Synthesis of Ophiocerins A, B and C, Botryolide E, Decarestrictine O, Stagonolide C and 9-epi-Stagonolide C Employing Chiral Hexane-1,2,3,5-tetraol Derivatives as Building Blocks

Article abstract of DOI:10.1002/ejoc.201600625

An organocatalytic approach to the synthesis of (2R,3S)-hexane-1,2,3,5-tetraol (11) derivatives (in the forms of different stereoisomers and bearing different protecting groups) has been developed. The key chiral intermediates 11 were prepared with complete stereocontrol through the proline-catalyzed intermolecular aldol reaction between acetone and d-glyceraldehyde acetonide. The synthetic utility of the intermediates was demonstrated by their transformation into the title hydroxylated pyrans and a variety of unsaturated lactones through standard synthetic protocols.

Full text of DOI:10.1002/ejoc.201600625

DOI: 10.1002/ejoc.201600625
Full Paper
Stereodivergence in Synthesis
Synthesis of Ophiocerins A, B and C, Botryolide E,
Decarestrictine O, Stagonolide C and 9-epi-Stagonolide C
Employing Chiral Hexane-1,2,3,5-tetraol Derivatives as Building
Blocks
Krishanu Show[a] and Pradeep Kumar*[a]
Abstract: An organocatalytic approach to the synthesis of ine-catalyzed intermolecular aldol reaction between acetone
(2R,3S)-hexane-1,2,3,5-tetraol (11) derivatives (in the forms of and D-glyceraldehyde acetonide. The synthetic utility of the in-
different stereoisomers and bearing different protecting termediates was demonstrated by their transformation into the
groups) has been developed. The key chiral intermediates 11 title hydroxylated pyrans and a variety of unsaturated lactones
were prepared with complete stereocontrol through the prol- through standard synthetic protocols.
Introduction
Despite extensive research, development of efficient and simple
protocols for the synthesis of complex organic molecules al-
ways poses a challenge to the synthetic organic chemist.[1]
Among these challenges, one of the most vital is to construct a
versatile and stereodivergent route that leads to various potent
compounds from a common starting material.[2] Simple chiral
synthons containing high functional density and multiple
stereogenic centres are of common interest in this regard. In
continuation of our interest in organocatalysis[3] and the enan-
tioselective synthesis of naturally occurring unsaturated lact-
ones,[4] we have taken up the asymmetric synthesis of bioactive
molecules such as 1–7 (Figure 1), by employing (2R,3S)-hexane-
1,2,3,5-tetraol derivatives 11 (in the form of different stereoiso-
mers and bearing different protecting groups) as important
building blocks and general structural motifs for the syntheses.
Here we have developed a conceptually new and efficient strat-
egy for the synthesis of the common chiral intermediates 11 by
employing the proline-catalyzed intermolecular aldol reaction
Figure 1. Structures of hydroxylated pyrans 1–3 and unsaturated lactones 4–
7.
between acetone and D-glyceraldehyde acetonide as the key
step. We used various stereoisomers based on the common in-
termediates 11 for the asymmetric synthesis of the following
molecules.
(i) Ophiocerins A, B and C (1, 2, 3), each based on a tetra-
hydropyran ring, with an interesting array of substituents, were
isolated from freshwater aquatic fungi Ophioceras venezuelense
and are found in a wide variety of natural products that show
broad spectrum biological activity.[5]
(ii) Botryolide E (4) was isolated from cultures of fungicolous
Botryotrichum sp. (NRRL 38180) and showed promising antibac-
terial activity against Bacillus subtilis (MTCC 441), Staphylococcus
aureus (MTCC 96) and Escherichia coli (MTCC 443), as well as
antifungal activity against Aspergillus niger (MTCC 1344) and
Saccharomyces cerevisiae (MTCC 171).[6]
(iii) Decarestrictine O (5), a secondary metabolite, was iso-
lated from various Penicillium strains and showed interesting
activity against cell line tests with HEP-G2 liver cells, having
an inhibitory effect on cholesterol biosynthesis. Thanks to this
property, decarestrictine O has been marked as a new class of
cholesterol-lowering drug.[7]
[a] Division of Organic Chemistry, CSIR - National Chemical Laboratory,
Pune 411008, India
E-mail: pk.tripathi@ncl.res.in
http://www.ncl-india.org/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600625.
(iv) Stagonolide C (6) was isolated from the liquid culture
filtrate of Stagonospora cirsii (a pathogen of Cirsium arvense),
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which has attracted considerable attention due to its potential employing the well-established RCM protocol, a chiral-pool ap-
mycoherbicide properties, acting by causing necrotic leison on proach or combined metal/enzyme DKR strategies.[12]
leaves.[8]
Due to their wide variety of biological activities and interest-
ing structural features with an array of functionalities, such as
Results and Discussion
stereochemically pure hydroxy appendages and/or olefinic
In this study, we report our successful attempts directed to-
moieties placed in strictly defined locations and having well-
wards the total synthesis of all these molecules (Figure 1, 1–7)
defined geometries, the above compounds have attracted the
by way of a common building block derived from a proline-
attention of synthetic chemists as prominent synthetic targets,
catalyzed diastereoselective intermolecular aldol reaction[13]
and therefore a great deal of interest has been devoted to their
and α-aminoxylation of aldehydes[14] as the key steps. Our ap-
synthesis. The previously described synthetic approaches to
proach to the synthesis of hydroxylated pyrans 1, 2 and 3 and
botryolide E involve either a chiral pool approach or the
to unsaturated lactones 4, 5, 6 and 7 was envisioned by the
asymmetric transformation of chiral propylene oxide or allyl-
retrosynthetic route shown in Scheme 1.
ation of acetaldehyde.[9] The previously reported syntheses of
ophiocerins A, B and C used chiral-pool sources such as carbo-
hydrates, (R)-(–)-pent-4-en-2-ol or tartaric acid, asymmetric
Preparation of Key Intermediate 11
transformation of chiral epoxides or Sharpless kinetic resolu-
tion.[10] Likewise, a few comparatively tedious and lengthy syn- The key intermediate 11 was synthesised by the reaction se-
theses of decarestrictine O have been reported, either from a quence shown in Scheme 2.
D
-Glyceraldehyde acetonide was
-proline to give the ꢀ-
chiral building block or through asymmetric dihydroxylation.[11] treated with acetone in the presence of
D
There are some reports on the synthesis of stagonolide C by hydroxy ketone aldol product 8 (de > 99 % by NMR and HPLC).
Scheme 1. Retrosynthetic analysis for the synthesis of target molecules 1–7.
Scheme 2. Reagents and conditions: (a) 30 mol-%
D-proline, 5 h, room temp., 65 %; (b) imidazole, TBDPSCl, room temp., 8 h, 95 %; (c) CeCl3·7 H2O, NaBH4,
MeOH, –78 °C, 2 h, 80 %; (d) (1) PMBCl, NaI, DIPEA, 150 °C, 3 h; (2) PPTS (catalytic), MeOH, 12 h, room temp., 90 % (over two steps).
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Protection of the alcohol as a tert-butyldiphenylsilyl (TBDPS) ary alcohol and subsequent internal nucleophilic substitution
ether provided compound 9 in good yield. We then examined of the secondary mesylate by treatment with base (K2CO3 in
the anti-selective reduction of 9 to give protected 1,3-anti-diol MeOH). Desilylation of compound 12 (TBAF in THF at room
10 directly (Table 1). The use of bulky reducing agents such as temp.) furnished 13 in 85 % yield. Ring opening of epoxide 13
LiAl(OtBu)3H, LS-Selectride or either (R)- or (S)-Alpine Hydride mediated by dimethylsulfonium methylide (generated from tri-
(combination with LiEt3BH) furnished inseparable diastereoiso- methylsulfonium iodide and nBuLi), followed by protection of
meric mixtures of protected 1,3-anti- and -syn-diols 10 with the diol as its acetonide with 2,2-dimethoxypropane in the
moderate selectivity (in each case the anti/syn ratio was deter- presence of catalytic amount of PPTS in dry CH2Cl2 afforded 14
mined by in situ desilylation of inseparable 10 with TBAF to in 80 % yield. Subsequent removal of the PMB group with DDQ
afford the corresponding easily separable 1,3-anti- and -syn-di- furnished hydroxy alkene 15 in 82 % yield. Ozonolysis of 15
ols). After examination of several reducing agents, it was ob- followed by reduction with NaBH4 and selective monotosylation
served that a combination of NaBH4 and CeCl3·7 H2O in meth- of the primary alcohol gave monotosylate 16 in 70 % yield, and
anol provided compound 10 in a ratio in favour of the anti this, upon base-induced cyclization under known conditions,
isomer (anti/syn 3:1) in 80 % yield. Under weakly basic condi-
tions,[15a] the free hydroxy group in the diastereoisomeric mix-
ture 10 was protected as a PMB ether, followed by acetonide
removal with PPTS (pyridinium p-toluenesulfonate) in methanol
to produce the easily separable diastereoisomers 11. Flash col-
umn chromatography separation of 11 afforded anti diastereo-
isomer 11a in 67.5 % yield along with syn diastereoisomer 11b
in 22.5 % yield.[15b,15c]
Table 1. Optimization of stereoselective keto reduction of 9.
[a] LS-Selectride: lithium triisoamylborohydride. [b] –78 °C for 8 h. [c] –78 °C
for
2 h. [d] Alpine-Hydride: lithium B-isopinocampheyl-9-borabicyclo-
[3.3.1]nonyl hydride. [e] Room temp., for 2 h. [f] Room temp., for 1 h. [g] 0 °C
for 1 h. [h] –78 °C for 1 h.
Scheme 3. Reagents and conditions: (a) (1) Bu2SnO, BzCl, NEt3, CH2Cl2;
(2) MsCl, NEt3, CH2Cl2; (iii) K2CO3, MeOH, room temp., 1 h, 70 % (three steps);
(b) TBAF, THF, room temp., 2 h, 85 %; (c) (1) (CH3)3S+I–, nBuLi, THF, –20 °C;
(2) 2,2-DMP, PPTS (catalytic), dry CH2Cl2, 3 h; (d) DDQ, CH2Cl2/H2O (18:1), room
temp., 1 h, 82 %; (e) (1) O3, CH2Cl2, –78 °C,1 h; (2) NaBH4, MeOH, room temp.,
0.5 h; (3) TsCl, NaH, THF, 2 h, 70 % (three steps); (f) (1) tBuO–K+, Et2O, 2 h;
(2) pTsA, MeOH, room temp., 2 h; (g) (1) Ph3P, DIAD, PNBA, THF, 0 °C to room
temp., 6 h; (2) K2CO3, MeOH; (h) (1) OsO4, NaIO4, dioxane/H2O (3:1), 12 h,
room temp.; (2) NaBH4, MeOH, room temp., 0.5 h; (i) (1) DDQ, CH2Cl2/H2O
(18:1), room temp., 1 h; (2) TsCl, NEt3, CH2Cl2, 3 h, 83 %; (j) (1) Bu2SnO, TsCl,
NEt3, CH2Cl2; (2) K2CO3, MeOH; (3) TBAF, THF, room temp., 2 h, 79 % (three
steps); (k) TsCl, NEt3, CH2Cl2, 3 h, 86 %; (l) (1) DDQ, CH2Cl2/H2O (18:1), room
temp., 1 h; (2) tBuO–K+, Et2O, 2 h; (3) pTsA, MeOH, room temp., 2 h, 82 %
(after three steps).
Synthesis of Ophiocerins A, B and C
According to the retrosynthetic analysis shown in Scheme 1,
compound 11 was envisioned as a common intermediate for
the synthesis of ophiocerins A, B and C, by the fine modulation
of the two free hydroxy groups of 11. The synthesis of ophioce-
rin C (1) from intermediate 11a is presented in Scheme 3. The
diol 11a was converted into the desired syn epoxide 12 in 70 %
yield by a three-step sequence involving chemoselective mono-
benzoylation of the diol followed by mesylation of the second-
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furnished ophiocerin C (1) in 92 % yield as a white solid. The in 88 % yield with Z/E ratio 95:5.[18] The cis isomer was easily
physical and spectroscopic data were in full agreement with separated by flash column chromatography, and upon treat-
literature data. [α]D25 = +42.4 (c = 0.1, CH2Cl2); ref.[5] [α]2D5 = +45.0 ment with 1
M HCl in THF at 0 °C for 2 h it provided botryolide E
(c = 0.1, CH2Cl2).
(4) in 65 % yield. The physical and spectroscopic data of 4 were
in full agreement with the reported data. [α]2D5 = –37.1 (c = 2.5,
CHCl3); ref.[6] [α]D25 = –36.7 (c = 0.05, CHCl3).
For the synthesis of ophiocerin A (2), we followed almost the
same reaction sequence as for the synthesis of ophiocerin C. To
this end, the required anti-epoxy alcohol 17 was achieved in
79 % yield by inversion of stereochemistry at the carbon atom
bearing the unprotected hydroxy group in syn epoxy alcohol
13 by use of the Mitsunobu reaction,[16] followed by basic hy-
drolysis (K2CO3 in MeOH). Epoxide 17 was then opened with
excess dimethylsulfonium methylide followed by acetonide pro-
tection to provide 18 in 80 % yield. Oxidative cleavage of olefin
18 (OsO4/NaIO4) followed by NaBH4 reduction gave the corre-
sponding alcohol 19 in good yield. Treatment of 19 with tosyl
chloride and the subsequent removal of the PMB group with
DDQ furnished tosylate 20. Finally, base-mediated cyclization
with potassium tert-butoxide followed by acetonide removal
furnished ophiocerin A (2) as a white solid. The spectroscopic
data for the synthetic compound were in full agreement with
Scheme 4. Reagents and conditions: (a) Ac2O, pyr, room temp., 4 h, 90 %
(b) (1) O3, DMS; (2) (CF3CH2O)2P(O)CH2CO2Et, KHMDS/18-crown-6, –78 °C, 6 h,
88 % (over two steps); (c) 1
M HCl in THF, 0 °C to room temp., 1 h, 65 %.
literature values [α]2D5 = –23.4 (c = 0.1, CH2Cl2); ref.[5] [α]2D5
–24.0 (c = 0.1, CH2Cl2).
