Assembly of the isoindolinone core of muironolide A by asymmetric intramolecular Diels-Alder cycloaddition

Article abstract of DOI:10.1021/ol201461n

The hexahydro-1H-isoindolin-1-one core of muironolide A was prepared by asymmetric intramolecular Diels-Alder cycloaddition using a variant of the MacMillan organocatalyst which sets the C4,C5 and C11 stereocenters.

Full text of DOI:10.1021/ol201461n

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3932–3935
Assembly of the Isoindolinone
Core of Muironolide A by Asymmetric
Intramolecular DielsꢀAlder Cycloaddition
Beatris Flores† and Tadeusz F. Molinski*,†,‡
Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and
Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive
MC0358, La Jolla, California 92093, United States
tmolinski@ucsd.edu
Received May 30, 2011
ABSTRACT
The hexahydro-1H-isoindolin-1-one core of muironolide A was prepared by asymmetric intramolecular DielsꢀAlder cycloaddition using a variant
of the MacMillan organocatalyst which sets the C4,C5 and C11 stereocenters.
Marine invertebrates show an astounding repertoire of
capabilities in biosynthesis of biologically active macro-
lides, a capacity likely owed to their associations with
stable consortia of marine bacteria that augment biosyn-
thetic expression and sequestration of natural products.
Sponge-derived macrolides, like peloruside,1a and hali-
chondrin B,1b have undergone preclinical or clinical trials
as antitumor agents. Muironolide A (1)2 is an uncommon
isoindolinone polyketide macrolide isolated from the same
specimen of marine sponge, Phorbas sp., that earlier
afforded phorboxazoles A and B (2a,b),3 and phorbasides
A-E,4 F,5 and G-I.6
The nitrogenous polyketide 1 is rare in three ways: it is
the singular representative of a natural product with an
esterified trichloromethylcarbinol, embodying three ketide
segments ꢀ two esters and an amide within a macrolide
ringꢀ and a rarely encountered hexahydro-1H-isoindolin-1-
one heterocycle (hereafter, referred to as an ’isoindolinone’).
Muironolide A (1) is also scarce: the total yield from
the only available specimen of Phorbas sp. was 90 μg.
Although 1 shows activity against the pernicious fungal
pathogenCryptococcusneoformans, theremaining amount
of sample precludes further biological evaluation. Recol-
lection of the sponge is not tenable (Phorbas sp. has not
† Department of Chemistry and Biochemistry.
‡ Skaggs School of Pharmacy and Pharmaceutical Sciences.
(1) (a) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem.
2000, 65, 445. (b) Bai, R. L.; Paull, K. D.; Herald, C. L.; Malspeis, L.;
Pettit, G. R.; Hamel, E. J. Biol. Chem. 1991, 266, 15882.
(2) Dalisay, D. S.; Morinaka, B. I.; Skepper, C. K.; Molinski, T. F.
J. Am. Chem. Soc. 2009, 31, 7552.
(3) (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117,
8126. (b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W.
J. Am. Chem. Soc. 1996, 118, 9422. (c) Molinski, T. F. Tetrahedron Lett.
1996, 37, 7879.
(4) (a) MacMillan, J. B.; Xiong-Zhou, G.; Skepper, C. K.; Molinski,
T. F. J. Org. Chem. 2008, 73, 3699. (b) Skepper, C. K.; MacMillan, J. B.;
Zhou, G. X.; Masuno, M. N.; Molinski, T. F. J. Am. Chem. Soc. 2007,
129, 4150. (c) MacMillan, J. B.; Xiong-Zhou, G.; Molinski, T. F. J. Org.
Chem. 2008, 73, 3699.
(5) Dalisay, D. S; Molinski, T. F. J. Nat. Prod. 2009, 72, 739.
