Total synthesis of cristatic acid based on late-stage decarboxylative allylic migration and biomimetic aromatization of a diketo dioxinone

Article abstract of DOI:10.1002/ejoc.201301102

A fifteen-step synthesis of methyl cristatate is described. tert-Butyl-[(E)-6-iodo-3-methylhex-2-enyloxy)]diphenylsilane, synthesized from geraniol, was coupled with 2-(diethoxymethyl)-4-lithiofuran and transformed - by acetal hydrolysis, Wittig olefinati

Full text of DOI:10.1002/ejoc.201301102

Job/Unit: O31102
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Date: 24-09-13 17:57:25
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201301102
Total Synthesis of Cristatic Acid Based on Late-Stage Decarboxylative Allylic
Migration and Biomimetic Aromatization of a Diketo Dioxinone
[a]
[a]
[a]
Nicolas S. George, Katie E. Anderson, and Anthony G. M. Barrett*
Keywords: Natural products / Total synthesis / Medicinal chemistry / Biomimetic synthesis / Terpenoids
A fifteen-step synthesis of methyl cristatate is described. tert-
Butyl-[(E)-6-iodo-3-methylhex-2-enyloxy)]diphenylsilane,
synthesized from geraniol, was coupled with 2-(diethoxy-
methyl)-4-lithiofuran and transformed – by acetal hydrolysis,
Wittig olefination, and desilylation – into a sesquiterpene
furan alcohol. This alcohol was converted into methyl cristat-
ate by sequential condensation with carbonyldiimidazole
and the enolate dianion derived from 2,2-dimethyl-6-(2-
oxopropyl)-4H-1,3-dioxin-4-one and subsequent Pd -cata-
lyzed decarboxylative allylic migration, biomimetic aromati-
zation, and transesterification with methanol.
0
Introduction
Terpene resorcylates exhibit an interesting array of bio-
logical activities and are widely found in nature (a selection
of examples is shown in Figure 1).[ Among them, cristatic
acid (6), isolated from the fruiting bodies of the higher
mushroom Albatrellus cristatus in 1981, exhibits a broad
range of biological properties, including antibiotic activity
against Gram-positive bacteria.[ In addition, it was found
to have strong hemolytic activity and inhibitory effects
1]
1o]
[
2]
against cells of the ascites form of the Ehrlich carcinoma.
Most resorcylate natural product syntheses depend on
the use of 6-alkylated derivatives of 2,4-dihydroxybenzoate
esters as the starting materials.[
2b,3]
These approaches in-
volve derivatization of this aromatic building block and
usually require the use of protecting groups, which can be
problematic to cleave chemoselectively at the end. This is
especially true for cristatic acid (6) due to the sensitive na-
ture of the furan moiety. Joullié’s synthesis can be taken as
an illustration of this major difficulty: only one of the two
MOM protecting groups could be removed from methyl di-
O-MOM-cristatate.[ Fürstner circumvented this problem
by using a SEM {[2-(trimethylsilyl)ethoxy]methyl} protect-
4]
[
2b]
ing group.
As an alternative strategy to solve these issues, we have
developed a flexible approach based on extending the meth-
ods of Harris, Hyatt, and Boeckman, which involve late-
[
5]
stage aromatization from diketo-dioxinone precursors.
Figure 1. Angelicoin A (1), hongoquercins 2 and 3, mycophenolic
This strategy has been utilized efficiently for the syntheses acid (4), grifolic acid (5), and cristatic acid (6).
[
6]
of several biologically active resorcylate natural products.
Recently, we discovered that allylic dioxinone diketo esters
readily undergo palladium(0)-catalyzed regiospecific allylic
migration followed by cesium-carbonate-mediated aromati-
zation. Here we report the extension of this methodology
to the synthesis of methyl cristatate.
[
a] Department of Chemistry, Imperial College London,
South Kensington, London SW7 2AZ, United Kingdom
E-mail: agm.barrett@imperial.ac.uk
www3.imperial.ac.uk/people/agm.barrett
[
7]
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301102.
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N. S. George, K. E. Anderson, A. G. M. Barrett
FULL PAPER
The retrosynthetic analysis is outlined in Scheme 1 with Results and Discussion
disassembly of the resorcylate 7, which should be available
Geraniol (14) was protected under modified Corey’s con-
(in a forward direction) through a late-stage regioselective
[
9]
ditions to provide silyl ether 15 (Scheme 2). Selective
epoxidation and oxidative cleavage (m-CPBA, H IO ) gave
palladium(0)-catalyzed decarboxylative allylic migration
5
6
and aromatization of diketo-dioxinone 9, via the dioxinone
[
10]
[
7]
aldehyde 17,
hydride, and the derived alcohol was converted into iodide
3 by mesylation and iodide displacement. This sequence
was successfully scaled up to provide 34 g of iodide 13
starting from 25 mL of geraniol, 147 mmol) with a 50%
which was reduced with sodium boro-
diketo ester 8. Dioxinone diketo ester 9 should be avail-
able through two successive C-acylations of keto dioxinone
1
1
0 with acetyl chloride and with an activated carbonate
[6c,6d,6f,8]
ester derivative of alcohol 11.
In turn, alcohol 11
(
should be available from bromofuran 12 and iodide 13,
which should be easily derived from geraniol (14).
yield over six steps and after only one final purification by
chromatography.
Scheme 2. Synthesis of iodide 13 from geraniol (14).
