Key words
oxa-Michael addition - Brown asymmetric allylation - ring-closing metathesis - cross
metathesis
Natural products possessing α,β-unsaturated δ-lactone moieties have attracted considerable
attention because of their promising pharmacological properties, which include anticancer,[1]
[2] antimicrobial,[3] antifungal,[4] and insecticidal activity.[5] Cryptopyranmoscatones A1, A2, A3, B1, B2, and B4 (1–6; Figure [1]) were isolated by Cavalheiro and Yoshida[6] from the branch and stem bark of Cryptocarya moschata, Lauraceae in 2000, together with other representative structures. This tree grows up to 30–40 m
high, mainly in the Southeastern Region of Brazil. The structures of these compounds
were established by spectroscopic methods. Based on circular dichroism measurements,
the authors were able to set the absolute configuration at C6 as R. Structurally, these styryl lactones incorporate a dihydro-α-pyrone moiety as well
as a tetra-substituted tetrahydropyran ring. In preliminary biological studies, the
cryptomoscatone family of compounds showed G2 checkpoint inhibitory properties[7] and cytotoxicity against human cervical carcinoma cell lines.[8] Cryptocaryalactones belonging to this group are natural germination inhibitors,
although they have no effect on corn.[9] Extracts of Cryptocarya species have shown cyclooxygenase-1 and -2 inhibition.[10] At least some of these pharmacological effects may be related to the presence of
the conjugated double bond, which acts as a Michael acceptor. The biological activity
of the cryptopyranmoscatones has not been studied, presumably because of the limited
supply from natural sources. The fascinating structural architecture and scarcity
of these natural products have attracted our attention with the aim to develop a general
synthetic strategy to prepare them.
As part of our continued efforts towards the synthesis of biologically active natural
lactones,[11] we have already reported the first total synthesis of cryptopyranmoscatones A1,[12] A2,[13] and B1.[14] In the present communication, we herein report the first stereoselective total synthesis
of cryptopyranmoscatones A3 and B4 either from but-3-ynol or from d-ribose in a synthetic pathway via an intermediate from which both cryptopyranmoscatone
A3 and B4 could be obtained.
Figure 1 Structures of natural cryptopyranmoscatones
Our retrosynthetic strategy for cryptopyranmoscatone A3 and B4 is depicted in Scheme
[1]. We envisaged that both cryptopyranmoscatone A3 and B4 could be obtained from a
common intermediate 7 by adopting a stereoselective reduction, oxa-Michael addition reaction protocol.
The analysis reveals that target compound 3 could be synthesized from bis-olefin 8 by utilizing a ring closing metathesis reaction, while the bis-olefin itself could
be obtained from 9 by successive reactions involving oxidation and allylation followed by acrylation.
The 2,6-trans-tetrasubstituted tetrahydropyran ring in compound 9 could be constructed from a common intermediate 7. In turn, intermediate 7 could be obtained via lactone 15 through a phenylacetylene addition reaction of the aldehyde, produced from the corresponding
primary alcohol 13, which could be derived from d-ribose. Cryptopyranmoscatone B4 (6) could be prepared from compound 10 by performing a cross-metathesis reaction as the key step; whereas, the precursor,
2,6-trans-tetrahydropyran 11 could be obtained from intermediate 7.
Scheme 1 Retrosynthetic analysis for cryptopyranmoscatone A3 and B4
The synthesis of the key intermediate 7 started with the known alcohol 13 (Scheme [2]). Initially, we planned to prepare 13 from benzoate diol 12
[15] in a three-step sequence by protecting group manipulations involving TBS protection
followed by removal of the benzoyl and benzyl groups. The known benzoate diol 12 could be prepared in five steps by following reported procedures. However, bearing
in mind the number of steps involved and overall yield in obtaining alcohol 13, it was alternatively prepared from d-ribose in five steps in an overall yield of 70%.[16] After protecting the free hydroxy group in 13 as its pivaloyl ether 16, the TBS group was removed with tetrabutylammonium fluoride (TBAF) to yield the corresponding
alcohol 17. Oxidation of alcohol 17 with 2-iodoxybenzoic acid (IBX) gave an aldehyde that was subjected to Grignard addition
with phenyl acetylene to give propargyl alcohol 18 as a mixture of diastereomers in 88:12 ratio (determined by chiral HPLC).[17] This inseparable mixture was carried on to the preparation of ketone intermediate
keto 7. Thus, partial reduction of the triple bond in 18 with Red-Al furnished diol 19. Oxidative cyclization of 1,5-diol 19 with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and [bis(acetoxy)iodo]benzene (BAIB)[18] produced the desired δ-lactone 15 in 86% yield. Lactone 15 was reduced to the lactol using diisobutylaluminum hydride (DIBAL-H) and subjected
to Wittig olefination using the two carbon stabilized ylide to furnish α.β-unsaturated
ester 20 in 78% overall yield (Scheme [2]). IBX oxidation of 20 furnished the key intermediate 7, from which both target molecules cryptopyranmoscatone A3 and B4 could be synthesized
by adopting a chemoselective reduction of the keto group.
