Enantioselective Total Syntheses of Various Amphilectane and Serrulatane Diterpenoids via Cope Rearrangements

Article abstract of DOI:10.1021/jacs.6b02624

Ampilectane and serrulatane natural products are structurally and stereochemically complex compounds that display various potent pharmacological activities ranging from anti-inflammatory to antituberculosis. A general synthetic route toward this family of natural products has been developed, which accomplished a number of amphilectane and serrulatane natural products. The key step employed a stereoselective Cope rearrangement either promoted by gold catalysis or thermal conditions, while a regioselective gold-catalyzed 6-endo-dig cyclization was optimized to afford a precursor. The preparation of the chiral β-ketoester as a starting material was established via an optimized asymmetric 1,4-addition followed by trapping with Manders reagent, and this initially installed stereogenic center provided good control in the subsequent introduction of all the other stereocenters. A rarely investigated one-pot conversion of α-pyrone into phenol was also examined to enable the syntheses. DFT calculations explain the high stereoselectivity of the Cope rearrangement of the intermediate that eventually led to amphilectolide and caribenol A.

Full text of DOI:10.1021/jacs.6b02624

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Article
Enantioselective Total Syntheses of Various Amphilectane
and Serrulatane Diterpenoids via Cope Rearrangements
Xuerong Yu, Fan Su, Chang Liu, Haosen Yuan, Shan Zhao, Zhiyao Zhou, Tianfei Quan, and Tuoping Luo
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Apr 2016
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Enantioselective Total Syntheses of Various Amphilectane and
Serrulatane Diterpenoids via Cope Rearrangements
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Xuerong Yu,† Fan Su,† Chang Liu,† Haosen Yuan,† Shan Zhao,† Zhiyao Zhou,† Tianfei Quan,‡
†,
‡
Tuoping Luo*,
†Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National
Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing
100871, China, ‡Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking
University, Beijing 100871, China
ABSTRACT: Ampilectane and serrulatane natural products are structurally and stereochemically complex compounds that
display various potent pharmacological activities ranging from anti-inflammatory to anti-tuberculosis. A general synthetic
route towards this family of natural products has been developed, which accomplished a number of amphilectane and
serrulatane natural products. The key step employed a stereoselective Cope rearrangement either promoted by gold catal-
ysis or thermal conditions, while a regioselective gold-catalyzed 6-endo-dig cyclization was optimized to afford a precursor.
The preparation of the chiral β-ketoester as a starting material was established via an optimized asymmetric 1,4-addition
followed by trapping with Mander’s reagent, and this initially installed stereogenic center provided good control in the
subsequent introduction of all the other stereocenters. A rarely investigated one-pot conversion of α-pyrone into phenol
was also examined to enable the syntheses. DFT calculations explain the high stereoselectivity of the Cope rearrangement
of the intermediate that eventually led to amphilectolide and caribenol A.
Introduction
sides have attracted most attention because of their prom-
ising anti-inflammatory and analgesic properties.8 At-
tempts to simplify the lipophilic aglycones have yet to pro-
vide analogs superior to their natural counterparts (such as
pseudopterosins A and E), revealing the privileged molec-
ular features of the corresponding amphilectane and ser-
rulatane skeletons.9 Investigation into their molecular
mode of action has been inconclusive, even though adeno-
sine receptors have been suggested as potential targets of
pseudopterosins to explain their capability of promoting
wound healing.9a,10 Seco-pseudopterosins, such as 2, also
have potent anti-inflammatory activities even though the
aglycone has a serrulatane instead of amphilectane skele-
ton.11 Interestingly, pseudopterosin A (1) has also been re-
ported to possess strong antibacterial activity against sev-
eral Gram-positive bacteria,12 while pseudopterosin G (3),
the aglycone of which is an epimer of pseudopterosin A
aglycone, has been recently reported to have similar anti-
bacterial spectrum and potency.13
The Cope rearrangement is particularly suited for con-
structing congested stereocenters in complex molecules.1,2
However, the reversibility of the Cope rearrangement
means that strategies must be designed to shift the equi-
librium between the starting material and the product. In
one recent noticeable advance of Cope rearrangement,
Tantillo and Gagné et al. realized the gold-catalyzed enan-
tioselective Cope rearrangement of 1,5-dienes with a termi-
nal methylenecyclopropane motif.3 Enabled by the release
of ring strain on rearrangement, their work remain the
only gold-catalyzed Cope rearrangement reported to date
even if gold-catalyzed heteroatom variants of Cope reac-
tion such as aza-Claisen have been well-documented.4 An-
other strategy of driving the Cope reaction is the introduc-
tion of conjugative stabilization or even aromaticity. This
was actually disclosed in the first Cope rearrangement re-
ported5 but remains rarely explored in total synthesis in
comparison to strain-release Cope and oxy-Cope rear-
rangements.2,6 Recognizing the structural features of am-
philectane and serrulatane diterpenoids isolated from
Pseudopterogorgia elisabethae (Figure 1)7 provide a unique
opportunity for advancing such strategy, we herein de-
scribe a concise and collective synthesis of various bioac-
tive natural products based on the powerful Cope rear-
rangement, promoted by either the gold catalyst or the
thermal conditions.