In order to link the furan moiety to the geraniol-derived
side chain 13 (Scheme 3), the commercially available sensi-
tive 4-bromofuran-2-carbaldehyde (12) was protected as
[4]
Scheme 1. Retrosynthetic analysis.
acetal 19 under mild conditions (NH NO , EtOH). At-
4 3
Scheme 3. Synthesis of the allylic alcohol 11.
2
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Total Synthesis of Cristatic Acid with Biomimetic Aromatization
tempted lithiation/halogen exchange with bromide 19, ad-
In consequence, we developed a milder alternative pro-
dition to the aldehyde 17, and reduction of the derived sec- cedure. Treatment of alcohol 11 with excess N,N-carbonyl-
ondary alcohol proved inefficient (Ͻ10%). diimidazole (3 equiv.) at –78 °C to room temperature
Fortunately, though, treatment of the lithiofuran derived cleanly gave the imidazolecarboxylate 29 (Scheme 5). This
from bromide 19 with iodide 13 gave furan 20 (Scheme 3, compound was directly used to acylate the zinc dienolate
6
0%) accompanied by bromofuran 21 (10%). There was derived from keto-dioxinone 10, to give dioxinone keto es-
[
6c,6d,6f,8]
clearly competition between lithium/bromide exchange and ter 30.
This was subjected to our key aldol and aro-
C2-lithiation assisted by the precomplexation of nBuLi by matization sequence, leading to isopropylidene-protected β-
the acetal. After optimization, introduction of HMPA after resorcylate 7 (Scheme 6).
the addition of nBuLi was found to be essential for ob-
taining furan 20 as the major product. Indeed, introduction
of HMPA prior to nBuLi furnished only bromofuran 21
[
11]
(73%).
Utilization of DMPU or N,NЈ-dimethylimid-
azolidin-2-one as substitutes for HMPA did not improve
[
12]
the yield of furan 20 (24% and 33% yields, respectively).
Indium-triflate-catalyzed deprotection of the diethyl
acetal 20 was clean (93%).[ The resulting aldehyde 22
13]
(Scheme 3) was directly condensed with isopropylidenetri-
phenylphosphorane, giving the alkene 24. Finally, deprotec-
tion of this product with tetrabutylammonium fluoride gave
allylic alcohol 11.
Attempted synthesis of the dioxinone keto ester 30
(
Scheme 5, below) by the known[
5f,6a,6b,6e,7b,7c,7d,14]
thermal
retro-Diels–Alder reaction of Meldrum’s acid in the pres-
ence of alcohol 11, subsequent treatment of the resulting
malonate half ester with oxalyl chloride, and condensation
with the enolate 27 (Scheme 4) failed on account of the high
instability of the delicate furan unit towards acid chloride
formation.
Scheme 6. Completion of the synthesis of methyl cristatate.
A regioselective MgCl -mediated Claisen condensation
2
of dioxinone 30 with acetyl chloride gave the dioxinone di-
keto ester 9 (Scheme 6), which was not isolated but was
subjected to a sequence consisting of palladium(0)-cata-
lyzed regioselective decarboxylative allyl migration, in situ
[
7]
Scheme 4. General pathway to dioxinone keto esters 28.
Cs CO -mediated cyclisation, and aromatization. All of
2 3
Scheme 5. Synthesis of dioxinone keto ester 30; CDI = N,N-carbonyldiimidazole.
Eur. J. Org. Chem. 0000, 0–0
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N. S. George, K. E. Anderson, A. G. M. Barrett
FULL PAPER
–
1
these reactions were compatible with the sensitive isobutyl- ν˜ max = 1473, 1428, 1379, 1110, 1056, 822 cm . HRMS (CI) calcd.
+
for C26
2 4
H40NO Si [M + NH ] 426.2828; found 426.2842.
ene-substituted furan. Finally, the synthesis of the furanyl
terpenoid resorcylate in its methyl ester form was completed
tert-Butyl-[(E)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enyloxy]-
by isopropylidene cleavage with sodium methoxide in hot diphenylsilane (16):[ m-CPBA (3.6 g, 15.83 mmol, 1.2 equiv.) in
10]
methanol (Scheme 6).
CH
5 (5.2 g, 13.2 mmol, 1.0 equiv.) in CH
mixture was filtered and Ca(OH) (4.2 g, 56.76 mmol, 4.3 equiv.)
was added. After 1 h stirring, the mixture was filtered, concentrated
rotary evaporator), and chromatographed (Et O/pentane 3:7) to
= 0.65 (Et O/
, 400 MHz, 25 °C): δ = 7.70–7.67
m, 4 H), 7.44–7.35 (m, 6 H), 5.43–5.39 (m, 1 H), 4.22 (d, J =
2
Cl
2
(50 mL) was added dropwise with stirring at 0 °C to alkene
1
2
2
Cl (50 mL). After 2 h, the
2
Conclusions
(
2
In conclusion, we have completed the synthesis of methyl afford epoxide 16 (4 g, 75%) as a colorless oil. R
f
2
1
pentane 3:7). H NMR (CDCl
3
cristatate with a 2.7% overall yield and in 15 linear steps
six purifications by chromatography) from inexpensive ge-
(
(
6
1
.0 Hz, 2 H), 2.71 (t, J = 5.0 Hz, 1 H), 2.19–2.03 (m, 2 H), 1.71–
raniol (14). Our late-stage decarboxylative allylic migration,
cyclization, and aromatization sequence leading to pro-
tected β-resorcylate from dioxinone diketo ester 7 proved
to be general, mild, and practical. The synthesis of interme-
diate 13 was adjusted from our previous approach because
.59 (m, 2 H), 1.46 (s, 3 H), 1.30 (s, 3 H), 1.26 (s, 3 H), 1.07 (s, 9
1
3
H) ppm. C NMR (CDCl
3
, 100 MHz, 25 °C): δ = 136.1, 135.6 (4
C), 134.0 (2 C), 129.5 (2 C), 127.6 (4 C), 124.6, 64.0, 61.0, 58.4,
3
1
6.1, 27.2, 26.8 (2 C), 24.9, 19.2, 18.7, 16.3 ppm. IR (neat): ν˜ max =
–1
473, 1428, 1378, 1112, 1057, 823 cm . HRMS (ESI) calcd. for
+
of the high sensitivity of the 2-isobutenylfuran unit to acidic C H O NaSi [M + Na] 431.2382; found 431.2369.