(6) Dalisay, D. S; Molinski, T. F. J. Nat. Prod. 2010, 73, 679.
r
10.1021/ol201461n
Published on Web 07/13/2011
2011 American Chemical Society

been encountered again by us or others7 since the original
isolation of 2a and 2b), and total synthesis is the only
feasible method to secure additional 1. We describe here
the assembly of the stereocomplex heterobicyclic core 3 of
muironolide A with control of all three stereocenters in the
isoindolinone core of 1, through asymmetric catalysis.
We anticipated the role of the N-protecting group P1
(viz. 5, Scheme 1) would be critical for two reasons: ease
of removal near completion of 1, but primarily to
provide steric bias to populate the s-cis rotamer of
tertiary amide, necessary to achieve the DA transition
state. Control of the three stereocenters C4, C5 and C11 in
the isoindolinone rings of 1 would follow from the conse-
quences of the endo rule and base-promoted epimerization
at C49 (c.f. 4, Scheme 1).
Scheme 1. Biomimetic Approach to 1: Retrosynthetic Analysis
These three objectives were realized through the com-
pletion of two pilot syntheses of model isoindolinones ꢀ
racemic (()-12a and optically enriched (5R)-4 ꢀ as de-
scribed below.
Scheme 2. Synthesis of Isoindolinones (()-12a and 4aꢀc by
Intramolecular DielsꢀAlder Cycloaddition (IMDA)a,b
Inspection of the molecular structure of 1 reveals a
potential biosynthesis based on assembly of three ketide
units and formation of the isoindolinone core through an
intramolecular DielsꢀAlder (IMDA) reaction. The latter
inspired a biomimetic approach which is outlined in
Scheme 1, proceeding through the isoindolinone enoate
ester 3 and the key cyclohexene carboxaldehyde 4, as-
sembled from IMDA of 5.
a Prepared from the acid chloride of 7b. b Yield over two steps.
The dienophile precursor, 8 (Scheme 2), for the IMDA
reaction was prepared from allylic bromide 1010 by SN2
displacement with p-methoxybenzylamine under conditions11
(Cs2CO3, DMF) that select for the monoalkylated product
(95%). Diene components ꢀ pentadienoic acid (7a)12 and
commercially available sorbic acid (7b) ꢀ were separately
coupled with 8 and 9 to give tertiary amides 6a,b in good
yields (73% and 80%, respectively). Thermal IMDA of 6a
Figure 1. MacMillan organocatalysts 11a,b (ref 8) and Kristen-
sen’s derivative 11c (ref 18).
Compound 5, in turn, is elaborated from the open-ring
allylic acetate ester 6, through intermediates 8-10, and
pentadienoic acid (7a) or sorbic acid (7b). Asymmetry
would be introduced by catalytic IMDA of 5 using Mac-
Millan’s imidazolidinones (Figure 1, 11a-c) which have
been proven to promote [4 þ 2] cycloadditions with high
enantioselectivity.8
˚
(toluene, 110 C) gave only sluggish conversion to the
(9) IMDA of R,β-unsaturated aldehydes with MacMillan organoca-
talysts does not always conserve the R,β-relative configuration of the
starting trienal.
(10) Prepared by 1,4-addition of the elements of Br and OAc to
isoprene (NBS, AcOH). Babler, J. H.; Buttner, W. J. Tetrahedron Lett.
1976, 17, 239.
(11) (a) Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K. W.
Org. Lett. 1999, 1, 1893. (b) Salvatore, R. N.; Nagle, A. S.; Schmidt,
S. E.; Shin, S. I.; Nagle, A. S.; Worrell, J. H.; Jung, K. W. Tetrahedron
Lett. 2000, 41, 9705. (c) Salvatore, R. N.; Nagle, A. S.; Jung, K. W.
J. Org. Chem. 2002, 67, 674.
(7) Capon, R. J.; Skene, C.; Liu, E. H.; Lacey, E.; Gill, J. H.; Heiland,
K.; Friedel, T. Nat. Prod. Res 2004, 18, 305. This report of occurrence of
2a,b in a sponge identified as Raspailia sp. from the Indian Ocean some
1200 km south of the site of collection of Phorbas sp. provokes the
intriguing speculation that the two sponges are one and the same and
that Raspailia sp. may contain 1.
