Enantioselective synthesis of (-)-maoecrystal v by enantiodetermining C-H functionalization

Article abstract of DOI:10.1021/ja510573v

The evolution of a program directed at the enantioselective total synthesis of maoecrystal V, a highly modified ent-kauranoid, is described. An early stage chiral auxiliary-directed asymmetric C-H functionalization for the construction of a key benzofuran intermediate enabled the first asymmetric synthesis of the natural enantiomer of maoecrystal V, confirming the assigned stereochemistry. A divergent course of the central intramolecular Diels-Alder reaction, which is dependent on the nature of the dienophile, initially led to the development of an unanticipated and previously unknown isomer of maoecrystal V, which we named maoecrystal ZG. In light of the reported selective and potent cytotoxic activity of maoecrystal V, the cytotoxic properties of maoecrystal ZG were also investigated.

Full text of DOI:10.1021/ja510573v

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Article
Enantioselective Synthesis of (–)-Maoecrystal V
by Enantiodetermining C—H Functionalization
Ping Lu, Artur Mailyan, Zhenhua Gu, David Guptill, Hengbin Wang, Huw M. L. Davies, and Armen Zakarian
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Nov 2014
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Journal of the American Chemical Society
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Enantioselective Synthesis of (–)-Maoecrystal V by Enanti-
odetermining C—H Functionalization
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†,⊥
§
‡
‡
‡,
†,
Ping Lu,†, Artur Mailyan, Zhenhua Gu, David M. Guptill, Hengbin Wang, Huw M. L. Davies, * Armen Zakarian *
⊥
‡Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
ABSTRACT: Evolution of a program directed at the enantioselective total synthesis of maoecrystal V, a highly modified ent-kauranoid, is
described. An early-stage chiral auxiliary-directed asymmetric C—H functionalization for the construction of a key benzofuran intermediate
enabled the first asymmetric synthesis of the natural enantiomer of maoecrystal V, confirming the assigned stereochemistry. Divergent course
of the central intramolecular Diels-Alder reaction dependent on the nature of the dienophile initially led to an unanticipated, previously un-
known isomer of maoecrystal V, which we named maoecrystal ZG. In light of the reported selective and potent cytotoxic activity of maoecrys-
tal V, cytotoxic properties of maoecrystal ZG were also investigated.
12
INTRODUCTION
13
11
9
1
14
7
The first investigations of diterpenoids from plants of the Isodon
genus date back over 100 years ago to 1910, when Yagi isolated a
crystalline principle plectranthin from “enmei-so”, a medication
from the leaves of I. japonica and I. trichocarpa that have been used
for the treatment of gastrointestinal disorders in Japan for centu-
2
3
10
8
5
4
6
6,7-seco-ent-kaurane ring system
ent-kaurane ring system
1
ries. In Henan province in China, the leaves of I. rubescnes are still
OH
used by the local people for the treatment of respiratory and gastro-
intestinal bacterial infections, inflammation, and cancer. Enmein
was the first compound isolated from I. japonica in 1958, and its
structure was established in 1968 by X-ray crystallography. Since
then, over 600 individual diterpenoids from Isodon plants display-
ing a broad spectrum of biological activity have been character-
ized. While the largest group is defined by the classic ent-kaurane
O
O
O
O
OH
HO
CO2H
O
O
OH
2
O
steviol
scuponeatin N
enmein
3
O
OH
carbon skeleton (Figure 1), another sizeable structural type is 6,7-
seco-ent-kauranes, examples of which include compounds like scu-
poneatin N, trichorabdals, longirabdolactone, and longikaurin.
O
O
H
O
O
O
O
O
HO
O
O
AcO
O
R
HO
4
5
Related maoecrystals L and O were both isolated from I. eriocalyx.
R = H, trichorabdal A
longikaurin E
longirabdolactone
More recently discovered constituents of I. eriocalyx, maoecrys-
6
7
R = OAc, trichorabdal B
tals V and Z, are special members of the ent-kaurane diterpenoid
family because of unprecedented, highly rearranged polycyclic ring
systems found in their molecular structures. The structure of maoe-
crystal Z combines a trans-fused 6,5,6-carbotricyclic framework
with a bridging six-membered lactone and has been classified as a
6,7:8,15-di-seco-7,20-olide-6,8-cyclo-ent-kaurane. Maoecrystal V is
characterized by an intricate blend of a bicyclo[2.2.2]octan-2-one,
δ-valerolactone, and cyclohexene subunits with a strained central
oxolane ring. Both compounds have been found to display notable
cytotoxic activity. The potency of maoecrystal Z was comparable
across the three human cells lines examined: K562 leukemia (IC50
2.9 µg/mL), MCF7 breast (IC50 1.6 µg/mL), and A2780 ovarian
(IC50 1.5 µg/mL). Remarkably, maoecrystal V showed high selec-
tivity against the HeLa cell line (IC50 2.9 µg/mL), with activity for
K562, A549 lung carcinoma, and BGC-823 adenocarcinoma lower
by at least 6 orders of magnitude.
O
O
O
O
O
O
O
HO
OAc
R
O
O
OAc
O
O
R = CHO, maoecrystal L
R = CO2H, maoecrystal O
maoecrystal Z
maoecrystal V (1)
Figure 1. General structures and selected members of ent-kaurane
diterpenoids from Isodon plants.
The total syntheses of only a few ent-kauranoids have been ac-
complished. Some of the pioneering achievements have been dis-
closed by the group of Mander who reported a total synthesis of 15-
deoxyeffusin almost three decades ago. The same group accessed
longirabdolactone from giberellic acid by semisynthesis. Steviol
and isosteviol are other ent-kauranes with a classic polycyclic skele-
ton that stimulated early interest as synthesis targets. The first syn-
8
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thesis by Mori in 1970 was followed by concise total syntheses by methyl group and the lactone ring. The six-membered lactone was
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1
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Ziegler, Snider, and Baran groups probing distinct strategies.
Isolation of structurally unique maoecrystal V, and subsequently
maoecrystal Z, is one of the recent events that reinvigorated inter-
est in the synthesis of ent-kauranoid natural products. Reisman and
co-workers developed and successfully executed a concise unified
strategy for the synthesis of (–)-maoecrystal Z, (–)-trichorabdal A,
to be constructed by a 6-exo radical cyclization of an acyl radical
onto the enol ether. This risky blueprint was faced with potential
complications due to 1) possible instability of the enol ether, 2)
lack of precedent and therefore limited confidence in reliability of
radical cyclizations onto enol ethers within complex substrates, and
3) the need for the 6-exo cyclization to occur contrary to the elec-
tronic preferences of the enol ether. After installation of the tether
at the C20 hydroxy group, the bycylo[2.2.2]octan-2-one retron was
disassembled via an IMDA process with a synthetic equivalent of
ethylene. In addition to enabling the IMDA reaction, the function
of the tether was to deliver the dienophile from the correct face of
the cyclohexadeinone ring system. After further analysis, which
involved ester enolate hydroxymethylation and phenol oxidation,
dihydrobenzofuran vii was identified as an early synthesis target,
thus fulfilling our goal to preserve the central oxolane ring during
the course of the synthesis. Essential for the plan was the prospect
of using the recent C—H functionalization technologies advanced
by the groups of Davies and Yu to effectively access dihydrobenzo-
14
and (–)-longikaurin E. Earlier this year, total syntheses of scu-
15
16
poneatin N were reported by Zhai and Thomson. Maoecrystal V
9
with its intricate structure distinct from other ent-kauranes proved
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to be an especially compelling synthesis target, and many research
17,18
groups reported different strategies for its synthesis.
