34
35
O-L-Men
The scalable route we finally developed to provide (S,S)-trans-
hydrindanone is summarized in Scheme 5. This sequence hinged
O
O
L
-Men-O
O
31
TBSO
O
O-
L-Men
H
H
36 (2.2 equiv)
on stereospecific reductive transposition of an allylic alcohol inter-
mediate to set the thermodynamically disfavored trans ring fusion of
31 48,49
O
O
H
+
O
OTBS
O
O
1 mol % [Ru(bpy)3](PF6)2
Hantzsch ester, i-Pr2NEt
CH2Cl2, rt, blue LEDs
.
The preparation begins with commercially available (S)-ene-
44 50
O
dione , which alternatively can be obtained reliably in 98% ee on
>20 g scales in two steps from 2-methylcyclopentane-1,3-dione.51
37 (38%)
38 (7%)
44
Selective ketalization of , followed by stereoselective 1,2-reduc-
45
tion of the enone provided allylic alcohol in 98% yield after a sim-
ple distillation. A number of approaches were investigated to convert
Synthesis of (S,S)-Trimethylhydrindanone 31 and Vinyl Iodide
31
29.
Several syntheses of enantioenriched trans-hydrindanone
have been reported.31 We initially examined the short route reported
by Granger and Snapper to prepare this ketone from 2-methylcyclo-
penten-2-one and prenylmagnesium bromide.31b After slight modifi-
cation, this approach provided initial quantities of (S,S)-trans-hy-
45
with o-nitrobenzenesulfonylhydrazine followed by
48
to the desired trans-hydrindene ketal . Treat-
allylic alcohol
45
warming of the reaction to room temperature, as described by My-
ment of
52
48
ers, led to the desired trans-fused ketal as a minor component of
a complex mixture of product. Unable to perform the desired trans-
formation in a single step, we turned to examine Tsuji’s palladium-
31
drindanone for our early studies. However, this route was deemed
31
impractical for a large-scale preparation of because of its modest
overall yield (20%) and scalability issues in several steps.37
We turned to examine a biomimetically inspired polyene cycliza-
mediated stereospecific reductive transpositions of b-allylic car-
49
bonates and formates. Carbonate readily underwent the desired
46
reductive transposition upon treatment with Pd(acac)2, (n-Bu)3P,
48
and finely crushed NH4HCO2 to provide trans-hydrindene ketal
31 42
tion route to trans-hydrindanone . Based on the reports from the
Yamamoto43 and Corey44 laboratories, we conjectured that dienyne
37
, obtained in two steps from geranyl chloride, would undergo en-
39
antioselective proton-initiated polyene cyclization upon exposure to
a chiral BINOL derivative in the presence of a strong Lewis acid,
in 77% yield. The choice of phosphine was critical to the success of
the reaction, as the use of other phosphines (Cy3P, t-Bu3P, Ph3P) led
largely to recovery of starting carbonate. The more commonly used
49 47
45
(Scheme 4). In our
42b
hands, subjection of dienyne to the reaction conditions reported
forming the alkylidene trans-hydrindane
39
allylic formate,
, was found to be inert under our reaction condi-
tions. Stereoselective cyclopropanation of the trisubstituted double
48
by Corey,44 using SbCl5 in combination with (R)-o,o’-dichloro-
bond of was achieved by reaction with diethylzinc and chloroio-
domethane,53 which after acidic workup delivered cyclopropyl ke-
41
BINOL (X = Cl) led to a 1:3 mixture of two regioisomeric bicy-
42a 42b
clic products
mediated cleavage of the exocyclic double bond of
and
in 35% combined yield (entry 1). Ozone-
42b
49
tone in 92% yield. It was important to use chloroiodomethane in
this reaction, as use of diiodomethane led largely to recovery of the
provided ra-
cemic trans-hydrindanone . Examination of other Lewis acids (en-
31
tries 2 and 3) revealed SnCl4 to be superior in terms of reaction
49
starting alkene. Hydrogenolysis of cyclopropane
using PtO2 in
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
acetic acid,54 followed by PCC oxidation of the resulting secondary
31
This sequence delivered (S,S)-trans-hydrindanone (98% ee) in 7
intermediate formed from vinyl iodide with aldehyde provided
low yields (<20% yields) of adducts as an equimolar mixture of al-
lylic alcohol epimers. We turned to the use of the Nozaki-Hiyama-
Kishi (NHK reaction) to achieve the desired fragment-coupling
29
30
1
2
3
4
alcohol gave trans-hydrindanone
in 88% yield over two steps.
31
44
steps and 59% overall yield from enone . Using the method of Bar-
ton, hydrindanone
2931a
55
was converted to the known vinyl iodide
(Scheme 7).60 Conditions that had been employed earlier to couple
31
in 78% yield. The sequence summarized in Scheme 5 readily
61
this iodide led to the formation of adduct in low yields and 3:1
52
stereoselectivity. To accelerate the rate of NHK coupling and im-
5
29
provided 7 g of the light-sensitive iodide in a single pass.
