A [Pd]-mediated ω-alkynone cycloisomerization approach for the central tetrahydropyran unit and the synthesis of C(31)-C(48) fragment of aflastatin A

Article abstract of DOI:10.1039/c1ob05251a

A concise assembly of the central tetrahydropyran unit of aflastatin A featuring a Pd-mediated alkynone cycloisomerization to provide a glycal and its subsequent stereoselective hydroboration to deliver the requisite stereochemistry at C(33) and C(34) cen

Full text of DOI:10.1039/c1ob05251a

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PAPER
A [Pd]-mediated x-alkynone cycloisomerization approach for the
central tetrahydropyran unit and the synthesis of C(31)–C(48) fragment
of aflastatin A†
Sachin B. Narute, Neella Chandra Kiran and Chepuri V. Ramana*
Received 16th February 2011, Accepted 27th April 2011
DOI: 10.1039/c1ob05251a
A concise assembly of the central tetrahydropyran unit of aflastatin A featuring a Pd-mediated
alkynone cycloisomerization to provide a glycal and its subsequent stereoselective hydroboration to
deliver the requisite stereochemistry at C(33) and C(34) centers is documented.
C(31)–C(48) fragment is the construction of the key pyran ring
Introduction
with requisite stereochemistry. The intent was to explore a Pd-
mediated w-alkynone cycloisomerization10 and subsequent regio-
Aflastatin A (1) was isolated by Sakuda and co-workers from
the mycelia of Streptomyces sp. MRI 142.1 Aflastatin A belongs
to the class of polyol natural products and contains a tetramic
acid derivative with a highly oxygenated long alkyl side chain,
as well as a tetrahydropyran ring. Aflastatin A shows strong in-
hibitory activity against aflatoxin production without significantly
affecting the growth of Aspergillus parasiticus.2 Sakuda and co-
workers proposed the relative and absolute structure of aflastatin
A with the help of chemical degradation and extensive NMR
studies.3 The assigned absolute stereochemistry of the degradation
product C(9)–C(27) polyol has been cross-checked by chemical
synthesis and correlation studies by Evans et al.4 The absolute
stereochemistry of the tetrahydropyran ring moiety of aflastatin
A was assigned based on the relative stereochemistry around the
ring and the absolute configuration at C(33). Initially proposed
configurations at the diol [C(8), C(9)] and pentaol [C(25)–C(29)]
moieties have been recently cross-checked by partial chemical
synthesis and NMR correlations in light of the remarks from
Kishi’s group.5 The absolute configuration of aflastatin A has
been revised as given in Fig. 1.6 In the context of our current
program pertaining to the total synthesis of complex polyol natural
products7 and Pd-mediated cycloisomerization on sugar building
blocks,8 aflastatin A has been selected as a particular target. As
a first step towards its total synthesis, herein we describe our
preliminary efforts culminating in a stereoselective approach for
the synthesis of the C(31)–C(48) fragment of aflastatin A.9
and stereoselective hydroboration11 of the resulting C-glycal 3.
Though there exist two competitive pathways for the proposed
cycloisomerization, considering our previous results, a preference
for 6-endo-dig over the 5-exo-dig cyclization was foreseen.8–10
The preceding hydroboration of the resulting C-glycal 3 can be
expected from the end opposite to that of the 35-benzyloxy group,
thus ensuring the requisite stereochemistry at C(33) and C(34).11
For the synthesis of the key w-ynone 4, the addition of alkyne
5 to epoxide 612 was identified as the principal coupling strategy.
For the construction of the key alkyne 5, D-ribose containing the
requisite stereochemistry at C(2) and C(3) matching with that of
C(35) and C(36), respectively, of aflastatin A (Fig. 1) was selected
as a chiral precursor. The C(1) of a ribose derivative can be further
extended to the alkyne C(33)–C(34) unit and C(4) to the carbonyl
present at C(37). In order to introduce the hydroxyl group at C(39),
a regioselective Wacker oxidation of an olefin 7 followed by 1,3-syn
reduction was envisaged.13
In order to check the feasibility of alkynone cycloisomerization,
a model study has been carried out with alkynol 12. The synthesis
of compound 12 started from the known alkyne 914 (Scheme 1).
The free hydroxyl group in compound 9 was protected as its
TBS ether 10. Treatment of compound 10 with n-BuLi followed
by BF3·Et2O at -78 ◦C and addition of ethylene oxide 6 to
the intermediate furnished compound 11 in 84% yield. The
free hydroxyl group in compound 11 was benzylated with NaH
and BnBr in DMF and then the TBS protecting group was
removed with TBAF in THF to deliver the key alkynol 12.