For amphilectane and serrulatane diterpenoids without
the sugar moiety, one promising biological activity is their
capability to inhibit the growth of H37Rv strain and multi-
drug resistant Mycobacterium tuberculosis.14 Among these
compounds, pseudopteroxazole (4) and erogorgiaene (5)
were isolated from P. elisabethae,14a,14b whereas leubethanol
(6) was isolated from the root bark of Leucophyllum fru-
tescens, an evergreen shrub used in Mexican traditional
medicine.14c The different origin may explain the variation
at the C3 and C6 stereochemistry. Moreover, amphilec-
Among numerous bioactive amphilectane and serru-
latane natural products, pseudopterosin diterpene glyco-
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tolide (7) and caribenol A (8), two natural products biosyn- and 8, would be difficult to access from the aromatic start-
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thetically related to amphilectanes, have also been re-
ported to be active against M. tuberculosis H37Rv.15 The
structure-activity relationship studies of pseudopteroxa-
zole (4) and leubethanol (6) have been carried out using
analogs obtained through semi-synthesis, but the associ-
ated mechanism-of-action has yet been identified.13b,16 Im-
portantly, a number of antibiotic resistant strains do not
exhibit cross-resistance to these amphilectane and serru-
latane diterpenoids, suggesting the unique mechanism-of-
action of this chemotype and the potential for drug devel-
opment.13b,14c,16c
ing materials. For the syntheses commencing from other
starting materials, cycloaddition reactions especially Diels-
Alder reactions have always been deployed to make the
highly substituted six-membered rings within the targeted
natural products.20 A new strategy towards these promis-
ing diterpenoids, especially that is amenable to the collec-
tive total synthesis,21 could not only complement to exist-
ing synthetic routes but also provide novel analogs and
corresponding small-molecule probes for chemical biology
studies.
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The chemical syntheses of various amphilectane and ser-
rulatane diterpenoids have been intensively investigated,
leading to the accomplishment of a variety of natural prod-
ucts within this family.17-20 As a matter of fact, the total syn-
thesis has significantly helped the structural revision of
natural products, such as pseudopterosin G aglycone,
pseudopteroxazole (4) and helioporins C-E.18 However,
probing the corresponding biological activity using the de
novo synthesized natural products or analogs have been
limited.
Results and Discussion
Retrosynthetic Design. Aiming for a modular and effi-
cient synthesis, we postulated that the key intermediate 9,
if realized in a diastereoselective and enantioselective ap-
proach, would be converted to a number of the desired nat-
ural products (Figure 2). Challenged by the absence of tra-
ditional neighboring controlling functionalities around C3,
C6 and C7 stereogenic centers (pseudopterosin A number-
ing, throughout), we envisioned a stereocontrolled Cope
rearrangement of 10 to transfer the desired chirality via a
chair-like transition state. This transformation would in-
troduce not only the vinyl moiety for subsequent manipu-
lations, but also the double bond in the A ring that is tai-
lored to the specific target. We believed the conversion of
10 to 9 could be readily achieved if appropriate thermody-
namic driving force were provided. Bicyclic intermediate
10 could in turn be prepared from substituted cyclohexa-
none 11 by the formation of ring A, while the trans relation-
ship of the methyl group and the alkene side chain could
be readily established by alkylation of the corresponding β-
ketoester 12. Therefore, the preparation of enantiomeri-
cally pure 12 would be the starting point for the enantiose-
lective total syntheses of amphilectane and serrulatane
diterpenoids.
Figure 1. Representative amphilectane and serrulatane
diterpenoids
From the starting material point of view, monoterpene
natural products and substituted benzenes have been
widely used.19 However, the available chiral monoterpenes
limits the potential structural changes that could be made
on the natural products, whereas amphilectane and serru-
latane diterpenoids without the benzene ring, such as 7
Figure 2. A unified retrosynthetic analysis of amphilectane
and serrulatane diterpenoids
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Scheme 1. Synthesis of 7-epi-erogorgiaene (20)a
closure of ring A through alkyne activation. Gratifyingly,
1
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7
8
we found that 5 mol% (PPh3)AuNTf2 enabled a cascade
reaction from 15 to give bicycle 19 in 57% yield as the only
isolable product, which furnished the desired skeleton in
one step. We propose that the reaction mechanism be-
gins with a 1,5-enyne cycloisomerization en route to 18 via
cyclopropyl gold carbene 16 and its resonance structure
17,23 and the following reverse aromatic Cope rearrange-
ment produces the final product 19. Notably, the mild
conditions of this Cope rearrangement suggest the in-
volvement of the cationic gold complex as a catalyst. Sub-
sequent hydroboration of 19 with 9-BBN followed by the
palladium-catalyzed coupling with 1-iodo-2-methylprop-
1-ene furnished 7-epi-erogorgiaene (20) in 60% yield over
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1
13
two steps. The H NMR and C NMR spectra of 20 pre-
pared by us are identical to those reported by Aggarwal
and co-workers.19q
Scheme 2. Gold-catalyzed reaction of enyne 26 led to
6,5-bicycle 28a
aReagents and conditions: a) NaH (1.1 equiv), crotyl bro-
mide (1.1 equiv), DMF, 0 °C, 3 h, 78% (E/Z = 6:1); b) LiHMDS
(1.1 equiv), THF, −78 °C to 0 °C, 0.5 h; then PhNTf2 (1.1
equiv), −78 °C to 25 °C, 3 h; c) Pd(PPh3)2Cl2 (0.1 equiv), CuI
(0.05 equiv), Et3N (3.0 equiv), propyne, DMF, 25 °C, 4 h, 84%
(2 steps); d) DIBAL-H (3.0 equiv), THF, −78 °C to 25 °C, 8
h; e) DMP (1.04 equiv), pyridine (5.0 equiv), DCM, 0 °C, 4
h; f) Ph3PCH3Br (1.7 equiv), KHDMS (1.7 equiv), THF,
−78 °C to 25 °C, 1 h, 75% (3 steps); g) (PPh3)AuNTf2 (0.05
equiv), DCE, 25 °C, 0.5 h, 57%; h) 9-BBN dimer (2.0 equiv),
THF, 25 °C, 3 h; Pd(dppf)Cl2•DCM (0.1 equiv), AsPh3 (0.1
equiv), Cs2CO3 (2.0 equiv), 1-iodo-2-methylprop-1-ene (1.5
equiv), H2O (40.0 equiv), DMF, 40 °C, 12 h, 60%.
