Total synthesis of cryptoacetalide

Article abstract of DOI:10.1021/jo100867v

(Figure presented) We are reporting the first total synthesis of the tetracyclic terpene natural product cryptoacetalide. Key steps of the synthesis are a microwave-mediated [2+2+2] cyclo-trimerization reaction to construct the central benzene ring, and a light-mediated radical cyclization to assemble the spiro-ketal moiety.

Full text of DOI:10.1021/jo100867v

pubs.acs.org/joc
Ni,10-12 Ru,13 Pd,14,15 Rh,16-20 Co/Zn,21,22 and Ni/Zr23,24
)
Total Synthesis of Cryptoacetalide
and the application of microwave irradiation25-30 to facili-
tate these reactions, only a surprisingly small number of
natural products have been assembled with benzene-forming
[2þ2þ2] cyclotrimerization reactions.27,28,31-41 Here, we are
reporting the synthesis of the tetracyclic terpene cryptoacet-
alide (1) via a cyclotrimerization key step.
Yan Zou and Alexander Deiters*
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695
alex_deiters@ncsu.edu
Received May 3, 2010
The diterpenoids cryptoacetalide (1) and epicryptoacet-
alide (epi-1) were isolated in 1990 from Dan-shen, the dried
root of Salvia miltiorrhiza (Lamiaceae),42 which is commonly
used as a Chinese medicine for the treatment of a wide range
of human diseases.43 Cryptoacetalide and epi-cryptoacetalide
were isolated as an inseparable mixture (1/epi-1=3:1), together
with danshenspiroketallactone (2), and its epimer.42 They
both contain a lactone group, a benzene ring, and also a spiro-
acetal moiety (Figure 1). To date, no synthesis of cryptoacet-
alide and epicryptoacetalide has been reported.
Our strategy is shown in Scheme 1. We envisioned the D
ring of cryptoacetalide 1 to be formed from 3 through a light-
mediated spiro-ketalization. The A, B, and C rings of 1 could
be assembled simultaneously by an intramolecular [2þ2þ2]
cyclotrimerization reaction of the triyne 4 to the benzene 3.
The tryine 4 would be synthesized by a coupling of the acid 5
to the corresponding secondary alcohol. The X and Y sub-
stituents represent the geminal dimethyl group, or a suitable
precursor functionality, e.g. a protected hydroxyl group
(X = H, Y = OTBS) that can be oxidized to a ketone, which
in turn could be converted to the geminal dimethyl group by
a Reetz reaction.44
We are reporting the first total synthesis of the tetracyclic
terpene natural product cryptoacetalide. Key steps of
the synthesis are a microwave-mediated [2þ2þ2] cyclo-
trimerization reaction to construct the central benzene
ring, and a light-mediated radical cyclization to assemble
the spiro-ketal moiety.
Cyclotrimerization reactions are versatile reactions for the
assembly of highly substituted benzene and pyridine rings.1-6
Despite their versatility and several recent advances in the
design of new cyclotrimerization catalysts (such as Co,7-9
First, we investigated the intramolecular cyclotrimeriza-
tion reaction of different model triynes (Table 1). We first used
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DOI: 10.1021/jo100867v
r
Published on Web 06/25/2010
J. Org. Chem. 2010, 75, 5355–5358 5355
2010 American Chemical Society

Zou and Deiters
JOCNote
Our synthesis of the acid 19 commenced with the TBDMS
protection of the known 6-chlorohex-2-yn-1-ol (14),46 fol-
lowed by a Finkelstein47 reaction with NaI to provide the
iodide 15 in excellent yield. The installation of the geminal
dimethyl group was accomplished by deprotonation of iso-
butyronitrile with LDA followed by a nucleophilic substitu-
tion with 15, delivering the nitrile 16 in 86% yield.48
Reduction of the nitrile 16 with DIBAL-H49 at -78 °C
afforded the aldehyde 17 in 93% yield. The second triple
bond was then installed via a Corey-Fuchs reaction50
directly followed by a deprotection, providing the diyne 18.