6
7
8
9
prove stereoselection, we elected to employ the oxazoline ligands
62
Scheme 5
53
developed by the Kishi group. To our delight, use of ligand (R)-
DMAP, MeOC(O)Cl
CH2Cl2, 35 ºC, 96%
O
52
resulted in the formation of adduct
as a single diastereomer in
O
1.ethylene glycol, TsOH
benzene, reflux
O
for 46
28% yield. The identical reaction using the enantiomeric ligand, led
to inversion of diastereoselectivity, giving the allylic alcohol epimer
in 18% yield and 4:1 dr. Upon further optimization of the reaction
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
or
2. LiAlH4, Et2O, 0 ºC
98% over 2 steps
O
HO
HCO2H, Ac2O
pyr, rt, 99%
for 47
44
45
53
with ligand (R)- , we discovered that employing the sensitive alde-
30
hyde in a slight excess (1.6 equiv) and performing the reaction on
a larger scale (3 mmol) led to the formation of the desired product
Pd(acac)2 (20 mol %)
Et2Zn, ClCH2I
CH2Cl2, rt
O
O
O
O
n-Bu3P (20 mol %)
63
NH4HCO2, benzene, rt
52
in 66% isolated yield.
then
HCl, MeOH
92%
XO
77% from 46
H
46: X = CO2Me
47: X = C(O)H
48
Scheme 7
MeO2C
H
OBn
I
O
HO
OBn
NiCl2 (10 mol %)
CrCl2, Et3N
MeO2C
O
O
I
O
1. PtO2 (20 mol %)
H2, AcOH, rt
1.H2NNH2, Et3N
EtOH, reflux
O
THF
15–36% (3:1 dr)
O
OHC
H
2. PCC, CH2Cl2, rt
88% over 2 steps
2. I2, TMG
THF, 90 ºC
H
H
H
H
29
(1 equiv)
30
(1 equiv)
52
78% over 2 steps
49
31
29
deviation from above
yield (dr)
Synthesis of Aldehyde 30 and its Coupling with a trans-Hydrin-
dene Nucleophile. 29
addition of (R)-53
28% (>20:1)
66% (>20:1)
With streamlined access to vinyl iodide
hand, we turned our attention to the synthesis of the aldehyde cou-
30
in
O
Me
NHMs
(R)-53
addition of (R)-53
30 (1.6 equiv)
N
pling partner (Scheme 6). The sequence began with tartrate-de-
32
i-Pr
rived acetonide , which was desymmetrized by LDA-mediated al-
50
kylation with BOM-Cl, as reported by Crich, to give benzyl ether
in 46% yield.32,56,57 Selective reduction of the less hindered ester
50 51
Having forged all of the C-C bonds of the radical cascade pre-
cursor, efforts were focused on allylic transposition of the alcohol
group of with DIBALH provided primary alcohol in 45% yield
functionality to a heteroatom capable of undergoing radical b-cleav-
age, while setting the required E-configuration of the exocyclic dou-
ble bond of the product (Scheme 8). We first investigated the possi-
bility of performing a [3,3]-sigmatropic rearrangement to an allylic
52
50
along with 36% of recovered starting material . All our attempts to
improve the efficiency of this conversion were unsuccessful, as the
use of alternate reductants (e.g., LiAlH4, Red-Al) or extra equiva-
lents of DIBALH led to complex mixtures of various reduction prod-
thiocarbonate.64,65 To this end, deprotonation of alcohol
with
51
30
could be
ucts. Oxidation of primary alcohol
achieved by a number of conventional methods; however, purifica-
30
to aldehyde
KHMDS at -78 ºC, followed by addition of phenyl chlorothionofor-
54
mate ( ) resulted in thioacylation and spontaneous [3,3]-sigma-
tropic rearrangement upon warming to room temperature to give al-
55
lylic thiocarbonate as a single stereoisomer in 68% yield. How-
ever, we were unable to selectively cleave the methyl ester group of
tion of proved to be challenging. We ultimately elected to oxidize
51
alcohol with the Dess-Martin reagent (DMP) in CH2Cl2 and fil-
ter the resulting mixture with n-hexanes over Celite to remove the
30
insoluble byproducts and give aldehyde in 93% yield and high pu-
55
in the presence of the sensitive thiocarbonate functionality under
58
rity. As a result of its unexpected instability, aldehyde was used
30
a variety of classical saponification, SN2 demethylation,66 or other
non-basic methods.67 To circumvent this selectivity issue, the order
52
of transformations was reversed. Saponification of methyl ester
immediately in the ensuing coupling step (vide infra).59 This proved
30
to be a short and scalable approach to aldehyde coupling partner
with >8 g being readily prepared in a single pass, albeit in modest
overall yield.
