Total Synthesis of Polycavernosides A and B, Two Lethal Toxins from Red Alga

Article abstract of DOI:10.1021/acs.joc.7b02293

Polycavernosides A and B are glycosidic macrolide natural products isolated as the toxins causing fatal human poisoning by the edible red alga Gracilaria edulis (Polycavernosa tsudai). Total synthesis of polycavernosides A and B has been achieved via a convergent approach. The synthesis of the macrolactone core structure is highlighted by the catalytic asymmetric syntheses of the two key fragments using hetero-Diels-Alder reaction and Kiyooka aldol reaction as the key steps, their union through Suzuki-Miyaura coupling, and Keck macrolactonization. Finally, glycosylation with the l-fucosyl-d-xylose unit and construction of the polyene side chain through Stille coupling completed the total synthesis of polycavernosides A and B.

Full text of DOI:10.1021/acs.joc.7b02293

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Article
Total Synthesis of Polycavernosides A
and B, Two Lethal Toxins from Red Alga
Kotaro Iwasaki, Satori Sasaki, Yusuke Kasai, Yuki Kawashima, Shohei
Sasaki, Takanori Ito, Mari Yotsu-Yamashita, and Makoto Sasaki
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02293 • Publication Date (Web): 10 Nov 2017
Downloaded from http://pubs.acs.org on November 10, 2017
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Total Synthesis of Polycavernosides A and B, Two Lethal Toxins from Red Alga
†
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†
†
Kotaro Iwasaki, Satori Sasaki, Yusuke Kasai, Yuki Kawashima, Shohei Sasaki, Takanori Ito,
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‡
*,†
Mari YotsuꢀYamashita, and Makoto Sasaki
†
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577,
Japan
‡
Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki-Aza-Aoba, Aoba-ku,
Sendai 980-0845, Japan
Eꢀmail: masasaki@m.tohoku.ac.jp
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ABSTRACT: Polycavernosides A and B are glycosidic macrolide natural products isolated as the
toxins causing fatal human poisoning by the edible red alga Gracilaria edulis (Polycavernosa
tsudai). Total synthesis of polycavernosides A and B has been achieved via a convergent approach.
The synthesis of the macrolactone core structure is highlighted by the catalytic asymmetric
syntheses of the two key fragments using heteroꢀDiels–Alder reaction and Kiyooka aldol reaction as
the key steps, their union through Suzuki–Miyaura coupling, and Keck macrolactonization. Finally,
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glycosylation with the LꢀfucosylꢀDꢀxylose unit and construction of the polyene side chain through
Stille coupling completed the total synthesis of polycavernosides A and B.
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INTRODUCTION
Polycavernosides A (1) and B (2) (Figure 1) were originally isolated in 1993 by Yasumoto and
coꢀworkers as the causative toxins for the fatal human poisoning in Guam in 1991 caused by
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ingestion of the edible red alga Gracilaria edulis (Polycavernosa tsudai). Thirteen people took ill,
of which three died. The same alga poisoned 36 people in the Philippines in 2002–2003, killing
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eight, and again polycavernoside A was identified as the causative agent. The LD99 values of
polycavernosides A and B in mice by intraperitoneal (ip) injection were estimated to be 200–400
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ꢀg/kg, and the symptoms observed in mice were similar to those observed in human patients. The
gross structure of polycavernoside A (1) was shown through extensive 2D NMR studies to be a
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novel glycosidic macrolide. The structures of polycavernoside B (2) and three minor analogues,
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polycavernosides A2, A3, and B2, were deduced in 1995 by comparison of their Hꢀ H COSY,
FABMS, FABMS/MS, and UV spectra with those of polycavernoside A, but further confirmation
by HMBC and NOE experiments of these analogues was prevented by the extremely small
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quantities of sample available. Thereafter, the complete configurational assignment of
polycavernoside A was established by the Murai/Fujiwara group through their first total synthesis in
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998. All these polycavernosides consist of the same 16ꢀmembered macrolide backbone
incorporating a tetrasubstituted tetrahydropyran ring and a fiveꢀmembered hemiacetal. Structural
variations among these analogues are found in a conjugated triene or diene side chain appended at
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C15 and a highly methylated LꢀfucosylꢀDꢀxylose residue attached at C5. Subsequently, Yamashita
and coꢀworkers isolated and structurally determined two minor analogues, polycavernosides C and
C2, from G. edulis collected in Guam in 1992–1994, which have a different aglycon structure from
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that of 1 and 2.
