A Biomimetic Synthesis of des -Hydroxy Paecilospirone

Article abstract of DOI:10.1055/s-0036-1592001

The carbon framework of des -hydroxy paecilospirone was rapidly synthesized using a biomimetic approach whereby an enol ether and an ortho -quinone methide (o- QM), each derived from the same lactone, were combined to arrive at the complete carbon skeleton of paecilospirone.

Full text of DOI:10.1055/s-0036-1592001

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–C
letter
A
en
Z.-G. Feng et al.
Letter
Synlett
A Biomimetic Synthesis of des-Hydroxy Paecilospirone
Zhen-Gao Feng
R'
O
H17C8
O
o-QM
Diels–Alder
O
C7H15
O
C7H15
G. Leslie Burnett
Thomas R. R. Pettus*
2 x
+
O
O
O
O
Department of Chemistry and Biochemistry, University of California,
Santa Barbara, California 93106, USA
OH
OH
pettus@chem.ucsb.edu
OBn
Dedicated to purveyors of truth: Tomáš Hudlický, Richard H.
Schlessinger, Samuel J. Danishefsky
Received: 07.03.2018
Accepted: 02.04.2018
Published online: 09.05.2018
DOI: 10.1055/s-0036-1592001; Art ID: st-2018-v0148-l
Paecilospirone was first collected from the marine fun-
gus Paecilomyces sp. near Yap Island.1 It was determined to
have a rather unique spiro[chroman-2,1′(3′H)-isobenzofu-
ran] structure that reportedly inhibited microtubule as-
sembly. In 2011, Brimble and coworkers reported a total
synthesis of (+)-paecilospirone in 19 steps.2
Abstract The carbon framework of des-hydroxy paecilospirone was
rapidly synthesized using a biomimetic approach whereby an enol ether
and an ortho-quinone methide (o-QM), each derived from the same lac-
tone, were combined to arrive at the complete carbon skeleton of pae-
cilospirone.
Our synthetic curiosity in this natural product emerged
from an appreciation of its putative biosynthesis, which we
propose (Scheme 1). We suppose that salicylic alcohol 2 ex-
trudes water by different mechanisms to either form the o-
quinone methide (o-QM) 3 or the enol ether 4. Nature then
combines these two entities to arrive at the tetracycle 5,
which undergoes further site selective benzylic oxidation to
afford paecilospirone A (1). We decided to attempt to repli-
cate this efficient process in the laboratory.
Key words ortho-quinone methide, Diels–Alder, paecilospirone, ben-
zylic oxidation, enol ether
O
We suspected that the unprotected salicylic alcohol 2
might prove particularly unstable and highly reactive under
chromatographic conditions, and thus it would not be a
prudent choice of starting material. We therefore chose to
begin our investigation with the phthalide 7, which we
imagined to be more easily harnessed for our synthetic pur-
poses (Scheme 2). Compound 7 was prepared in a regiose-
lective manner as first shown by Buehler.3 Benzoic acid (6)
and formalin were combined at ambient temperature for 24
hours in the presence of concentrated hydrogen chloride.
These slightly modified conditions afforded the stable lac-
OH
O
O
OH
paecilospirone (1)
selelective
oxidation
O
5
O
O
OH
O
O
O
O
formalin
BnBr
dimerization
OH
HCl (conc.)
K2CO3
O
O
35%
acetone
95%
O
3
4
OH
6
OH
OBn
8
7
O
Br
–H2O
OH
10
–H2O
C7H15
H15C7
Br
O
OH
OH
TiCl4, TMEDA
O
Zn, PbCl2, THF
87%
2
OBn
9
Scheme 2 Synthesis of o-QM precursor 8 and enol ether 9
Scheme 1 The structure of paecilospirone (1) and speculated biosynthesis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