aReagents and conditions: a) NaH (1.1 equiv), 1-bromo-2-bu-
tyne (1.1 equiv), DMF, 0 °C, 3 h, 78%; b) Lindlar cat. (0.5
equiv), toluene, 25 °C, 20 h, 95%; c) LiHMDS (1.1 equiv), THF,
−78 °C to 0 °C, 0.5 h; then PhNTf2 (1.1 equiv), −78 °C to 25 °C,
97%; d) Pd(PPh3)2Cl2 (0.1 equiv), CuI (0.05 equiv), Et3N (3.0
equiv), propyne, DMF, 25 °C, 4 h, 98%; e) DIBAL-H (3.5
equiv), THF, −78 °C to 25 °C, 8 h; f) DMP (1.06 equiv), pyri-
dine (5.0 equiv), DCM, 0 °C, 4 h, 82% (2 steps); g) Ph3PCH3Br
(1.5 equiv), KHDMS (1.4 equiv), 94%; h) (PPh3)AuNTf2 (0.05
equiv), DCE, 25 °C, 0.5 h, 77%; i) NaClO2 (2.0 equiv),
NaH2PO4•2H2O (10.0 equiv), 2-Methyl-2-butene (30.0
equiv), H2O : tBuOH (1:8), 0 °C, 3 h, 90%.
Synthesis of 7-epi-Erogorgiaene Based on A Gold-
catalyzed Cascade Reaction. To quickly evaluate our
proposed strategy, in particular the feasibility of the Cope
rearrangement, our first aim was to synthesize racemic 7-
epi-erogorgiaene (Scheme 1, 20). To this end, alkylation
of known compound 1222 with (E)-crotylbromide pro-
vided racemic 13 in 78% yield. Ketone 13 was then con-
verted to corresponding enol triflate that underwent So-
nogashira reaction with propyne to afford enyne 14. A
three-step sequence involving DIBAL reduction, Dess-
Martin oxidation and Wittig reaction was followed to
provide 15 in 75% overall yield. Subsequently, enyne 15
was subjected to the cationic gold catalyst to achieve the
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The Effect of Olefin Geometry on the Gold-cata-
Table 1. Optimization of the 6-endo-dig Cyclization
for the Synthesis of 31 from 29.
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lyzed Cyclization. Encouraged by the discovery of the
cascade reaction that converted 15 to 20, we were eager
to complete the total synthesis of erogorgiaene (5) by pre-
paring enyne 26 with a (Z)-alkene side chain (Scheme 2).
In this scenario, alkylation of 12 with 1-bromo-2-butyne
afforded 21 in 78% yield with high diastereoselectivity
(dr>19:1). Cis-selective alkyne hydrogenation was carried
out in the presence of Lindlar catalyst to give 22, after
which installation of the triflate afforded 23 in 92% yield
over two steps. Sonogashira reaction afforded 24 in 98%
yield. Subsequent redox manipulation and Wittig reac-
tion furnished racemic enyne 26. However, in the pres-
ence of 5 mol% (PPh3)AuNTf2, enyne 26 intriguingly gave
rise to 5,6-bicyclic compound 28 in 77% yield (see the
Scheme S1 in Supporting Information for the unequivocal
determination of the structure of 28). A cursory inspec-
tion of the reaction mechanism leading to 28 suggests the
facile formation of cyclopropyl gold carbene 27 via a 5-
exo-dig cyclization in this scenario.24 The observation
that enynes 15 and 26, a pair of configurational isomers,
took different reaction pathways under the same reaction
conditions could be rationalized by the higher reactivity
of cis-alkene than trans-alkene. Our results not only
demonstrate the subtlety and versatility of gold-cata-
lyzed reactions, but also exemplify the conversion of ste-
reochemical diversity to skeletal diversity.25
9
Yield, %b
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Entry
Catalyst
Conditionsa
30 31 32
c
1
(PPh3)AuNTf2
DCE, RT, 60 min 22 22
-
(PPh3)AuCl/
AgNTf2
2
3
4
DCM, RT, 60 min 30 27 - c
AuCl
DCM, RT, 60 min
THF, RT, 60 min
-
-
26 26
22 55d
(IPr)AuCl/
AgOTf
(PPh3)AuCl/
AgOTf
c
5
DCM, RT, 20 min
9
63
74
-
(PPh3)AuCl/
AgOTf
DCM, reflux, 30
min
c
c
6
-
-
a [29] = 0.01 M (0.1 mmol). b Isolated yield after flash chro-
matography. c Trace. d 6 mol% Et3N was added.
