Studies directed toward the synthesis of the massileunicellins

Article abstract of DOI:10.1016/j.tetlet.2004.02.112

An approach to the massileunicellins is described that employs a cycloaldol reaction to assemble the isobenzofuran bicyclic core. A stereoselective rearrangement-epoxidation-oxidation cascade and a chelation controlled addition to a hindered acyl furan are used to install the C3, C11, C12, and C13 oxygens. The synthesis establishes eight of the nine stereocenters present in the isobenzofuran core of the massileunicellins.

Full text of DOI:10.1016/j.tetlet.2004.02.112

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3269–3272
Studies directed toward the synthesis of the massileunicellins
Yonghai Chai and Matthias C. McIntosh*
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA
Received 26 November 2003; revised 26 January 2004; accepted 23 February 2004
Abstract—An approach to the massileunicellins is described that employs a cycloaldol reaction to assemble the isobenzofuran
bicyclic core. A stereoselective rearrangement–epoxidation–oxidation cascade and a chelation controlled addition to a hindered acyl
furan are used to install the C3, C11, C12, and C13 oxygens. The synthesis establishes eight of the nine stereocenters present in the
isobenzofuran core of the massileunicellins.
Ó 2004Published by Elsevier Ltd.
The massileunicellins are a family of densely function-
alized eunicellin diterpenes that possess an isobenzo-
furan core in which all eight of the ring carbons are
stereocenters (Fig. 1).1;2 In addition, they possess a
tertiary alcohol stereocenter at C3 adjacent to the furan
ring. A key challenge facing any projected synthesis will
be the efficient and stereocontrolled introduction of the
four oxygen containing stereocenters at C3, C11, C12,
and C13.
via aldehyde 2 (Scheme 1). We reasoned that an alkyne
functionality at C4–C5 would offer a synthetically flexi-
ble handle for closure of the oxonane ring by a variety of
possible strategies. The aldehyde should be accessible
from epoxide 3 via base-mediated ring opening of the
epoxide followed by reduction of the resulting C9–C10
alkene. Epoxide 3 in turn could be prepared from keto
alkene 4, with the C3–C4alkene serving as a precursor
to a methyl ketone. The keto alkene could be derived
from 3° allylic alcohol 5, which could be synthesized
We recently reported a cycloaldol approach to the iso-
benzofuran cores of less highly functionalized eunicel-
lins.3 We describe herein the first reported efforts toward
the synthesis of the most stereochemically complex
members of the eunicellin diterpenes.4–6
R
R
5
9
CHO
O
TIPSO
4
H
O
H
We anticipated that the oxonane ring of our first target,
massileunicellin D, could be formed late in the synthesis
H
1
OH
H
OH
HO
H
H
H
O
AcO
AcO
3
AcO
AcO
OH
O
O
2
7
TIPSO
4
TIPSO
O
O
H
H
H
H
H
H
H
H
3
3
O
O
2
O
H
H
H
O
OH
H
OH
OAc
H
H
AcO
AcO
H
AcO
AcO
AcO
AcO
11
12
H
O
H
H
14
OH
4
5
13
AcO
AcO
AcO
EtO2C
O
HO
H
O
O
O
Figure 1. Massileunicellins C, D, and K (1).
H
H
H
Keywords: Aldol reaction; Asymmetric synthesis; Rearrangements;
Isobenzofurans.
6
8
7
* Corresponding author. Tel.: +1-479-575-4692; fax: +1-479-575-4049;
e-mail: mcintosh@uark.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2004Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.02.112