,
and subsequent esterification with N-hydroxyphthalimide (NHP)
56
provided the crystalline NHP ester in 69% yield, whose structure
was confirmed by single-crystal X-ray analysis.26c Unfortunately, sub-
Scheme 6
56
jection of allylic alcohol to the reaction conditions that were suc-
OBn
LDA, BOM-Cl
THF/HMPA
MeO2C
O
O
MeO2C
MeO2C
DIBALH, THF
52
N-acyloxyphthalimide functionality.68 Deprotonation of
cessful for thioacylation of led to immediate decomposition of the
56
O
-78 ºC to 0ºC
-78 ºC to 0 ºC
with
MeO2C
O
46%
45%
54
LiHMDS or NaHMDS followed by reaction with led to recovery
56
of the starting material, whereas reaction of with other potassium
bases uniformly resulted in instantaneous decomposition. Unable to
56
selectively activate hindered allylic alcohol for thioacylation with
54
phenyl chlorothionoformate ( ), we turned to investigating allylic
32
50
OBn
OBn
MeO2C
OHC
DMP
MeO2C
HO
O
O
CH2Cl2, rt
93%
O
O
OH
Cl transformations. Reaction of alcohol with 2 equiv of
® 56
51
30
SOCl2 in a 10:1 mixture of Et2O/pyridine at –40 ºC induced the de-
sired suprafacial rearrangement to deliver crystalline N-
Next, we focused on uniting the trans-hydrindene and aldehyde
fragments. Early attempts to directly couple the vinyllithium
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Journal of the American Chemical Society
Page 6 of 13
60
57 69
57
acetonide radical formed from . In contrast, tetracyclic lactone
acyloxyphthalimide radical precursor , whose structure was con-
firmed by single-crystal X-ray analysis,26d in 62% yield on gram-scale.
This stereoselective conversion could also be accomplished on the
product of the NHK coupling , followed by saponification to the
corresponding carboxylic acid. However, in contrast to NHP ester
57
, the non-crystalline acid produced was difficult to purify.
1
2
3
4
57
arose from coupling of the dioxolane radical with acceptor anti to
the vicinal hydrophobic fragment. The resulting R configuration at
C-12 prevents ensuing 5-exo cyclization.70
52
Although the initial coupling of dioxolane radical to butenolide
58
occurred with 7.6:1 diastereoselectivity favoring the desired ad-
5
6
7
8
duct, minimizing premature reduction of the a-acyl radical interme-
61
diate leading to the significant byproduct, lactone , would be im-
portant for optimizing the efficiency of the ACF cascade. Formation
Scheme 8
MeO2C
S
RO2C
H
OBn
OBn
H
O
O
Cl
OPh 54
KHMDS
HO
H
61
duced in the Giese coupling step by either single-electron transfer
of product
indicated that quenching of the a-acyl radical pro-
9
O
O
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
THF, −78 ºC to rt
S
68%
(SET) to form an enolate followed by protonation or by hydrogen
59
OPh
H
atom abstraction from Hantzsch ester was competitive with 5-exo
O
52
cyclization.39 In an attempt to minimize the SET pathway,39 i-Pr2NEt
was omitted from the reaction mixture, significantly decreasing the
55: R = Me
1. KOH, MeOH/H2O, 50 ºC
2. N-hydroxyphthalimide
DCC, DMAP, THF, rt
69% over 2 steps
X
R = H
61
yield of product to 14% (entry 2). To further reduce premature
quenching of the radical intermediate, we performed the reaction at
higher dilution, resulting in a further decrease in the yield of product
PhthNO2C
OBn
H
O
HO
SOCl2, pyr
54, base
61
to 3% (entry 3). However, these more dilute conditions also re-
sulted in less efficient coupling of the dioxolane radical and bu-
58 62
O
Et2O, −40 ºC
X
62%
tenolide
leading to lower yields of pentacyclic products and
. To attenuate hydrogen atom abstraction by the a-acyl radical in
reactions carried out at higher concentration, we employed 4,4-
59
H
56
PhthNO2C
H
PhthNO2C
OBn
OBn
63
H
O
O
O
O
dideuterio analogue of Hantzsch ester
(entry 4). Under these
62 63
creased to 70%, with tetracyclic lactone being formed in only 6%
S
Cl
conditions, the combined yield of cyclization products and in-
OPh
61
H
H
O
57
yield.
Having attenuated premature quenching of the a-acyl radical in-
termediate, we sought to explore the effects of temperature, solvent,
Initial Exploration of the ACF Radical Cascade.