Figure 1. Structures of polycavernosides A (1), B (2), and D (3).
The macrolide skeleton with an embedded tetrahydropyran ring, the polyene side chain, and the
distinctive Oꢀmethylated sugar unit of polycavernosides, highly resemble the structural features of
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other marine cyanobacterial metabolites, such as lyngbouilloside, lyngbyaloside B, and cyanolide
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A. It has therefore been speculated that polycavernosides are also secondary metabolites of
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cyanobacteria. Gerwick and coꢀworkers recently reported the isolation of a closely related
analogue of polycavernosides, polycavernoside D (3, Figure 1), from an environmental sample of
the marine cyanobacterium Okeania sp., thus providing the first experimental evidence that these
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lethal toxins represent new additions to the family of glycosidic macrolides from cyanobacteria.
The unique structural features of polycavernoside A, the major polycavernoside, coupled with its
lethal toxicity and very limited availability from natural sources, has attracted considerable interest
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from the synthetic community. Six total and formal total syntheses, including ours, and several
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synthetic approaches, have been disclosed to date, but synthetic studies toward other congeners,
including polycavernoside B, have not yet been reported in the literature. In addition, although
structureꢀactivity relationship studies and the pharmacological actions of polycavernosides were
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investigated using synthetic polycavernoside A analogues, their detailed mechanism of action and
the molecular targets of these lethal toxins, remain unknown mainly due to the very limited
amounts of these natural compounds.
As part of our studies toward the total synthesis of polycavernosides for detailed biological
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studies, we reported a preliminary total synthesis of polycavernoside A. We describe herein in
detail the total synthesis of polycavernosides A and B, allowing elucidation of the complete
stereostructure of the latter glycosidic macrolide natural product.
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RESULTS AND DISCUSSION
Synthesis Plan. Our retrosynthetic analysis of polycavernosides A (1) and B (2) is depicted in
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5,11a–e,12
Scheme 1. We planned to synthesize 1 and 2 from the known compound 4
as a common
intermediate through glycosylation with disaccharide unit 5a or 5b, and introduction of the
conjugated polyene side chain by Stille coupling with vinylstannane 6a or 6b. The compound 4
was envisioned to be derived from bisꢀpyran 7 through oxidation of the enol ether moiety to the
1,2ꢀdicarbonyl functionality at C9–C10, followed by macrolactone formation. The cyclic enol ether
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, in turn, could be synthesized from the C1–C8 exoꢀolefin 8 and the C9–C16 enol phosphate 9a or
15,16
triflate 9b via Suzuki–Miyaura coupling.
These two fragments, 8 and 9, of comparable
complexity would be constructed through catalytic asymmetric reactions.
Scheme 1. Retrosynthetic Analysis of Polycavernosides A (1) and B (2)
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Synthesis of the C1–C8 Fragment. The synthesis of the C1–C8 exoꢀolefin 8 started with the
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known enone 10, which is readily available in three steps from 1,3ꢀpropanediol (Scheme 2).