=
Synthesis of Decarestrictine O
The synthesis of ophiocerin B (3) began with intermediate
11a. In order to obtain the anti-epoxy alcohol 21 from diol 11a,
we applied a three-step sequence: firstly regioselective primary
monotosylation[17] (Bu2SnO, tosyl chloride, NEt3) of diol 11a,
followed by base-induced epoxide formation through intramo-
lecular nucleophilic displacement of the tosyl group and then
TBAF-mediated removal of the TBDPS group. Inversion of the
stereochemistry of the free hydroxy group of 21 under Mitsu-
nobu reaction conditions followed by basic hydrolysis provided
the required syn epoxy alcohol 22. Opening of the epoxide with
excess trimethylsulfonium iodide and nBuLi produced a syn-
diol, which upon treatment with 2,2-dimethoxypropane and
catalytic amounts of PPTS provided acetonide compound 23 in
good yield. OsO4/NaIO4-mediated oxidative cleavage of olefin
23 followed by NaBH4 reduction gave primary alcohol 24. Ester-
ification of 24 with tosyl chloride afforded the O-tosyl derivative
25. Finally, PMB removal from 25 with DDQ and base-mediated
cyclization followed by acetonide removal gave ophiocerin B (3)
in 82 % yield as a pale yellow oil. The correct stereochemistry
of the three stereogenic centres was confirmed by comparison
of its specific rotation value and spectroscopic data with those
reported. [α]D25 = –35.2 (c = 1.0, CH2Cl2); ref.[5] [α]2D5 = –37.0 (c =
0.1, CH2Cl2).
Our retrosynthetic analysis of decarestrictine O (Scheme 1) is
based on a convergent approach. We envisioned that the target
molecule could be accessed by the esterification of acid 33 with
hydroxy olefin 15, followed by cyclization of diene by the
Grubbs RCM protocol. The acid fragment 33 could be prepared
by sequential α-aminoxylation of 4-(4-methoxybenzyloxy)-
butanal (28, Scheme 5) whereas the alcohol fragment 15 was
also the common intermediate for ophiocerin C and for botry-
olide E, easily obtained from 11a (Scheme 3).
Scheme 5. Reagents and conditions: (a) (1) D-proline, PhNO, DMSO; (2) NaBH4,
MeOH, room temp., 0.5 h; (b) CuSO4·5 H2O, MeOH, 10 h, 78 % (over three
steps); (c) (1) Bu2SnO, TsCl, NEt3, CH2Cl2; (2) K2CO3, MeOH, 0.5 h, room temp.,
80 % (over two steps); (d) (1) (CH3)3S+I–, nBuLi, THF, –20 °C; (2) TBSCl, imidaz-
ole, CH2Cl2, 82 % (over two steps); (e) (1) DDQ, CH2Cl2/H2O (18:1), room
temp.,1 h; (2) TEMPO (catalytic), BAIB, CH3CN/H2O (3:1), room temp., 7 h. 75 %
(over two steps).
Synthesis of Botryolide E
Synthesis of Acid Fragment 33
From the retrosynthetic analysis shown in Scheme 1, we envi- The synthesis of acid fragment 33 started from 4-(4-methoxy-
sioned hydroxy olefin 15 as a common intermediate both for benzyloxy)butanal (28) as illustrated in Scheme 5. α-Aminoxyl-
ophiocerin C (Scheme 3) and for botryolide E. For the synthesis ation of 28 in the presence of D-proline followed by reduction
of botrylide E (Scheme 4), the hydroxy group of 15 was pro- with NaBH4 provided unstable anilinoxy compound 29. This
tected as an acetyl ester by use of acetic anhydride in pyridine was further treated with 30 mol-% CuSO4·5 H2O in methanol,
to provide acetylated compound 26. Ozonolysis of the olefin which eventually led to the cleavage of the O–N bond, afford-
followed by modified Horner–Emmons olefination with electro- ing diol 30 in 78 % yield. Regioselective primary monotosyl-
philic bis(trifluoroethyl)phosphono ester (CF3CH2O)2P(O)- ation of diol 30 and subsequent base treatment furnished ep-
CH2CO2Et and KHMDS/18-crown-6 gave the Wittig product 27 oxide 31 in 80 % yield.
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Opening of the epoxide by use of excess dimethylsulfonium ole at reflux for 4 h to give olefin 36 in 83 % yield. Cleavage of
methylide followed by protection of the hydroxy group as a the PMB protecting group with DDQ furnished the target alco-
TBS ether gave olefin 32 in 82 % yield. Finally, DDQ-mediated hol 37 in 80 % yield (Scheme 7).
removal of the PMB group followed by one-pot oxidation of
the primary alcohol with TEMPO/BAIB provided the required
acid 33.
Synthesis of Decarestrictine O by Coupling of Acid Fragment
33 and Alcohol Fragment 15 through RCM
Scheme 7. Reagents and conditions: (a) Ph3P, I2, imidazole, THF, reflux, 4 h,
83 %; (b) DDQ, CH2Cl2/H2O (18:1), room temp.,1 h, 80 %.
With both fragments 15 and 33 to hand, we proceeded with
the coupling of the two components by use of the Shiina esteri-
fication[19] protocol to provide the diene ester 34 (Scheme 6) in
95 % yield. The diene ester was then subjected to ring closing
Synthesis of Alcohol Fragment 39
For the synthesis of 9-epi-stagonolide C, the required alcohol
fragment 39 (Scheme 8) was synthesized from the diol interme-
diate 11b by the same reaction sequence as described in
Scheme 7.
metathesis[20] under high-dilution conditions (0.001
M in dry
CH2Cl2) in the presence of the second-generation Grubbs cata-
lyst (10 mol-%) to give the unsaturated macrocyclic lactone 35
in 75 % yield and exclusively as the E isomer. Compound 35,
upon exposure to 1
M HCl in THF, underwent removal of both
TBS ether and acetonide groups to provide decarestrictine O
(5) in 68 % yield. All the spectroscopic and physical data of the
synthesized compound were in full agreement with literature
data. [α]D25 = –20.2 (c = 0.2, MeOH); ref.[11b] [α]2D5 = –19.6 (c =
0.2, MeOH).
Scheme 8. Reagents and conditions: (a) Ph3P, I2, imidazole, THF, reflux, 4 h,
82 %; (b) DDQ, CH2Cl2/H2O (18:1), room temp., 1 h, 84 %.
Synthesis of Common Acid Fragment 45 for Both
Stagonolide C and Its Epimer
The synthesis of acid fragment 45 commenced from
5-(4-methoxybenzyloxy)pentanal as illustrated in Scheme 9. D-
Proline-catalyzed α-aminoxylation of aldehyde 40 under a set
of reaction conditions similar to those described in Scheme 5
(synthesis of acid fragment for decarestrictine O) afforded diol
42 in 77 % yield. Selective primary monotosylation of the diol
and subsequent base treatment gave the epoxide 43 in 81 %
yield. Epoxide ring opening mediated by dimethylsulfonium
methylide, followed by protection of the secondary hydroxy
group (TBDPSCl/imidazole), afforded TBDPS ether 44 in 78 %
yield. Removal of the PMB group (DDQ) then furnished the pri-
mary alcohol, which upon one-pot oxidation (TEMPO/BAIB)
gave the acid 45 in 70 % yield.
Scheme 6. Reagents and conditions: (a) 2-methyl-6-nitrobenzoic anhydride,
NEt3, DMAP, CH2Cl2, 12 h, 95 %; (b) second-generation Grubbs catalyst
(10 mol-%), CH2Cl2, reflux, 12 h, 75 %; (c) 1
1 h, 68 %.
M HCl in THF, CH2Cl2, room temp.,
Synthesis of Stagonolide C and 9-epi-Stagonolide C
Analogously, by a similar strategy, stagonolide C and its 9-epi-
mer could be obtained by coupling of olefinic acid 45
(Scheme 9, below) with olefinic alcohols 37 (Scheme 7, below)
and 39 (Scheme 8, below), respectively, and subsequent cycliza-
tion of the diene by the Grubbs RCM protocol. The olefinic alco-
hol fragment 37 could easily be obtained from the common
intermediate 11a (Scheme 7), whereas the other alcoholic frag-
ment 39 could be prepared from the diol isomer 11b by the
same reaction sequence (Scheme 8). Similarly, the acid frag-
ment 45 could be prepared from 5-(4-methoxybenzyloxy)-
pentanal (40) through α-aminoxylation and epoxide ring open-
ing.
Scheme 9. Reagents and conditions: (a) (1) D-proline, PhNO, DMSO; (2) NaBH4,
MeOH, room temp., 0.5 h; (b) CuSO4·5 H2O, MeOH, 10 h, 77 % (over three
steps); (c) (1) Bu2SnO, TsCl, NEt3, CH2Cl2; (2) K2CO3, MeOH, 0.5 h, room temp.,
81 % (over two steps); (d) (1) (CH3)3S+I–, nBuLi, THF, –20 °C; (2) TBDPSCl, imid-
azole, CH2Cl2, 78 % (over two steps); (e) (1) DDQ, CH2Cl2/H2O (18:1), room
temp., 1 h; (2) TEMPO (catalytic), BAIB, CH3CN/H2O (3:1), room temp., 7 h,
75 % (over two steps).
Synthesis of Stagonolide C through RCM
With substantial amounts of alcohol 37 and acid 45 to hand,
the stage was set to couple the two fragments for the diene
Synthesis of Alcohol Fragment 37
To synthesize the alcohol fragment, the diol 11a was subjected ester formation (Scheme 10). To this end, the alcohol 37 was
to direct reductive elimination[21] with iodine, Ph3P and imidaz- coupled with acid 45 under the Shiina protocol[19] to give diene
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46 in 93 % yield. Removal of both TBDPS group with NH4F in tial esterification and RCM. We believe that this synthetic se-
methanol[22] gave the required diol, which was immediately quence should be employable for several other hydroxylated
subjected to RCM in the presence of the second-generation pyrans and for 10-membered unsaturated lactones and macrol-
Grubbs catalyst (10 mol-%) to afford the target molecule ides.
stagonolide C (6) in 78 % yield. The constitution and configura-
tion of the assigned structure were in full agreement with the
literature data. [α]2D5 = +46.2 (c = 0.08, MeOH); ref.[12c] [α]D25
+43.9 (c = 1.0, MeOH).
=
Experimental Section
General Experimental Methods: All reactions were carried out un-
der anhydrous conditions, with use of flame-dried glassware under
a positive pressure of argon unless otherwise mentioned. CH2Cl2,
Et3N and iPr2NEt were distilled from CaH2; Et2O and THF were dis-
tilled from Na/benzophenone. Other reagents were obtained from
commercial suppliers and used as received. Air-sensitive reagents
and solutions were transferred by syringe or cannula and were in-
troduced into the apparatus through rubber septa. Reactions were
monitored by thin layer chromatography (TLC) with 0.25 mm pre-
coated silica gel plates (60 F254). Visualization was accomplished
with UV light, iodine adsorbed on silica gel, or by immersion in an
ethanolic solution of phosphomolybdic acid (PMA), p-anisaldehyde,
or KMnO4 followed by heating with a heat gun for ca. 15 s. Flash
chromatography was performed on silica gel (230–400 mesh). All
1H NMR and 13C NMR spectra were obtained with a 200, 400 or
500 MHz spectrometer in CDCl3 or CD3OD. Coupling constants were
measured in Hertz. All chemical shifts are quoted in ppm, relative
to TMS, with use of the residual solvent peak as a reference stan-
dard. The following abbreviations are used to describe the multi-
plicities: s = singlet, d = doublet, t = triplet, quin = quintet, m =
multiplet and br = broad. HRMS (ES+) were recorded with an ORBI-
TRAP mass analyzer. Infrared (IR) spectra were recorded with a FTIR
spectrometer as thin films with use of NaCl plates; wavenumbers
are in cm–1. Optical rotations were measured with a polarimeter
with a 1 dm path length. Chemical nomenclature was generated
with Chem. Bio Draw Ultra 14.0.
Scheme 10. Reagents and conditions: (a) 2-methyl-6-nitrobenzoic an-
hydride, NEt3, DMAP, CH2Cl2, 6 h, 93 %; (b) (i) NH4F, MeOH, 40 °C, 24 h; (ii) sec-
ond-generation Grubbs catalyst (10 mol-%), CH2Cl2, reflux, 48 h, 78 % (over
two steps).
Completion of the Synthesis of 9-epi-Stagonolide C through
RCM
For the synthesis of the 9-epi isomer, coupling of acid fragment
45 with alcohol 39 was carried out under Shiina's esterification
conditions followed by removal of both TBDPS groups (NH4F in
methanol[22]) to give the diene 48 in 73 % yield (Scheme 11).
On treatment with the second-generation Grubbs catalyst
(10 mol-%), compound 48 furnished 9-epi-stagonolide C (7) as
the sole product. The geometry of the newly formed double
bond was unambiguously determined by the olefinic Jtrans cou-
pling constant (16.14 Hz between the protons at δ = 5.98 and
5.62 ppm).
(S)-4-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-4-hydroxybutan-2-
one (8):
D-Proline (0.046 g, 0.40 mmol) was added to a solution of
D
-glyceraldehyde acetonide (0.260 g, 2.00 mmol) in acetone (4 mL)
and chloroform (1 mL) and the mixture was stirred at room temper-
ature for 5 h. Subsequently, the mixture was diluted with water
(5 mL) and diethyl ether (5 mL) and partitioned. The aqueous layer
was washed with diethyl ether (3 × 5 mL), and the combined or-
ganic layers were dried with Na2SO4. Evaporation of the solvent
and purification by flash column chromatography (100–200 mesh,
eluent: EtOAc/petroleum ether 30 %) afforded the desired product
1
8 as a pale yellow liquid (0.244 g, 65 %, de > 99 % by H NMR and
HPLC, Kromasil Rp-18, MeOH/H2O 20:80; major isomer 9.36 min,
minor isomer 8.00 min). [α]2D5 = –24.40 (c = 4.0, CHCl3); ref.[23] [α]2D5
=
–27.00 (c = 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 4.13–4.05 (m,
1 H), 4.00–3.88 (m, 3 H), 3.21 (br. s, 1 H), 2.89–2.80 (dd, J = 1.6,
17.5 Hz, 1 H), 2.61 (dd, J = 8.1, 17.9 Hz, 1 H), 2.21 (s, 3 H), 1.40 (s, 3
H), 1.34 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 209.7, 109.4,
Scheme 11. Reagents and conditions: (a) 2-methyl-6-nitrobenzoic acid
anhydride, NEt3, DMAP, CH2Cl2, 6 h, 92 %; (b) NH4F, MeOH, 40 °C, 24 h, 70 %;
(c) second-generation Grubbs catalyst (10 mol-%), CH2Cl2, reflux, 48 h, 73 %.
69.0, 66.8, 46.2, 30.8, 26.6, 25.1 ppm. IR (CHCl ): ν
= 3492, 3018,
˜
3
max
2954, 2901, 1720, 1363, 1299, 1205, 1069, 859 cm–1
.