2
6
36
2
conditions.
(
(
E)-6-(tert-Butyldiphenylsilyloxy)-4-methylhex-4-enal (17):[10]
4.14 g, 19.51 mmol, 2.0 equiv.) in H O (20 mL) was added with
5 6
H IO
2
stirring at 0 °C to epoxide 16 (4 g, 9.76 mmol, 1.0 equiv.) in THF
(32 mL). After 30 min, saturated aqueous NaHCO3 (50 mL) was
Experimental Section
added, and the mixture was extracted with Et
combined organic layers were dried (MgSO ), concentrated (rotary
evaporator), and chromatographed (Et O/pentane 3:7) to give alde-
hyde 17 (2 g, 60%) as a colorless oil. R = 0.60 (Et O/pentane 3:7).
, 500 MHz, 25 °C): δ = 9.75 (t, J = 1.0 Hz, 1 H),
.69–7.67 (m, 4 H), 7.42–7.36 (m, 6 H), 5.40–5.37 (m, 1 H), 4.22
d, J = 6.0 Hz, 2 H), 2.50 (td, J = 6.0, 1.0 Hz, 2 H), 2.30 (t, J =
2
O (2ϫ 200 mL). The
General Methods: All reactions were carried out in oven-dried
4
glassware under dry N
ing reaction solvents were distilled under N
MeOH over Na, and CH Cl , pyridine, and Et
refers to redistilled H O. Other solvents and all reagents were ob-
tained from commercial suppliers and, if purity was Ͼ98%, used
as obtained. NaI was recrystallized from Me CO. Isopropyltri-
2
or Ar unless otherwise stated. The follow-
: THF over Na/Ph CO,
2
N from CaH . H O
2
2
2
f
2
2
2
3
2
1
H NMR (CDCl
3
2
7
(
6
2
1
3
.0 Hz, 2 H), 1.45 (s, 3 H), 1.04 (s, 9 H). C NMR (CDCl
3
,
phenylphosphonium iodide was recrystallized three times from
PhMe; the crystals were washed with diethyl ether and dried under
vacuum. Cs CO was oven-dried at 120 °C overnight. Flash column
2 3
125 MHz, 25 °C): δ = 202.2, 135.6 (2 C), 134.9, 133.9 (4 C), 129.6
(
2 C), 127.6 (4 C), 125.0, 60.9, 41.8, 31.5, 26.8 (3 C), 19.1,
1
8
6.4 ppm. IR (neat): ν˜ max = 1722, 1472, 1428, 1390, 111, 1069,
chromatography was performed with Merck silica gel 60, particle
size 40–63 mm (eluents are given in parentheses). “Hexanes” refers
to petroleum spirit of boiling range 40–60 °C. Thin layer
chromatography (TLC) was performed on pre-coated aluminum-
backed plates (Merck Kieselgel 60 F254); visualization was ac-
complished under UV light (254 nm) and/or by staining with
aqueous potassium permanganate or vanillin followed by gentle
heating with a heat gun. 1H NMR and C NMR spectra were
recorded by operating at 400 or 500 MHz and at 100 or 125 MHz,
respectively, with chemical shifts (δ) quoted in parts per million
–
1
+
4
22 cm . MS (CI) [M + NH ] requires 340; found 340; [M +
+
H] requires 323; found 323.
(E)-6-(tert-Butyldiphenylsilyloxy)-4-methylhex-4-en-1-ol
NaBH (330 mg, 8.67 mmol, 2.0 equiv.) was added with stirring at
(18):
4
0 °C to aldehyde 17 (1.6 g, 4.34 mmol, 1.0 equiv.) in EtOH (80 mL).
After 3 h, the mixture was concentrated (rotary evaporator) and
13
saturated aqueous NaHCO
extracted with EtOAc (2ϫ 200 mL), and the combined organic lay-
ers were dried (MgSO ), concentrated (rotary evaporator), and
chromatographed (Et O/pentane 2:1) to give alcohol 18 (1.3 g,
81%) as a colorless oil. R
(CDCl , 500 MHz, 25 °C): δ = 7.70–7.68 (m, 4 H), 7.44–7.36 (m, 6
H), 5.43–5.40 (m, 1 H), 4.22 (d, J = 7.0 Hz, 2 H), 4.63 (m, J =
.0 Hz, 2 H), 2.05 (t, J = 6.0 Hz, 2 H), 1.69–1.63 (m, 2 H), 1.46 (s, 3
3
(100 mL) was added. The mixture was
4
(
7
(
ppm) and referenced to the residual CDCl
.26, δ = 77.16 ppm). Coupling constants (J) are quoted in Hertz
Hz) to the nearest 0.1 Hz.