Asymmetric heteroꢀDiels–Alder reaction between 2ꢀsilyloxy diene 11, derived from 10 with
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chromium(III) catalyst 13 (3 mol%), giving the desired cycloadduct 14. Subsequent treatment
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tetrahydropyranꢀ4ꢀone 15a with the desired configuration of the methyl group at the C4 stereogenic
center and its diastereomer 15b. The major diastereomer 15a could be separated from isomer 15b
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by flash column chromatography on silica gel. Isomerization of the minor diastereomer 15b was
realized by treatment with DBU (toluene, room temperature) to avoid loss of material. After two
cycles of isomerization, the desired 15a was obtained in 60% total yield from 10. Reduction of 15a
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as a single stereoisomer at C5 (dr >20:1). At this stage, the enantiomer ratio (er 98:2) of the
heteroꢀDiels–Alder reaction and the relative and absolute configuration of the C5 stereogenic
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center of 16 were established by the coupling constants and a modified Mosher analysis (Figure
2). After protection of alcohol 16 as its TIPS ether with TIPSOTf/2,6ꢀlutidine (94%), the primary
TBS ether of the resultant 18 was selectively removed under acidic conditions (CSA,
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MeOH/CH Cl , 0 °C) to deliver alcohol 19 in quantitative yield. Iodination of alcohol 19 (I , Ph P,
imidazole, THF) provided iodide 20 in 99% yield. Finally, treatment of 20 with tꢀBuOK in THF at
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°C effected βꢀelimination to furnish exoꢀolefin 8, which was directly used in the next coupling
reaction without purification.
Scheme 2. Synthesis of the C1–C8 exo-Olefin 8
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Figure 2. Stereochemical assignment of alcohol 16. Doubleꢀheaded arrows denote key NOEs. The
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Improved Synthesis of the C9–C16 Fragment. The previous synthesis of lactone 21, the
precursor of the C9–C16 fragment 9 and containing only three stereogenic centers on the
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1ꢀcarbon skeleton, required a lengthy 14ꢀstep sequence from (R)ꢀ(+)ꢀcitronellal. Consequently,
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we developed the more efficient alternative route to lactone 21 depicted in Scheme 3. Lactone 21
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would be derived from diene 22 through ringꢀclosing metathesis (RCM) followed by
stereoselective hydrogenation. The stereogenic center at C13 of 22 would be generated by an
appropriate diastereoselective reduction of ketone 23, which in turn would be derived through a
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Kiyooka asymmetric aldol reaction.
Scheme 3. Retrosynthetic Analysis of Lactone 21
An improved synthesis of the C9–C16 fragment 9 commenced with the Kiyooka aldol
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reaction of methyl trimethylsilyl dimethylketene acetal 24 with the known aldehyde 25. The
aldol reaction of 25 with 24 in the presence of the chiral oxazaborolidinone, derived from
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NꢀtosylꢀLꢀvaline (26) and BH ·THF, in CH Cl at –78 °C proceeded enantioselectively to provide
the corresponding (S)ꢀβꢀhydroxy ester 27 in 65% yield (Scheme 4). Methyl ester 27 was then
converted to the corresponding Weinreb amide 28 in 79% yield by reaction with
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N,Oꢀdimethylhydroxylamine hydrochloride and nꢀBuLi (THF, −20 °C). At this stage, the
enantiomer ratio of the Kiyooka aldol reaction was determined to be 22:1 by chiral HPLC analysis.
Subsequent treatment of 28 with 2ꢀmethylallylmagnesium chloride (THF, –20 to 0 °C) provided
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ketone 29 (82%), which was protected with TESCl/imidazole to give TES ether 23 in 95% yield.
We next investigated the diastereoselective reduction of ketone 23 to the corresponding
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monoprotected 1,3ꢀantiꢀdiol 30, but this turned out to be more problematic than expected.