The oxidation of the 2◦-OH in 12 with IBX gave the w-ynone
which was subjected to cycloisomerization [Pd(OAc)2 in MeOH]
without purification to afford the dihydropyrans 13a and 13b
(3 : 1) in 69% yield. The constitution of the dihydropyrans 13a
and 13b was determined with the help of spectral and analytical
data and the anomeric configuration was determined after the
hydroboration. Whilst the major isomer was found to be stable,
the minor isomer was hydrolysed slowly in CDCl3 giving a
Results and discussion
The retrosynthetic strategy for the C(31)–C(48) fragment is
described in Fig. 1. The central issue of the synthesis of the
National Chemical Laboratory, Dr Homi Bhabha Road, Pune, 411 008,
India. E-mail: vr.chepuri@ncl.res.in
† Electronic supplementary information (ESI) available: Experimen-
tal details and spectral data of all the new compounds. See DOI:
10.1039/c1ob05251a
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Fig. 1 Key [Pd]-mediated w-ynone cycloisomerization for synthesis of the C(31)–C(48) fragment of aflastatin A (1).
1,5-diketone 15. Hydroboration–oxidation of 13a and 13b was
carried out separately with BH3·DMS in THF at 0 ◦C followed by
addition of NaOH–30% aq. H2O2 and the resulting alcohols were
converted to the corresponding acetates 14a and 14b for structural
76% yield and with complete regioselectivity.13a The resulting
ketone after stereoselective reduction employing lithium iodide
and LAH delivered alcohol 1713b and the diastereomeric ratio
was found to be 9 : 1. The major diastereomer 17 was separated
and the stereochemistry of the newly generated asymmetric centre
was fixed by converting it into the acetonide derivative 20 by a
sequence of reactions: hydrolysis, Ohira–Bestmann homologation
and acetonide protection.16 In the 13C NMR, the acetal carbon
was seen to resonate at 98.5 ppm and the two methyl carbons at
19.6 and 30.1 ppm, characteristic of the acetonide of a 1,3-syn
diol.17 After determining the stereochemistry at C(39) in 17, we
proceeded further for the synthesis of the alkyne 5. The protection
of the free hydroxyl group in 17 as its benzyl ether 18 followed
by hydrolysis and treatment of intermediate lactal with Ohira–
Bestmann reagent afforded the alkyne 21. The free hydroxy group
in compound 21 was protected as its TBS ether to complete the
synthesis of the key alkyne fragment 5.
Next, the opening of ethylene oxide 6 with the alkyne 5 was
carried out to secure the alcohol 22 in 87% yield. Benzylation
of the free hydroxyl group in compound 22 gave 23, which upon
deprotection of the TBS ether gave the key alkynol 24. Oxidation
of the alkynol 24 (IBX/ethyl acetate) followed by Pd-mediated
cycloisomerization of the resulting carbonyl compound gave 3a
(the anomeric configuration was fixed at a later stage) as the main
product. Subsequently, the hydroboration of glycal 3a followed
by acetylation gave 2a in 65% yield. The structure of compound
2a was established with the help of the 2D NMR studies. In the
1H NMR of 2a, the C(34)–H appeared at 5.23 ppm as a broad
1
characterization. In the H NMR of 14a, the C–H attached to
acetate appeared down field at 5.24 ppm with diaxial coupling
constants (J ª 10 Hz) indicating a trans-orientation with respect
to the adjacent methine hydrogens. The anomeric configuration
of 14a was determined as alpha with the help of nOe studies. The
anomeric configuration of minor product 14b was also determined
in a similar fashion.
After the successful synthesis of the highly substituted tetrahy-
dropyran ring [C(31)–C(38) fragment] of aflastatin A, next we
proceeded further for the synthesis of the C(31)–C(48) fragment
of aflastatin A. As a first step, the synthesis of the alkyne fragment
5 was undertaken (Scheme 2). The synthesis started with the
oxidation of the primary hydroxyl group of known ribofuranoside
derivative 815 under Swern conditions and the subsequent Wittig
reaction with the ylide generated from decyltriphenylphospho-
nium bromide and base (n-BuLi) to afford 7(Z). In the 1H NMR
spectrum of 7(Z), the two olefinic protons resonated down field
at 5.35 (J = 10.8 Hz) and 5.69 ppm (J = 10.8 Hz) while in the
13C NMR, the olefinic carbons appeared at 129.5 and 134.9 ppm
respectively.
