Total synthesis of (+)-przewalskin B

Article abstract of DOI:10.1021/jo201111w

An efficient strategy for the total synthesis of (+)-przewalskin B is reported. The key steps feature an intermolecular S_N2′ substitution of iodoallylic phosphate with organocupper reagent, a diastereoselective organocatalytic aldol cyclization

Full text of DOI:10.1021/jo201111w

NOTE
pubs.acs.org/joc
Total Synthesis of (+)-Przewalskin B
Xiaotao Zhuo, Kai Xiang, Fu-Min Zhang,* and Yong-Qiang Tu*
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S Supporting Information
b
ABSTRACT:
An efficient strategy for the total synthesis of (+)-przewalskin B is reported. The key steps feature an intermolecular SN20
substitution of iodoallylic phosphate with organocupper reagent, a diastereoselective organocatalytic aldol cyclization, as well as a
Rh2(OAc)4-mediated intramolecular carbene insertion to the tertiary CꢀH bond.
rzewalskin B, which was isolated in 2007 by Zhao and co-
workers from a chinese medicinal plant Salvia przewalskii, is a
anti-SN20 reaction6 followed by a formylation from iodoallylic
phosphate 5 and the Grignard reagent 6.7
P
As depicted in Scheme 2, iodoallylic phosphate 58 was treated
with an organocuprate generated in situ from Grignard reagent 6
in the presence of CuCN to give the desired SN20 substitution
product 7 in 90% yield. Iodide 7 was lithiated using t-BuLi
at ꢀ78 °C and then reacted with DMF to install a formyl group
on the A-ring system, giving dioxolane 8.9 Treating 8 with formic
acid in THF at 50 °C for 10 h afforded dialdehyde 4 as the
precursor of intramolecular aldol reaction.10 Exposure of the
resulting dialdehyde 4 to aldol condensation conditions pro-
duced the B-ring closure product, which was quickly converted to
its MOM ether without purification, to avoid dehydration of the
β-hydroxyaldehyde. Initially, however, the expected diastereose-
lective aldol condensation of 4 under the promotion of
(n-BuO)4Ti/t-BuOK failed to give the sole product 10a but a
mixture of compound 10a and its diastereoisomer 10b in the
ratio of 1:2.11 The generation of 10b could be attributed to the
stabilization of the cyclic chelated intermediate 9b (Figure 1).
Therefore, a series of condition optimizations of this aldol
reaction were undertaken for avoiding the formation of 10b.
To our delight, using 0.1 equivalent of L-prolinamide in NMP
resulted in the formation of 10a as a sole product.12 Based on the
mechanism of the CoreyꢀBakshiꢀShibata reduction for pre-
paration of compound 513 and the relative configuration of
the tetracyclic compound 15, we propose the intermediacy of
transition state A, which also represents the lower energy
conformation than state B (Figure 1). In transition state A, the
Re face of the carbonyl of R,β-unsaturated aldehyde is much
more accessible to Re face of enamine and thus the anti product
10a was formed absolutely. While in state B the repulsion
novel diterpenoid and exhibits modest anti-HIV-1 activity
(EC50 = 30 μg/mL).1 It possesses an unprecedented tetracyclic
framework with two spiro rings, an R-hydroxy-γ-lactone moiety,
and an all-carbon quaternary center. Since it has a typical structure
and biologically important properties, przewalskin B as a challen-
ging synthetic target has attracted the interest of synthetic
chemists. Recently, She and co-workers determined the absolute
configuration of the natural product by the asymmetric synthesis
of (ꢀ)-przewalskin B via an intramolecular nucleophilic acyl
substitution (INAS) reaction.2 Herein we report the total synth-
esis of (+)-enantiomer of this natural product, with the purpose
of examining its biological activity and generating a new synthetic
route to the enantiomeric structure.
Among the methodologies for constructing the fused poly-
cyclic system, the Rhodium-catalyzed intramolecular carbene
insertion reactions have played a particularly important role.
This reaction usually tends to take a carbene insertion of tertiary
CꢀH bond and forms a five-membered ring containing a
quaternary center.3 By use of this procedure many challenging
syntheses of polycyclic natural products have been accomplished
perfectly,4 which greatly inspires us. In considering of our total
synthesis of 1, we recognized that the most challenging steps
would be the formation of the fused tricyclic system (B, C and D
rings), which contains an all-carbon quaternary stereogenic
center. So, as described in our retrosynthetic analysis (Scheme 1),
we postulated that C- and D-rings of this tricyclic core could be
constructed through a Rh2(OAc)4ꢀmediated intramolecular
CꢀH insertion reaction5 of 4-(Z)-β-vinyl-R-diazo-β-ketoester
2, followed by a lactonization. The aldehyde 3 would be used to
give 2 via carbon chain elongation, and its B-ring would be
formed via a diastereoselective aldol cyclization from dialdehyde
4. We planned to assemble the requisite dialdehyde 4 through an
Received: May 31, 2011
Published: July 13, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201111w J. Org. Chem. 2011, 76, 6918–6924
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Retrosynthetic Analysis for (+)-Przewalskin B
diastereoselective organocatalytic aldol condensation and an
intramolecular CꢀH insertion reaction. In particular, the key
Rh(II)-mediated intramolecular insertion of keto-carbene to
CꢀH allowed the highly efficient construction of C/D-rings,
the all-carbon quaternary center as well as three of the oxygenic
functional groups in the target molecule, which has corroborated
the use of carbenoid insertion as a convenient strategy in the
synthesis of natural products. Investigation of the biological
activities of (+)-przewalskin B is currently underway and will
be reported in due course.