(8) (a) Wilson, R. M.; Jen, W. S.; MacMillan, D. J. Am. Chem. Soc.
2005, 127, 11616. (b) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2000, 122, 4243.
(12) (a) Idoux, J. P.; Ghane, H. J. Chem. Eng. Data 1979, 24, 157.
(b) Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Org. Synth. 1988,
6, 95.
Org. Lett., Vol. 13, No. 15, 2011
3933

racemic cycloaddition product (()-12a. In contrast, mi-
˚
crowave-promoted reaction of 6a (200 C, chlorobenzene,
30 min), in the presence of a radical inhibitor, gave smooth
conversion to (()-12a in very good yield (86%) but with
poor diastereoselectivity (1:2 trans to cis). When the
product was redissolved in ethanol and subjected to micro-
˚
wave conditions (120 C), product 12a (dr ∼1:2) equili-
brated completely to cis-12a (dr > 30:1). Formation of the
predominantly cis-product suggested R-epimerization of
12a, similar to that observed during IMDA of allylic
sorbates to bicyclic γ-butyrolactones.13 The stage was set
to explore optimzed conditions for asymmetric IMDA.
The precursor asymmetric IMDA was prepared in two
steps by methanolysis (K2CO3, MeOH) of the acetate ester
6a to the corresponding allylic alcohol which was oxidized
(MnO2, CH2Cl2) to aldehyde 5a14 in good overall yield
(53% over two steps). Exposure of 5a to either catalyst 11a
or 11b (Scheme 2) gave slow [4 þ 2] cycloaddition, a
disappointing yield of cycloadduct 4a (∼4%) and poor
recovery of starting material, probably due to the tendency
of the diene to polymerize.15 Reasoning that a terminally
substituted diene may fare better in the IMDA, aldehyde
5b was prepared using the same sequence of reactions and
replacement of pentadienoic acid with sorbic acid 11b. In
the presence of catalyst 11b, aldehyde 5b underwent clean
asymmetric IMDA in good yield (Table 1, Entry 2, 84%),
exclusively in endo mode, to give mostly (þ)-(4S,5R,8R)-
4b16 with a lesser amount of (4R,5R,8R)-4b (dr > 20:1),
albeit in modest enantiomeric excess (42% ee). The relative
configurations of the separated pure isomers (HPLC) were
determinedfrom extensive1D-NOE experiments (Figure 2
and Supporting Information).
Figure 2. 1D-NOE of (4S)- and (4R)- isomers of 4b (mixing time,
m = 400 mS). Numbering follows that of 1 (see ref ).
t
workers17 as an intermediate in the preparation of
copolymer-supported catalysts, gave the best outcomes.18
Under conditions similar to those used with 11b (Entry 2),
˚
IMDA of 5b in the presence of 11c (20 mol %, 23 C, Entry
5) gave (þ)-4b with almost double the enantioselectivity
(72% ee), albeit with lower diastereoselectivity (73%, dr =
3.8:1). Optimal conditions for IMDA of 5b (Entry 9, 20
˚
mol
% 11c, 0 C, 73 h) gave 4b (84% yield,
dr = 6:1, 88% ee).19 Base treatment of 4b (DBU, C6D6, 23
C, 13 h, Scheme 3) epimerized C4 and inverted the 4R:4S
ratio to >20:1 in favor of the configuration required for
1.20 Thus, pure (þ)-(4R,5R,8S,11S)-4b was obtained in
70% yield over two steps after preparative HPLC.
