Biomimetic total synthesis of cruentaren A via aromatization of diketodioxinones

Article abstract of DOI:10.1021/jo300225z

The total synthesis of cruentaren A, a biologically active resorcylate natural product, is reported. The aromatic unit was constructed via late-stage cyclization and aromatization from a diketodioxinone intermediate and macrocyclization using Fuerstner ring-closing alkyne metathesis.

Full text of DOI:10.1021/jo300225z

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pubs.acs.org/joc
Biomimetic Total Synthesis of Cruentaren A via Aromatization
of Diketodioxinones
Marianne Fouche,† Lisa Rooney,‡ and Anthony G. M. Barrett*,†
́
†Department of Chemistry, Imperial College, London SW7 2AZ, England
‡Novartis, Wimblehurst Road, Horsham, West Sussex RH12 5AB, England
S
* Supporting Information
ABSTRACT: The total synthesis of cruentaren A, a biologically active resorcylate
natural product, is reported. The aromatic unit was constructed via late-stage cyclization
and aromatization from a diketodioxinone intermediate and macrocyclization using
Furstner ring-closing alkyne metathesis.
̈
an IC50 value of 1.2 ng mL,1 and selectively inhibits mito-
chondrial F-ATPase.2 Structurally related resorcylate lactones
include the estrone agonist zearalenone (2), the antimalarial
and cyclin kinase dependent inhibitor aigialomycin D (3), and
MEK inhibitor LL-783,277 (4).3
INTRODUCTION
Cruentaren A (1) was isolated in 2006 by Hofle et al. from the
myxobacterium Byssovorax cruenta. It is a member of the
extensive resorcylic acid lactone family of natural products and
contains a 12-membered lactone with a Z-double bond and an
unsaturated amide side chain (Figure 1).1 Cruentaren A (1)
■
̈
As a result of its interesting biological properties, two groups
have already reported the total synthesis of cruentaren A (1)
and analogues in 2007 and 2008.4,5 The retrosynthetic
strategies proposed by Maier4 and Furstner5 have similar key
̈
disconnections. Both started with the derivatization of the
aromatic unit (resorcylic and orsellinic acid respectively), and
the macrolactone was elaborated using an esterification reaction
followed by ring-closing alkyne metathesis and Lindlar
hydrogenation to afford the unsaturated lactone desired (Z)-
configuration. The esterification approach is commonly used
for the synthesis of resorcylic acid lactones, despite being often
low yielding because of the deactivation and steric hindrance of
the carbonyl functionality due to the (protected) phenolic ring
substituents. In addition to this, Furstner and Maier faced
̈
another problem with the formation of the unwanted 6-
membered lactone being observed under basic or acidic
conditions.4,5 Since many resorcylic acid lactones have highly
promising diverse biologically activities and can be considered,
in many cases, as medicinal chemistry hits (Figure 1),3 we
recently sought to develop a flexible biomimetic inspired
strategy for the synthesis of this class of natural product.6 The
key features of our approach, which was inspired by the earlier
work of Hyatt,7 Harris,8 and Boeckman,9 are the trapping of the
ketene intermediate 6, obtained via retro-Diels−Alder reaction
of diketo-dioxinone 57 with an alcohol, providing triketoester 7,
which can subsequently undergo aromatization to produce
Figure 1. Cruentaren A and related natural products (resorcylate units
are highlighted in red).
strongly inhibits the growth of yeast and filamentous fungi,
shows high cytotoxicity against L929 mouse fibroblast cells with
Received: February 1, 2012
Published: March 8, 2012
© 2012 American Chemical Society
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resorcylate 8 (Scheme 1). This flexible methodology has
already been applied in total syntheses of (S)-zearalenone
oxidation to the corresponding aldehyde using IBX,12 the
acetylene moiety was introduced using a Seyferth−Gilbert
reaction13 by treatment with diazophosphonate 1614 to give
acetylene 17 in 92% yield over two steps. Methylation of
terminal alkyne 17 was carried out by deprotonation with
n-butyllithium and alkylation with methyl iodide. Selective
deprotection of the TBS group was achieved by allowing
diether 18 to react with p-toluenesulfonic acid. Finally,
TEMPO oxidation15 of the resultant primary alcohol gave
carboxylic acid 19.
Scheme 1. Synthesis of Resorcylates 8 Using Diketo-
dioxinones 5
Diketo-dioxinone 22 was synthesized in two steps from acid
19 using a method developed in our group (Scheme 4).16,17
Acid 19 was converted to the corresponding Weinreb amide
20, which was allowed to react with the dianion derived from
keto-dioxinone 21 in presence of diethylzinc. This straightfor-
ward variation of a crossed Claisen condensation reaction gave
diketo-dioxinone 22 on gram scale in 12 steps.
(2),6a,c aigialomycin D (3),6b LL-Z1640-2 (4)6d (Figure 1), and
other natural products. Herein, we describe the application of
this methodology to a more complex natural product,
cruentaren A (1).
Alcohol 33 was synthesized from the chiral pool (S)-Roche
ester 23 (Scheme 5). Following trityl protection, reduction with
DIBAl-H gave the corresponding primary alcohol, which was 4-
toluenesulfonylated. Subsequent nucleophilic substitution of
tosylate 24 with the acetylide derived from propargyl 4-
methoxybenzyl ether (25)18 in DMSO and THF19 gave the
hexynediol derivative 26. Interestingly, the use of HMPA as
solvent resulted in elimination and not substitution. Depro-
tection of the trityl ether followed by Lindlar reduction gave
(Z)-alkenol 27. Swern oxidation of alkenol 27 followed by an
Evans aldol reaction20 gave the corresponding aldol 29 in good
yield and high diastereoselectivity. Subsequent TBS protection
followed by reductive cleavage of the chiral auxiliary using
lithium borohydride gave alcohol 30. The final steps in the
elaboration of acetylene 33 were asymmetric propargylation
and terminal acetylene methylation. After oxidation of 30 to the
corresponding aldehyde, a Barbier type reaction, using indium
and amino alcohol 31 as a chiral ligand,21 gave the acetylenic
alcohol 32 in good yield and with excellent diastereoselectivity.
However, acetylene 32 was isolated admixed with the
RESULTS AND DISCUSSION
■
Our retrosynthetic analysis is illustrated in Scheme 2. The last
step of the synthesis was projected to be a Lindlar reduction of
the macrocyclic lactone alkyne functionality, which should
afford cruentaren A (1) with a high Z/E selectivity.4,5
Furthermore, the presence of the triple bond should prevent
unwanted trans-lactonization involving the unprotected C-9
alcohol during earlier stages of the synthesis. Lactone 9 should
be available using ring closing alkyne metathesis of the fully
protected precursor 10. The aromatic ring should be available
from reaction of alcohol 12 with diketo-dioxinone 11 via ketene
trapping and aromatization.
The initial target for synthesis was the carboxylic acid 19
(Scheme 3), which would later be converted to the key diketo-
dioxinone 22 via C-acylation. Brown crotylation10 of aldehyde
13 gave homoallylic alcohol 14 with the desired anti-
configuration, which was subjected to sequential silyl ether
protection and hydroboration11 to give alcohol 15. After
Scheme 2. Retrosynthesic Analysis of Cruentaren A (1)
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Scheme 3. Synthesis of Carboxylic Acid 19
Scheme 4. Synthesis of Diketo-dioxinone 22 via C-Acylation
corresponding (S)- and (R)-Mosher esters.22 Finally, direct
methylation of the terminal alkyne gave the key alcohol 33, and
at this stage, the allene contaminant was easily removed by flash
chromatography.
With alcohol 33 and diketo-dioxinone 22 in hand, we sought
to examine the synthesis of the core resorcylate unit of
cruentaren A (1) (Scheme 6). Thermolysis of diketo-dioxinone
22 in dichloromethane at 110 °C in a sealed tube presumably
afforded the corresponding highly reactive ketene, which was
trapped in situ with alcohol 33. Direct treatment of the reaction
mixture with cesium carbonate followed by acidification in
methanol as solvent gave the resorcylate 34 (R = H) and its
corresponding methyl ether 34 (R = Me) in a combined yield
of 55% on a gram scale.6 It is reasonable to suggest that the
corresponding allene. The stereochemistry of acetylene 32 was
confirmed by comparison of the H NMR spectrum of the
1
Scheme 5. Synthesis of Alcohol 33
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Scheme 6. Synthesis of 36, the Core Structure of Cruentaren A
methyl ether arose via formation of the cyclohexanedione ketal
37 and aromatization (Figure 2). The mixture of phenols 34
sterically hindered silyl group at C-17 underwent deprotection
slowly, which necessitated the higher temperature for reac-
tion (40 °C), however, no degradation was observed. Finally,
Lindlar reduction of the remaining alkyne gave cruentaren A
(1). The spectroscopic properties of the synthetic 1 were in full
accordance with data reported for the natural product.1,2
CONCLUSION
■
Cruentaren A (1) was successfully obtained using our
resorcylate biomimetic synthetic strategy in 23 steps for the
longest linear sequence. The synthesis of the core of cruentaren
A (1) was achieved on gram scale from diketo-dioxinone 22
and alcohol 33. The successful synthesis of 34 and the stability
of delicate functionalities during the generation of the
resorcylate unit by late stage aromatization proved that this
biomimetic strategy is a powerful method for the synthesis of
complex polyfunctional macrocyclic resorcylate natural prod-
ucts and appropriate for the convergent parallel synthesis of
analogues.
Figure 2. Presumed intermediate 37 leading to the resorcylate 34
(R = Me).
(R = H) and 34 (R = Me) was converted into the
corresponding dimethyl ether by reaction with methyl iodide
and potassium carbonate in acetone. It is worth noting that
when the thermolysis of 33 with 22 was carried out under the
usual conditions of toluene at reflux, degradation of diketo-
dioxinone 22 was observed before complete reaction with
alcohol 33. Ring-closing alkyne metathesis using the excellent
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out in oven-dried
glassware under N2, using commercially supplied solvents and reagents
unless otherwise stated. THF, CH2Cl2, Et3N, and MeOH were
redistilled from Na−Ph2CO, CaH2, CaH2, and Mg turnings−I2,
respectively. Hexanes refers to the petroleum fraction with bp
40−60 °C. Column chromatography was carried out on silica gel
using flash techniques (eluants are given in parentheses). Analytical
thin-layer chromatography was performed on precoated silica gel F254
aluminum plates with visualization under UV light or by staining using
either acidic vanillin, anisaldehyde, or ninhydrin spray reagents.
Melting points were obtained using a melting point apparatus and are
uncorrected. Infrared data were carried out neat unless otherwise
Furstner molybdenum nitride precatalyst 3523 smoothly gave
̈
the macrolactone 36 in 75% yield. However, a high catalyst
loading was required in order to shorten the reaction time and
obtain an acceptable yield since degradation of diyne 34 was
observed on extended heating.