After screening several Pd-complexes and conditions, the
regioselective oxidation of 7 could successfully be carried out
employing PdCl2 in dimethyl acetamide and water at 90 ◦C
for 12 h under O2 atmosphere. The ketone 16 was obtained in
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Scheme 1 Reagents and conditions: (a) TBSCl, Im., DMF, rt, 4 h; (b) n-BuLi, BF3·Et2O, ethylene oxide, THF, -78 ◦C; (c) NaH, BnBr, DMF, 0 ◦C–rt,
2 h; (d) TBAF, THF, rt, 4 h; (e) i. IBX, EtOAc, reflux, 3 h; ii. Pd(OAc)2, MeOH, rt, 2 h; (f) i. BH3·DMS, THF, 0 ◦C, 3 h, then H2O2 (30%), 3 N NaOH,
rt, 8 h; ii. Ac2O, Py, CH2Cl2, 3 h.
triplet with characteristic diaxial coupling constant J = 9.8 Hz. In
the 13C NMR, C(33) and C(37) appeared at 79.1 and 102.0 ppm,
respectively. Further, in the NOESY spectrum of 2a, a cross peak
between the –OCH3 group and C(33)–H suggested the assigned
anomeric configuration.
Experimental part
Pd(II)-mediated cycloisomerization and synthesis of glycals 13
To a solution of alcohol 12 (100 mg, 0.18 mmol) in ethyl acetate
(10 mL) was added IBX (76 mg, 0.26 mmol) at room temperature
and the mixture was stirred at reflux temperature for 3 h. After
the complete consumption of the starting material, the reaction
mixture was cooled in an ice bath and filtered through a Celite bed,
and the combined filtrate was evaporated under reduced pressure.
The residual crude ketone (89 mg) was dissolved in anhydrous
methanol (10 mL) and the solution was degassed by passing
argon for 45 min. To this, Pd(OAc)2 (4 mg, 16 mmol) was added
and stirred for 2.5 h. After consumption of starting material, the
reaction mixture was filtered through a Celite bed and the filtrate
was concentrated under reduced pressure. The resulting crude was
purified by column chromatography (silica 230–400 mesh, 2 : 8
ethyl acetate/petroleum ether) to procure compound 13a (60 mg,
52% yield) and 13b (19 mg, 17% yield) as colorless oils.
In order to address whether the observed a-anomeric selectivity
was apparent due to the hydrolysis of the corresponding b-anomer
during the isolation (considering the hydrolysis of b-anomer 13b
noticed in the model studies) the crude cycloisomerization reaction
mixture was subjected to the hydroboration–oxidation. This
resulted in the isolation of the b-anomer 2b as a minor compound
(6 : 1 anomeric selectivity) indicating the ready hydrolysis of the
corresponding glycal. The spectral data of 2b are similar to those
1
of 14b. For example, in the H NMR, the C(34)–H appeared at
5.26 ppm (J = 9.2 Hz) as a broad triplet and the C(33) and C(37)
appeared at 77.3 and 100.8 ppm, respectively, in the 13C NMR.
Conclusion
Spectral data of compound 13a. [a]2D5 +19.4 (c 1.1, CHCl3);
-1
1
˜
In conclusion, the synthesis of the C(31)–C(48) subunit of
aflastatin A was documented. The 6-endo-dig w-ynone cycloiso-
merization and hydroboration are the key reactions that addressed
the central tetrahydropyran ring construction with the requisite
stereochemistry at the C(33), C(34) centers. Further studies to
extend this strategy in the direction of the total synthesis of
aflastatin A are in progress.
IR (CHCl3): n 3015, 2928, 1454, 1099 cm ; H NMR (CDCl3,
400 MHz): d 2.38 (t, J = 6.9 Hz, 2H), 3.16 (s, 3H), 3.51 (d, J =
10.3 Hz, 1H), 3.55–3.60 (m, 2H), 3.70 (d, J = 10.3 Hz, 1H), 4.02
(dd, J = 1.8, 4.1 Hz, 1H), 4.34 (d, J = 12.1 Hz, 1H), 4.38–4.40 (m,
1H), 4.48 (bs, 2H), 4.51 (d, J = 6.6 Hz, 1H), 4.57 (bs, 2H), 4.62
(d, J = 11.7 Hz, 1H), 4.82 (bs, 1H), 4.93 (d, J = 11.7 Hz, 1H),
7.27–7.33 (m, 20H); 13C NMR (CDCl3, 100 MHz): d 34.1 (t), 48.5
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Scheme 2 Reagents and conditions: (a) (COCl)2, DMSO, NEt3, DCM, -78 ◦C; (b) C10H21·PPh3Br, n-BuLi, THF, 0 ◦C–rt, 2 h; (c) PdCl2, DMA,
H2O, O2, 90 ◦C, 12 h; (d) LiI, LAH, Et2O, -100 ◦C, 45 min; (e) NaH, BnBr, DMF, 0 ◦C–rt, 3 h; (f) H2SO4, dioxane : H2O, reflux, 6 h; (g)
dimethyl-1-diazo-2-oxopropylphosphonate, K2CO3, MeOH, rt, 7 h; (h) p-TSA, dimethoxy propane (DMP), 0 ◦C–rt, 2 h; (i) TBSOTf, NEt3, DCM,
-15 ◦C, 2 h; (j) n-BuLi, BF3·Et2O, ethylene oxide, THF, -78 ◦C, 2.5 h; (k) NaH, BnBr, DMF, 0 ◦C–rt, 3 h; (l) TBAF, THF, rt, 2.5 h; (m) i. IBX, EtOAc,
reflux, 3 h; ii. Pd(OAc)2, MeOH, 2.5 h; (n) i. BH3·DMS, THF, 0 ◦C, 2 h, then 30% aq. H2O2, 3 N NaOH, rt, 6 h; ii. Ac2O, Py, CH2Cl2, 3 h.