˚
Scheme 3. Base-Promoted Isomerization of (4S,8R)-4b
Optimization of the asymmetric IMDA (Table 1) was
undertaken and, similar to observations by MacMillan,8 it
was found that the catalyst structure, counterion, and
temperature all played important roles in affecting the
yield, diastereoselectivity and enantioselectivity. Catalyst
11a (HCl salt) gave poorer yields of 4b (Entry 1, 5%), even
after 72 h. A slight gain in enantioselectivity in formation
of the major epimer 4S-4b (Entry 3, 50% ee) was seen with
catalyst 11b (HClO4 salt) when the temperature was
The steric bulk of the N-protecting group influences the
outcome of the IMDA reaction through torsional strain
that also populates the required s-cis conformation of the
tertiary amide. Replacement of the N-PMB protecting
group with a 2,4-dimethoxybenzyl group (N-DMB) was
investigated to determined the effect on yield, enantio- and
stereoselectivity. Compound 5c, prepared from 9 using a
similar sequence for 5b, was treated with 11c (20 mol %,
3 °C, 54 h) to afford 4c in 67% yield, with slightly lower
enantioselectivity (84% ee) but with high 4S:4R diaster-
eoselectivity (dr > 20:1).21
˚
˚
lowered from 23 C to 10 C, however, at the expense of
lower yield, diastereoselectivity (60%, dr 6:1) and reaction
time (57 h instead of 4.5 h).
Gratifyingly, N-(2-hydroxy-1-ethyl)-imidazolidone 11c,
a MacMillan-type catalyst reported by Kristensen and co-
The kinetics of base-equilibration of purified (4S,8R)-4b
(DBU, C6D6, 23 °C, Scheme 3 and Supporting Informa-
tion) were briefly investigated. H NMR revealed rapid
conversion of the (4S,8R)-4b to the more stable isomer
(4R,8R)-4b,22 and finally, slower conversion of the latter to
a third isomer, (4R,8S)-4b.
(13) (a) Wu, J.; Yu, H.; Wang, Y.; Xing, X.; Dai, W.-M. Tetrahedron
Lett. 2007, 48, 6543. (b) Guy, A.; Lemaire, M.; Guiette, M. Tetrahedron
Lett. 1985, 26, 3575. (c) Boeckman, R. K., Jr.; Demko, D. M. J. Org.
Chem. 1982, 47, 1789. (d) Martin, S. F.; Williamson, S. A.; Gist, R. P.;
Smith, K. M. J. Org. Chem. 1983, 48, 5170.
1
(14) Contained ∼5ꢀ10% of the Z-isomer.
(15) Inclusion of a radical inhibitor C (Scheme 1) did not suppress
formation of polymer; therefore, the mechanism of polymerization is
likely ionic in nature.
(19) The hydroxyethyl side chain in 11c may play an important role in
stabilizing either the transition state by hydrogen bonding or through
intramolecular nucleophilic capture of the incipient iminium ion.
(20) The relative configurations of (4S,8R)-4b and (4R,8R)-4b were
assigned by 1D NOESY studies.
(16) The absolute configuration follows from the expected sense of
asymmetric induction demonstrated by McMillan and co-workers.
(17) Kristensen, T. E.; Vestli, K.; Jakobsen, M. G.; Hansen, F. K.;
Hansen, T. J. Org. Chem. 2010, 75, 1620–1629.
(21) See Table S1, Supporting Information, for optimization of
conditions for IMDA of 5c to give 4c.
(22) The cyclohexene ring conformation changed to a pseudoboat.
(18) Catalyst 11c is more conveniently prepared from L-phenylala-
nine methyl ester and inexpensive ethanolamine than 11a,b, which
requires the more expensive “controlled substance” MeNH2.
