Total synthesis of mycophenolic acid by a palladium-catalyzed decarboxylative allylation and biomimetic aromatization sequence

Article abstract of DOI:10.1002/ejoc.201300974

This paper describes the total synthesis of the fungal natural product mycophenolic acid through palladium-catalyzed allylation, biomimetic cyclization, and aromatization. Methyl (4E)-6-hydroxy-4-methylhex-4-enoate, which was converted in four steps into the key diketo ester dioxinone via two selective C-acylation reactions, was transformed into a resorcylate. Subsequent phenol methylation, lactonization, iodo-ether formation, and halogenation gave a tricyclic intermediate. Palladium-catalyzed cross-coupling with DABCO-(AlMe₃)₂ and saponification gave mycophenolic acid. An alternative approach with early stage arene methyl incorporation unexpectedly resulted in the formation of a γ-pyrone. A total synthesis of mycophenolic acid was developed. In a one-pot reaction, a diketo ester dioxinone was transformed into a resorcylate by Pd-catalyzed decarboxylative allylation and biomimetic cyclization and aromatization. Methylation, lactonization, iodo-ether formation, and halogenation led to a tricyclic intermediate. Pd-catalyzed cross-coupling and ester hydrolysis completed the synthesis. Copyright

Full text of DOI:10.1002/ejoc.201300974

FULL PAPER
DOI: 10.1002/ejoc.201300974
Total Synthesis of Mycophenolic Acid by a Palladium-Catalyzed
Decarboxylative Allylation and Biomimetic Aromatization Sequence
[a]
[a]
[a]
[a]
Paul A. Brookes, Jens Cordes, Andrew J. P. White, and Anthony G. M. Barrett*
Dedicated to Professor Robert M. Williams on the occasion of his 60th birthday
Keywords: Natural products / Total synthesis / Medicinal chemistry / Biomimetic synthesis / Allylation / Cyclization
This paper describes the total synthesis of the fungal natural
product mycophenolic acid through palladium-catalyzed
allylation, biomimetic cyclization, and aromatization. Methyl
ylate. Subsequent phenol methylation, lactonization, iodo-
ether formation, and halogenation gave a tricyclic intermedi-
ate. Palladium-catalyzed cross-coupling with DABCO–
(
4E)-6-hydroxy-4-methylhex-4-enoate, which was converted
3 2
(AlMe ) and saponification gave mycophenolic acid. An al-
in four steps into the key diketo ester dioxinone via two se-
ternative approach with early stage arene methyl incorpora-
lective C-acylation reactions, was transformed into a resorc-
tion unexpectedly resulted in the formation of a γ-pyrone.
Introduction
As early as 1893, an astonishing 120 years ago, Italian
physician Bartolomeo Gosio extracted, purified, and char-
acterized (with the limited methods of his time) a crystalline
material from a Penicillium fungal strain. Furthermore,
Gosio discovered that this compound, later termed myco-
Figure 1. Mycophenolic acid (MPA, 1).
[1]
phenolic acid (MPA, 1, Figure 1), inhibited the growth of
the anthrax bacillus.[ MPA therefore constitutes the then several other syntheses have been achieved.[8] These
world’s first purified antibiotic natural product. The correct syntheses were generally low-yielding and/or had long
determination of its structure was completed six decades multistep sequences, so we sought to devise a short and
2]
[
3]
later in the 1950s, and today MPA is known to be pro- efficient total synthesis of 1 based on our recently devel-
[4]
duced by several Penicillium species. Its biological activity oped allylation and biomimetic polyketide aromatization
[
9]
is remarkable; it is, for example, a potent inhibitor of inos- methodology. Our retrosynthetic analysis is outlined in
ine monophosphate dehydrogenase (IMPDH). Further- Scheme 1.
more, MPA (in pro-drug form) has been successfully used
as an immunosuppressant to prevent rejection in organ strategies to access the hexasubstituted arene 1 by biomime-
In the course of this project, we investigated two different
[
5]
transplantation. Several medicinal chemistry campaigns tic aromatization. The direct approach (R = Me) would be
have tried to derive more active compounds from MPA, but to assemble the bicyclic structure of 1 by cyclization and
no significant improvements on the original natural product aromatization of diketo dioxinone 2 and subsequent lacton-
have been observed.[
1,6]
ization. The allylic side chain of 2 could be attached by a
Aside from its biological activity, MPA attracted the at- palladium-catalyzed decarboxylation and alkenylation reac-
tention of synthetic organic chemists because of its chal- tion, starting from allyl ester 3 (R = Me). This diketo ester
lenging structure. Notably, the central core contains an ar- dioxinone should in turn be available by two subsequent C-
ene with six different substituents. The first total synthesis acylations from dioxinone 4 and acid chlorides 5 (R = Me)
of MPA was reported by A. J. Birch in 1969,[ and since and 6. Ester 5 could be obtained in two steps from Meld-
rum’s acid derivative 7 (R = Me) and alcohol 8. In this
7]
strategy, the arene methyl group is introduced right at the
beginning of the synthesis as part of acid chloride 5 via its
[
a] Department of Chemistry, Imperial College London,
South Kensington, London SW7 2AZ, United Kingdom
E-mail: agm.barrett@imperial.ac.uk
precursor 7. In this regard, the second strategy (R = H) is
the exact opposite, because the arene is assembled with only
five of the six required substituents, and the methyl group
is incorporated at a late stage of the synthesis.
www3.imperial.ac.uk/people/agm.barrett
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300974.
Eur. J. Org. Chem. 2013, 7313–7319
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7313

P. A. Brookes, J. Cordes, A. J. P. White, A. G. M. Barrett
FULL PAPER
transformations towards dioxinone 2. A selective Claisen
reaction between a β-keto ester and an acid chloride, medi-
[
12]
ated by magnesium chloride and pyridine,
which had
previously proved very reliable with several systems,[
proved to be incompatible when the α-position was substi-
tuted. A side reaction that could not be suppressed led to
O-acylation of the ketone in addition to the desired C-acyl-
ation (Scheme 3). Because this could not be prevented, we
increased the number of equivalents of acid chloride 6 in
the hope of achieving full conversion into the doubly acyl-
ated product 10, which should be able to react as the O-
acylated analogue of 2. The subsequent palladium-cata-
lyzed reaction, however, unexpectedly led to the formation
of γ-pyrone 12 in 66% yield over three steps. Apparently,
the O-acylated intermediate 11, which is formed from 10 by
deallylation and decarboxylation, does not undergo a cross-
coupling reaction with the thereby formed Pd-allyl species.
This distinguishes it from the related, non-O-acylated sub-
9]
[
9]
strates. Instead a rearrangement of the O-acyl moiety, loss
of acetone, and another decarboxylation occurred, resulting
Scheme 1. Retrosynthetic analysis of mycophenolic acid (1). R =
Me for the direct approach and R = H for the late methylation
strategy, whereas RЈ = Me or Et.
Results and Discussion
Meldrum’s acid derivative 7a (Scheme 2) was heated with
[
10]
allyl alcohol 8a,
and the resultant malonic acid mono-
ester was converted into acid chloride 5a with oxalyl chlor-
ide.[ The lithium enolate derived from dioxinone 4 was
allowed to react with acyl chloride 5a, to afford keto ester
dioxinone 9a in 35% yield over three steps.