(q), 64.7 (t), 67.6 (t), 70.3 (d), 70.9 (t), 72.1 (d), 72.9 (t), 73.3 (t),
74.6 (t), 98.9 (d), 101.4 (s), 127.33 (d, 2C), 127.42 (d, 2C), 127.51
(d), 127.57 (d), 127.68 (d, 2C), 127.9 (d), 128.12 (d, 3C), 128.22
(d, 2C), 128.30 (d, 4C), 128.41 (d, 2C), 137.5 (s), 138.3 (s), 138.66
(s, 2C), 147.8 (s) ppm; MALDI-TOF: 603.19 (12% [M + Na]+),
619.15 (100% [M + K]+); Anal. Calcd for C37H40O6: C, 76.53; H,
6.94; Found: C, 76.75; H, 6.81.
ppm; MALDI-TOF: 603.10 (100% [M + Na]+); Anal. Calcd for
C37H40O6: C, 76.53; H, 6.94; Found: C, 76.40; H, 6.99.
Characterization data of diketone 15
During the collection of the spectral data, compound 13b (minor)
in CDCl3 was found to convert into diketone 15. [a]2D5 -8.7 (c 0.8,
-1
˜
CHCl3); IR (CHCl3): n 3031, 2924, 1727, 1712, 1455, 1101 cm ;
Spectral data of compound 13b. [a]2D5 +29.1 (c 0.7, CHCl3);
1H NMR (CDCl3, 400 MHz): d 2.67 (t, J = 6.2 Hz, 2H), 2.74 (dd,
J = 5.6, 17.5 Hz, 1H), 2.85 (dd, J = 7.1, 17.5 Hz, 1H), 3.69 (t,
J = 6.2 Hz, 2H), 4.12 (d, J = 3.1 Hz, 1H), 4.31 (s, 2H), 4.39 (ddd,
J = 3.1, 5.6, 7.1 Hz, 1H), 4.43–4.47 (m, 3H), 4.51–4.58 (m, 5H),
7.19–7.37 (m, 20H); 13C NMR (CDCl3, 100 MHz): d 43.7 (t), 44.1
(t), 64.9 (t), 72.8 (t), 72.9 (t), 73.2 (t), 73.3 (t), 74.2 (t), 75.7 (d), 84.0
(d), 127.68 (d, 4C), 127.81 (d, 2C), 127.92 (d, 3C), 128.03 (d, 2C),
128.1 (d), 128.31 (d, 2C), 128.37 (d, 2C), 128.43 (d, 2C), 128.51 (d,
2C), 137.1 (s), 137.2 (s), 137.8 (s), 138.0 (s), 206.8 (s), 207.5 (s) ppm;
MALDI-TOF: 589.17 (30% [M + Na]+), 605.13 (100% [M + K]+);
HRMS: 589.2566 ([M + Na]+) calculated, 589.2493 ([M + Na]+)
-1
1
˜
IR (CHCl3): n 3019, 2928, 1455, 1096 cm ; H NMR (CDCl3,
400 MHz): d 2.41 (t, J = 6.8 Hz, 2H), 3.33 (s, 3H), 3.62 (t, J =
6.8 Hz, 2H), 3.69 (d, J = 8.9 Hz, 1H), 3.87–3.92 (m, 2H), 4.01
(d, J = 5.3 Hz, 1H), 4.48 (s, 2H), 4.52–4.55 (m, 2H), 4.56–4.61
(m, 3H), 4.70 (d, J = 11.9 Hz, 1H), 4.85 (d, J = 4.8 Hz, 1H),
7.24–7.36 (m, 20H); 13C NMR (CDCl3, 100 MHz): d 34.3 (t), 50.0
(q), 66.2 (d), 67.4 (t), 68.6 (t), 71.0 (t), 72.6 (t), 72.9 (t), 73.5 (t),
74.1 (d), 97.3 (d), 100.2 (s), 127.4 (d), 127.47 (d, 2C), 127.58 (d,
3C), 127.76 (d, 2C), 128.13 (d, 2C), 128.24 (d, 4C), 128.32 (d, 4C),
128.38 (d, 2C), 138.0 (s), 138.1 (s), 138.2 (s), 139.0 (s), 150.3 (s)
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procure compound 14b (14 mg, 65% yield) as a colorless oil. [a]D25
-15.4 (c 0.5, CHCl3); IR (CHCl3): n 3019, 2927, 1738, 1452, 1095
observed; Anal. Calcd for C36H38O6: C, 76.30; H, 6.76; Found: C,
76.38; H, 6.89.