Presently,
the total synthesis of maoecrystal V in racemic form has been com-
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21
pleted by the groups of Yang, Danishefsky, and ours.
Herein, we provide a full account of the enantioselective total
22
synthesis of (–)-maoecrystal V and of its non-natural isomer
maoecrystal ZG. The enantiodetermining step of the synthesis is a
Rh-catalyzed C—H-functionalization forming a dihydrobenzofu-
ran intermediate ii (Scheme 1). We discovered that the course of
the synthesis critically depended on the choice of dienophile part-
ner in the central intramolecular Diels-Alder (IMDA) cycloaddi-
tion of intermediate iii forging the bicyclo[2.2.2]octan-2-one sub-
unit. Our first effort unexpectedly delivered maoecrystal ZG, a
structural isomer of the original target, which provided an oppor-
tunity to explore its antiproliferative properties. Compound 2 ap-
pears to have an unprecedented ring system. Modification of the
dienophile in iii allowed for the ultimate completion of the first
enantioselective total synthesis of maoecrystal V.
23,26,28,30
furan vii from precursors like viii.
Scheme 2. Synthesis Plan.
aldol condensation
2. IMDA
enolate methylation
or ring-closing metathesis
addition
O
O
O
R1
O
O
R1
O
16
Y
Y
O
20
O
O
O
O
6-exo radical
OH
O
O
cyclization
v
1
iv
Y = CH2, or O, or H, OR
1. tether
Scheme 1. Abbreviated presentation of the total synthesis of
installation
(–)-maoecrystal V (1) and maoecrystal ZG (2).
ester enolate
alkylation
O
Z
O
O
H
Y
O
O
X
O
O
O
MeO2C
O
20
O
IMDA
path a
O
OEt
OEt
O
N2
N2
Y
R1
O
O
O
O
O
R
O
O
Y
H
O
H
OEt
OEt
O
O
i
Y
maoecrystal ZG (2)
viii
R'O
R
asymmetric
vii
vi
Rh-catalyzed
IMDA
path b
Rh-catalyzed
H functionalization
phenol oxidation
O
CH functionalization
C
—
X
O
O
O
O
iii
MeO2
C
The main variables intentionally left open to experimental feed-
back were the identity of groups X, Y, and Z (Scheme 2). For group
Y, the preferred options were either CH2 or a protected hydroxyl
group (aldehyde was deemed too reactive). We initially selected
the methylene group because it promised a more direct elaboration
to the cyclohexenone via RCM, recognizing its potential reactivity
during the radical cyclization onto the enol ether. The nature of the
tether (group X) was to be guided by two parameters; the ease of
installation and then removal. The main purpose of group Z in
diazo precursor viii was to support effective C—H-
functionalization, in terms of both chemical efficiency and enanti-
oselectivity.
X = B(OR): path a
X = SiMe2: path b
O
R
H
O
O
O
ii
maoecrystal V (1)
RESULTS AND DISCUSSION
Synthesis Plan. A central factor that influenced the design of the
synthesis was the realization that the assembly of the central tetra-
hydrofuran ring, highlighted in Scheme 2, at first a seemingly sim-
ple operation, was going to present a substantial challenge. This
notion was validated by the growing number of reports on the pro-
gress toward the total synthesis of 1 from several groups that halted
at this stage, after successfully addressing other challenges such as
Development of the enantioselective synthesis of benzofu-
ran intermediates by Rh-catalyzed C—H-functionalization.
Catalytic asymmetric approaches. Catalytic enantioselective synthe-
sis of dihydrobenzofurans via intramolecular C—H insertions in
the presence of chiral rhodium catalysts has been developed by
17
the installation of the quaternary centers. The challenge was as-
cribed to the well-recognized strain associated with the five-
membered heterocycle in 1. Guided in part by these observations,
our goal was to preserve the oxolane ring for as long as reasonable
during the progressive bond disconnection process. The cyclohex-
enone subunit was envisioned to arise either from an aldol cy-
clocondensation of a methyl ketone-aldehyde precursor or ring
closing metathesis. Subsequent simplification was aimed at the C16
24
25,26
Davies and Hashimoto.
These findings provided the basis for
the development of the synthesis of (–)-maoecrystal V by the
aforementioned strategy, in which the early construction of a dihy-
drobenzofuran intermediate would be the enantiodetermining
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Journal of the American Chemical Society
R
N
stage of the synthesis. Although the majority of examples involve
insertions into benzylic ether C—H bonds, a few examples with
H
H
H
H
O
O
O
H
O
O
Rh
Rh
1
2
Rh
Rh
O
O
Rh
Rh
O
O
N
P
SO2Ar
aliphatic ethers were also reported. Perhaps the most relevant prec-
24
4
N
R
O
3
edent is illustrated in Scheme 3a.
4
2
Ar = p-C12H25C6H4
Rh2(S-DOSP)4
4
5
R = SO2-2,4,6-tri-i-PrC6H2
Rh2(S-biTISP)2
The synthesis of the first substrate for the enantioselective C—H
functionalization studies began by O-alkylation of sesamol with
readily accessible neopentylic alcohol 6 under Mitsunobu condi-
tions (Scheme 3b). The resulted ether was advanced through di-
rected ortho-metalation followed by acylation with methyl
chloroxoacetate via an arylzinc intermediate. The diazo ester (9)
was accessed in two steps from 8 by tosylhydrazone formation and
subsequent fragmentation under basic conditions in the presence
of DBU.
Rh2(R-BNP)4
6
H
O
O
Rh
Rh
i-Pr
t-Bu
Rh
Rh
O
O
H
O
7
8
R1
O
O
N
O
Rh
Rh
N
Ph
O
O
R2
9
4
4
10
11
12
13
14
15
16
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22
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4
R1 = Ph, R2 = 4-BrPh
R1 = H, R2 = Ph
Rh2(R-BTPCP)4
Rh2(R-DPCP)4
Rh2(S-NTTL)4
Rh2(R-BPTV)4
R2
Rh
Rh
O
O
Scheme 3.
H
O
R1 = H, R2 = t-Bu
Rh2(S-PTTL)4
R1 = H, R2 = adamantyl Rh2(S-PTAD)4
O
N
R1
R1
a
R1 = H, R2 = i-Pr
R1 = Cl, R2 = t-Bu
Rh2(S-PTV)4
MeO
N2
O
Rh2(S-TCPTTL)4
R1 = Cl, R2 = adamantyl Rh2(S-TCPTAD)4
R1
1 mol % Rh2(S-PPTL)4
toluene, -78 oC, 7 h
O
MeO2
C
R1
O
4
O
3
O
H
91% yield, dr 96:4, 96% ee
Figure 2. Chiral rhodium catalysts used in asymmetric C—H-
functionalization of 9, 11, and 22.
