Protecting-group-free synthesis of haterumadienone- and puupehenone-type marine natural products

Article abstract of DOI:10.1039/c7gc00704c

A divergent and expeditious access to haterumadienone- and puupehenone-type marine natural products has been achieved by using a newly developed hemiacetalization/dehydroxylation/hydroxylation/retro-hemiacetalization tandem reaction as one of the key steps. Its applicability is showcased by the first synthesis of haterumadienone, 20-hydroxyhaterumadienone, 20-epihydroxy-haterumadienone and 20-acetoxy-haterumadienone, as well as the facile synthesis of puupehenone, puupehedione and puupehenol. The synthesis is efficient, and atom- and step-economical (6 to 9 steps from commercially available starting materials), and requires no protecting groups and transition metals.

Full text of DOI:10.1039/c7gc00704c

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Protecting-group-free synthesis of haterumadienone-
and puupehenone-type marine natural products
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
ab
Hong-Shuang Wang, Hui-Jing Li,* Jun-Li Wang and Yan-Chao Wu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
OH
O
O
OH
O
OH
O
2
0
19
O
O
OH
OH
2
1
16
D
A divergent and expeditious access to haterumadienone- and
puupehenone-type marine natural products has been achieved by
18
1
5
9
1
0
4
1
C
17
8
O
8
8
2
3
1
1
A
B
13
H
H
5
using
a
newly developed hemiacetalization/dehydroxylation/
4
7
H
12
6
H
H
H
1
hydroxylation/retro-hemiacetalization tandem reaction as one of
the key steps. Its applicability is showcased by the first synthesis
puupehenone (1)
puupehedione (2)
puupehenol (3)
8-epipuupehenol (4)
O
O
O
O
O
HO
HO
of
haterumadienone,
20-hydroxyhaterumadienone,
20-
O
epihydroxy-haterumadienone and 20-acetoxy-haterumadienone,
as well as the facile synthesis of puupehenone, puupehedione and
puupehenol. The synthesis is efficient, atom- and step-economical
O
O
O
O
H
H
H
H
(
6 to 9 steps from commercially available starting materials), and
haterumadienone (5) 20-hydroxyhate-
rumadienone (6)
20-epihydroxyhat-
erumadienone (7)
20-acetoxyhate-
rumadienone (8)
requires no protecting groups and transition metals.
F
ig. 1 Selected Haterumadienone- and Puupehenone- type marine natural products.
8-11
Green chemistry, which emphasizes the development of
environmentally benign chemical processes and sustainable
technologies, has attracted much attention over the past few
puupehenones have already been reported,
in which the
use of protecting groups not only made the puupehenone
syntheses redundant, but also lead sometimes to undesired
7,8
1
decades. Accordingly, the field of green chemical synthesis
has made great advances, but synthesis of bioactive natural
products with each step in agreement with the principle of
green chemistry still remains a significant challenge to
synthetic chemists. Among the strategies used for the green
side reactions during their removal. As mentioned by
Quideau, the deprotection of benzopyran
boron tribromide (BBr ) did not afford the desired puupehenol
but 8-epipuupehenol even under mild conditions (CH Cl , -78
C, Scheme 1) because the expected natural product is less
9 in the presence of
3
2
a−d
2
2
synthesis of natural products, atom-/step-economical
2
protecting-group-free
and
3
syntheses and tandem reactions are
°
e−g
8
8 8
stable than its C -epimer. Indeed, the unnatural C -epimers
7
are usually formed instead of the natural compounds. To
desirable because of their intrinsic properties of high efficiency
and low waste disposal. As a proof of concept, the
9
overcome this inherent problem, palladium-
10
organoselenium-promoted
or
4
5
puupehenone- and haterumadienone-type marine natural
products (Fig. 1) have been selected here as synthetic targets
because of their promising biological activities such as
cycloisomerization of olefinic
phenols followed by reduction have been elegantly developed
8,11
for the construction of the natural unepimerized products.
6
a−e
6f
4b
6h
antitumor,
antituberculosis,
antiviral,
antimalarial,
anti-HIV,
These indirect modifications are helpful in reducing problems
6
h,i
6j
anti-cancer and immunomodulatory.