Although we examined several reducing reagents, including NaBH /CeCl ·7H O, LiBH ,
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LꢀSelectride, and KꢀSelectride, in appropriate solvents, either no diastereoselectivity or no reaction
was observed. After extensive experimentation, we found that DIBALH reduction of ketone 23
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(CH Cl , –78 °C) gave the desired alcohol 30 with moderate diastereoselectivity (dr 7:3) in high
yield. Finally, the best result was obtained using the ate complex generated from DIBALH and
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nꢀBuLi in THF at –78 °C, giving a 7:1 mixture of alcohol 30 and its diastereomer at C13. The
minor diastereomer was removed by flash column chromatography on silica gel, and the desired
alcohol 30 was obtained in pure form in 62% yield. The relative configuration of the 1,3ꢀantiꢀdiol
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moiety of 30 was established by C NMR analysis of the acetonide derivative 31, as shown in
Figure 3.
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Scheme 4. Improved Synthesis of the C9–C16 Fragment 9
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Figure 3. Assignment of the relative configuration between C13 and C15 of alcohol 30. The
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Acylation of alcohol 30 with acryloyl chloride/iꢀPr
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which was subjected to RCM using the Grubbs secondꢀgeneration catalyst (G-II) in toluene at
7
0 °C to deliver unsaturated lactone 32 in quantitative yield (Scheme 4). Hydrogenation of 32 (H2,
1
2
32,33
Pd/C, toluene) provided the requisite lactone 21 in 98% yield with 7:1 diastereoselectivity.
Thus, lactone 21, the precursor of the C9–C16 fragment 9, was available in only eight steps with an
overall yield of 22% from readily available starting material. Finally, lactone 21 was converted to
2
the corresponding enol phosphate 9a and enol triflate 9b (KHMDS, THF, HMPA, (PhO) P(O)Cl or
PhNTf
2
, –78 °C), setting the stage for the crucial Suzuki–Miyaura coupling.
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9
Synthesis of the Macrolactone Core through Suzuki–Miyaura Coupling and Keck
Macrolactonization. With the requisite two fragments in hand, we set out to couple them through
15,16
the Suzuki–Miyaura reaction
(Scheme 5). We first attempted the Suzuki–Miyaura reaction
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
using enol phosphate 9a. However, all attempts to effect coupling of the alkylborane, derived from
hydroboration of exoꢀolefin 8 with 9ꢀBBNꢀH, with enol phosphate 9a in the presence of aqueous
2 3 3 4 2 2 2
Cs CO solution and various palladium catalysts, such as Pd(PPh ) , PdCl (dppf)·CH Cl , or
PdCl (dppf)·CH Cl (dppf = 1,1’ꢀbis(diphenylphosphino)ferrocene)/Ph As, in DMF at 50 °C
2
2
2
3
provided disappointingly low yields (5–35%) of the desired coupling product 7 (Table 1, entries
1
–3). Prolonged reaction times proved ineffective, and a significant amount of the starting lactone
with loss of the TES group was recovered (22–87%). These results could be attributable to the low
reactivity of enol phosphate 9a in this Suzuki–Miyaura reaction. Therefore, we decided to exploit
the triflate counterpart 9b as a more reactive substrate for the Suzuki–Miyaura reaction (entry 4).
As expected, reaction of the alkylborane generated from exoꢀolefin 8 (9ꢀBBNꢀH, THF, 0 °C to
room temperature) with enol triflate 9b proceeded smoothly under the influence of aqueous
Cs
2
CO
3
2 2 2 3
solution and the PdCl (dppf)·CH Cl /Ph As catalysis system in THF/DMF at room
34,35
temperature,
giving the desired product 7 in high yield (86–90%). The enol ether 7 thus
obtained was unstable and was immediately subjected to epoxidation followed by in situ epoxide
ring opening with MeOH (mꢀCPBA, CH Cl /MeOH, 0 °C) to afford an inconsequential epimeric
2
2
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1
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2
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2
2
2
2
2
2
2
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4
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5
5
5
5
5
6
mixture of alcohols 33a and 33b in 58% and 24% overall yield from iodide 20, respectively
(Scheme 5). At this stage, the minor diastereomer at C11 resulting from hydrogenation of 32 was
removed by flash column chromatography on silica gel. The configuration of the hydroxy group of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
3a and 33b was established by its JH,H value, as shown in Figure 4. Each alcohol was
36
individually oxidized with tetraꢀnꢀpropylammonium perruthenate (TPAP)/NMO to the same
ketone 34 in high yield. It is interesting to note that the reactivity of alcohol 33b with the axial
hydroxy group at C10 was low and that the use of MeCN as a coꢀsolvent was essential to attain a
higher yield of ketone 34. Selective cleavage of the TES ether of 34 under acidic conditions (CSA,
2 2
CH Cl /MeOH, 0 °C), followed by oxidative removal of the PMB group with DDQ, provided diol
3
5 in 84% yield for the two steps. Chemoselective oxidation of the primary alcohol of 35 was
37
2 2 2 2
realized with TEMPO/PhI(OAc) in CH Cl /H O (10:1) to deliver the corresponding carboxylic
acid 36 in 97% yield. Subsequent macrolactonization of 36 proved to be unexpectedly difficult.