A Jones oxidation51 of the alcohol 18 then delivered the acid
19 in 97% yield (Scheme 2).
To assemble the triyne [2þ2þ2] cyclotrimerization pre-
cursor, the secondary alcohol 21 was generated as a 1:1 dia-
stereomeric mixture in 90% yield by the addition of ethynyl-
magnesium bromide into the known, enantiomerically pure
aldehyde 20 (synthesized in five steps from methyl (S)-3-
hydroxy-2-methylpropionate).52 The coupling reaction be-
tween the acid 19 and the alcohol 21 in the presence of DCC
and DMAP provided the cyclotrimerization precursor 22
in 79% yield. On the basis of the model studies shown in
Table 1, the [2þ2þ2] cyclotrimerization reaction was con-
ducted with Cp*RuCl(COD) in toluene under microwave
irradiation (300 W) affording the tricyclic product 23 in 90%
yield. Deprotection of the PMB ether with DDQ generated
the corresponding alcohol 24, which set the stage for the
spiroketalization reaction.53 The lacton 24 was irradiated
with light (200 W Xe/Hg lamp) in the presence of iodine and
iodobenzene diacetate for 1 h. The natural products crypto-
acetalide (1) and epi-cryptoacetalide (epi-1) were isolated as
a 2:1 mixture in an excellent yield of 84% (Scheme 3). As
previously reported, 1 and epi-1 could not be separated by
column chromatography, HPLC, or GC. The NMR spectrum
of the mixture matches the NMR spectrum of the material
isolated from nature.42
In summary, the first synthesis of the terpene natural
product cryptoacetalide was accomplished in 12 steps in an
overall yield of 26% from known, easily accessible starting
materials. Key steps of the developed synthetic approach
are a microwave-mediated intramolecular [2þ2þ2] cyclo-
trimerization reaction and a light-mediated spiro-ketaliza-
tion. Moreover, the intramolecular cyclotrimerization reactions
of different triynes were investigated under various conditions
with different catalyst systems in the absence and presence of
microwave irradiation.
FIGURE 1. Structures of cryptoacetalide (1), epi-cryptoacetalide,
danshenspiroketallactone (2), and epi-danshengspiroketallactone.
SCHEME 1. Retrosynthetic Analysis of 1a
aX, Y represent the geminal dimethyl substituents (X, Y=CH3), or a
suitable precursor (e.g., X=H and Y=OTBS).
the triyne ether 6 as a model system, since it is the simplest
triyne based on our retrosynthetic analysis. The triyne 6
underwent a smooth cyclotrimerization reaction to 10 in the
presence of 10 mol % of Cp*RuCl(COD) and microwave
irradiation in 88% yield (entry 1). A literature reported
cyclotrimerization of the same compound furnished 10 in
the absence of any catalyst in 80% yield, using microwave
irradiation (Biotage AG Emrys microwave synthesizer) in
DMF at 200 °C for 1 h.25 However, we were not able to
reproduce this result using 6 under identical reaction condi-
tions (except we used a CEM Discover microwave syn-
thesizer). A model triyne 7, more similar to the compound
4 due to its ester linkage, underwent an efficient cyclotrimeri-
zation reaction to 11 using the same catalyst (Cp*RuCl-
(COD), 10 mol %) and microwave irradiation (entry 3).
Good yields were also obtained by employing (Ph3P)2Ni(CO)2
(10 mol %) at room temperature (entry 4). We then increased
the complexity of the triyne to investigate the effects of addi-
tionalsubstituents. The triyne 8 was transformed smoothly in
a microwave-assisted [2þ2þ2] cyclotrimerization reaction
under Ru or Ni catalysis in 78-81% yield (entry 6 and 7).