11]
Scheme 3. Synthesis and X-ray crystal structure of γ-pyrone 12.[18]
Scheme 2. Synthesis of keto ester dioxinone 9a.
With keto ester dioxinone 9a to hand, elaboration to
MPA was planned as follows: a selective Claisen reaction
with acid chloride 6, decarboxylative alkenylation to attach
the allyl side chain, and a biomimetic cyclization and aro-
matization. Unfortunately, the initial acylation step (9aǞ3)
proved problematic, which further complicated downstream Scheme 4. Synthesis of keto ester dioxinone 9b.
7
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Total Synthesis of Fungal Natural Products
Scheme 5. Synthesis of iodohydrins 16 and 17 and X-ray crystal structures of lactone 15 and iodo-ether 16.[18]
in the formation of pyrone 12.[13] The structure of pyrone Because neither increased amounts of iodine and tert-
12 was unambiguously assigned by X-ray crystallography.
butylamine, nor longer reaction time or elevated tempera-
The attempted direct synthesis of mycophenolic acid 1 tures significantly changed the ratio of product 16 to prod-
was unsuccessful, although it led to the interesting alterna- uct 17, we assume that only the free phenol 15 is reactive
tive observation of pyrone ring closure. We therefore turned enough to allow arene iodination under these conditions.
our attention to late-stage arene methylation, which should The competing formation of iodo-ether 16 thus prevents
circumvent the critical failure of C-acylation and decarb- efficient arene iodination.
oxylative allylic rearrangement. The starting point of this
route was Meldrum’s acid (7b, Scheme 4) and alcohol 8b,
Although this method did not provide a compound with
the required arene halogen substituent, but instead led to
[
8f]
which were converted over three steps via acid chloride 5b selective formation of an iodo-ether, we sought to use iodo-
into keto ester dioxinone 9b in 48% yield. ether 16 to protect the double bond for more forcing arene
A selective Claisen reaction between keto ester 9b and electrophilic halogenation reaction conditions. Treatment of
acyl chloride 6 gave diketo ester dioxinone 3b (Scheme 5). iodo-ether 16 with NBS and sulfuric acid gave bromide 18
Palladium-catalyzed decarboxylation and alkenylation oc- (91%, Scheme 6).
curred without any problems and with the anticipated re-
[
9]
gioselectivity, giving the diketo dioxinone intermediate 2b.
Subsequent morpholine-catalyzed cyclization[ smoothly
provided resorcylate 13 in 41% yield over three steps.
Phenol methylation with iodomethane and cesium carbon-
ate gave ether 14 (94%). Potassium-carbonate-mediated
transesterification, acetone loss, and lactonization directly
gave lactone 15 (87%), a demethylmycophenolate deriva-
14]
[
15]
tive.
It was planned to introduce the arene methyl group
through a cross-coupling reaction. However, the required
halogenation of arene 15 proved to be troublesome. Treat-
ment with NBS, NIS, bromine, or iodine under various con-
ditions led to intractable mixtures, mainly due to side reac-
tions at the alkene unit. In contrast, treatment with iodine
and tert-butylamine[ gave clean conversion to iodo-ether
Scheme 6. Synthesis of mycophenolic acid (1).
16]
1
6 (Scheme 5, 82%) and diiodide 17 (5%). Both iodides 16
Cross-coupling of bromide 18 under Suzuki or Stille con-
[17]
and 17 were isolated as single diastereoisomers,
crystal structure determinations of the starting material and DABCO–(AlMe ) complex
both products confirmed their structures unambiguously. dium catalyst (Pd dba and XPhos), however, not only me-
X-ray ditions proved completely unsatisfactory. Treatment with
[
19]
in the presence of a palla-
3
2
[
18]
2
3
Eur. J. Org. Chem. 2013, 7313–7319
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. A. Brookes, J. Cordes, A. J. P. White, A. G. M. Barrett
FULL PAPER
diated the critical cross-coupling reaction, but also conve- upon dioxinone 4 (4.8 mL, 36.0 mmol, 3.6 equiv.) was added drop-
wise with stirring. After 1 h, the crude acid chloride 5a was dis-
solved in THF (7 mL) and added dropwise with stirring to the di-
niently resulted in deprotection of the double bond, thereby
providing methyl mycophenolate (19) in 72% yield. It is
oxinone enolate at –78 °C. After 2 h, saturated aqueous NH
4
Cl
noteworthy that, despite the deprotection of the iodo-ether,
both the ester and the lactone functionality were tolerated
under these reaction conditions. Furthermore, the deprotec-
tion resulted in formation of only one geometric isomer (E)
(
5 mL) was added, the mixture was allowed to warm to 20 °C and
2
diluted with Et O (150 mL), and HCl (1 m) was added to adjust
the pH to ≈2. The mixture was extracted, the organic layer was
separated, and the aqueous layer was reextracted with EtOAc (3ϫ
[
17]
for the alkene.
Final saponification of the methyl ester
5
0 mL). The combined organic layers were dried (MgSO
4
) and con-
gave mycophenolic acid (1) in 66% yield. The analytical centrated (rotary evaporator), and the residue was chromato-
data for synthetically produced 1 are in full agreement with graphed on silica (hexanes/Et
2
O 3:1Ǟ2:1Ǟ1:1Ǟ1:2) to afford β-
reported values for the isolated natural product.[
7,8,21]
keto ester 9a (1.37 g, 3.46 mmol, 35% over two steps from alcohol
1
8a) as a yellow oil. R
f 2 3
= 0.21 (hexanes/Et O 1:1). H NMR (CDCl ,
400 MHz, 25 °C): δ = 5.32 (tq, J = 7.1, 1.3 Hz, 1 H, 5Hex-H), 5.32
(
7
s, 1 H, 5dioxin-H), 4.62 (d, J = 7.2 Hz, 2 H, 6Hex-H), 4.08 (q, J =
Conclusions
.3 Hz, 2 H, CO CH CH ), 3.55 (q, J = 7.1 Hz, 1 H, 2Bu-H), 3.50
2
2
3
a
b
In conclusion, we describe the total synthesis of the fun- (d, J = 16.8 Hz, 1 H, 4Bu-H ), 3.42 (d, J = 16.8 Hz, 1 H, 4Bu-H ),
2
.41–2.38 (m, 2 H, 2Hex-H), 2.35–2.32 (m, 2 H, 3Hex-H), 1.69 (s, 3
H, 4Hex-Me), 1.67 (s, 6 H, 2dioxin-Me ), 1.33 (d, J = 7.1 Hz, 3 H,
Bu-Me), 1.21 (t, J = 7.1 Hz, 3 H, CO
CDCl , 100 MHz, 25 °C): δ = 198.6 (C-3Bu), 172.7 (CO
gal natural product mycophenolic acid (1) from alcohol 8b
in twelve steps and 6% overall yield. Key steps were a palla-
dium-catalyzed decarboxylation and allylation (3bǞ2b)
with subsequent biomimetic cyclization and aromatization
2
1
3
2
2
CH
2
CH
3
) ppm. C NMR
Et), 169.5
(
(
(
(
3
2
C-1Bu), 163.9 (C-4dioxin), 160.5 (C-6dioxin), 141.6 (C-4Hex), 118.1
C-5Hex), 107.2 (C-2dioxin), 96.9 (C-5dioxin), 62.2 (C-6Hex), 60.3
CO
(2bǞ13), and a cross-coupling with DABCO–(AlMe ) for
3 2
late-stage arene methyl incorporation (18Ǟ19). Attempts
to introduce this methyl group at an early stage led to the
2 2 3
CH CH ), 52.8 (C-2Bu), 45.5 (C-4Bu), 34.2 (C-3Hex), 32.4 (C-
a
b
2
Hex), 24.9 (2dioxin-Me ), 24.8 (2dioxin-Me ), 16.4 (4Hex-Me), 14.1
unexpected formation of γ-pyrone 12 instead of a myco- (CO CH CH ), 12.4 (2Bu-Me) ppm. IR: ν˜ = 1720, 1638, 1442, 1452,
2
2
3
phenolate derivative.