4
Overall, although the results in entry 8 were found to fall short of
desired, they provided a reasonable starting point for a potential
application in a total synthesis setting. In particular, a 53% yield and
the observed 10:1 diastereoselectivity would minimize the impact
of enantioselectivity erosion in subsequent transformations. Alt-
hough the enantioselectivity at 60% was not very high, there was a
reasonable expectation that it could be further upgraded during the
course of the synthesis.
b
Ph3P, (EtO2C)2N2
THF, toluene, reflux
n-BuLi, THF, 23 o
C
O
O
O
O
ZnCl2, ClCOCO2Me
+
HO
63% yield
46% yield
HO
O
(71% brsm)
6
7
5
O
O
Table 1. Enantioselective C—H insertion with diazo ester 9.a
MeO2
C
O
O
O
O
MeO2C
1. TsNHNH2, TsOH, PhH
N2
2. DBU, CH2Cl2, 23 o
C
O
~2 mol % catalyst
4A MS, solvent
23 oC, 3 h
MeO2
C
O
O
O
MeO2C
MeO2
C
75% yield
10
O
O
O
8
9
N2
+
5
O
O
O
The initial screening focused on identifying the preferred cata-
lyst/solvent system at ambient temperature (Table 1). The library
of catalysts used in this study is depicted in Figure 2. With Rh2(S-
PTTL)4 catalyst, the best diastereo- and enantioselectivity was
observed in dichloromethane (DCM), although moderately higher
yields were obtaining in hexane and toluene (entries 3, 4). Exten-
sive catalyst screening in DCM was disappointingly unproductive,
and generally did not lead to improvement in stereoselectivity,
although a somewhat higher yield of 42% was observed with Rh2(S-
TCPTTL)4 (entry 6).
trans-10
cis-10
9
entry
catalyst
solvent
CH2Cl2
cis:trans ee,
ee,
yield
a
%
cis trans
1
2
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(R-PTTL)4
Rh2(S-NTTL)4
25
9.1:1
-
70% 50%
EtOAc trace
-
-
-
3
hexane
PhMe
34
47
27
42
6.7:1
51%
4
5.9:1 -60% -33%
Further incremental progress was reached when the temperature
of the reaction was increased to reflux in DCM. Rh2(S-PTTL)4
catalyst was again the best, delivering a 53% combined yield of the
two diastereomers with a 10:1 ratio, where the major isomer was
formed in 60% ee (entry 8). Additional screening under these con-
ditions (reflux in DCM) led to no further improvement, and Rh2(S-
PTTL)4 was found to be the optimal catalyst system for a potential
application in total synthesis. Importantly, the high diastereoselec-
tivity of 10:1 was critical to maintaining the original enantiomer
ratio, since the catalyst controls the absolute stereochemistry at
5
CH2Cl2
9.1:1
54%
-
6
Rh2(S-TCPTTL)4 CH2Cl2
-
-
30% 18%
7
Rh2(R-BPTV)4
Rh2(S-PTTL)4
Rh2(S-PTAD)4
CH2Cl2 trace
-
-
-
-
-
-
-
-
c
8
CH2Cl2
53
10.0:1 60%
c
9
CH2Cl2
22
3.7:1
-
48%
c
10
11
12
Rh2(R-BTPCP)4 CH2Cl2 NR
-
-
c
Rh2(R-BPTV)4
Rh2(S-biTISP)2
CH2Cl2 trace
-
c
CH2Cl2 trace
1:1
3:1
-
24
C10 rather than C5 (maoecrystal V numbering). Position C10 is
epimerizable, and in fact is inverted later on in the course of the
synthesis, with a net result of erosion of the ee.
c
13 Rh2(S-TCPTAD)4 CH2Cl2
24
8%
adiastereomer ratios and enantiomeric excess were determined by
HPLC analysis. bcombined isolated yield of cis-10 and trans-10. at
c
reflux.
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Another reaction that was extensively studied with a view for a
potential application in the enantioselective total synthesis of
Scheme 4.
1
2
3
4
5
6
7
8
a
enantioselective 2,3-dihydrobenzofuran synthesis by Yu and Davies
maoecrystal V is depicted in Table 2. The substrate (11) was pre-
21,27
pared analogously to 9.
Here, the nature of the ester substituent
1 mol %
Rh2(R-PTTL)4
OMe
was also varied (Me or t-Bu). In general, higher chemical yields of
products cis-12 and trans-12 were observed with these substrates.
One important conclusion from this study is that replacing the
terminal alkene in 9 with p-methoxybenzyloxy substituent resulted
in a loss of diastereoselectivity across the range of catalysts in sever-
al solvents. Although rather high enantioselectivity of up to 80%
could be achieved with catalysts Rh2(S-PTTL)4 and Rh2(S-
BPTV)4, the low diastereoselectivity of ~1:1 observed for 11
(R=Me) negated the ability to control stereochemistry at C5 (en-
tries 1 and 11). In fact, with any of the catalysts examined, the criti-
cally important diastereoselectivity never reached the levels ob-
served for diazo ester 9. While the t-butyl ester (11, R = t-Bu) gen-
erally displayed higher diastereoselectivity, the highest level of 3.8:1
among the studied reactions was recorded for the methyl ester with
catalyst Rh2(S-BTPCP)4 (entry 13). However, enantioselectivity
was low for both cis-12 (ee 36%) and trans-12 (ee 11%).
OMe
CO2Me
N2
MeO2C
DMB, 50 o
C
MeO
MeO
+
OTBS
76% yield
OTBS
>97:3 dr, 93% ee
1. HCl, EtOH
9
2. 10 mol % Pd(OAc)2
Li2CO3, PhI(OAc)2
CO2Me
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
MeO
OMe
O
56% yield
93% ee
10 mol %
Rh2(OAc)4, CH2Cl2
23 oC, 2 h; TBAF
MeO2
C
O
O
+
OTBS
TBSO
N2
0% yield
MeO
O
sm recovered
O
14
13
O
RO
OH
Table 2. Enantioselective C—H insertion with diazo esters 11.a
LDA, THF;
MeO2C
O
ZnCl2, -78 o
C
O
15a: R = TBS
15b: R = PMB
PMBO
+
O
1 mol % catalyst
4A MS, solvent
99% yield
RO2
C
O
O
O
RO2
C
RO2
C
syn:anti 12:1
10
O
O
reflux
16
O
PMBO
N2
+
5
PMBO
PMBO
O
O
O
O
O
MeO2
C
10 mol % Pd(OAc)2
PhI(OAc)2, Li2CO3
C6F6, 100 oC, 21 h
trans-12
cis-12
11
MeO
O
O
+
O
O
PMBO
O
entry
R
catalyst
solvent yield cis:
ee,
ee,
PMBO
OH
15b
24
b
%
trans cis trans
MeO
MeO
O
O
O
1
2
Me
Me
Me
Rh2(S-PTTL)4
Rh2(S-PTTL)4
DMB
71 1.4:1 45
80
67
77
66
57
59
57
O
O
+
CHCl3 63 1.6:1 49
PMBO
O
PMBO
OH
syn-15b
17
3
Rh2(S-PTTL)4 c-C6H12 69 1.6:1 41
15, syn:anti
conversion
16:17:syn-15b
4
t-Bu Rh2(S-PTTL)4
t-Bu Rh2(S-PTTL)4
DMB
55 3.0:1 <5
syn only
0:1:2.6
1:1:5
28%
5
CHCl3 28 3.0:1 <5
anti: 100%
syn: 50%
~2:1
6
t-Bu Rh2(S-PTTL)4 c-C6H12 70 3.5:1 23
7
Me
Me
Me
Me
Me
Rh2(S-PTA)4
Rh2(R-PTV)4
c-C6H12 79 1.0:1 18
Davies and Yu recently reported an elegant enantioselective ap-
proach to 2,3-dihydrobenzofurans based on consecutive C—C and
C—O bond-forming C—H functionalization reactions, which we
also explored for our purposes. The desired transformation was