4d
due to the undesired epimerization at the C
8
position but also
The significance and prevalence of this class of compounds
have served to stimulate continual interest within the
increase the number of synthetic operations that must be
7
-11
synthetic community. Accordingly, synthetic routes to some
OH
O
OH
O
OMe
OH
8
BBr
3
8
H
CH Cl , -78 °C, 3 h
H
2
2
3
7%
H
H
9
8-epipuupehenol (4)
Scheme 1 Undesired Epimerization over Deprotection of Benzopyran 9.
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Journal Name
O
O
O
OH O
HO
H
OH
12
performed. Moreover, the synthesis of haterumadienones is
still blank. In this context, we wish to describe here a versatile
hemiacetalization/dehydroxylation/hydroxylation/retro-hemi-
acetalization tandem reaction as one of the key steps for an
atom- and step-economical synthesis of haterumadienones
and puupehenones without the use of protecting groups and
transition metals. The tandem reaction not only avoids the
11
H
H
1
6
12
16
H
11
1
4
9
11
O
O
O
2
3
1
0
8
13
a
13
b
9
c
5
6
7
H
5
14
H
H
18
19
20
23
1
d
O
O
O
O
1
6
13
8
O
16
OH
O
O
8
1
0
9
10
9
O
13
8
undesired epimerization at the C position, but also facilitates
H
H
H
16
H
25
H
many desired transformations in only one-pot.
e
ref 36
O
O
From a structural point of view, the main difference among
these natural products resides on their D rings. We thought to
develop a modular approach that allows the introduction of
this structural element at the late stage of the synthesis (Fig.
O
H
HO
11
HO
O
HO
H
OH
OH
HO
H
H
H
11
O
9
9
H
+
H
H
H
22 (x-ray)
2
1
24
2). Compounds 15 seemed to satisfy this criterion since it is
potentially amenable to all of these haterumadienone- and Scheme 2 Synthesis of β-Hydroxy Aldehyde 16. Reagents and Conditions: (a) H SO (3.3
2
4
puupehenone-type natural products. Considering dehydration, equiv), HCO
2
H, RT, 3 h, 98%. (b) KHMDS (1.5 equiv), THF, -78 °C, 0.5 h, then P(OMe)
1.5 equiv), O , -78 °C, 1 h, 77%. (c) LiAlH (3 equiv), THF, RT, 1 h, 98%. (d) K CO (1.5
equiv), NaIO (2 equiv), MeOH, RT, 2 h, 89%. (e) (DA) Mg (3 equiv), THF, RT, 0.5 h then -
8 °C, 2 h, and then MoOPH (2 equiv), -78 °C to -25 °C, overnight, 21 (59%), 22 (24%).
3
1
2
12
hydration, retro-hemiacetalization and hemiacetalization
13
(
2
4
2
3
4
2
processes might occur under certain acidic conditions, we
envisioned that a suitable acid might facilitate the dehydration
7
RT
=
room temperature, KHMDS
Mg = magnesium bis(diisopropylamide), MoOPH =
5
·pyridine·HMPA, HMPA = hexamethylphosphoramide.
= potassium hexamethyldisilazide, THF =
of compounds 15 to compounds 14, hemiacetalization of tetrahydrofuran, Me = methyl, (DA)
hydroxy ketones 14 to hemiacetals 13, dehydroxylation of MoO
hemiacetals 13 to compounds 12, hydroxylation of compounds
2
1
2
to hemiacetals 11
,
and retro-hemiacetalization of
and 5’ in a one-pot fashion.
could in turn be used for the synthesis of haterumadienones. Following Quideau’s procedure
As shown in Scheme 2, the synthesis commenced with
hemiacetals 11 to enones
5
5
commercially available and inexpensive sclareolide (18).
1
1a
,
2 4
treatment of 18 with H SO
On the other hand, puupehenones would be synthesized by α- in HCO H at room temperature for 3 hours afforded 8-
2
hydroxylation of enone 5’ followed by redox reactions. Finally, episclareolide 19 in 98% yield, in which the release of the 1,3-
compounds 15 were thought to be prepared by the aldol diaxial interaction between the 13- and 16-methyl groups
reaction of β-hydroxy aldehyde 16 and β-alkoxy enones 17. We facilitated the inversion of configuration at C
report herein the realization of this strategy by developing 19 was α-hydroxylated by treatment with KHMDS at -78 °C and
protecting-group-free synthesis of seven haterumadienone- subsequent reaction with O in the presence of P(OMe) gave
α-hydroxy lactone 20 in 77% yield as the sole diastereoisomer,
8
. The lactone of
2
3
and puupehenone-type marine natural products.
