Total synthesis of (±)-cafestol: A late-stage construction of the furan ring inspired by a biosynthesis strategy

Article abstract of DOI:10.1021/ol500623w

An efficient bioinspired approach to the total synthesis of (±)-cafestol features a late-stage installation of the furan ring with a mild Au-catalyzed cycloisomerization. The Et₂AlCl-promoted aldehyde-ene cyclization and subsequent Friedel-Crafts reaction deliver a requisite tricyclic system in gram scale with high stereo- and regioselectivity. Moreover, a highly stereoselective SmI₂-mediated aldehyde-alkene radical cyclization furnishes the key bicyclo[3.2.1]octane skeleton to offer an advanced intermediate for the synthesis of other oxygenated ent-kaurene diterpenoids.

Full text of DOI:10.1021/ol500623w

Letter
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Total Synthesis of ( )-Cafestol: A Late-Stage Construction of the
Furan Ring Inspired by a Biosynthesis Strategy
Lili Zhu,† Jisheng Luo,† and Ran Hong*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An efficient bioinspired approach to the total
synthesis of ( )-cafestol features a late-stage installation of the
furan ring with a mild Au-catalyzed cycloisomerization. The Et2AlCl-
promoted aldehyde−ene cyclization and subsequent Friedel−Crafts
reaction deliver a requisite tricyclic system in gram scale with high
stereo- and regioselectivity. Moreover, a highly stereoselective SmI2-
mediated aldehyde−alkene radical cyclization furnishes the key
bicyclo[3.2.1]octane skeleton to offer an advanced intermediate for the synthesis of other oxygenated ent-kaurene diterpenoids.
ent-Kaurene is an important member of diterpenoids, and the
diverse and intriguing structural features have been extensively
studied from both the enzymology and chemical synthesis
prospects.1 Cafestol (2) and kahweol (3), two ent-kaurene (1)
derived diterpenoids bearing a unique furan ring, were isolated
from unfiltered coffee drinks (Figure 1).2 These diterpenoids
Scheme 1. Inspiration of Biosynthesis Strategy
Figure 1. Representative ent-kaurene diterpenoids.
approach to construct the requisite pentacyclic system. As a
proof of concept, the total synthesis of cafestol is presented here.
With continuing interest in the biomimetic synthesis of natural
products,8 we envisaged the efficient construction of the
pentacyclic structure may generate an array of downstream
compounds in parallel with the pipeline of cafestol biosynthesis.9
An essential late-stage construction of furan, whose sensitivity
was revealed in Corey’s landmark synthesis,10 is outlined
(Scheme 1B). A SmI2-mediated radical cyclization of an aldehyde
and alkene is designed as the linchpin for the construction of
bicyclo[3.2.1]octane, and a Claisen rearrangement will furnish
the quaternary carbon center of C(8). To achieve this goal, the
aldehyde−ene initiated cyclization programmed for the tricylic
system should be highly stereo- and regioselective. To the best of
our knowledge, the polyene-type cyclization begun from
have exhibited interesting bioactivities, such as anti-inflamma-
tion, cholesterol elevation, and a neuroprotective effect,3 and
were recently discovered to induce apoptosis through regulation
of specificity protein 1 (Sp1) expression in human malignant
pleural mesothelioma (HMPM)4 which is considered a highly
aggressive cancer with a poor prognosis. Biogenetic derivatiza-
tion of ent-kaurene (1) to cafestol (2) may consist of a methyl
migration from C(18) or C(19) and subsequent furan formation
in conjunction with the A-ring (Scheme 1A). The exhausted
degradation of three carbons at C(4), C(18), and C(19) was
found in a recently isolated potent antibiotic platensimycin (4).5
Moreover, ample hydroxyl groups in the ent-kaurene skeleton
play a vital role in potent anticancer agent oridonin A (5).6 The
common feature of a bicyclo[3.2.1]octane in the complex
structures above emphasizes that a general strategy shall embrace
flexibility in installing hydroxyl groups at C(11) and C(14),
respectively.7 We have been engaged in devising an efficient
Received: February 26, 2014
Published: April 1, 2014
© 2014 American Chemical Society
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Letter
aldehyde is not well-established and remains largely unexplor-
ed.8c
Table 1. Optimization of Aldehyde−Ene Initiated
a
Cyclization
A chain elongation of 3-methoxystyrene was realized through a
Suzuki coupling with vinyliodide 6, which was readily prepared
with Negishi’s protocol (Scheme 2).11 Initial Swern oxidation of
Scheme 2. Cyclization of (E)-Enal 8
cis-10
9
yield
(%)
yield
c
b
b
entry
reaction conditions
c/t
p/o
(%)
1
2
3
4
5
6
SnCl4 (1.5), −78 °C, 9 h
TiCl4 (1.5), −78 °C, 9 h
BF3·Et2O (1.5), −78 °C, 9 h
EtAlCl2 (1.5), −78 °C, 9 h
Me2AlCl (1.5), −78 °C, 9 h
Et2AlCl (1.5), −78 °C, 9 h
Me3Al (3.5), −78 °C, 9 h
Et2AlCl (1.5), −78 °C, 14 h
−
−
−
−
10
10
−
3/1
2.4/1
2.1/1
4.2/1
3.1/1
11.8/1
12.8/1
>20/1
12.5/1
8/1
56
47
65
55
80
81
3.7/1
5/1
4.5/1
13/1
13/1
a
d
e
Yield includes cis-9p and cis-9o (ds 3/1 for the relative configuration
7
<1/20
12.3/1
<1/20
46
f
of C(4) and C(5) in 9; regioselectivity, cis-9p/cis-9o = 2.4/1).