57
Exposure of N-
to standard reductive photoredox reaction
acyloxyphthalimide
58
and structural modifications of butenolide on diastereoselection
conditions39 in the presence of 4 equiv of enantioenriched (89% ee)
of the 5-exo cyclization. As illustrated in Scheme 9, the major penta-
62
cyclic product arose from cyclization taking place by a transition
30a,c
58
(R)-5-methoxybutenolide (
)
gave a mixture of four products
accounting for 95% of the mass balance (Scheme 9, entry 1). Penta-
62 63
D
state related to radical conformer , not by way of a transition struc-
ture related to conformer . Varying the temperature of the reaction
cyclic products (35%) and (25%) arose from the desired ACF
62
were based on detailed analyses of their NMR spectra. Particu-
E
cascade reaction. Initial structural assignments of products and
63
(0 ºC to 40 ºC) did not have a significant impact on the ratio of the
62
epimeric products and . Likewise, using butenolides harboring
acetoxy or menthoxy substituents at the acetal stereocenter, led to
63
1
larly useful were H NOE correlations between the C-8, C-17, and
C-14 methine hydrogens.37 Further confirmation of the structures of
these two C-8 epimers was obtained by eventual conversion of cas-
63
The ratio was slightly enhanced in reactions conducted in acetoni-
no improvement in the yield of the desired tetracyclic product
.
63
11
cade product to (-)-chromodorolide B ( ). The stereochemical
relationship of lactone and hydrophobic fragments in the two tetra-
cyclic products was assigned based on a strong 1H NOE correlation
between the C-17 methine hydrogen and the C-11 hydrogens of the
61
benzyloxymethyl substituent of isomer . Products
are derived from the desired syn addition of butenolide
63
trile, allowing the desired epimer to be isolated in 27% yield (en-
try 5). Unable to further increase the yield of the desired ACF prod-
63
uct , we decided to advance pentacycle forward to validate our
post fragment-coupling strategy.
61 62
, and
58
63
to the
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Journal of the American Chemical Society
Scheme 9
PhthNO2C
O
O
BnO
O
BnO
O
1
2
3
H(D)
H(D)
OBn
OMe
O
OMe
O
O
O
1 mol % [Ru(bpy)3](PF6)2
Hantzsch ester 59 (1.5 equiv)
i-Pr2NEt, CH2Cl2 (0.1 M)
H
H
H
H
OMe
O
H
O
BnO
BnO
11
17
17
O
O
OMe
OMe
14
14
8
O
O
8
H
H
12
H
H
O
17
H
H
4
5
6
blue LEDs, rt
O
O
O
O
Cl
O
Cl
60
Cl
61
H
57
58
(4 equiv)
H
H
(1 equiv)
H
H
62
63
7
8
9
5-exo cyclization
β-fragmentation
yielda
61
entry
deviation from above
OBn
H
60
62
63
OMe
H
10
11
12
13
14
15
16
17
18
OBn
Cl
H
4
EtO2C
CO2Et
1
2
none
11%
7%
29%
14%
35%
34%
20%
18%
O
OMe
O
H
H
O
O
no i-Pr2NEt
O
O
N
3
4
no i-Pr2NEt, CH2Cl2 (0.02 M)
no i-Pr2NEt, d2-59
6%
3%
29%
45%
16%
25%
Cl
H
O
Hantzsch ester (59)
H
10% (d1)
6% (d1)
O
5
no i-Pr2NEt, d2-59, MeCN (0.1 M)
13% (d1)
8% (d1)
37%
27%b
H
aDetermined by 1H NMR integration relative to an internal standard (1,4-dimethoxybenzene).
bIsolated yield.
E
D
Scheme 10
Completion of a First-Generation Total Synthesis of (-)-chro-
modorolide B 63
BnO
O
BnO
O
. Product of the ACF cascade was converted to (–
11
OMe
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
OMe
O
DIBALH
touene
−78 ºC
H
H
H
H
)-chromodorolide B ( ) by way of two isolated and purified inter-
O
H
O
H
17
O
O
1. Pd/C, HCO2H, MeOH, rt
64
65
63
mediates, and (Scheme 10). Reduction of with DIBALH at
H
15
H
then
2. PtO2, H2, MeOH, rt
86% over 2 steps
–78 ºC and in situ acetylation with Ac2O and DMAP afforded diac-
71
etal as a single epimer at C-15, which was assigned the a-orien-
O
OAc
Ac2O, DMAP
pyr, 83%
64
tation on the basis of 1H NOE correlations between the C-15 and C-
17 methines. We speculate that stereoselection in this reduction re-
sulted from prior coordination of DIBALH with the benzyl ether
substituent. Following unsuccessful attempts to accomplish reduc-
tion of the alkene and deprotection of the benzyl ether in one step,
we first unveiled the primary alcohol under transfer-hydrogenation
conditions, followed by conventional PtO2-mediated alkene hydro-
genation. The latter step proceeded exclusively from the alkene face
H
63
64
O
O
O
R
OMe
O
O
O
DMAP
Ac2O
pyr
HO
HO
AcO
H
AcO
H
H
H
1:1 HCl
(4 M)/THF
O
O
H
H
H
rt
CH2Cl2
rt
H
H
OAc
OH
OAc
H
H
H
49%
(from 65)
H
H
65
opposite the angular methyl group to afford a single product in
86% yield. Without purifying subsequent intermediates, the primary
alcohol of was oxidized to carboxylic acid , which upon expo-
sure of the crude reaction mixture to 1:1 solution of 4 M HCl and
THF for 72 h at room temperature delivered pentacyclic intermedi-
65: R = CH2OH
66: R = CO2H
67
(-)-chromodorolide B (11)
[α]D = -67 (c = 0.12, CH2Cl2)
1. DMP
2. NaOCl
65
66
Computational Analysis of Stereoselection in the 5-exo Radical
Cyclization Step of ACF Cascade.