Deprotection of the p-methoxybenzyl group in ether 36
using DDQ gave alcohol 38, which was subsequently converted
into the corresponding azide via a Mitsunobu reaction using
zinc azide (Scheme 7).24 Staudinger reduction gave access to
the corresponding amine 39, which was used immediately in
the next step on account of its surprising and frustrating
instability. Coupling between amine 39 and acid 4020,25 using
HBTU and HOBt in DMF furnished the corresponding amide
41 in 67% yield. Regioselective monocleavage of the methyl
ether group at the arene C-3 center was carried out using boron
trichloride26 while the silyl ether protecting groups were
removed by treatment with hexafluorosilicic acid in acetonitrile
at 40 °C to give resorcylate amide 42. It was observed that the
stated with adsorptions reported in wavenumbers (cm−1). H NMR
1
spectra were recorded at 400 or 500 MHz with chemical shifts (δ)
quoted in parts per million (ppm) and coupling constants (J) recorded
in hertz (Hz). 13C NMR spectra were recorded at 100 or 125 MHz
with chemical shifts (δ) quoted in ppm.
Synthesis of Acid 19. (3R,4S)-1-[(tert-Butyldimethylsilyl)oxy]-
4-methylhex-5-en-3-ol (14). n-BuLi (2.5 M in hexanes, 53 mL)
was added with stirring to t-BuOK in THF (1 M; 146 mL) and
trans-2-butene (30 mL) at −78 °C. After complete addition, the
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Scheme 7. Total Synthesis of Cruentaren A (1)
mixture was stirred at −45 °C for 10 min, recooled to −78 °C,
and (−)-(Ipc)2BOMe in THF (1 M; 175 mL) added dropwise.
After a further 30 min, BF3·Et2O (24 mL, 196 mmol) and
aldehyde 1327 (27.5 g, 146 mmol) were added sequentially
dropwise at −78 °C. After 4 h at −78 °C, aqueous NaOH
(3 M; 150 mL) and H2O2 in H2O (50 wt %; 40 mL) were added,
and the mixture was heated at reflux for 1 h. The organic layer
was separated, washed with H2O and brine, dried (MgSO4),
filtered, and rotary evaporated and the residue chromato-
graphed (Et2O/hexanes 1:19) to afford the alcohol 14 (19.0 g,
74%) as a colorless oil: Rf 0.20 (Et2O/hexanes 1:9); [α]D −9.2
(c 2, CHCl3); NMR analysis of the crude material showed the
presence of one diastereoisomer (dr ≥ 97: 3); IR νmax 3417,
(3S,4R)-6-[(tert-Butyldimethylsilyl)oxy]-3-methyl-4-{[tris(propan-
2-yl)silyl]oxy}hexan-1-ol (15). 1. 2,6-Lutidine (19 mL, 195 mmol) and
i-Pr3SiOTf (31 mL, 94 mmol) were added sequentially with stirring to
alcohol 14 (19 g, 78 mmol) in CH2Cl2 (500 mL) at 0 °C. After 4 h,
saturated aqueous NH4Cl was added and the aqueous layer extracted
with CH2Cl2 (2×). The combined organic layers were dried (MgSO4),
filtered, and rotary evaporated, and the residue was chromatographed
(Et2O/hexanes 1:9) to afford the corresponding silyl ether (30 g, 97%)
as a colorless oil: Rf 0.85 (EtOAc/hexanes 1:9); [α]D +4.9 (c 2.1,
1
CH2Cl2); IR νmax 1464, 1391, 1253, 1097, 883, 834 cm−1; H NMR
(400 MHz, CDCl3) δ 5.84−5.76 (m, 1H), 5.03−4.98 (m, 2H), 3.98
(td, J = 6.1, 3.1 Hz, 1H), 3.66 (t, J = 5.7 Hz, 2H), 2.43−2.35 (m, 1H)
1.62 (dd, J = 12.9, 6.5 Hz, 2H), 1.08 (s, 21H), 1.05 (d, J = 6.9 Hz, 3H),
0.88 (s, 9H); 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 140.8,
114.4, 72.7, 60.2, 43.2, 36.5, 25.9, 18.2, 14.5, 12.9, −5.5; MS (ESI) m/z
401 [M + H]+; HRMS (ESI) m/z calcd for C22H49O2Si2 [M + H]+
401.3271, found 401.3260. Anal. Calcd for C22H48O2Si2: C, 65.93; H,
12.07. Found: C, 66.02; H, 12.03.
2. BH3 in THF (1 M; 135 mL) was slowly added with stirring to the
previously prepared silyl ether (18.0 g, 45 mmol) in THF (150 mL) at
0 °C and the mixture allowed to warm to room temperature. After
18 h, it was cooled to 0 °C and slowly added via cannula to aqueous
NaOH (2.5 M; 300 mL) at 0 °C, aqueous H2O2 (30 wt %, 150 mL)
1
1465, 1386, 1254, 1086, 832, 775, 671 cm−1; H NMR (400
MHz, CDCl3) δ 5.88−5.82 (m, 1H), 5.12−5.07 (m, 2H),
3.95−3.90 (m, 1H), 3.86−3.81 (m, 1H), 3.74−3.70 (m, 1H),
2.28−2.20 (m, 1H) 1.66−1.61 (m, 2H), 1.04 (d, J = 6.9 Hz,
3H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 140.7, 115.1, 75.1, 62.8, 43.9, 35.5, 25.9, 18.1, 15.8, −5.5; MS
(CI) m/z 245 [M + H]+; HRMS (CI) m/z calcd for
1
C13H29O2Si [M + H]+ 245.1937, found 245.1934. The H
and 13C NMR spectra and [α]D were in full agreement with a
sample prepared by a published route.28
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was added, and stirring was continued stirred for 1 h at room
temperature. The mixture was diluted with Et2O, and the organic layer
was washed with saturated aqueous NaHCO3 and brine, dried
(MgSO4), filtered, and rotary evaporated. The crude material was
chromatographed (Et2O/hexanes 1:4) to afford disilyl ether 15
(15.4 g, 82%) as a colorless oil: Rf 0.30 (Et2O/hexanes 1:9); [α]D +9.1
(c 2.2, CH2Cl2); IR νmax 3330, 1464, 1384, 1253, 1092, 1052, 1005,
940, 832, 774, 674 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.97 (td, J =
6.1, 3.1 Hz, 1H), 3.75−3.57 (m, 4H), 1.86−1.50 (m, 5H), 1.08 (s,
21H), 0.98 (d, J = 6.9 Hz, 3H), 0.09 (s, 9H), 0.03 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 73.2, 60.5, 60.2, 36.1, 35.0, 25.9, 18.2, 15.0,
12.9, −5.4; MS (ESI) m/z 419 [M + H]+; HRMS (ESI) m/z calcd for
C22H51O3Si2 [M + H]+ 419.3377, found 419.3366. Anal. Calcd for
C22H50O3Si2: C, 63.09; H, 12.03. Found: C, 63.15; H, 12.05.
(7R)-2,2,3,3,10-Pentamethyl-7-[(2S)-pent-4-yn-2-yl]-9,9-bis-
(propan-2-yl)-4,8-dioxa-3,9-disilaundecane (17). 1. Iodoxybenzoic
acid (9.0 g, 30 mmol) and, after 10 min, alcohol 15 (6.5 g, 15.5 mmol)
in DMSO (10 mL) were added with stirring to DMSO (50 mL). After
4 h, the mixture was filtered, and the filtrate diluted with Et2O and
washed with H2O. The organic layer was dried (MgSO4), filtered, and
rotary evaporated. The residue was filtered through silica (Et2O/
hexanes 1:19) to provide the corresponding aldehyde (4.8 g, 74%) as a
colorless oil: Rf 0.90 (Et2O/hexanes 1:9); IR νmax 2712, 1727, 1464,
1252, 1093, 1049, 832, 774, 668 cm−1; 1H NMR (400 MHz, CDCl3) δ
9.78 (s, 1H), 3.94 (dt, J = 6.1, 2.8 Hz, 1H), 3.67 (t, J = 6.1 Hz, 2H),
2.51−2.44 (m, 1H), 2.32−2.23 (m, 2H), 1.77−1.48 (m, 3H), 1.07 (s,
21H), 1.02 (d, J = 6.9 Hz, 3H), 0.87 (s, 9H); 0.03 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 202.6, 73.1, 59.8, 46.3, 36.8, 32.9, 25.9, 18.2,
16.3, 12.9, −5.4; MS (ESI) m/z 417 [M − H]+; HRMS (ESI) m/z
calcd for C22H49O3Si2 [M + H]+ 417.3220, found 417.3213.
mixture allowed to warm to room temperature. After 2 h, NaHCO3
(1.5 g) was added, and the mixture was stirred for 10 min, filtered, and
rotary evaporated. The residue was diluted with Et2O, washed with
brine, dried (MgSO4), filtered, rotary evaporated, and chromato-
graphed (Et2O/hexanes 1:9) to afford the corresponding unprotected
alcohol (2.7 g, 92%) as a colorless oil: Rf 0.2 (Et2O/hexanes 1:9); [α]D
+8.1 (c 1.8, CH2Cl2); IR νmax 3347, 1463, 1384, 1092, 1060, 1034, 882,
1
676 cm−1; H NMR (400 MHz, CDCl3) δ 4.15 (td, J = 5.7, 4.4 Hz,
1H), 3.79 (t, J = 6.3 Hz, 2H), 2.09−2.05 (m, 2H), 1.95−1.89 (m, 1H),
1.76 (t, J = 2.5 Hz, 3H), 1.71−1.67 (m, 2H), 1.09 (s, 21H), 0.97 (d,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 77.7, 77.2, 73.5, 60.7,
38.6, 34.0, 22.6, 18.2, 14.4, 13.0, 3.4; MS (ESI) m/z 313 [M + H]+;
HRMS (ESI) m/z calcd for C18H37O2Si [M + H]+ 313.2563, found
313.2547.
2. Phosphate buffer (H3PO4/NaH2PO4; 0.5 M, pH = 7; 60 mL),
NaClO2 (1.8 g, 20.0 mmol), TEMPO (0.1 g, 0.64 mmol), and aqueous
NaClO (0.05 mL) were added with stirring to the previously prepared
alcohol (2.5 g, 8 mmol) in MeCN (60 mL) at 0 °C. After 20 min,
saturated aqueous Na2S2O3 (10 mL) was added, the aqueous layer was
extracted with EtOAc (2×), and the combined organic layers were
washed with H2O, dried (MgSO4), filtered, and rotary evaporated. The
residue was chromatographed (EtOAc/hexanes 1:4) to afford acid 19
(2.0 g, 79%) as a colorless oil: Rf 0.25 (EtOAc/hexanes 1:9); [α]D +3.5
(c 0.8, CHCl3); IR νmax 1712, 1467, 1300, 1090, 1068, 1002, 948, 882,
1
750 cm−1; H NMR (400 MHz, CDCl3) δ 4.47−4.43 (m, 1H), 2.54
(ddq, J = 15.6, 5.2, 2.4 Hz 1H), 2.47 (ddq, J = 15.6, 6.4, 2.4 Hz, 1H),
2.11−2.08 (m, 2H), 2.00−1.94 (m, 1H), 1.78 (t, J = 2.4 Hz, 3H), 1.08
(s, 21H), 1.00 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
176.5, 77.2, 77.1, 71.8, 39.1, 37.6, 22.4, 18.1, 14.4, 12.7, 3.4; MS (ESI)
m/z 325 [M − H]+; HRMS (ESI) m/z calcd for C18H33O3Si [M −
H]+ 325.2199, found 325.2200. Anal. Calcd for C18H34O3Si: C, 66.21;
H, 10.49. Found: C, 66.26; H, 10.39.