(S)-4-[(tert-Butyldiphenylsilyl)oxy]-4-[(R)-2,2-dimethyl-1,3-di-
oxolan-4-yl]butan-2-one (9): TBDPSCl (0.8 mL, 3.30 mmol)
was added dropwise at 0 °C to a stirred solution of compound 8
(0.517 g, 2.75 mmol) and imidazole (0.375 g, 5.50 mmol) in dry
CH2Cl2, and the reaction mixture was stirred for 8 h at room temper-
ature. After completion of the reaction, water was added to quench
the reaction mixture and the organic layer was washed with excess
water and brine. The organic layer was dried with Na2SO4 and con-
Conclusions
In summary, we have successfully synthesized key precursors
for the synthesis of ophiocerins A, B and C, botryolide E, decare-
strictine O, stagonolide C and 9-epi-stagonolide C by employing
proline-catalyzed aldol reaction as the key step. This route dem-
onstrates coupling of two different fragments through sequen- centrated to afford the crude silylated compound, which was puri-
Eur. J. Org. Chem. 0000, 0–0
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Full Paper
fied by silica gel chromatography (100–200 mesh, eluent: EtOAc/
Stereoisomer 11a: [α]2D5 = –12.59 (c = 3.3, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.68–7.70 (m, 4 H), 7.48–7.33 (m, 6 H), 7.05
(d, J = 8.1 Hz, 2 H), 6.82 (d, J = 8.1 Hz, 2 H), 4.29 (d, J = 10.8 Hz, 1
H), 3.96 (d, J = 4.6 Hz, 1 H), 3.87 (d, J = 11.0 Hz, 1 H), 3.80 (s, 3 H),
3.74–3.61 (m, 3 H), 3.11–2.97 (m, 1 H), 2.55 (br. s, 2 H), 1.78 (ddd,
J = 5.9, 9.5, 15.2 Hz, 1 H), 1.57 (td, J = 3.4, 15.2 Hz, 1 H), 1.07 (s, 9
H), 0.90 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
petroleum ether 5 %) to afford 9 (1.110 g, 95 %) as a viscous liquid.
1
[α]2D5 = –10.37 (c = 3.4, CHCl3). H NMR (CDCl3, 200 MHz): δ = 7.77–
7.64 (m, 4 H), 7.47–7.34 (m, 6 H), 4.32–4.17 (m, 1 H), 4.14–4.01 (m,
1 H), 3.92 (dd, J = 6.4, 8.3 Hz, 1 H), 3.64 (dd, J = 6.3, 8.3 Hz, 1 H),
2.60 (dd, J = 3.4, 5.7 Hz, 2 H), 1.91 (s, 3 H), 1.29 (s, 6 H), 1.03 (s, 9
H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 206.1, 135.92, 135.9, 135.2,
134.8, 133.5, 133.3, 129.9, 129.8, 129.6, 127.7, 127.65, 127.63, 109.3, 159.2, 135.9, 133.8, 133.1, 129.9, 129.9, 129.8, 129.4, 127.8, 127.7,
78.7, 70.6, 66.9, 48.3, 30.6, 26.9, 26.5, 26.2, 25.1, 19.3 ppm. IR (CHCl3): 113.7, 75.0, 73.7, 72.8, 70.0, 63.3, 55.2, 42.2, 27.0, 19.4,19.3 ppm. IR
νmax = 3392, 3008, 2558, 1732, 1458, 1263, 1099, 759 cm–1. HRMS (CHCl3): νmax = 3479, 2978, 1554, 1358, 1063, 851, 742 cm–1. HRMS
˜
˜
(ESI): calcd. for C25H34O4SiNa [M + Na]+ 449.2119; found 449.2120.
(ESI): calcd. for C30H40O5SiNa [M + Na]+ 531.2537; found 531.2537.
Stereoisomer 11b: [α]2D5 = +38.20 (c = 2.5, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.68–7.63 (m, 4 H), 7.49–7.36 (m, 6 H), 7.26–
7.19 (m, J = 8.2 Hz, 2 H), 6.92–6.85 (m, J = 8.5 Hz, 2 H), 4.53–4.50
(m, 1 H), 4.35–4.33 (m, 1 H), 3.94–3.87 (m, 1 H), 3.84–3.80 (m, 4 H),
3.79–3.75 (m, 1 H), 3.68–3.63 (m, 1 H), 3.45 (dd, J = 7.0, 11.0 Hz, 1
H), 2.66 (br. s, 2 H), 1.82 (ddd, J = 2.3, 8.8, 15.2 Hz, 1 H), 1.53 (dd,
(4S)-4-[(tert-Butyldiphenylsilyl)oxy]-4-[(R)-2,2-dimethyl-1,3-di-
oxolan-4-yl]butan-2-ol (10): CeCl3·7 H2O (0.057 g, 0.16 mmol) and
NaBH4 (0.006 g, 0.15 mmol) were added at –78 °C to a stirred solu-
tion of ꢀ-hydroxy ketone 9 (0.063 g, 0.15 mmol) in MeOH (1 mL)
in a 25 mL flask, and the mixture was allowed to warm to room
temperature. It was then stirred for 1 h until analysis of the mixture
by TLC (silica gel) indicated completion of reaction. The reaction
was diluted with aq. NH4Cl (5 mL) and extracted with CH2Cl2 (3 ×
10 mL), washed with brine and dried with Na2SO4. Removal of the
solvent under reduced pressure provided the crude hydroxy com-
pound, which was purified by silica gel column chromatography
(100–200 mesh, eluent: EtOAc/petroleum ether 20 %) to afford 10
J = 4.3, 15.3 Hz, 1 H), 1.07 (s, 9 H), 0.97 (d, J = 6.1 Hz, 3 H) ppm. 13
C
NMR (125 MHz, CDCl3): δ = 159.4, 135.9, 134.0, 133.2, 129.9, 129.8,
129.7, 129.6, 128.6, 127.7, 127.6, 113.9, 113.7, 73.6, 71.7, 70.5, 70.3,
64.1, 55.2, 39.9, 27.0, 19.4, 19.2 ppm. IR (CHCl3): νmax = 3379, 2988,
˜
1546, 1308, 1136, 987, 842 cm–1. HRMS (ESI): calcd. for C30H40O5SiNa
[M + Na]+ 531.2537; found 531.2538.
1
(0.051 g, 80 %) as a pale yellow oil. H NMR (CDCl3, 500 MHz): δ =
tert-Butyl{(1S,3R)-3-[(4-methoxybenzyl)oxy]-1-[(S)-oxiran-2-
yl]butoxy}diphenylsilane (12): Bu2SnO (0.007 g, 0.03 mmol) was
added under argon to a stirred solution of diol 11a (0.665 g,
1.31 mmol) in dry CH2Cl2 (2 mL), followed by addition of benzoyl
chloride (0.18 mL, 1.44 mmol) and Et3N (0.22 mL, 1.57 mmol). The
resulting mixture was stirred at room temperature for 2 h,
quenched with water and then extracted with CH2Cl2. Removal of
volatiles under reduced pressure gave an oily crude monobenzoyl
ester. This compound was then dissolved in dry CH2Cl2 (10 mL)
under argon and treated with MsCl (0.11 mL, 1.44 mmol), Et3N
(0.22 mL, 1.57 mmol) and a catalytic amount of DMAP. The reaction
mixture was stirred at room temperature for 2 h and then diluted
with water. The water layer was extracted with CH2Cl2 (3 × 15 mL)
and the combined organic layer was washed with brine, dried
(Na2SO4) and concentrated to give a crude product, which was dis-
solved in MeOH (10 mL) and treated with K2CO3 (0.180 g,
1.31 mmol). The mixture was stirred for 1 h at room temperature
and then filtered through celite. Removal of the volatiles under re-
duced pressure, followed by column chromatography on silica gel
(100–200 mesh, eluent: EtOAc/petroleum ether 5 %) produced the
7.74–7.64 (m, 4 H), 7.50–7.34 (m, 6 H), 4.17 (qd, J = 6.7, 13.2 Hz, 1
H), 4.05–3.96 (m, 1 H), 3.91–3.76 (m, 1 H), 3.63 (ddd, J = 7.0, 8.4,
15.7 Hz, 1 H), 2.76 (br. s, 1 H), 1.77–1.61 (m, 2 H), 1.34–1.18 (m, 5
H), 1.10–1.04 (m, 9 H), 1.01–0.96 (m, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 135.9 (135.94), 135.9 (135.91), 135.9 (135.85), 135.8,
133.6, 133.3, 133.1, 130.1, 130.0, 129.9, 129.9, 127.9, 127.8, 127.7,
127.7, 127.6, 109.4, 109.3, 78.63, 78.58, 74.3, 73.9, 72.4, 71.9, 67.8,
67.7, 64.8, 64.1, 63.7, 63.4, 43.9, 43.6, 41.3, 30.9, 27.0, 26.99, 26.94,
26.3, 25.31, 25.30, 24.0, 23.7, 23.5, 19.4 ppm. IR (CHCl3): νmax = 3382,
˜
3068, 2893, 1632, 1435, 1250, 1136, 889, 743 cm–1. HRMS (ESI):
calcd. for C25H36O4SiNa [M + Na]+ 451.2275; found 451.2268.
(2R,3S,5R)-3-[(tert-Butyldiphenylsilyl)oxy]-5-[(4-methoxybenz-
yl)oxy]hexane-1,2-diol (11a) and (2R,3S,5S)-3-[(tert-Butyldi-
phenylsilyl)oxy]-5-[(4-methoxybenzyl)oxy]hexane-1,2-diol
(11b): Alcohol 10 (0.428 g, 1.00 mmol), p-methoxybenzyl chloride
(0.172 g, 0.15 mL, 1.10 mmol), NaI (10 mol-%), and DIPEA (0.34 mL,
2.00 mmol) were placed under argon in a reaction vessel equipped
with a magnetic stirring bar. The mixture was heated at reflux in a
150 °C bath for 3 h. Consumption of the starting material was moni-
tored by TLC. The resulting mixture was diluted with ethyl acetate
(5 mL) and aqueous sodium bisulfate (10 %, 5 mL) and extracted
twice with EtOAc (2 × 10 mL). The combined organic layers were
dried with Na2SO4 and the solvent was evaporated in vacuo. The
crude PMB-protected product was used for the next step without
further purification.
epoxide 12 (0.449 g, overall yield 70 %) as a yellow liquid. [α]D25
=
–43.50 (c = 1.8, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.81–7.66 (m,
4 H), 7.43–7.30 (m, 6 H), 7.00 (d, J = 8.8 Hz, 2 H), 6.80 (d, J = 8.6 Hz,
2 H), 4.28–4.25 (m, 1 H), 3.92 (d, J = 10.8 Hz, 1 H), 3.80 (s, 3 H), 3.68–
3.48 (m, 2 H), 3.03 (ddd, J = 2.7, 4.1, 6.9 Hz, 1 H), 2.65 (t, J = 4.5 Hz,
1 H), 2.43 (dd, J = 2.7, 4.9 Hz, 1 H), 1.84–1.61 (m, 2 H), 1.10 (s, 9 H),
1.06 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.9,
136.1, 136.0, 133.9, 133.8, 130.8, 129.6, 129.1, 127.5, 127.4, 113.6,
73.1, 71.4, 70.0, 56.0, 55.2, 45.0, 42.6, 27.0, 19.9, 19.5 ppm. IR (CHCl3):
PPTS (0.021 g, 0.08 mmol) was added to a stirred solution of the
crude PMB-protected compound (0.450 g, 0.82 mmol) in MeOH
(10 mL) and the mixture was then stirred overnight at room temper-
ature. After completion of the reaction, a saturated aqueous NaH-
CO3 solution (10 mL) was added to the reaction mixture, which
was then concentrated under reduced pressure and extracted with
νmax = 2818, 1632, 1521, 1498, 1332, 1063, 809 cm–1. HRMS (ESI):
˜
calcd. for C30H38O4Si Na [M + Na]+ 513.2432; found 513.2435.
(1S,3R)-3-[(4-Methoxybenzyl)oxy]-1-[(S)-oxiran-2-yl]butan-1-ol
(13): TBAF in THF (1
M, 0.52 mL, 0.52 mmol) was added at room
CH2Cl2 (4 × 15 mL). The combined organic layers were washed with temperature to a stirred solution of epoxide 12 (0.170 g, 0.35 mmol)
brine and dried with Na2SO4. Solvent was concentrated under vac- in dry THF (10 mL) and the mixture was stirred for 4 h. It was then
uum. The crude residue was purified by column chromatography
on silica gel (230–400 mesh. eluent: EtOAc/petroleum ether 45 %)
to give the major product 11a (0.281 g, 67.5 %) along with minor
product 11b (0.093 g, 22.5 %) as a colourless liquid.
diluted with saturated aq. NH4Cl (20 mL) and extracted with ethyl
acetate (2 × 15 mL). The combined organic layers were washed with
brine and then dried with Na2SO4 and concentrated in vacuo. The
crude product was purified by silica gel column chromatography
Eur. J. Org. Chem. 0000, 0–0
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(100–200 mesh, eluent: EtOAc/petroleum ether 5 %) to give 13
(0.074 g, 85 %) as a light yellow oil. [α]2D5 = –28.75 (c = 3.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.32–7.22 (d, J = 8.5 Hz, 2 H), 6.95–
6.83 (d, J = 8.5 Hz, 2 H), 4.57 (d, J = 11.0 Hz, 1 H), 4.40 (d, J =
{(4S,5S)-5-[(R)-2-Hydroxypropyl]-2,2-dimethyl-1,3-dioxolan-4-
yl}methyl 4-Methylbenzenesulfonate (16): Olefin 15 (0.084 g,
0.45 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to –78 °C.