As discussed earlier, we had pre-
67
ate as a mixture of lactol epimers. Reaction of a pyridine solution
of this intermediate with a large excess of acetic anhydride in the
dicted erroneously that the 5-exo cyclization in the ACF cascade
would occur preferentially from a conformation wherein A1,3 inter-
actions would dictate which face of the alkene would be attacked. In
an attempt to gain insight into the observed stereoselection of this
step, we analyzed the origin of the stereoselectivity computationally.
Two mechanistic scenarios for the 5-exo cyclization were consid-
11
presence of DMAP gave (-)-chromodorolide B ( ) as a colorless
solid in 49% overall yield from tetracyclic alcohol precursor
65
.
11
Spectroscopic data for synthetic
compared well with that re-
ported for the natural product.17b The magnitude of the levorotatory
rotation, [a]D = -67 (c = 0.12, CH2Cl2), was somewhat less than
that reported, [a]D = -95 (c = 0.12, CH2Cl2), for a non-crystalline
sample of the natural product.17b Recrystallization of synthetic (-)-
ered: (1) direct cyclization of an a-acyl radical onto the pendant al-
kene (the scenario outlined in Figure 2 and Scheme 9), and (2) ini-
tial SET to the radical intermediate formed in the bimolecular cou-
pling step to form a lactone enolate that subsequently undergoes
SN2’ cyclization. To identify the most likely pathway, energies and
structures of diastereomeric transition states for the stereochemistry
determining step of both modes of cyclization were computed using
the TPSS72a and TPSSh72b functionals and the def2-TZVP basis sets73
in combination with the BJ-damped D3-disperion correction.74,75 In
the case of the radical pathway, the lowest-energy transition state,
11
chromodorolide B ( ) provided single crystals, mp = 236–238 °C,
allowing its structure to be unambiguously confirmed by X-ray anal-
ysis.26e
TS-A-trans
62
, leading to the undesired C-8 epimer , was found to be
1.0 kcal/mol (in CH2Cl2) or 0.5 kcal/mol (in MeCN) lower in en-
TS-A-cis 63
ergy than
leading to epimer having the C-8 configura-
tion of (–)-chromodorolide B. The computed ratio of cyclized prod-
62 63
of 2.5:1 in MeCN agreed reasonably well with the exper-
ucts
:
imentally observed ratio of 1.4:1. In contrast, computed
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 13
diastereomeric transition states for the polar reaction pathway (eno- carbon of the butenolide carried a chloride or bromide substituent,
1
2
3
4
5
6
7
8
late formation followed by concerted SN2’ cyclization, Supporting
Information Figure S2) found the transition state leading to product
63
to be lower in energy by 0.7 kcal/mol (in MeCN) or 0.5 kcal/mol
(in CH2Cl2). Although the energy differences of the computed dia-
stereoisomeric transitions states in the two mechanisms are small,
the radical pathway, which we consider the most plausible, was more
consistent with the observed reaction outcome. As a result, further
computational studies focused on this pathway.
the halogen substituents would clash a helical trans-transition struc-
ture, yet would point in opposite directions in a cis-transition struc-
ture. In addition, introduction of a halogen should shift the transi-
tion states later by decreasing the nucleophilicity of the butenolide
radical, which could further increase a destabilizing halogen-halogen
interaction.
The computationally predicted lowest energy transition struc-
tures for the 3-chloride analogue are shown in Figure 3B. As envi-
TS-B-trans
sioned, the
is affected significantly, with the forming C–
9
A.
C bond distance decreased from 2.38 Å to 2.18 Å. As a consequence,
the kinetic barrier for forming the trans product is increased from 7.9
kcal/mol to 11.3 kcal/mol (Supporting Information Figure S5). The
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
TS-B cis
forming bond in
is also shortened slightly (from 2.25 Å to
2.15 Å) and the kinetic barrier slightly is increased from 8.9 kcal/mol
to 9.4 kcal/mol. The transition state that would lead to the ACF
TS-
product having the C-8 configuration of (–)-chromodorolide B,
B-cis
, is now predicted to be more stable by 1.9 kcal/mol. For the
bromide analogue, the selectivity is predicted to be even slightly
higher (Table 1).76
Table 1. The relative Gibbs free energies of TS-cis and TS-trans for
α-H, α-Cl and α-Br butenolide substrates in CH2Cl2.