3270
Y. Chai, M. C. McIntosh / Tetrahedron Letters 45 (2004) 3269–3272
O
EtO2C
10
9
OR
Cr
O
OR
Cr
O
a
c
b
d, e
O
O
6
8
7
5
O
OTIPS
OTIPS
85%
98%
OH
H
65-70%
O
86%
5
O
O
9
H
H
H
H
Scheme 2. Reagents and conditions: (a) LDA, THF, )78 °C, meth-
acrolein, HOAc; (b) Ag2O, BrCH2CO2 Et, 2,6-lutidine, DMF, 4 °C,
7 d; (c) KHMDS, THF, )78 °C; (d) LAH, ether, )78 °C; (e) TIPSOTf,
2,6-lutidine, CH2Cl2.
12
13
OR
OR
O
O
Cr
O
Cr
O
OTIPS
OTIPS
O
O
O
O
O
from (S)-dihydrocarvone7 (8) via an aldol–cycloaldol
sequence.
10
H
H
H
H
We have previously reported the synthesis of an iso-
benzofuran directly analogous to 5 that possesses a C14
isopropenyl susbstituent.3 Alcohol 5, possessing the C14
isopropyl substituent, was prepared from (S)-carvone in
four steps (Scheme 2). Aldol reaction of (S)-dihydro-
carvone7 (8) with methacrolein followed by etherifica-
tion gave glycolate 6. Cycloaldolization of keto glycolate
6 then yielded isobenzofuran 9 in 85% yield.8 Reduction
of the ester and protection then afforded TIPS ether 5.
14
15
Scheme 4.
involves formation of a 3° Cr(VI) ester such as 12 fol-
lowed by [3,3]-rearrangement (or ionization–readdition)
to 2° Cr(VI) ester 13. Epoxidation of the allylic alkene
by the Cr(VI) ester would afford the Cr(IV) ester
epoxide 14. Exchange of Cr(IV) ester 14 to Cr(VI) ester
15 is presumably required for oxidation to ketone 10.
Our original synthetic strategy entailed an oxidative
rearrangement of allylic alcohol 5 to enone 11 (Scheme
3). In the course of optimizing the oxidative rearrange-
ment, we found that treatment of allylic alcohol 5 with
PCC and NaOAc led directly to epoxy ketone 10 in
preparatively useful yield. This one-step conversion of
allylic alcohol 5 to epoxy ketone 10 is the first example
of a stereo- and regioselective variant of this transfor-
mation (vide infra).
This result has precedent in the work of Sundararaman
and Herz,9 who found that oxidation of acyclic 3° allylic
alcohols with Collins reagent [CrO3(pyr)2] gave moder-
ate to good yields of rearranged epoxy aldehydes albeit
with no relative stereocontrol at the epoxide stereocen-
ters. Ishihara et al. later reported that rearranged epoxy
alcohols were the major products upon treatment of
[5.3.0]carbobicyclic allylic alcohols with PCC.10;11
However, the reaction lacked both regio- and stereo-
control with respect to preexisting stereocenters.
Resubjection of enone 11 to the reaction conditions
returned only starting material. The lack of conversion
of enone 11 into epoxide 10 using PCC/NaOAc suggests
that an allyloxy Cr(VI) intermediate is the epoxide
precursor (Scheme 4). The mechanism presumably
The oxidative rearrangement–epoxidation sequence has
several noteworthy features. Attempts at nucleophilic
epoxidation of enone 11 under standard conditions
(H2O2, NaOH) returned only starting material, pre-
sumably due to the sterically hindered nature of the
enone.12;13 Thus the reaction may allow for the forma-
tion of epoxy ketones that are not otherwise readily
accessible. Furthermore, it avoids the use of strong base
that may cause undesired side reactions such as enoli-
zation or hydrolysis. Finally, it is inherently more effi-
cient than the two step procedure.
TIPSO
TIPSO
O
O
H
H
a
+
H
H
5
H
H
O
O
O
10 70%
11 10%
a or b
The stereochemistry of the epoxide was confirmed by
independent synthesis using directed epoxidation
(Scheme 5). Axially selective reduction of enone 11 gave
Scheme 3. Reagents and conditions: (a) PCC, NaOAc, CH2Cl2, rt; (b)
H2O2, NaOH, H2O, MeOH.
TIPSO
TIPSO
O
O
H
H
c
a
b
H
H
10
11
H
H
O
13
HO
HO
H
H
Hβ
17
16 J12-13β = 7.9 Hz
Scheme 5. Reagents and conditions: (a) LAH, ether, )78 °C, 100%; (b) VO(acac)2, t-BuOOH, CH2Cl2, 60%; (c) PCC, CH2Cl2, 89%.