’ EXPERIMENTAL SECTION
(R)-2-(3-(2-Iodo-6,6-dimethylcyclohex-2-en-1-yl)propyl)-
1,3-dioxolane (7). Magnesium turnings (510 mg, 21.3 mmol) were
placed into an argon-filled flask. A solution of 2-(3-bromopropyl)-1,3-
dioxolane (1.50 g, 7.7 mmol) in 1.5 mL of THF was added, and the
mixture was warmed in a 70 °C bath at which temperature the reaction
began with no need for further measure to initiate Grignard reagent
formation. The mixture was stirred at 25 °C for 20 min and then diluted
with additional THF (5 mL) and stirred for further 30 min. To a
suspension of CuCN (700 mg, 7.8 mmol) in THF (5 mL) at ꢀ40 °C was
added dropwise the freshly prepared Grignard reagent. The reaction
mixture was allowed to warm to 0 °C over 1 h. The solution was recooled
to ꢀ40 °C, and a solution of 5 (1.70 g, 4.4 mmol) in THF (5 mL) was
added dropwise. The resulting mixture stirred overnight and quenched
with saturated aqueous NH4Cl solution (10 mL). The mixture was
extracted with Et2O (3 ꢁ 50 mL). The combined organic layers were
washed with water (3 ꢁ 20 mL) and brine (30 mL) and dried over
Na2SO4. After solvent removal, the crude oil was purified by flash
chromatography (petroleum ether/ethyl acetate = 10/1) to give 7
(1.47 g) as a colorless liquid in 96% yield: Rf 0.6 (petroleum ether/ethyl
acetate = 4/1); [R]20D = +67 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 6.27 (t, J = 4.0 Hz, 1H), 4.87 (t, J = 4.8 Hz, 1H), 4.02ꢀ3.94
(m, 2H), 3.90ꢀ3.82 (m, 2H), 2.10ꢀ2.06 (m, 2H), 1.98 (brs, 1H),
1.72ꢀ1.62 (m, 2H), 1.60ꢀ1.42 (m, 5H), 1.26ꢀ1.20 (m, 1H), 0.99 (s,
3H), 0.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.2 (CH), 105.1
(C), 104.5 (CH), 64.8 (CH2), 56.3 (CH), 35.0 (C), 34.4 (CH2), 31.8
(CH2), 30.3 (CH2), 28.1 (CH3), 27.5 (CH3), 27.0 (CH2), 24.0 (CH2);
IR ν (cmꢀ1) 2950, 2872, 1632, 1467, 1409, 1364, 1138, 1042; HRMS
(ESI) calcd for C14H27INO2 [M + NH4]+ 368.1081, found 368.1077.
(R)-6-(3-(1,3-Dioxolan-2-yl)propyl)-5,5-dimethylcyclohex-
1-enecarbaldehyde (8). To a solution of vinyl iodide 7 (900 mg,
2.57 mmol) in 6 mL of dry THF was added 3.2 mL of t-BuLi (5.12 mmol,
1.6 M in pentane) at ꢀ78 °C under argon, and the mixture was stirred
at ꢀ78 °C for 10 min. Then 1.5 mL (8 equiv) of dry DMF was added in
one portion. The mixture was allowed to warm to room temperature
and stirred for 10 min, and then the THF solution was poured into a
vigorously stirred biphasic solution prepared from a 10% aqueous
solution of KH2PO4 (20 mL, 15 mmol) and methyl tert-butyl ether
(20 mL) cooled over ice. Organic layers were separated, and the
combine organic layers were washed with water (3 ꢁ 10 mL) and brine
(20 mL) and dried over Na2SO4. After solvent removal, the crude oil
was purified by flash chromatography (petroleum ether/ethyl acetate =
4/1) to give aldehyde 8 (533 mg) as a pale yellow oil in 82% yield: Rf
between pyrrolidine and cyclohexene moiety of the substrate 4
would led it unfavorable to form the syn product 10b.
Having demonstrated that highly diastereoselective construc-
tion of bicyclic intermediate 3 was indeed feasible, we turned our
attention to formation of C/D rings of the core skeleton.
Transformation of aldehyde 3 to alkyne 11 was best realized
by the Shioiri protocol using TMSCHN2 in combination with n-
BuLi.14 Terminal alkyne 11 was lithiated and then reacted with
DMF to give R,β-acteylenic aldehyde 12 in excellent yield as long
as a reverse quench into an aqueous KH2PO4 solution was
employed.15 The aldol-type condensation of alkynyl aldehyde 12
with ethyl diazoacetate was carried out using NaH as the base.