Ozone was passed through the solution until a blue tint was ob-
11.0 Hz, 1 H), 3.98–3.88 (m, 1 H), 3.85–3.76 (m, 4 H), 2.99 (dt, J = served, and dimethyl sulfide (3 mL) was added to this resulting
2.9, 4.2 Hz, 1 H), 2.80–2.73 (m, 2 H), 2.72 (d, J = 5.8 Hz, 1 H), 1.78
blue solution. The reaction mixture was allowed to warm to room
temperature and stirred for 12 h, at which point the reaction mix-
(ddd, J = 2.4, 4.4, 7.5 Hz, 2 H), 1.27 (d, J = 6.1 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 159.2, 130.5, 129.3, 113.8, 71.9, 70.4, ture was concentrated and the crude aldehyde was used for the
68.2, 55.3, 55.2, 44.4, 40.8, 19.6 ppm. IR (CHCl3): νmax = 3410, 3118, next step without purification. The residue was redissolved in MeOH
˜
2584, 1638, 1239 cm–1. HRMS (ESI): calcd. for C14H20O4Na [M + Na]+ (10 mL), and NaBH4 (0.045 g) was added. After 30 min, the mixture
275.1254; found 275.1255.
was concentrated and the residue was partitioned between EtOAc
(50 mL) and H2O (20 mL). The organic layer was dried with Na2SO4,
filtered and concentrated, and the residue was purified by silica gel
column chromatography. NaH (0.010 g, 0.45 mmol) was added to a
stirred solution of this alcohol in dry THF cooled to 0 °C, and after
10 min TsCl (0.086 g, 0.45 mmol) was added and the reaction mix-
ture was stirred at same temperature for another 3 h, at which point
TLC analysis of the reaction mixture shows consumption of starting
material. The reaction mixture was diluted with water and extracted
with EtOAc (3 × 20 mL). The combined organic layers were washed
with water and brine, dried with Na2SO4 and concentrated. The
residual oil was purified by silica gel column chromatography with
EtOAc/petroleum ether 15 % as eluent to furnish compound 16
(4S,5S)-4-{(R)-2-[(4-Methoxybenzyl)oxy]propyl}-2,2-dimethyl-5-
vinyl-1,3-dioxolane (14): Trimethylsulfonium iodide (1.230 g,
6.05 mmol) was added at –20 °C to stirred dry THF, followed by
nBuLi (3.8 mL, 1.6 M, 6.05 mmol). The reaction mixture was stirred
for 1 h, after which epoxide 13 (0.300 g, 1.21 mmol) in THF was
added dropwise. The reaction mixture was stirred at –20 °C for 3 h
and completion of the reaction was monitored by TLC. The mixture
was diluted with saturated ammonium chloride solution and ex-
tracted with EtOAc (2 × 50 mL). The combined organic layers were
washed with water (2 × 50 mL) and brine, dried with Na2SO4 and
concentrated. The crude diol was used for the next step without
further purification.
1
(0.108 g, 70 %) as a colourless oil. [α]2D5 = +3.20 (c = 0.3, CHCl3). H
NMR (500 MHz, CDCl3): δ = 7.79 (d, J = 8.2 Hz, 2 H), 7.35 (d, J =
8.2 Hz, 2 H), 4.14–4.11 (m, 2 H), 4.09–4.05 (m, 1 H), 4.02–3.99 (m, 1
H), 3.88–3.85 (m, 1 H), 2.47 (s, 3 H), 1.71–1.68 (m, 2 H), 1.37 (s, 3
H),1.31 (s, 3 H), 1.21 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 145.1, 132.6, 129.9, 127.9, 109.5, 78.0, 75.3, 68.9, 65.0,
2,2-DMP (0.25 mL, 2.00 mmol) and PPTS (0.023 g, 0.10 mmol) were
added to a solution of crude diol (0.280 g, 1.00 mmol) in dry CH2Cl2
(30 mL), and the mixture was stirred for 4 h and then quenched
with satd. aq. NaHCO3 (15 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 15 mL), and the combined organic layers were
dried with Na2SO4 and concentrated in vacuo. The crude product
was purified by silica gel column chromatography (100–200 mesh,
eluent: EtOAc/petroleum ether 5 %) to give 14 (0.290 g, 80 %) as a
pale yellow oil. [α]D25 = –3.70 (c = 3.5, CHCl3); ref.[11a] [α]D25 = –4.40
41.0, 27.2, 26.6, 23.8, 21.6 ppm. IR (CHCl3): νmax = 3455, 2903, 1445,
˜
1185, 790 cm–1
.
Ophiocerin C (1): tBuOK (0.087 g, 0.78 mmol) was added at 0 °C
to a stirred solution of tosylate 16 (0.089 g, 0.26 mmol) in dry Et2O
(3 mL), and the mixture was stirred for 1 h at 0 °C and monitored
by TLC. After completion of the reaction the mixture was diluted
with saturated aq. NH4Cl (10 mL) and extracted with Et2O (4 ×
5 mL). The combined organic layers were washed with H2O and
brine, concentrated in vacuo and then treated with PTSA (0.003 g)
and MeOH (5 mL) with stirring at room temperature for another 2 h.
The reaction was quenched with saturated aq. NaHCO3 solution,
the mixture was extracted with CH2Cl2 (3 × 20 mL), and the com-
bined organic layers were washed with H2O and brine, dried with
Na2SO4 and concentrated. The residue was purified by silica gel
column chromatography (100–200 mesh, eluent: EtOAc/petroleum
ether 5 %) to furnish ophiocerin C (3, 0.028 g, 82 %) as a white
solid. [α]2D5 = +42.40 (c = 1.3, CH2Cl2); ref.[5] [α]2D5 = +45.00 (c = 0.1,
1
(c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.27 (d, J = 8.5 Hz,
2 H), 6.88 (d, J = 8.9 Hz, 2 H), 5.85–5.74 (m, 1 H), 5.40–5.31 (m, 1 H),
5.29–5.15 (m, 1 H), 4.55 (d, J = 11.3 Hz, 1 H), 4.41 (d, J = 11.6 Hz, 1
H), 4.08–3.88 (m, 2 H), 3.81 (s, 3 H), 3.78–3.70 (m, 1 H), 1.81–1.73
(m, 1 H), 1.62–1.55 (m, 1 H), 1.42 (s, 3 H), 1.41 (s, 3 H), 1.23 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.1, 135.1, 131.0,
129.2, 129.1, 118.8, 113.7, 108.5, 82.9, 77.3, 71.8, 70.4, 55.2, 39.5,
27.4, 27.3, 26.9, 20.3 ppm. IR (CHCl3): νmax = 3092, 2954, 1658, 1563,
˜
1412, 1099, 829 cm–1. HRMS (ESI): calcd. for C18H26O4Na [M + Na]+
329.1723; found 329.1718.
(R)-1-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]propan-2-
ol (15): Compound 14 (0.168 g, 0.55 mmol) was dissolved in
CH2Cl2/H2O (18:1, 10 mL). DDQ (0.187 g, 0.82 mmol) was added in
one portion. The reaction mixture was stirred at room temperature
for 1 h. Completion of the reaction was monitored by TLC. The
reaction mixture was diluted with NaHCO3 solution (5 %), water and
brine and was extracted with CH2Cl2 (3 × 20 mL). The organic layer
was dried with Na2SO4 and concentrated in vacuo. Purification by
silica gel chromatography (100–200 mesh, eluent: EtOAc/petroleum
ether 5 %) afforded the pure compound 15 (0.083 g, 82 %) as a
1
CH2Cl2). H NMR (200 MHz, CDCl3): δ = 3.97 (dd, J = 5.0, 11.3 Hz, 1
H), 3.65–3.45 (m, 3 H), 3.16 (dd, J = 9.9, 11.0 Hz, 1 H), 2.00 (ddd, J =
1.8, 4.3, 12.6 Hz, 1 H), 1.38 (ddd, J = 11.1, 11.1, 12.8 Hz, 1 H), 1.22
(d, J = 6.2 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 73.3,
72.7,72.2, 69.6, 40.5, 21.2 ppm. IR (CHCl ): ν
= 3392, 3018, 2854,
˜
3
max
1458, 1263, 1099, 759 cm–1
.
(1R,3R)-3-[(4-Methoxybenzyl)oxy]-1-[(S)-oxiran-2-yl]butan-1-ol
(17): DIAD (diisopropyl azodicarboxylate, 0.36 mL, 1.86 mmol) was
light yellow oil. [α]2D5 = –11.91 (c = 2.2, CHCl3); ref.[11b] [α]2D5 = –12.25 added to a precooled (0 °C) solution of alcohol 13 (0.116 g,
(c = 0.4, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.77 (ddd, J = 7.3,
10.2, 17.2 Hz, 1 H), 5.34 (d, J = 17.1 Hz, 1 H), 5.24 (d, J = 10.4 Hz, 1
H), 4.08–3.99 (m, 2 H), 3.90 (dt, J = 3.4, 8.4 Hz, 1 H), 2.71 (br. s, 1 H),
1.70–1.67 (m, 1 H), 1.65–1.58 (m, 1 H), 1.40 (s, 3 H), 1.39 (s, 3 H),
0.46 mmol), triphenylphosphine (0.366 g, 1.39 mmol) and p-nitro-
benzoic acid (0.386 g, 2.32 mmol) in dry THF (2 mL). The reaction
mixture was stirred at room temperature for 5 h and monitored by
TLC. After completion of the reaction, the solvent was removed and
1.20 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 134.8, the crude residue was purified by silica gel column chromatography
119.1, 108.8, 82.3, 77.7, 64.9, 39.4, 27.2, 26.8, 23.6 ppm. IR (CHCl3): with petroleum ether/EtOAc (9:1) to give p-nitrobenzoate as a yel-
νmax = 3414, 2987, 2918, 1736, 1408 cm–1. HRMS (ESI): calcd. for
low oil along with DIAD as an impurity. K2CO3 (0.190 g, 1.38 mmol)
was added to the solution of p-nitrobenzoate (obtained above) in
˜
C10H18O3 [M + Na]+ 209.1148; found 209.1149.
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MeOH (3 mL), and the mixture was stirred at room temperature for
1 h, at which point it was filtered through Celite and washed with
ethyl acetate (20 mL). The solvent was concentrated in vacuo, and
the crude residue was purified by column chromatography with
EtOAc/petroleum ether 15 % as eluent to furnish compound 17
(0.091 g, 79 %) as a colourless oil. [α]2D5 = –53.13 (c = 1.8, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.88 (d, J =
8.6 Hz, 2 H), 4.60 (d, J = 11.0 Hz, 1 H), 4.36 (d, J = 11.0 Hz, 1 H),
3.92–3.82 (m, 1 H), 3.82–3.77 (s, 3 H), 3.70–3.64 (m, 1 H), 2.94–2.87
(m, 1 H), 2.81–2.71 (m, 2 H), 1.84–1.76 (m, 2 H), 1.28 (d, J = 5.9 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.6, 40.6, 45.2, 54.3, 55.2,
bined organic layers were washed with H2O and brine, dried with
Na2SO4 and concentrated in vacuo. The crude tosylate product was
used in the next step without further purification. Crude tosylate
(1.100 g, 2.37 mmol) was dissolved in CH2Cl2/H2O (18:1, 15 mL).
DDQ (0.805 g, 3.55 mmol) was added in one portion. The reaction
mixture was stirred at room temperature for 1 h. Completion of the
reaction was monitored by TLC. The reaction mixture was diluted
with NaHCO3 solution (5 %), water and brine and extracted with
CH2Cl2 (3 × 20 mL). The organic layer was dried with Na2SO4 and
concentrated in vacuo. Purification by silica gel chromatography
(100–200 mesh, eluent: EtOAc/petroleum ether 5 %) afforded the
1
70.0, 71.0, 74.9, 113.9, 129.4, 129.9, 159.3 ppm. IR (CHCl3): νmax
=
pure compound 20 (1.00 g, 83 %). [α]2D5 = –6.20 (c = 1.0, CHCl3). H
˜
3402, 3108, 2564, 1618, 1219 cm–1. HRMS (ESI): calcd. for NMR (200 MHz, CDCl3): δ = 7.80 (d, J = 8.2 Hz, 2 H), 7.37 (d, J =
C14H20O4Na [M + Na]+ 275.1254; found 275.1251.
8.2 Hz, 2 H), 4.40–4.22 (m, 2 H), 4.05–3.88 (m, 3 H), 2.46 (s, 3 H),
1.73–1.49 (m, 2 H), 1.35 (s, 3 H),1.32 (s, 3 H),1.18 (d, J = 6.2 Hz, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 145.0, 132.5, 129.9, 127.9,
109.2, 74.3, 71.8, 68.7, 64.7, 34.0, 29.8, 22.0, 21.6, 19.6 ppm. IR
(4R,5S)-4-{(R)-2-[(4-Methoxybenzyl)oxy]propyl}-2,2-dimethyl-5-
vinyl-1,3-dioxolane (18): Compound 18 was synthesized by the
same procedure as described for compound 14, in 82 % yield.
(CHCl3): νmax = 3455, 2903, 1445, 1185, 790 cm–1. C16H24O6S
˜
1
[α]2D5 = +69.90 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.27
(344.42): calcd. C 55.80, H 7.02; found C 55.69, H 6.99.
(d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 5.85–5.71 (m, 1 H),
5.27–5.17 (m, 2 H), 4.52 (d, J = 11.5 Hz, 1 H), 4.42–4.35 (m, 2 H),
4.27 (td, J = 5.6, 8.6 Hz, 1 H), 3.81 (s, 3 H), 3.67–3.56 (m, 1 H), 1.91
(ddd, J = 6.2, 8.3, 14.1 Hz, 1 H), 1.53–1.49 (m, 1 H), 1.48 (s, 3 H), 1.36
Ophiocerin A (2): Ophiocerin A was synthesized from 20 by the
same procedure as described for ophiocerin C. [α]2D5 = –23.40 (c =
0.1, CH2Cl2); ref.[3] [α]D25 = –24.00 (c = 0.1, CH2Cl2). 1H NMR (500 MHz,
(s, 3 H), 1.22 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): CDCl3): δ = 4.10 (m, 1 H), 3.83 (ddq, J = 2.0, 6.4, 11.3 Hz, 1 H), 3.71–
δ = 159.1, 134.4, 130.9, 129.3, 118.4, 113.8, 108.2, 79.8, 75.0, 71.6, 3.78 (m, 2 H), 3.60–3.53 (m, 1 H), 1.89 (ddd, J = 2.1, 3.5, 14.3 Hz, 1
69.8, 55.3, 37.1, 28.3, 25.7, 19.3 ppm. IR (CHCl3): νmax = 3102, 2964, H), 1.53 (ddd, J = 2.5, 11.0,13.9 Hz, 1 H), 1.16 (d, J = 6.3 Hz, 3 H) ppm.
˜
1668, 1573, 1422, 1199, 839 cm–1. HRMS (ESI): calcd. for C18H26O4Na 13C NMR (125 MHz, CDCl3): δ = 67.3, 67.1, 67.0, 65.9, 39.0, 20.8 ppm.
[M + Na]+ 329.1723; found 329.1721.
IR (CHCl3): νmax = 3401, 2930, 1454, 1389, 1185, 1011 cm–1
.