2. Freshly prepared diazophosphonate (16)29 (5.7 g, 22.6 mmol)
was added with stirring to the foregoing aldehyde (4.7 g, 11.3 mmol)
and anhydrous K2CO3 (5.7 g, 33.9 mmol) in MeOH (200 mL) at
room temperature and the mixture rapidly turned milky green. After
3 h, the mixture was diluted with Et2O, and the organic layer was washed
with H2O and brine, dried (MgSO4), filtered, and rotary evaporated.
The residue was chromatographed (Et2O/hexanes 1:19) to afford
acetylene 17 (4.3 g, 92%) as a colorless oil: Rf 0.90 (Et2O/hexanes
1:19); [α]D +5.4 (c 2.6, CH2Cl2); IR νmax 3318, 1467, 1390, 1256,
1092, 1011, 939, 882, 834, 777, 680 cm−1; 1H NMR (400 MHz,
CDCl3) δ 4.04 (td, J = 6.2, 3.8 Hz, 1H), 3.74−3.65 (m, 2H), 2.20
(ddd, J = 16.8, 6.3, 2.6 Hz, 1H), 2.08 (ddd, J = 16.8, 8.2, 2.6 Hz, 1H),
1.94 (t, J = 2.8 Hz, 1H), 1.92 − 1.89 (m, 1H), 1.67−1.51 (m, 2H),
1.07 (s, 21H), 1.03 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H); 0.04 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 83.8, 72.1, 69.0, 60.0, 38.0, 35.9, 25.9,
21.3, 18.3, 15.1, 12.9, −5.4; MS (ESI) m/z 413 [M + H]+; HRMS
(ESI) m/z calcd for C23H49O2Si2 [M + H]+ 413.3271, found 413.3271.
Anal. Calcd for C23H48O2Si2: C, 66.92; H, 11.72. Found: C, 66.94; H,
12.00.
(7R)-7-[(2S)-Hex-4-yn-2-yl]-2,2,3,3,10-pentamethyl-9,9-bis-
(propan-2-yl)-4,8-dioxa-3,9-disilaundecane (18). n-BuLi in hexanes
(2.5 M; 6.2 mL) was added slowly with stirring to acetylene 17 (4.3 g,
10.4 mmol) in THF (60 mL) at −78 °C. After 45 min, MeI (1.3 mL,
20.8 mmol) was added and the mixture stirred at room temperature
for 3 h. Saturated aqueous NH4Cl was added, and the aqueous layer
was extracted with Et2O (2×). The combined organic layers were
washed with brine, dried (MgSO4), filtered, rotary evaporated, and
chromatographed (Et2O/hexanes 1:19) to afford acetylene 18 (4.0 g,
90%) as a colorless oil: Rf 0.95 (Et2O/hexanes 1: 19); [α]D +8.1 (c 1.8,
CH2Cl2); IR νmax 3317, 1465, 1391, 1363, 1253, 1097, 834, 376 cm−1;
1H NMR (400 MHz, CDCl3) δ 4.07 (td, J = 5.8, 3.7 Hz, 1H), 3.75−
Synthesis of Diketodioxinone 22. (3R,4S)-N-Methoxy-N,4-
dimethyl-3-{[tris(propan-2-yl)silyl]oxy}oct-6-ynamide (20). i-
Pr2NEt (4.0 mL, 23 mmol) was added with stirring to
carboxylic acid 19 (2.5 g, 7.7 mmol), N-methoxy-N-methyl-
amine (1.0 g, 10 mmol), and PyBOP (benzotriazol-1-
yloxy)tripyrrolidinophosphonium hexafluorophosphate)
(4.0 g, 8 mmol) in CH2Cl2 (20 mL) at 0 °C and allowed to
warm to room temperature. After 30 min, the mixture was
poured into Et2O, and the organic layer was washed with
aqueous HCl (1 M), saturated aqueous NaHCO3, and brine,
dried (MgSO4), filtered, rotary evaporated, and chromato-
graphed (EtOAc/hexanes 1:4) to afford amide 20 (2.1 g, 74%)
as a colorless oil: Rf 0.20 (CH2Cl2); [α]D +16.3 (c 0.3, CHCl3);
IR νmax 1664, 1383, 1181, 1093, 1064, 1013, 940, 882, 741, 674
1
cm−1; H NMR (400 MHz, CDCl3) δ 4.53 (ddd, J = 7.5, 4.8,
3.3 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.64 (dd, J = 15.2, 7.5
Hz, 1H), 2.42 (dd, J = 15.2, 4.8 Hz, 1H), 2.17−2.10 (m, 1H),
2.05−1.89 (m, 2H), 1.77 (t, J = 2.44 Hz, 3H), 1.06 (s, 21H),
1.03 (d, J = 6.70 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 77.8,
76.6, 71.5, 61.2, 39.3, 35.2, 32.1, 22.0, 18.1, 14.6, 12.7, 3.5; MS
(ESI) m/z 370 [M − H]+; HRMS (ESI) m/z calcd for
C20H40NO3Si [M + H]+ 370.2777, found 370.2771. Anal. Calcd
for C20H39NO3Si: C, 64.99; H, 10.64, N 3.79. Found: C, 65.12;
H, 10.71, N 3.82.
(6R,7S)-1-(2,2-Dimethyl-6-oxo-2,6-dihydro-1,3-dioxin-4-yl)-7-
methyl-6-{[tris(propan-2-yl)silyl]oxy}undec-9-yne-2,4-dione (22).
Keto-dioxinone 216b (2.4 g, 12.8 mmol) was added dropwise with
stirring to freshly prepared LiN(i-Pr)2 (27.8 mmol) in THF (25 mL)
at −78 °C. After 30 min at −40 °C, the mixture was recooled to −78 °C,
and Et2Zn in THF (1 M; 25.7 mL) was added. After another
30 min at −40 °C, amide 20 (1.6 g, 4.28 mmol) was added, and after a
further 4 h at −5 °C, the reaction was quenched with aqueous HCl
(1 M) and the mixture extracted with EtOAc (2×). The combined
organic layers were washed with brine, dried (MgSO4), filtered, rotary
evaporated, and chromatographed (Et2O/hexanes 1:9 to 1:4) to give
dioxinone 22 (1.4 g, 67%) as a light yellow oil: Rf 0.55 (EtOAc/
hexanes 1:4); [α]D +9.5 (c 0.6, CHCl3); IR νmax 1731, 1604, 1378,
1271, 1014, 882 cm−1; 1H NMR (400 MHz, CDCl3) δ 15.1 (br s, 1H),
3.66 (m, 2H), 2.12−1.98 (m, 2H), 1.89−1.82 (m, 1H), 1.76 (t, J = 2.4
Hz, 3H), 1.62−1.58 (m, 2H), 1.07 (s, 21H), 0.97 (d, J = 6.8 Hz, 3H),
0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 78.2, 76.2,
71.9, 60.2, 38.7, 35.5, 25.9, 22.0, 18.2, 14.8, 12.9, 3.5, −5.3; MS (ESI)
m/z 427 [M + H]+; HRMS (ESI) m/z calcd for C24H51O2Si2 [M +
H]+ 427.3428, found 427.3415.
(3R,4S)-4-Methyl-3-{[tris(propan-2-yl)silyl]oxy}oct-6-ynoic Acid
(19). 1. p-TsOH (0.9 g, 4.7 mmol) was added with stirring to silyl
ether 18 (4.0 g, 9.4 mmol) in MeOH (100 mL) at 0 °C and the
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5.63 (s, 1H), 5.40 (s, 1H), 4.47−4.43 (m, 1H), 3.20 (s, 2H), 2.42 (dd,
J = 14.2, 4.7 Hz, 1H), 2.34 (dd, J = 14.2, 7.8 Hz, 1H), 2.07−2.05 (m,
2H), 1.97−1.87 (m, 1H), 1.77 (t, J = 2.46 Hz, 3H), 1.7 (s, 6H), 1.04
(s, 21H), 0.98 (d, J = 6.83 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
190.8, 188.3, 164.9, 160.6, 107.1, 101.4, 96.4, 77.2, 76.7, 72.1, 43.5,
41.1, 39.1, 25.0, 22.2, 18.1, 14.4, 12.8, 3.4; MS (ESI) m/z 493 [M +
H]+; HRMS (ESI) m/z calcd for C27H45O6Si [M + H]+ 493.2985,
found 493.3003. Anal. Calcd for C27H44O6Si: C, 65.82; H, 9.00.
Found: C, 65.75; H, 8.99.
Synthesis of Alcohol 33. (2S)-2-Methyl-3-(triphenylmethoxy)-
propyl 4-Methylbenzenesulfonate (24). 1. Et3N (52 mL,
372 mmol), DMAP (4.1 g, 33.9 mmol) and methyl (2S)-3-hydroxy-
2-methyl-propanoate (23) (20 g, 169 mmol) were added with
stirring to Ph3CCl (95 g, 339 mmol) in CH2Cl2 (600 mL).
After 12 h at room temperature, H2O was added, and the
mixture extracted with CH2Cl2 (2×). The combined organic
layers were washed with brine, dried (MgSO4), filtered, and
rotary evaporated to leave the crude ester, which was used
without further purification.
23.2, 16.8; MS (ESI) m/z 513 [M + Na]+, 529 [M + K]+, 243
[CPh3]+; HRMS (ESI) m/z calcd for C34H34O3Na [M + Na]+
513.2406; found 513.2414. Anal. Calcd for C34H34O3: C, 83.23; H,
6.98. Found: C, 83.17; H, 6.86.
(2R,4Z)-6-[(4-Methoxyphenyl)methoxy]-2-methylhex-4-en-1-ol
(27). 1. p-TsOH (13.7 g, 720 mmol) was added with stirring to
acetylene 26 (23.5 g, 480 mmol) in MeOH (250 mL) at 0 °C and the
mixture allowed to warm to room temperature. After 2 h, saturated
aqueous NaHCO3 was added, and after 15 min, the mixture was
filtered and rotary evaporated. The residual oil was dissolved in Et2O
and washed with brine, and the organic layer was dried (MgSO4),
filtered, and rotary evaporated. The residue was chromatographed
(Et2O/hexanes 3:17 to 1:4) to give the corresponding alcohol (8.5 g,
72%) as a colorless oil: Rf 0.20 (EtOAc/hexanes 1:4); [α]D +6.0 (c 1,
CH2Cl2); IR νmax 1614, 1588, 1516, 1461, 1356, 1356, 1246, 1175,
1034, 989, 817 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.7
Hz, 2H), 6.88 (d, J 8.7 Hz, 2H), 4.52 (s, 2H), 4.13 (t, J = 2.2 Hz, 2H),
3.81 (s, 3H), 3.58 (d, J = 6.1 Hz, 2H), 2.34 (ddt, J = 16.8, 6.2, 2.2 Hz,
1H), 2.27 (ddt, J = 16.8, 6.4, 2.2 Hz, 1H), 1.96−1.84 (m, 1H), 1.02 (d,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 129.7, 113.8,
85.0, 71.0, 67.1, 57.3, 55.3, 33.1, 22.7, 16.3 (one quaternary C
missing); MS (CI) m/z 266 [M + NH4]+; HRMS (ESI) m/z calcd for
C15H24NO3 [M + NH4]+ 266.1756, found 266.1686. Anal. Calcd for
C15H20O3: C, 72.55; H, 8.12. Found: C, 72.61; H, 7.96.