Scheme 2 Synthesis of key intermediate 7. Reagents and conditions: (a) PivCl, Et3N, CH2Cl2, 0 °C, 4 h, 90%; (b) TBAF, THF, 0 °C, 0.5 h, 90%; (c) (i) IBX, CH3CN, ∆, 1 h; (ii) EtMgBr, phenylacetylene, THF, r.t., 1 h, 80%; (d) Red-Al, THF/r.t.,
90%; (e) BAIB, TEMPO, CH2Cl2, r.t., 2 h, 86%; (f) (i) DIBAL-H, CH2Cl2, –78 °C; (ii) Ph3P=CHCO2Et, C6H6, reflux, 1 h, 85%; (g) IBX, CH3CN, ∆, 1 h, 90%.
Accordingly, the synthesis of A3 (3) commenced with stereoselective reduction of the keto group in 7 using NaBH4 in the presence of CeCl3·7H2O at –78 °C in MeOH to furnish the syn alcohol 21, the properties of which correlated with those reported.[19] The hydroxyester 21, on exposure to t-BuOK[20] in THF at –78 °C, readily underwent intramolecular oxa-Michael reaction to afford
2,6-trans tetrahydropyran 9 as a single diastereomer (>20:1) in 95% yield (Scheme [3]).
Scheme 3 Synthesis of cryptopyranmoscatone A3 (3). Reagents and conditions: (a) NaBH4,CeCl3·7H2O, MeOH, 1 h, 85%; (b) t-BuOK, THF, –78 °C, 0.5 h, 95%; (c) (i) DIBAL-H, CH2Cl2, –78 °C; (ii) (+)-IPC2B(allyl), ether, –100 °C, 1 h, 80%; (d) cinnamic acid, Et3N, N,N-dicyclohexylcarbodiimide (DCC), 4-(N,N-dimethylamino)pyridine (DMAP), CH2Cl2, 0 °C, 12 h, 85%; (e) Grubbs II catalyst, CH2Cl2, reflux, 6 h, 90%; (f) TiCl4, CH2Cl2, 0 °C, 15 min, 80%.
The trans-stereochemistry of the newly generated ring junction of tetrahydropyran 9 was assigned based on 1H NMR (600 MHz, CDCl3) data and assignments were made with the aid of TOCSY and NOESY experiments (see
SI, Figure 2). The medium NOE enhancement between C2H/C6H suggested that both protons
are anti to each other (trans related). This was further supported by the NOE correlations between C2H/Me-a, C4H/C6H,
C2H/C5H, and C3H/C4H.
After confirming the structure, the ester group in 9 was reduced with DIBAL-H and the resulting aldehyde was subjected to Brown’s asymmetric
allylation[21] using (+)-Ipc2B-allyl to furnish the homoallylic alcohol 22 in 80% overall yield over the two-step sequence. Subsequent coupling of alcohol 22 with cinnamic acid using DCC-DMAP provided diene 8 in 85% yield. Ring closing metathesis (RCM)[22] of diene 8 using the second-generation Grubbs’ catalyst in CH2Cl2 under refluxing conditions yielded lactone 23 exclusively. Finally, removal of the acetonide group using trifluoroacetic acid (TFA)
in CH2Cl2 at 0 °C to room temperature for 0.5 h furnished cryptopyranmoscatone A3 (3) in 80% yield. The spectroscopic and physical data of synthetic 3 are in agreement with those of the natural compound; thereby confirming its structure
and absolute stereochemistry.
Scheme 4 Synthesis of cryptopyranmoscatone B4 (6). Reagents and conditions: (a) DIBAL-H, CH2Cl2, –78 °C, 85%; (b) t-BuOK, THF, –78 °C, 0.5 h, 90%; (c) (i) DIBAL-H, CH2Cl2, –78 °C, 2 h; (ii) Ph3P=CH2, n-BuLi, THF, –78 °C, 60%; (d) Grubbs-II catalyst, CH2Cl2, reflux, 4 h, 90%; (e) TiCl4, CH2Cl2, 0 °C, 15 min, 80%.