The Catalytic Asymmetric and Scalable Preparation
of Chiral 12. With the optimal conditions for the 6-endo-
dig cyclization in hand, we refocused on the enantioselec-
tive syntheses of the target diterpenoids, which necessi-
tated the preparation of enantiopure 12 (Scheme 3). Even
though the preparation of enantio-enriched 12 through a
chemoenzymatic approach has been reported,28 we de-
cided to use a catalytic method to install the C3 stereogenic
center using asymmetric copper-catalyzed conjugated ad-
dition29 of dimethylzinc to cyclohexenone.30 Given that
trapping zinc enolates at the carbon terminus with alkyl or
allyl electrophiles, Michael acceptors or halides has been
documented,31 we were curious about using Mander’s rea-
gent 34 in this scenario. Intriguingly, upon the addition of
1.1 equiv 34, we only isolated the desired product 12 in trace
amount and the major product was identified to be cyclo-
heptenone 35. Based on the proposed mechanism (Figure
S2), we hypothesized that the zinc(II) species could func-
tion as a Lewis acid leading to the formation of 35. Inspired
by a report describing how dimethyl zinc could aid the C-
acylation of lithium enolates,32 we envisaged that the addi-
tion of 1 equiv methyllithium to the reaction mixture of
zinc enolate might generate a similar lithium alkoxydial-
kylzincate species, which could undergo facile C-acylation.
Gratifyingly, this modified procedure did afford (+)-12 as
the major product, providing a useful method for the syn-
thesis of chiral β-ketoesters from enones in one pot. Fur-
ther optimization of the reaction revealed that with only
0.5 mol% Cu(OTf)2 and 1 mol% ligand (+)-33 in the first
catalytic 1,4-addition step, (+)-12 could be obtained in good
The Optimization of the 6-endo-dig Cyclization.
The predominant 1,6-enyne cycloisomerization in the re-
action pathway prompted us to switch our substrate to
29, an acid prepared by the Pinnick oxidation of aldehyde
25. We hypothesized that the aromatic A ring could be
obtained from the α-pyrone framework and hence the 6-
endo-dig cyclization of the acid to the alkyne was envis-
aged. However, as well as the formation of the 1,6-enyne
cycloisomerization product (acid 30), the potential for-
mation of 5,6-bicyclic lactone 32 via a 5-exo-dig cycliza-
tion also had to be avoided. We screened various condi-
tions to enable the selective formation of 31 (Table 1 and
Table S1). Under the previous reaction conditions, 30 and
31 were obtained in a 1:1 ratio (entry 1), indicating the su-
perior reactivity of the acid compared with the vinyl
group. Another set of similar reaction conditions pro-
vided a consistent results (entry 2). When the reaction
was carried out in the presence of AuCl, 31 and 32 were
isolated in a 1:1 ratio, and the formation of 30 was totally
inhibited (entry 3). Interestingly, conditions reported to
favor 6-endo-dig cyclization in the system of N-propargyl
carboxamides gave more 5-exo-dig cyclization product 32
in our scenario (entry 4).26 Further optimization revealed
that employment of triflate anion as the counterion of the
cationic gold catalyst was the key for achieving the de-
sired chemo- and regioselectivity (entry 5).27 Eventually,
in the presence of 5% (PPh3)AuCl / AgOTf in refluxing
DCM, the reaction proceeded smoothly to give 31 in 74%
isolated yield as the predominant product (entry 6).
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yield with over 95% ee on a multi-gram scale. This modi- Synthesis of (+)-Erogorgiaene (5). With abundant chi-
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8
fied procedure could be a useful method for the synthesis
of chiral β-ketoesters from enones in one pot.
ral 12 in hand, we continued to complete the total synthesis
of erogorgiaene (5) (Scheme 4). Chiral aldehyde 25 was ob-
tained from (+)-12 following the 6 steps described in
Scheme 2. The clean Pinnick oxidation of 25 enabled the
direct use of the resulting acid in the gold-catalyzed cy-
clization without flash chromatography, affording 31 in 63%
yield on a gram-scale. Fortunately, after screening a num-
ber of gold catalysts, we found that 8 mol% BINAP(AuCl)2
/ AgNTf2 successfully promoted the stereoselective Cope
rearrangement of 31 to produce α-pyrone 36 as a single di-
astereomer in 70% yield on a gram-scale. The elongation of
the side chain was achieved by 9-BBN hydroboration fol-
lowed by palladium-catalyzed Suzuki coupling to give 37.
By invoking a cascade involving the intermolecular Diels-
Alder reaction of the α-pyrone and norbornadiene fol-
lowed by elimination of CO2 and cyclopentadiene,33 (+)-er-
ogorgiaene (5) was obtained from 37 in 75% yield under
microwave irradiation conditions. The analytic data of 5
corresponded well with those in the literature.14a
Scheme 3. Synthesis of chiral 12a
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aReagents and conditions: a) Me2Zn (1.0 equiv), Cu(OTf)2 (0.01
equiv), (+)-33 (0.02 equiv), toluene, −30 °C, 3 h; then 34 (1.1
equiv), −78 °C, 3 h, 50%; b) Me2Zn (1.05 equiv), Cu(OTf)2
(0.005 equiv), (+)-33 (0.01 equiv), toluene, −30 °C, 3 h; MeLi (1.1
equiv), −78 °C, 0.5 h; then 34 (1.15 equiv), −78 °C to 25 °C, 8 h,
75~85%, ee ≥ 95%.