B
Z.-G. Feng et al.
Letter
Synlett
tone 7 in a respectable 35% yield. The lactone 7 displays
three sp2 atoms, positioning its five-membered ring into a
nearly planar arrangement, which positions RC(=O)–O bond
orthogonal to the aromatic π-system. Thus, when the phe-
nol is deprotonated, it is not expelled as carboxylate to form
the corresponding o-QM, affording stability to this interme-
diate. For this reason, phenol 7 underwent smooth benzyla-
tion under standard basic conditions to afford the benzyl
ether 8 in a 95% yield. The carbonyl of the lactone 8 was
subsequently found to form the hereto unknown enol ether
9 as a single geometric isomer in an 87% yield by applica-
tion of Takai’s method with the dibromide 10.4–7 Compound
9 thus served as a surrogate of intermediate 4 postulated in
the biosynthesis (Scheme 1).
Table 1 Oxidation of Amide 14
Entry
Conditions
Main product
1
2
3
4
DDQ, H2O, DCM
15
15
16
17
DDQ, AcOH, DCM
DDQ, MeOH
NaIO4, RuCl3·H2O, CCl4, H2O, MeCN
N
O
N
O
C7H15
C7H15
O
O
O
O
OBn
OBn
15
16
OMe
O
O
N
O
1) Ac2O, Et3N,
DMAP, CH2Cl2
C7H15
N
O
pyrrolidine
N
8
2) Pd/C, H2,
EtOAc/EtOH
78% from 8
Me3Al, CH2Cl2
O
OBn OH
OH OAc
12
O
OBn
17
11
Scheme 3 Synthesis of a more manageable o-QM precursor from 8
With this material in hand, we were now poised to ex-
plore selective oxidation of the chroman core (Table 1). One
of the reasons that we chose the amide 14 (Scheme 4), in-
stead of something more closely resembling the ketone 5
(Scheme 1), was that the knowledge that amides could
serve as surrogates for the respective ketone and acid func-
tionalities. Unfortunately, the amide 14 failed to undergo
the desired oxidation. Instead, we found that upon expo-
sure of compound 14 to DDQ in water or acetic acid, the
chromene 15 formed in low yield. On the other hand, when
the DDQ oxidation was performed in methanol, a methoxy
group was installed on the isobenzofuran ring resulting in a
diastereomeric mixture of the acetals 16. Furthermore, we
found that application of ruthenium tetroxide caused oxi-
dation of the pyrrolidine ring to afford the corresponding
lactam 17. While the chromene 15 might have proven use-
ful in accessing the desired alcohol, the low yield of the
chromene (<20%) dissuade further investigations. In addi-
tion, our attempts to remotely deprotonate amide 14 at its
γ-position and oxidize the corresponding enolate, or some de-
rivative of it, with DMDO or other suitable oxidants, also failed.
We therefore decided to investigate the conversion of
the amide into the corresponding carboxylic acid in the
hope that this functional group might facilitate oxidation of
the chroman ring. This task was accomplished by a two-
step procedure. First, the amide 14 was converted into the
aldehyde 18 in 63% yield by its reduction with Schwartz’s
reagent. Subsequent Pinnick oxidation afforded the acid 19
in 87% yield (Scheme 5).10 Unfortunately, we were unable to
oxidize this material in the desired manner using a variety
of procedures, such as hypervalent iodide,11,12 lead tetraace-
tate,13 or Pd(II).14
To construct a more manageable o-QM precursor lead-
ing to something resembling compound 3 in the proposed
biosynthesis, the lactone ring in 8 would be opened, an ap-
propriate electron-deficient leaving group installed on the
benzylic alcohol, and the phenol protecting group then
cleaved (Scheme 2). This proposition was accomplished in
three steps by exposure of compound 8 to pyrrolidine and
trimethylaluminum to form benzyl alcohol 11, subsequent
acetylation, and careful debenzylation under as neutral
conditions as possible to provide the phenol 12 in 78% over-
all yield (Scheme 3).
N
O
N
O
t-BuMgCl
enol ether 9
C7H15
12
THF, –78 °C
64%
O
O
O
OBn
14
13
Scheme 4 Base-triggered o-QM generation and cycloaddition
As anticipated from our earlier work with base-promot-
ed generation of o-QMs,8,9 we found that when an ethereal
mixture of phenol acetate 12 and enol ether 9 was treated
at –78 °C with tert-butylmagnesium chloride, the spiroketal
14 was formed in 64% yield (Scheme 4). We presume this
smooth reaction is due to the controlled generation of the
o-QM intermediate 13 by base-mediated elimination of the
acetate, and subsequent inverse demand cycloaddition with
the enol ether 9.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