1390, 1374, 1334, 1272, 1251, 1200, 1116, 1089, 1013, 963, 932,
–
1
9
29 8
01, 855, 807, 636 cm . HRMS (ESI) calcd. for C20H O [M +
+
H] 397.1862; found 397.1868.
[5-(2-Acetoxyacetyl)-3,6-dimethyl-4-oxo-4H-pyran-2-yl]methyl
Acetate (12): Pyridine (0.52 mL, 6.40 mmol, 3.0 equiv.) and MgCl
203 mg, 2.13 mmol) were added at 0 °C with stirring to β-keto
ester 9a (750 mg, 2.13 mmol, 1.0 equiv.) in CH Cl (8.5 mL). After
5 min, acetoxyacetyl chloride (6, 0.57 mL, 5.34 mmol, 2.5 equiv.)
was added dropwise and the resulting mixture was stirred at 0 °C
for 1.5 h. Saturated aqueous NH Cl (5 mL) was added, followed
Experimental Section
2
General Methods: All reactions were carried out in oven-dried
glassware under argon, with commercially supplied solvents and
reagents unless otherwise stated. THF was redistilled from Na/
(
2
2
1
2
Ph CO. “Hexanes” refers to petroleum spirit (boiling range 40–
60 °C). Column chromatography was carried out on silica gel by
4
flash techniques (eluents are given in parentheses). Analytical TLC
was performed on pre-coated silica gel F254 aluminum plates with
visualization under UV light or by staining with acidic vanillin or
anisaldehyde spray reagents. Melting points were measured with a
by HCl (1 m) to adjust the pH to ≈2. The mixture was extracted,
the organic layer was separated, and the aqueous layer was reex-
tracted with EtOAc (3ϫ 50 mL). The combined organic layers were
dried (MgSO
ter 10 was dissolved in THF (11 mL), and the solution was purged
with argon through a cannula for 15 min. Pd(PPh (96 mg,
.08 mmol, 0.04 equiv.) was added and the reaction mixture was
4
) and concentrated (rotary evaporator), the crude es-
1
hot-stage apparatus. IR spectra were recorded neat. H NMR spec-
tra were recorded at 400 or 500 MHz, whereas 13C NMR spectra
were recorded at 100 or 125 MHz. Chemical shifts (δ) are quoted
in ppm.
3 4
)
0
stirred at 20 °C for 21 h. Silica (3.0 g) was added, and the solvent
was evaporated. The crude product was chromatographed on silica
Synthesis of γ-Pyrone 12
(hexanes/Et O 1:1) to afford γ-pyrone 12 (415 mg, 1.40 mmol, 66%
2
over three steps from β-keto ester 9a) as colorless crystals. R
f
= 0.47
). H NMR (CDCl
00 MHz, 25 °C): δ = 5.10 [s, 2 H, 5-(CO)CH ], 4.96 (s, 2 H, 2-
), 2.43 (s, 3 H, 6-Me), 2.13 [s, 3 H, 5-(CO)CH O(CO)Me], 2.11
O(CO)Me], 2.00 (s, 3 H, 3-Me) ppm. C NMR
, 100 MHz, 25 °C): δ = 194.9 [5-(CO)CH ], 177.2 (C-4),
70.6 [2 C, C-6, 5-(CO)CH -O(CO)Me], 170.0 [2-CH O(CO)Me],
56.5 (C-2), 125.0 (C-3), 122.3 (C-5), 70.0 [5-(CO)CH ], 60.0 (2-
), 20.4 [2 C, 2ϫO(CO)Me], 19.4 (6-Me), 9.1 (3-Me) ppm. IR:
ν˜ = 1744, 1736, 1715, 1689, 1660, 1619, 1543, 1425, 1390, 1370,
Ethyl (E)-6-[4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2-methyl-3-
oxobutanoyloxy]-4-methylhex-4-enoate (9a): 2,2,5-Trimethyl-1,3-di-
1
(
hexanes/Et
2
O 1:1), m.p. 93–96 °C (CH
2
Cl
2
3
,
4
2
oxane-4,6-dione (7a, 1.58 g, 10.0 mmol, 1.0 equiv.) was dissolved in
toluene (10 mL), and alcohol 8a[
10]
CH
2
2
(1.72 g, 10.0 mmol, 1.0 equiv.)
1
3
[s, 3 H, 2-CH
2
was added. The solution was heated at 100 °C for 6 h. After the
system had cooled to 20 °C, the solvent was evaporated and the
resulting (E)-3-(6-ethoxy-3-methyl-6-oxohex-2-enyloxy)-2-methyl-
(CDCl
3
2
1
1
2
2
2
3
-oxopropanoic acid (2.72 g, 10.0 mmol, 1.0 equiv.) was dissolved
in CH Cl (24 mL) and cooled to 0 °C. Oxalyl chloride (1.1 mL,
3.0 mmol, 1.3 equiv.) and a drop of DMF were added and the
CH
2
2
2
1
1
8
C
361, 1257, 1224, 1208, 1153, 1112, 1075, 1028, 989, 974, 948, 907,
reaction mixture was stirred at 0 °C for 1.5 h. The solvents were
evaporated, and the resulting oil was dried in vacuo to afford crude
acid chloride 5a as a brown oil. Hexamethyldisilazane (8.1 mL,
–
1
43, 786, 768, 701, 695, 650, 623 cm . HRMS (ESI) calcd. for
[M + H]+ 297.0969; found 297.0976. C14
(296.27):
14
H
17
O
7
16 7
H O
calcd. C 56.76, H 5.44; found C 56.69, H 5.37.