The newly formed β-alkynyl-β-hydroxy-R-diazo ester 13 was
subjected to MnO2 oxidation and then efficiently hydrogenated
in the presence of Lindlar catalyst to afford 4-(Z)-β-vinyl-R-
diazo-β-ketoester 2. The slow addition of 2 in CH2Cl2 to a
suspension of rhodium(II) acetate in CH2Cl2 resulted in the
formation of spiro-enone 14. Upon exposure of 14 to p-tolue-
nesulfonic acid, the tetracyclic ketolactone 15 was obtained as a
single stereoisomer.16 At this point, the AꢀD rings of 1 had been
successfully constructed. Single-crystal X-ray analysis of 1517
confirmed the relative stereochemistry as 5R,8S,9S (Scheme 3).
With the key tetracyclic intermediate 15 in hand, we next
tackled the installation of the isopropyl and hydroxy groups in
the cyclopentone ring to complete the total synthesis. Direct
alkylation of R-iodinated 15 with isopropylzinc in the presence of
a Pdꢀphosphine complex unfortunately gave an undesired
isomerized n-propyl product.18 An indirect approach was there-
fore adopted. As depicted in Scheme 4, iodination at the
R-position of the cyclopentenone moiety, followed by Negishi
coupling with isopropenylmagnesium bromide yielded the term-
inal alkene 16.19 Subsquently, 16 was carefully hydrogenated
at atmospheric pressure with PtO2 catalysis to give tetracyclic
β-ketone 17.20 Finally, the treatment of 17 with LDA and Davis0
oxaziridine21 gave (+)-przewalskin B (1) in 59% yield, which was
identical in all respects (1H, 13C NMR, and HRMS) with the
natural product, except for the opposite sign of its optical rotation
([R]20D = +16.7 (c = 0.48, CHCl3) [lit. [R]20D = ꢀ26 (c = 0.49,
CHCl3)]). Based on the X-ray determined configuration of
compound 15 (Scheme 3), Davis0 reagent preferred to attack
the convex face of the C/D-rings system and R-OH was
introduced. In fact, we were not able to isolate and detect the
C-11 epimer with β-OH. The total synthesis of the unnatural
enantiomer was thus achieved.
0.3 (petroleum ether/ethyl acetate =4/1); [R]20 = +164 (c = 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 6.70 (t, J = 3.6
Hz, 1H), 4.80 (t, J = 4.8 Hz, 1H), 3.95ꢀ3.89 (m, 2H), 3.86ꢀ3.80
(m, 2H), 2.41ꢀ2.23 (m, 3H), 1.70ꢀ1.52 (m, 5H), 1.42ꢀ1.31 (m, 2H),
1.20ꢀ1.10 (m, 1H), 1.00 (s, 3H), 0.78 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 194.4 (CH), 150.2 (CH), 145.7 (C), 104.5 (CH), 64.8
(CH2), 40.7 (CH), 34.5 (CH2), 32.4 (CH2), 31.7 (C), 30.4 (CH2),
28.0 (CH3), 26.7 (CH3), 24.6 (CH2), 23.6 (CH2); IR ν (cmꢀ1) 2952,
In summary, we have developed an asymmetric synthesis
of (+)-przewalskin B via a Cu(I)-mediated SN20 substitution, a
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NOTE
Scheme 2. Synthesis of Bicyclic Compound 3
2873, 1684, 1638, 1460, 1415, 1201, 1138, 1042; HRMS (ESI) calcd
for C15H28NO3 [M + NH4]+ 270.2064, found 270.2059.
(s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.9 (CH),
137.4 (C), 117.0 (CH), 95.5 (CH2), 77.4 (CH), 58.0 (CH), 56.1
(CH3), 46.8 (CH), 32.6 (CH2), 31.1 (C), 28.0 (CH2), 27.6 (CH3),
26.9 (CH3), 25.0 (CH2), 22.3 (CH2); IR ν (cmꢀ1) 2946, 2862, 1728,
1449, 1362, 1149, 1096, 1036; HRMS (ESI) calcd for C15H25O3
[M + NH4]+ 270.2064, found 270.2057.
(R)-5,5-Dimethyl-6-(4-oxobutyl)cyclohex-1-enecarbalde-
hyde (4). To a solution of dioxolane 8 (2.317 g, 9.19 mmol) in THF
(50 mL) was added at 50 °C a solution of formic acid in water (88%,
27 mL). After 10 h of stirring at 50 °C, the THF solution was cooled to
0 °C, and a saturated aqueous solution of Na2CO3 was added until a
basic pH was reached. The aqueous layers were extracted with EtOAc
(2 ꢁ 150 mL), and the combined organic layers were washed with water
(3 ꢁ 20 mL) and brine (30 mL) and dried over Na2SO4. After solvent
removal, the crude oil was purified by flash chromatography (petroleum
ether/ethyl acetate = 5/1) to give dialdehyde 4 (1.347 g) as a pale
yellow oil in 70% yield: Rf 0.4 (petroleum ether/ethyl acetate = 4/1);
[R]20D = +147 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.71
(s, 1H), 9.43 (s, 1H), 6.72 (t, J = 3.6 Hz, 1H), 2.43ꢀ2.30 (m, 4H),
2.23ꢀ2.22 (m, 1H), 1.66ꢀ1.51 (m, 4H), 1.29ꢀ1.24 (m, 1H), 1.14ꢀ
1.08 (m, 1H), 0.99 (s, 3H), 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 202.7 (CH), 194.5 (CH), 150.7 (CH), 145.4 (C), 44.2 (CH2), 40.4
(CH), 31.9 (CH2), 31.7 (C), 30.3 (CH2), 28.0 (CH3), 26.6 (CH3), 24.6
(CH2), 21.7 (CH2); IR ν (cmꢀ1) 2954, 2872, 1724, 1682, 1638, 1458,
1387, 1201, 1138; HRMS (ESI) calcd for C13H21O2 [M + H]+ 209.1536,
found 209.1540.