˜
cm-1; 1H NMR (CDCl3, 400 MHz): d 1.84–1.94 (m, 2H), 1.97 (s,
3H), 3.28 (s, 3H), 3.46–3.52 (m, 3H), 3.56 (dd, J = 3.0, 9.1 Hz,
1H), 3.59 (dd, J = 4.9, 9.1 Hz, 1H), 3.62–3.66 (m, 1H), 4.10 (d, J =
3.0 Hz, 1H), 4.23 (d, J = 12.4 Hz, 1H), 4.37 (d, J = 4.1 Hz, 1H),
4.39 (d, J = 4.3 Hz, 1H), 4.46–4.52 (m, 3H), 4.69 (d, J = 12.1 Hz,
1H), 4.87 (d, J = 12.1 Hz, 1H), 5.21 (bt, J = 8.7 Hz, 1H), 7.16–
7.40 (m, 20H); 13C NMR (CDCl3, 100 MHz): d 21.1 (q), 32.8 (t),
49.4 (q), 65.8 (t), 66.8 (t), 70.7 (d), 71.1 (t), 71.9 (d), 72.9 (t), 73.4
(t), 74.2 (d), 74.9 (t), 76.6 (d), 100.3 (s), 127.3 (d), 127.53 (d, 2C),
127.60 (d, 2C), 127.69 (d, 2C), 127.75 (d, 2C), 127.9 (d), 128.01
(d, 2C), 128.23 (d, 4C), 128.34 (d, 2C), 128.52 (d, 2C), 137.6 (s),
138.1 (s), 138.4 (s), 138.8 (s), 170.0 (s) ppm; MALDI-TOF: 658.63
Synthesis of acetate 14a
To an ice-cooled solution of compound 13a (44 mg, 0.076 mmol)
in anhydrous THF (4 ml), was added neat BH3·DMS (16.4 mL,
0.152 mmol) and stirring was continued at room temperature for 3
h. The reaction mixture was cooled to 0 ◦C, treated with 3 N NaOH
(0.5 mL) followed by 30% H2O2 (0.5 mL), and stirred at room
temperature for 8 h. Then THF was evaporated under reduced
pressure, residual material was extracted with diethyl ether (5 mL)
and water (2 mL), the organic layer dried over sodium sulphate
and evaporated under reduced pressure. The crude product was
dissolved in 1 mL anhydrous DCM. To this solution, acetic
anhydride (0.5 mL) and pyridine (0.5 mL) were added. The
contents were stirred for 3 h. After completion of the reaction, the
reaction mixture was concentrated under reduced pressure; traces
of solvent were removed by co-evaporation with toluene (10 mL)
three times. The residue was purified by column chromatography
(silica 230–400 mesh, 15 : 85 ethyl acetate/petroleum ether) to
procure compound 14a (32 mg, 68% yield) as a colorless oil. [a]D25
(100% [M + NH4 ]), 663.48 (31% [M + Na]+); HRMS: 679.2673
+
([M + K]+) calculated, 679.2650 ([M + K]+) observed; Anal. Calcd
for C39H44O8: C, 73.10; H, 6.92; Found: C, 73.37; H, 6.66.