2. Quinoline (11 mL, 6.6 mmol) and Lindlar catalyst (5 wt % Pd on
CaCO3, poisoned with lead, 130 mg, 10 wt %) were added to the
preceding alcohol (13.5 g, 54 mmol) in EtOAc (150 mL). The mixture
was placed under H2, stirred for 2 h, and filtered through Celite, and
the filtrate was washed with aqueous HCl (1 M). The organic layer
was rotary evaporated and chromatographed (short pad, EtOAc/
hexanes 1:4) to give alkenol 27 (12.2 g, 90%, Z/E > 95:5 by 1H NMR)
as a colorless oil: Rf 0.15 (EtOAc/hexanes 1:4); [α]D −2.0 (c 1.1,
CH2Cl2); IR νmax 3423, 1614, 1590, 1515, 1464, 1356, 1303, 1248,
1178, 1080, 1034, 986, 820 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29
(d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 5.74−5.62 (m, 2H), 4.47
(s, 2H), 4.09−4.00 (m, 2H), 3.81 (s, 3H), 3.48−3.40 (m, 2H), 2.21−
2.15 (m, 1H), 2.04−1.97 (m, 1H), 1.77−1.69 (m, 1H), 0.94 (d, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 132.5, 130.1, 129.5,
127.0, 113.8, 72.1, 67.0, 65.1, 55.3, 35.8, 31.0, 16.5; MS (ESI) m/z 251
[M + H]+, HRMS (ESI) m/z calcd for C15H23O3 [M + H]+ 251.1647;
found 251.1643. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found:
C, 71.89; H, 8.73.
(4S)-4-Benzyl-3-[(2S,3R,4R,6Z)-3-hydroxy-8-[(4-methoxyphenyl)-
methoxy]-2,4-dimethyloct-6-enoyl]-1,3-oxazolidin-2-one (29). 1.
DMSO (11.2 mL, 157 mmol) and after 20 and a further 45 min,
respectively, alcohol 27 (11.2 g, 44.8 mmol) in CH2Cl2 (40 mL) and
Et3N (30.0 mL, 179 mmol) were added dropwise with stirring to
oxalyl chloride (7.6 mL, 89.6 mmol) in CH2Cl2 (200 mL) at −78 °C.
The mixture was slowly allowed to warm to 0 °C and the reaction
quenched with saturated aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2 (3×), and the combined organic layers were
washed with saturated aqueous CuSO4, brine, and H2O, dried
(MgSO4), filtered, and rotary evaporated to afford the crude aldehyde
(11.0 g, 100%) which was used immediately without any further
purification.
2. Bu2BOTf (40 mL, 1 M) followed by i-Pr2NEt (7 mL, 40.3 mmol)
were added slowly with stirring to oxazolidinone 28 (11.5 g,
49.2 mmol) in CH2Cl2 (100 mL) at −78 °C, and the mixture was allowed
to warm to room temperature. After 1 h, the mixture was recooled to
−78 °C, and the preceding aldehyde (11.0 g, 44.8 mmol) in CH2Cl2
(10 mL) was added slowly with stirring. After 3 h at −78 °C, the
mixture was allowed to warm to −20 °C and added to saturated
aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2
(2×), and the combined organic layers were dried (MgSO4), filtered,
and rotary evaporated. The residue was chromatographed (EtOAc/
hexane 1:4 to 2:3) to give the aldol adduct 29 (15.7 g, 73% yield over
two steps, dr = 96: 4 by 1H NMR of the crude material) as a colorless
oil: Rf 0.20 (EtOAc/hexanes 1:9); [α]D +27.5 (c 2.3, CH2Cl2); IR νmax
3529, 1776, 1693, 1612, 1585, 1512, 1454, 1384, 1351, 1241, 1208,
1075, 1032, 983, 819, 750, 701 cm−1; 1H NMR δ 7.36−7.19 (m, 7H),
2. DIBAl-H in CH2Cl2 (1.0 M; 400 mL) was added dropwise with
stirring to the preceding ester in CH2Cl2 (500 mL) at −40 °C. After
4 h, the mixture was allowed to warm to room temperature, when H2O
followed by aqueous NaOH (10 wt %) were added with stirring. After
1 h, the aqueous layer was extracted with CH2Cl2 (2 ×), and the
combined organic layers were washed with brine, dried (MgSO4), and
rotary evaporated. The residue was chromatographed (Et2O/hexanes
3:7) to give the corresponding alcohol (34 g, 60%) as white needles:
mp 72−74 °C (EtOAc/hexane); Rf 0.20 (EtOAc/hexanes 1: 4); [α]D
1
+25 (c 2.7, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.44−7.41 (m,
6H), 7.33−7.22 (m, 9H), 3.63−3.55 (m, 2H), 3.23 (dd, J = 9.1, 4.5
Hz, 1H), 3.03 (dd, J = 9.1, 5.1 Hz, 1H), 2.33 (m, 1H), 0.86 (d, J = 7.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9, 128.6, 127.8, 127.0,
86.9, 67.8, 67.5, 36.0, 13.8. These data are in agreement with literature
values.30
3. The preceding ester (20 g, 60 mmol) in pyridine (50 mL) was
added with stirring to TsCl (17 g, 90 mmol) in pyridine (50 mL) at
0 °C. After 5 h at 0 °C, reaction was quenched with H2O and stirring
continued for 10 min to hydrolyze the excess TsCl. The aqueous layer
was extracted with CH2Cl2 (2×), and the combined organic layers
were washed with brine, dried (MgSO4), filtered, and rotary
evaporated. The residue was triturated in hexanes to afford sulfonate
24 as a white solid (28 g, 98%): mp 90−92 °C (CH2Cl2/hexane); Rf
0.70 (EtOAc/hexanes 1:4); [α]D: +10.0 (c 1.8, CH2Cl2); IR νmax 1492,
1448, 1360, 1174, 976, 809, 778 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.77−7.74 (m, 2H), 7.34−7.22 (m, 17H), 4.13 (dd, J = 9.0, 4.6 Hz,
1H), 4.00 (dd, J = 9.0, 5.2 Hz, 1H), 3.03 (dd, J = 10.9, 5.0 Hz, 1H),
2.93 (dd, J = 10.9, 6.5 Hz, 1H), 2.43 (s, 3H), 2.08−2.00 (m, 1H), 0.89
(d, J = 7.06 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144 6, 143.9,
133.0, 129.8, 128.6, 127.9, 127.7, 127.0, 86.4, 72.5, 64.2, 34.0, 21.7,
13.9; MS (ESI) m/z 509 [M + Na]+, 525 [M + K]+, 243 [CPh3]+;
HRMS (ESI) m/z calcd for C30H30O4SNa [M + Na]+ 509.1763, found
509.1743.
1-Methoxy-4-({[(5R)-5-methyl-6-(triphenylmethoxy)hexyl]oxy}-
methyl)benzene (26). n-BuLi in hexanes (2.5 M; 40.6 mL) was added
dropwise with stirring to propargylic ether 2518 (17.9 g, 101 mmol) in
THF (20 mL) at −78 °C. After 30 min at 0 °C, sulfonate 24 (26.0 g,
53 mmol) in DMSO (180 mL) was added, and, after a further 2 h,
reaction was quenched with saturated aqueous NH4Cl. The aqueous
layer was extracted with Et2O (2×), and the combined organic layers
were washed with brine, dried (MgSO4), filtered, and rotary
evaporated. The residue was chromatographed (Et2O/hexanes 1:19)
to give acetylene 26 (22.0 g, 89%) as a colorless oil: Rf 0.25 (EtOAc/
hexanes 1:4); [α]D +4.3 (c 1, CHCl3); IR νmax 1611, 1586, 1512, 1490,
1
1461, 1356, 1247, 1173, 1067, 1033, 986, 819, 763, 697 cm−1; H
NMR δ 7.46−7.44 (m, 6H), 7.31−7.20 (m, 11H), 6.90−6.86 (m, 2H),
4.46 (s, 2H), 4.08 (t, J = 2.1 Hz, 2H), 3.81 (s, 3H), 3.05 (dd, J = 8.9,
5.5 Hz, 1H), 3.01 (dd, J = 8.9, 6.9 Hz, 1H), 2.47 (dt, J = 16.6, 5.6, 2.0
Hz, 1H), 2.28 (dt, J = 16.6, 7.2, 2.0 Hz, 1H), 2.06−1.95 (m, 1H), 1.02
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 144.3,
129.7, 128.7, 127.7, 126.8, 113.8, 86.2, 85.4, 70.9, 67.0, 57.3, 55.3, 33.6,
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6.87 (d, J = 8.6 Hz, 2H), 5.72−5.61 (m, 2H), 4.69−4.63 (m, 1H), 4.44
(s, 2H), 4.19−4.17 (m, 2H), 4.12−4.02 (m, 2H), 3.93 (qd, J = 6.9, 2.1
Hz, 1H), 3.79 (s, 3H), 3.63 (dd, J = 8.8, 3.0 Hz, 1H), 3.26 (dd, J =
13.4, 3.3 Hz, 1H), 2.79 (dd, J = 13.4, 9.5 Hz, 1H), 2.39 (dt, J = 15.4,
5.3 Hz, 1H), 2.14 (dt, J = 15.6, 6.0 Hz 1H), 1.76−1.66 (m, 1H), 1.23
(d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 177.7, 159.1, 152.8, 135.0, 131.5, 130.4, 129.4, 128.9, 127.7,
127.4, 113.7, 74.3, 71.9, 66.1, 65.5, 55.2, 55.1, 39.4, 37.7, 35.8, 30.7,
15.3, 9.5; MS (ESI) m/z 482 [M + H]+, 504 [M + Na]+, 520 [M +
K]+; HRMS (ESI) m/z calcd for C28H36NO6 [M + H]+ 482.2543,
found 482.2535. Anal. Calcd for C28H35NO6: C, 69.83; H, 7.33.
Found: C, 69.98; H, 7.50.
(25 mL) at −20 °C. After 45 min, the preceding aldehyde (1.8 g,
4.3 mmol) was added with stirring, and, after 16 h, the mixture was
allowed to warm to room temperature. Aqueous HCl (1 M) was
added, the aqueous layer was extracted with EtOAc and hexanes (1: 1;
2×), and the combined organic layers were dried (MgSO4), filtered,
and rotary evaporated. The residue was chromatographed (EtOAc/
hexanes 1:9) to afford a mixture of acetylene 32 and the corresponding
1
allene (10: 1, 1.5 g, 75%) as a colorless oil. The H NMR spectrum
and Mosher ester analysis showed the presence of one diastereoisomer
in the acetylene component (dr ≥ 97: 3): Rf 0.50 (EtOAc/hexanes
1:4); [α]D −8.5 (c 0.8, CH2Cl2); IR νmax 1686, 1613, 1513, 1463,
1
1302, 1249, 1173, 1086, 1034, 836, 774 cm−1; H NMR (400 MHz,
CDCl3) δ 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.68−5.54
(m, 2H), 4.44 (s, 2H), 4.03 (d, J = 6.0 Hz, 2H), 3.80−3.77 (s, 4H),
3.66 (dd, J = 4.6, 2.6 Hz, 1H), 2.38 (dd, J = 6.5, 2.6 Hz, 2H), 2.19−
2.13 (m, 1H), 2.01 (t, J = 2.62 Hz, 1H), 1.89−1.83 (m, 2H), 1.78−
1.72 (m, 1H), 0.94−0.89 (m, 15H), 0.08 (s, 3H), 0.07 (s, 3H), (allene
10%, characteristic peaks δ 5.20−5.18 (m, 1H), 4.86 (dt, J = 6.5, 2.2
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 159.2, 132.3, 130.4, 129.4,
127.2, 113.8, 81.2, 77.9, 72.9, 71.9, 70.5, 65.6, 55.3, 38.9, 38.8, 31.0,
26.1, 25.0, 18.3, 16.0, 8.81, −3.5, −4.2; MS (ESI) m/z 461 [M + H]+,
483 [M + Na]+, 499 [M + K]+; HRMS (ESI) m/z calcd for
C27H45O4Si [M + H]+ 461.3087, found 461.3085. Anal. Calcd for
C27H44O4Si: C, 70.39; H, 9.63. Found: C, 72.46; H, 9.57.