(1R,2S,4aR)-1-(Methoxymethoxy)-5,5-dimethyl-1,2,3,4,
4a,5,6,7-octahydronaphthalene-2-carbaldehyde (3). To a so-
lution of dialdehyde 4 (769 mg, 3.70 mmol) in NMP (16 mL) was added
L-prolinamide (40 mg, 0.35 mmol) at room temperature. After 12 h of
stirring, the reaction was quenched with H2O (2 mL) and extracted with
Et2O (2 ꢁ 60 mL). The combined organic layers were washed with
water (3 ꢁ 20 mL) and brine (20 mL), dried over Na2SO4, and
concentrated. Residue (878 mg, 4.22 mmol) was dissolved in CH2Cl2
(30 mL) and cooled to 0 °C, N,N-diisopropylethylamine (3.9 mL,
22.4 mmol) and MOMCl (1.3 mL, 17.0 mmol) were added, and the
reaction solution was warmed to room temperature and stirred for an
additional 15 h. After that, saturated aqueous NH4Cl solution (5 mL)
was added to quench the reaction. Aqueous layers were back-extracted
with Et2O (2 ꢁ 50 mL), and the combined organic layers were washed
with water (3 ꢁ 10 mL) and brine (20 mL) and dried over Na2SO4.
After solvent removal, the crude oil was purified by flash chromatography
(petroleum ether/ethyl acetate = 25/1) to give MOM ether 3 (593 mg)
as a colorless oil in 64% yield (two steps): Rf 0.5 (petroleum ether/ethyl
acetate = 4/1); [R]20D = +365 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 9.72 (d, J = 4.0 Hz, 1H), 5.63 (brs, 1H), 4.71 (d, J = 6.8 Hz,
1H), 4.58 (d, J = 7.2 Hz, 1H), 4.20 (dd, J1 = 10.4 Hz, J2 = 1.6 Hz, 1H),
3.35 (s, 3H), 2.38ꢀ2.30 (m, 1H), 2.04ꢀ2.03 (m, 2H), 1.92ꢀ1.85 (m, 2H),
1.57ꢀ1.46 (m, 2H), 1.41ꢀ1.37 (m, 1H), 1.22ꢀ1.10 (m, 2H), 0.91
(1R,2R,4aR)-2-Ethynyl-1-(methoxymethoxy)-5,5-dimethyl-
1,2,3,4,4a,5,6,7-octahydronaphthalene (11). To a ꢀ78 °C so-
lution of trimethylsilyldiazomethane (2 M in hexane, 4.6 mL, 9.2 mmol)
in THF (20 mL) was added n-BuLi (1.6 M in hexane, 4.5 mL, 7.2 mmol).
After 30 min, a solution of aldehyde 3 (1186 mg, 4.7 mmol) in THF
(5 mL) was added, and the mixture was allowed to stir for 30 min at
ꢀ78 °C then for 15 min between ꢀ10 and 0 °C. Saturated aqueous
NH4Cl solution (2 mL) was added. The organic layers were separated,
and the aqueous layers were extracted with Et2O (2 ꢁ 60 mL). The
combined organic layers were washed, dried (Na2SO4), filtered, and
concentrated in vacuo. Purification of residue by flash chromatography
(petroleum ether/ethyl acetate = 200/1) gave terminal alkyne 11 (938
mg) as a brown yellow oil in 80% yield: Rf 0.6 (petroleum ether/ethyl
acetate =8/1); [R]20D = +292 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.65 (brs, 1H), 4.77 (d, J = 6.8 Hz, 1H), 4.75 (d, J = 6.8 Hz,
1H), 3.87 (d, J = 10.4 Hz, 1H), 3.50 (s, 3H), 2.34ꢀ2.26 (m, 1H),
2.15ꢀ2.06 (m, 2H), 2.02ꢀ2.00 (m, 2H), 1.80ꢀ1.74 (m, 1H),
1.65ꢀ1.54 (m, 1H), 1.50ꢀ1.47 (m, 1H), 1.42ꢀ1.34 (m, 1H),
1.19ꢀ1.14 (m, 1H), 1.10ꢀ1.00 (m, 1H), 0.89 (s, 3H), 0.86 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 138.2 (C), 116.5 (CH), 95.5 (CH2),
86.6 (C), 80.0 (CH), 69.2 (CH), 56.0 (CH3), 47.0 (CH), 38.8 (CH),
32.4 (CH2), 31.8 (CH2), 31.0 (C), 28.5 (CH2), 27.5 (CH3), 27.1
(CH3), 22.3 (CH2); IR ν (cmꢀ1) 3308, 2943, 2865, 1448, 1363, 1149,
1100, 1034; HRMS (ESI) calcd for C16H25O2 [M + Na]+ 271.1669,
found 271.1675.