The TBS protected propargyloxy triyne 9 underwent cyclo-
trimerization under microwave irradiation with Cp*RuCl-
(COD) in 84% yield (entry 8). To our surprise, the triyne 9
underwent a cyclotrimerization reaction even in the absence
of any catalysts (in contrast to 6 and 7) with only microwave
irradiation (DMF, 200 °C, 1 h), yielding 13 in 81% yield
(entry 9).
Experimental Section
(5R)-6-(4-Methoxybenzyloxy)-5-methylhex-1-yn-3-yl 7,7-Di-
methylnona-2,8-diynoate (22). At 0 °C, the solution of the acid
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139, 241.
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M. A. E. J. Org. Chem. 2003, 68, 6153.
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131, 24.
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R. C. Org. Lett. 2009, 11, 2591.
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3441.
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49, 189.
5356 J. Org. Chem. Vol. 75, No. 15, 2010

Zou and Deiters
JOCNote
TABLE 1. Cyclotrimerization Reactions of Model Substrates 6-9
yield,
%
entry
compd
X
R1
R2
catalyst R1
product
1
2
3
4
5
6
7
8
9
6
6
7
7
7
8
8
9
9
H2
H2
O
O
O
O
O
O
O
H
H
H
H
H
H
H
OTBS
OTBS
H
H
H
H
H
Cp*RuCl (COD)a
none b
10
10
11
11
11
12
12
13
13
88
-
c
Cp*RuCl (COD)a
(Ph3P)2Ni(CO)2
83
70
-
81
78
84
81
d
none b
C3H6OTBS
C3H6OTBS
C3H6OTrt
C3H6OTrt
Cp*RuCl (COD)a
(Ph3P)2Ni(CO)2
a
Cp*RuCl (COD)a
none b
aConditions: toluene, catalyst, MW 300 W, 130 °C, 20 min. bConditions: DMF, MW 200 W, 200 °C, 1 h. cConditions: ref 25 reported an 80% yield.
dConditions: THF, rt, 17 h; see ref 45.
SCHEME 2. Synthesis of the Diyne 19
SCHEME 3. Synthesis of the Alcohol 21, the Cyclotrimerization
Precursor 22, and Completion of the Total Synthesis of 1
19 (19.1 mg, 0.107 mmol) in the DCM (0.7 mL) was added drop-
wise to the solution of the alcohol 21 (22.1 mg, 0.0891 mmol) and
DMAP (6.5 mg, 0.053 mmol) in DCM (0.7 mL). The solution
was stirred at 0 °C for 10 min and a solution of DCC (23.9 mg,
0.116 mmol) in DCM (0.7 mL) was added dropwise at 0 °C and
the resulting mixture was stirred at rt overnight. The mixture
was cooled to 0 °C and additional DCC (23.9 mg, 0.116 mmol) in
DCM (0.7 mL) was added and the resulting mixture was stirred
overnight. The mixture was concentrated and the crude was
purified by column chromatography on SiO2 (eluted with
hexanes/ethyl acetate=50:1, 25:1, 10:1, and 5:1), delivering
3-((R)-3-(4-Methoxybenzyloxy)-2-methylpropyl)-6,7,8,9-tetra-
hydro-6,6-dimethylnaphtho[2,1-c]furan-1(3H)-one (23). To a flame-
dried microwave vial was added the triyne 22 (10.0 mg, 0.025
mmol) and toluene (1 mL) under argon. Cp*RuCl(COD) (0.9 mg,
0.0025 mmol) was added and the vial was sealed and heated in a
CEM Discover microwave synthesizer (power mode, 300 W, 130°C
final temperature) for 20 min. An additional 0.1 equiv (0.9 mg) of
Cp*RuCl(COD) was added and the reaction was continued for
30 min. The solid was filtered off and solvent was removed in vacuo.