complicated by the need to use challenging neopentylic ether 13 as
the substrate while the precedent existed only for benzylic ethers. A
preliminary evaluation of the first step of the process was carried
8
c-C6H12 76 1:1.1 -42 -78
28
9
Rh2(S-NTTL)4 c-C6H12 74 2.2:1 29
Rh2(S-PTAD)4 c-C6H12 79 1.4:1 41
56
54
10
11
12
13
14
15
16
Rh2(R-BPTV)4 c-C6H12 76 1:1.1 -43 -80
Me Rh2(S-biTISP)4 c-C6H12 78 1:1.4 -10 38
Me Rh2(S-BTPCP)4 c-C6H12 65 3.8:1 -36 -11
29
out with ether 13 or 14 and Rh2(OAc)4 in dichloromethane. No
conversion was observed in this reaction, confirming that 13 is
indeed a challenging substrate. To explore the C—O bond for-
mation, substrate 15b was prepared by aldol reaction between al-
dehyde 16 and ester methyl 2-(benzo[d][1,3]dioxol-4-yl)acetate
(99% yield, dr 12:1). After a partial separation of the syn and anti
aldol products, the Pd-catalyzed oxidative cyclization to 2,3-
Me
Me
Me
Rh2(R-DPCP)4 c-C6H12 74 1:1.1 19 -18
Rh2(S-DOSP)4 c-C6H12 71 1.0:1 <5
Rh2(S-BNP)4
7
c-C6H12 73 1.9:1 -19 -45
17 t-Bu Rh2(S-BTPCP)4 c-C6H12 77 2.8:1 42
63
18 t-Bu Rh2(S-biTISP)2 c-C6H12 77 2.5:1 -46 46
dyhydrobenzofuran was studied. Under the reported condi-
28,30
19 t-Bu
Rh2(S-BNP)4
c-C6H12 83 3.3:1 13
24
tions,
the pure syn-15b showed low reactivity, and only oxida-
tion to keto ester 17 was observed. On the other hand, a mixture of
syn-15b and anti-15b (~2:1) afforded trans 2,3-dihydrobenzofuran
24, ketone 17, and isomerically pure syn-15b.
a
diastereomer ratios were determined by 1H NMR analysis of crude
reaction mixture, enantiomeric excesses were determined by HPLC
analysis. bcombined isolated yield of cis-12 and trans-12.
These outcomes suggest that, unlike syn-15b, anti-15b can po-
tentially serve as a useful substrate for the synthesis of 2,3-
ACS Paragon Plus Environment

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Journal of the American Chemical Society
entry point to enantioenriched 2,3-dihydrobenzofuran 24 for applica-
tion in the total synthesis of maoecrystal V.
dihydrobenzofuran 24 via oxidative C—H functionalization, pro-
vided it is accessible in an enantio- and diastereoselective fashion.
32
1
2
3
4
5
6
7
8
An approach based on a trans-annular cyclization was also as-
sessed (Scheme 5). Nine-membered diazo lactone 19 was prepared
from keto ester 18 in 4 steps. No CH insertion product 20 was
observed upon treatment with Rh2(OAc)4, and only the corre-
sponding keto lactone was isolated along with the recovered start-
ing material.
Scheme 6.
1. NaOH, aq. MeOH, 0 o
C
2. C6H5COCl, Et3N, toluene;
then
O
R
O
O
O
O
O
O
O
N
O
O
O
MeO
OH
N
Scheme 5.
R
O
O
9
21a, 80% yield
21b, 63% yield
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
PMBO
PMBO
2 mol %
O
O
Rh2(OAc)4
N2
O
O
O
O
O
O
O
O
4A MS, CH2Cl2
18
4 steps
21a: R = CH3
21b: R = Ph
O
O
MeO2C
38%
yield
PMBO
O
O
O
N2
O
O
1. TsNHNH2, PhH
2. Et3N, CH2Cl2
18
19
20
O
O
N
R
O
In summary, among the catalytic asymmetric methods, the cur-
rent results suggest that only the conversion of 9 to cis-10 in the
presence of Rh2(S-PTTL)4 at reflux in DCM (53% yield, 10:1 dr,
60% ee, Table 1, entry 8) could be considered for a potential appli-
cation in the enantioselective total synthesis of 1.
22a, 77% yield
22b, 63% yield
PMBO
22a: R = CH3
22b: R = Ph
Table 3. Lactamide and mandelamide as chiral auxiliaries
Auxiliary based approaches. Chiral auxiliaries attached at the ester
carbonyl group have been shown to be effective instruments for
controlling stereochemistry in C—H-functionalization reactions of
2 mol % catalyst
4A MS solvent
23 oC, 24 h
O
CH3ONa
CH3OH, 23 o
5 min
O
N
O
C
O
31
O
O
MeO
O
diazo esters, with several applications in total synthesis. Our initial
22a
or
10
O
R
PMBO
foray into the auxiliary-based methods began with menthol as the
stereodirecting group, which was found to be ineffective. Signifi-
cantly improved stereocontrol was achieved when pyrrolidine am-
ides from lactic and mandelic acids were investigated. The prepara-
tion of the substrates from keto ester 18 was accomplished in 4
steps as illustrated in Scheme 6.
yield 1
PMBO
yield 2
22b
O
O
23a: R = CH3
23b: R = Ph
24
entry
sm
catalyst
solvent
yield
1 a
yield
2b
ee
e
%
-
Diastereoselective C—H insertions with lactamide 22a and man-
delamide 22b have been investigated with a selected group of catalysts
under different reaction conditions. Although only the cis-23a and cis-
23b are shown in Table 3, up to four diastereomeric products are pro-
duced in the reaction. To simplify analysis, the mixture of diastere-
1
2
22a Rh2(S-PTAD)4
22a Rh2(R-PTAD)4
22a Rh2(S-DOSP)4
22a Rh2(R-DOSP)4
22a Rh2(OAc)4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
PhMe
<10%
<10%
63%
74%
84%
0%
-
-
-
3
83%
86%
84%
-
62
70
65
-
omers was subjected to
a rather facile methanolysis (CH3ONa,
4
CH3OH, 23 °C, 5 min), which also accomplishes complete isomeriza-
tion at C10 giving only the trans-substituted product (24) in pure
form, enantiomeric excess of which was then measured by HPLC. The
initial screening with Rh2(R-DOSP)4 catalyst revealed that CH2Cl2 was
the optimal solvent, while the reactivity was lower in toluene and, espe-
cially, in cyclohexane (entries 4, 8-10), while the use of acetonitrile
resulted in decomposition. The diastereoselectivity was low in dichlo-
roethane (entry 7). The catalysts Rh2(S-PTAD)4 , Rh2(R-PTAD)4, and
Rh2(pfb)4 were also unreactive (entries 1, 2, 6). The highest yields and
diastereoselectivities in the formation of 23a were first observed with
both Rh2(S-DOSP)4 and Rh2(R-DOSP)4 (entries 3, 4). After meth-
anolysis, the same enantiomer of 24 was produced from both catalysts
in 62 and 70% ee, respectively. The use of the simple achiral catalyst
Rh2(OAc)4 led to comparable results, giving 24 in 65% ee in good yield
(entry 5). Further improvements were achieved with mandelamide
substrate 22b. While the enantiomeric purity of the final methanolysis
product 24 was somewhat lower with Rh2(S-DOSP)4 and Rh2(R-
DOSP)4 (entries 11, 12), dirhodium tetraacetate provided 24 in 76%
ee.