3
solvent peak (δ
H
=
2
1
f 2
= 0.55 (Et O/pentane 2:1). H NMR
C
3
tert-Butyl-[(E)-3,7-dimethylocta-2,6-dienyloxy]diphenylsilane (15):
Imidazole (1.3 g, 19.02 mmol, 1.1 equiv.) and tBuPh SiCl
5 mL,19.02 mmol, 1.1 equiv.) were added at 0 °C with stirring to
geraniol (14, 2.7 g, 17.3 mmol, 1.0 equiv.) in CH Cl (90 mL), and
the mixture was allowed to warm to 20 °C. After 12 h, H
6
2
1
3
3
H), 1.28 (t, J = 6.0 Hz, 1 H), 1.04 (s, 9 H) ppm. C NMR (CDCl ,
(
1
1
25 MHz, 25 °C): δ = 136.8, 135.6 (2 C), 134.0 (4 C), 129.5 (2 C),
27.6 (4 C), 124.4, 62.7, 61.0, 35.7, 30.5, 26.8 (3 C), 19.1, 16.2 ppm.
2
2
2
O
–
1
IR (neat): ν˜ max = 3343, 1473, 1428, 1112, 1052, 998, 823 cm .
(100 mL) was added, and the mixture was extracted with CH
2
Cl
2
+
HRMS (ESI) calcd. for C23
86.2517.
2 4
H36NO Si [M + NH ] 386.2515; found
(2ϫ 100 mL). The combined organic layers were dried (MgSO
4
),
3
concentrated (rotary evaporator), and chromatographed (EtOAc/
hexanes 1:9 to 2:8) to afford silyl ether 15 (6 g, 88%) as a colorless tert-Butyl-[(E)-6-iodo-3-methylhex-2-enyloxy]diphenylsilane
oil. R , 400 MHz, Et N (6.3 mL, 45.52 mmol, 2.0 equiv.), followed by MsCl (2.1 mL,
= 0.8 (EtOAc/hexanes 2:8). 1H NMR (CDCl
5 °C): δ = 7.71–7.68 (m, 4 H), 7.44–7.35 (m, 6 H), 5.40–5.36 (m, 27.3 mmol, 1.2 equiv.), were added with stirring at 0 °C to alcohol
H), 5.12–5.08 (m, 1 H), 4.22 (d, J = 8.0 Hz, 2 H), 2.09–1.96 (m, 18 (8.4 g, 22.76 mmol, 1.0 equiv.) in CH Cl (115 mL). After
(13):
f
3
3
2
1
4
9
2
2
H), 1.68 (d, J = 0.5 Hz, 3 H), 1.61 (s, 3 H), 1.43 (s, 3 H), 1.04 (s,
45 min, saturated aqueous NaHCO
mixture was extracted with CH Cl
3
(100 mL) was added and the
(2ϫ 100 mL). The combined
H) ppm. 13C NMR (CDCl
, 100 MHz, 25 °C): δ = 137.0, 135.6
3
2
2
(
4 C), 135.2 (2 C), 134.1, 131.5 (2 C), 129.5 (4 C), 124.1, 124.0 (2
organic layers were successively washed with aqueous HCl (1 m,
100 mL) and brine (200 mL), dried (MgSO ), and concentrated (ro-
C), 61.2, 39.5, 26.8 (3 C), 26.4, 25.7, 19.2, 17.7, 16.3 ppm. IR (neat):
4
4
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Total Synthesis of Cristatic Acid with Biomimetic Aromatization
tary evaporator). The product was used directly without further
purification. NaI (4.438 g, 29.6 mmol, 1.3 equiv.) was added with
(s, 1 H), 5.45 (s, 1 H), 5.40–5.38 (m, 1 H), 4.22 (d, J = 6.0 Hz, 2
H), 3.65–3.54 (m, 4 H), 2.59 (t, J = 7.0 Hz, 2 H), 1.99 (t, J =
7.0 Hz, 2 H), 1.72 (quin, J = 7.0 Hz, 2 H), 1.42 (s, 3 H), 1.22 (t, J
stirring to the crude methanesulfonate in Me
mixture was heated at 50 °C for 18 h and concentrated (rotary
evaporator). A 1:1 mixture of saturated aqueous Na and satu-
rated aqueous NaHCO (100 mL) was added, and the mixture was
extracted with Et O (2ϫ 100 mL). The organic layers were dried
), concentrated (rotary evaporator), and chromatographed
O/pentane 1:99) to give iodide 13 (9.2 g, 84% over two steps)
2
CO (200 mL). The
1
3
3
= 8.0 Hz, 6 H), 1.04 (s, 9 H). C NMR (CDCl , 125 MHz, 25 °C):
2
S
2
O
3
δ = 152.8, 150.1, 136.2, 135.6 (4 C), 134.0 (2 C), 129.5 (2 C), 127.6
(4 C), 124.7, 111.8, 96.3, 96.0, 61.3 (2 C), 61.1, 38.7, 26.8 (3 C),
25.7, 25.6, 19.2, 16.1, 15.1 (2 C) ppm. IR (neat): ν˜ max = 3457, 1725,
3
2
–
1
(
(
MgSO
Et
4
1436, 1368, 1217, 1111, 1092, 900 cm . HRMS (ESI) calcd. for
NaSiBr [M + Na]+ 621.2012; found 621.2013.