We then focused on the synthesis of cryptopyranmoscatone B4 (6) from common intermediate 7, which, on DIBAL-H reduction,[23] produced anti-alcohol 24 following a reported precedent (Scheme [4]). The hydroxy ester 24, on exposure to t-BuOK in THF at –78 °C, readily underwent intramolecular oxa-Michael reaction[20] to afford 2,6-trans tetrahydropyran 11 as mainly a single diastereomer (>20:1) in 90% yield. The trans-stereochemistry of the newly generated ring-junction of tetrahydropyran 11 was assigned based on 1H NMR (600 MHz, CDCl3) analysis, with the aid of TOCSY and NOESY experiments. The moderate NOE between
C2H/C6H suggested that both protons are anti to each other (trans related). This was further supported by the NOE correlations between C2H/Me-a, C4H/C6H,
C2H/C5H, and C3H/C4H, confirming the structure.
After establishing the structure, the ester group in 11 was converted into a terminal alkene by reduction using DIBAL-H in CH2Cl2 followed by Wittig reaction to afford 10. Cross-metathesis[24] reaction of terminal alkene with the known vinyl lactone 25
[25] was carried out using Grubbs’ second generation catalyst in CH2Cl2 under refluxing conditions for 4 h to afford the desired lactone 26. Finally, removal of the acetonide was achieved by treatment with TFA in CH2Cl2 at 0 °C to room temperature for 0.5 h to give the cryptopyranmoscatone B4 (6) in 80% yield. The spectroscopic and physical data of synthetic 6 are in agreement with those of the natural compound, thereby confirming its structure
and absolute stereochemistry.
In conclusion, we have achieved the first total synthesis of cryptopyranmoscatones
A3 and B4. The key steps involved in the synthesis are oxa-Michael addition, asymmetric
allylation, and metathesis reactions.
All reactions were performed under inert atmosphere. All glassware used for performing
the reactions was oven- or flame-dried. Anhydrous solvents were distilled prior to
use: THF from Na and benzophenone; CH2Cl2 from CaH2; MeOH from Mg. Commercial reagents were used without purification. Column chromatography
was carried out using silica gel (60–120 mesh) unless otherwise mentioned. Analytical
thin-layer chromatography (TLC) was run on silica gel 60 F254 pre-coated plates (250 μm thickness). Specific rotations [α]D were measured with a polarimeter and given in 10–1 deg cm2 g−1. Infrared spectra were recorded in CHCl3 or as KBr discs (as mentioned) and reported in wavenumber (cm−1). High-resolution mass spectra (HRMS) [ESI+] were obtained by using either a TOF
or a double focusing spectrometer. 1H NMR spectra were recorded at 300, 400, 500 MHz and 13C NMR spectra were obtained at 75, 100, 125 MHz in CDCl3 solution unless otherwise mentioned. Chemical shifts are reported in ppm downfield
from tetramethylsilane and coupling constants (J) are reported in Hertz (Hz). The following abbreviations are used to designate signal
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br
= broad.
Ethyl (E)-4-((4R,5R)-5-Cinnamoyl-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (7)
Ethyl (E)-4-((4R,5R)-5-Cinnamoyl-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (7)
To an ice-cooled solution of 2-(iodooxy)benzoic acid (1.8 g, 6.5 mmol) in anhydrous
CH3CN (20 mL) was added a solution of alcohol 20 (1.5 g, 4.3 mmol). The mixture was heated to reflux for 1 h, and then allowed to
cool to r.t. The solvent was removed under reduced pressure and the compound was purified
by silica gel column chromatography (hexane/EtOAc, 8:2) to give 7.
Yield: 1.3 g (90%); liquid; [α]D
25 +9.5 (c = 0.26, CHCl3).
IR (neat): 3449, 2928, 2847, 1720, 1476, 1374, 1216, 1147, 1070, 771 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.7 (d, J = 16.0 Hz, 1 H), 7.62–7.58 (m, 2 H), 7.44–7.39 (m, 3 H), 7.25 (d, J = 7.8 Hz, 1 H), 6.92 (dt, J = 13.9, 6.9 Hz, 1 H), 5.86 (dt, J = 15.7, 1.4 Hz, 1 H), 4.71 (d, J = 7.5 Hz, 1 H), 4.58–4.53 (m, 1 H), 4.13 (q, J = 6.9 Hz, 2 H), 2.47–2.40 (m, 1 H), 2.30–2.21 (m, 1 H), 1.68 (s, 3 H), 1.43 (s, 3 H),
1.24 (t, J = 7.0, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 197.7, 166.1, 144.4, 143.9, 134.3, 131.6, 128.9, 128.7, 123.9, 121.1,
110.3, 81.9, 76.6, 60.2, 33.6, 27.2, 24.9, 14.1.