˜
((4S,5R)-5-{(R)-2-[(4-Methoxybenzyl)oxy]propyl}-2,2-dimethyl-
1,3-dioxolan-4-yl)methanol (19): 2,6-Lutidine (0.19 mL,
1.62 mmol) was added to a stirred solution of compound 18
(0.248 g, 0.81 mmol) in dioxane/water (3:1, 8 mL), followed by OsO4
(1S,3R)-3-[(4-Methoxybenzyl)oxy]-1-[(R)-oxiran-2-yl]butan-1-ol
(21): Dibutyltin oxide (0.009 g, 0.04 mmol) was added under argon
to a mixture of diol 11a (0.900 g, 1.77 mmol) in dry CH2Cl2 (2 mL),
followed by p-toluenesulfonyl chloride (0.337 g, 1.77 mmol) and
(0.165 g, 0.02 mmol) and NaIO4 (0.695 g, 3.25 mmol). The mixture Et3N (0.25 mL, 1.77 mmol). The resulting mixture was stirred at
was stirred at room temperature for 12 h. After completion of the room temperature for 2 h, quenched with water and then extracted
reaction (checked by TLC), water (10 mL) was added, and the mix- with CH2Cl2 (3 × 10 mL). The combined organic phase was washed
ture was extracted with CH2Cl2 (2 × 20 mL). The combined organic
layer was washed with brine and dried with Na2SO4. The solvent
was removed, and the crude aldehyde was used for the next step
immediately. The aldehyde was dissolved in MeOH (10 mL), and
NaBH4 (0.030 g) was added. After 30 min the mixture was concen-
trated and the residue was partitioned between EtOAc (50 mL) and
with water, dried (Na2SO4) and concentrated to give a crude mono-
tosylate product, which was dissolved in MeOH (10 mL) and treated
with K2CO3 (0.500 g, 3.61 mmol). This mixture was stirred for 1 h at
room temperature and then filtered through celite. Removal of the
volatiles under reduced pressure gave the crude epoxide. TBAF in
THF (1
M, 2.5 mL, 2.60 mmol) was added at room temperature to
H2O (20 mL). The organic layer was dried with Na2SO4 and concen- the stirred soln. of crude epoxide in dry THF (10 mL) and the mix-
trated, and the residue was purified by silica gel column chromatog- ture was stirred for 4 h. It was then diluted with saturated aq. NH4Cl
raphy (100–200 mesh, eluent: EtOAc/petroleum ether 5 %) to afford (20 mL) and extracted with ethyl acetate (2 × 15 mL). The combined
the pure compound 19 as a colourless liquid in 80 % (0.200 g) yield. organic layers were washed with brine, dried with Na2SO4 and con-
[α]2D5 = +48.20 (c = 1.5, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.27 centrated in vacuo. The crude product was purified by silica gel
1
(d, J = 8.3 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 4.53 (d, J = 11.5 Hz, 1
H), 4.39 (d, J = 11.2 Hz, 1 H), 4.36–4.26 (m, 1 H), 4.11–4.07 (m, 1 H),
3.81 (s, 3 H), 3.73–3.64 (m, 1 H), 3.62–3.54 (m, 2 H), 1.96 (ddd, J =
5.5, 8.4, 13.8 Hz, 1 H), 1.80 (br. s, 1 H), 1.69–1.56 (m, 1 H), 1.46 (s, 3
H), 1.36 (s, 3 H), 1.26 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.2, 130.6, 129.3, 113.8, 108.0, 77.9, 73.6, 71.9, 70.0,
column chromatography (100–200 mesh, eluent: EtOAc/petroleum
ether 5 %) to give 21 (0.352 g, 79 %) as a light yellow oil. [α]D25
=
1
–32.30 (c = 0.3, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.27 (d, J =
8.5 Hz, 2 H), 6.89 (d, J = 8.5 Hz, 2 H), 4.59 (d, J = 11.0 Hz, 1 H), 4.39
(d, J = 11.3 Hz, 1 H), 3.99–3.86 (m, 2 H), 3.81 (s, 3 H), 3.02–2.94 (m,
1 H), 2.80–2.68 (m, 2 H), 1.87–1.66 (m, 2 H), 1.27 (d, J = 6.1 Hz, 3
61.7, 55.3, 35.5, 28.2, 25.5, 19.0 ppm. IR (CHCl3): νmax = 3392, 3018, H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.3, 129.4, 113.9, 71.9,
˜
2854, 1458, 1263, 1099, 759 cm–1. HRMS (ESI): calcd. for C17H26O5Na 70.3, 67.1, 55.3, 54.3, 44.4, 39.8, 19.4 ppm. IR (CHCl3): νmax = 3420,
˜
[M + Na]+ 333.1672; found 333.1670.
3128, 2594, 1648, 1249 cm–1. HRMS (ESI): calcd. for C14H20O4Na [M
+ Na]+ 275.1254; found 275.1248.
{(4S,5R)-5-[(R)-2-Hydroxypropyl]-2,2-dimethyl-1,3-dioxolan-4-
yl}methyl 4-Methylbenzenesulfonate (20): Et3N (1.0 mL,
7.2 mmol) and DMAP (0.044 g, 0.40 mmol) were added at room
(1R,3R)-3-[(4-Methoxybenzyl)oxy]-1-[(R)-oxiran-2-yl]butan-1-ol
(22): Compound 22 was synthesized from 21 by the same proce-
temperature to a stirred solution of alcohol 19 (1.100 g, 3.60 mmol) dure as described for compound 17, in 75 % yield. [α]2D5 = –42.4
1
in dry CH2Cl2, and the mixture was stirred for 10 min. TsCl (0.900 g,
4.80 mmol) was added and stirring was continued at room tempera-
ture for another 3 h. The mixture was diluted with saturated aq.
(c = 2.5, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz,
2 H), 6.88 (d, J = 8.3 Hz, 2 H), 4.59 (d, J = 11.0 Hz, 1 H), 4.36 (d, J =
11.2 Hz, 1 H), 3.86–3.81 (m, 1 H), 3.80 (s, 3 H), 3.75–3.67 (m, 1 H),
NH4Cl (20 mL) and extracted with CH2Cl2 (5 × 10 mL). The com- 3.37 (d, J = 2.7 Hz, 1 H), 3.02–2.94 (m, 1 H), 2.78–2.72 (m, 1 H), 2.70–
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2.60 (m, 1 H), 1.86 (td, J = 9.2, 14.4 Hz, 1 H), 1.74–1.61 (m, 1 H), 1.26
(d, J = 6.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.3,
residue was used for the next step without further purification.
tBuOK (0.248 g, 2.20 mmol) was added at 0 °C to the stirred solution
130.0, 129.4, 113.9, 74.1, 70.7, 69.9, 55.2, 54.9,44.3, 40.3, 19.6 ppm. of crude tosylate in dry Et2O (3 mL), and the mixture was stirred for
IR (CHCl3): νmax = 3410, 3118, 2584, 1638, 1239 cm–1. HRMS (ESI):
1 h at 0 °C and monitored by TLC. After completion of the reaction
it was diluted with satd. aq. NH4Cl (10 mL) and extracted with Et2O
(4 × 5 mL). The combined organic layers were washed with H2O
and brine, concentrated in vacuo and then treated with PTSA
(0.003 g) and MeOH (5 mL) with stirring at room temperature for
another 2 h. The reaction was quenched with saturated aq. NaHCO3
solution, the mixture was extracted with CH2Cl2 (3 × 20 mL), and
the combined organic layers were washed with H2O and brine,
dried with Na2SO4 and concentrated. The residue was purified by
silica gel column chromatography (100–200 mesh, eluent: EtOAc/
petroleum ether 5 %) to produce ophiocerin B (3, 0.059 g, overall
yield 82 %) as a yellow oil. [α]2D5 = –35.20 (c = 1.3, CH2Cl2); ref.[5]
[α]2D5 = –37.00 (c = 0.1, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 4.01–
3.94 (m, 2 H), 3.91–3.81 (m, 1 H), 3.73 (dd, J = 12.5, 1.8 Hz, 1 H),
3.48 (m, 1 H), 2.27 (br. s, 2 H), 1.81 (ddd, J = 3.2, 10.9, 14.3 Hz, 1 H),
1.63–1.60 (m, 1 H), 1.19 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (125 MHz,
˜
calcd. for C14H20O4Na [M + Na]+ 275.1254; found 275.1249.
(4R,5S)-4-{(R)-2-[(4-Methoxybenzyl)oxy]propyl}-2,2-dimethyl-5-
vinyl-1,3-dioxolane (23): Compound 23 was synthesized from 22
by the same procedure as described for compound 14. [α]2D5 = –8.47
1
(c = 2.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 8.6 Hz,
2 H), 6.88 (d, J = 8.6 Hz, 2 H), 5.79 (ddd, J = 7.3, 10.1, 17.3 Hz, 1 H),
5.36 (d, J = 17.1 Hz, 1 H), 5.24 (d, J = 10.3 Hz, 1 H), 4.50 (d, J =
11.2 Hz, 1 H), 4.38 (d, J = 11.0 Hz, 1 H), 4.05 (t, J = 7.8 Hz, 1 H), 3.81
(s, 3 H), 3.80–3.77 (m, 1 H), 3.76–3.66 (m, 1 H), 1.96 (td, J = 7.1,
14.0 Hz, 1 H), 1.68 (ddd, J = 4.4, 6.5, 14.1 Hz, 1 H), 1.43 (s, 3 H), 1.41
(s, 3 H), 1.24 (d, J = 5.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.1, 135.2, 130.9, 129.2, 119.0, 113.7, 108.6, 82.8, 77.6, 71.8,
69.9, 55.3, 38.5, 27.3, 26.9, 19.6 ppm. IR (CHCl3): νmax = 3082, 2964,
˜
1648, 1573, 1402, 1119, 789 cm–1. HRMS (ESI): calcd. for C18H26O4Na
[M + Na]+ 329.1723; found 329.1725.
CDCl3): δ = 68.4, 68.3, 67.4, 67.3, 36.0, 21.2 ppm. IR (CHCl3): νmax
=
˜
3398, 1467, 1389, 1287, 1104, 987 cm–1. HRMS (ESI): calcd. for
C6H12O3Na [M + Na]+ 155.0679; found 155.0680.
((4S,5R)-5-{(R)-2-[(4-Methoxybenzyl)oxy]propyl}-2,2-dimethyl-
1,3-dioxolan-4-yl)methanol (24): Compound 24 was synthesized
from 23 by the same procedure as described for compound 19.
[α]2D5 = +0.81 (c = 5.8, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.26
(d, J = 8.3 Hz, 2 H), 6.87 (d, J = 8.3 Hz, 2 H), 4.51 (d, J = 11.2 Hz, 1
H), 4.38 (d, J = 11.0 Hz, 1 H), 4.06–3.96 (m, 1 H), 3.80 (s, 3 H), 3.74
(m, 2 H), 3.66–3.56 (m, 1 H), 2.09–1.92 (m, 2 H), 1.76–1.65 (m, 2 H),
1.41 (s, 3 H), 1.39 (s, 3 H), 1.26 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.1, 130.6, 129.3, 129.2, 113.8, 108.5, 81.4,
74.1, 71.8, 69.9, 61.9, 55.3, 39.6, 27.3, 27.0, 19.4 ppm. IR (CHCl3):
(R)-1-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]propan-2-
yl Acetate (26): Acetic anhydride (1.0 mL, 7.74 mmol) and DMAP
(cat.) were added to a precooled (0 °C) solution of 15 (0.725 g,
3.90 mmol) in dry pyridine (5 mL), and the mixture was stirred at
room temperature for 4 h. After completion of the reaction, the
mixture was diluted with aq. CuSO4·5 H2O solution (10 %) and ex-
tracted with ethyl acetate (3 × 20 mL). The combined organic ex-
tract was washed with brine solution and dried with Na2SO4, and
the solvents were evaporated under vacuum to furnish the crude
residue, which was purified by silica gel column chromatography
(100–200 mesh, eluent: EtOAc/petroleum ether 5 %) to give acetate
compound 26 (0.800 g, 90 %) as a yellow oil. [α]2D5 = –16.48 (c =
νmax = 3412, 3018, 2854, 1458, 1263, 1099, 759 cm–1. HRMS (ESI):
˜
calcd. for C17H26O5Na [M + Na]+ 333.1672; found 333.1674.
((4S,5R)-5-{(R)-2-[(4-Methoxybenzyl)oxy]propyl}-2,2-dimethyl-
1,3-dioxolan-4-yl)methyl 4-Methylbenzenesulfonate (25): Et3N
(0.5 mL, 3.60 mmol) and DMAP (0.022 g, 0.20 mmol) were added at
room temperature to a stirred solution of alcohol 24 (0.560 g,
1.80 mmol) in dry CH2Cl2, and the mixture was stirred for 10 min.
TsCl (0.900 g, 4.80 mmol) was added and stirring was continued at
room temperature for another 3 h. The reaction mixture was diluted
with saturated aq. NH4Cl (20 mL) and extracted with CH2Cl2 (5 ×
10 mL). The combined organic layers were washed with H2O and
brine, dried with Na2SO4 and concentrated in vacuo. The crude tos-
ylate product was purified by column chromatography (100–
200 mesh, eluent: EtOAc/petroleum ether 5 %) to give the tosyl
ester 25 (0.720 g, 86 %) as a yellow liquid. [α]2D5 = –12.3 (c = 0.3,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.83–7.72 (d, J = 8.2 Hz, 2 H),
7.32 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 8.2 Hz, 2 H), 6.91–6.85 (d, J =
8.5 Hz, 2 H), 4.56–4.46 (m, 1 H), 4.35 (d, J = 11.3 Hz, 1 H), 4.14–4.02
(m, 2 H), 3.96 (dt, J = 4.9, 7.5 Hz, 1 H), 3.91–3.85 (m, 1 H), 3.81 (s, 3
H), 3.73–3.67 (m, 1 H), 2.44 (s, 3 H), 1.93 (td, J = 6.8, 13.9 Hz, 1 H),
1.74–1.62 (m, 1 H), 1.37 (s, 3 H), 1.30 (s, 3 H), 1.23 (d, J = 6.4 Hz, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.1, 144.9, 132.7,130.7,
129.8, 129.1, 127.9, 113.7, 109.3, 78.3, 74.6, 71.5, 69.8, 69.0, 55.3,
1
2.5, CHCl3). H NMR (400 MHz, CDCl3): δ = 5.86–5.71 (m, 1 H), 5.38
(d, J = 17.1 Hz, 1 H), 5.27 (d, J = 10.3 Hz, 1 H), 5.14–4.97 (m, 1 H),
4.01–3.90 (m, 1 H), 3.80–3.61 (m, 1 H), 2.03 (s, 3 H), 1.92–1.79 (m, 1
H), 1.74–1.64 (m, 1 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.27 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 134.9, 119.2, 108.8,
82.7, 77.2, 68.6, 38.2, 27.2, 26.9, 21.3, 20.6 ppm. IR (CHCl3): νmax
=
˜
3081, 2854, 1685, 1458, 1263, 1009, 917 cm–1. HRMS (ESI): calcd. for
C12H20O4Na [M + Na]+ 251.1254; found 251.1254.
Ethyl (Z)-3-{(4S,5S)-5-[(R)-2-Acetoxypropyl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}acrylate (27): Olefin 26 (0.251 g, 1.10 mmol) was dis-
solved in CH2Cl2 (10 mL), and the mixture was cooled to –78 °C.