5
6
22a Rh2(O2CC4F9)4
22a Rh2(R-DOSP)4
22a Rh2(R-DOSP)4
22a Rh2(R-DOSP)4
22a Rh2(R-DOSP)4
23b Rh2(S-DOSP)4
23b Rh2(R-DOSP)4
23b Rh2(OAc)4
7
72%
61%
<10%
0%
-
-
8
-
-
9
c-C6H12
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-
-
10
11
12
13
14
-
-
84%
57%
72%
61%d
89%
77%
85%c
84%
59
52
76
84
23b Rh2(OAc)4
a isolated yield bcombined isolated yield c isolated yield, complete isom-
d
erization to the trans isomer is observed major diastereomer is isolat-
ed in pure form by column chromatography. e determined by HPLC
Investigation of the IMDA reaction. As illustrated in Schemes
1 and 2, a key reaction en route to 1 is the formation of the bicy-
clo[2.2.2]octan-2-one subunit by an IMDA addition. We intend-
ed to pursue a tether-based delivery of ethylene as a dienophile in
the IMDA reaction. A range of tether groups that we considered for
this purpose is indicated in Figure 3. Among constrains placed on
The optimal enantiomeric purity of 84% ee was obtained from 22b
with Rh2(OAc)4 after a careful chromatographic purification of the
major diastereomer, which prevented erosion of enantiomeric purity
upon methanolysis (entry 14). Overall, this result provided a practical
33
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Journal of the American Chemical Society
Page 6 of 13
the tether groups for the total synthesis applications are 1) efficient drolytic workup, the final product 31 with a free hydroxyl is isolat-
1
2
3
4
5
6
7
8
installation, 2) capacity to enable a high-yielding IMDA process,
and 3) efficient removal, ideally in one step. We previously de-
scribed preliminary studies that targeted compounds 25a-c. Alt-
hough they have been very informative in validating the IMDA
approach, the third constrain was not fulfilled as the tether removal
from compounds 25a-c required several steps at best and was
deemed inefficient.
ed. An alternative, more complex pathway is depicted in Scheme 8.
Here, the first step is an admittedly speculative and, as far as we
know, unprecedented formation of cyclopropanol intermediate 33
from the initial [4+2] cycloadduct 25d. This apparent intramolecu-
lar nucleophilic attack of an alkylboronate on the carbonyl group is
possibly aided by a secondary overlap between the πC—O and σ∗C—B
bonds. The resulting enol ether in 33 should be particularly suscep-
tible to protonation because of the strong stabilizing effect of the
adjacent cyclopropanol substituent, which should give a highly
stabilized non-classical carbocation represented by resonance
34
OEt
OEt
OEt
O
O
O
OEt
OEt
OEt
BnO
BnO
BnO
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
O
O
O
O
20
O
37
O
S
O
O
forms 34a, 34b, and 34 c. Its deprotonation affords 30c directly.
O
O
O
Scheme 7.
25a
25b
25c
LDA, THF; Et2Zn
OEt
OEt
O
O
BnO
OEt
OEt
BnOCH2Cl, DMPU
-15 oC, 1 h; 23 oC, 1 h
O
O
BnO
BnO
MeO2C
MeO2C
O
LiAlH4, THF, 0 o
C
O
O
O
O
O
B
Si
95% yield
dr> 20:1
O
O
93% yield
OBu-n
26
trans-10
25d
25e
Figure 3. Potential products of the key IMDA reaction considered for
the total synthesis of maoecrystal V.
PhI(O2CCF3)2
NaHCO3, EtOH
23 oC, 15 min
BnO
BnO
O
CH3MgBr, Et2O
PhH, 80 oC, 8 h
OH
HO
HO
O
OEt
The butyl boronate (25d) and dimethylsilyl tethers (25e) ap-
peared to be more promising. We were especially intrigued by the
borinate tether because it has found limited application in the con-
text of total synthesis and promised the development of new chem-
O
O
98% yield
94% yield
28
27
35
Bu
istry during the course of its removal. With the goal of exploring
B(OBu)2
O
BnO
BnO
the boronate tether, the synthesis of the substrate (29) was initiat-
ed by benzyloxymethylation of trans-10 (Scheme 7). Consistently
with our previous experience, the enolate alkylation was best per-
O
BHT, o-C6H4Cl2
130 oC, 4 h
O
B
OEt
OEt
OEt
OEt
HO
O
O
O
36
formed through the intermediacy of the zinc-ate enolate. Alkyla-
30a
29
tion product 26 was produced in 95% yield as a single isomer. Re-
duction of the methyl ester with LiAlH4 was followed by elabora-
tion of the dioxolane ring in 27 by the action of methylmagnesium
bromide at 80 °C in benzene, which delivered 2-ethoxy phenol 28
in 91% yield over the 2 steps. A rapid oxidation of the phenol with
PhI(O2CCF3)2 in ethanol (15 min, 94% yield) provided the sub-
strate for the IMDA reaction.
OEt
O
OEt
OEt
OEt
O
OEt
O
O
OEt
BnO
H+
BnO
[4+2]
BnO
R
O
O
O
B
O
B
O
B
OBu
OBu
OBu
30a
25d
30b
not isolated
Vinylboronate 30a was generated from 29 and commercially
available vinylboronic acid dibutyl ester in situ through a facile
exchange reaction. Upon heating at 130 °C in o-dichlorobenzene, a
new product was formed in 72% yield in a rather clean reaction.
Contrary to our expectations, the product was not the direct IMDA
addition product 25d, but appeared to lack the boronic ester group.
Based on NMR studies of the product, including NOE and ho-
modecoupling experiments, our initial hypothesis was that we for-
tuitously obtained protodeboronation product 32 (Scheme 7),
which is well suited for our synthesis plans. However, the true iden-
tity of the product has only been conclusively deduced after com-
pletion of the total synthesis, which revealed that the product (31)
contained the rearranged bicyclo[3.2.1]octan-7-one ring system
(vide infra).
EtO
O
EtO
O
OEt
OEt
OEt
EtO
O
H2O
(workup)
O
O
O
(BuO)2B
O
HO
72%
yield
HO
BnO
BnO
OBn
30c
31
31
OEt
O
OEt
BnO
32
O
OH
Several reaction pathways can be considered for the formation of
31 from 30a. Although details are not clear at present, our current
hypothesis favors a simplest path and involves the initial formation
of [4+2] cycloadduct 25d. Proton transfer to enol ether 25d forms
a stabilized oxycarbenium ion 30b. The 1,2-shift of the acyl group,
which should be further facilitated by the properly aligned carbon-
boron bond, leads directly to deborylation product 30c. After hy-
Evaluation of the silicon tether began with silylation of interme-
diate 29 with dimethylvinylchlorosilane (Scheme 9a). The IMDA
reaction of silyl ether 35 took place smoothly upon heating at 120
°C for 6 h, giving the intended product in an excellent 96% yield.
An intermolecular variant of Diels-Alder reaction with two
dienophiles, nitroethylene and vinyl phenyl sulfide, was also ex-
amined for the construction of the bicyclo[2.2.2]octan-2-one ring
38
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Journal of the American Chemical Society
system of maoecrystal V (Scheme 9b). If successful, the nitro or ing conditions upon heating at 50 °C with DDQ, which afforded
1
2
3
4
5
6
7
8
phenylthio group could be removed by reduction under radical
conditions.
primary alcohol 39 in 75% yield along with recovered starting ma-
terial.