3-((1R,2R,4aR)-1-(Methoxymethoxy)-5,5-dimethyl-1,2,3,
4,4a,5,6,7-octahydronaphthalen-2-yl)propiolaldehyde (12).
The alkyne 11 (938 mg, 3.78 mmol) was dissolved in THF (20 mL), and
the solution was cooled to ꢀ40 °C under argon. n-BuLi (1.6 M in
hexane, 2.7 mL, 4.32 mmol) was added dropwise. After completion of
the addition, anhydrous DMF (2.0 mL, 25.8 mmol) was added in one
portion. The reaction mixture was allowed to warm to room temperature
and stirred for 15 min. The THF solution was poured into a vigorously
stirred biphasic solution prepared from a 10% aqueous solution of
KH2PO4 (20 mL, 15 mmol) and methyl tert-butyl ether (20 mL) cooled
over ice. Organic layers were separated, and the aqueous layers were
extracted with Et2O (2 ꢁ 30 mL). The combined organic layers were
washed with water (3 ꢁ 10 mL) and brine (10 mL) and dried over
Na2SO4. After solvent removal, the crude oil was purified by flash
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The Journal of Organic Chemistry
NOTE
Figure 1. Proposed process of aldol reaction.
Scheme 3. Synthesis of Tetracyclic Compound 15
chromatography (petroleum ether/ethyl acetate = 50/1) to give acet-
ylenic aldehyde 12 (860 mg) as a brown yellow oil in 82% yield: Rf 0.3
(petroleum ether/ethyl acetate =8/1); [R]20D = +353 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 5.66 (brs, 1H), 4.73 (d, J =
6.8 Hz, 1H), 4.69 (d, J = 6.8 Hz, 1H), 3.93 (d, J = 10.0 Hz, 1H), 3.49 (s,
3H), 2.55ꢀ2.48 (m, 1H), 2.18ꢀ2.14 (m, 1H), 2.05ꢀ2.03 (m, 2H),
1.84ꢀ1.80 (m, 1H), 1.70ꢀ1.59 (m, 1H), 1.50ꢀ1.47 (m, 1H),
1.42ꢀ1.34 (m, 1H), 1.19ꢀ1.13 (m, 1H), 1.10ꢀ1.03 (m, 1H), 0.89 (s,
3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.0 (CH), 137.5
(C), 117.3 (CH), 100.4 (C), 95.3 (CH2), 82.1 (C), 79.1 (CH), 56.1
(CH3), 46.8 (CH), 39.3 (CH), 32.3 (CH2), 31.0 (C), 30.7 (CH2), 28.4
(CH2), 27.4 (CH3), 27.0 (CH3), 22.2 (CH2); IR ν (cmꢀ1) 2949, 2865,
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The Journal of Organic Chemistry
NOTE
Scheme 4. Total Synthesis of (+)-Przewalskin B
ether/ethyl acetate = 4/1); [R]20D = +160 (c = 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.06 (dd, J1 = 11.6 Hz, J2 = 0.8 Hz, 1H), 6.20 (dd,
J1 = 11.6 Hz, J2 = 9.6 Hz, 1H), 5.56 (brs, 1H), 4.66 (d, J = 6.8 Hz, 1H),
4.54 (d, J = 6.8 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.78 (d, J = 10.0 Hz,
1H), 3.38 (s, 3H), 2.05ꢀ1.93 (m, 3H), 1.81ꢀ1.77 (m, 1H), 1.51ꢀ1.38
(m, 2H), 1.32 (t, J = 6.8 Hz, 3H), 1.30ꢀ1.27 (m, 3H), 1.18ꢀ1.11 (m,
1H), 0.89 (s, 3H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.3
(C), 161.2 (C), 152.7 (CH), 138.2 (C), 123.4 (CH), 116.0 (CH), 95.2
(CH2), 82.1 (CH), 77.2 (C), 61.3 (CH2), 55.9 (CH3), 47.3 (CH), 46.7
(CH), 32.7 (CH2), 31.1 (C), 30.4 (CH2), 28.6 (CH2), 27.6 (CH3), 27.0
(CH3), 22.3 (CH2), 14.3 (CH3); IR ν (cmꢀ1) 2928, 2851, 2132, 1717,
1646, 1305, 1227, 1097, 1035; HRMS (ESI) calcd for C21H31N2O5
[M + H]+ 391.2227, found 391.2232.