TS-A-trans (0 kcal/mol)
TS-A-cis (1.0 kcal/mol)
O
B.
BnO
O
BnO
O
X
OMe
O
OMe
O
O
H
X
H
X
H
BnO
O
O
OMe
O
H
H
H
5-exo
O
O
O
cyclization
Cl
Cl
Cl
H
H
H
via TS-cis
via TS-trans
ΔG(TS-cis–TS-trans), kcal/mol
functional
TPSS-D3
X = H
1.0
X = Cl
–1.9
X = Br
–2.4
Second-Generation Total Synthesis of (–)-Chromodorolide B by
Way of a Stereoselective ACF Cascade.
computational prediction by utilizing a 3-chlorobutenolide in the
radical coupling step.77 This possibility was particularly attractive, as
we have shown previously that the addition of a 3-Cl substituent to
a butenolide increases the yields of radical coupling reactions, and in
We opted to explore this
TS-B-trans (2.0 kcal/mol)
TS-B-cis (0 kcal/mol)
Figure 3
. Structures and energies of diastereoisomeric transition
states of the 5-exo radical cyclization step of the ACF cascade. For
A.
the intermediate generated by addition of the acetonide radical to
B.
addition the a-chloride substituent in a coupled product can be re-
moved directly in the photoredox-catalyzed coupling step.2b Salient
results of our investigation of the use of enantiopure 3-chlorobu-
682b
(R)-5-methoxybutenolide. For the intermediate generated by ad-
dition of the acetonide radical to (R)-3-chloro-5-methoxy-
butenolide. Values enclosed in parentheses are relative energies
computed using the TPSS functional and def2-TZVP basis set
(CH2Cl2 solvent); the values by the dotted line are the lengths of the
forming C–C bond in Å. The transition structures labeled “cis” lead
to the formation of the configuration at C-8 found in (–)-chromo-
dorolide B. To reduce computation time, the benzyloxy substituent
at C-11 was replaced with methoxy.
tenolide
in the ACF cascade are summarized in Table 2. Using
the reaction conditions optimized earlier (entry 5, Scheme 9) and
carrying out the reaction with 1 equiv of both N-acyloxyphthalimide
57
68
and chlorobutenolide , followed by addition of n-Bu3N and ad-
ditional irradiation to promote dechlorination,2b,78 provided an ACF
cascade product that still contained the chloride substituent. Hy-
pothesizing that under these conditions the dechlorination step was
slow, the crude product after aqueous extraction was isolated and re-
subjected to dechlorination using n-Bu3N and the iridium photo-
catalyst, Ir[dF(CF3)ppy]2(dtbbpy)PF6. This sequence provided a
Examination of the transition structures of the two diastereo-
meric transition states of the radical pathway (Figure 3A) was in-
TS-
structive. The lower-energy diastereomeric transition structure,
69
single ACF cascade product in 41% yield (Table 2, entry 1). The
69
pentacyclic C-8 epimer of was not detectable by NMR analysis.
Increasing the concentration of the reaction to 0.6 M led to ACF
being formed in 58% yield (entry 2). We eventually
found that the desired cascade sequence and dechlorination of the
product could be accomplished in a single step by utilizing 2 mol %
A-trans
, has a longer forming bond (2.38 vs 2.25 Å) and a somewhat
helical shape. Further analysis suggested a potential destabilizing ste-
ric interaction between the chloride of the hydrindane fragment and
a substituent larger than hydrogen at the a-carbon of the butenolide
69
product
TS-A-trans
. If the a-
fragment in a transition structure analogous to
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Journal of the American Chemical Society
paralleled the final steps of our first-generation synthesis (Scheme
of Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the sole photocatalyst (entry 3).
1
2
3
4
5
6
7
8
69
59
69
11). Reduction of lactone functionality of and in situ acetylation
of the resulting aluminum hemiacetal intermediate with Ac2O pro-
The yield of was similar using Hantzsch ester (entry 4), which
was expected as by-products resulting from premature quenching of
the a-acyloxy radical intermediate had not been observed. In addi-
71
ceeded smoothly to deliver diacetal in 98% yield. Deprotection of
the primary alcohol proved challenging once again. Debenzylation
tion, we were able to use an organic photocatalyst, 4CzIPN,79-81 in
place of the Ir catalyst, giving the desired ACF cascade product in
54% isolated yield (entry 5). Thus, the computationally-guided
structural modification of the butenolide coupling partner resulted
in doubling the yield of the pivotal pentacyclic intermediate and
decreasing the amount of butenolide acceptor required in this step
by four-fold.
71
of employing the acidic transfer hydrogenolysis conditions devel-
11
oped during our first-generation synthesis of , resulted in cycliza-
tion of the newly unveiled C-11 alcohol onto C-16 forming a bridg-
ing tetrahydrofuran ring. We were able to suppress this undesired cy-
clization by performing the reaction with basic Pd(OH)2 and H2.83
Without purification, the trisubstituted alkene was reduced stereose-
69
9
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
72
lectively with PtO2 to deliver saturated-pentacycic product
in
72
88% over two steps. Finally, we successfully converted
11
to (-)-
chromodorolide B ( ) in 45% yield over four steps by the sequence
of transformations employed in our first-generation synthesis.