39
Scheme 8.
The final phase of the synthesis began with oxidation of 39 to al-
dehyde 40 with Dess-Martin periodinane (DMP) (88% yield)
followed by chemoselective addition of vinylmagnesium bromide
to aldehyde in the presence of the lactone and ketone groups (68%
yield, dr 5:1). Ring-closing metathesis in the presence of 20 mol %
Hoveyda-Grubbs II catalyst (HGII) accomplished the formation of
the last ring of the target compound in 86% yield. The resulting
product was oxidized to enone 43 with DMP in 85% yield. In the
final step, methylation of zincate enolate generated from 43 with
LiN(SiMe3)2 and Et2Zn occurred in excellent yield and essentially
complete diastereocontrol. NMR data of the final product did not
match those published for maoecrystal V, which prompted X-ray
crystallographic analysis of the product. A single crystal suitable for
analysis was produced by crystallization of the compound from
ethyl acetate and hexane. The XRD analysis revealed a fascinating,
unexpected structure 2, which we refer to as maoecrystal ZG. Its
origin was traced to 31, the product of the unusual reaction be-
tween cyclohexadienone 29 and dibutyl vinylboronate, and allowed
for unambiguously assignment of its structure.
Bu
O
H
OEt
OEt
OEt
HO
HO
O
OEt
OEt
OEt
BnO
BnO
BnO
H+
O
O
O
9
O
O
B
O
OBu
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
B(OBu)2
B(OBu)2
Bu
O
25d
33
34a
H
OEt
HO
EtO
O
OEt
HO
OEt
OEt
OEt
BnO
BnO
-H+
O
O
O
(BuO)2BO
BnO
O
O
B(OBu)2
B(OBu)2
34c
30c
34b
delocalized, O-stabilized
Scheme 10.
"non-classical" cation
OEt
OEt
EtO
O
EtO
O
1. Im2CO, THF, 35 oC, 3 h
Scheme 9.
2. (PhSe)2, NaBH4, DMF, 23 o
C
O
O
94% yield
a
HO
31
O
Si(CH3)2Cl
OBn
OBn
36
BnO
BnO
PhSe
O
O
ImH, CH2Cl2
0 oC, 30 min
Si
OEt
OEt
O
OEt
OEt
HO
O
120 oC, 6 h
96% yield
O
O
60% yield
OEt
O
O
EtO
n-Bu3SnH, AIBN
PhH, 70 oC, 14 h
SmI2, MeOH
THF, 23 oC, 2 h
35
X
29
O
O
87% yield
53% yield
b
O
O
O
O
OBn
OBn
OEt
O
38
OEt
37
BnO
PhMe
up to 160 oC
no DA addition
products
O
CH2=CHMgBr
THF, -78 o
29
Si
O
O
O
C
DMP, NaHCO3
DDQ, CH2Cl2
H2O, 50 oC, 19 h
X = NO2, SPh
30-45 min
CH2Cl2
25e
O
O
88%
yield
75% yield
68% yield
dr 5:1
O
O
O
O
(91% brsm)
The principal lessons that we drew from these studies are 1) the
IMDA reactions with the boron and silicon tethers were the most
valuable in meeting our synthetic needs, albeit giving drastically
different outcomes, and 2) intermolecular Diels-Alder reactions
with nitroethylene and vinyl phenyl sulfide as ethylene equivalents
did not appear to be promising.
O
OH
40
39
O
H
O
DMP, NaHCO3
CH2Cl2
20 mol % HGII
(CH2Cl)2, 80 o
H
C
O
O
86% yield
85% yield
OH
OH
Total synthesis of maoecrystal ZG (2). Even with some uncer-
tainty whether compound 32 was the product of the reaction be-
tween cyclohexadienone 29 and dibutyl vinylboronate, the synthe-
sis was advanced as delineated in Scheme 10. In retrospect, it be-
came clear that the actual product was in fact 31. Formation of the
lactone by radical cyclization was set up by the efficient conversion
of 31 to phenyl selenocarbonate 36 in 94% yield. Lactone 37
formed readily upon treatment of 36 with tri-n-butyltin hydride in
the presence of AIBN at reflux in benzene, requiring little optimiza-
tion (53% yield). Minor reduction to the corresponding formate
was also observed (~5%), in addition to other unidentified byprod-
ucts. At this stage the gem-ethoxy substituents were removed by
reduction with samarium(II) iodide in the presence of methanol
(87% yield). Cleavage of the benzyl ether was achieved under forc-
O
O
O
O
41
42
Li(NSiMe3)2, THF
Et2Zn, DMPU, CH3I
-78 oC, 30 min
O
O
H
H
O
O
93% yield
dr >20:1
O
O
O
O
O
O
(X-ray structure)
43
2
Although falling short of completing the total synthesis of 1, this
effort resulted in several important contributions. First, the efficient
conversion of cyclohexadienone 29 to 31 in the presence of vinyl-
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Journal of the American Chemical Society
Page 8 of 13
boronic esters is of fundamental interest and provides an effective reaction 54. In accord with the previous experience, its clean con-
1
2
3
4
5
6
7
8
entry to functionalized bicyclo[3.2.1]octan-6-one ring systems.
Second, maoecrystal ZG, an isomer of 1, is appears to be a new
natural-product-like chemical entity. Its pentacyclic 6,7-dinor-
5,8;9a,20-diepoxy-ent-kaurane skeleton appears to have no prece-
dent among natural products or other known organic compounds.
Given its fairly efficient synthesis in 18 straightforward steps and
~4% overall yield from sesamol, over 10 mg was produced after the
first effort; an amount sufficient for a preliminary biological evalua-
tion of 2.
version to [4+2] adduct 55 was achieved after heating in toluene at
110 °C for 24 h, which was followed by reductive removal of the
two germinal ethoxy groups with samarium(II) iodide.
Desilylation of 56 and related [4+2] cycloadducts was compli-
cated by competing formation of rearranged products b and c (Ta-
ble 4). The reaction was studied in greater detail to optimize the
yield of the requisite product a. The initial attempts focused on
screening solvents using n-Bu4NF as the reagent (entries 1-11).
These studies revealed that the ratio of the three products was sig-
nificantly influenced by the choice of solvent. Low reactivity was
observed in protic solvents. Among the polar aprotic solvents,
DMPU emerged as the optimal medium to maximize the fraction
of the requisite product a (entry 8). Tetrabutylammonium tri-
phenyldifluorosilicate, a milder desilylation reagent, strongly fa-
vored rearranged product b (entry 13), or showed no reactivity in
tert-butanol (entry 14), as did cesium fluoride (entry 12). These
data indicate that a balance between the pH and reactivity is need-
ed to achieve the desired outcome in the desilylation reaction.
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
Enatioselective total synthesis of (–)-maoecrystal V (1).
Given the unforeseen creation of 2, the approach to maoecrystal V
had to be reevaluated. The success was eventually achieved
through the use of the silyl tether in the key IMDA reaction (cf.
25e, Scheme 9). The initial incursion entailed desilylation of 25e,
which turned out to be challenging. During the course of our work
we found it to be advantageous to carry out the removal of the gem-
ethoxy substituents and enolate methylation first. In the event,
treatment of 25e with SmI2 and subsequent exposure of the zincate
enolate from 44 to CH3I provided intermediate 45 (Scheme 11).