(1R,10S,4a0R)-Ethyl 10-(Methoxymethoxy)-50,50-dimethyl-
4-oxo-30,40,4a0,50,60,70-hexahydro-10H-spiro[cyclopent[2]ene-
1,20-naphthalene]-5-carboxylate (14). To a suspension of
Rh2(OAc)4 (8 mg, 0.018 mmol) in CH2Cl2 (40 mL) at room temperature
was added dropwise 2 (414 mg, 1.06 mmol) in CH2Cl2 (10 mL) over
15 min. After being stirred for another 3 h, the reaction mixture was
concentrated in vacuo. The residue was purified by chromatography
(petroleum ether/ethyl acetate = 20/1) to give the tricyclic material
14 (343 mg) as a colorless oil in 89% yield: Rf 0.2 (petroleum ether/ethyl
acetate =4/1); [R]20D = +97 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.34 (d, J = 5.6 Hz, 1H), 6.17 (d, J = 5.6 Hz, 1H), 5.71 (brs,
1H), 4.59 (d, J = 6.8 Hz, 1H), 4.41 (d, J = 6.8 Hz, 1H), 4.22ꢀ4.04 (m,
2H), 3.97 (brs, 1H), 3.47 (s, 1H), 3.26 (s, 3H), 2.26ꢀ2.21 (m, 1H),
2.08ꢀ2.05 (m, 2H), 1.68ꢀ1.61 (m, 2H), 1.56ꢀ1.53 (m, 1H),
1.39ꢀ1.31 (m, 1H), 1.25(t, J = 7.2 Hz, 3H), 1.20ꢀ1.15 (m, 1H),
1.00ꢀ0.93 (m, 1H), 0.90 (s, 3H), 0.84 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 204.6 (C), 169.7 (C), 169.5 (CH), 135.8 (C), 132.1
(CH), 118.9 (CH), 94.9 (CH2), 79.9 (CH), 61.1 (CH2), 57.1 (C),
56.0 (CH3), 54.9 (CH), 47.0 (CH), 32.1 (CH2), 31.10 (CH2), 31.05
(C), 27.3 (CH3), 27.0 (CH3), 26.2 (CH2), 22.4 (CH2), 14.0 (CH3);
IR ν (cmꢀ1) 2952, 1737, 1707, 1449, 1315, 1224, 1142, 1036; HRMS (ESI)
calcd for C21H34NO5 [M + NH4]+ 380.2431, found 380.2429.
(5aR,7aR,11bS)-8,8-Dimethyl-6,7,7a,8,9,10-hexahydrocy-
clopenta[c]naphtho[1,2-b]furan-2,3(2aH,11bH)-dione (15).
Compound 14 (134 mg, 0.37 mmol) was dissolved in dry benzene
2201, 1667, 1449, 1386, 1148, 1038; HRMS (ESI) calcd for C17H25O3
[M + NH4]+ 294.2064, found 294.2066.
Ethyl 2-Diazo-3-hydroxy-5-((1R,2R,4aR)-1-(methoxymethoxy)-
5,5-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)-
pent-4-ynoate (13). To a suspension of NaH (190 mg, 80%,
6.33 mmol) in THF (10 mL) at 0 °C was added dropwise ethyl diazoacetate
(0.51 mL, 4.92 mmol) in THF (2 mL). The reaction mixture was
stirred for 15 min at 0 °C and then warmed to room temperature.
Stirring was continued for another 1 h. Acetylenic aldehyde 12
(860 mg, 3.12 mmol) in THF (3 mL) was then added dropwise to
this mixture. The reaction mixture was stirred for another 1 h at room
temperature. After that, the solution was cooled to 0 °C. H2O (2 mL)
was added slowly to quench the reaction. Organic layers were
separated, and the aqueous layers were back-extracted with EtOAc
(2 ꢁ 80 mL). The combined organic layers were washed, dried
(Na2SO4), filtered, and concentrated in vacuo. Purification of the
residue by flash chromatography (petroleum ether/ethyl acetate = 4/1)
gave 13 (1061 mg) (inseparable isomers) as a brown yellow oil in 87%
yield: Rf 0.2 (petroleum ether/ethyl acetate =4/1); [R]20 = +162
D
(c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.65 (brs, 1H), 5.53
(d, J = 4.4 Hz, 1H), 4.75ꢀ4.71 (m, 2H), 4.26 (q, J = 7.2 Hz, 2H),
3.85ꢀ3.81 (m, 1H), 3.48 (s, 1.3H), 3.47 (s, 1.4H), 2.84 (brs, 1H),
2.39ꢀ2.31 (m, 1H), 2.12ꢀ2.01 (m, 3H), 1.80ꢀ1.75 (m, 1H),
1.62ꢀ1.53 (m, 1H), 1.49ꢀ1.41 (m, 1H), 1.38ꢀ1.34 (m, 1H), 1.30
(t, J2 = 7.2 Hz, 3H), 1.20ꢀ1.14 (m, 1H), 1.10ꢀ1.00 (m, 1H), 0.89
(s, 3H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3 (C), 138.1
(C), 116.8 (CH), 95.7 (CH2), 90.6 (C), 90.5 (C), 80.31 (CH), 80.28
(CH), 77.2 (C), 61.2 (CH2), 58.5 (CH), 56.0 (CH3), 47.0 (CH), 38.9
(CH), 32.5 (CH2), 31.9 (CH2), 31.8 (CH2), 31.1 (C), 28.4 (CH2), 27.5
(CH3), 27.0 (CH3), 22.3 (CH2), 14.5 (CH3); IR ν (cmꢀ1) 3416, 2943,
2866, 2101, 1696, 1372, 1290, 1106, 1035; HRMS (ESI) calcd for
C21H34N3O5 [M + NH4]+ 408.2493, found 408.2486.