The product was purified by column chromatography on SiO2
(eluted with hexanes/ethyl acetate =10:1), delivering the product
23 (9.0 mg, 90% yield) as a colorless liquid. 1H NMR (400 MHz,
CDCl3) δ 7.61 (d, J=7.6 Hz, 1H), 7.28-7.25 (m, 2H), 7.19-7.16
(m, 1H), 6.90-6.87 (m, 2H), 5.45-5.40 (m, 1H), 4.48 (s, 1H), 4.43
(s, 1H), 3.81 (s, 3H), 3.52-3.48 (m, 0.5H), 3.41-3.34 (m, 0.5H),
3.37-3.34 (m, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.25-2.21 (m, 1H),
1
28.7 mg (79% yield) of triyne 22 as colorless liquid. H NMR
(400 MHz, CDCl3) δ 7.25-7.20 (m, 2H), 6.85 (d, J = 8.4 Hz,
2H), 5.52-5.44 (m, 1H), 4.41 (s, 2H), 3.79 (s, 3H), 3.28 (d, J =
7.8 Hz, 2H), 2.47 (t, J=0.8 Hz, 1H), 2.35 (t, J=7.2 Hz, 2H), 2.07
(s, 1H), 2.01-1.96 (m, 2H), 1.78-1.65 (m, 3H), 1.55-1.45 (m,
2H), 1.20 (s, 6H), 0.96 (d, J=6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.3, 152.9, 130.77, 130.74, 129.4, 114.0, 91.4, 90.50,
90.48, 81.0, 80.6, 75.1, 74.9, 74.6, 74.4, 73.1, 72.92, 72.86, 68.5,
64.3, 63.9, 55.5, 42.4, 39.0, 38.6, 31.0, 30.4, 30.2, 29.3, 23.8, 19.3,
17.3, 17.2; HRMS calcd for [M þ Na]þ C26H32NaO4 431.2198,
found 431.2195.
J. Org. Chem. Vol. 75, No. 15, 2010 5357

Zou and Deiters
JOCNote
1.86-1.84 (m, 0.5H), 1.86-1.78 (m, 3H), 1.72-1.69 (m, 2H), 1.52-
1.47 (m, 0.5H), 1.32 (s, 6H), 1.10 (d, J=6.0 Hz, 1.5H), 1.05 (d, J=
6.0 Hz, 1.5H); 13C NMR (100 MHz, CDCl3) δ 171.2, 159.4, 159.3,
149.08, 149.06, 147.3, 138.1, 132.8, 130.8, 129.43, 129.37, 123.0,
122.9, 119.03, 118.98, 114.02, 113.96, 79.1, 78.3, 75.5, 74.8, 73.0,
72.8, 55.5, 40.0, 39.7, 38.7, 34.2, 32.1, 32.0, 31.0, 30.6, 29.9,
26.1, 18.8, 18.3, 17.0; HRMS calcd for [M þ Na]þ C26H32NaO4
431.2198, found 431.2198.
Xe/Hg lamp (Newport) for 1 h. After cooling to rt, 10 mL of
ether was added and the mixture was washed with H2O (2 mL)
and brine (2 mL), dried over anhydrous Na2SO4, and filtered
and the filtrate was concentrated in vacuo. The product was
purified by column chromatography on SiO2 (eluted with
hexanes/ethyl acetate=20:1, 10:1), delivering 5.2 mg (84% yield)
of the natural product 1 as a yellow solid. 1H NMR showed a 2:1
diastereomeric ratio of 1 to epi-1. HRMS calcd for [M þ H]þ
1
3-((R)-3-Hydroxy-2-methylpropyl)-6,7,8,9-tetrahydro-6,6-di-
methylnaphtho[2,1-c]furan-1(3H)-one (24). The PMB ether 23
(9.0 mg, 0.022 mmol) was dissolved in DCM (0.8 mL) and H2O
(0.03 mL), and the solution was cooled to 0 °C. DDQ (5.5 mg,
0.024 mmol) was added and the reaction mixture was stirred at rt
overnight. Saturated NH4Cl (1 mL) was added to quench the
reaction and the mixture was extracted with DCM (4 ꢀ 2 mL).