Its elaboration to selenocarbonate 47 was followed by radical cy-
clization upon treatment with n-Bu3SnH and azo-
bis(cyclohexanecarbonitrile) (ABCN) at 80 °C in benzene. Sur-
prisingly, 8-membered lactone 48 was the major product, which
was produced in addition to ~10% of formate 49. None of the ex-
pected six-membered lactone formed by cyclization of the acyl
radical onto the enol ether was observed.
We also found that carrying out desilylation immediately after
the IMDA reaction before removal of the gem-ethoxy substituents
(X = OEt) was less efficient (entries 15-18, cf. entries 15 and 18).
The presence of the ethoxy groups favored the formation of rear-
ranged byproduct to a greater extent.
Scheme 12.
LDA, THF; Et2Zn
BnO
BnOCH2Cl, DMPU
-15 oC, 1 h; 23 oC, 1 h
O
O
MeO2C
Scheme 11.
MeO2C
LiAlH4, THF, 0 o
C
O
O
PMBO
PMBO
O
Li(NSiMe3)2, THF
O
80% yield
over 2 steps
dr >30:1
OEt
O
O
Et2Zn, DMPU, CH3I
-50 oC, 20 min
SmI2, MeOH
THF, 23 oC, 2.5 h
OEt
24
50
BnO
BnO
(88% ee)
O
O
94% yield
95% yield
dr >20:1
PhI(O2CCF3)2
NaHCO3, EtOH
23 oC, 15 min
Si
O
Si
BnO
BnO
O
O
CH3MgBr, Et2O
PhH, 80 oC, 8 h
OH
HO
HO
O
OEt
25e
44
PMBO
PMBO
O
O
91% yield
99% yield
1. Im2CO, THF, 40 oC, 1.5 h
2. (PhSe)2, NaBH4, DMF
23 oC, 1.5 h
52
51
n-Bu4NF, DMSO
23 oC, 10 min
O
O
H
H
BnO
BnO
Si(CH3)2Cl
O
76% yield
30% yield
BnO
O
BnO
O
PhMe
110 oC, 24 h
O
ImH, CH2Cl2
0 oC, 30 min
Si
Si
OH
46
OEt
OEt
OEt
OEt
O
HO
O
45
PMBO
PMBO
O
O
97% yield
87% yield
54
53
n-Bu3SnH
ABCN, PhH
80 oC, 2h
O
H
O
H
BnO
O
O
H
BnO
BnO
OEt
O
O
+
OEt
SmI2, MeOH
BnO
BnO
O
O
PMBO
THF, 23 o
C
PMBO
O
O
O
O
O
O
85% yield
O
H
Si
O
SePh
Si
O
O
49
~10%
47
48
55
56
63% yield
Finally, desilylation of the selected total synthesis intermediate
56 (X = H, Y = H, OPMB, entry 20, Table 4) was best accom-
plished upon treatment with tetrabutylammonium fluoride at 0 °C
for 1 h, which afforded the desired product in 50% yield. It is note-
worthy that the desilylation was greatly activated by the C15 car-
bonyl group. The reactivity of the corresponding C15 alcohol was
substantially lower, requiring heating at 80 °C for 12 h for the reac-
tion to reach completion. No improvement in the chemical yield
was observed with the reduced substrate.
After exploring alternatives, a decision has been made to set the
synthesis back to p-methoxybenzyl ether 24 that lacks the terminal
olefin competing in the radical cyclization (Scheme 12). Starting
with enantioenriched 24 (84% ee), the synthesis followed the same
blueprint through the IMDA reaction. The lithium enolate gener-
ated from 24 was successively treated with Et2Zn and
BnOCH2Cl/DMPU, affording 50 in 20:1 dr. Reduction of the
methyl ester, dioxolane cleavage, phenol oxidation, and silylation
with vinyldimethylchlorosilane provided precursor of the IMDA
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There are some noteworthy similarities in the results of the desi-
Table 4.
1
lylation reaction in Table 4 and the proposed formation of 30c
depicted in Scheme 8. In particular, the structures of cyclopropanol
byproduct c in Table 4, and intermediate 33 (Scheme 8) are very
similar. Both appear to be unstable and readily converted to distinct
bicyclo[3.2.1]octan-6-one derivatives b (Table 4) or 30c (Scheme
8), respectively, although the reasons for the divergent reactivity of
the cyclopropanol intermediates are not clear.
O
X
X
O
X
BnO
2
3
X
reagent
solvent
BnO
HO
Y
+
X
O
X
O
temp., time
4
5
BnO
O
15
Y
OH
Y
b
O
a
X
HO
6
7
X
Si
O
BnO
Y
8
9
O
The next immediate goal after desilylation of 56 was introduc-
tion of the six-membered lactone by radical cyclization onto enol
ether, with regioselectivity opposite to its electronic preferences
(Scheme 13). This is a relatively uncommon transformation with
HO
c
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
entry
X
Y
reagent
solvent
temp,
time
a:b:cx
40
only few examples reported in the literature. In our case, only one
(yield, a)
regiochemical outcome is possible due to structural constrains
within the starting material. In the current substrate, selenocar-
bonate 58, the 4-methoxybenzyloxy substituent at C3 replaces the
terminal double bond to avoid competitive cyclization to 8-
membered lactone, the reactivity mode overwhelmingly favored for
selenocarbonate 47 (Scheme 11).
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H, OBn
Bu4NF, DMSO
Bu4NF, DMSO
Bu4NF, DMF
Bu4NF, DMF
Bu4NF, DMF
0 °C,
0.2 h
1.0:1.8:1
(20%)
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
H, OBn
CH2
0.9:1.5:1
1.5:1.3:1
2.3:1.8:1
1.9:1.6:1
1.6:1.3:1
1.4:1.7:1
3.2:1.8:1
2.4:1.7:1
0.3:1.2:1
n. r.
23 °C,
0.2 h
3
-20 °C,
2 h
Scheme 13.
4
0 °C,
0.5 h
O
O
BnO
Bu4NF, DMPU, 0 oC, 1 h
BnO
PMBO
PMBO
5
23 °C,
0.3 h
O
O
40-50% yield
Si
O
HO
6
Bu4NF, DMF,
(slow addition)
23 °C,
3.2 h
57
56
7
Bu4NF, NMP
Bu4NF, DMPU
Bu4NF, DMA
0 °C,
1.0 h
O
1. Im2CO, THF, 23 oC, 14 h
2. (PhSe)2, NaBH4, DMF, 23 o
(Me3Si)3SiH, AIBN
PhH, 80 oC, 12 h
BnO
3
C
PMBO
8
0 °C,
1.0 h
O
O
87% yield
40-55% yield
SePh
O
9
0 °C,
0.5 h
58
10
11
12
13
14
15
16
17
18
19
20
x
Bu4NF, DMSO-t- 75 °C,
LiN(SiMe3)2
CH3I, THF
-40 oC, 5 h
1. DDQ, CH2Cl2-H2O
2. DMP, CH2Cl2
BuOH (4:1)
1 h
O
O
BnO
BnO
3. Ph3P=CH2, THF
Bu4NF, AcOH,
THF
0 °C,
1.0 h
PMBO
O
O
O
90% yield
dr 7:1
55% yield
O
O
O
CsF, t-BuOH
n. r.