3
8
39
Macrolactonization under Yamaguchi or Shiina conditions resulted in only a low yield
40
(
14–34%) or no trace of the desired macrolactone 37. After extensive experimentation, we found
41
that the best result was obtained by using the Keck protocol with a combination of DCC,
42
pyridine, and PPTS in DCE under reflux conditions to afford macrolactone 37 in 89% yield.
Selective cleavage of the primary TBDPS ether of 37 was performed with buffered HF·pyridine to
4
3
afford primary alcohol 38 in 85% yield. Dess–Martin oxidation of 38 provided aldehyde 39
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9
4
4
(
3 2
88%), which was subjected to Takai–Utimoto olefination (CHI , CrCl ) to afford (E)ꢀvinyliodide
40 in 81% yield as a single stereoisomer (E/Z >20:1). Ensuing treatment of 40 with aqueous TFA
5
in THF effected hydrolysis of the TIPS ether and methyl acetal with concomitant construction of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
the fiveꢀmembered hemiacetal to furnish alcohol 4 in 98% yield. The specific rotation value of 4,
2
D
5
5,11a–e
[
α]
3
–49.1 (c 1.00, CHCl ), matched those reported in the literature.
Scheme 5. Synthesis of Macrolactone 4.
Table 1. Optimization of the Suzuki–Miyaura coupling of 8 and 9
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2
2
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2
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4
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4
4
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5
5
5
5
5
5
5
6
entry
substrate
Pd catalyst (equiv)
Pd(PPh (0.2)
PdCl (dppf)·CH Cl (0.1)
ligand (equiv) temp (°C)
yield (%)
a
1
2
3
4
9a
9a
9a
9b
3
)
4
—
—
50
50
50
rt
35
a
5
2
2
2
a
PdCl (dppf)·CH Cl (0.1)
Ph As (0.2)
19
2
2
2
3
0
1
2
3
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7
8
9
0
1
2
3
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7
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9
0
1
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
PdCl
2
(dppf)·CH
2
Cl
2
(0.1)
Ph
3
As (0.4)
86–90
a
The starting lactone with loss of the TES ether was recovered in 22–87% yields.
Figure 4. Assignment of the relative configuration of the C10 stereogenic center of 33a and 33b.
Total Synthesis of Polycavernoside A. Total synthesis of polycavernoside A was carried out by
5,11a–e
11c,d
adapting a literature route.
Glycosylation of alcohol 4 with the known thioglycoside 5a
was
50
performed under the influence of NBS in the presence of 4 Å molecular sieves in MeCN at –40 to
–
10 °C to provide the desired glycoside 41, albeit in moderate yield (41%) (Scheme 6). Oxidative
cleavage of the benzyl ether within the sugar part of 41 with DDQ provided alcohol 42 in 78% yield.