(40 mL), and the solution was warmed to 40 °C. p-TsOH H2O (30 mg,
3
0.16 mmol) was added every 12 h, two times daily for 3 days. After that,
the reaction mixture was quenched with saturated aqueous solution of
NaHCO3 (3 mL). The solvent was removed in vacuo. The resulting
mixture was extracted with EtOAc (2 ꢁ 50 mL), and the combined
organic layers were washed, dried (Na2SO4), filtered, and concentrated
in vacuo. Purification of residue by flash chromatography (petroleum
ether/ethyl acetate = 10/1) provided 15 (57 mg) as a white solid in
56% yield: Rf 0.3 (petroleum ether/ethyl acetate = 2/1); [R]20D = ꢀ10
(c = 1.0, CHCl3); mp 189ꢀ192 °C; 1H NMR (400 MHz, CDCl3) δ 7.62
(d, J = 5.6 Hz, 1H), 6.18 (d, J = 5.6 Hz, 1H), 5.87 (brs, 1H), 4.83 (d, J =
1.6 Hz, 1H), 3.13 (s, 1H), 2.07ꢀ2.06 (m, 2H), 1.94ꢀ1.89 (m, 1H),
1.86ꢀ1.75 (m, 2H), 1.66ꢀ1.62 (m, 1H), 1.42ꢀ1.35 (m, 1H),
1.32ꢀ1.22 (m, 2H), 0.96 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 198.0 (C), 169.9 (C), 167.5 (CH), 135.1 (C), 132.0 (CH),
122.5 (CH), 80.9 (CH), 56.2 (CH), 55.5 (C), 44.7 (CH), 32.9 (CH2),
31.4 (CH2), 31.3 (C), 27.8 (CH3), 25.3 (CH3), 25.0 (CH2), 22.4
(CH2); IR ν (cmꢀ1) 3406, 2919, 2858, 1770, 1709, 1451, 1156, 1110,
1014; HRMS (ESI) calcd for C17H24NO3 [M + NH4]+ 290.1762, found
290.1758.
(Z)-Ethyl 2-Diazo-5-((1R,2R,4aR)-1-(methoxymethoxy)-
5,5-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)-3-
oxopent-4-enoate (2). Activated MnO2 (1500 mg, 17.2 mmol) was
added in two portions over 5 h to a solution of 13 (664 mg, 1.70 mmol)
in CH2Cl2 (15 mL). After the mixture was stirred for 12 h at room
temperature, the manganese dioxide was removed by filtration. The
filtrate was concentrated in vacuo, and the residue (477 mg, 1.23 mmol)
was dissolved in CH2Cl2 (10 mL). Lindlar catalyst (390 mg, 5 wt %,
0.18 mmol) was added, and the reaction mixture was stirred vigorously
for 1 h at room temperature under hydrogen gas balloon. The precipitate
was filtrated, and then the solvent was removed in vacuo. The residue
was purified by chromatography (petroleum ether/ethyl acetate = 50/1)
to give 2 (262 mg) as a yellow oil in 40% yield (2 steps): Rf 0.5 (petroleum
(5aR,7aR,11bS)-8,8-Dimethyl-4-(prop-1-en-2-yl)-6,7,7a,8,9,10-
hexahydrocyclopenta[c]naphtho[1,2-b]furan-2,3(2aH,11bH)-
dione (16). The tetracyclic material 15 (33 mg, 0.12 mmol) was
dissolved in a mixed solution of pyridineꢀCH2Cl2 (1: 10, 4 mL). To this
was added dropwise I2 (60 mg, 0.24 mmol) in a solution of pyridineꢀ
CH2Cl2 (1: 10, 1 mL). The mixture was stirred for 12 h at room
6922
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The Journal of Organic Chemistry
NOTE
temperature, quenched with 1 N HCl (1 mL), and extracted with EtOAc
(2 ꢁ 30 mL). The combined organic layers were washed with a saturated
aqueous solution of Na2S2O3 (5 mL), NaHCO3 (5 mL), and brine
(5 mL), dried, and concentrated. The resulting crude material was used
in the next step without further purification. A solution of flame-dried
ZnBr2 (66 mg, 0.29 mmol) in dry, degassed THF (0.5 mL) was cooled
to ꢀ78 °C. Isopropenylmagnesium bromide (0.5 M in THF, 0.44 mL,
0.22 mmol) was then added, and the reaction temperature was raised to
room temperature over 2 h. In a separate flask, a mixture of R-iodoenone
(46 mg, 0.12 mmol) freshly prepared and (tetrakis)triphenylphosphine
palladium (6.6 mg, 0.006 mmol) was dissolved in a 1:1 mixture of dry,
degassed DMF/THF (1 mL) and then added to the flask containing the
Grignard solution and ZnBr2 mixture. Upon completion, saturated
aqueous NH4Cl (2 mL) solution was added. The aqueous layers were
extracted with EtOAc (3 ꢁ 30 mL), and the combined organic layers
were washed, dried (Na2SO4), filtered, and concentrated in vacuo.