3
9.0 mmol, 3.9 equiv.) was dissolved in THF (150 mL) and the mix-
ture was cooled to 0 °C. nBuLi in n-hexane (2.5 m, 16.4 mL,
1.0 mmol, 4.1 equiv.) was added dropwise, and the resulting mix-
ture was stirred at 0 °C. After 1 h, it was cooled to –78 °C, where-
Analytical data for intermediate 10: Yellow oil. R
f
= 0.36 (hexanes/
1
4
Et
2
O 1:1). H NMR (CDCl
3
, 400 MHz, 25 °C): δ = 5.97 (s, 1 H,
4Bu-H), 5.39 (s, 1 H, 5dioxin-H), 5.31 (t, J = 6.8 Hz, 1 H, 5Hex-H),
7316
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2013, 7313–7319

Total Synthesis of Fungal Natural Products
–1
4
.91 [d, J = 17.3 Hz, 1 H, 2Bu-(CO)CH a
2
], 4.86 [d, J = 17.3 Hz, 1
1375, 1271, 1252, 1200, 1158, 1015, 982, 902, 807 cm . HRMS
(ESI) calcd. for C18
[M + H]+ 369.1549; found 369.1541.
b
a
H, 2Bu-(CO)CH
2
], 4.72 [d, J = 16.6 Hz, 1 H, 3Bu-O(CO)CH
2
],
25 8
H O
b
4
6
4
.67 [d, J = 16.6 Hz, 1 H, 3Bu-O(CO)CH ], 4.66 (dd, J = 15.1,
2
Methyl (E)-6-[5-(Acetoxymethyl)-7-hydroxy-2,2-dimethyl-4-oxo-4H-
benzo[d][1,3]dioxin-8-yl]-4-methylhex-4-enoate (13): β-Keto ester 9b
a
b
.9 Hz, 2 H, 6Hex-H ), 4.63 (dd, J = 15.1, 6.9 Hz, 2 H, 6Hex-H ),
.08 (q, J = 7.1 Hz, 2 H, CO CH CH ), 2.41–2.37 (m, 2 H, 3Hex
O(CO)
2
2
3
-
(
2.28 g, 6.19 mmol, 1.0 equiv.) was dissolved in CH
and cooled to 0 °C. Pyridine (1.0 mL, 12.4 mmol, 2.0 equiv.) and
MgCl (589 mg, 6.19 mmol, 1.0 equiv.) were added with stirring at
2 2
Cl (60 mL)
H), 2.34–2.31 (m, 2 H, 2Hex-H), 2.13 [s, 3 H, 2Bu-(CO)CH
Me], 2.10 [s, 3 H, 3Bu-O(CO)CH O(CO)Me], 1.69 (s, 3 H, 4Hex
Me), 1.66 (s, 3 H, 2dioxin-Me
2
2
-
2
a
b
2
), 1.64 (s, 3 H, 2dioxin-Me
H, 2tBu-Me), 1.20 (t, J = 7.1 Hz, 3 H, CO CH CH
, 100 MHz, 25 °C): δ = 196.8 [2Bu-(CO)CH
2
2
), 1.58 (s,
0
1
°C. After 15 min, acetoxyacetyl chloride (6, 1.0 mL, 7.4 mmol,
.2 equiv.) was added dropwise with stirring at 0 °C. After 1 h, satu-
rated aqueous NH Cl (10 mL) was added, followed by HCl (1 m)
4
to adjust the pH to ≈2. The mixture was extracted, the organic
1
3
3
2
2
3
) ppm.
C
NMR (CDCl
3
], 172.7
(
(
1
(
(
CO
C-4dioxin), 160.8 (C-6dioxin), 160.2 [3Bu-O(CO)CH
42.5 (C-4Hex), 117.4 (C-5Hex), 113.9 (C-4Bu), 107.2 (C-2dioxin), 98.2
C-5dioxin), 65.9 [2Bu-(CO)CH ], 63.3 (C-2Bu), 63.2 (C-6Hex), 60.3
CO CH CH ), 59.8 [3Bu-O(CO)CH ], 34.1 (C-3Hex), 32.4 (C-2Hex),
4.8 (2dioxin-Me
9.1 (2Bu-Me), 16.4 (4Hex-Me), 14.1 (CO
2
Et), 169.7 [2 C, 2ϫO(CO)Me], 167.7 (C-1Bu), 164.4
2
], 148.9 (C-3Bu),
layer was separated, and the aqueous layer was reextracted with
CH
2
Cl
2
(2ϫ 100 mL). The combined organic layers were dried
) and concentrated (rotary evaporator), and the resulting
2
(
MgSO
4
2
2
3
2
crude diketo ester dioxinone 3b was dissolved in THF (18.5 mL),
and degassed by purging with argon for 15 min. Pd(PPh
215 mg, 0.19 mmol, 0.03 equiv.) was added and the mixture was
stirred at 20 °C for 24 h. Morpholine (0.54 mL, 6.2 mmol,
.0 equiv.) was added, the mixture was stirred at 20 °C for 18 h and
diluted with Et O (100 mL), and HCl (1 m, 50 mL) was added. The
mixture was extracted, the organic layer was separated, and the
aqueous layer was further extracted with Et O (2ϫ 100 mL). The
combined organic layers were dried (MgSO ), concentrated (rotary
evaporator), and chromatographed on silica (hexanes/Et
2:1Ǟ1:1) to afford resorcylate 13 (1.03 g, 2.54 mmol, 41% over
three steps from β-keto ester 9b) as a yellow oil. R = 0.38 (hexanes/
, 400 MHz, 25 °C): δ = 8.30 (s, 1 H,
OH), 6.67 (s, 1 H, 6HetAr-H), 5.46 (s, 2 H, CH OAc), 5.15 (t, J =
.1 Hz, 1 H, 5Hex-H), 3.59 (s, 3 H, OMe), 3.25 (d, J = 7.1 Hz, 2 H,
Hex-H), 2.39–2.35 (m, 2 H, 2Hex-H), 2.26–2.23 (m, 2 H, 3Hex-H),
.08 [s, 3 H, CH O(CO)Me], 1.72 (s, 3 H, 4Hex-Me), 1.64 (s, 6 H,
b
2
1
2
a), 24.4 (2dioxin-Me
2
), 20.2 [2 C, 2ϫO(CO)Me],
CH CH ) ppm. Diox-
3 4
)
2
2
3
(
[17]
inone 10 was obtained as mainly one diastereoisomer, although
the configuration of the C3Bu=C4Bu double bond could not be de-
termined.
1
2
2
Total Synthesis of Mycophenolic Acid (1)
4
2
O
Methyl (E)-6-[4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobut-
anoyloxy]-4-methylhex-4-enoate (9b): Alcohol 8b[
8f]
(1.64 g,
f
1
1
0.4 mmol, 1.0 equiv.) was added to Meldrum’s acid (7b, 1.49 g,
0.4 mmol, 1.0 equiv.) in toluene (3 mL), and the mixture was
1
2 3
Et O 1:3). H NMR (CDCl
2
heated at 100 °C for 13 h. After the system had cooled to 20 °C,
the solvent was evaporated. The resulting (E)-3-(6-methoxy-
7
6
2
2
3
1
-methyl-6-oxohex-2-enyloxy)-3-oxopropanoic
0.4 mmol, 1.0 equiv.) was dissolved in CH
acid
(2.53 g,
2
2
2
Cl (11 mL) and 2-
1
3
HetAr-Me
2
) ppm. C NMR (CDCl
3
, 100 MHz, 25 °C): δ = 174.3
Me), 171.0 [CH O(CO)Me], 161.0 (C7HetAr), 160.9 (C-4HetAr),
methyl-2-butene (amylene, 11 mL, 104 mmol, 10 equiv.) and cooled
to 0 °C. A drop of DMF was added, followed by oxalyl chloride
(
CO
2
2
1
1
56.3 (C8aHetAr), 139.1 (C-5HetAr), 134.0 (C-4Hex), 121.9 (C-5Hex),
15.1 (C8HetAr), 109.7 (C-6HetAr), 105.2 (C-2HetAr), 102.8
OAc), 51.5 (OMe), 34.5 (C-3Hex), 32.3 (C-
Hex), 25.0 (2 C, 2HetAr-Me ), 21.6 (C-6Hex), 20.7 [CH O(CO)Me],
5.8 (4Hex-Me) ppm. IR: ν˜ = 1718, 1598, 1298, 1275, 1209, 1228,
(1.0 mL, 11.4 mmol, 1.1 equiv.), and the mixture was stirred at 0 °C
for 30 min and subsequently at 20 °C for 2.5 h. Concentration (ro-
tary evaporator) and further drying in vacuo gave the crude acid
chloride 5b as a brown oil. Under argon, hexamethyldisilazane
(
C-4aHetAr), 64.1 (CH
2
2
1
1
2
2
(
6.8 mL, 32.8 mmol, 3.2 equiv.) was dissolved in THF (56 mL) and
cooled to 0 °C. nBuLi in n-hexane (2.5 m, 13.9 mL, 34.8 mmol,
.4 equiv.) was added dropwise, and the resulting mixture was
stirred at 0 °C for 2.5 h and cooled to –78. Dioxinone 4 (4.1 mL,
–
1
166, 1030, 906, 726, 648, 614 cm . HRMS (ESI) calcd. for
C
21
H
27
O
8
[M + H]+ 407.1706; found 407.1710.