Construction of the conjugated triene side chain by Stille coupling with the known dienylstannane
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9
1
1a,b
6
a
(PdCl
2
(MeCN)
2
, DMF, 45%) completed the total synthesis of (–)ꢀpolycavernoside A (1). The
2
spectroscopic data of the synthetic 1 matched with those reported for the natural material. Mouse
lethality of the synthetic polycavernoside A was comparable to that of the natural product.
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21
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35
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Total Synthesis of Polycavernoside A
Synthesis of the Polycavernoside B Disaccharide Unit. The LꢀfucosylꢀDꢀxylose disaccharide unit
5
b, required for the synthesis of polycavernoside B, was prepared from fucosyl thioglycoside 43
4
5
and xylosyl thioglycoside 44 based on the armedꢀdisarmed concept (Scheme 7). Armed fucosyl
1
1b,48
donor 43 was prepared by Oꢀmethylation of the known thioglycoside 45
in 94% yield. The
46
synthesis of xylosyl thioglycoside 44 started with the known alcohol 46. OꢀMethylation followed
47
by acidic hydrolysis of the butaneꢀ2,3ꢀdiacetal provided diol 47 in 93% yield for the two steps.
Regioselective acylation of the less hindered alcohol at the C4 position of 47 was realized with
pivaloyl chloride in pyridine at low temperature to afford disarmed xylosyl acceptor 44 in 96%
49
yield. Glycosylation of 44 with 43 was carried out under NIS/TfOH conditions (4 Å molecular
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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5
5
5
5
5
5
5
6
sieves, CH
2
Cl
2
, –78 °C) to afford the desired αꢀlinked disaccharide 48 in 62% yield. Under these
1
conditions, βꢀlinked disaccharide 49, in which the xylose unit was restricted in the
C
4
conformation, was obtained in 7% yield. The relative configurations of 48 and 49 were assigned on
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
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3
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7
8
9
0
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2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
the basis of the JH,H values in the H NMR spectrum, as shown in Figure 5. Reductive removal of
the pivaloyl ester of 48 with DIBALH (92%), followed by acetylation of the resultant hydroxy
group, provided the desired disaccharide unit 5b in 93% yield.
Scheme 7. Synthesis of
L-Fucosyl-D-Xylose Disaccharide Unit 5b
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Stereochemical assignment of disaccharides 48 and 49.
Total Synthesis of Polycavernoside B. Glycosylation of alcohol 4 with thioglycoside 5b was again
performed with NBS in the presence of 4 Å molecular sieves (MeCN, –40 to –10 °C) to afford the
requisite βꢀglycoside 50 in 51% yield (Scheme 8). Finally, Stille coupling of 50 with the known
54
vinylstannane 6b using PdCl (MeCN) in DMF furnished (–)ꢀpolycavernoside B (2) in 58% yield.
2
2
1
The H NMR spectrum of the synthetic 2 was identical with that reported for the natural
4
polycavernoside B. In addition, mouse lethality of the synthetic polycavernoside B was
comparable to that of the natural sample, and observed symptoms in mice elicited upon
intraperitoneal administration resembled those caused by the natural sample. Thus, the complete
stereostructure of polycavernoside B was unambiguously established by our total synthesis.
Scheme 8. Total Synthesis of Polycavernoside B
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2
2
2
2
2
2
3
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0
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0
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2
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONCLUSION
In conclusion, we have achieved the total synthesis of polycavernosides A and B in 23 and 22 steps
(longest linear sequence) and with 0.96% and 2.0% overall yield, respectively. The synthesis of the
C1–C8 fragment involved asymmetric heteroꢀDiels–Alder reaction using Jacobsen catalysis for the
construction of the tetrasubstituted tetrahydropyran unit. The C9–C16 fragment was efficiently
constructed by exploiting the Kiyooka aldol reaction and diastereoselective reduction to establish
the two stereogenic centers at C15 and C17, and a ringꢀclosing metathesis/hydrogenation sequence
to form a sixꢀmembered lactone unit. Convergent union of the two fragments was achieved through
Suzuki–Miyaura coupling, and the macrolactone core was formed through a modified Keck
protocol. Late–stage introduction of the LꢀfucosylꢀDꢀxylosyl disaccharide unit and polyene side
chain completed the total synthesis of polycavernosides A and B, establishing for the first time the
complete stereostructure of the latter glycosidic macrolide natural product. Our convergent
synthetic route allows for the synthesis of sufficient amounts of polycavernosides and their
unnatural analogues for detailed biological studies. Further studies along this line are underway
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and will be reported in due course.