Purification of the residue by flash chromatography (petroleum ether/
ethyl acetate = 30/1) gave the desired 16 (23 mg) as a white solid in
60% yield (two steps): Rf 0.4 (petroleum ether/ethyl acetate =4/1);
[R]20D = +15 (c = 1.0, CHCl3); mp 209 ꢀ 212 °C; 1H NMR (400 MHz,
CDCl3) δ 7.30 (s, 1H), 6.14 (s, 1H), 5.86 (t, J = 2.0 Hz, 1H), 5.28 (s,
1H), 4.82 (d, J = 2.0 Hz, 1H), 3.21 (d, J = 0.4 Hz, 1H), 2.07ꢀ2.06 (m,
2H), 1.94 (s, 3H), 1.85ꢀ1.77 (m, 2H), 1.64ꢀ1.60 (m, 1H), 1.42ꢀ1.35
(m, 1H), 1.30ꢀ1.23 (m, 3H), 0.96 (s, 3H), 0.90 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 196.3 (C), 170.3 (C), 159.7 (CH), 140.8 (C), 135.3
(C), 133.0 (C), 122.2 (CH), 119.7 (CH2), 81.4 (CH), 57.6 (CH), 52.0
(C), 44.9 (CH), 32.7 (CH2), 31.7 (CH2), 31.3 (C), 27.7 (CH3), 25.6
(CH3), 25.2 (CH2), 22.4 (CH2), 21.7 (CH3); IR ν (cmꢀ1) 3427, 2919,
2855, 1773, 1708, 1634, 1449, 1154, 1106, 1011; HRMS (ESI) calcd for
C20H28NO3 [M + NH4]+ 330.2064, found 330.2060.
1H), 2.12ꢀ2.06 (m, 2H), 1.85ꢀ1.71 (m, 3H), 1.60ꢀ1.56 (m, 2H), 1.45ꢀ
1.41 (m, 1H), 1.27ꢀ1.23 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H), 1.10 (d, J =
6.6 Hz, 3H), 0.96 (s, 3H), 0.91 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
200.3 (C), 173.0 (C), 158.3 (CH), 149.0 (C), 135.8 (C), 121.2 (CH), 82.1
(CH,C), 54.2 (C), 45.0 (CH), 32.3 (CH2), 31.2 (C), 29.4 (CH2), 27.6
(CH3), 26.4 (CH3), 25.3 (CH), 25.2 (CH2), 22.4 (CH2), 20.6 (CH3), 20.5
(CH3);IRν(cmꢀ1) 3474, 2922, 2853, 1765, 1704, 1652, 1616, 1458, 1373,
1269, 1211, 1114; HRMS (ESI) calcd for C20H30NO4 [M + NH4]+
348.2169, found 348.2164.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra for all new compounds and X-ray crystallographic data of
compound 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Authors
*E-mail: (Y.-Q.T.) tuyq@lzu.edu.cn; (F.-M.Z.) zhangfm@lzu.
edu.cn.
’ ACKNOWLEDGMENT
We gratefully acknowledge financial support from the NSFC
(Nos. 20921120404, 21072085, 20732002, and 20972059), “973”
program of 2010CB833200, “111” program of MOE, and the
fundamental research funds for the central universities (lzujbky-
2010-k09, lzujbky-2009-76, lzujbky-2009-158).
(5aR,7aR,11bS)-4-Isopropyl-8,8-dimethyl-6,7,7a,8,9,10-
hexahydrocyclopenta[c]naphtho[1,2-b]furan-2,3(2aH,11bH)-
dione (17). Compound 16 (12 mg, 0.038 mmol) was dissolved in
methanol (4 mL), PtO2 (8 mg, 0.035 mmol) was added, and the mixture
was hydrogenated at atmospheric pressure at room temperature.
Hydrogenation was interrupted after uptake of 1 equiv of H2, and the
catalyst was filtered off. After solvent removal, the residue was chroma-
tographed on silica gel (petroleum ether/ethyl acetate = 50/1) to give 17
(6.0 mg) as a white solid in 50% yield: Rf 0.3 (CH2Cl2/hexane = 10/1);
[R]20D = +10 (c = 1.0, CHCl3); mp 172ꢀ175 °C; 1H NMR (600 MHz,
CDCl3) δ 7.12 (s, 1H), 5.86 (brs, 1H), 4.77 (s, 1H), 3.15 (s, 1H), 2.62
(dq, J1 = 19.8 Hz, J2 = 6.6 Hz, 1H), 2.07 (brs, 2H), 1.92ꢀ1.88 (m, 1H),
1.82ꢀ1.70 (m, 2H), 1.64ꢀ1.62 (m, 1H), 1.41ꢀ1.36 (m, 1H),
1.30ꢀ1.24 (m, 2H), 1.12 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.6 Hz,
3H), 0.96 (s, 3H), 0.89 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 197.8
(C), 170.4 (C), 158.2 (CH), 150.9 (C), 135.4 (C), 122.2 (CH), 81.4
(CH), 57.0 (CH), 52.7 (C), 44.8 (CH), 32.9 (CH2), 31.9 (CH2), 31.3
(C), 27.8 (CH3), 25.5 (CH3), 25.1 (CH2), 24.9 (CH), 22.4 (CH2), 21.0
(CH3), 20.8 (CH3); IR ν (cmꢀ1) 2920, 2853, 1770, 1708, 1453, 1383,
1155, 1107, 1014; HRMS (ESI) calcd for C20H30NO3 [M + NH4]+
332.2220, found 332.2216.
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5.81 (brs, 1H), 4.80 (s, 1H), 3.63 (s, 1H), 2.64 (dq, J1 = 19.8 Hz, J2 =6.6Hz,
6923
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NOTE
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