Ozone was passed through the solution until a blue tint was ob-
served (ca. 3 min), and dimethyl sulfide (6 mL) was added to this
resulting blue solution. The reaction mixture was allowed to warm
to room temperature and stirred for 12 h, at which point it was
concentrated and the crude aldehyde was used for the next step
without purification. Ethyl [bis(2,2,2-trifluoroethoxy)phosphinyl]-
acetate (0.320 g, 1.40 mmol) and 18-crown-6 (2.470 g, 9.36 mmol)
were taken up in dry THF (10 mL) at –78 °C, KHMDS (0.670 g,
2.93 mmol) was added, and the reaction mixture was stirred for 1 h.
Then, the above crude aldehyde (0.179 g, 0.95 mmol) dissolved in
THF (5 mL) was added, and stirring was continued for another 6 h at
–78 °C, at which point it showed complete consumption of starting
material. Then the reaction mixture was quenched with saturated
aq. NH4Cl and extracted with ethyl acetate (3 × 20 mL). The com-
bined organic layers were washed with brine, dried with Na2SO4
and concentrated in vacuo, and the residue was purified over silica
gel (100–200 mesh, eluent EtOAc/hexane 10 %) to give the product
27 (0.290 g, 88 %) as a colourless syrup. [α]2D5 = –7.10 (c = 1.2,
39.5, 27.3, 26.6, 21.6, 13.4 ppm. IR (CHCl3): νmax = 3392, 2754, 1858,
˜
1463, 1009, 959 cm–1. HRMS (ESI): calcd. for C24H32O7SNa [M + Na]+
487.1761; found 487.1762.
Ophiocerin B (3): Compound 25 (0.255 g, 0.55 mmol) was dis-
solved in CH2Cl2/H2O (18:1, 15 mL), and DDQ (0.187 g, 0.83 mmol)
was added in one portion. The reaction mixture was stirred at room
temperature for 1 h. Completion of the reaction was monitored by
TLC. The reaction mixture was diluted with NaHCO3 solution (5 %),
water and brine and extracted with CH2Cl2 (3 × 20 mL). The organic
layer was dried with Na2SO4 and concentrated in vacuo. The crude
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1
CHCl3). H NMR (400 MHz, CDCl3): δ = 6.11 (dd, J = 8.8, 11.7 Hz, 1
which was dissolved in MeOH (10 mL) and treated with K2CO3
(0.500 g, 3.61 mmol). This mixture was stirred for 1 h at room tem-
perature and then filtered through celite. Removal of the volatiles
under reduced pressure gave crude epoxide, which was purified by
column chromatography (silica gel mesh 100–200, EtOAc/petro-
H), 5.95 (d, J = 12.2 Hz, 1 H), 5.28–5.23 (m, 1 H), 5.14–4.94 (m, 1 H),
4.18 (q, J = 7.3 Hz, 2 H), 3.84–3.66 (m, 1 H), 2.00 (s, 3 H), 1.91–1.69
(m, 2 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.24 (d,
J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.4, 165.4,
145.2, 123.3, 109.5, 77.9, 76.4, 68.5, 60.5, 38.2, 29.6, 27.3, 26.9, 21.3, leum ether 20 %) to provide epoxide 31 (0.295 g, 80 % yield).
14.1 ppm. IR (CHCl3): νmax = 2975, 2940, 1732, 1645, 1357, 1263,
[α]2D5 = –13.5 (c = 2.5, CHCl3); ref.[25] [α]2D5 = –13.1 (c = 0.58, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.26 (d, J = 8.5 Hz, 2 H), 6.90 (d, J =
8.5 Hz, 2 H), 4.47 (s, 2 H), 3.81 (s, 3 H), 3.62–3.57 (m, 2 H), 3.09–3.03
(m, 1 H), 2.78 (t, J = 4.5 Hz, 1 H), 2.52 (dd, J = 2.7, 4.9 Hz, 1 H), 1.95–
1.84 (m, 1 H), 1.77 (qd, J = 6.0, 14.3 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 159.1, 130.3, 129.2, 113.7, 72.7, 66.6, 55.2, 50.0, 47.0,
˜
1199, 1019 cm–1. HRMS (ESI): calcd. for C15H24O6Na [M + Na]+
323.1465; found 323.1460.
Botryolide E (4): The ester 27 (0.150 g, 0.50 mmol) was dissolved
in THF, HCl solution (1
M, 1 mL) was added, and the mixture was
stirred for 2 h at 0 °C. After consumption of starting material (moni-
tored by TLC), the reaction mixture was quenched with saturated
NaHCO3 and extracted into EtOAc (3 × 10 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4) and concen-
trated under reduced pressure to provide crude lactone, which was
purified by column chromatography (silica gel 100–200 mesh,
EtOAc/petroleum ether 40 %) to afford pure lactone 4 (0.069 g,
65 %). [α]2D5 = –37.10 (c = 2.5, CHCl3); ref.[6] [α]2D5 = –36.70 (c = 0.05,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.50 (dd, J = 1.5, 6.1 Hz, 1
H), 6.19 (dd, J = 2.1, 5.8 Hz, 1 H), 5.18–5.08 (m, 1 H), 5.07–4.98 (m,
1 H), 3.96–3.84 (m, 1 H), 2.04 (s, 3 H), 1.95–1.88 (m, 1 H), 1.80–1.73
(m, 1 H), 1.31 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 172.8, 170.8, 153.7, 122.8, 85.3, 69.0, 68.7, 39.1, 21.3, 20.0 ppm.
32.9 ppm. IR (CHCl3): νmax = 3036, 2987, 2915, 2870, 1643 cm–1
.
˜
HRMS (ESI): calcd. for C12H16O3Na [M + Na]+ 231.0992; found
231.0988.
(S)-tert-Butyl({5-[(4-methoxybenzyl)oxy]pent-1-en-3-yl}oxy)-
dimethylsilane (32): Trimethylsulfonium iodide (1.230 g,
6.05 mmol) was added at –20 °C to stirred dry THF, followed by
nBuLi (3.8 mL, 1.6 M, 6.05 mmol). The reaction mixture was stirred
for 1 h, after which epoxide 31 (0.251 g, 1.21 mmol) in THF was
added dropwise. The reaction mixture was stirred at –20 °C for 3 h,
and completion of the reaction was monitored by TLC. The reaction
mixture was diluted with saturated ammonium chloride solution
and extracted with EtOAc (2 × 50 mL). The combined organic layers
were washed with water (2 × 50 mL) and brine, dried with Na2SO4
and concentrated. The crude alcohol was used for the next step
without further purification. tert-Butylchlorodimethylsilane (0.212 g,
1.41 mmol) was added slowly at 0 °C to the stirred solution of crude
alcohol and imidazole (0.129 g, 1.90 mmol) in dry CH2Cl2, and the
reaction mixture was stirred for 4 h at room temperature. After
completion of the reaction, water was added to quench the reac-
tion mixture, and the organic layer was washed with excess water
and brine, dried with Na2SO4 and concentrated to afford the crude
silylated compound, which was purified by silica gel column chro-
matography (100–200 mesh, eluent: EtOAc/petroleum ether 5 %) to
afford 32 (0.330 g, 82 %) as a viscous liquid. [α]2D5 = +3.5 (c = 1.6,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.27 (d, J = 8.2 Hz, 2 H), 6.89
(d, J = 8.5 Hz, 2 H), 5.81 (ddd, J = 6.1, 10.5, 16.9 Hz, 1 H), 5.16 (d,
J = 17.1 Hz, 1 H), 5.02 (d, J = 10.4 Hz, 1 H), 4.48–4.36 (m, 2 H), 4.30
(q, J = 6.0 Hz, 1 H), 3.82 (s, 3 H), 3.59–3.43 (m, 2 H), 1.78 (q, J =
5.7 Hz, 2 H), 0.90 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 159.1, 141.6, 130.7, 129.3, 113.7, 72.6, 70.8,
IR (CHCl3): νmax = 3432, 3008, 2844, 1743, 1720, 1658, 1256 cm–1
.
˜
HRMS (ESI): calcd. for C10H14O5Na [M + Na]+ 237.0733; found
237.0733.
(S)-4-[(4-Methoxybenzyl)oxy]butane-1,2-diol (30): D-Proline
(0.187 g, 1.63 mmol) was added at room temperature to a solution
of PMB-protected butanal 28 (1.130 g, 5.43 mmol) and nitroso-
benzene (0.581 g, 5.43 mmol) in anhydrous DMSO (29 mL), turning
the solution green. The reaction mixture was vigorously stirred for
1 h under argon (the colour changed from green to yellow during
this time). Then the temperature was lowered to 0 °C, followed by
addition of methanol and sodium borohydride to the reaction mix-
ture. After completion of the reaction (monitored by TLC), the re-
sulting mixture was diluted with water and extracted with EtOAc
(4 × 20 mL), and the combined organic phases were washed with
brine, dried with Na2SO4 and concentrated to give the crude
aminoxy alcohol, which was used directly for the next step without
purification. CuSO4·5 H2O (1.350 g, 5.43 mmol) was added to a well-
stirred solution of this aminoxy alcohol in methanol, and the mix-
ture was stirred overnight at room temp. The reaction mixture was
filtered through celite and concentrated in vacuo. The compound
was purified by column chromatography (silica gel mesh 100–200,
EtOAc/petroleum ether 40 %) to afford diol 30 in 78 % yield
(0.958 g). [α]D25 = –4.80 (c = 1.7, CHCl3); ref.[24] [α]2D5 = –5.20 (c = 2.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.24 (d, J = 8.6 Hz, 2 H), 6.87
(d, J = 8.6 Hz, 2 H), 4.44 (s, 2 H), 3.91–3.82 (m, 1 H), 3.79 (s, 3 H),
3.68–3.54 (m, 3 H), 3.50–3.41 (m, 1 H), 3.17 (br. s, 2 H), 1.81–1.68 (m,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2, 129.8, 129.3, 113.8,
66.4, 55.3, 38.1, 25.9, 18.2, –4.4, –4.9 ppm. IR (CHCl3): νmax = 3072,
˜
3028, 2967, 2912, 1709, 1613, 1485, 1203, 1099 cm–1. HRMS (ESI):
calcd. for C19H32O3Si Na [M + Na]+ 359.2013; found 359.2014.
(S)-3-[(tert-Butyldimethylsilyl)oxy]pent-4-enoic Acid (33): Olefin
32 (0.250 g. 0.74 mmol) was dissolved in CH2Cl2/H2O (18:1, 15 mL).
DDQ (0.253 g, 1.12 mmol) was added in one portion. The reaction
mixture was stirred at room temperature for 1 h. Completion of the
reaction was monitored by TLC. The reaction mixture was diluted
with NaHCO3 solution (5 %), water and brine and extracted with
CH2Cl2 (3 × 20 mL). The organic layer was dried with Na2SO4 and
concentrated in vacuo. The crude alcohol was used for the next
step without further purification. TEMPO (0.029 g, 0.10 mmol) and
BAIB (0.900 g, 2.8 mmol) were added at 0 °C to a stirred solution of
crude primary alcohol (0.194 g, 0.90 mmol) in CH3CN (3 mL) and
H2O (1 mL) with monitoring by TLC. The reaction mixture was
stirred for 7 h, until TLC indicated the complete consumption of
starting material. The reaction mixture was diluted by the addition
72.8, 71.0, 67.6, 66.4, 55.2, 32.7 ppm. IR (CHCl3): νmax = 3446, 2980,
˜
2932, 2853, 1623, 1533 cm–1. HRMS (ESI): calcd. for C12H18O4Na [M
+ Na]+ 249.1097; found 249.1095.
(S)-2-{2-[(4-Methoxybenzyl)oxy]ethyl}oxirane (31): Dibutyltin ox-
ide (0.009 g, 0.04 mmol) was added under argon to a mixture of diol
30 (0.4 g, 1.77 mmol) in dry CH2Cl2 (20 mL), followed by addition of
p-toluenesulfonyl chloride (0.337 g, 1.77 mmol) and Et3N (0.25 mL,
1.77 mmol). The resulting mixture was stirred at room temperature of saturated aqueous Na2SO3 (20 mL), and the aqueous layer was
for 2 h, quenched with water and then extracted with CH2Cl2 (3 ×
10 mL). The combined organic phase was washed with water, dried
(Na2SO4) and concentrated to give a crude monotosylate product,
extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine, dried with Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel column
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chromatography (EtOAc/hexane 25 %) to give 33 (0.128 g, 75 %) as
crude lactone, which was purified by column chromatography (sil-
a light yellow oil. [α]2D5 = +2.8 (c = 1.8, CHCl3); ref.[11b] [α]D25 = +2.1 ica gel 100–200 mesh, EtOAc/petroleum ether 40 %) to afford pure
(c = 0.4, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 5.86 (ddd, J = 6.2,
10.5, 17.0 Hz, 1 H), 5.27 (dd, J = 1.1, 17.2 Hz, 1 H), 5.13 (dd, J = 1.1,
10.4 Hz, 1 H), 4.69–4.50 (m, 1 H), 2.56 (dd, J = 2.7, 6.1 Hz, 2 H), 0.90
(s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 175.7, 139.4, 115.4, 70.6, 43.0, 25.7, 18.1, –4.4, –5.2 ppm. IR
lactone 5 (0.034 g, 68 %) as a colourless thick liquid. [α]2D5 = –20.2
(c = 0.8, MeOH); ref.[11b] [α]2D5 = –19.6 (c = 0.2, MeOH). 1H NMR
(400 MHz, CD3OD): δ = 5.89 (dd, J = 3.1, 15.8 Hz, 1 H), 5.52 (dd, J =
10.8, 15.8 Hz, 1 H), 4.80–4.69 (m, 1 H), 4.63–4.62 (m, 1 H), 3.75 (t,
J = 9.2 Hz, 1 H), 3.38 (t, J = 9.3 Hz, 1 H), 2.52 (dd, J = 3.8, 11.9 Hz,
1 H), 2.43 (dd, J = 3.5, 11.9 Hz, 1 H), 1.95–1.88 (m, 1 H), 1.75 (d, J =
15.9 Hz, 1 H), 1.20 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CD3OD): δ = 171.9, 137.6, 127.1, 80.0, 77.2, 70.9, 68.1, 44.5, 44.2,
(CHCl3): νmax = 2954, 2856, 1741, 1446, 812 cm–1. HRMS (ESI): calcd.
˜
for C11H22O3Si Na [M + Na]+ 253.1230; found 253.1231.