3
Methyl
(E)-6-[5-(Acetoxymethyl)-7-methoxy-2,2-dimethyl-4-oxo-
3
0.7 mmol, 3.0 equiv.) in dry THF (5 mL) was added dropwise with 4H-benzo[d][1,3]dioxin-8-yl]-4-methylhex-4-enoate (14): Cs
stirring. After 1 h, the crude acid chloride 5b was dissolved in THF (1.68 g, 5.17 mmol, 3.0 equiv.) and MeI (0.32 mL, 5.17 mmol,
5 mL) and added dropwise with stirring to the dioxinone enolate
at –78 °C. After 1.5 h, saturated aqueous NH Cl (20 mL) was
added, and after warming to 20 °C, the solution was diluted with
Et O (100 mL), and HCl (1 m) was added to adjust the pH to ≈2.
The mixture was extracted, the organic layer was separated, and
the aqueous layer was further extracted with Et O (2ϫ 100 mL).
The combined organic layers were dried (MgSO ), concentrated
rotary evaporator), and chromatographed on silica (hexanes/Et
2 3
CO
(
3.0 equiv.) were added with stirring at 20 °C to phenol 13 (700 mg,
1.72 mmol, 1.0 equiv.) in THF (17 mL). After 18 h, saturated aque-
4
ous NH
was extracted, the organic layer was separated, and the aqueous
layer was reextracted with Et O (2ϫ 50 mL). The combined or-
ganic layers were dried (MgSO ) and the solvents were evaporated.
The crude product was chromatographed on silica (hexanes/Et
1:1) to afford methyl ether 14 (682 mg, 1.62 mmol, 94%) as a color-
4 2
Cl (50 mL) and Et O (50 mL) were added. The mixture
2
2
2
4
4
2
O
(
2
O
1
1
:1Ǟ1:2) to give β-keto ester 9b (1.82 g, 4.94 mmol, 48% over three
= 0.33 (hexanes/Et
, 400 MHz, 25 °C): δ = 5.36 (s, 1 H, 5dioxin
, 1 H, 5Hex-H), 4.65 (d, J = 7.0 Hz, 2 H, 6Hex-H), 3.66
s, J = 7.3 Hz, 3 H, CO Me), 3.50 (s, 2 H, 2Bu-H), 3.49 (s, 2 H,
Bu-H), 2.46–2.42 (m, 2 H, 2Hex-H), 2.38–2.34 (m, 2 H, 3Hex-H), 1.74 (s, 3 H, 4Hex-Me), 1.67 (s, 6 H, 2HetAr-Me
.72 (s, 3 H, 4Hex-Me), 1.70 (s, 6 H, 2dioxin-Me (CDCl , 100 MHz, 25 °C): δ = 173.7 (CO Me), 170.4 [CH
) ppm. 13C NMR
, 100 MHz, 25 °C): δ = 195.6 (C-3Bu), 173.3 (CO Me), 166.3 Me], 162.4 (C7HetAr), 160.2 (C-4HetAr), 155.5 (C8aHetAr), 139.9 (C-
less oil. R
25 °C): δ = 6.69 (s, 1 H, 6HetAr-H), 5.55 (s, 2 H, CH
J = 7.3 Hz, 1 H, 5Hex-H), 3.89 (s, 3 H, ArOMe), 3.59 (s, 3 H,
CO Me), 3.26 (d, J = 7.3 Hz, 2 H, 6Hex-H), 2.39–2.34 (m, 2 H,
Hex-H), 2.28–2.23 (m, 2 H, 3Hex-H), 2.15 [s, 3 H, CH O(CO)Me],
f
= 0.24 (hexanes/Et
2
O 1:1). H NMR (CDCl
3
, 400 MHz,
steps from alcohol 8b) as a yellow oil. R
1
H), 5.34 (m
(
4
1
f
2
O
-
2
OAc), 5.08 (t,
1
:3). H NMR (CDCl
3
c
2
2
2
2
1
3
2
) ppm. C NMR
O(CO)
2
3
2
2
(
(
(
(
(
CDCl
3
2
C-1Bu), 163.5 (C-4dioxin), 160.4 (C-6dioxin), 141.6 (C-4Hex), 118.1
C-5Hex), 107.3 (C-2dioxin), 97.1 (C-5dioxin), 62.3 (C-6Hex), 51.6
OMe), 49.0 (C-2Bu), 46.9 (C-4Bu), 34.2 (C-3Hex), 32.3 (C-2Hex), 25.0 (ArOMe), 51.5 (CO
2 C, 2dioxin-Me ), 16.4 (4Hex-Me) ppm. IR: ν˜ = 1722, 1638, 1390,
5
2
HetAr), 133.8 (C-4Hex), 122.0 (C-5Hex), 117.0 (C8HetAr), 105.2 (C-
HetAr), 104.5 (C-6HetAr), 104.2 (C-4aHetAr), 64.3 (CH OAc), 55.7
Me), 34.6 (C-3Hex), 32.8 (C-2Hex), 25.7 (2 C,
), 21.7 (C-6Hex), 20.9 [CH O(CO)Me], 15.9 (4Hex
2
2
2
2HetAr-Me
2
2
-
Eur. J. Org. Chem. 2013, 7313–7319
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7317

P. A. Brookes, J. Cordes, A. J. P. White, A. G. M. Barrett
H, ArOMe), 3.72 (s, 3 H, CO Me), 3.68 (dd, J = 16.2, 9.6 Hz, 1
FULL PAPER
Me) ppm. IR: ν˜ = 1724, 1608, 1580, 1295, 1219, 1206, 1166, 1119,
2
–1
Na [M + Na]+
a
b
1
4
030, 987 cm . HRMS (ESI) calcd. for C22
43.1682; found 443.1690.