2
32 43 4
C H O
1
as a colorless oil. R
f
= 0.90 (Et
2 3
O/pentane 1:9). H NMR (CDCl ,
tert-Butyl-{3-methyl-6-[(E)-5-(2-methylprop-1-enyl)furan-3-yl]hex-2-
enyloxy}diphenylsilane (24): In(OTf) (51 mg, 0.09 mmol,
.1 equiv.) was added with stirring to (diethoxymethyl)furan 20
5
5
2
00 MHz, 25 °C): δ = 7.72–7.71 (m, 4 H), 7.46–7.39 (m, 6 H), 5.46–
3
.43 (m, 1 H), 4.25 (d, J = 6.0 Hz, 2 H), 3.14 (t, J = 7.0 Hz, 2 H),
.08 (t, J = 7.0 Hz, 2 H), 1.91 (quin., J = 7.0 Hz, 2 H), 1.44 (s, 3
0
13
2
(500 mg, 0.91 mmol, 1.0 equiv.) in Me CO (18.2 mL). After 5 min,
saturated aqueous NH Cl (20 mL) was added and the mixture was
4
H), 1.07 (s, 9 H) ppm. C NMR (CDCl
3
, 125 MHz, 25 °C): δ =
35.6, 134.9 (2 C), 133.9 (4 C), 129.5 (2 C), 127.6 (4 C), 125.4, 61.0,
9.8, 31.3, 26.8 (3 C), 19.1, 16.1, 6.4 ppm. IR (neat): ν˜ max = 1427,
1
3
1
extracted with Et
were dried (MgSO
2
O (2ϫ 50 mL). The combined organic layers
) and concentrated (rotary evaporator) to afford
–1
4
388, 1217, 1110, 1051, 823 cm . HRMS (CI) calcd. for
+
aldehyde 22 (380 mg, 93%) as a colorless oil. The product was used
directly without further purification. nBuLi (0.35 mL, 1.2 m in hex-
anes, 0.42 mmol, 1.2 equiv.) was added dropwise with stirring at
C
23
H
35NOSiI [M + NH
-Bromo-2-(diethoxymethyl)furan
.032 mmol, 0.05 equiv.) was added with stirring to aldehyde 12
4
]
496.1533; found 496.1542.
4
0
(19):[4]
NH NO
4
3
(3 mg,
–
0
78 °C to isopropyltriphenylphosphonium iodide (182 mg,
.42 mmol, 1.2 equiv.) in THF (3.5 mL), giving an orange solution.
(0.1 g, 0.63 mmol, 1.0 equiv.) in EtOH (3.15 mL), and the mixture
was heated to reflux. After 2 h, the solution was cooled to 20 °C
and concentrated (rotary evaporator). Brine (50 mL) was added
After 30 min at 0 °C the color had turned deep red, the mixture
was recooled to –78 °C, and crude aldehyde 22 (141 mg, 0.32 mmol,
and the mixture was extracted with Et
bined organic layers were dried (MgSO
evaporator), and chromatographed (Et O/pentane 1:49) to afford
bromofuran 19 (120 mg, 77%) as a pale yellow oil. R = 0.90 (Et O/
, 400 MHz, 25 °C): δ = 7.40 (d, J =
.5 Hz, 1 H), 6.47 (d, J = 0.5 Hz, 1 H), 5.49 (s, 1 H), 3.66–3.54 (m,
H), 1.23 (t, J = 8.0 Hz, 6 H). 13C NMR (CDCl
, 100 MHz,
5 °C): δ = 152.8, 140.5, 111.6, 100.0, 95.8, 61.4 (2 C), 15.1 (2
2
O (2ϫ 50 mL). The com-
1
.0 equiv.) in THF (0.5 mL) was added dropwise. After the mixture
had been kept for 30 min at 0 °C, saturated aqueous NH Cl
20 mL) was added and the mixture was extracted with Et O (2ϫ
0 mL). The combined organic layers were washed with brine
30 mL), dried (MgSO ), concentrated (rotary evaporator), and
O/pentane 2:98) to afford alkene 24 (120 mg,
4
), concentrated (rotary
4
2
(
4
(
2
f
2
1
pentane 1:9). H NMR (CDCl
3
4
0
4
2
chromatographed (Et
2
3
1
70%) as a colorless oil. R
f 2
= 0.95 (Et O/pentane 1:9). H NMR
(
CDCl , 400 MHz, 25 °C): δ = 7.72–7.70 (m, 4 H), 7.44–7.38 (m, 6
3
C) ppm. IR (neat): ν˜ max = 3147, 1737, 1372, 1320, 1218, 1138, 1050,
H), 7.11 (s, 1 H), 6.07 (s, 1 H), 6.04 (s, 1 H), 5.40 (t, J = 6.0 Hz, 1
H), 4.25 (d, J = 6.0 Hz, 2 H), 2.37 (t, J = 8.0 Hz, 2 H), 2.02 (t, J
–1
9 13 3
H O
Br [M + H]+
9
2
23, 898, 790 cm . HRMS (EI) calcd. for C
48.0048; found 248.0041.
=
2
8.0 Hz, 2 H), 2.00 (s, 3 H), 1.91 (s, 3 H), 1.65 (quin. J = 8.0 Hz,
H), 1.45 (s, 3 H), 1.06 (s, 9 H) ppm. C NMR (CDCl , 100 MHz,
3
tert-Butyl-{(E)-6-[5-(diethoxymethyl)furan-3-yl]-3-methylhex-2-enyl-
oxy}diphenylsilane (20) and {(E)-6-[4-Bromo-2-(diethoxymethyl)-
furan-3-yl]-3-methylhex-2-enyloxy}(tert-butyl)diphenylsilane (21):
nBuLi (0.9 mL, 1.2 m in hexanes, 1.09 mmol, 2.0 equiv.) was added
dropwise with stirring at –78 °C to bromofuran 19 (270 mg,
13
25 °C): δ = 153.7, 136.8, 135.6 (4 C), 134.8 (2 C), 134.1 (2 C), 129.5
(
2 C), 127.6 (4 C), 126.4, 124.4, 114.6, 108.7, 61.13, 38.9, 27.9, 27.0,
2
1
+
6.9 (3 C), 24.4, 20.1, 19.2, 16.2 ppm. IR (neat): ν˜ max = 1472, 1428,
–1
41 2
261, 1111, 1059, 823 cm . HRMS (CI) calcd. for C31H O Si [M
1
.09 mmol, 2.0 equiv.) in THF (4 mL). After 5 min, HMPA
0.25 mL, 1.417 mmol, 2.6 equiv.) was added dropwise and stirring
continued for 30 min. Iodo-olefin 13 (261 mg, 0.55 mmol,
.0 equiv.) in THF (1 mL) was added dropwise, and the resulting
solution was allowed to warm to 20 °C. After 18 h, saturated aque-
ous NH Cl (50 mL) was added and the mixture was extracted with
Et O (2 ϫ 50 mL). The combined organic layers were dried
MgSO ), concentrated (rotary evaporator), and chromatographed
Et O/pentane 1:29 to 3:27) to afford furan 20 (175 mg, 60%) as a
+
H] 473.2876; found 473.2874.