MS (ESI): m/z = 367 [M + Na]+.
Ethyl (E)-4-((4R,5S)-5-[(R,E)-1-Hydroxy-3-phenylallyl]-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (21)
Ethyl (E)-4-((4R,5S)-5-[(R,E)-1-Hydroxy-3-phenylallyl]-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (21)
To a solution of 7 (0.6 g, 1.7 mmol) in MeOH (15 mL), CeCl3·7H2O (0.85 g, 2.2 mmol) was added, and the mixture was cooled to 0 °C and stirred for
10 min at that temperature. The resultant suspension was then cooled to –78 °C and
stirred for 10 min, NaBH4 (0.2 g, 5.2 mmol) was added portionwise to the suspension and the mixture was stirred
at the same temperature for 0.5 h. After completion of the reaction (TLC) it was cautiously
quenched by the addition of water (3 mL). Excess MeOH was evaporated off and the resulting
residue was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column
chromatography (hexane/EtOAc, 7:3) to afford α,β-unsaturated ester 21.
Yield: 0.5 g (85%); pale-yellow liquid; [α]D
25 +39.5 (c = 0.23, CHCl3).
IR (neat): 3447, 2948, 2857, 1735, 1238, 1170, 1039, 770 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.39 (d, J = 7.2 Hz, 2 H), 7.32 (t, J = 6.9 Hz, 2 H), 7.26 (t, J = 3.3 Hz, 1 H), 6.97 (dt, J = 15.7, 6.9 Hz, 1 H), 6.70 (d, J = 15.8 Hz, 1 H), 6.19 (dd, J = 15.9, 6.9 Hz, 1 H), 5.92 (dt, J = 15.7, 1.5 Hz, 1 H), 4.34–4.27 (m, 2 H), 4.21–4.13 (m, 3 H), 2.72–2.62 (m, 1 H),
2.58–2.47 (m, 2 H), 1.54 (s, 3 H), 1.39 (s, 3 H), 1.28 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 166.2, 144.6, 136.2, 128.5, 128.0, 127.6, 126.6, 123.5, 108.5, 79.9,
75.6, 70.6, 60.2, 33.0, 27.6, 25.1, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd. for C20H26O5Na: 369.1677; found: 369.1678.
(R)-6-{[(2S,4R,5R,6R)-4,5-Dihydroxy-6-[(E)-styryl]tetrahydro-2H-pyran-2-yl]methyl}-5,6-dihydro-2H-pyran-2-one (3)
(R)-6-{[(2S,4R,5R,6R)-4,5-Dihydroxy-6-[(E)-styryl]tetrahydro-2H-pyran-2-yl]methyl}-5,6-dihydro-2H-pyran-2-one (3)
To a stirred solution of 23 (30 mg, 0.08 mmol) in anhydrous CH2Cl2 (5 mL), TiCl4 (0.01 mL, 0.08 mmol) was added at 0 °C and the reaction mixture was stirred at this
temperature for 1 h. The reaction was quenched with solid NaHCO3, and the mixture was filtered. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography (EtOAc/hexane, 50%) to
afford 3.
Yield: 21 mg (80%); colorless oil; [α]D
25 +5.2 (c = 0.1, CHCl3).
IR (neat): 3468, 2987, 2983, 1714, 1648, 1452, 1254, 1168, 769 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.437.23 (m, 5 H), 6.95–6.84 (m, 1 H), 6.68 (d, J = 16.0 Hz, 1 H), 6.23 (dd, J = 16.0, 6.9 Hz, 1 H), 6.09–5.99 (m, 1 H), 4.83–4.90 (m, 1 H), 4.0–4.15 (m, 1 H),
3.88–3.67 (m, 2 H), 3.66–3.52 (m, 1 H), 2.45–2.40 (m, 1 H), 2.34–2.28 (m, 1 H), 2.02–1.91
(m, 2 H), 1.87–1.79 (m, 1 H), 1.65–1.50 (m, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 164.4, 145.2, 136.6, 132.3, 128.6, 127.9, 126.5, 125.8, 121.4, 78.4,
76.4, 74.3, 71.0, 69.4, 41.3, 35.2, 29.9.
HRMS (ESI): m/z [M + Na]+ calcd. for C19H22O5Na: 353.1365; found: 353.1366.
