Total Synthesis of (-)-Phorbaketal A

Article abstract of DOI:10.1021/acs.orglett.7b01797

A convergent asymmetric total synthesis of phorbaketal A was achieved in 10 steps through a Au(I)-catalyzed intramolecular spiroketalization reaction of an alkyne diol intermediate prepared from (R)-carvone and geranial. The spiroketalization reaction was

Full text of DOI:10.1021/acs.orglett.7b01797

Letter
pubs.acs.org/OrgLett
Total Synthesis of (−)-Phorbaketal A
Seewon Joung, Rira Kim, and Hee-Yoon Lee*
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
S Supporting Information
*
ABSTRACT: A convergent asymmetric total synthesis of phorbaketal A was achieved in 10 steps through a Au(I)-catalyzed
intramolecular spiroketalization reaction of an alkyne diol intermediate prepared from (R)-carvone and geranial. The
spiroketalization reaction was regio- and stereoselective and was accompanied by isomerization of an exo-olefin into the
trisubstituted olefin to form a unique spiroketal structure of phorbaketals.
arine sponge Phorbas sp. has been a source of various
natural products with great structural diversity that
M
1
2
3
4
includes phorboxazoles, gagunins, phorbasins, phorbasides,
5
and muironolide A. In 2009, we reported new natural products
with yet unprecedented didehydrospiroketal structure, phorba-
ketals A−C. Since then, more phorbaketals and new natura7l
products with related structural features were reported.
Phorbaketal A exhibited various biological activities such as
cytotoxicity against human colorectal, hepatoma, and lung cancer
6
a
6b
6
a
cell lines. Phorbaketal A was also reported to stimulate
osteoblast differentiation through TAZ-mediated Runx2 activa-
8
a
tion to inhibit adipogenic differentiation through the
8
b
suppression of PPARγ-mediated gene transcription and to
8c
exert an anti-inflammatory effect through NF-κb inhibition.
Phorbaketals possess a novel 1,7-dioxaspiro[5.5]undecane
fused to a hydrobenzopyran ring. Phorbaketals share the basic
9
structural features with alotaketals that were isolated from
marine sponge Hamigera sp. (Figure 1). Diverse biological
activities of these natural products along with a unique structural
feature containing unsaturated spiroketals posed a formidable
challenge to the synthetic chemistry community to afford total
Figure 1. Phorbaketals and related natural products.
6c
phorbaketal A based on the CD spectrum suggested the
opposite absolute stereochemistry though Snatzke’s rule for
determining the absolute stereochemistry of the 4-hydroxycy-
clohexenone system appeared unreliable.
1
0a,b
10c
syntheses of alotaketal A
and its analogues, and synthetic
10d
approaches to phorbaketals were reported. The total synthesis
of alotaketal confirmed the absolute stereochemistry of the
natural product and cleared the ambiguity as the absolute
stereochemistry of alotaketal A was originally assigned following
Interesting biological activities and further isolation of natural
6
,7
products with biogenetically related structures along with
stereochemical ambiguity lead us to explore the total synthesis of
phorbaketal A to confirm the absolute stereochemistry as well as
to devise an efficient synthetic route to the structurally related
natural products and analogues.
1
1
Snatzke’s rule of CD spectroscopy and later corrected by the
report of X-ray crystallography of a structurally related natural
7b
product, ansellone A. It was noticeable that the absolute
stereochemistry of structurally related natural products,
Whereas all the synthetic efforts toward phorbaketals and
10a,b
3
alotaketals assembled spiroketals onto the existing B-ring
or
phorbasins, was also assigned based on the CD method and
10d
7a
12
the C-ring, the proposed biogenetic pathway to phorbake-
tals guided us to envision that the key transformation for the
later corrected through the total synthesis. In previous work,
we assigned the absolute configuration of phorbaketal A by
reduction to phorbaketal B, whose absolute configuration was
6a
assigned through analysis of its bis-Mosher (S-MTBA) esters.
On the other hand, assignment of the absolute stereochemistry of
Received: June 14, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
facile synthesis of phorbaketal would be the intramolecular
Scheme 3. Preparation of Alkyne Fragment 4
10e
spiroacetalization of 2 to form the B- and C-rings.
The
spiroketal could be obtained through precious metal-catalyzed
13
intramolecular spiroacetalization of the alkynyl diol 2, which
would be a good surrogate of the divinyl ketone of 2′. The alkynyl