8
<5
75
g
e
9
Et2AlCl (0.9), 0 °C, 30 min;
rt, 8 h
−
73
corresponding alcohol 7 gave (E)-enal 8 in 45% yield along with
a considerable amount of tricyclic products (stereochemistry
undefined, ∼20% combined yield). Further experiments revealed
a trace amount of acid, generated under the oxidation conditions,
was responsible for the contaminated cyclization. IBX was finally
identified as the optimal oxidation reagent, affording enal 8 in
excellent yield (94%, 20-g scale). Following Yamamoto’s
conditions,12 SnCl4 promoted the cyclization to give cyclized
compounds cis-9p and cis-9o in a combined 56% yield. However,
both stereoselectivity (ds 3/1) and regioselectivity (para-/ortho-,
2.4/1) were not appealing (Scheme 2). The preference of an axial
hydroxyl group at C(4) (ds 3/1) was confirmed by 2D NOE
analyses of cis-9o and cis-9p.13 During the cyclization reaction,
the major intermediate cis-10 was also identified. This product,
which lacks the conjunct B-ring, is probably derived from the
Lewis acid mediated aldehyde−ene reaction or incomplete
cationic cyclization.14
a
Reaction conditions: aldehyde 8 (125 mg, 0.5 mmol, 0.2 M), CH2Cl2
(2.5 mL), Lewis acid (1.0 M in CH2Cl2 or hexanes, 0.9−3.5 equiv),
b
−78 °C to rt. Stereoselectivity (c/t: cis/trans) and regioselectivity (p/
1
o: para-/ortho-) were determined by H NMR (400 MHz, CDCl3).
c
Combined yields of cis-9p and cis-9o for entries 1−6; isolated yield of
d
cis-9p for entry 8. A severe nucleophilic addition of aldehyde with the
e
Me group from Me3Al was found. Trans-9p was isolated (C4−OH is
equatorial) for entries 7 and 9. 2.4-g scale. 13-g scale; Et2AlCl (0.9 M
in toluene) was used.
f
g
thermodynamically favorable trans-isomer may be derived from
an ene cyclization through a boatlike conformation or a cationic
process (Scheme 3).14b The diastereoselectivity switch benefi-
cially provides impetus for initiating strategic C−H activation to
access different synthetic targets.21
Scheme 3. Stereochemistry Switch in Cyclization
As denoted in Snider and Brown’s model, the stereoselectivity
of aldehyde−ene cyclization shows a preference for a chairlike
conformation if an aluminum complex was chosen.14 The low
selectivity associated in the cyclization of enal 8 may be attributed
to complex reaction pathways under the promotion of SnCl4.
Moreover, application of an ene cyclization in a system such as 8
is not yet explored in total synthesis.12a,15 Therefore, we decided
to investigate the aldehyde−ene reaction instead of a direct
cationic cyclization which may result in several cyclized products.
Several Lewis acids were thus examined. Moderate regioselectiv-
ities and isolated yields of cis-9p were obtained when TiCl4, BF3·
Et2O, and EtAlCl2 were used (entries 1 to 4 in Table 1). Milder
Lewis acids such as Me2AlCl and Et2AlCl yielded good cis-
selectivity and isolated yields for the carbonyl−ene cyclization
(entries 5 and 6). When Me3Al was chosen, exceptional
regioselectivity (p/o: >20/1) and trans-selectivity (c/t: <1/20)
were achieved, albeit in a lower isolated yield due to the
nucleophilic addition of aldehyde (trans-9p, 46%, entry 7).16 For
a synthetically useful scale (>2 g), the optimized conditions still
maintain high stereo- and regioselectivity to deliver cis-9p in 75%
yield (entry 8 vs 6).17 Since the meta-methoxyphenyl termination
in cationic cyclization has been challenging in literature
precedents,18−20 the excellent regioselectivity achieved here is
particularly rewarding.