Scheme 4. Total synthesis of (+)-erogorgiaene (5)a
Figure 3. Annulation cascades converting α-pyrones to phe-
nols
Synthesis of the Aglycone of Seco-Pseudopterosin A
by Optimizing an Annulation Reaction of α-Pyrone
with Alkyl Phosphonate. The collective total synthesis of
pseudopterosins necessitates the efficient conversion of
the α-pyrone motif to a catechol, ideally in one step. We
noticed two reported transformations, in which the anion
of dimethyl methylphosphonate reacted with α-pyrone 38
and benzopyranone 40 to afford phenol 39 and naphthol
41 respectively (Figure 3, eq. 1 and eq. 2).34 By employing
the same phosphonate reagent, our substrate 37 was suc-
cessfully converted to phenol 43 (eq. 3), effectively com-
pleting the synthesis of 7-epi-leubethanol. Over 3 equiva-
lent dimethyl methylphosphonate and nBuLi were required
aReagents and conditions: a) NaClO2 (2.0 equiv), NaH2PO4•
2H2O (10.0 equiv), 2-methyl-2-butene (30.0 equiv), H2O :
tBuOH (1:8), 0 °C, 3 h; then (PPh3)AuCl / AgOTf (0.05 equiv),
DCM, 45 °C, 0.5 h, 63%; b) BINAP(AuCl)2 / AgNTf2 (0.08
equiv), DCM, 40 °C, 12 h, 70%; c) 9-BBN (2.0 equiv), THF, 25 °C,
3 h; Pd(dppf)Cl2•DCM (0.1 equiv), AsPh3 (0.1 equiv), Cs2CO3
(2.0 equiv), 1-iodo-2-methylprop-1-ene (1.5 equiv), H2O (40.0
equiv), DMF, 40 °C, 90%; d) 2,5-norbornadiene (30 equiv), tol-
uene, microwave, 200 °C, 75%.
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to achieve the complete conversion of α-pyrone 37 and the
corresponding phenol 43 was obtained in 79% isolated
yield.
Scheme 5. Total synthesis of (+)-pseudopteroxazole
(4)a
1
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4
5
6
Table 2. Optimization of the Annulation Reaction for
the Synthesis of Seco-Pseudopterosin A Aglycone 45.
7
8
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
Entry
Conditionsa
Yieldb
0%
1
3.5 equiv nBuLi, THF, −78 °C
3.5 equiv LDA, THF, −78 °C
3.5 equiv LDA, THF, −100 °C
3.5 equiv LDA, Et2O, −116 °C
2
3
4
0%
15%
50%c
a [37] = 0.1 M (0.04 mmol), 4 equiv 44, after reacting under
low temperature, the reaction mixture was allowed to warm
b
slowly to room temperature. Isolated yield after column
aReagents and conditions: a) Pd(OAc)2 (0.1 equiv), 1-iodo-2-
methylprop-1-ene (1.5 equiv), Ag2CO3 (1.1 equiv), DMF, 60 °C,
12 h, 88%; b) methanesulfonic acid (3.0 equiv), DCM, 0 °C to
25 °C, 12 h; 47, 41%; 48, 45%; c) 44 (3.5 equiv), LDA (3.0 equiv),
2,5-norbornadiene (25 equiv), Et2O, −116 °C, 20 min; then 47, -
116 °C, 3 h; −116 °C to 25 °C, 12 h, 64%, 82% brsm; d) 44 (3.5
equiv), LDA (3.0 equiv), 2,5-norbornadiene (25 equiv), Et2O, -
116 °C, 20 min; then 46, −116 °C, 3 h; −116 °C to 25 °C, 12 h; e)
methanesulfonic acid (3.0 equiv), DCM, -35 °C, 12 h, 62% over
two steps (dr = 10:1); f) BBr3 (1.5 equiv), DCM, 0 °C, 15 min;
Ag2O (1.4 equiv), glycine (12.0 equiv), MeOH, 65 °C, 18 h, 43%.
chromatography. c Starting material 37 was recovered in 24%
yield.
However, when we examined phosphonate 4435 under
the same reaction conditions, only decomposition was ob-
served (Table 2, entry 1). Switching the base to LDA also
led to decomposition (entry 2), but the desired product 45
was afforded in 15% yield if the reaction temperature was
lowered to −100 °C (entry 3). By changing the solvent from
THF to Et2O, we were able to further lower the reaction
temperature, which gave rise to the aglycone of seco-pseu-
dopterosin A 45 in synthetically useful yield (66% based on
starting material recovery, entry 4).
Scheme 6. Total synthesis of (−)-pseudopterosin A (1)a
Syntheses of (+)-Pseudopteroxazole (4) and (−)-
Pseudopterosin A (1). As the key intermediate in our col-
lective total synthesis, α-pyrone 36 underwent a regioselec-
tive intermolecular Heck reaction36 to afford diene 46 in 88%
yield with an E/Z ratio >19:1 (Scheme 5). Treatment of 46
with methanesulfonic acid provided a separable pair of di-
astereomers 47 and 48 in 41% and 45% yield, respectively.