diol 2 immediately revealed geraniol and carvone partial
structures (Scheme 1). The alkyne diol intermediate 2 could
Scheme 1. Retrosynthetic Analysis of Phorbaketal A
Scheme 4. Coupling, Cyclization, and Completion of the
Synthesis
be synthesized through coupling of the allylic halide 3 and the
alkyne 4. Each fragment would readily be derived from (R)-
carvone 5 and geranial 6.
Synthesis of the allylic chloride fragment 3 was started from
(R)-carvone (Scheme 2). The known compound 7 was prepared
Scheme 2. Preparation of Allylic Chloride Fragment 3
1
0a
from (R)-carvone 5 in a three-step sequence of iron(III)
Cu(I)-catalyzed coupling reaction of the alkyne 4 with the allylic
halide 3 to form the intermediate 10 as an inseparable mixture
with its minor diastereomer, which became separable at the
spiroketal stage. The intermediate 10 possessed all the necessary
carbon atoms with the necessary connectivity and stereo-
chemistry for phorbaketal A. One other task of the synthesis
after spiroketalization was to functionalize a specific olefin among
four olefins in 10, and these four olefins did not appear to be
easily distinguishable after spiroketal formation. Thus, the free
hydroxyl group in the cyclohexenone ring of the intermediate 10
was utilized to distinguish the olefin near the cyclohexenone ring
chloride-catalyzed regioselective enol ether formation followed
14
by the vinylogous O-nitroso Mukaiyama aldol reaction and
subsequent electrophilic chlorination of the propenyl group. The
stereochemistry of the alcohol of 7 was inverted to form 3 using
Mitsunobu reaction followed by basic hydrolysis of the resulting
acetate.
Synthesis of the other fragment started from geranial (Scheme
). Although a brief exploration of the enantioselective allylation
3
15a
reaction
ketone
or asymmetric reduction of the corresponding
did not yield satisfactory results, resolution of the
1
5b
racemic alcohol 8 through enzymatic acetylation provided a rapid
as the alcohol-induced homoallylic epoxidation with VO(acac)
2
1
6
10d,22
access to 9. Barbier reaction of geranial 6 with 2,3-
dibromopropene resulted in the racemic allylic alcohol 8. The
racemic alcohol 8 was resolved using lipase A from the Candida
18
generated epoxide 11.
The hydroxyl group directed
epoxidation oxidized the homoallylic olefin regioselectively and
10d,22d
stereoselectively.
The stereochemistry of the epoxide
1
7
antarctica to produce the resolved chiral acetate 9.
could be assumed as S-configuration based on the literature
19
22d
Sonogashira coupling of the alkenyl bromide 9 with TMS-
acetylene yielded alkyne 4 after removal of the TMS group using
precedent, though the stereogenic center in the epoxide would
be lost on rearrangement to the allylic alcohol. After hydrolysis of
the acetate of 11 to produce 2, the alkyne diol 2 was subjected to
a Au(I)-catalyzed spiroketalization reaction. Fortuitously, the
reaction produced a 6,6-spiroketal ring with migration of the exo-
cyclic olefin conjugated to the alkyne in 11 into the ring during
20
ammonium fluoride.
With the desired fragments in hand, the crucial stage of the
synthesis, the key cyclization reaction sequence was commenced
21
(
Scheme 4). Coupling of 3 and 4 was achieved through a
B
DOI: 10.1021/acs.orglett.7b01797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the cyclization reaction to form the trisubstituted olefin in the C-
ring of phorbaketal A.
The spiroketalization reaction started with the formation of
either the conjugated dihydropyran intermediate 13 through
initial endo-cyclization or intermediate 13′ through initial exo-
cyclization (Scheme 5). During formation of the oxonium ion
from (R)-carvone. This work firmly confirmed the absolute
stereochemistry of phorbaketal A as reported, though some steps
were not rigorously optimized. The total synthesis is efficient and
convergent enough to be readily applied to the synthesis of other
natural phorbaketals and alotaketals as well as various analogues.
ASSOCIATED CONTENT
Supporting Information
■
Scheme 5. Au(I)-Catalyzed Spiroacetalization of the Alkyne
Diol Intermediate
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01797.
1
13
Experimental procedures and spectroscopic data ( H, C
NMR, HRMS, [α] ) (PDF)
D
AUTHOR INFORMATION
Corresponding Author
E-mail: leehy@kaist.ac.kr.
■
*
ORCID
Hee-Yoon Lee: 0000-0002-3558-2894
Notes
The authors declare no competing financial interest.
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■
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26
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Org. Lett. XXXX, XXX, XXX−XXX