H
28
O
8
H, 3HetAr-H ), 3.49 (dd, J = 16.1, 7.1 Hz, 1 H, 3HetAr-H ), 2.73
a
(ddd, J = 16.1, 11.0, 5.0 Hz, 1 H, 2Pent-H ), 2.61 (ddd, J = 16.3,
b
1
3
3
1.1, 5.3 Hz, 1 H, 2Pent-H ), 2.30 (ddd, J = 16.1, 11.0, 5.0 Hz, 1 H,
Methyl (E)-6-(4-Hydroxy-6-methoxy-3-oxo-1,3-dihydroisobenzofur-
an-5-yl)-4-methylhex-4-enoate (15): Ester 14 (392 mg, 0.93 mmol,
a
b
Pent-H ), 2.05 (ddd, J = 15.1, 11.0, 5.3 Hz, 1 H, 3Pent-H ), 1.89 (s,
1
3
H, 5Pent-H) ppm. C NMR (CDCl
Me), 167.8 (C8HetAr), 159.9 (C-4HetAr), 159.8 (C8bHetAr), 153.1
C-5aHetAr), 116.1 (C-3aHetAr), 105.6 (C8aHetAr), 91.8 (C-2HetAr),
3.1 (C-5HetAr), 71.8 (C-6HetAr), 59.8 (ArOMe), 56.0 (C-4Pent), 52.0
CO Me), 38.5 (C-3Pent), 34.2 (C-3HetAr), 32.6 (C-2Pent), 27.8 (C-
Pent) ppm. IR: ν˜ = 2923, 1759, 1629, 1437, 1386, 1295, 1253, 1219,
3
, 100 MHz, 25 °C): δ = 172.9
1.0 equiv.) was dissolved in dry MeOH (19 mL). K
2 3
CO (387 mg,
(
(
CO
2
2.80 mmol, 3.0 equiv.) was added, and the reaction mixture was
stirred at 20 °C for 18 h. The solvent was evaporated and Et
50 mL) was added, followed by HCl (1 m) to adjust the pH to ≈2.
The mixture was extracted, the organic layer was removed, and the
aqueous layer was reextracted with Et O (2ϫ 50 mL). The com-
bined organic layers were dried (MgSO ) and concentrated (rotary
evaporator) to leave pure lactone 15 (260 mg, 0.81 mmol, 87%) as
a colorless solid. R = 0.34 (hexanes/Et O 1:3), m.p. 100–102 °C
O). H NMR (CDCl
.48 (s, 1 H, 7HetAr-H), 5.23 (s, 2 H, 1HetAr-H), 5.20 (t, J = 7.2 Hz,
H, 5Hex-H), 3.89 (s, 3 H, ArOMe), 3.60 (s, 3 H, CO Me), 3.34
2
O
7
(
5
1
[
(
2
2
–
1
6 2
128, 1065, 1021, 980 cm . HRMS (ESI) calcd. for C17H19NO I
4
M + H]+ 572.9271; found 572.9272.
Methyl (S*)-4-Iodo-4-[(R*)-5-Bromo-4-methoxy-8-oxo-2,3,6,8-tetra-
, 400 MHz, 25 °C): δ = 7.72 (s, 1 H, OH), hydro-1H-furo[3,4-g]benzofuran-2-yl]pentanoate (18): N-Bromo-
f
2
1
(Et
2
3
6
1
succinimide (26 mg, 0.15 mmol, 1.5 equiv.) and concentrated
H SO (20 μL) were added sequentially with stirring at 20 °C to
2 4
2
(
(
1
6
d, J = 7.2 Hz, 2 H, 6Hex-H), 2.40–2.36 (m, 2 H, 2Hex-H), 2.30–2.25 arene 16 (51 mg, 0.11 mmol, 1.0 equiv.) in THF (0.6 mL). After
m, 2 H, 3Hex-H), 1.77 (s, 3 H, 4Hex-Me) ppm. 13C NMR (CDCl
12 h, saturated aqueous NaHCO (1 mL) and Na (1 mL)
were added and the mixture was extracted with EtOAc (3ϫ
HetAr), 154.5 (C-4HetAr), 146.0 (C7aHetAr), 134.1 (C-4Hex), 122.2 10 mL). The combined organic layers were dried (MgSO ), concen-
3
,
3
2 2 3
S O
2
00 MHz, 25 °C): δ = 173.9 (CO Me), 172.8 (C-3HetAr), 164.8 (C-
4
(
(
2
1
C-5Hex), 116.5 (C-5HetAr), 104.2 (C-3aHetAr), 96.0 (C7HetAr), 70.4 trated (rotary evaporator), and chromatographed on silica (hex-
C-1HetAr), 56.1 (ArOMe), 51.4 (CO
Me), 34.7 (C-3Hex), 32.9 (C- anes/Et O 1:1) to give bromide 18 (54 mg, 0.10 mmol, 91%) as a
Hex), 21.5 (C-6Hex),15.9 (4Hex-Me) ppm. IR: ν˜ = 1729, 1615, 1469,
white crystalline solid. R = 0.40 (hexanes/Et O 1:3), m.p. 65–68 °C
(EtOAc). H NMR (CDCl , 400 MHz, 25 °C): δ = 5.09 (s, 2 H,
HetAr-H), 4.75 (m , 1 H, 2HetAr-H), 4.07 (s, 3 H, ArOMe), 3.72 (s,
3 H, CO Me), 3.66 (dd, J = 16.2, 9.6 Hz, 1 H, 3HetAr-H ), 3.48 (dd,
J = 16.4, 7.1 Hz, 3HetAr-H ), 2.73 (ddd, J = 16.1, 10.9, 5.1 Hz, 1
2
2
f
2
–
1
1
438, 1345, 1289, 1252, 1202, 1168, 1127, 1077, 1055 cm . HRMS
3
+
(CI) calcd. for C17
H24NO
6
Na [M + NH
4
]
338.1604; found
6
c
a
3
38.1598.
2
b
Methyl
H-furo[3,4-g]benzofuran-2-yl]pentanoate (16) and Methyl (S*)-4-
Iodo-4-[(R*)-5-iodo-4-methoxy-8-oxo-2,3,6,8-tetrahydro-1H-furo-
3,4-g]benzofuran-2-yl]pentanoate (17): (307 mg, 1.21 mmol,
.0 equiv.) and tBuNH (0.25 mL, 2.42 mmol, 4.0 equiv.) in toluene
9 mL) were stirred for 15 min, after which phenol 15 (194 mg,
(S*)-4-Iodo-4-[(R*)-4-methoxy-8-oxo-2,3,6,8-tetrahydro-
a
b
H, 2Pent-H ), 2.61 (ddd, J = 16.2, 11.1, 5.3 Hz, 1 H, 2Pent-H ), 2.31
1
a
(
1
ddd, J = 15.9, 11.0, 5.1 Hz, 1 H, 3Pent-H ), 2.06 (ddd, J = 15.1,
b
13
1.0, 5.3 Hz, 1 H, 3Pent-H ), 1.89 (s, 3 H, 5Pent-H) ppm. C NMR
, 100 MHz, 25 °C): δ = 172.8 (CO Me), 167.4 (C8HetAr),
58.4 (C-4HetAr), 157.8 (C8bHetAr), 148.8 (C-5aHetAr), 117.7
[
I
2
(CDCl
3
2
2
(
0
2
5
2
1
(
(
3
2
C-3aHetAr), 104.9 (C8aHetAr), 99.1 (C-5HetAr), 91.9 (C-2HetAr), 70.0
C-6HetAr), 59.9 (ArOMe), 56.0 (C-4Pent), 51.9 (CO Me), 38.6 (C-
Pent), 34.2 (C-3HetAr), 32.6 (C-2Pent), 27.8 (C-5Pent) ppm. IR: ν˜ =
.61 mmol, 1.0 equiv.) in CH
0 °C. After 18 h, CH Cl
mL), and saturated aqueous Na
2
Cl
(50 mL), water (20 mL), HCl (1 m,
(5 mL) were added. The
2
(3 mL) was added with stirring at
2
2
2
2 2 3
S O
–
1
941, 1757, 1738, 1626, 1435, 1390, 1248, 1194, 1133, 961 cm .