The annulation reaction of α-pyrone 47 and 44 produced
pseudopterosins G-J aglycone 49 in 64% yield (82% based
on starting material recovery), while we found the addition
of excess 2,5-norbornadiene was beneficial in this scenario.
Alternatively, converting 46 to the catechol followed by
treatment with methanesulfonic acid also provided 49 but
as a 10:1 diastereomeric mixture at C9 in 62% overall yield.
The preference for the S configuration at C9 in this sce-
nario was consistent with an analogous result reported by
the Kerr group.37 Deprotection of the benzyl ether followed
by a published procedure16a converted 49 to (+)-pseu-
dopteroxazole (4) in 43% yield.
aReagents and conditions: (a) 44 (2.5 equiv), LDA (2.0 equiv),
2,5-norbornadiene (25 equiv), Et2O, −116 °C, 20 min; then 48,
−116 °C, 3 h; −116 °C to 25 °C, 12 h, 56%, 80% brsm; (b) NaH (1.6
equiv), 51 (2.2 equiv), MeCN, 25 °C, 5 h, 56%, 90% brsm; (c)
KOH (6.0 equiv), H2O:MeOH (1:10), 25 °C, 1 h; (d) Li/naphtha-
lene (1.5 equiv), THF, −78 °C, 0.5 h, 76% (2 steps).
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Similarly, the annulation reaction of α-pyrone 48 and 44
prepare (−)-12 with excellent enantiopurity (Scheme 7). It
is noteworthy that (−)-12 could be used to synthesize the
aglycone of pseudopterosins K-L38 following our estab-
lished route (Schemes 4, 5 and 6). The same three-step se-
quence as shown in Scheme 1, involving crotylation of (−)-
12, installation of the triflate and Sonogashira reaction af-
forded (+)-14 in 82% yield over 3 steps. Subsequent redox
manipulation followed by Gold-catalyzed cyclization pro-
vided 53 successfully. The gold-catalyzed Cope rearrange-
ment proceeded smoothly to give α-pyrone 54 in 86% yield.
Finally, hydroboration of 54 with 9-BBN followed by the
palladium-catalyzed coupling and annulation with dime-
thyl methylphosphonate furnished (−)-leubethanol (6) in
52% yield over two steps. The spectroscopic data of the
synthesized samples of 6 were in good agreement with
those in the literature.14c,19t
1
2
3
4
5
6
7
8
produced pseudopterosin A-F aglycone 50 in 56% yield (80%
based on starting material recovery, Scheme 6). Eventually,
glycosylation of 50 followed by deprotection was achieved
by executing the reported procedures to afford the anti-in-
flammatory natural product, (−)-pseudopterosins A (1).19a
The analytic data of 4 and 1 corresponded well with those
in the literature.14b,19a
9
Scheme 7. Total synthesis of (−)-leubethanol (6)a
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
To our knowledge, the Cope rearrangement catalyzed by
cationic gold(I) complexes under mild reaction conditions
only applies to substrates containing the strained meth-
ylenecyclopropane.3 The gold-catalyzed Cope rearrange-
ment driven by the construction of benzene or α-pyrone
ring system in our synthesis is an unique addition to exist-
ing methodologies, which suggests the scope of corre-
sponding transformation could be further expanded by de-
liberated designs.
Syntheses of (+)-Amphilectolide (7) and (+)-Cari-
benol A (8). Encouraged by the completion of amphilec-
tane and serrulatane diterpenoids with a phenyl A ring, we
were intrigued by the possibility to prepare amphilectolide
(7) and caribenol A (8) without the substituted aromatic
ring. Trauner and co-workers have elegantly used a furan
building block in the first total syntheses of amphilectolide
(7) and sandresolide B, another diterpenoid also isolated
from Pseudopterogorgia elisabethae.19u We therefore envis-
aged a similar intermediate, furan 58, to efficiently con-
struct both our targeting natural products. To this end, the
ester of triflate (−)-23 was first reduced to a hydroxymethyl
group, which was followed by Pd-catalyzed intramolecular
carbonylative cyclization to afford 56 (Scheme 8).39 The
stage was set for the key Cope rearrangement of 56 to 57.
Various gold catalysts were screened but failed to catalyze
the desired transformation in this scenario. We eventually
found microwave irradiation conditions successfully pro-
vided butenolide 57 as a single diastereomer in 88% yield.
In order to realize the subsequent annulations, 57 was first
converted to furan 58 via DIBAL-H reduction and aroma-
tization. The following hydroboration of olefin 58 and oxi-
dation afforded alcohol 59 in 90% yield. Compound 59 was
subjected to the treatment of triflate anhydride and 2,6-
lutidine to effect the cyclization to give tricycle 60,40 which
was followed by oxidation and elimination under acid con-
ditions to afford 61 in 40% yield over 2 steps. Natural prod-
uct (+)-amphilectolide (7) was obtained by the 1,6-conju-
gative addition of the in situ generated isobutenyl cuprate
reagent to 61.