3934
Org. Lett., Vol. 13, No. 15, 2011

Table 1. Optimization of Asymmetric IMDA of 5b Using MacMillan-Type Catalysts (See Figure 1 and Scheme 2)
entry
catalyst 11 HXa
temp, °C
time, h
yield,b %
drc 4S-4b/4R-4b
% eed
3
1
2
11a
11b
11b
11c
11c
11c
11c
11c
11c
11c
none
HCl
23
23
10
23
23
23
23
23
0
72
4.5
57
36
40
39
6
5
84
60
38
73
25
48
86
73
69
83e
1.6:1
>20:1
6:1
14
42
50
10
72
78
52
36
88
HClO4
HClO4
HCl
3
4
1.1:1
3.8:1
2.6:1
10:1
3.4:1
6:1
5
HClO4
6
CF3COOH
7
HClO4
8
CF3COOH
HClO4
18
84
48
90
9
10
11
HClO4
10
80
4:1
71
f
3.2:1
a 20 mol % catalyst, CH3CN, 2% H2O, [5b] = 0.5 M. b Combined isolated yield of 4S- and 4R-isomers. c From 1H NMR integrations. d % ee of major
isomer, determined by chiral HPLC (Chiracel OD, 3:7 i-PrOHꢀhexane). e Carried out in toluene. f Racemic product.
At equilibrium in C6D6 (12 h), (4S,8R)-4b was absent,
and the relative concentration of (4R,8R)-4b to (4R,8S)-4b
was 2:1. Interestingly, very rapid epimerization of C4 was
observed with NaH (DMF, 23 °C, 15 min) with complete
conversion of (4S,8R)-4b to a mixture of (4R,8R)-4b and
(4R,8S)-4b (dr = 4:1). Deuterium incorporation studies
(NaOCD3, CD3OD) confirmed that H4 was rapidly ex-
changed for D followed by slower replacement of H8,
consistent with the higher pKa of the H8 in the β,
γ-unsaturated lactam.
Finally, aldehyde 4b was chain-extended (Scheme 4) by
HornerꢀWadsworthꢀEmmons reaction under Roushꢀ
Masamune conditions26 to give exclusively E-3 in 86% yield.
Scheme 4. Chain Extension of Aldehyde (4R,5R,8R,11S)-4b
No conjugated double bond isomers of 4b were detected
under any of the isomerization conditions tried (NaOMeꢀ
MeOH, DBUꢀbenzene, NaHꢀDMF). Attempted kinetic
trapping of the dienolate generated from 4b with strong
base (KHMDS, ꢀ78 °C; 1 equiv CH3COOH) returned only
starting materials as a mixture of C4 and C8 epimers.23,24
From these results, we deduced that enolization of the
IMDA product occurred by deprotonation-reprotonation
at C8, but the β,γ-double bond isomer is more stable than
the conjugated isomer.25
In summary, a simple stereocontrolled asymmetric route
to 3, embodying the isoindolinone core of muironolide A
(1), was achieved by asymmetric intramolecular Dielsꢀ
Alder cycloaddition of an acyclic trienal precursor cata-
lyzed by 11c.
Efforts toward extending the IMDA approach to com-
pletion of 1 are underway in our laboratories.
(23) Clearly, the biosynthesis of 1 favors the R,β-unsaturated lactam.
Models show that the macrolide ring adopts a “ring flipped” cyclohex-
ene half-chair compared to models of 4b in which the C4 and C5
substituents are held in the pseudoequatorial orientation, which may
favor the conjugated lactam.
(24) Alternative methods can be used to move the CdC double bond
into conjugation with the lactam CdO as required for 1 (e.g., hydro-
genation R-selenation, followed by H2O2 oxidationꢀselenoxide
elimination).
Acknowledgment. We thank B. Morinaka for assis-
tance with NMR measurements, J. Pigza for helpful dis-
cussions, J. Haeckl and B. Ruby for preparation of some
catalysts and intermediates, Y. Su for HRMS measure-
ments (all UCSD), and R. New (UC Riverside) for addi-
tional MS data. This work was supported by the NIH
(AI-039987, CA-122256).
(25) Molecular modeling and semiempirical calculations (PM3) of
enthalpies of formation of models of 4 (the N-protecting group was
removed for simplicity) show that the nonconjugated iꢀso1mers are
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
disfavored over the R,β-conjugated isomers by ∼1 kcal mol
.
3
(26) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
Org. Lett., Vol. 13, No. 15, 2011
3935