70 °C,
15 h
59
60
0:20:1
Bu4NPh3SiF2,
DMSO
50 °C,
36 h
1. DDQ. CH2Cl2-H2O
2. DMP, CH2Cl2,
1. 20 mol % HGII
(CH2Cl)2, 80 o
n. r.
Bu4NPh3SiF2, t-
BuOH
50 °C,
15 h
O
O
OH
C
BnO
16
3. CH2=CHMgBr
2. DMP, CH2Cl2
OEt
OEt
OEt
H
Bu4NF, DMF
Bu4NF, THF
Bu4NF, MeCN
Bu4NF, DMF
Bu4NF, DMA
Bu4NF, DMPU
23 °C,
0.2 h
0.8:5.1:1
(7%)
O
O
O
88%
yield
65% yield
dr >10:1
O
O
O
CH2
n. r.
(–)-maoecrystal V
(1)
23 °C,
0.5 h
62
61
CH2
0:3.4:1
23 °C,
0.2 h
In analogy to selenocarbonate 47, the initial attempts at the radi-
cal cyclization of 58 utilized n-Bu3SnN/AIBN reagent system un-
der various conditions. The results were disappointing. Although
the acyl radical was clearly generated, the rate of the 6-exo-
cyclization on to the enol ether was very low in comparison to its
reduction to the corresponding formate ester, which occured in up
to 84% yield. To reduce the rate of hydrogen abstraction by the acyl
radical, and thus favor the cyclization, we investigated
CH2
1.1:3.6:1
2.9:2.2:1
23 °C,
0.5 h
H
H, OPMB
H, OPMB
0 °C,
1.0 h
H
0 °C,
1.0 h
3.2:1.9:1
40-50%
41
tris(trimethylsilyl)silane as a replacement for n-Bu3SnH. An im-
deteremined by NMR analysis of the crude mixture of products.
mediate improvement was observed, apparently due to the longer
Isolated yield of a is given in parenthesis
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lifetime of the acyl radical. Under optimized reaction conditions, ly used because it performed best in the presence of functional
1
2
3
4
5
6
7
8
the isolated yields of the desired lactone 59 were in the range of 40-
55%. Notably, the main side product in this reaction results from
decarboxylative fragmentation of the acyl radical rather than its
groups necessary for the total synthesis application. The synthesis
required 26 linear steps from sesamol (3 steps longer than our syn-
thesis of racemic 1), affording (–)-maoecrystal V in ~0.21% overall
yield.
21
reduction to the formate.
The final phase of the total synthesis began with a three-step
conversion of 59 to alkene 60 by oxidative removal of the PMB
ether with DDQ, oxidation of the primary alcohol with Dess-
Martin periodinane (DMP), and Wittig methylenation (55% yield
over 3 steps). Diastereoselective installation of the methyl group at
An unexpected course of the IMDA reaction with a tethered vi-
nylboronate led to the initial synthesis of an isomeric product,
which we refer to as maoecrystal ZG (2). This compound has a
rearranged pentacyclic 6,7-dinor-5,8;9a,20-diepoxy-ent-kaurane
skeleton which apparently has no precedent in the realm of natural
products, or in fact of any known organic compounds. Evaluation
of its cytotoxic activity in the NCI 60 Cell Panel revealed no growth
inhibition across the entire panel, underscoring the unique and
selective activity of maoecrytsal V itself, which displays selective
nanomolar activity against the HeLa cell line.
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
C16 has been problematic in the previously reported total synthe-
19,20
ses of 1.
With ketone 60 as the substrate, α-methylation at C16
was accomplished with 7:1 diastereoselectivity in excellent yield. If
this alkylation reaction is postponed until the last step, after instal-
lation of the cyclohexenone, a 1:1 mixture of diastereomers is pro-
duced. Also, when LDA is used in place of LiN(SiMe3)2 for enolate
generation, substantially lower yields of 61 were observed due to
unidentified side reactions.
The expected outcome of the central IMDA reaction using a sili-
con tether provided the bicyclo[2.2.2]octan-2-one ring system,
thus enabling the successful completion of the enantioselective
total synthesis of (–)-maoecrystal V, which confirmed the assign-
ment of its absolute stereochemistry.
Oxidative cleavage of the benzyl ether (61) was accomplished in
the presence of DDQ in aqueous dichloromethane at 50 °C for 12
h. Oxidation with DMP followed by the addition of vinylmagnesi-
um bromide in the presence of CeCl3 afforded allylic alcohol 62 as
a single diastereomer in 65% overall yield after the three steps.
Ring-closing methathesis (20 moll % Hoveyda-Grubbs II catalyst,
1,2-dichloroethane, 80 °C, 3 h) afforded a mixture of the expected
allylic alcohol along with the oxidation product, (–)-maoecrystal V.
A full oxidation of the mixture with DMP completed the enantiose-
lective synthesis of 1, affording 10 mg of the natural product
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures, charac-
terization data, copies of 1H, 13C NMR spectra, HPLC traces, and crys-
tallographic CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
25
([ α ]25 –101.1° (c 0.3, CH3OH); lit. ([ α ] –92.9° (c 0.7,
6
AUTHOR INFORMATION
D
D
CH3OH).
Corresponding Author
Investigation of antiproliferative properties of maoecrystal
ZG (2). Maoecrystal V (1) has shown potent and selective cytotox-
ic activity against HeLa cell line, with activity for K562, A549 lung
carcinoma, and BGC-823 adenocarcinoma reduced by at least 6
orders of magnitude. Because maoecrystal ZG (2), and artificial
structural isomer of 1, retains the electrophilic cyclohexenone moi-
ety of the natural product and apparently represents a novel chemi-
cal entity, we explored its cytotoxic properties with the assistance of
the NCI-60 DTP Human Tumor Cell Line Screen. Somewhat
* hmdavie@emory.edu, zakarian@chem.ucsb.edu
Present Addresses
§ Present address: Department of Chemistry, University of Science and
Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China.
Author Contributions
⊥
Authors A.M. and P.L. contributed equally.
ACKNOWLEDGMENT
remarkably, 2 showed virtually no growth inhibition at 10 µM con-
centration across the entire cell panel, underscoring the remarkable
cytotoxicity profile of maoecrystal V.
We thank the Developmental Therapeutics Program at NCI for per-
forming the in vitro antitumor screen of 2. A.Z. thanks the NSF (CHE-
0836757) and NIGMS (R01 GM077379) for supporting this research.
H.M.L.D., D.M.G, and H.W. were supported by NSF under the CCI
for Selective C—H Functionalization, CHE-1205646. NMR instru-
mentation at UC Santa Barbara was supported by the NIH
#1S10OD012077-01A1. We thank Dr. Hongjun Zhou (UCSB) for
assistance with NMR spectroscopy, and Dr. Guang Wu (UCSB) for
assistance with X-ray crystallography.
CONCLUSION
The first enantioselective synthesis of (–)-maoecrystal V was en-
abled by a stereoselective Rh-catalyzed C—H functionalization as
the enantiodetermining step. This reaction provided the key 2,3-
dihydrobenzofuran precursor in 84% ee. Catalytic asymmetric and
auxiliary-enabled approaches have been investigated. Although
both proved promising, the auxiliary-based approach was ultimate-
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38
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39 For removal of nitro group under radical conditions, see: (a) Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron Lett.
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O
O
O
H
O
O
O
O
O
O
O
(–)-maoecrystal V
maoecrystal ZG
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