18BrINaO
[M + Na]+ 546.9229;
18BrINaO (523.93): calcd. C 38.88, H 3.45;
found C 38.91, H 3.38.
mixture was extracted, the organic layer was separated, and the
aqueous layer was reextracted with CH Cl (2ϫ 50 mL). The com-
bined organic layers were dried (MgSO ), concentrated (rotary
evaporator), and chromatographed on silica (hexanes/Et
:3ǞEt O) to afford iodo-ether 16 (221 mg, 0.50 mmol, 82%) and
diiodide 17 (19 mg, 0.03 mmol, 5%) as colorless solids.
HRMS (ESI) calcd. for C17
found 546.9224. C17
H
6
2
2
H
6
4
2
O
1
2
Methyl (E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-
isobenzofuran-5-yl)-4-methylhex-4-enoate (19): Bromide 18 (50 mg,
0
[
.10 mmol,
Pd (dba) , 2.6 mg, 2.9 μmol, 0.03 equiv.], and 2-dicyclohexylphos-
phanyl-2Ј,4Ј,6Ј-triisopropylbiphenyl (XPhos, 2.7 mg, 5.7 μmol,
.06 equiv.) were suspended in THF (0.8 mL) and stirred for 10 min
at 20 °C. Bis(trimethylaluminum)–1,4-diazabicyclo[2.2.2]octane
DABCO–(AlMe , 39 mg, 0.15 mmol, 1.5 equiv.] was added in
one portion with stirring and the resulting red solution was kept at
0 °C for 12 h. The mixture was cooled to 20 °C and quenched by
1.0 equiv.),
tris(dibenzylidenacetone)dipalladium
Analytical data for 16: R = 0.18 (hexanes/Et O 1:3), m.p. 122–
). H NMR (CDCl , 400 MHz, 25 °C): δ = 6.45 (s,
H, 5HetAr-H), 5.19 (s, 2 H, 6HetAr-H), 4.80 (pseudo-t J = 8.4 Hz,
H, 2HetAr-H), 3.90 (s, 3 H, ArOMe), 3.69 (s, 3 H, CO Me), 3.36
f
2
1
2
3
1
1
1
24 °C (CH
2
Cl
2
3
0
2
a
(dd, J = 16.4, 9.8 Hz, 1 H, 3HetAr-H ), 3.20 (dd, J = 16.4, 7.3 Hz,
[
3 2
)
b
a
1
2
1
1
1
4
1
5
H, 3HetAr-H ), 2.71 (ddd, J = 16.1, 11.1, 5.0 Hz, 1 H, 2Pent-H ),
.59 (ddd, J = 16.2, 11.1, 5.2 Hz, 1 H, 2Pent-H ), 2.29 (ddd, J =
5.6, 11.3, 5.2 Hz, 1 H, 3Pent-H ), 2.08 (ddd, J = 15.2, 11.1, 5.2 Hz,
H, 3Pent-H ), 1.85 (s, 3 H, 5Pent-H) ppm. C NMR (CDCl
b
6
a
addition of aqueous HCl (2 m, 2 mL). The mixture was extracted
with EtOAc (3ϫ 5 mL), and the combined organic extracts were
b
13
3
,
00 MHz, 25 °C): δ = 172.9 (CO Me), 168.2 (C8HetAr), 161.3 (C-
2
washed with brine (2 mL), dried (MgSO
evaporator), and chromatographed on silica (hexanes/Et
give resorcylate 19 (23 mg, 69 μmol, 72%) as an off-white crystal-
line solid. R = 0.49 (hexanes/Et O 1:3), m.p. 98–101 °C (Et O),
ref.[ 96–97 °C (MeOH and hexane). H NMR (CDCl
, 400 MHz,
5 °C): δ = 7.69 (s, 1 H, OH), 5.26 (t, J = 7.1 Hz, 1 H, 5Hex-H),
.23 (s, 2 H, 1HetAr-H), 3.79 (s, 3 H, ArOMe), 3.65 (s, 3 H, CO Me),
.41 (d, J = 6.9 Hz, 2 H, 6Hex-H), 2.45–2.43 (m, 2 H, 2Hex-H), 2.36–
4
), concentrated (rotary
HetAr), 158.1 (C8bHetAr), 150.3 (C-5aHetAr), 114.1 (C-3aHetAr),
02.1 (C8aHetAr), 96.6 (C-5HetAr), 91.9 (C-2HetAr), 69.4 (C-6HetAr),
2
O 1:1) to
6.5 (ArOMe), 55.9 (C-4Pent), 51.8 (CO
2
Me), 38.7 (C-3Pent), 32.7
f
2
2
(
1
C-2Pent), 32.5 (C-3HetAr), 27.4 (C-5Pent) ppm. IR: ν˜ = 1753, 1633,
20]
1
–
1
3
613, 1457, 1355, 1332, 1298, 1226, 1201, 1140, 1089, 1015 cm .
2
5
3
+
HRMS (ESI) calcd. for C17
69.0116.
6
H19NO NaI [M + Na] 469.0124; found
2
4
Analytical data for 17: R
f
= 0.39 (hexanes/Et
). H NMR (CDCl , 400 MHz, 25 °C): δ = 4.99 (s, Me) ppm. C NMR (CDCl
H, 6HetAr-H), 4.74 (dd, J = 8.9, 7.4 Hz, 1 H, 2HetAr-H), 4.06 (s, 3 (CO Me), 172.9 (C-3HetAr), 163.7 (C-6HetAr), 153.7 (C-4HetAr),
2
O 1:3), m.p. 124–
2.33 (m, 2 H, 3Hex-H), 2.18 (s, 3 H, 7HetAr-Me), 1.83 (s, 3 H, 4Hex-
1
13
1
2
28 °C (CH
2
Cl
2
3
3
, 100 MHz, 25 °C): δ = 173.8
2
7318
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7313–7319

Total Synthesis of Fungal Natural Products
1
1
5
43.9 (C7aHetAr), 134.2 (C-4Hex), 122.7 (C7Hex), 122.1 (C-5Hex),
16.7 (C-5HetAr), 106.4 (C-3aHetAr), 70.0 (C-1HetAr), 60.9 (ArOMe),
[5] a) D. N. Planterose, J. Gen. Virol. 1969, 4, 629–630; b) A. Mit-
sui, S. Suzuki, J. Antibiot. 1969, 22, 358–363; c) A. C. Allison,
E. M. Eugui, Immunol. Rev. 1993, 136, 5–28; d) S. Gabardi, J.
Cerio, Prog. Transplant. 2004, 14, 148–156; e) T. R. Srinivas,
J. D. Schold, H.-U. Meier-Kriesche, Expert Rev. Clin. Immunol.
1.5 (CO
2
Me), 34.6 (C-3Hex), 32.9 (C-2Hex), 22.6 (C-6Hex), 16.1
(4
Hex-Me), 11.6 (7HetAr-Me) ppm. IR: ν˜ = 3438, 2930, 1729, 1625,
–1
1
451, 1367, 1165, 1132, 1073, 1027, 969 cm . HRMS (ESI) calcd.