(2R,3R,4R,6Z)-3-[(tert-Butyldimethylsilyl)oxy]-8-[(4-
methoxyphenyl)methoxy]-2,4-dimethyloct-6-en-1-ol (30). i-Pr2NEt
(16.4 mL, 94 mmol) followed by t-BuMe2SiOTf (11 mL, 47 mmol)
were added with stirring to the aldol adduct 29 (11.3 g, 23.5 mmol) in
CH2Cl2 (150 mL) at 0 °C. After 3 h, the mixture was added to
saturated aqueous NaHCO3, and the aqueous layer was extracted with
CH2Cl2 (2×). The combined organic layers were dried (MgSO4),
filtered, rotary evaporated, and chromatographed (EtOAC/hexanes
1:9) to afford the corresponding silyl ether (12.7 g, 91%) as a colorless
oil: Rf 0.60 (EtOAc/hexanes: 7); [α]D +52.1 (0.6, CH2Cl2); IR νmax
1781, 1696, 1612, 1513, 1463, 1381, 1351, 1249, 1210, 1085, 1036,
1
971, 836, 774, 702 cm−1; H NMR (400 MHz, CDCl3) δ 7.35−7.19
(m, 7H), 6.86 (d, J = 8.6 Hz, 2H), 5.65−5.52 (m, 2H), 4.61−4.55 (m,
1H), 4.41 (s, 2H), 4.15−3.96 (m, 6H), 3.79 (s, 3H), 3.25 (dd, J = 13.3,
3.2 Hz, 1H), 2.75 (dd, J = 13.3, 9.6 Hz, 1H), 2.23−2.17 (m, 1H),
1.84−1.76 (m, 1H), 1.64−1.58 (m, 1H), 1.23 (d, J = 6.5 Hz), 0.94−
0.92 (m, 12H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.9, 159.1, 152.9, 135.3, 132.3, 130.5, 129.4, 129.3, 128.9,
127.4, 113.8, 76.4, 71.8, 66.0, 65.6, 55.6, 55.2, 41.4, 39.2, 37.6, 30.0,
26.1, 18.4, 16.3, 13.9, −3.7, −4.1 (CTBS); MS (ESI) m/z 596 [M +
H]+, 618 [M + Na]+, 634 [M + K]+; HRMS (ESI) m/z calcd for
C34H50NO6Si [M + H]+ 596.3407; found 596.3417. Anal. Calcd for
C34H49NO6Si: C, 68.54; H, 8.29, N, 2.35. Found: C, 68.58; H, 8.18, N
2.29.
Preparation of the (S)- and (R)-Mosher Esters of Alcohol 32. EDC
(3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine) (65 mg,
0.34 mmol), (S)-PhC(OMe)(CF3)CO2H (80 mg, 0.34 mmol),
and DMAP (42 mg, 0.34 mmol) were added with stirring to alcohol
32 (50 mg, 0.11 mmol) in CH2Cl2 (1 mL). After 48 h, H2O was
added, the aqueous layer was extracted with Et2O (2×), and the
combined organic layers were dried (MgSO4), filtered, and rotary
evaporated. The residue was chromatographed (Et2O/hexanes 1:19)
1
to give the (S)-Mosher ester of 32 (30 mg, 40%) as a white gum: H
NMR (400 MHz, CDCl3) δ 7.54−7.53 (m, 2H), 7.42−7.40 (m, 3H),
7.26 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 5.68−5.61 (m,
1H), 5.59−5.53 (m, 1H), 5.16 (dd, J = 5.8 Hz, 1H), 4.43 (s, 2H), 4.04
(d, J = 6.2 Hz, 1H), 3.80 (s, 3H), 3.50 (s, 3H), 3.40 (t, J = 4.7 Hz,
1H), 2.65−2.54 (m, 2H), 2.23−2.14 (m, 2H), 1.91 (t, J = 2.6 Hz, 1H),
1.88−1.82 (m, 1H), 1.74−1.67 (m, 1H), 0.93 (d, J = 6.9 Hz, 3H), 0.90
(s, 9H), 0.85 (d, J = 6.8 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H).
In an entirely analogous fashion, the (R)-Mosher-ester of 32 was
prepared using (R)-PhC(OMe)(CF3)CO2H: 1H NMR (400 MHz,
CDCl3) δ 7.60−7.58 (m, 2H), 7.42−7.40 (m, 3H), 7.28 (d, J = 8.6 Hz,
2 H), 6.89 (d, J = 8.6 Hz, 2 H), 5.69−5.63 (m, 1H), 5.59−5.52 (m,
1H), 5.19−5.15 (m, 1H), 4.45 (s, 2H), 4.05 (d, J = 6.2 Hz, 1H), 3.81
(s, 3H), 3.63 (s, 3H), 3.35 (t, J = 4.7 Hz, 1H), 2.70 (ddd, J = 7.5, 2.5,
2.5 Hz, 1H), 2.62 (ddd, J = 7.5, 2.7, 2.7 Hz, 1H), 2.20−2.13 (m, 2H),
2.02 (t, J = 2.4 Hz, 1H), 1.84−1.78 (m, 1H), 1.68−1.65 (m, 1H), 0.90
(s, 9H), 0.82 (d, J = 6.9 Hz, 3H), 0.78 (d, J = 6.9 Hz, 3H), 0.02 (s,
3H), 0.01 (s, 3H).
2. LiBH4 (0.7 g, 30 mmol) was added with stirring to the preceding
oxazolidinone (9.0 g, 15.1 mmol) in CH2Cl2 and MeOH (10: 1;
100 mL) at 0 °C. After 15 min at 0 °C and 2 h at room temperature,
saturated aqueous NH4Cl was added and the aqueous layer was
extracted with CH2Cl2 (2×). The combined organic layers were dried
(MgSO4), filtered, rotary evaporated, and chromatographed (EtOAc/
hexanes 1:4) to afford the alcohol 30 (3.8 g, 63%) as a colorless oil: Rf
0.20 (EtOAc/hexanes 1:4); [α]D −5.2 (c 0.6, CH2Cl2); IR νmax 1613,
1
1513, 1463, 1381, 1302, 1249, 1172, 1092, 1037, 836, 773 cm−1; H
NMR (400 MHz, CDCl3) δ 7.27 (d, J = 7.9 Hz, 2H), 6.88 (d, J = 8.6
Hz, 2H), 5.68−5.55 (m, 2H), 4.45 (s, 2H), 4.10−3.96 (m, 2H), 3.81
(s, 3H), 3.69 (dd, J = 5.2, 2.2 Hz, 1H), 3.50−3.37 (m, 2H), 2.28−2.21
(m, 1H), 1.88−1.69 (m, 3H), 0.90−0.83 (m, 15H), 0.07 (s, 3H), 0.05
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 132.9, 130.3, 129.5,
126.7, 113.8, 75.4, 72.1, 66.3, 65.5, 55.2, 38.2, 38.1, 31.3, 26.0, 18.3,
16.5, 11.7, −4.0, −4.3; MS (ESI) m/z 423 [M + H]+, 445 [M + Na]+,
461 [M + K]+; HRMS (ESI) m/z calcd for C24H43O4Si [M + H]+
423.2931, found 423.2936. Anal. Calcd for C24H42O4Si: C, 68.20; H,
10.02. Found: C, 68.20; H, 9.88.
(4S,5R,6R,7R,9Z)-6-[(tert-Butyldimethylsilyl)oxy]-11-[(4-
methoxyphenyl)methoxy]-5,7-dimethylundec-9-en-1-yn-4-ol (32).
1. DMSO (2.2 mL, 32 mmol) and after 20 min and a further 45
min, respectively, alcohol 30 (3.8 g, 9 mmol) in CH2Cl2 (5 mL) and
Et3N (750 μL, 4.4 mmol) were added dropwise with stirring to oxalyl
chloride (1.5 mL, 18 mmol) in CH2Cl2 (60 mL) at −78 °C. The
mixture was allowed to warm to 0 °C, and saturated aqueous NaHCO3
was added. The aqueous layer was extracted with CH2Cl2 (3×), and
the combined organic layers were washed with saturated aqueous
CuSO4, brine, and H2O, dried (MgSO4), filtered, and rotary
evaporated to afford the crude aldehyde (3.6 g, 95%), which was
used without any further purification: Rf 0.80 (EtOAc/hexanes 1:9).
2. Amino alcohol 31 (2.8 mg, 13 mmol), pyridine (1.0 mL,
13 mmol), and propargyl bromide (80 wt % in PhMe, 1.4 mL, 13 mmol)
were added with stirring to indium powder (1.5 g, 3.07 mmol) in THF
(5S,6R,7R,8R,10Z)-7-[(tert-Butyldimethylsilyl)oxy]-12-[(4-
methoxyphenyl)methoxy]-6,8-dimethyldodec-10-en-2-yn-5-ol (33).
n-BuLi in hexanes (2.5 M; 3.0 mL) followed by MeI (1.2 mL, 18.5
mmol) were added with stirring to acetylene 32 (1.7 g, 3.7 mmol) in
THF (3 mL) at −78 °C. After 2 h, the mixture was added to saturated
aqueous NH4Cl, and the aqueous layer was extracted with CH2Cl2
(2×). The combined organic layers were washed with brine, dried
(MgSO4), filtered, rotary evaporated, and chromatographed (Et2O/
hexanes 1:9) to afford acetylene 33 (1.0 g, 60%) as a colorless oil: Rf
0.45 (EtOAc/hexanes 1:4); [α]D −9.5 (0.4, CHCl3); IR νmax 3450,
1
1613, 1513, 1463, 1302, 1249, 1173, 1086, 1034, 836, 774 cm−1; H
NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6
Hz, 2H), 5.68 5.55 (m, 2H), 4.44 (s, 2H), 4.04 (d, J = 5.8 Hz, 2H),
3.81 (s, 3H), 3.73−3.68(m, 1H), 3.63 (dd, J = 4.6, 3.4 Hz, 1H), 2.34−
2.31 (m, 2H), 2.20−2.14 (m, 1H), 1.91−1.81 (m, 2H), 1.79−1.70 (m,
4H), 0.94−0.88 (m, 15H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 159.2, 132.4, 130.4, 129.4, 127.2, 113.8, 78.1, 77.8,
75.6, 72.9, 71.9, 65.6, 55.3, 39.3, 38.7, 30.9, 26.1, 25.5, 18.3, 16.1, 9.1,
3.5, −3.5, −4.1; MS (ESI) m/z 475 [M + H]+, 497 [M + Na]+, 513 [M
+ K]+; HRMS (ESI) m/z calcd for C28H47O4Si [M + H]+ 475.3244,
3067
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The Journal of Organic Chemistry
Featured Article
found 475.3245. Anal. Calcd for C28H46O4Si: C, 70.84; H, 9.77.