Table 2. Optimization of the fragment coupling between NHP ester
57 and chlorobutenolide 68.
Scheme 11
BnO
O
BnO
O
BnO
O
PhthNO2C
H
OBn
OL-Men
OL-Men
11
O
L
-Men
1. Pd(OH)2, H2, EtOAc, rt
H
H
DIBALH
touene
−78 ºC
H
H
OL-Men
H
O
O
O
H
O
H
16
O
O
O
O
conditions
O
8
H
H
O
H
O
O
then
2. PtO2, H2, EtOAc, rt
69% over 2 steps
2 X 34 W
blue LEDs, rt
H
O
Cl
Cl
OAc
Ac2O, DMAP
pyr, 98%
H
H
57
68
69
H
69
71
(1 equiv)
(1 equiv)
entry
conditions
isolated yield
41%
O
O
O
R
OL-Men
O
O
DMAP
Ac2O
pyr
HO
HO
AcO
H
H
H
H
(a) 2 mol % [Ru(bpy)3](PF6)2,
d2-Hantzsch ester 59, MeCN (0.1 M)
(b) 2 mol % Ir[dF(CF3)ppy]2(dtbbpy)PF6,
n-Bu3N, THF (0.1 M)
1
2
1:1 HCl
(4 M)/THF
AcO
O
O
O
OAc
H
H
H
rt
CH2Cl2
rt
H
H
OAc
OH
H
H
H
(a) 2 mol % [Ru(bpy)3](PF6)2,
d2-Hantzsch ester 59, MeCN (0.6 M)
(b) 2 mol % Ir[dF(CF3)ppy]2(dtbbpy)PF6,
n-Bu3N, THF (0.1 M)
58%
49%
(from 72)
H
H
72: R = CH2OH
73: R = CO2H
67
(-)-chromodorolide B (11)
1. DMP
2. NaOCl
2 mol % Ir[dF(CF3)ppy]2(dtbbpy)PF6,
d2-Hantzsch ester 59, THF (0.6 M), then Bu3N
56%
57%
54%
3
4
5
2 mol % Ir[dF(CF3)ppy]2(dtbbpy)PF6,
Hantzsch ester 59, THF (0.6 M), then Bu3N
CONCLUSION
The structurally intricate marine diterpenoid chromodorolide B,
which harbors 10 contiguous stereocenters and two chiral attached
ring fragments, has been successfully synthesized. This total synthe-
sis establishes the absolute configuration of chromodorolide B,
which had previously been proposed on biogenetic grounds. The
synthetic sequence features a novel late-stage radical addition/cy-
clization/fragmentation (ACF) cascade that unites two chiral frag-
2 mol % 4CzIPN, Hantzsch ester 59,
THF (0.6 M), then Bu3N
To confirm that the chlorine, and not the menthoxy, substituent
was responsible for the high stereoselection observed in the frag-
ment coupling summarized in Table 2, we examined the reaction of
57
NHP ester
with 3-chloro-5-methoxybutenolide. Although this
ments by forming two C-C bonds and four contiguous stereocen-
ters in a single, highly stereoselective step. A notable feature of this
late-stage fragment union is the use of the two coupling partners in
equimolar amounts. The coupling step is initiated by visible-light
photocatalytic fragmentation of a redox-active ester, which can be
accomplished in the presence of 2 mol % of an iridium photocatalyst
or 2 mol % of a less-precious electron-rich dicyanobenzene photo-
catalyst. The high degree of stereocontrol eventually realized in the
cascade sequence was made possible by in-depth DFT computa-
tional modeling of the 5-exo cyclization step of the ACF cascade.
butenolide is not available in enantioenriched form,2b this investiga-
tion could be carried out using racemic 3-chloro-5-methoxy-
82
butenolide ( ), as authentic samples of the diastereomeric ACF
70
62
63
tion of NHP ester with racemic butenolide provided as the
products and were available. As summarized in eq 1, the reac-
57 70 63
62
major product, with no trace of its C-8 epimer, , being seen by
careful 1H NMR analysis of the crude reaction mixture37
BnO
O
PhthNO2C
H
OBn
OMe
O
H
H
OMe
O
O
H
Our second-generation total synthesis of (-)-chromodorolide B
conditions
8
O
H
(1)
+
62
not detected
O
O
11
(
) proceeds in in 21 steps from commercially available (S)-enedi-
entry 4
Table 2
Cl
Cl
O
44
one in 2% overall yield. We anticipate that the results delineated
in this study will find applications in future syntheses of other struc-
turally intricate natural products.