(
3
-Methyl-6-[5-((E)-2-methylprop-1-enyl)furan-3-yl]hex-2-en-1-ol
(
11): nBu NF in THF (1 m, 0.18 mL, 0.18 mmol, 1.5 equiv.) was
added dropwise with stirring to silyl ether 24 (60 mg, 0.12 mmol,
.0 equiv.) in THF (0.6 mL). After 18 h, saturated aqueous
NaHCO (20 mL) was added and the mixture was extracted with
Et O (2ϫ 20 mL). The combined organic layers were washed with
brine (30 mL), dried (MgSO ), concentrated (rotary evaporator),
and chromatographed (Et O/pentane 1:1) to afford alcohol 11
(25 mg, 81%) as a colorless gum. R
NMR (CDCl , 500 MHz, 25 °C): δ = 7.12 (s, 1 H), 6.06 (s, 1 H),
.03 (s, 1 H), 5.45–5.42 (m, 1 H), 4.17 (d, J = 6.0 Hz, 2 H), 2.37
4
1
1
4
3
2
(
(
4
2
4
2
clear gum and bromofuran 21 (32 mg, 10%) as a clear oil.
O/pentane 1:9). 1H NMR (CDCl
Furan 20: R = 0.70 (Et
00 MHz, 25 °C): δ = 7.71–7.69 (m, 4 H), 7.42–7.36 (m, 6 H), 7.17
d, J = 0.5 Hz, 1 H), 6.30 (br. s, 1 H), 5.50 (s, 1 H), 5.40–5.37 (m,
2
1
f
2
= 0.42 (Et O/pentane 1:1). H
f
2
3
,
3
5
(
6
(
(
t, J = 8.0 Hz, 2 H), 2.08 (t, J = 8.0 Hz, 2 H), 1.99 (s, 3 H), 1.90
1
7
H), 4.24 (d, J = 6.0 Hz, 2 H), 3.67–3.58 (m, 4 H), 2.35 (t, J =
.0 Hz, 2 H), 2.00 (d, J = 7.0 Hz, 2 H), 1.63 (quin. J = 7.0 Hz. 2
s, 3 H), 1.74–1.66 (m, 2 H), 1.69 (s, 3 H) 1.40 (br. s, 1 H) ppm.
1
3
1
3
3
C NMR (CDCl , 125 MHz, 25 °C): δ = 153.7, 139.5, 136.8, 134.7,
H), 1.44 (s, 3 H), 1.25 (t, J = 8.0 Hz, 6 H), 1.05 (s, 9 H) ppm.
C
1
1
1
2
26.3, 123.6, 114.5, 108.7, 59.4, 39.1, 27.9, 27.0, 24.6, 20.1,
NMR (CDCl
C), 134.1 (2 C), 129.5 (2 C), 127.6 (4 C), 125.5, 124.4, 109.4, 96.4,
1.3 (2 C), 61.1, 38.9, 27.7, 26.8 (3 C), 24.3, 19.2, 19.2, 15.15 (2
3
, 125 MHz, 25 °C): δ = 151.8, 138.6, 136.7, 135.6 (4
6.2 ppm. IR (neat): ν˜ max = 3453 (br.) 1739, 1441, 1366, 1217, 1229,
–
1
+
206, 985 cm . HRMS (EI) calcd. for C15
34.1620; found 234.1635.
22 2
H O [M + H]
6
C) ppm. IR (neat): ν˜ max = 1683, 1461, 1427, 1361, 1109, 1051, 1005,
22 cm–1. HRMS (ESI) calcd. for C32
59.2856; found 599.2856.
44 5
H O
NaSi [M + Na]+
8
5
3
-Methyl-6-[5-((E)-2-methylprop-1-enyl)furan-3-yl]hex-2-enyl 4-
(
2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (30):
1
Bromofuran 21: R
f
0.75 (Et
2
O/pentane 1:9). H NMR (CDCl
3
,
Alcohol 11 (200 mg, 0.85 mmol) in THF (6 mL) was added with
stirring at –78 °C to N,NЈ-carbonyldiimidazole (413 mg,
500 MHz, 25 °C): δ = 7.70–7.68 (m, 4 H), 7.41–7.36 (m, 6 H), 6.38
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O31102
/KAP1
Date: 24-09-13 17:57:25
Pages: 8
N. S. George, K. E. Anderson, A. G. M. Barrett
(neat): ν˜ max = 1692, 1607, 1592, 1294, 1276, 1208, 1166, 1107, 1042,
FULL PAPER
2
.55 mmol) in THF (11 mL) and the mixture was allowed to warm
to room temperature overnight. H O (50 mL) was added and the
mixture was extracted with AcOEt (3ϫ 50 mL). The combined or-
ganic layers were dried (MgSO ) and concentrated (rotary evapora-
–
1
+
2
908, 730 cm . HRMS (ES): calcd. for C26
425.2328; found 425.2322.