Found: C, 70.96; H, 9.69.
145.5, 132.1, 130.5, 129.4, 127.5, 113.8, 112.2, 106.5, 101.7,
78.3, 77.7, 75.9, 75.7, 75.6, 74.2, 71.9, 65.7, 55.3, 39.4, 38.5,
38.2, 37.6, 30.1, 26.1, 22.7, 22.0, 18.2, 18.1, 16.1, 14.7, 13.0,
10.8, 3.5 (2 C), −3.7; MS (ESI) m/z 891 [M + H]+, 913 [M +
Na]+; HRMS (ESI) m/z calcd for C52H83O8Si2 [M + H]+
891.5681, found 891.5654. Resorcylate 34 (R = Me): Rf 0.65
(EtOAc/hexanes 3:7) [α]D +14.0 (c 0.4, CHCl3); IR νmax 3475,
Synthesis of Acid 40. (2R,3S)-2-Methyl-3-{[tris(propan-2-
yl)silyl]oxy}hexanoic Acid (40). 1. i-Pr3SiOTf (1.2 mL, 4.7
mmol) was added with stirring to (4R)-4-benzyl-3-[(2R,3S)-
3-hydroxy-2-methylhexanoyl]-1,3-oxazolodin-2-one4,5 (1.1 g,
3.6 mmol) and 2,6-lutidine (1 mL, 9 mmol) in CH2Cl2 (75 mL)
at 0 °C. After 4 h, H2O was added, the aqueous layer was
extracted with CH2Cl2 (2×), and the combined organic layers
were washed with brine, dried (MgSO4), and rotary evaporated.
The residue was chromatographed (EtOAc/hexanes 1:9) to
afford the corresponding silyl ether (1.3 g, 78%) as a white
gum: Rf 0.60 (EtOAc/hexanes 1:9) [α]D −60.1 (c 1.5, CHCl3);
1
1618, 1462, 1248, 1086, 1039, 834, 773, 673 cm−1; H NMR
(400 MHz, CDCl3) δ 11.26 (s, 1H), 7.27 (d, J = 8.6 Hz, 2H),
6.88 (d, J = 8.6 Hz, 2H), 6.41 (d, J = 2.5 Hz, 1H), 6.31 (d, J =
2.5 Hz, 1H), 5.68−5.52 (m, 2H), 5.30−5.27 (m, 1H), 4.44 (s,
2H), 4.25−4.22 (m, 1H), 4.06 (d, J = 6.1 Hz, 2H), 3.80 (s,
3H), 3.79 (s, 3H), 3.51 (dd, J = 5.7, 2.8 Hz, 1H), 3.30 (dd, J =
14.1, 4.3 Hz, 1H), 2.95 (dd, J = 14.1, 8.6 Hz, 1H), 2.70−2.56
(m, 2H), 2.33−2.20 (m, 3H), 2.09−2.01 (m, 1H), 1.93−1.68
(m, 9H), 1.06−0.86 (m, 39H), 0.08 (s, 3H), 0.04 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.9, 164.7, 163.5, 159.2, 144.6,
132.1, 130.5, 129.4, 127.5, 113.8, 111.9, 106.1, 99.3, 78.8, 78.3,
75.9, 75.8, 75.5, 74.2 (2 C), 71.9, 65.7, 55.3 (2 C), 39.4, 38.5,
38.4, 37.7, 30.9, 26.1, 22.7, 22.0, 18.2, 18.1, 16.1, 14.8, 13.0,
10.8, 3.5 (2 C), −3.7; MS (ESI) m/z 905 [M + H]+, 927 [M +
Na]+; HRMS (ESI) m/z calcd for C53H85O8Si2 [M + H]+
905.5783, found 905.5786.
1
IR νmax 3526, 1719, 1693, 1385, 1209 cm−1; H NMR (400
MHz, CDCl3) δ 7.35−7.21 (m, 5H), 4.58, (ddd, J = 9.8, 7.3, 2.6
Hz, 1H), 4.24 (dt, J = 8.1 Hz, 4.3 Hz, 1H), 4.20−4.08 (m, 2H),
3.85 (dq, J = 6.9, 4.0 Hz, 1H), 3.32 (dd, J = 13.4, 2.1 Hz, 1H),
2.79 (dd, J = 13.4, 9.4 Hz, 1H), 1.65−1.53 (m, 2 H), 1.40−1.30
(m, 2 H), 1.23 (d, J = 6.9 Hz, 3H), 1.07 (s, 21 H), 0.97 (t, J =
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.9, 153.1,
135.4, 129.4, 128.9, 127.3, 73.0, 66.0, 55.9, 42.5, 38.0, 37.0,
18.2, 17.7, 14.4, 13.1, 10.3; MS (ESI) m/z 462 [M + H]+;
HRMS (ESI) m/z calcd for C26H44NO4Si [M + H]+ 462.3040,
found 462.3035.
(3S,8S,9R)-3-[(2R,3R,4R,6Z)-3-[(tert-Butyldimethylsilyl)oxy]-8-[4-
methoxyphenyl)methoxy]-4-methyloct-6-en-2-yl]-12,14-dime-
thoxy-8-methyl-9-{[tris(propan-2-yl)silyl]oxy}-3,4,7,8,9,10-hexahy-
dro-1H-2-benzoxacyclododecan-1-one (36). 1. K2CO3 (1.5 mg,
21.1 mmol) followed by MeI (1.3 mL, 21.1 mmol) were added with
stirring to resorcylate 34 (R = H, Me) (0.9 g, 1.06 mmol) in Me2CO
(40 mL), and the mixture was heated at 60 °C for 2 h. Saturated aqueous
NH4Cl was added, and the aqueous layer was extracted with EtOAc
(2×). The combined organic layers were dried (MgSO4), filtered, rotary
evaporated, and chromatographed (Et2O/hexanes 1:19) to afford the
corresponding protected resorcylate (0.80 mg, 82%) as a colorless oil:
Rf 0.60 (EtOAc/hexanes 1:4) [α]D +14.0 (c 0.6, CHCl3); IR νmax
2. Aqueous H2O2 (30 wt %; 2 mL) and LiOH (0.4 g, 10 mmol) in
H2O (10 mL) were added with stirring to the preceding oxazolidinone
(1.9 g, 4.1 mmol) in THF (40 mL). After 4 h, aqueous Na2SO3 (1.3 M)
was added with stirring and, after a further 30 min, the aqueous
layer was first extracted with CH2Cl2 and acidified to pH 3 with
aqueous HCl (1 M) and finally re-extracted with CH2Cl2 (3X). The
combined organic layers (of the second extraction) were dried
(MgSO4), filtered and rotary evaporated to afford carboxylic acid 40
(0.9 g, 70%) as a colorless oil: Rf 0.50 (EtOAc/hexanes 1:9) [α]D −9.8
1
(c 2.1, CHCl3); IR νmax 1706, 1462, 1385, 1234, 1137, 881 cm−1; H
NMR (400 MHz, CDCl3) δ 4.15 (td, J = 10.0, 5.5 Hz, 1H), 2.72−2.66
(qd, J = 7.1, 5.5 Hz, 1H), 1.61−1.50 (m, 2H), 1.43−1.31 (m, 2H),
1.14 (d, J = 7.1 Hz, 3H), 1.10 (s, 21H), 0.92 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 74.3, 44.0, 36.1, 18.6, 18.0, 17.7, 14.3,
12.6, 11.25; MS (ESI) m/z 301 [M−H]−; HRMS (ESI) m/z calcd for
C16H33O3Si [M − H]− 301.2199, found 301.2192.
1
1721, 1605, 1513, 1463, 1249, 1159, 1087, 1044, 835, 773 cm−1; H
NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6
Hz, 2H), 6.50 (d, J = 2.6 Hz, 1H), 6.31 (d, J = 2.6 Hz, 1H), 5.67−5.56
(m, 2H), 5.11−5.04 (m, 1H), 4.44 (s, 2H), 4.31−4.27 (m, 1H), 4.07
(d, J = 6.1 Hz, 2H), 3.79 (s, 6H), 3.75 (s, 3H), 3.58−3.55 (m, 1H),
2.75−2.58 (m, 4H), 2.29−1.74 (m, 7H), 1.77 (t, J = 2.3 Hz, 3H), 1.76
(t, J = 2.3 Hz, 3H), 1.00−0.88 (m, 39H), 0.07(s, 3H), 0.06 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 167.7, 160.7, 159.1, 157.8, 139.1,
132.6, 130.5, 129.4, 127.2, 117.8, 113.8, 107.0, 96.7, 78.1, 78.0, 76.3,
75.2, 74.6, 71.8, 65.7, 55.6, 55.2 (2 C), 38.8, 37.9, 37.8, 36.1, 30.1, 26.1,
22.7, 22.0, 18.2, 18.1, 16.7, 14.6, 13.0, 10.4, 3.6, 3.5, −3.7, (2 quaternary
C of low intensity); MS (ESI) m/z 919 [M + H]+, 941 [M + Na]+;
HRMS (ESI) m/z calcd for C54H87O8Si2 [M + H]+ 919.5940, found
919.5960.
2. Catalyst 35 (130 mg, 40 mol %) was added to the preceding
resorcylate (300 mg, 0.33 mmol) in PhMe (20 mL) at 110 °C under a
closed Ar atmosphere. After 8 h, the mixture was filtered through a
short pad of silica, and the resulting filtrate was rotary evaporated. The
residue was chromatographed (Et2O/hexanes 1:9) to afford macro-
cycle 36 (215 mg 75%) as a colorless oil: Rf 0.60 (EtOAc/hexanes 1:4)
[α]D −14,4 (c 0.6, CHCl3); IR νmax 1739, 1604, 1514, 1466, 1258,
1157, 1087, 1055, 837, 772, 751 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.26 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.43 (d, J = 2.5 Hz,
1H), 6.33 (d, J = 2.5 Hz, 1H), 5.65−5.53 (m, 2H), 5.47 (br s, 1H),
4.43 (s, 2H), 4.06−4.00 (m, 3H), 3.80−3.72 (m, 10H), 3.49 (dd, J =
4.2, 4.2 Hz, 1H), 2.51−2.39 (m, 4H), 2.19−2.13 (m, 2H), 1.99−1.94
(m, 1H) 1.88−1.77 (m, 3H), 1.06 (d, J = 6.9 Hz, 3H), 0.97−0.91 (m,
33H), 0.88 (d, J = 6.3 Hz, 3H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 167.4, 160.3, 159.2, 157.3, 139.5, 132.4, 130.5,
129.3, 127.2, 118.2, 113.8, 108.3, 96.7, 81.4, 79.7, 77.3, 76.5, 74.8, 71.9,
65.7, 55.8, 55.3 (2 C), 40.9, 38.7, 37.7, 37.6, 30.12, 26.1, 23.8, 23.3,
18.5, 18.1, 17.9, 17.0, 13.0, 11.4, −3.6, −3.5; MS (ESI) m/z 865 [M +
H]+, 882 [M + H2O]+, 887 [M + Na]+, 903 [M + K]+; HRMS (ESI)
m/z calcd for C50H80O8Si2 [M + H]+ 865.5470, found 865.5468.