(R)-1-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]propan-2-
yl (S)-3-[(tert-Butyldimethylsilyl)oxy]pent-4-enoate (34): DMAP
(0.003 g, 0.020 mmol) was added to a stirred solution of triethyl-
amine (0.066 g, 0.65 mmol) in dry CH2Cl2 (5 mL), followed by 2-
methyl-6-nitrobenzoic anhydride (0.083 g, 0.24 mmol) and acid 33
(0.056 g, 0.24 mmol). The reaction mixture was stirred for another
45 min, hydroxy olefin 15 (0.037 g, 0.2 mmol) in dry CH2Cl2 was
then added, and the progress of the reaction was monitored by
TLC. This reaction mixture was then stirred for 12 h and quenched
by addition of saturated aqueous NH4Cl solution. The aqueous layer
was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with brine, dried with Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel col-
umn chromatography with petroleum ether/EtOAc (80:20) as an
23.4 ppm. IR (CHCl3): νmax = 3412, 2918, 1754, 1485 cm–1. HRMS
˜
(ESI): calcd. for C10H16O5Na [M + Na]+ 239.0890; found 239.0889.
tert-Butyl({(3S,5R)-5-[(4-methoxybenzyl)oxy]hex-1-en-3-yl}oxy)-
diphenylsilane (36): Triphenylphosphine (3.000 g, 11.40 mmol)
and imidazole (1.560 g, 22.90 mmol) were added at 0 °C to a stirred
solution of compound 11a (1.930 g, 3.80 mmol) in dry THF
(150 mL), followed by iodine (2.900 g, 11.40 mmol). Then the reac-
tion mixture was heated at reflux for 4 h and allowed to cool to
room temperature, after which it was diluted with saturated aque-
ous Na2S2O3 (100 mL) and extracted with ethyl acetate (2 × 30 mL).
The combined organic phase was washed with brine and dried
(Na2SO4), and the solvent was evaporated under reduced pressure.
The crude product was purified by column chromatography (100–
200 mesh silica gel, EtOAc/hexane 5 % as an eluent) to afford olefin
36 (1.500 g, 83 %) as a colourless oil. [α]2D5 = +13.45 (c = 5.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.71–7.67 (m, 4 H), 7.46–7.32 (m, 6
eluent to afford 34 (0.075 g, 95 %) as a colourless liquid. [α]D25
=
–6.92 (c = 1.1, CHCl3); ref.[11b] [α]D25 = –5.25 (c = 0.4, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 5.90–5.71 (m, 2 H), 5.37 (d, J = 17.1 Hz, 1 H),
5.29–5.17 (m, 2 H), 5.13–4.98 (m, 2 H), 4.63–4.52 (m, 1 H), 4.02–3.90 H), 7.14 (d, J = 8.2 Hz, 2 H), 6.85 (d, J = 8.2 Hz, 2 H), 5.85–5.75 (m,
(m, 1 H), 3.78–3.60 (m, 1 H), 2.52 (dd, J = 7.0, 15.0 Hz, 1 H), 2.41
(dd, J = 5.8, 14.6 Hz, 1 H), 1.95–1.79 (m, 1 H), 1.77–1.59 (m, 1 H),
1.39 (s, 3 H), 1.38 (s, 3 H), 1.27 (d, J = 6.1 Hz, 3 H), 0.87 (s, 9 H), 0.06
(s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.3,
140.2, 134.8, 119.3, 114.6, 108.9, 82.8, 77.2, 68.9, 43.8, 38.4, 27.2,
1 H), 4.95–4.85 (m, 2 H), 4.40–4.29 (m, 2 H), 4.15 (d, J = 10.7 Hz, 1
H), 3.81 (s, 3 H), 3.63–3.54 (m, 1 H), 1.81 (td, J = 6.5, 13.5 Hz, 1 H),
1.74–1.64 (m, 1 H), 1.09–1.05 (m, 12 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 158.9, 141.0, 136.0, 135.9, 134.3, 131.1, 129.5, 129.4,
129.1, 129.0, 127.5, 127.3, 114.5, 113.6, 72.5, 71.7, 69.8, 55.3, 45.6,
26.9, 25.8, 20.6, 18.1, –4.4, –4.5 ppm. IR (CHCl3): νmax = 3023, 2909, 27.0, 19.9, 19.3 ppm. IR (CHCl3): νmax = 3072, 2932, 2866, 1614,
˜
˜
2875, 1773, 1664, 1436, 1337, 1252 cm–1. HRMS (ESI): calcd. for 1459, 1426, 1377, 1260, 1106, 1046, 992 cm–1. HRMS (ESI): calcd. for
C21H38O5Si Na [M + Na]+ 421.2381; found 421.2381.
C30H38O3SiNa [M + Na]+ 497.2482; found 497.2479.
(3S,5R,9S,11S,E)-9-(tert-Butyldimethylsilyloxy)-2,2,5-trimethyl-
4,5,8,9-tetrahydro-3-[1,3]dioxolo[4,5]oxecin-7-one (35): The sec-
ond-generation Grubbs catalyst (0.027 g, 10 mol-%) was added to
a solution of diene 34 (0.125 g, 0.31 mmol) in freshly distilled CH2Cl2
(250 mL, degassed for 15 min by argon bubbling), and the solution
was then again degassed for 1 h. The reaction mixture was heated
at reflux at 45 °C for 24 h (completion of the reaction was checked
by TLC). The solvent was removed in vacuo and the crude product
was purified by silica gel column chromatography (silica gel, 230–
400 mesh, EtOAc/petroleum ether 30 %) to afford compound 35
(2R,4S)-4-[(tert-Butyldiphenylsilyl)oxy]hex-5-en-2-ol (37): Olefin
36 (0.150 g, 0.32 mmol) was dissolved in CH2Cl2/H2O (18:1, 15 mL),
and DDQ (0.108 g, 0.47 mmol) was added in one portion. The reac-
tion mixture was stirred at room temperature for 1 h. Completion
of the reaction was monitored by TLC. The reaction mixture was
diluted with NaHCO3 solution (5 %), water and brine and extracted
with CH2Cl2 (3 × 20 mL). The organic layer was dried with Na2SO4
and concentrated in vacuo. The crude product was purified by col-
umn chromatography (100–200 mesh silica gel, EtOAc/hexane 15 %
as an eluent) to afford olefin 37 (0.089 g, 80 %) as a colourless oil.
(0.087 g, 75 %) as a colourless oil. [α]2D5 = –9.81 (c = 1.5, CHCl3); [α]D25 = –6.25 (c = 1.2, CHCl3); ref.[12c] [α]D25 = –5.30 (c = 1.3, CHCl3).
ref.[11b] [α]2D5 = –8.10 (c = 0.4, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1H NMR (400 MHz, CDCl3): δ = 7.76–7.64 (m, 4 H), 7.49–7.36 (m, 6
5.97–5.87 (m, 1 H), 5.70–5.58 (m, 1 H), 5.04–4.92 (m, 1 H), 4.72–4.63 H), 5.86 (ddd, J = 5.9, 10.7, 16.9 Hz, 1 H), 5.12–4.99 (m, 2 H), 4.47
(m, 1 H), 4.10 (t, J = 8.8 Hz, 1 H), 3.63 (t, J = 8.8 Hz, 1 H), 2.46 (d, (q, J = 5.1 Hz, 1 H), 4.11–4.03 (m, 1 H), 1.69 (ddd, J = 4.4, 9.8, 14.4 Hz,
J = 3.4 Hz, 2 H), 2.06–1.85 (m, 2 H), 1.41 (s, 6 H), 1.22 (d, J = 6.4 Hz, 1 H), 1.55–1.47 (m, 1 H), 1.10 (s, 12 H) ppm. 13C NMR (100 MHz,
3 H), 0.93 (s, 9 H), 0.11 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 139.5, 136.0, 135.9, 133.3, 133.2, 129.9, 129.8,
CDCl3): δ = 168.4, 138.1, 122.8, 107.9, 84.1, 81.6, 69.0, 67.9, 45.2,
127.7, 127.5, 115.0, 73.8, 64.6, 44.8, 27.0, 23.4, 19.2 ppm. IR (CHCl3):
38.5, 27.0, 26.9, 25.7, 21.8, 18.3, –5.0, –5.2 ppm. IR (CHCl3): νmax
=
νmax = 3479, 2924, 2845, 1436, 1471, 1206, 1119, 969, 942, 812,
˜
˜
2919, 2837, 1753, 1126, 1087 cm–1. HRMS (ESI): calcd. for C19H34O5Si 716 cm–1. HRMS (ESI): calcd. for C22H30O2SiNa [M + Na]+ 377.1907;
Na [M + Na]+ 393.2068; found 393.2064.
found 377.1904.
Decarestrictine O: The protected lactone 35 (0.087 g, 0.24 mmol)
tert-Butyl({(3S,5S)-5-[(4-methoxybenzyl)oxy]hex-1-en-3-yl}oxy)-
diphenylsilane (38): Compound 38 was synthesized from 11b by
the same procedure as described for the synthesis of compound
was dissolved in THF, HCl solution (1
M, 1 mL) was added, and the
mixture was stirred for 2 h at 0 °C. After consumption of starting
material (monitored by TLC), the reaction was quenched with satu- 36, in 82 % yield. [α]2D5 = +22.58 (c = 8.0, CHCl3). 1H NMR (500 MHz,
rated NaHCO3 and the mixture was extracted into EtOAc (3 ×
10 mL). The combined organic layers were washed with brine, dried
(Na2SO4) and concentrated under reduced pressure to provide
CDCl3): δ = 7.72–7.67 (m, 4 H), 7.48–7.35 (m, 6 H), 7.13 (d, J = 8.2 Hz,
2 H), 6.83 (d, J = 8.2 Hz, 2 H), 5.86–5.75 (m, 1 H), 4.93 (d, J = 10.4 Hz,
1 H), 4.84 (d, J = 17.7 Hz, 1 H), 4.41–4.30 (m, 2 H), 4.24 (d, J =
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11.3 Hz, 1 H), 3.82 (s, 3 H), 3.58–3.48 (m, 1 H), 2.04–1.95 (m, 1 H),
1.59–1.50 (m, 1 H), 1.08 (s, 12 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 158.9, 140.7, 136.0, 135.9, 134.2, 134.1, 131.1, 129.5, 129.4, 129.0,
127.5, 127.3, 114.6, 113.6, 72.6, 71.3, 69.5, 55.2, 45.2, 27.0, 19.8,
leum ether 5 %) to afford 44 (0.890 g, 78 %) as a viscous liquid.
1
[α]2D5 = +16.9 (c = 3.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.74–
7.70 (m, 4 H), 7.48–7.37 (m, 6 H), 7.25 (s, 2 H), 6.91 (d, J = 8.5 Hz, 2
H), 5.83 (ddd, J = 6.3, 10.5, 17.1 Hz, 1 H), 5.07–4.97 (m, 2 H), 4.41 (s,
2 H), 4.28–4.20 (m, 1 H), 3.84 (s, 3 H), 3.40–3.31 (m, 2 H), 1.68–1.55
19.3 ppm. IR (CHCl3): νmax = 3052, 2922, 2836, 1617, 1449, 1416,
˜
1317, 1267, 1162, 1056 cm–1. HRMS (ESI): calcd. for C30H38O3SiNa (m, 4 H), 1.12 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.0,
[M + Na]+ 497.2482; found 497.2476.
140.5, 135.9, 135.8, 134.4, 134.2, 129.5, 129.4, 129.1, 127.4, 127.3,
114.5, 113.7, 74.3, 72.3, 70.0, 55.2, 34.0, 27.0, 24.6, 19.3 ppm. IR
(2S,4S)-4-[(tert-Butyldiphenylsilyl)oxy]hex-5-en-2-ol (39): Com-
pound 39 was synthesized by the same procedure as described for
the synthesis of compound 37, in 84 % yield. [α]2D5 = –2.87 (c = 2.5,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.79–7.61 (m, 4 H), 7.48–7.33
(m, 6 H), 5.79 (ddd, J = 6.7, 10.4, 17.1 Hz, 1 H), 4.95–4.85 (m, 2 H),
4.40 (q, J = 6.3 Hz, 1 H), 4.04–3.96 (m, 1 H), 2.13 (br. s, 1 H), 1.71
(ddd, J = 6.7, 9.0, 14.3 Hz, 1 H), 1.53 (ddd, J = 2.9, 5.9, 14.2 Hz, 1 H),
1.11 (d, J = 6.4 Hz, 3 H), 1.08 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 140.5, 136.0, 135.9, 133.8, 133.7, 129.8, 129.6, 127.6,
(CHCl3): νmax = 3408, 3049, 2912, 2867, 1632, 1445, 1406, 1372,
˜
1351, 1109, 1031, 963, 851, 717, 652 cm–1. HRMS (ESI): calcd. for
C
30H38O3SiNa [M + Na]+ 497.2482; found 497.2482.
(S)-4-[(tert-Butyldiphenylsilyl)oxy]hex-5-enoic Acid (45): Com-
pound 45 was synthesized in 70 % yield by the same procedure as
described for the synthesis of compound 33. [α]2D5 = +15.2 (c = 2.5,
CHCl3); ref.[10c] [α]D25 = +14.5 (c = 0.6, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 7.70–7.66 (m, 4 H), 7.47–7.30 (m, 6 H), 5.76 (ddd, J =
5.8, 10.6, 16.9 Hz, 1 H), 5.12–4.95 (m, 2 H), 4.28 (d, J = 4.9 Hz, 1 H),
2.46–2.26 (m, 2 H), 1.86–1.72 (m, 2 H), 1.09 (s, 9 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 179.7, 139.6, 135.9, 135.8, 133.9,133.8,
129.7,129.5, 127.5, 127.4, 115.4, 73.2, 31.8, 28.8, 27.0, 19.3 ppm. IR
127.4, 114.9, 74.3, 65.8, 46.3, 27.0, 23.7, 19.3 ppm. IR (CHCl3): νmax
=
˜
3472, 2942, 2855, 1466, 1451, 1216, 1039, 869, 802, 746 cm–1. HRMS
(ESI): calcd. for C22H30O2SiNa [M + Na]+ 377.1907; found 377.1907.
(S)-5-[(4-Methoxybenzyl)oxy]pentane-1,2-diol (42): Compound
42 was synthesized from 40 in 77 % yield by the same procedure
as described for the synthesis of compound 30. [α]2D5 = –2.51 (c =
(CHCl3): νmax = 3460, 3051, 2941, 2869, 1721, 1637, 1453, 1412,
˜
1215, 1119, 947 cm–1. HRMS (ESI): calcd. for C22H28O3SiNa [M + Na]+
391.1700; found 391.1696.