33 5
H O [M + H]
4
Methyl
2,4-Dihydroxy-6-methyl-3-{(E)-3-methyl-6-[5-(2-meth-
tor) to leave the crude imidazole carbonate, which was used without
further purification. 2,2-Dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-
ylprop-1-enyl)furan-3-yl]hex-2-enyl}benzoate, Methyl Cristatate:
Freshly prepared NaOMe [from Na (6 mg), 0.26 mmol, 10 equiv.]
in MeOH (1 mL) was added to solid dioxinone resorcylate 7
4
-one (10, 344 mg, 1.87 mmol, 2.2 equiv.) in THF (2 mL) was
added at –78 °C to freshly prepared LiN(iPr) (3.88 mmol,
.5 equiv.) in THF (5 mL). After 10 min, the mixture had solidified
and was allowed to warm to –40 °C and left for 1 h. Et Zn in hex-
anes (1 m, 3.9 mL, 3.9 mmol, 4.6 equiv.) was added and, after
0 min, the mixture was cooled to –78 °C and the crude imidazole
carboxylate 29 in THF (3 mL) was added dropwise. After the sys-
tem had been kept at –78 °C for 45 min, saturated aqueous NH Cl
5 mL) was added slowly. The solution was allowed to warm to
2
(
11 mg, 0.026 mmol). The mixture was heated at 65 °C in a sealed
4
tube for 20 h. Aqueous HCl (0.1 m, 15 mL) and AcOEt (20 mL)
were added. After phase separation, the aqueous layer was ex-
tracted with AcOEt (3ϫ 20 mL). The combined organic layers were
2
2
dried (MgSO
4
), concentrated (rotary evaporator), and chromato-
graphed (AcOEt/hexanes 15:85) to afford methyl cristatate (6.6 mg,
4
1
6
4%) as a colorless oil. R
f
= 0.42 (AcOEt/hexanes 2:8). H NMR
(
(
CDCl , 400 MHz, 25 °C): δ = 12.13 (s, 1 H), 7.10 (s, 1 H) 6.25 (s,
3
2
room temperature, after which H O (40 mL) was added and the
1
1
H), 6.05 (s, 1 H), 6.02 (m, 1 H), 5.72 (s, 1 H), 5.32 (t, J = 7.2 Hz,
H), 3.94 (s, 3 H), 3.45 (d, J = 7.3 Hz, 2 H), 2.48 (s, 3 H), 2.37 (t,
pH was adjusted to about 3 with aqueous HCl (1 m, 5 mL). After
separation, the aqueous layer was extracted with Et O (3ϫ 50 mL).
The combined organic layers were dried (MgSO ), concentrated
rotary evaporator), and chromatographed (AcOEt/hexanes 3:7) to
give dioxinone keto ester 30 containing 20% of the corresponding
enol (228 mg, 60% over two steps) as a light yellow oil. R = 0.44
, 400 MHz, 25 °C) of the
dioxinone keto ester: δ = 7.11 (s, 1 H), 6.05 (s, 1 H), 5.38 (s, 1 H),
.36 (m, 1 H), 4.68 (d, J = 7.2 Hz, 2 H), 3.53 (s, 2 H), 3.51 (s, 2
H), 2.38 (t, J = 7.5 Hz, 2 H), 2.09 (t, J = 7.4 Hz, 2 H), 1.98 (s, 3
2
J = 7.5 Hz, 2 H), 2.09 (t, J = 7.5 Hz, 2 H), 1.98 (s, 3 H) 1.90 (s, 3
4
13
H) 1.83 (s, 3 H), 1.69 (multiplet, J = 7.6 Hz, 2 H) ppm. C NMR
(
(
1
5
CDCl
3
, 100 MHz, 25 °C): δ = 172.6, 162.6, 159.2, 153.7, 140.9,
38.6, 136.8, 134.8, 126.3, 121.8, 114.5, 111.4, 111.3, 108.7, 105.2,
1.8, 39.2, 28.1, 27.0, 24.4, 24.1, 22.0, 20.1, 16.2 ppm. IR (neat):
f
1
(
AcOEt/hexanes 4:6). H NMR (CDCl
3
–1
ν˜ max = 1651, 1620, 1455, 1419, 1378, 1272, 1195, 908, 730 cm .
[M + H]+ 399.2171; found
HRMS (ES): calcd. for C24
99.2186.
31 5
H O
5
3
H), 1.90 (s, 3 H), 1.72–1.67 (m, 11 H) ppm. 1 C NMR (CDCl
3
Supporting Information (see footnote on the first page of this arti-
3
,
1
13
cle): Copies of the H and C NMR spectra for 7, 11, 13, 15, 16,
7, 18, 19, 20, 21, 24, 30 and methyl cristatate.
1
1
3
1
00 MHz, 25 °C): δ = 195.7, 166.4, 163.6, 160.5, 153.7, 143.4,
36.8, 135.0, 126.1, 117.6, 114.5, 108.6, 107.4, 97.1, 62.6, 49.1, 47.0,
8.9, 27.8, 27.0, 25.0 (2 C), 24.4, 20.1, 16.4 ppm. IR (neat): ν˜ max
1
=
–1
722, 1639, 1390, 1375, 1272, 1253, 1203, 1016 cm . HRMS (ES)
Acknowledgments
+
33 7
calcd. for C25H O [M + H] 445.2226; found 445.2229.