aReagents and conditions: a) Me2Zn (1.05 equiv), Cu(OTf)2
(0.01 equiv), (−)-33 (0.02 equiv), toluene, −30 °C, 3 h; MeLi (1.1
equiv), −78 °C, 0.5 h; then 34 (1.15 equiv), −78 °C to 25 °C, 8 h,
75%, ee ≥ 97%; b) NaH (1.1 equiv), crotyl bromide (1.1 equiv),
DMF, 0 °C, 3 h; c) LiHMDS (1.1 equiv), THF, −78 °C to 0 °C, 0.5
h; then PhNTf2 (1.1 equiv), −78 °C to 25 °C, 3 h; d) Pd(PPh3)2Cl2
(0.1 equiv), CuI (0.05 equiv), Et3N (3.0 equiv), propyne, DMF,
25 °C, 4 h, 82% (3 steps); e) DIBAL-H (3.0 equiv), THF, −78 °C
to 25 °C, 8 h; f) DMP (1.04 equiv), pyridine (5.0 equiv), DCM,
0 °C, 4 h; g) NaClO2 (2.0 equiv), NaH2PO4•2H2O (10.0 equiv),
2-methyl-2-butene (30.0 equiv), H2O : tBuOH (1:8), 0 °C, 3 h,
57% (3 steps); h) (PPh3)AuCl / AgOTf (0.05 equiv), DCM, 45 °C,
0.5 h, 70%; i) BINAP(AuCl)2 / AgNTf2 (0.08 equiv), DCM, 40 °C,
12 h, 86%; j) 9-BBN dimer (2.0 equiv), THF, 25 °C, 3 h;
Pd(dppf)Cl2•DCM (0.1 equiv), AsPh3 (0.1 equiv), Cs2CO3 (2.0
equiv), 1-iodo-2-methylprop-1-ene (1.5 equiv), H2O (40.0
equiv), DMF, 40 °C, 12 h, 78%; k) n-BuLi (3.0 equiv),dimethyl
methylphosphonate (3.5 equiv), THF, -78 °C, 3 h, 67%.
Synthesis of (−)-Leubethanol (6). The synthetic strat-
egy we developed is applicable to not only natural products
isolated from P. elisabethae, but also diterpenoids with dif-
ferent stereochemical elements, such as leubethanol (6).8c
To illustrate this point, we first used chiral ligand (−)-33 to
Intrigued by the excellent diastereoselectivity of the
Cope rearrangement of 56, we performed preliminary den-
sity functional theory (DFT) calculations using the M06-2X
functional (Figure 4).41 Both the chair- and boat-like Cope
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rearrangement transition states TS1 and TS2, leading to 57 a pair of inseparable diastereomer (C9, α-H:β-H = 3:1) from
1
2
3
4
5
6
7
8
and its epimer 57' respectively, were located. DFT calcula-
tions indicated that TS1 is favored over TS2 by 10.8
kcal/mol, suggesting that 57 should be formed exclusively,
which is in good agreement of the experimentally observed
diastereoselectivity.42 Moreover, the activation Gibbs free
energy of the Cope rearrangement via the chair-like tran-
sition state TS1 is 36.1 kcal/mol, which is also in good ac-
cordance with the high reaction temperature (200 °C) em-
ployed. The significantly exothermic nature of this Cope
rearrangement (5.9 kcal/mol) is also revealed by the calcu-
lation, resulting in 57 that is thermodynamically more sta-
ble than 56.
the reaction mixture. Selective oxidation of the furan ring
in 67 by NaClO2 ultimately resulted in (+)-caribenol A (8).
The analytic data of the synthesized samples of natural
products 7 and 8 corresponded well with those in the liter-
ature.15,19u,20a
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
Scheme 8. Total synthesis of (+)-amphilectolide (7)a
Figure 4. Free-energy profile of the Cope rearrangement
Scheme 9. Total synthesis of (+)-caribenol A (8)a
aReagents and conditions: (a) DIBAL-H (2.7 equiv), DCM; (b)
Pd(OAc)2 (0.15 equiv), PPh3 (0.3 equiv), Et3N (3.0 equiv),
MeOH (50.0 equiv), DMF, 82% (2 steps); (c) PhCl, microwave,
200 °C, 88%; (d) DIBAL-H (1.2 equiv), toluene; then HCl, 85%;
(e) 9-BBN dimer (2.0 equiv), THF; then H2O2 (6.0 equiv),
EtOH, NaOH(aq), 90%; (f) Tf2O (1.1 equiv), DCM, 2,6-lutidine
(2.5 equiv); (g) NaClO2 (3.0 equiv), NaH2PO4▪2H2O (1.5 equiv),
t-BuOH, H2O; then TsOH▪H2O (2.0 equiv), benzene, 40% (2
steps); (h) 1-bromo-2-methylpropene (4.0 equiv), t-BuLi (8.0
equiv), CuI (2.0 equiv), Et2O, 37%.
Finally, we turned our attention to the total synthesis of
caribenol A (8) (Scheme 9). Furan 58 underwent 9-BBN hy-
droboration followed by Pd-catalyzed Suzuki coupling
with iodide 62 to furnish enone 63 in 82% yield. We were
delighted to find an intramolecular Michael addition cata-
lyzed by AuCl343 delivered tricyclic compound 65 in 85%
yield with 10:1 diastereoselectivity at C15 favoring the de-
sired diastereomer.44 The high diastereoselectivity could
be rationalized by invoking the chair-like transition state
64, whereas it invites further investigation to determine
whether the C-H activation was involved. By exposing 65
to lithio-TMS-diazomethane, an alkylidene carbene-medi-
ated 1,5-CH insertion45 was achieved presumably via inter-
mediate 66, and tetracycle 67 was isolated in 37% yield as
aReagents and conditions: (a) 9-BBN dimer (2.0 equiv), THF,
40 °C, 3 h; Pd(dppf)Cl2•DCM (0.1 equiv), AsPh3 (0.1 equiv),
Cs2CO3 (5.0 equiv), 62 (1.2 equiv), H2O (40.0 equiv), DMF,
45 °C, 5 h, 82%; (b) AuCl3 (0.1 equiv), DCM, −20 °C, 10 h, 85%
(dr = 10:1); (c) TMSCHN2 (4.0 equiv), n-BuLi (3.0 equiv), DME,
−56 °C to 25 °C over 5 h, 37% (dr = 3:1); (d) NaClO2 (3.2 equiv),
NaH2PO4•2H2O (2.0 equiv), 2-methyl-2-butene (10.0 equiv),
H2O:t-BuOH (1:5), 25 °C, 10 h, 48%.