Synthesis of Cruentaren A (1). (5S,6R,7R,8R,10Z)-7-[(tert-
Butyldimethylsilyl)oxy]-12-[4-methoxyphenyl)methoxy]6,8-dime-
thyldodec-10-en-2-yn-5-yl 2,4-Dihydroxy-6-[(2R,3S)-3-methyl-2-
{[tris(propan-2-yl)silyl]oxy}hept-5-yn-1-yl]benzoate (34, R = H)
and (5S,6R,7R,8R,10Z)-7-[(tert-Butyldimethylsilyl)oxy]-12-[4-
methoxyphenyl)methoxy]6,8-dimethyldodec-10-en-2-yn-5-yl 2-di-
hydroxy-4-methoxy-6-[(2R,3S)-3-methyl-2-{[tris(propan-2-yl)silyl]-
oxy}hept-5-yn-1-yl]-4-methoxybenzoate (34, R = Me). Diketo-
dioxinone 22 (1.26 g, 2.55 mmol) and alcohol 33 (1.15 g,
2.42 mmol) in CH2Cl2 (20 mL) were heated to 110 °C in a
sealed tube. After 2 h, the solvent was rotary evaporated, the
residue was dissolved in MeOH (20 mL), and Cs2CO3 (2.4 g,
7.0 mmol) was added. After 20 min, HCl in MeOH (1.25 M;
30 mL) was added and the mixture stirred for 30 min and
extracted with EtOAc (3×). The combined organic extracts
were washed with aqueous HCl (1 M) and brine, dried
(MgSO4), filtered, and rotary evaporated. The residue was
chromatographed (Et2O/hexanes 1: 19) to afford resorcylates
34 (R = H) (0.68 g) and 34 (R = Me) (0.52 mg) with a
combined yield of 55%. Resorcylate 34 (R = H): Rf 0.55
(EtOAc/hexanes 3:7) [α]D +12.0 (0.4, CHCl3); IR νmax 3372,
1
1614, 1515, 1466, 1248, 1086, 1035, 834, 772, 675 cm−1; H
NMR (400 MHz, CDCl3) δ 11.24 (s, 1H), 7.27 (d, J = 8.6 Hz,
2H), 6.87 (d, J = 8.6 Hz, 2H), 6.34 (d, J = 2.6 Hz, 1H), 6.28 (d,
J = 2.6 Hz, 1H), 5.68−5.52 (m, 2H), 5.30−5.26 (m, 1H), 5.10
(s, 1H), 4.45 (s, 2H), 4.22 (dt, J = 8.2, 4.0 Hz), 4.07−4.05 (m,
2H), 3.80 (s, 3H), 3.50 (dd, J = 5.7, 2.8 Hz, 1H), 3.30 (dd, J =
14.1, 4.0 Hz, 1H), 2.90 (dd, J = 14.1, 8.2 Hz, 1H), 2.70−2.56
(m, 2H), 2.32 − 2.31 (m, 3H), 2.08−2.01 (m, 1H), 1.93−1.70
(m, 9H), 1.06−0.86 (m, 39H), 0.08 (m, 3H), 0.04 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 169.8, 164.6, 160.0, 159.6,
3068
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The Journal of Organic Chemistry
Featured Article
(3S,8S,9R)-3-[(2R,3R,4R,6Z)-3-[(tert-Butyldimethylsilyl)oxy]-8-hy-
droxy-4-methyloct-6-en-2-yl]-12,14-dimethoxy-8-methyl-9-{[tris-
(propan-2-yl)silyl]oxy}-3,4,7,8,9,10-hexahydro-1H-2-benzoxacyclo-
dodecan-1-one (38). DDQ (100 mg, 0.3 mmol) was added with
vigorous stirring to ether 36 (200 mg, 0.23 mmol) in CH2Cl2 and H2O
(1: 1; 2 mL). After 20 min, the solution was added to saturated
aqueous NaHCO3 and the aqueous layer was extracted with CH2Cl2
(2×) The combined organic extracts were dried (MgSO4), filtered,
rotary evaporated, and chromatographed (Et2O/hexanes 1:19 to 1:4)
to give alcohol 38 (150 mg, 87%) as a colorless oil: Rf 0.30 (EtOAc/
hexanes 1:4) [α]D −16.0 (c 0.9, CHCl3); IR νmax 3427, 1732, 1603,
CD2Cl2) δ 6.44 (t, J = 5.3 Hz), 6.43 (d, J = 2.2 Hz, 1H), 6.34 (d, J =
2.2 Hz, 1H), 5.54−5.49 (m, 1H), 5.46−5.41 (m, 2H), 4.00−3.95 (m,
2H), 3.90−3.78 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.72 (d, J = 13.0
Hz, 1H), 3.51 (dd, J = 4.6, 4.6 Hz, 1H), 2.54−2.38 (m, 5H), 2.23−
2.14 (m, 2H), 1.97−1.76 (m, 4H), 1.53−1.27 (m, 4H), 1.10−0.88 (m,
66H), 0.09 (s, 6H); 13C NMR (125 MHz, CD2Cl2) δ 174.0, 167.8,
160.9, 157.8, 140.0, 132.3, 127.3, 118.7, 109.0, 97.0, 81.6, 80.2, 77.9,
77.0, 75.8, 75.2, 56.3, 55.8, 46.0, 41.4, 39.1, 38.2 (2 C), 38.1, 36.9, 36.,
30.3, 26.5, 24.3, 23.8, 19.8, 18.9, 18.6, 18.5, 18.4, 18.2, 17.4, 14.7, 13.6,
13.3, 12.9, 11.6, −3.3, −3.4; MS (ESI) m/z 1028 [M + H]+, 1050
[M + Na]+; HRMS (ESI) m/z calcd for C58H106NO8Si3 [M + H]+
1028.7226, found 1028.7225.
1
1461, 1265, 1158, 1083, 1051, 832, 769, 674 cm−1; H NMR (400
MHz, CDCl3) δ 6.43 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H),
5.68−5.62 (m, 1H), 5.57 − 5.48 (m, 2H), 5.48 (s, 1H), 4.25 − 4.12
(m, 2H), 4.01 (d, J = 8.8 Hz, 1H), 3.80−3.73 (m, 7H), 3.50 (dd, J =
4.4, 4.4 Hz, 1H), 2.55−2.39 (m, 4H), 2.27−2.14 (m, 2H), 1.99−1.92
(m, 1H), 1.90−1.77 (m, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.98−0.91 (m,
36H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
167.5, 160.3, 157.3, 139.5, 131.8, 129.5, 118.1, 108.4, 96.7, 81.3, 79.6,
77.2, 74.8, 58.6, 55.8, 55.2, 41.0, 38.6, 37.6, 37.4, 29.8, 26.1, 23.9, 23.3,
18.4, 18.1, 17.9, 17.3, 13.0, 11.6, −3.7, (1 C missing, underneath
CDCl3 peak); MS (ESI) m/z 745 [M + H]+, 767 [M + Na]+, 783
[M + K]+; HRMS (ESI) m/z calcd for C42H73O7Si2 [M + H]+
745.4895, found 745.4921.
(2R,3S)-N-[(2Z,5R,6R,7S)-7-[(3S,8S,9R)-9,14-Dihydroxy-12-methoxy-
8-methyl-1-oxo-3,4,7,8,9,10-hexahydro-1H-2-benzoxacyclodode-
can-3-yl]-6-hydroxy-5-methyloct-2-en-1-yl]-3-hydroxy-2-methyl-
hexanamide (42). BCl3 in CH2Cl2 (1 M; 75 μL) was added
with stirring to amide 41 (35 mg, 0.034 mmol) in CH2Cl2 at −78 °C.
After 1 h, reaction was quenched by the addition of MeOH and the
resulting solution rotary evaporated. The residue was dissolved again
in MeOH and the solution rotary evaporated. The crude oil was
chromatographed (MeOH/CH2Cl2 1:19) to afford the corresponding
macrocycle (26 mg, 75%) as an amorphous solid: Rf 0.65 (EtOAc/
hexanes 1:4) [α]D −17.5 (c 0.4, CH2Cl2); IR νmax 3347, 1649, 1620,
1
1469, 1276, 1260, 1163, 1100, 1041, 765, 750 cm−1; H NMR (500
(3S,8S,9R)-3-[(2R,3R,4R,6Z)-8-Amino-3-[(tert-butyldimethylsilyl)-
oxy]-4-methyloct-6-en-2-yl]-12,14-dimethoxy-8-methyl-9-{[tris-
(propan-2-yl)silyl]oxy}-3,4,7,8,9,10-hexahydro-1H-2-benzoxacyclo-
dodecan-1-one (39). 1. Zn(N3)2·(pyridine)2 (213 mg, 0.7 mmol) and
PPh3 (190 mg, 0.7 mmol) were added with stirring to alcohol 38
(130 mg, mmol) in PhMe (20 mL), and the mixture was cooled to 0 °C,
when i-PrO2CNNCO2-i-Pr (140 μL, 0.7 mmol) was added. After
4 h at room temperature, the mixture was filtered and the filtrate rotary
evaporated. The residue was chromatographed (Et2O/hexanes 1:9) to
give the corresponding azide (115 mg, 85%) as an amorphous solid: Rf
0.70 (EtOAc/hexanes 1:4) [α]D −24.1 (c 0.8, CH2Cl2); IR νmax 2099,
MHz, CD2Cl2) δ 11.09 (s, 1H), 6.48 (t, J = 5.4 Hz, 1H), 6.37 (d, J =
2.2 Hz, 1H), 6.34 (d, J = 2.2 Hz, 1H), 5.49−5.41 (m, 2H), 5.22 (br s,
1H), 4.24−4.22 (m, 2H), 3.98 (ddd, J = 5.7, 5.6, 3.6 Hz, 1H), 3.89
(ddd, J = 14.6, 5.9, 5.5 Hz, 1H), 3.81 (ddd, J = 14.6, 5.9, 5.5 Hz, 1H),
3.79 (s, 3H), 3.53 (dd, J = 5.8, 2.1 Hz, 1H), 2.89−2.86 (m, 1H), 2.63−
2.60 (m, 1H), 2.52 (dq, J = 7.3, 3.6 Hz, 1H), 2.47 (d, J = 7.0 Hz, 1H),
2.31−2.26 (m, 1H), 2.23−2.18 (m, 2H), 2.08−2.05 (m, 1H), 1.92−
1.85 (m, 2H), 1.72−1.67 (m, 1H), 1.54−1.27 (m, 4H), 1.10−076 (m,
66H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CD2Cl2) δ
174.1, 171.6, 164.9, 164.0, 144.3, 132.0, 127.6, 107.4 (2 C), 99.4, 76.6
(2 C), 76.2, 75.8, 55.8, 46.1, 39.5, 39.4 (2 C), 38.2, 37.1, 36.5, 31.3,
26.4, 22.4 (2 C), 19.8, 18.9, 18.6, 18.5, 16.2, 14.7, 13.7, 13.4, 12.9, 11.6,
−3.3, −3.4 (2 quaternary C missing); MS (ESI) m/z 1014 [M + H]+,
1036 [M + Na]+; HRMS (ESI) m/z calcd for C57H104NO8Si3 [M +
H]+ 1014.7070, found 1014.7049.