The combined organic layers were washed with brine (2 mL),
dried over anhydrous Na2SO4, and filtered and the filtrate was
concentrated in vacuo. The product was purified by column
chromatography on SiO2 (eluted with hexanes/ethyl acetate =
5:1 to 2:1), delivering the alcohol 24 (6.3 mg, 99% yield) as a
white solid. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J=8.0 Hz
and J=1.2 Hz, 1H), 7.16 (dd, J=8.0 Hz and J=3.6 Hz, 1H),
5.46-5.38 (m, 1H), 3.68-3.57 (m, 1H), 3.55-3.53 (m, 1H), 3.21
(t, J=6.0 Hz, 2H), 2.14-2.02 (m, 1.5H), 1.86-1.77 (m, 2.5H),
1.69-1.64 (m, 2H), 1.62-1.49 (m, 2H), 1.28 (s, 6H), 1.07 (d J=
6.8 Hz 1.5H), 1.02 (d J=6.8 Hz 1.5H); 147.49, 147.45 13C NMR
(100 MHz, CDCl3) δ 174.0, 148.94, 148.91, 138.2, 134.7, 132.95,
132.92, 122.8, 118.96, 118.88, 78.8, 78.5, 68.3, 67.5, 39.5, 39.3,
38.7, 34.2, 33.3, 33.1, 32.1, 32.0, 29.9, 26.1, 18.7, 17.7, 16.7;
HRMS calcd for [M þ Na]þ C18H24NaO3 311.1623, found
311.1626.
C18H23O3 287.1647, found 287.1647. Cryptoacetalide (1): H
NMR (300 MHz, CDCl3) 7.62 (d, J=8.1 Hz, 1H), 7.24 (d, J=
8.1 Hz, 1H), 4.37 (t, J=8.1 Hz, 1H), 3.71 (t, J=8.1 Hz, 1H), 3.18
(t, J=6.3 Hz, 2H), 2.88-2.80 (m, 1H), 2.42 (dd, J=6.8 Hz and
J = 13.3 Hz, 1H), 2.00-1.90. (m, 1H), 1.85-1.75 (m, 2H),
1.69-1.60 (m, 2H), 1.29 (s, 3H), 1.28 (s, 3H), 1.18 (d, J=6.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 149.2, 144.9, 138.0,
133.3, 124.4, 119.5, 113.2, 77.2, 45.7, 38.6, 34.3, 32.7, 32.0, 26.2,
18.7, 17.6. epi-Cryptoacetalide (epi-1): 1H NMR (300 MHz,
CDCl3) 7.62 (d, J=8.1 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 4.31 (t,
J=8.1 Hz, 1H), 3.81 (t, J=8.1 Hz, 1H), 3.18 (t, J=6.3 Hz, 2H),
2.70-2.60 (m, 1H), 2.58 (dd, J=9.4 Hz and J=13.3 Hz, 1H),
2.10 (dd, J=4.5 Hz and J=13.3 Hz, 1H), 2.05-2.01 (m, 1H),
1.85-1.75 (m, 2H), 1.69-1.60 (m, 2H), 1.29 (s, 3H), 1.28 (s, 3H),
1.24 (d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7,
149.1, 145.7, 137.8, 133.4, 124.0, 119.3, 113.1, 77.2, 44.7, 38.6,
34.3, 33.6, 29.9, 26.2, 18.4, 17.6.
Acknowledgment. Financial support by the National Science
Foundation is acknowledged (CAREER Award 0846756 to
A.D.).
Cryptoacetalide (1). The alcohol 24 (6.2 mg, 0.022 mmol) was
dissolved in dry benzene (1.5 mL). Iodobenzene diacetate (20.8 mg,
0.065 mmol) and iodine (10.9 mg, 0.043 mmol) were added
under nitrogen. The vial was sealed and irradiated with a 200 W
Supporting Information Available: 1H and 13C NMR spec-
tra of all new compounds, additional experimental procedures,
and analytical data. This material is available free of charge via
the Internet at http://pubs.acs.org.
5358 J. Org. Chem. Vol. 75, No. 15, 2010