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Figure 5. Summary of the natural products prepared
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32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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59
60
Conclusion
ASSOCIATED CONTENT
In summary, we have developed an efficient and modu-
lar synthesis to accomplish, in an enantioselective manner,
pseudopterosin A (1), pseudopteroxazole (4), erogorgiaene
(5), seco-pseudopterosin A aglycone (45), pseudopterosin
G-J aglycone (49), amphilectolide (7) and caribenol A (8)
within 32 transformations starting from cyclohexenone
(Figure 5). In addition, (−)-leubethanol (6) was separately
synthesized in 11 steps based on the same strategy. Even if
the step count of our synthesis towards a particular target
might not be the shortest—for instance, Sherburn and
coworkers reported an impressive 11-step synthesis of the
aglycone of ent-pseudopterosin G-J20c—we took full ad-
vantage of the power of collective total synthesis to max-
imize the number of bioactive natural products that could
be provided by our approaches.
Supporting Information. Detailed experimental procedures,
compound characterization data and the CIF for S7. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
tuopingluo@pku.edu.cn
ACKNOWLEDGMENT
This work was supported by generous start-up funds from the
National “Young 1000 Talents Plan” Program, College of
Chemistry and Molecular Engineering, Peking University and
Peking-Tsinghua Center for Life Sciences, and the National
Science Foundation of China (Grant No. 21472003 and
31521004). We thank Dr. Nengdong Wang and Prof. Wenxiong
Zhang (Peking University) for their help in analyzing the X-
ray crystallography data, Mr. Yi Wang and Prof. Zhi-Xiang Yu
(Peking University) for their help in the density functional
theory calculations, Prof. Jian Wang (Tsinghua University) for
his help in chiral HPLC analysis and Prof. Yefeng Tang (Tsing-
hua University) for helpful discussions. Dedicated to Professor
Stuart L. Schreiber on the occasion of his 60th birthday.
Besides the gold-catalyzed chemo- and regioselective cy-
clization and Cope rearrangement, the salient features of
our synthesis include a modified procedure to prepare chi-
ral β-ketoesters from enones and the use of α-pyrone as a
masked benzene ring. More importantly, our route offers
great flexibility to allow deep-seated structural changes of
the interested natural products and enables the design and
preparation of small-molecule probes for identifying cor-
responding biochemical targets, which is underway and
will be reported in due course.
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[24] A mechanism of the transformation of 26 to 28 is proposed in Figure S1.
For precedent gold-catalyzed skeletal rearrangement of 1,6-enynes in-
volving Z-alkenes, see: a) Nieto-Oberhuber, C.; Muñoz, M. P.; López,
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Núñez, E.; Claverie, C. K.; Bour, C.; Cárdenas, D. J.; Echavarren, A. M.
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[26] Hashmi, A. S. K.; Schuster, A. M.; Gaillard, S.; Cavallo, L.; Poater, A.;
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[27] For a selection of recent reports on the role of counterions in homoge-
[36] Jeffery, T. J. Chem. Soc., Chem. Commun. 1991, 324-325.
[37] Ferns, T. A.; Kerr, R. G. J. Org. Chem. 2005, 70, 6152-6157.
[38] Roussis, V.; Wu, Z.; Fenical, W.; Strobel, S. A.; VanDuyne, G. D.;
Clardy, J. J. Org. Chem. 1990, 55, 4916-4922.
neous gold catalysis, see: a) Zhdanko, A.; Maier, M. E. ACS Cataly-
sis 2014 4, 2770-2775. b) Jia, M.; Cera, G.; Perrotta, D.; Monari, M.;
Bandini, M. Chem. Eur. J. 2014, 20, 9875-9878.
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[28] Fráter, G.; Günther, W.; Müller, U. Helv. Chim. Acta 1989, 72, 1846-
1851.
[39] Levin, S.; Nani, R. R.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133,
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S. Copper-Catalyzed Asymmetric Conjugate Addition. In Copper-Cata-
lyzed Asymmetric Synthesis, Alexakis, A.; Krause, N.; Woodward, S.,
Eds.; Wiley-VCH: Weinheim, 2014; Chapter 2, pp 33-68.
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[41] Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215-241.
[42] Considering that 57 and 57' are isoenergetic, the Cope rearrangement
of 56 should be under typical kinetic control under the reaction condi-
tions employed.
[30] Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc.
2002, 124, 5262-5263.
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[43] Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L. Adv. Synth. Catal. 2003,
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[44] An alternative mechanism suggested by a reviewer is that the AuCl3
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Scheme 9
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Table 1
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Table 2
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