The authors thank the European Research Council (ERC) for gen-
erous grant support, GlaxoSmithKline for the generous endow-
ment to A. G. M. B, and P. R. Haycock and R. N. Sheppard for
high-resolution NMR spectroscopy.
7
-Hydroxy-2,2,5-trimethyl-8-{(E)-3-methyl-6-[5-(2-methylprop-1-
enyl)furan-3-yl]hex-2-enyl}-4H-benzo[d][1,3]dioxin-4-one (7): MgCl
82 mg, 0.86 mmol, 2 equiv.) and (after 5 min and 30 min, respec-
2
(
tively) pyridine (0.93 mL, 1.16 mmol, 2.7 equiv.) and subsequently
AcCl (0.37 mL, 0.52 mmol, 1.2 equiv.) were added dropwise with
stirring at –10 °C and –5 °C (AcCl) to dioxinone keto ester 13
[
1] a) N. Wissinger, S. Barluenga, Chem. Commun. 2007, 22–36;
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192 mg, 0.43 mmol) in CH
aqueous NH Cl (25 mL) and CH
separation, the aqueous phase was extracted with CH
5 mL). The combined organic layers were dried (MgSO ) and con-
2
Cl
2
(5 mL). After 30 min, saturated
Cl (25 mL) were added. After
Cl (3ϫ
4
2
2
2
2
54, 717–718; for hongoquercins, see: d) D. M. Roll, J. K. Man-
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centrated (rotary evaporator) to leave crude dioxinone, which was
used without further purification. The crude dioxinone diketo ester
9
in THF (5 mL) was degassed by bubbling argon through the solu-
tion for 15 min. Pd(PPh (24 mg, 0.022 mmol, 0.05 equiv.) was
added and the mixture was stirred at room temperature for 70 h.
Dry Cs CO (420 mg, 1.29 mmol, 3 equiv.) was added and the mix-
ture was further stirred for 15 h. H O (5 mL) and AcOEt (25 mL)
were added and the pH was adjusted to about 5 with aqueous HCl
0.1 m, 20 mL). After phase separation, the aqueous phase was ex-
tracted with AcOEt (3ϫ 25 mL). The combined organic layers were
dried (MgSO ), concentrated (rotary evaporator), and chromato-
graphed (AcOEt/hexanes 2:8) to afford the cristatic acid derivative
(77 mg, 42% over two steps) as a yellow oil. R = 0.52 (AcOEt/
, 400 MHz, 25 °C): δ = 7.08 (s, 1
H), 6.97 (br. s, 1 H), 6.49 (s, 1 H), 6.04 (s, 1 H), 6.01 (s, 1 H), 5.21
3 4
)
2
3
6
51; i) R. Bentley, Chem. Rev. 2000, 100, 3801–3826; j) K. Bor-
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Baquero, J. S. Calderon, Rev. Latinoam. Quim. 2005, 33, 76–
81; m) R. D. Tressier, L. J. Garvin, D. L. Slate, Int. J. Cancer
1994, 57, 568–573; n) W. W. Epinette, C. M. Parker, E. L. Jones,
M. C. Greist, J. Am. Acad. Dermatol. 1987, 17, 962–971; for
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G. Kusano, S. Nozoe, Chem. Pharm. Bull. 1988, 36, 2918–2924;
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col. 2009, 380, 247–255; r) Q. Sun, T. Hara, A. Hirasawa, I.
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yata, G. Tsujimoto, Mol. Pharmacol. 2010, 78, 804–810.
(
4
7
f
1
hexanes 3:7). H NMR (CDCl
3
(
(
(
t, J = 7.2 Hz, 2 H), 3.33 (t, J = 7.5 Hz, 2 H), 2.60 (s, 3 H), 2.36
t, J = 7.5 Hz, 2 H), 2.05 (t, J = 7.4 Hz, 2 H), 1.97 (s, 3 H), 1.89
s, 3 H), 1.80 (s, 3 H), 1.72–1.67 (m, 9 H) ppm. 13C NMR (CDCl
,
3
1
1
3
00 MHz, 25 °C): δ = 161.7, 160.4, 156.2, 153.7, 142.6, 137.0,
36.8, 134.8, 126.3, 121.4, 114.5, 113.6, 113.3, 108.7, 104.9 (ϫ2),
9.2, 28.1, 27.0, 25.7 (ϫ2), 24.4, 22.0, 21.8, 20.1, 16.1 ppm. IR
6
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Job/Unit: O31102
/KAP1
Date: 24-09-13 17:57:25
Pages: 8
Total Synthesis of Cristatic Acid with Biomimetic Aromatization
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Received: July 24, 2013
Published Online: ᭿
[
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O31102
/KAP1
Date: 24-09-13 17:57:25
Pages: 8
N. S. George, K. E. Anderson, A. G. M. Barrett
FULL PAPER
Natural Product Synthesis
N. S. George, K. E. Anderson,
A. G. M. Barrett* ............................. 1–8
Total Synthesis of Cristatic Acid Based on
Late-Stage Decarboxylative Allylic Mi-
gration and Biomimetic Aromatization of
a Diketo Dioxinone
Keywords: Natural products / Total syn-
thesis / Medicinal chemistry / Biomimetic
synthesis / Terpenoids
The terpenoid resorcylate methyl cristate
was synthesized by use of a regioselective
Claisen condensation reaction to give a di-
oxinone diketo ester that subsequently
underwent Pd -catalyzed allylic migration
and biomimetic aromatization.
0
8
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