Y. Chai, M. C. McIntosh / Tetrahedron Letters 45 (2004) 3269–3272
3271
OTIPS
H
H
OTIPS
O
H
O
H
H
H
CH3
O
2
2
O
H
O
3
3
H
X
3
a
b
CH3
O
H
O
O
H
10
H
80%
100%
O
H
HO
HO
O
12
O
14
OH
OH
13
RO
13
OH
O-C2-C3-O =
ca.130-140°
O-C2-C3-O = 0°
OR
4
18 R=H, X=CH2
19 R=Ac, X=CH2, 80%
20 R=Ac, X=O, 95%
c
Figure 2.
d
Scheme 6. Reagents and conditions: (a) KHMDS, TMSCl, ether,
)78 °C; mCPBA, hexanes, NaHCO3, )20 °C; (b) LiHAl(O-t-Bu)3,
ether, )78 °C to rt; (c) Ac2O, NEt3, DMAP, CH2Cl2; (d) O3, PPh3,
CH2Cl2/MeOH, )78 °C.
O
OTIPS
O
O
H
3
H
O
H
OH
a
20
3
b,c
CH3
1
H
68%
O
H
O
C12 b-alcohol 16. The stereochemistry of reduction was
assigned on the basis of the J12–13b coupling (7.9 Hz).
Vanadium catalyzed directed epoxidation14 gave epoxy
alcohol 17, which was then oxidized to epoxy ketone 10.
H
NOE
AcO
AcO
iPr
OAc
OAc
21
22
Scheme 7. Reagents and conditions: (a) ethynylMgBr, Ti(O-i-Pr)4,
ether, )78 °C; (b) Bu4NF, THF, 92%; (c) PCC, CH2Cl2, 45%.
With epoxy ketone 10 in hand, the a-C13 oxygen of
alcohol 4 was installed via Rubottom oxidation (Scheme
6). The stereochemical outcome of the oxidation was as
expected, but opposite to that obtained earlier in the
Rubottom oxidation of an enone similar to 11.3 The
a-stereochemistry was assigned on the basis of the J13;14
coupling (12.4Hz).
interaction between the ketone methyl and the isopropyl
groups. Thus it was unclear whether the requisite chelate
ring would be energetically accessible.
Reduction of ketone 4 with LiHAl(O-t-Bu)3 afforded
diol 18 in quantitative yield as a single stereoisomer. The
C12 stereochemistry was assigned on the basis of the
J12;13 coupling (2.8 Hz). Diol 18 was converted to diac-
etate 19 in good yield. Ozonolysis of the alkene then
afforded ketone 20.
In the event, addition of ethynylMgBr to ketone 20
using the protocol of Hirama et al.16 afforded a single
stereoisomeric alcohol 21 consistent with chelation
1
controlled addition based on H NMR analysis of the
crude reaction mixture (Scheme 7).17 For the purpose of
determining the C3 stereochemistry, alcohol 21 was
converted to tetracyclic lactone 22. NOESY analysis
showed cross peaks between the C3 methyl substituent
and H1.18
In planning the total synthesis of the massileunicellins,
we had originally considered an approach that would
employ a more highly substituted aldehyde corre-
sponding to C2–C7 in the initial aldol reaction with
(S)-dihydrocarvone (cf. Fig. 1 and Scheme 1). However,
we were concerned that this would restrict the flexibility
of the synthesis by locking in the C2–C7 fragment too
early in the synthesis. We decided in favor of a more
flexible strategy that would involve a carbonyl addition
to install the 3° C3 stereocenter and the C2–C7 frag-
ment. We recognized that a chelation controlled addi-
tion to the C3 methyl ketone 20 might afford the
requisite C3 stereochemistry.
In summary, we have found that an oxidative rear-
rangement–epoxidation of cycloaldol adduct 5 allows
for the efficient installation of the C11, C12, and C13
oxygens of the massileunicellins in a stereocontrolled
fashion. Chelation controlled alkynyl metal addition to
the C3 methyl ketone gave the 3° alcohol with high
stereoselectivity. Isobenzofuran 21 possesses eight of the
nine stereocenters present in the massileunicellins. Fur-
ther studies are in progress to complete the synthesis of
massileunicellin D.
There are scattered reports of chelation controlled
additions of carbon nucleophiles to monocyclic and
polycyclic 2-acyl-tetrahydrofurans that proceeded with
variable levels of diastereoselectivity.5b;15 However, it
was by no means obvious that a chelation controlled
addition would be feasible in this context. Molecular
modeling studies using the Titanâ modeling program of
a simplified analog of ketone 20 revealed a substantial
preference for conformations with the carbonyl oxygen
disposed toward the C14isopropyl substituent (Fig. 2).
Conformations that possessed a small O–C2–C3–O
dihedral angle, as would be necessary in a chelate ring,
were ca. 4–5 kcal/mol higher in energy due to steric
Acknowledgements
This publication was made possible by NIH Grant
Number P20 RR15569 from the COBRE Program of
the National Center for Research Resources. Additional
support was provided by NIH (GM-59406), the
Arkansas Biosciences Institute and Research Corpora-
tion. M.C.M. is a Cottrell Scholar of Research Corpo-
ration. Thanks to John Wood, Yale University, for
helpful discussions.

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Y. Chai, M. C. McIntosh / Tetrahedron Letters 45 (2004) 3269–3272
6. The ‘‘D’’ and ‘‘K’’ designations are provided by the
References and notes
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