1
4.2, CHCl3); ref.[24] [α]D25 = –2.00 (c = 1.1, CHCl3); H NMR (400 MHz,
CDCl3): δ = 7.21–7.14 (m, J = 8.6 Hz, 2 H), 6.84–6.78 (m, J = 8.6 Hz,
2 H), 4.37 (s, 2 H), 3.73 (s, 3 H), 3.64–3.55 (m, 1 H), 3.51 (dd, J = 3.1,
11.1 Hz, 1 H), 3.45–3.31 (m, 3 H), 2.90 (br. s, 2 H), 1.74–1.59 (m, 2
H), 1.58–1.45 (m, 1 H), 1.43–1.34 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.2, 129.9, 129.4, 113.8, 72.7, 71.9, 70.1, 66.7, 55.2,
(2R,4S)-4-[(tert-Butyldiphenylsilyl)oxy]hex-5-en-2-yl (S)-4-[(tert-
Butyldiphenylsilyl)oxy]hex-5-enoate (46): Compound 46 was
synthesized in 93 % yield by the same procedure as described for
the synthesis of compound 34. [α]2D5 = –44.26 (c = 3.0, CHCl3);
ref.[12c] [α]2D5 = 48.30 (c = 0.33, CHCl3). 1H NMR (500 MHz, CDCl3):
δ = 7.77–7.63 (m, 8 H), 7.49–7.34 (m, 12 H), 5.85–5.68 (m, 2 H), 5.10–
4.79 (m, 5 H), 4.32–4.19 (m, 1 H), 4.17–4.04 (m, 1 H), 2.25–2.13 (m,
2 H), 1.86–1.63 (m, 4 H), 1.11 (s, 9 H), 1.09 (s, 9 H), 1.05 (d, J = 5.8 Hz,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.8, 140.2, 139.8, 136.0,
135.9, 135.8, 134.1, 134.0, 133.9, 129.6, 129.5, 129.4, 129.5, 127.5,
127.4, 127.38, 127.3, 115.1, 115.0, 73.5, 72.4, 67.8, 44.2, 32.2, 29.5,
30.7, 26.1 ppm. IR (CHCl3): νmax = 3412, 2924, 2872, 1602, 1522,
˜
1236, 1076, 809 cm–1. HRMS (ESI): calcd. for C13H20O4Na [M + Na]+
263.1254; found 263.1252.
(S)-2-{3-[(4-Methoxybenzyl)oxy]propyl}oxirane (43): Compound
43 was synthesized from 42 in 81 % yield by the same procedure
as described for the synthesis of compound 31. [α]2D5 = –5.2 (c =
1
3.5, CHCl3); ref.[26] [α]D25 = –4.5 (c = 0.88, CHCl3). H NMR (400 MHz,
˜
27.0, 26.9, 20.2, 19.4, 19.3 ppm. IR (CHCl3): νmax = 3079, 2942, 2891,
2837, 1744, 1617, 1417, 1334, 1265, 1027, 957, 830, 682 cm–1. HRMS
(ESI): calcd. for C44H56O4Si2Na [M + Na]+ 727.3609; found 727.3581.
CDCl3): δ = 7.27–7.22 (m, J = 8.6 Hz, 2 H), 6.89–6.84 (m, J = 8.6 Hz,
2 H), 4.42 (s, 2 H), 3.79 (s, 3 H), 3.54–3.41 (m, 2 H), 2.96–2.87 (m, 1
H), 2.73 (t, J = 4.5 Hz, 1 H), 2.45 (dd, J = 2.8, 5.0 Hz, 1 H), 1.79–1.55
(m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.1, 130.5, 129.2,
Stagonolide C (6): A solution of 46 (0.138 g, 0.20 mmol) and NH4F
(0.110 g, 2.94 mmol) in MeOH (5 mL) was stirred at 40 °C for 24 h
and monitored by TLC. After completion of the reaction, the reac-
tion mixture was concentrated and immediately filtered through a
small pad of silica gel (60–120 mesh, eluent: EtOAc/petroleum ether
50 %) to give RCM precursor diene, which was used for the subse-
quent RCM reaction. The second-generation Grubbs catalyst
(0.015 g, 10 mol-%) was added to a solution of crude diene (0.040 g,
113.7, 72.5, 69.4, 55.2, 52.1, 47.0, 29.3, 26.1 ppm. IR (CHCl3): νmax
=
˜
2913, 2836, 1652, 1510, 1266, 1074, 1034, 811 cm–1. HRMS (ESI):
calcd. for C13H18O3Na [M + Na]+ 245.1148; found 245.1145.
(S)-tert-Butyl({6-[(4-methoxybenzyl)oxy]hex-1-en-3-yl}oxy)-
diphenylsilane (44): Trimethylsulfonium iodide (2.460 g,
12.10 mmol) was added at –20 °C to stirred dry THF, followed by
nBuLi (7.6 mL, 1.6 M, 12.10 mmol). The reaction mixture was stirred 0.18 mmol) in freshly distilled CH2Cl2 (250 mL, degassed for 15 min
for 1 h, after which epoxide 43 (0.537 g, 2.42 mmol) in THF was
added dropwise. The reaction mixture was stirred at –20 °C for 3 h,
and completion of the reaction was monitored by TLC. The reaction
mixture was diluted with saturated ammonium chloride solution
and extracted with EtOAc (2 × 50 mL). The combined organic layers
were washed with water (2 × 50 mL) and brine, dried with Na2SO4
and concentrated. The crude alcohol was used for the next step
without further purification. TBDPSCl (0.6 mL, 2.60 mmol) was
added dropwise to a stirred solution of alcohol (0.510 g, 2.16 mmol)
and imidazole (0.294 g, 4.32 mmol) in dry CH2Cl2 at 0 °C, and the
by argon bubbling), and the solution was then again degassed for
1 h. The reaction mixture was heated at reflux at 45 °C for 24 h
(completion of the reaction was checked by TLC). The solvent was
removed in vacuo and the crude product was purified by silica gel
column chromatography (silica gel, 230–400 mesh, EtOAc/petro-
leum ether 50 %) to afford compound 6 (0.03 g, 78 % over two
steps) as a colourless oil. [α]2D5 = +46.2 (c = 0.08, MeOH); ref.[12c]
1
[α]2D5 = +43.9 (c = 1.0, MeOH). H NMR (500 MHz, CDCl3): δ = 5.60
(dd, J = 9.3, 15.4 Hz, 1 H), 5.44 (dd, J = 9.2, 15.3 Hz, 1 H), 5.21–5.10
(m, 1 H), 4.18–4.02 (m, 2 H), 2.32–2.28 (m, 1 H), 2.24–2.14 (m, 2 H),
reaction mixture was stirred for 4 h at room temperature. After 2.09–2.01 (m, 3 H), 1.90 (dd, J = 2.6, 13.9 Hz, 1 H), 1.78 (td, J = 11.1,
completion of the reaction, water was added to quench the reac-
tion mixture, and the organic layer was washed with excess water
and brine. The organic layer was dried with Na2SO4 and concen-
trated to afford the crude silylated compound, which was purified
13.7 Hz, 1 H), 1.23 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 174.4, 135.8, 133.0, 74.4, 72.1, 67.7, 43.3, 34.4, 31.5,
21.3 ppm. IR (CHCl3): νmax = 3389, 2918, 2854, 1725, 1453, 1367,
˜
1213, 1023 cm–1. HRMS (ESI): calcd. for C10H16O4Na [M + Na]+
by silica gel chromatography (100–200 mesh, eluent: EtOAc/petro- 223.0941; found 223.0943.
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man-Perez, Angew. Chem. Int. Ed. 1998, 37, 388; Angew. Chem. 1998, 110,
2092; c) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New
York, 1994.
a) S. Chatterjee, S. Ghadigaonkar, P. Sur, A. Sharma, S. Chattopadhyay, J.
Org. Chem. 2014, 79, 8067; b) S. AnkiReddy, P. AnkiReddy, G. Sabitha,
Org. Biomol. Chem. 2015, 13, 10487; c) T. A. Grese, K. D. Hutchinson, L. E.
Overman, J. Org. Chem. 1993, 58, 2468; d) V. Popsavin, G. Benedeković,
B. Srećo, M. Popsavin, J. Francuz, V. Kojić, G. Bogdanović, Org. Lett. 2007,
9, 4235.
a) N. B. Kondekar, P. Kumar, Org. Lett. 2009, 11, 2611; b) V. Jha, N. B.
Kondekar, P. Kumar, Org. Lett. 2010, 12, 2762; c) P. Kumar, V. Jha, R. Gon-
nade, J. Org. Chem. 2013, 78, 11756.
a) P. Kumar, S. V. Naidu, P. Gupta, J. Org. Chem. 2005, 70, 2843; b) P.
Kumar, S. V. Naidu, J. Org. Chem. 2005, 70, 4207; c) P. Kumar, P. Gupta,
S. V. Naidu, Chem. Eur. J. 2006, 12, 1397; d) P. Kumar, S. V. Naidu, J. Org.
Chem. 2006, 71, 3935; e) P. Gupta, P. Kumar, Eur. J. Org. Chem. 2008,
1195; f) P. Kumar, M. Pandey, P. Gupta, S. V. Naidu, D. D. Dhavale, Eur. J.
Org. Chem. 2010, 6993; g) P. Kumar, M. Pandey, P. Gupta, D. D. Dhavale,
Org. Biomol. Chem. 2012, 10, 1820.
(2S,4S)-4-[(tert-Butyldiphenylsilyl)oxy]hex-5-en-2-yl (S)-4-[(tert-
Butyldiphenylsilyl)oxy]hex-5-enoate (47): Compound 47 was
synthesized in 92 % yield by the same procedure as described for
the synthesis of compound 46. [α]2D5 = +18.48 (c = 2.3, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.72–7.60 (m, 8 H), 7.44–7.31 (m, 12 H),
5.81–5.65 (m, 2 H), 5.03–4.83 (m, 5 H), 4.20 (q, J = 5.8 Hz, 1 H), 4.17–
4.10 (m, 1 H), 2.24–2.05 (m, 2 H), 1.85 (ddd, J = 4.6, 8.9, 13.7 Hz, 1
H), 1.74–1.63 (m, 2 H), 1.56–1.53 (m, 1 H), 1.07 (s, 18 H), 1.05 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.8, 139.8, 139.7,
135.94, 135.92, 135.89, 135.8, 134.1, 134.06, 134.0, 133.9, 129.7,
129.6, 129.5, 127.6, 127.5, 127.4, 127.3, 115.1, 115.0, 73.5, 72.0, 67.6,
43.8, 32.1, 29.4, 27.1, 27.0, 20.5, 19.4, 19.3 ppm. IR (CHCl3):
[2]
[3]
[4]
νmax = 3077, 2937, 2899, 1749, 1626, 1423, 1343, 1255, 1020, 977,
˜
840 cm–1. HRMS (ESI): calcd. for C44H56O4Si2Na [M + Na]+ 727.3609;
found 727.3610.
(2S,4S)-4-Hydroxyhex-5-en-2-yl (S)-4-Hydroxyhex-5-enoate (48):
A solution of 47 (0.069 g, 0.10 mmol) and NH4F (0.055 g, 1.47 mmol)
in MeOH (5 mL) was stirred at 40 °C for 24 h and monitored by TLC.
After completion of the reaction, the reaction mixture was concen-
trated. The crude diol was purified by silica gel column chromatog-
raphy (60–120 mesh, EtOAc/petroleum ether 40 %) to afford com-
pound 48 (0.016 g, 70 %) as a colourless oil. [α]2D5 = +12.4 (c = 1.5,
CHCl3). 1H NMR (200 MHz, CDCl3): δ = 5.93–5.76 (m, 2 H), 5.31–5.06
(m, 5 H), 4.18 (qd, J = 6.1, 12.1 Hz, 2 H), 2.45–2.37 (m, 2 H), 2.30 (br.
s, 2 H), 1.93–1.80 (m, 3 H), 1.70–1.62 (m, 1 H), 1.26 (d, J = 6.4 Hz, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 173.6, 140.3, 136.2, 115.1,
[5]
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115.0, 72.2, 70.6, 69.0, 43.0, 31.6, 30.6, 20.3 ppm. IR (CHCl3): νmax
=
˜
3411, 3071, 2837, 1779, 1403, 1313, 1020, 907, 841 cm–1. HRMS
(ESI): calcd. for C12H20O4Na [M + Na]+ 251.1254; found 251.1253.
[10]
9-epi-Stagonolide C (7): The second-generation Grubbs catalyst
(0.006 g, 10 mol-%) was added to a solution of diene 48 (0.016 g,
0.07 mmol) in freshly distilled CH2Cl2 (100 mL, degassed for 15 min
by argon bubbling), and the solution was then again degassed for
1 h. The reaction mixture was heated at reflux at 45 °C for 24 h
(completion of the reaction was checked by TLC). The solvent was
removed in vacuo and the crude product was purified by silica gel
column chromatography (silica gel, 230–400 mesh, EtOAc/petro-
leum ether 30 %) to afford compound 7 (0.010 g, 73 %) as a colour-
[11]
[12]
1
less oil. [α]2D5 = +164.28 (c = 0.5, CHCl3). H NMR (400 MHz, CDCl3):
δ = 5.98 (d, J = 16.1 Hz, 1 H), 5.62 (d, J = 16.1 Hz, 1 H), 5.46–5.29
(m, 1 H), 4.61–4.53 (m, 2 H), 2.54–2.40 (m, 1 H), 2.22 (t, J = 13.7 Hz,
1 H), 2.06 (ddd, J = 2.4, 5.4, 14.1 Hz, 1 H), 1.98–1.85 (m, 3 H), 1.68
(br. s, 2 H), 1.23 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 176.6, 130.6, 127.4, 69.0, 68.2, 64.5, 42.0, 32.9, 28.0, 21.1 ppm.
IR (CHCl3): νmax = 3402, 2981, 2864, 1735, 1413, 1347, 1231,
˜
1033 cm–1. HRMS (ESI): calcd. for C10H16O4Na [M + Na]+ 223.0941;
found 223.0940.
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Acknowledgments
K. S. thanks the University Grants Commission (UGC), New Delhi
for generous financial support in the form of a senior research
fellowship (S.R.F.). The financial support from the Council of Sci-
entific and Industrial Research (CSIR), New Delhi, in the form of
12th five year project (Origin CSC0108) is gratefully acknowl-
edged.
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Keywords: Asymmetric synthesis · Aldol reactions ·
Metathesis · α-Aminoxylation
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Received: May 20, 2016
Published Online: ■
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Stereodivergence in Synthesis
K. Show, P. Kumar* ......................... 1–16
Synthesis of Ophiocerins A, B and C,
Botryolide E, Decarestrictine O,
Stagonolide C and 9-epi-Stagonol-
ide C Employing Chiral Hexane-
1,2,3,5-tetraol Derivatives as Build-
ing Blocks
An organocatalytic approach to the intermediates was demonstrated by
synthesis of (2R,3S)-hexane-1,2,3,5- their transformation into hydroxylated
tetraol derivatives (in the forms of dif- pyrans and a variety of unsaturated
ferent stereoisomers and bearing lactones through standard synthetic
different protecting groups) has been protocols.
developed. The synthetic utility of the
DOI: 10.1002/ejoc.201600625
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