C
Z.-G. Feng et al.
Letter
Synlett
H
O
O
OH
C7H15
NaClO2, NaH2PO4
2-methyl-2-butene
C7H15
(C5H5)2ZrHCl
THF
14
t-BuOH
87%
63%
O
O
O
O
OBn
OBn
18
19
Scheme 5 Synthesis of acid 19
H17C8
C8H17MgBr
THF, 0 °C
OH
R
O
Supporting Information
C7H15
C7H15
Supporting information for this article is available online at
90%
https://doi.org/10.1055/s-0036-1592001.
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References and Notes
(COCl)2, DMSO
Et3N, CH2Cl2
90%
(1) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Meguro, S. Chem.
Lett. 2000, 308.
(2) (a) Yuen, T.-Y.; Yang, S.-H.; Brimble, M. A. Angew. Chem. Int. Ed.
2011, 50, 8350. (b) Jay-Smith, M.; Furkert, D. P.; Sperry, J.;
Brimble, M. A. Synlett 2011, 1395.
H17C8
O
H17C8
O
Pd/C, H2
EtOH
C7H15
C7H15
89%
(3) Buehler, C. A.; Powers, T. A.; Michels, J. G. J. Am. Chem. Soc. 1944,
66, 417.
(4) Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1987,
52, 4410.
O
O
O
O
OH
OBn
5
21
Scheme 6 Synthesis of des-hydroxy paecilospirone (5)
(5) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem.
1994, 59, 2668.
(6) Hoffmann, R. W.; Bovicelli, P. Synthesis 1990, 657.
(7) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. J. Org.
Chem. 2007, 72, 2216.
(8) Green, J. C.; Burnett, G. L.; Pettus, T. R. R. Pure Appl. Chem. 2012,
84, 1621.
(9) Bai, W.-J.; David, J. G.; Feng, Z.-G.; Weaver, M. G.; Wu, K.-L.;
Pettus, T. R. R. Acc. Chem. Res. 2014, 47, 3655.
(10) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
(11) Togo, H.; Muraki, T.; Hoshina, Y.; Yamaguchi, K.; Yokoyama, M.
J. Chem. Soc., Perkin Trans. 1 1997, 787.
(12) Togo, H.; Muraki, T.; Yokoyama, M. Tetrahedron Lett. 1995, 36,
7089.
Unable to facilitate the desired benzylic oxidation of the
either the amide 14 or then acid 19 in an acceptable yield
the aldehyde 18 was elaborated into des-hydroxy paecilo-
spirone (5) over three steps (Scheme 6). Nucleophilic addi-
tion of octyl magnesium bromide to the aldehyde 18 afford-
ed the alcohol 20 in 90% yield. This material was converted
into ketone 21 in 90% yield by a Swern oxidation. Hydroge-
nolysis of the benzylated phenol group furnished des-hy-
droxy paecilospirone (5) in 89% yield.15
In summary, a synthetic strategy resembling what we
believe to be the biosynthesis of paecilospirone has been
completed. Our approach utilizes an o-QM and an enol
ether synthesized from the same starting material and ar-
rives at des-hydroxy paecilospirone (5) in just ten steps. The
approach may be amenable to enantioselective control
through a chiral amide. Perhaps a method for the selective
oxidation of such complex systems, as compounds 14, 19,
and 5 with their numerous benzylic sites, will be discov-
ered that can emulate nature’s abilities which routinely sur-
pass our own.
(13) Davies, D. I.; Waring, C. J. Chem. Soc. C 1968, 2337.
(14) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(15) Compound 5: 1H NMR (500 MHz, CDCl3) δ = 7.30–7.24 (m, 2 H),
7.16 (t, J = 7.9 Hz, 1 H), 6.95–6.90 (m, 2 H), 6.80 (d, J = 7.9 Hz, 1
H), 5.30 (s, 1 H), 5.25 (d, J = 12.8 Hz, 1 H), 5.07 (d, J = 12.8 Hz, 1
H), 3.30 (dd, J = 17.6, 5.5 Hz, 1 H), 3.01–2.84 (m, 3 H), 2.36–2.25
(m, 1 H), 1.77–1.67 (m, 2 H), 1.46–1.07 (m, 22 H), 0.87 (t, J = 7.0
Hz, 3 H), 0.83 (t, J = 7.1 Hz, 3 H). 13C NMR (126 MHz, CDCl3) δ =
204.8, 153.5, 150.0, 141.0, 138.2, 129.8, 126.9, 126.7, 122.4,
121.4, 120.6, 115.7, 114.5, 111.6, 70.6, 41.9, 38.2, 31.8, 31.8,
30.6, 29.6, 29.4, 29.4, 29.2, 29.1, 26.8, 26.1, 24.6, 22.7, 22.6, 14.1,
14.1. IR νmax (neat): 3393, 2925, 2854, 1670, 1607, 1455, 1287,
1258, 927. HRMS (ESI+) calcd for
515.3137; found: 515.3126
C
32H44O4Na [M+Na]+:
Funding Information
T.R.R.P. is grateful for past financial support from the National Science
Foundation (CHE-0806356) for this work.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C