Pd(II)-Mediated cycloisomerization and synthesis of glycals 3
To a solution of alcohol 24 (40 mg, 58 mmol) in ethyl acetate
(5 mL) was added IBX (32 mg, 116 mmol) at room temperature
and the mixture was stirred at reflux temperature for 3 h. After
the complete consumption of the starting material, the reaction
mixture was cooled in and ice bath and filtered through a Celite
bed. The filtrate was evaporated under reduced pressure. The
residual crude ketone (38 mg, 55 mmol) was dissolved in anhydrous
methanol (10 mL) and the solution was degassed by passing argon
for 30 min. To this, Pd(OAc)2 (4 mg, 17 mmol) was added and
stirred for 2.5 h. After consumption of starting material, the
reaction mixture was filtered through a Celite bed and the filtrate
was concentrated under reduced pressure. The resulting crude was
purified by column chromatography (silica 230–400 mesh, 2 : 8
ethyl acetate/petroleum ether) to procure compound 3a (22 mg,
54% yield) as colorless oils. [a]2D5 +29.4 (c 0.3, CHCl3); IR (neat):
˜
-2.4 (c 0.96, CHCl3); IR (CHCl3): n 3019, 2929, 1739, 1371, 1115
1
cm-1; H NMR (CDCl3, 500 MHz): d 1.66–1.72 (m, 1H), 1.80–
1.87 (m, 1H), 1.97 (s, 3H), 3.12 (s, 3H), 3.42 (d, J = 10.1 Hz,
1H), 3.48–3.52 (m, 1H), 3.59 (dd, J = 4.9, 9.4 Hz, 1H), 3.63 (d,
J = 10.1 Hz, 1H), 3.71 (dt, J = 2.4, 10.1, 1H), 3.98 (dd, J = 2.9,
9.8 Hz, 1H), 4.07 (d, J = 2.9 Hz, 1H), 4.40 (d, J = 12.1 Hz, 1H),
4.43 (s, 1H), 4.44 (s, 1H), 4.49 (d, J = 12.2 Hz, 1H), 4.53 (s, 1H),
4.56 (s, 1H), 4.65 (d, J = 12.1 Hz, 1H), 4.90 (d, J = 11.2 Hz, 1H),
5.24 (bt, J = 9.9 Hz, 1H), 7.23–7.37 (m, 20H); 13C NMR (CDCl3,
125 MHz): d 21.1 (q), 31.6 (t), 47.8 (q), 65.2 (t), 66.0 (t), 67.7 (d),
71.7 (t), 71.8 (d), 72.9 (t), 73.4 (t), 74.8 (d), 74.9 (t), 78.4 (d), 100.8
(s), 127.28 (d, 2C), 127.39 (d), 127.42 (d), 127.5 (d), 127.63 (d, 2C),
127.9 (d), 127.97 (d, 2C), 128.13 (d, 2C), 128.21 (d, 2C), 128.27 (d,
2C), 128.30 (d, 2C), 128.44 (d, 2C), 137.6 (s), 138.1 (s), 138.5 (s),
138.6 (s), 170.1 (s) ppm; MALDI-TOF: 663.23 (100% [M + Na]+),
679.19 (87% [M + K]+); HRMS: 663.2934 ([M + Na]+) expected,
663.2907 ([M + Na]+) observed.; Anal. Calcd for C39H44O8: C,
73.10; H, 6.92; Found: C, 73.02; H, 6.98.
-1
1
˜
n 3018, 2925, 1454, 1215, 1095, 759, 667 cm ; H NMR (CDCl3,
400 MHz): d 0.81 (t, J = 6.8 Hz, 3H), 1.19 (bs, 14H), 1.43–1.54
(m, 2H), 1.92 (dd, J = 4.7, 14.8 Hz, 1H), 2.29 (dd, J = 7.3, 14.8 Hz,
1H), 2.32 (t, J = 6.8 Hz, 2H), 3.23 (s, 3H), 3.47–3.50 (m, 1H), 3.55
(t, J = 6.8 Hz, 2H), 3.71 (d, J = 5.2 Hz, 1H), 3.81 (t, J = 5.2 Hz,
1H), 4.26 (d, J = = 11.3 Hz, 1H), 4.30–4.36 (m, 2H), 4.40–4.43 (m,
2 H), 4.46–4.54 (m, 3H), 4.81 (d, J = 5.1 Hz, 1H), 7.18–7.28 (m,
20H); 13C NMR (CDCl3, 100 MHz): d 14.1 (q), 22.7 (t), 24.7 (t),
29.3 (t), 29.6 (t), 29.7 (t), 29.9 (t), 31.9 (t), 34.3 (t), 34.4 (t), 35.6 (t),
49.3 (q), 66.0 (d), 67.5 (t), 70.7 (t), 70.9 (t), 72.0 (t), 72.9 (t), 75.7
(d), 77.0 (d), 97.2 (d), 100.2 (s), 127.35 (d, 2C), 127.5 (d), 127.65
(d, 3C), 127.77 (d, 2C), 128.08 (d, 4C), 128.09 (d, 2C), 128.26 (d,
2C), 128.32 (d, 2C), 128.44 (d, 2C), 138.1 (s), 138.2 (s), 138.8 (s),
139.1 (s), 149.9 (s) ppm; MALDI-TOF: 743.62 (100%, [M + Na]+),
759.60 (33% [M + K]+); Anal. Calcd for C47H60O6: C, 78.30; H,
8.39; Found: C, 78.25; H, 8.45.