Ethyl (E)-4-{(4R,5S)-5-[(S,E)-1-Hydroxy-3-phenylallyl]-2,2-dimethyl-1,3-dioxolan-4-yl}but-2-enoate (24)
Ethyl (E)-4-{(4R,5S)-5-[(S,E)-1-Hydroxy-3-phenylallyl]-2,2-dimethyl-1,3-dioxolan-4-yl}but-2-enoate (24)
A stirred solution of 7 (0.6 g, 1.7 mmol) in CH2Cl2 (10 mL) was cooled to –78 °C, then DIBAL-H (1.6 M in toluene, 2.2 mL) was added slowly.
After 1 h, the reaction was quenched with MeOH (10 mL) and sodium potassium tartrate
(15 mL), and stirred at r.t. for 0.5 h. The layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the pure α,β-unsaturated ester 24.
Yield: 1.6 g (85%); pale-yellow oil; [α]D
25 +27.3 (c = 0.2, CHCl3).
IR (neat): 3446, 2984, 2977, 1643, 1449, 1372, 1264, 1168, 1058, 977 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.43–7.39 (m, 2 H), 7.33 (t, J = 7.1 Hz, 2 H), 7.28–7.25 (m, 1 H), 7.04 (dt, J = 15.6, 6.9 Hz, 1 H), 6.69 (dd, J = 16.0, 1.0 Hz, 1 H), 6.37 (dd, J = 16.0, 6.1 Hz, 1 H), 5.94 (dt, J = 15.6, 1.5 Hz, 1 H), 4.22–4.37 (m, 1 H), 4.36–4.31 (m, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.08 (dd, J = 7.7, 5.7 Hz, 1 H), 2.76–2.69 (m, 1 H), 2.63–2.54 (m, 1 H), 1.47 (s, 3 H), 1.35
(s, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 166.4, 145.6, 136.3, 132.0, 129.1, 128.5, 127.9, 126.6, 123.3, 108.6,
79.8, 76.3, 70.9, 60.2, 33.0, 27.9, 25.5, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd. for C20H26O5Na: 369.1677; found: 369.1676.
(R)-6-[(E)-3-{(2S,4R,5R,6S)-4,5-Dihydroxy-6-[(E)-styryl]tetrahydro-2H-pyran-2-yl}prop-1-en-1-yl]-5,6-dihydro-2H-pyran-2-one (6)
(R)-6-[(E)-3-{(2S,4R,5R,6S)-4,5-Dihydroxy-6-[(E)-styryl]tetrahydro-2H-pyran-2-yl}prop-1-en-1-yl]-5,6-dihydro-2H-pyran-2-one (6)
To a stirred solution of 26 (20 mg, 0.25 mmol) in anhydrous CH2Cl2 (5 mL), TiCl4 (0.03 mL, 0.25 mmol) was added at 0 °C. The mixture was stirred at this temperature
for 0.5 h, then the reaction was quenched with solid NaHCO3 and the mixture was filtered. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography (EtOAc/hexane, 1:1) to
afford 6.
Yield: 14 mg (80%); pale-yellow oil; [α]D
25 +5.2 (c = 0.1, CHCl3).
IR (neat): 3448, 2983, 2854, 1712, 1648, 1542, 1484, 1263, 1090, 755 cm−1.
1H NMR (CDCl3, 500 MHz): δ = 7.43–7.37 (m, 2 H), 7.30 (t, J = 7.7 Hz, 2 H), 7.25–7.19 (m, 1 H), 6.87 (dt, J = 16.1, 5.4 Hz, 1 H), 6.68 (dd, J = 16.0, 1.1 Hz, 1 H), 6.27 (dd, J = 16.1, 5.4 Hz, 1 H), 6.04 (dt, J = 9.6, 1.7 Hz, 1 H), 5.96–5.87 (m, 1 H), 5.70 (dd, J = 15.5, 6.4 Hz, 1 H), 4.94–4.87 (m, 1 H), 4.53–4.47 (m, 1 H), 4.05 (dd, J = 9.1, 4.6 Hz, 1 H), 4.01–3.92 (m, 1 H), 3.82 (dd, J = 9.2, 4.7 Hz, 1 H), 2.47–2.36 (m, 3 H), 2.34–2.24 (m, 1 H), 1.92 (dt, J = 14.9, 2.9 Hz, 1 H), 1.80–1.71 (m, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 164.0, 144.7, 136.1, 133.6, 131.0, 129.6, 128.7, 128.3, 126.5, 124.9,
121.5, 77.2, 76.1, 69.7, 68.3, 65.2, 37.2, 33.6, 28.8.
HRMS (ESI): m/z [M + Na]+ calcd. for C21H24O5Na: 379.1521; found: 379.1520.