1
1739, 1608, 1461, 1263, 1161, 1091, 1057, 833, 774 cm−1; H NMR
(400 MHz, CD2Cl2) δ 6.41 (d, J = 2.2 Hz, 1H), 6.32 (d, J = 2.2 Hz,
1H), 5.76−5.69 (m, 1H), 5.58−5.51 (m, 1H), 5.46−5.37 (m, 1H),
3.97 (d, J = 8.9 Hz, 1H), 3.79−3.68 (m, 9H), 3.50 (dd, J = 4.6, 4.6 Hz,
1H), 2.49−2.36 (m, 4H), 2.24−2.12 (m, 2H), 1.96−1.74 (m, 4H),
1.03 (d, J = 7.1 Hz, 3H), 0.96−0.89 (m, 36 H), 0.07 (s, 6H); 13C
NMR (100 MHz, CD2Cl2) δ 167.8, 161.0, 157.8, 140.0, 135.6, 123.7,
118.7, 109.1, 97.1, 81.7, 80.2, 77.9, 77.0, 75.1, 56.3, 55.8 (2 C), 47.3,
41.5, 39.1, 38.2, 38.1, 30.4, 26.5, 24.3, 23.8, 18.9, 18.5, 18.2, 17.5, 13.6,
11.7, −3.3, −3.4; MS (ESI) m/z 770 [M + H]+, 792 [M + Na]+, 808
[M + K]+; HRMS (ESI) m/z calcd for C42H73O7Si2 [M + H]+
770.4960, found 770.4966.
2. PPh3 (360 mg, 13.7 mmol) was added with stirring to the pre-
ceding azide (105 mg, 0.14 mmol) in THF and H2O (10:1; 1.5 mL).
The reaction mixture was stirred at 50 °C for 4 h and rotary evapo-
rated and the residue chromatographed (CH2Cl2/MeOH/NH3·H2O
9:1:0.1) to afford amine 39 (90 mg, 91%) as an amorphous solid: Rf
0.40 (CH2Cl2/MeOH/NH3·H2O 9:1:0.1). Due to its high instability,
amine 39 was not characterized but directly used without delay
whatsoever.
2. H2SiF6 in H2O (25 wt %; 0.5 mL) was added with stirring to the
preceding macrocycle (20 mg, 0.02 mmol) in MeCN (0.5 mL) at
room temperature. The mixture was stirred at 40 °C for 8 h, cooled to
0 °C, diluted with CH2Cl2, and poured into saturated aqueous
NaHCO3. The aqueous layer was extracted with CH2Cl2 (3×), and the
combined organic layers were dried (MgSO4), filtered, and rotary
evaporated. The residue was chromatographed (MeOH/CH2Cl2 1:19)
to afford macrocycle 42 (9 mg, 76%) as an amorphous solid: Rf 0.40
(MeOH/CH2Cl2 1:19); [α]D +1.5 (c 0.2, CH2Cl2); IR νmax 3355,
1
1712, 1616, 1460, 1260, 1162, 1097, 1019, 803 cm−1; H NMR (500
MHz, CD2Cl2) δ 10.93 (s, 1H), 6.40 (d, J = 2.5 Hz, 1H), 6.37 (d, J =
2.5 Hz, 1H), 6.25 (s, 1H), 5.65−5.59 (m, 1H), 5.445.39 (m, 1H), 5.36
(ddd, J = 8.2, 4.1, 4.1 Hz, 1H), 4.00 (dddd, J = 14.9, 7.6, 6.5, 1.2 Hz,
1H), 3.94 (ddd, J = 10.3, 3.0, 3.0 Hz, 1H), 3.81 (s, 3H), 3.80−3.70 (m,
3H), 3.46−3.40 (m, 2H), 3.05 (br s, 1H), 2.80−2.76 (m, 2H), 2.63−
2.58 (m, 1H), 2.42−2.36 (m, 1H), 2.31−2.22 (m, 3H), 2.18−2.12 (m,
2H), 2.05−2.00 (m, 1H), 1.75−1.67 (m, 2H), 1.47−1.38 (m, 2H),
1.34−1.26 (m, 2H), 1.11 (d, J = 7.1 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H),
0.93−0.87 (m, 9H); 13C NMR (125 MHz, CD2Cl2) δ 176.5, 170.7,
164.0, 163.4, 143.4, 130.0, 127.0, 111.3, 107.0, 99.3, 82.7, 79.4, 77.6,
74.9, 73.6, 71.8, 55.4, 44.9, 38.1, 37.3, 36.8, 36.6, 36.5, 35.8, 30.6, 22.6,
21.3, 19.2, 15.8, 15.1, 13.9, 11.0, 8.2; MS (ESI) m/z 588 [M + H]+,
610 [M + Na]+; HRMS (ESI) m/z calcd for C33H50NO8 [M + H]+
588.3536, found 588.3522.
(2R,3S)-N-[(2Z,5R,6R,7S)-7-[(3S,8S,9R)-9,14-Dihydroxy-12-methoxy-
8-methyl-1-oxo-3,4,7,8,9,10-hexahydro-1H-2-benzoxacyclodode-
cin-3-yl]-6-hydroxy-5-methyloct-2-en-1-yl]-3-hydroxy-2-meth-
ylhexanamide (1). Quinoline (2.5 μL, mmol) followed by Lindlar’s
catalyst (5 wt % Pd on CaCO3, poisoned with lead, 6 mg, 100 wt %)
were added with stirring to macrocycle 42 (6 mg, 0.015 mmol) in
EtOAc (2 mL). The mixture was stirred under a H2 atmosphere for
(2R,3S)-N-[(2Z,5R,6R,7R)-6-[(tert-Butyldimethylsilyl)oxy]-7-
[(3S,8S,9R)-12,14-dimethoxy-8-methyl-1-oxo-9-{[tris(propan-2-yl)-
silyl]oxy}-3,4,7,8,9,10-hexahydro-1H-2-benzoxacyclododeca-3-yl]-
5-methyloct-2-en-1-yl]-2-methyl-3-{[tris(propan-2-yl)silyl]oxy}-
hexanamide (41). HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrame-
thyluronium hexafluorophosphate) (80 mg, 0.33 mmol), HOBt
(30 mg, 0.33 mmol), and i-Pr2NEt (0.1 mL, 0.62 mmol) were added
with stirring to acid 40 (100 mg, 0.33 mmol) in DMF (5 mL). After
30 min, amine 39 (75 mg, 0.1 mmol) was added, and after an
additional 30 min, the reaction was quenched with by addition of H2O.
The aqueous layer was extracted with Et2O (2×), and the combined
organic layers were dried (MgSO4), filtered, and rotary evaporated.
The residue was chromatographed (EtOAc/hexanes 1:4) to afford 41
(85 mg, 67%) as a white gum: Rf 0.60 (EtOAc/hexanes 1:4) [α]D
−17.5 (c 0.4, CH2Cl2); IR νmax 3347, 1735, 1660, 1611, 1464, 1260,
1
1224, 1163, 1091, 1062, 883, 838, 779 cm−1; H NMR (500 MHz,
3069
dx.doi.org/10.1021/jo300225z | J. Org. Chem. 2012, 77, 3060−3070

The Journal of Organic Chemistry
Featured Article
20 min, filtered through Celite, and rotary evaporated. The residue was
chromatographed (MeOH/CH2Cl2 1:19) to afford cruentaren A (1)
(7.5 mg, 83%) as a colorless oil (in total, 15 mg of 1 were prepared in
two batches): Rf 0.45 (MeOH/CH2Cl2 1:19); [α]D −3.0 (c 0.4,
CH2Cl2); IR νmax 3345, 1643, 1616, 1580, 1542, 1460, 1444, 1380,
1317, 1253, 1224, 1204, 1141, 1104, 1055, 1041, 1017, 990, 955 cm−1;
1H NMR (500 MHz, CDCl3) δ 11.48 (s, 1H), 6.37 (d, J = 2.7 Hz,
1H), 6.31 (d, J = 2.7 Hz, 1H), 6.14 (t, J = 5.7 Hz, 1H), 5.64−5.60 (m,
1H), 5.48 (ddd, J = 11.0, 2.9, 1.0 Hz, 1H), 5.44 (ddd, J = 11.0, 4.5, 1.9
Hz, 1H), 5.42−5.39 (m, 1H), 5.30 (ddd, J = 11.6, 5.6, 1.8 Hz, 1H),
3.92 (dddd, J = 14.9, 7.5, 5.7, 1.2 Hz, 1H), 3.87−3.82 (m, 2H), 3.80 (s,
3H), 3.76 (dd, J = 12.8, 1.4 Hz, 1H), 3.65 (ddd, J = 10.8, 2.3, 1.4 Hz,
1H), 3.46 (d, J = 8.9 Hz, 1H), 3.15 (br s, 1H), 2.83 (dt, J = 14.3, 11.6
Hz, 1H), 2.76 (br s, 1H), 2.33 (dt, J = 14.3, 11.8 Hz, 1H), 2.28 (qd, J =
7.2, 2.8 Hz, 1H), 2.30−2.20 (m, 4H), 2.05−1.95 (m, 3H), 1.70 (qddd,
J = 6.8, 6.8, 2.3, 2.0 Hz, 1H), 1.52−1.42 (m, 2H), 1.38 (br s, 1H),
1.29−1.36 (m, 2H), 1.15 (d, J = 7.2 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H),
0.93 (t, J = 7.1 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.80 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 176.4, 171.5, 165.7, 163.5,
143.7, 132.1, 130.9, 126.7, 125.8, 112.3, 104.9, 99.7, 78.0, 74.7, 73.1,
71.8, 55.4, 44.8, 39.2, 38.2, 36.8, 36.6, 36.5, 35.8, 31.6, 30.7, 29.8, 19.2,
16.1, 14.2, 14.0, 11.2, 8.6; MS (ESI) m/z 590 [M + H]+, 497 [M +
Na]+; HRMS (ESI) m/z calcd for C33H52NO8 [M + H]+ 590.3693,
found 590.3701. The 1H and 13C NMR spectra, [α]D, and IR spectrum
were in full agreement with the isolated natural product1 and samples
prepared by published routes.2
(9) (a) Boeckman, R. K. Jr.; Shao, P.; Wrobleski, S. T.; Boehmler,
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra corresponding to all
(21) (a) Hirayama, L. C.; Dunham, K. K.; Singaram, B. Tetrahedron
Lett. 2006, 47, 5173. (b) For an example using this method, see:
reported compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
́
Franca̧ is, A.; Leyva-Perez, A.; Etxebarria-Jardi, G.; Pena, J.; Ley, S. V.
̃
Chem.Eur. J. 2011, 17, 329.
(22) Haye, T. R.; Jeffrey, C. S.; Shao, F. Nature Protocol 2007, 2,
AUTHOR INFORMATION
■
2451.
Corresponding Author
*E-mail: agm.barrett@imperial.ac.uk.
(23) (a) Heppekausen, J.; Stade, R.; Goddard, R.; Furstner, A. J. Am.
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̈
̈
(24) For the preparation of the zinc azide/bis-pyridine complex, see:
Viaud, M. C.; Rollin, P. Synthesis 1990, 130.
ACKNOWLEDGMENTS
■
We thank the European Research Council (ERC) for grant
support, GlaxoSmithKline for the generous Glaxo endown-
ment, and P. R. Haycock and R. N. Sheppard (Imperial College
London) for high-resolution NMR spectroscopy.
(25) For the preparation of acid 40, see the Experimental Section.
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