H
70
racemic
57
(1 equiv)
63
major product
(1 equiv)
ASSOCIATED CONTENT
Supporting Information
69
With sufficient amounts of lactone in hand, we elaborated it
11
to (-)-chromodorolide B ( ) by a seven-step sequence that
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Journal of the American Chemical Society
Page 10 of 13
(8) For reviews of rearranged spongian diterpenoids, see: (a) Keyzers, R. A.;
Experimental procedures, characterization data, and CIF files for X-ray
structures of compounds 11
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Corresponding Authors
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Chem. 1983, 48, 1141–1142.
*leoverma@uci.edu
ORCID
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232.
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(16) Rudi, A.; Kashman, Y. Tetrahedron 1990, 46, 4019–4022.
(17) Chromodorolide A and B: (a) Dumdei, E. J.; De Silva, E. D.; Andersen,
R. J.; Choudhary, M. L.; Clardy, J. J. Am. Chem. Soc. 1989, 111, 2712–2713.
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768–771.
Yuriy Slutskyy: 0000-0002-3059-5362
Mikko Muuronen : 0000-0001-9647-7070
Philipp Kohler: 0000-0002-2424-9527ꢀ
Larry E. Overman: 0000-0001-9462-0195ꢀ
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Present Addresses
D.J.T.: Process Research and Development, AbbVie Inc., 1 North
Waukegan Road, North Chicago, IL 60064.
M.M.
: BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Ger-
many.
P.K.
Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
: Process Chemistry R&D, Idorsia Pharmaceuticals Ltd.,
Notes
The authors declare no competing financial interest.
(18) Chromodorolide C: Rungprom, W.; Chavasiri, W.; Kokpol, U.; Kotze,
A.; Garson, M. J. Mar. Drugs 2004, 2, 101–107.
(19) Chromodorolide D and E: (a) Uddin, M. H.; Hossain, M. K.; Nigar,
M.; Roy, M. C.; Tanaka, J. Chem. Nat. Compd. 2012, 48, 412–415. (b) Kata-
vic, P. L.; Jumaryatno, P.; Hopper, J. N. A.; Blanchfield, J. T.; Garson, M. J.
Aust. J. Chem. 2012, 65, 531–538.
ACKNOWLEDGMENTS
Financial support was provided by the U. S. National Science Founda-
tion (CHE1265964 and CHE-1661612) and U. S. National Institute of
General Medical Sciences by research grant R01GM098601 and a grad-
uate fellowship award to YS (1F31GM113494). NMR spectra, mass
spectra, and X-ray analyses were obtained at UC Irvine using instrumen-
tation acquired with the assistance of NSF and NIH Shared Instrumen-
tation grants. We thank Professor Filipp Furche for hosting M.M. in his
laboratory and for his support of the computational studies by the Na-
tional Science Foundation under CHE-1464828.
(20) All natural products having the spongian skeleton are reported to have
a
the absolute configuration depicted in .
H
H
O
H
H
spongian skeleton (a)
(21) For leading references to the distinctly different Golgi modifying activ-
ities of norrisolide and macfarlandin E, see (a) Takizawa P. A.; Yucel, J. K.;
Veit, B.; Faulkner, D. J.; Deerinck, T.; Soto, G.; Ellisman, M.; Malhotra, V.
Cell 1993, 73, 1079–1090. (b) Guizzunti, G.; Brady, T. P.; Fischer, D.; Mal-
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Schnermann, M. J.; Beaudry, C. M.; Egovora, A. V.; Polishchuk, R. S.; Süt-
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(22) For a study of the reactivity and biological activity of simplified ana-
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Genung, N. E.; Canham, S. M.; Untiedt, N. L.; Karanikolas, B. D. W.; Sütter-
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(23) Wang, H.; Kohler, P.; Overman, L. E.; Houk, K. N. J. Am. Chem. Soc.
2012, 134, 16054–16058.
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α-acyloxy radical intermediate and favor reactivity by the enolate pathway,
we confirmed that formation of the ACF product having the C-8 configura-
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see Supporting Information, Figure S7.
1
2
3
4
5
6
7
8
(77) Use of an a-bromobutenolide is also predicted to favor formation of
the desired ACF product (Table 1). However, this prediction could not be
verified experimentally because of decomposition of the bromide-contain-
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(75) For a detailed discussion of the computational methods utilized in the
study, see the Supporting Information.
ene or ammonium formate did not result in debenzylation of 71
.
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Insert Table of Contents artwork here
1
2
OL-Men
3
4
5
6
7
8
9
O
BnO
O
O
OL-Men
O
AcO
AcO
Cl
H
H
H
O
Bimolecular
Radical Cascade
O
O
O
O
PhthNO2C
H
OBn
H
H
O
2 C−C Bonds
Stereocenters
H
OAc
H
4
O
54% yield (>20:1 dr)
H
H
Cl
(−)-chromodorolide B
H
10
11
12
13
14
15
16
17
18
19
20
21
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23
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29
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38
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40
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42
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49
50
51
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60
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