2
006, 2, 495–518.
+
for C18
23 6
H O [M + H] 335.1495; found 335.1501. The spectra
[
[
[
6] G. Cholewinski, M. Malachowska-Ugarte, K. Dzierzbicka,
[8a,8f,20]
match the reported data for 19.
Curr. Med. Chem. 2010, 17, 1926–1941.
7] a) A. J. Birch, J. J. Wright, J. Chem. Soc. C 1969, 788–789; b)
A. J. Birch, J. J. Wright, Aust. J. Chem. 1969, 22, 2635–2644.
8] a) L. Canonica, B. Rindone, E. Santaniello, C. Scolastico, Tet-
rahedron 1972, 28, 4395–4404; b) R. L. Danheiser, S. K. Gee,
J. J. Perez, J. Am. Chem. Soc. 1986, 108, 806–810; c) J. W. Pat-
terson, G. T. Huang, J. Chem. Soc., Chem. Commun. 1991,
1579–1580; d) J. W. Patterson, Tetrahedron 1993, 49, 4789–
4798; e) J. W. Patterson, J. Org. Chem. 1995, 60, 4542–4548; f)
P. A. Plé, A. Hamon, G. Jones, Tetrahedron 1997, 53, 3395–
(
E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzo-
furan-5-yl)-4-methylhex-4-enoic Acid (Mycophenolic Acid, 1):
Methyl ester 19 (10 mg, 0.03 mmol, 1.0 equiv.) and LiOH (2.8 mg,
0.12 mmol) were suspended in a mixture of H
2
O and THF (1:4,
1.2 mL) and stirred at 20 °C for 24 h. THF (5 mL) was added, and
the solution was concentrated to dryness. The resulting residue was
treated with aqueous HCl (1 m, 1 mL), H O (4 mL), and EtOAc
10 mL). The mixture was extracted with EtOAc (3ϫ 5 mL), the
combined organic extracts were washed with brine (2 mL) and
dried (MgSO ), and the solvents were evaporated. The crude prod-
uct was chromatographed on silica (CH Cl /EtOAc 1:1) and recrys-
tallized (CH Cl and pentane) to give acid 1 (6.3 mg, 20 μmol,
6%) as an off-white crystalline solid. R
:1), m.p. 137–140 °C (CH Cl
and pentane), ref.[
Cl
and hexane). 1H NMR (CDCl
2
(
3
400; g) R. A. de la Cruz, F. X. Talamás, A. Vázquez, J. M.
Muchowski, Can. J. Chem. 1997, 75, 641–645; h) A. Covarrub-
ias-Zúñiga, A. Gonzalez-Lucas, Tetrahedron Lett. 1998, 39,
4
2
2
2881–2882; i) I. Shimizu, Y. Lee, Y. Fujiwara, Synlett 2000,
1285–1286; j) Y. Lee, Y. Fujiwara, K. Ujita, M. Nagatomo, H.
2
2
6
1
f
= 0.29 (CH
2
Cl
2
/EtOAc
140 °C
Ohta, I. Shimizu, Bull. Chem. Soc. Jpn. 2001, 74, 1437–1443;
k) A. Covarrubias-Zúñiga, A. Gonzalez-Lucas, M. M.
Domínguez, Tetrahedron 2003, 59, 1989–1994.
8g]
2
2
(CH
2
2
3
, 400 MHz, 25 °C): δ =
5
.27 (t, J = 6.6 Hz, 1 H, 5Hex-H), 5.25 (s, 2 H, 1HetAr-H), 3.77 (s, 3 [9] a) K. Anderson, F. Calo, T. Pfaffeneder, A. J. P. White,
A. G. M. Barrett, Org. Lett. 2011, 13, 5748–5750; b) J. Cordes,
F. Calo, K. Anderson, T. Pfaffeneder, S. Laclef, A. J. P. White,
A. G. M. Barrett, J. Org. Chem. 2012, 77, 652–657; c) J. Cordes,
S. Laclef, A. J. P. White, A. G. M. Barrett, J. Org. Chem. 2012,
H, ArOMe), 3.41 (d, J = 6.8 Hz, 2 H, 6Hex-H), 2.47–2.43 (m, 2 H,
2
Hex-H), 2.34–2.30 (m, 2 H, 3Hex-H), 2.16 (s, 3 H, 7HetAr-Me), 1.82
s, 3 H, 4Hex-Me) ppm. 13C NMR (CDCl
(
3
, 100 MHz, 25 °C): δ =
2
78.2 (CO H), 172.9 (C-3HetAr), 163.7 (C-6HetAr), 153.7 (C-4HetAr),
43.9 (C7aHetAr), 133.9 (C-4Hex), 122.9 (C7Hex), 122.1 (C-5Hex),
16.7 (C-5HetAr), 106.4 (C-3aHetAr), 70.0 (C-1HetAr), 60.9 (ArOMe),
4.2 (C-3Hex), 32.5 (C-2Hex), 22.6 (C-6Hex), 16.1 (4Hex-Me), 11.6
HetAr-Me) ppm. IR: ν˜ = 3418, 2934, 1738, 1701, 1623, 1410, 1328,
1
1
1
3
77, 3524–3530.
[
[
10] A. D. Fischer, A. Barakat, Z. Xin, M. E. Weiss, R. Peters,
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11] The diketo dioxinones and triketo compounds exist as mixtures
of keto–enol tautomers. For simplicity, all are drawn in the all-
keto form.
(7
–1
1
203, 1131, 1073, 1027, 964, 914 cm . HRMS (ESI) calcd. for
[M – H]+ 319.1182; found 319.1172. The spectra match
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[13] A detailed discussion of the possible mechanism for the forma-
tion of 12 from 10 can be found in the Supporting Information.
[14] J. Cordes, A. G. M. Barrett, Eur. J. Org. Chem. 2013, 1318–1326.
[15] Unfortunately, the arene methyl group is essential for the ac-
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C H O
the reported data for 1.
[7,8,21]
Supporting Information (see footnote on the first page of this arti-
1
13
cle): Copies of the H and C NMR spectra of mycophenolic acid
1), keto ester dioxinones 9a–b, intermediate 10, γ-pyrone 12, resor-
(
[
cylates 13–15 and 19, and iodo-ethers 16–18, X-ray structural data
for γ-pyrone 12, resorcylate 15, iodo-ether 16, and diiodide 17, and
possible mechanism for the formation of 12 from 10.
Acknowledgments
The authors thank the European Research Council (ERC) for gen-
erous grant support, GlaxoSmithKline for the Glaxo endowment,
and P. R. Haycock and R. N. Sheppard for high-resolution NMR
spectroscopy.
1998, 63, 5831–5837.
1
[17] Determined by H NMR spectroscopy.
[
18] For details on the X-ray crystal structure determinations see
the Supporting Information. CCDC-945709 (for γ-pyrone
1
2), -945710 (for lactone 15), -945711 (for iodo-ether 16) and
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graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
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Published Online: September 24, 2013
Eur. J. Org. Chem. 2013, 7313–7319
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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