1
4
which avoided the use of transition metal. The 9,11-cis
relative stereochemistry of 20 was deduced from the observed
coupling constant between H /H (J = 3.6 Hz) and was
OH
O
D
O
9
11
confirmed by comparing its NMR data with the one of α-
11a
C
-
redox
O
α
hydroxylation
O
hydroxy lactone 21
.
The authentic 9,11-trans relative
puupehenones
A
B
stereochemistry of 21 was established by Quideau by single-
11
O
H
H
crystal X-ray analysis of its dimer (22
)
and was consistent
10
5'
D
with the expectation that the MoOPH would preferentially
15
approach the enolate from the less hindered face. Our and
n = 2
C
O
retro-hemi-
acetalization
haterumadienones
A
B
Quideau’s 8-episclareolide α-hydroxylation strategies would
complement each other to enrich the reaction diversity.
Subsequently, the reduction of the lactone ring of 20 using
LiAlH4 occurred smoothly at room temperature to afford
n = 1
H
5
- ROH
OR
n
OR
OR
OH
n
n
2
H O
H
exclusively lactol 23 in 98% yield as a single diastereomer, and
11a,16
OH
O
O
O
-
H
2
O
-
H
no triol 24
.
The 11,12-cis relative stereochemistry of 23
dehydroxylation
hydroxylation
was tentatively established from the observed coupling
H
H
H
13
12
OR
11
constant between H11/H12 (J = 4.2 Hz) and supported by the
17
hemiacetalization
OR
4
subsequent effective NaIO oxidation reaction. Treatment of
n
n
23 with NaIO in the presence of K CO at room temperature
2 3
4
HO
H
O
afforded the desired β-hydroxy aldehyde 16 in 89% yield. The
stereospecific 8-episclareolide α-hydroxylation, highly selective
lactone reduction, and in situ lactol-oxidation/ester-hydrolysis
facilitated the synthesis of β-hydroxy aldehyde 16 with an
obviously higher overall yield in comparison to the previous
OR
n
O
O
OH
OH - H O
OH
2
+
dehydration
Fig. 2 Retrosynthetic Analysis.
aldol
O
H
H
14
15
16
17
1
1a,17
literature reports (i.e., 66% versus 10−25%).
The synthesis
2
| J. Name., 2012, 00, 1-3
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COMMUNICATION
OEt
O
the alcohols are double activated by the ketone and the C-C
double bond moieties, and thereby facilitate their conversion
to haterumadiendione (26). The facile alcohol oxidation
O
OEt
O
HO
OH
O
OH
8 O
a
b
+
indicated that reduction of 26 to
6/7 might be somewhat
H
H
problematic. Indeed, a large variety of reducing agents led
either to no reaction, or, under stronger conditions, to
degradation. Fortunately, it was found that 26 could be
H
16
17a
15a
haterumadienone (5)
Scheme 3 Synthesis of haterumadienone (5). Reagents and conditions: a) 17a, LDA,
THF, −78 °C, 0.5 h, then 16, 1 h, 75%; b) pTsOH, toluene, RT, 4 h, 65%. LDA = lithium
diisopropylamide, pTsOH = p-toluenesulfonic acid.
reduced by LiBH
4
in THF at -78 °C to give 20-
hydroxyhaterumadienone
(
6
)
and
) in 58% and 12% yields,
with acetic anhydride
) in 95% yield.
Scheme 5 illustrated how the synthesis of puupehenone-
type natural products was completed by using the tandem
20-
epihydroxyhaterumadienone (
7
of β-hydroxy aldehyde 16 is attractive from an atom-
economical point of view.
respectively. Acylation of alcohol
6
afforded 20-acetoxyhaterumadienone (
8
With β-hydroxy aldehyde 16 in hand, the first synthesis of
haterumadienone was achieved as shown in Scheme 3.
Treatment of ketone 17a with LDA in THF at -78 °C and
subsequent reaction with aldehyde 16 gave aldol adduct 15a in
1−3
reaction mentioned previously. Treatment of ketone 17b with
LDA in THF at -78 °C and subsequent reaction with aldehyde 16
7
5% yield. We envisaged then to achieve the
dehydration/hemiacetalization/dehydroxylation/hydroxylation
retro-hemiacetalization tandem reaction mentioned in Fig. 2.
gave
aldol
adduct
15b
in
67%
yield.