With a sufficient amount of compound cis-9p in hand, we
turned our attention to the construction of the bicyclo[3.2.1]-
octane architecture (Scheme 4). The Birch reduction using
lithium, tert-butyl alcohol, and liquid ammonia in THF with an
acidic workup afforded enone 11 in 78% yield. Luche reduction
yielded allylic alcohol 12 in a 9:1 ratio favoring the β-
configuration. The subsequent Eschenmoser−Claisen rearrange-
ment proceeded smoothly establishing the quaternary carbon
center of C(8) in 13 (72% yield).22 Neutral conditions in this
step were crucial for diminishing a dehydration side reaction,
observed with reaction conditions in other variants of the Claisen
rearrangement which require acid catalysts. Subsequently, the
It was further discovered that the stereoselectivity can be
switched where trans-9p13 was isolated in 73% yield when the
reaction temperature was quickly raised to rt (entry 9, Table 1). A
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Letter
(MoO5(py)(HMPA))28 to give 20 as a single diastereomer in
89% yield (b.r.s.m., 77% conv). After reaction with ethynyl-
magnesium bromide in THF, the major stereoisomer of
corresponding adduct 21 was isolated and its structure was
unambiguously established by X-ray analysis.25 The following
furan formation was realized with a protocol developed by Akai
and co-workers.29 However, the original gold-catalyst system
afforded furan 22 with contamination of the double bond
migrated product.30 We envisioned the existence of a silver salt
may elicit the exoalkene isomerization.31 Therefore, after the
anion metathesis, the silver salt was filtered off through a nylon
membrane and the resulting “Au catalyst” was directly used for
the subsequent cycloisomerization. The requisite furan was
formed in 93% yield without any detectable isomerized product.
Dihydroxylation with stoichiometric osmium tetroxide followed
by cleavage of the bisosmate with sodium sulfite completed the
total synthesis of ( )-cafestol (2) whose spectra were identical
with the reported data.10a,32
Scheme 4. Synthesis of Core Structure
The synthesis described here illustrates a bioinspired approach
to ( )-cafestol in 20 steps from vinyliodide 6. Two aldehyde−
alkene cyclizations are particularly noteworthy. Namely, the
aldehyde−ene cyclization coupled with a Friedel−Crafts reaction
furnished the requisite tricyclic system in high stereo- and
regioselectivity. The following SmI2-promoted lactol−alkene
coupling established the key bicyclo[3.2.1]octane skeleton to
offer an advanced intermediate for the synthesis of other
oxygenated ent-kaurene diterpenoids, especially those bearing a
C(14)−β-OH group (such as in 5). Furthermore, it features a
late-stage Au-catalyzed furan formation leading to a mild and
efficient protocol to introduce the sensitive furan moiety in
complex targets. Future manipulation of the A-ring would
provide versatile analogues for enriching the structure−activity
relationship of cafestol. Development of enantioselective syn-
thesis of the potent lead and further exploration of the
bioinspired approach leading to diverse ent-kaurene diterpenoids
are currently underway in this laboratory.
iodine-mediated esterification and base-promoted elimination
provided a bonus in double bond migration from C(13)−C(14)
to C(12)−C(13).23 DIBALH reduction of the lactone to the
lactol, followed by SmI2-mediated radical cyclization,24 ex-
clusively furnished diol 15 in 98% yield. The stereochemistry of
15 was unambiguously established by X-ray analysis of 16 after
removal of the TBS protecting group.25 The excellent stereo-
chemistry control in the radical cyclization may rely on the
participation of the β-OH at C(14) through the coordination
with Sm(III).26
Oxidative differentiation of two secondary alcohols at C(14)
and C(16) in 15 was realized due to differences in steric
hindrance. Wittig olefination and subsequent Barton−McCom-
bie radical deoxygenation27 furnished the requisite
bicyclo[3.2.1]octane 18 in excellent yield (Scheme 5). To
complete the synthesis, oxidative manipulation of the A-ring in
18 required hydroxylation at C(3) and the formation of the fused
furan. Thus, after removal of the TBS protecting group and
subsequent oxidation, the corresponding ketone 19 was then
treated with LiHMDS and hydroxylated with Vedejs’ reagent
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, spectra of synthetic intermediates, and X-
ray diffractions of compounds 16 and 21. This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 5. Completion of the Synthesis of ( )-Cafestol
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rhong@sioc.ac.cn.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program of
China (2010CB833200 and 2011CB710800 in part), the
National Natural Science Foundation of China (21290184 and
21302208), and Chinese Academy of Sciences is greatly
appreciated.
REFERENCES
■
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