Synthesis of acetate 14b
To an ice-cooled solution of compound 13b (19 mg, 0.033 mmol)
in anhydrous THF (4 ml), was added neat BH3·DMS (7.1 mL,
0.066 mmol) and stirring was continued at room temperature for 3
h. The reaction mixture was cooled to 0 ◦C, treated with 3 N NaOH
(0.3 mL) followed by 30% H2O2 (0.3 mL), and stirred at room
temperature for 8 h. Then THF was evaporated under reduced
pressure, residual material was extracted with diethyl ether (3 mL)
and water (1 mL), the organic layer was dried over sodium sulphate
and evaporated under reduced pressure. The crude product was
dissolved in 0.5 mL anhydrous DCM. To this solution, acetic
anhydride (0.5 mL) and pyridine (0.5 mL) were added. The
contents were stirred for 3 h. After completion of the reaction, the
reaction mixture was concentrated under reduced pressure; traces
of solvent were removed by co-evaporation with toluene (5 mL)
four times. The residue was purified by column chromatography
(silica 230–400 mesh, 15 : 85 ethyl acetate/petroleum ether) to
Synthesis of acetate 2a
To an ice-cooled solution of compound 3a (18 mg, 0.025 mmol)
in anhydrous THF (2 ml), was added neat BH3·DMS (4.4 mL,
0.050 mmol) and stirring was continued at room temperature for 3
h. The reaction mixture was cooled to 0 ◦C, treated with 3 N NaOH
(0.2 mL) followed by 30% H2O2 (0.3 mL), and stirred at room
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temperature for 6 h. Then THF was evaporated under reduced
pressure, residual material was extracted with diethyl ether (5 mL)
and water (2 mL), the organic layer was dried over sodium sulphate
and evaporated under reduced pressure. The crude product was
dissolved in 0.5 mL anhydrous DCM. To this solution, acetic
anhydride (0.5 mL) and pyridine (0.5 mL) were added. The
contents were stirred for 3 h. After completion of the reaction,
the reaction mixture was concentrated under reduced pressure;
traces of solvent were removed by co-evaporation with toluene (3
¥ 5 mL). The residue was purified by column chromatography
(silica 230–400 mesh, 15 : 85 ethyl acetate/petroleum ether) to
procure compound 2a (12 mg, 65% yield) as colorless oil. [a]D25
and evaporated under reduced pressure. The crude product was
dissolved in 0.5 mL anhydrous DCM. To this solution, acetic
anhydride (0.5 mL) and pyridine (0.5 mL) were added. The
contents were stirred for 3 h. After completion of the reaction,
the reaction mixture was concentrated under reduced pressure;
traces of solvent were removed by co-evaporation with toluene (3 ¥
5 mL). The residue was purified by column chromatography (silica
230–400 mesh, 15 : 85 ethyl acetate/petroleum ether) to procure
compound 2a (30 mg, 26.5% yield, 4 steps) and 2b (5 mg, 4.4%
yield, 4 steps) as colorless oils.
Spectral data for 2b. [a]2D5 +17.2 (c 0.2, CHCl3); IR (CHCl3):
-1
1
˜
n 3021, 2928, 1742, 1452, 1221, 1088, 769, 672 cm ; H NMR
(CDCl3, 400 MHz): d 0.88 (t, J = 6.7 Hz, 3H), 1.27 (bs, 14H),
1.41–1.45 (m, 1H), 1.49–1.54 (m, 1H), 1.77 (dd, J = 4.5, 15.2 Hz,
1H), 1.81–1.94 (m, 3H), 2.00 (s, 3H), 3.35 (s, 3H), 3.38–3.43 (m,
1H), 3.51–3.55 (m, 1H), 3.56–3.64 (m, 3H), 3.76 (d, J = 3.1 Hz,
1H), 4.31 (d, J = 12.5 Hz, 1H), 4.38–4.43 (m, 3H), 4.45–4.49 (m,
2H), 4.72 (d, J = 12.0 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H), 5.26
(t, J = 9.2 Hz, 1H), 7.17–7.24 (m, 6H), 7.26–7.38 (m, 14H); 13C
NMR (CDCl3, 100 MHz): d 14.1 (q), 21.1 (q), 22.7 (t), 24.8 (t),
29.3 (t), 29.6 (t), 29.63 (t), 29.7 (t), 29.9 (t), 31.9 (t), 32.4 (t), 34.9
(t), 36.1 (t), 50.1 (q), 66.1 (t), 69.4 (d), 71.2 (t), 71.5 (t), 71.8 (d),
73.0 (t), 74.6 (t), 75.3 (d), 76.8 (d), 77.3 (d), 100.8 (s), 127.3 (d),
127.49 (d, 2C), 127.5 (d), 127.6 (d), 127.67 (d, 4C), 128.03 (d,
2C), 128.27 (d, 2C), 128.30 (d, 6C), 128.4 (d), 138.1 (s), 138.4 (s),
138.6 (s), 138.8 (s), 169.9 (s) ppm; MALDI-TOF: 803.64 (25%
[M + Na]+), 819.61 (100% [M + K]+); HRMS: 803.4499 ([M +
Na]+) calculated, 803.4446 ([M + Na]+) observed; Anal. Calcd for
C49H64O8: C, 75.35; H, 8.26; Found: C, 75.41; H, 8.45.