Hemiacetalization/dehydroxylation/hydroxylation/retro-hemi-
acetalization of 15b with consequent dehydration was
achieved with HCl in MeOH at room temperature to provide
enone 5’ in 92% yield without detectable epimerization.
Treatment of 5’ with KHMDS at -78 °C for 0.5 hour and
/
After much experimentation, this tandem reaction was
realized by treatment of 15a with pTsOH in toluene at room
temperature for
4
hours to afford the desired
haterumadienone in 65% yield. The spectroscopic and
1
13
spectrometric data ( H NMR, C NMR, [α]
2 3
subsequent reaction with O in the presence of P(OMe)
D
and HRMS) of the
afforded the α-hydroxylated product 10 and puupehenone (1)
synthetic material are identical to those of natural
5
in 19% and 38% yields, respectively.
haterumadienone.
To our delight, the undesired
8
position is avoided during the tandem
The in situ dehydrogenation of 10 to
processes of alcohol oxidation and ketone enolization via a
diketone intermediate The inherent stability associated with
the large conjugated system in could also facilitate the
conversion of 10 to . Considering that the HMDS from KHMDS
1 might involve
epimerization at the C
reaction mentioned above. The concurrent installation of the C
and D rings of haterumadienone in a one-pot fashion
facilitated its first synthesis in 32% overall yield (only 6 steps)
from the abundant feedstock chemical sclareolide, which can
provide sufficient quantities for investigation of its biological
and medical properties.
.
1
1
might silyllate the oxygen atom of alcohol 10 and thus be
disadvantageous for this dehydrogenation, a series of other
Encouraged by these promising results, we anticipated to
synthesize the derived haterumadienone-type natural
OEt
O
products. Treatment of
subsequent reaction with O
not afford the corresponding α-hydroxylated products (
and/or ), but haterumadiendione (26) was isolated in 76%
yield (Scheme 4). In contrast to α-hydroxy lactone 20 (Scheme
5
with KHMDS at -78 °C and
O
OEt
HO
2
in the presence of P(OMe) did
3
OH
O
OH
8
O
a
b
6
+
O
7
H
H
H
1
6
17b
15b
5'
OH
OH
OH
2), the α-hydroxy enones 6/7 are relatively unstable because
O
O
OH
O
O
HO
O
O
O
HO
8
O
e
8
O
2
0
20
20
20
c
8
O
+
ref 18
8
O
8
O
8
O
8
O
a
b
H
H
H
+
10
puupehenone (1)
puupehenol (3)
d
H
H
H
H
5
haterumadiendione (26)
20-epihydroxyhat- 20-hydroxyhate-
erumadienone (7) rumadienone (6)
O
O
c
HO
O
O
O
20
20
O
f
8
O
ref 9b
8
O
8
O
H
puupehedione (2)
H
H
6
and/or 7
20-acetoxyhaterumadienone (8)
Scheme 5 Synthesis of puupehenone-type marine natural products. Reagents and
Conditions: (a) 17b, LDA, THF, -78 °C, 0.5 h, then 16, 1 h, 67%. (b) HCl, MeOH, RT, 0.5 h,
9
2%. (c) KHMDS, THF, -78 °C, 0.5 h, then P(OMe)
3
, O
, EtOH, RT, 20 min, 92%. (f) DDQ, 1,4-dioxane,
reflux, 2 h, 71%. Bu = tert-butyl, DDQ= 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
2
, -78 °C, 1 h, 10 (19%), 1 (38%). (d)
Scheme 4 Synthesis of haterumadienone-type marine natural products. Reagents and
, O
conditions: a) KHMDS, THF, −78 °C, 0.5 h, then P(OMe) , −78 °C, 1 h, 76%; b) LiBH
THF, −78 °C, 0.5 h, 6 (58%), 7 (12%); c) Ac
O, pyridine, 0 °C, 12 h, 95%. Ac = acetyl.
t
t
BuOK, BuOH, RT, 1 h, 86%. (e) NaBH
4
3
2
4
,
t
2
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Journal Name
t
bases were investigated and BuOK was found to be relatively
(c) M. T. Hamann, P. J. Scheuer and M. Kellyborges, J. Org.
Chem., 1993, 58, 6565; (d) S. S. Nasu, B. K. Yeung, M. T.
Hamann, P. J. Scheuer, M. Kelly-Borges and K. Goins, J. Org.
Chem., 1995, 60, 7290.
(a) K. Ueda, T. Ueta, E. R. O. Siwu, M. Kita and D. Uemura,
Chem. Lett., 2005, 34, 1530; (b) K. Ueda, T. Ogi and A. Sato,
Heterocycles, 2007, 72, 655; (c) M. L. Ciavatta, M. P. L. Gresa,
M. Gavagnin, V. Romero, D. Melck, E. Manzo, Y. W. Guo, R.
van Soest and G. Cimino, Tetrahedron, 2007, 63, 1380; (d) S.
J. Robinson, E. K. Hoobler, M. Riener, S. T. Loveridge, K.
Tenney, F. A. Valeriote, T. R. Holman and P. Crews, J. Nat.
Prod., 2009, 72, 1857.
t
effective. Indeed, by treating 10 with BuOK in tert-butyl
alcohol at room temperature for 1 hour, puupehenone (
obtained in 86% yield. Reduction of with NaBH in EtOH at
room temperature for 20 minutes afforded puupehenol ( ) in
with DDQ in 1,4-dioxane
under reflux for 2 hours provided puupehedione ( ) in 71%
1) was
1
4
5
6
3
1
8
9
2% yield. Besides, oxidation of 3
2
9
b
yield.
Conclusions
(a) S. Kohmoto, O. J. McConnell, A. Wright, F. Koehn, W.
Thompson, M. Lui and K. M. Snader, J. Nat. Prod., 1987, 50
,
In conclusion, we described a newly developed versatile
hemiacetalization/dehydroxylation/hydroxylation/retro-hemi-
acetalization tandem reaction, which is employed to the atom
and step-economical synthesis of haterumadienone- and
puupehenone-type marine natural products. This key tandem
reaction together with stereoselective 8-episclareolide α-
hydroxylation, and aerobic enone α-hydroxylation facilitated
the preparation of sufficient quantities of these natural
products for biological and medical studies. An additional
feature of the present natural product synthesis is the design
and preparation of the common intermediates 15 that can be
used for the synthesis of both haterumadienones and
puupehenones without the use of protecting groups. Further
applications of these strategies for the green synthesis of
other bioactive natural products with related heterocyclic
skeletons are currently under investigation, and will be
reported in due course.
3
4
36; (b) V. Sova and S. A. Fedoreev, Khim. Prir. Soedin., 1990,
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1
J. Nat. Prod., 1999, 62, 1304; (h) K. A. El Sayed, P. Bartyzel, X.
Y. Shen, T. L. Perry, J. K. Kjawiony and M. T. Hamann,
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,
Acknowledgements
This project was supported by the National Science Foundation
of China (Grant No. 21272046, 21672046, and 21372054).
M. Hmamouchi and H. BouanouE, J. Org. Chem., 2007, 72
3
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Pleas Ge rdeo e nn o Ct ah de j mu si ts mt r ya rgins
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DOI: 10.1039/C7GC00704C
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Green Chemistry
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DOI: 10.1039/C7GC00704C
Graphical Abstract
Protecting-group-free synthesis of haterumadienone- and puupehenone-type marine
natural products
Hong-Shuang Wang, Hui-Jing Li, Jun-Li Wang and Yan-Chao Wu
OEt
OH
O
OH
O
O
OH
n
HO
H
O
OH
8 O
8 O
8 O
H
H
H
H
intermediates I
puupehenone puupehedione
puupehenol
n = 1
O
O
O
HO
HO
O
O
1
step
O
D
8
O
8 O
8 O
C
O
A
B
8
H
H
H
H
2
0-hydroxyhat- 20-epihydroxyh-
20-acetoxyhat-
erumadienone
haterumadienone erumadienone aterumadienone
The atom- and step-economical synthesis of seven puupehenone- and
haterumadienone-type marine natural products without the use of protecting groups
and transition metals has been achieved from the abundant feedstock chemical
sclareolide in only
6
to
9
steps. The proposed hemiacetalization/
dehydroxylation/hydroxylation/retro-hemiacetalization of intermediates I facilitated
the construction of the labile C ring without the accident-prone epimerization at the
C position.
8