˜
+37.9 (c 0.3, CHCl3); IR (CHCl3): n 3018, 2925, 1736, 1459, 1216,
1095, 767, 669 cm-1; 1H NMR (CDCl3, 400 MHz): d 0.88 (t, J =
6.8 Hz, 3H), 1.27–1.32 (m, 14H), 1.59–1.66 (m, 3H), 1.69–1.72 (m,
1H), 1.79–1.85 (m, 1H), 1.97 (s, 3H), 2.34 (dd, J = 10.1, 15.4 Hz,
1H), 3.11 (s, 3H), 3.50–3.54 (m, 1H), 3.56–3.59 (m, 3H), 3.60–3.63
(m, 1H), 3.64–3.68 (m, 1H), 3.92 (dd, J = 2.6, 9.8 Hz, 1H), 4.02 (d,
J = 2.6 Hz, 1H), 4.31–4.41 (m, 3H), 4.44–4.47 (m, 2H), 4.50 (d, J =
12.4 Hz, 1H), 4.60 (d, J = 10.6 Hz, 1H), 4.62 (d, J = 10.6 Hz, 1H),
5.23 (bt, J = 9.8 Hz, 1H), 7.17–7.24 (m, 6H), 7.27–7.35 (m, 14H);
13C NMR (CDCl3, 100 MHz): d 14.1 (q), 21.1 (q), 22.7 (t), 24.6 (t),
29.4 (t), 29.6 (t), 29.7 (t), 30.0 (t), 31.7 (t), 31.9 (t), 33.7 (t), 35.1 (t),
47.7 (q), 66.2 (t), 67.8 (d), 71.42 (t, 2C), 71.8 (d), 72.9 (t), 74.1 (t),
75.9 (d), 76.5 (d), 79.1 (d), 102.0 (s), 126.9 (d), 127.2 (d), 127.3 (d),
127.5 (d), 127.61 (d, 2C), 127.69 (d, 2C), 127.85 (d, 2C), 128.06 (d,
2C), 128.23 (d, 2C), 128.29 (d, 4C), 128.37 (d, 2C), 138.3 (s), 138.4
(s), 138.7 (s), 139.3 (s), 170.2 (s) ppm; MALDI-TOF: 803.66 (40%
[M + Na]+), 819.64 (100% [M + K]+); HRMS: 803.4499 ([M +
Na]+) expected, 803.4424 ([M + Na]+) observed; Anal. Calcd for
C49H64O8: C, 75.35; H, 8.26; Found: C, 75.39; H, 8.55.
Acknowledgements
We thank the Ministry of Science and Technology for funding
through the Department of Science and Technology under the
Green Chemistry Program (NO. SR/S5/GC-20/2007). SBN and
NCK thank CSIR, New Delhi for the financial assistance in the
form of a research fellowship.
Representative experiment for the sequence of
oxidation–cyclization–hydroboration–acetylation to isolate the
minor 2b-acetate
To a solution of alcohol 24 (100 mg, 0.14 mmol) in ethyl acetate
(10 mL) was added IBX (81 mg, 0.28 mmol) at room temperature
and the mixture was stirred at reflux temperature for 3 h. After
the complete consumption of the starting material, the reaction
mixture was cooled in an ice bath and filtered through a Celite bed.
The filtrate was evaporated under reduced pressure. The residual
crude ketone (96 mg) was dissolved in anhydrous methanol
(15 mL) and the solution was degassed by passing argon for
30 min. To this, Pd(OAc)2 (9 mg, 42 mmol) was added and the
mixture stirred for 2.5 h. After consumption of starting material,
the reaction mixture was filtered through a Celite bed and the
filtrate was concentrated under reduced pressure to procure crude
compound 3 (64 mg). The resulting crude glycal mixture was used
immediately for hydroboration–oxidation and acetylation without
any purification.
To an ice-cooled solution of crude compound 3 (64 mg, 89 mmol)
in anhydrous THF (3 ml), was added neat BH3·DMS (8.8 mL, 178
mmol) and stirring was continued at room temperature for 3 h.
The reaction mixture was cooled to 0 ◦C, treated with 3 N NaOH
(0.3 mL) followed by 30% H2O2 (0.4 mL), and stirred at room
temperature for 6 h. Then, the THF was evaporated under reduced
pressure, residual material was extracted with diethyl ether (5 mL)
and water (2 mL), the organic layer was dried over sodium sulphate
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