EXPERIMENTAL SECTION
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16
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18
19
20
21
22
23
24
25
26
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
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59
60
General Methods. All reactions sensitive to moisture and/or air were carried out under an
atmosphere of argon in dry, freshly distilled solvents under anhydrous conditions using ovenꢀdried
2 2
glassware unless otherwise noted. Anhydrous CH Cl was purchased and anhydrous diethyl ether
(Et O), THF, and toluene were purified by a Glass Contour solvent purification system. Acetonitrile
2
(MeCN), 1,2ꢀdichloroethane (DCE), diisopropylethylamine, pyridine, 2,6ꢀlutidine, methanol
3
(MeOH), and triethylamine (Et N) were distilled from calcium hydride under an atmosphere of
argon. DMF was distilled from magnesium sulfate under reduced pressure. HMPA was distilled
from calcium hydride under reduced pressure. All other chemicals were purchased at highest
commercial grade and used directly. Analytical TLC was performed using preꢀcoated glass plate
(silica gel 60 F254, 0.25ꢀmm thickness). Flash column chromatography was carried out using silica
gel (spherical, neutral, 40–100 mesh; granular, 200–400 mesh). HPLC was performed using an
UV/Visible detector. Optical rotations were measured on a digital polarimeter at 589 nm. IR spectra
were recorded as a thin film on a KBr disk using an FTꢀIR spectrometer and reported in
–1
1
13
wavenumbers (cm ). H and C NMR spectra were recorded at 600 MHz and 150 MHz NMR
spectrometers, respectively. Chemical shift values are reported in ppm (δ) downfield from
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
1
tetramethylsilane with reference to internal residual solvent [ H NMR, CHCl
3
(7.26), C
6
HD
5
(7.16),
13
2 3 6 6 3
CHD CN (1.90); C NMR, CDCl (77.0), C D (128.0), CD CN (118.2)]. Coupling constants (J)
are reported in hertz (Hz). The following abbreviations were used to designate the multiplicities: s =
singlet; d = doublet; t = triplet; q = quartet; m = multiplet or unresolved; br = broad. Highꢀresolution
mass spectra (HRMS) were measured on an ESIꢀTOF mass spectrometer. Diastereomer ratio (dr)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
and E/Z isomer ratio were estimated by H NMR spectroscopic analysis, unless otherwise noted.
(2S,3S,6S)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(2-((4-methoxybenzyl)oxy)ethyl)-3-
methyltetrahydro-4H-pyran-4-one(15a). To a solution of enone 10 (2.085 g, 8.400 mmol) and
Et N (2.34 mL, 16.8 mmol) in Et O (16.8 mL) at 0 °C was added TMSOTf (1.60 mL, 8.82 mmol).
3
2
The resultant solution was stirred at 0 °C for 30 min and then at room temperature for 1 h. The
3
mixture was diluted with hexanes, washed with saturated aqueous NaHCO solution, dried over
2 4
Na SO , filtered, and concentrated under reduced pressure to give the crude 2ꢀsilyloxy diene 11
(
2.638 g) as a yellow oil. This material was immediately used in the next reaction without further
purification.
To a mixture of the above 2ꢀsilyloxy diene 11 (2.638 g), activated 4 Å molecular sieves (823.2
mg), and Jacobsen’s chiral chromium(III) catalyst 13 (120.3 mg, 0.247 mmol) was added aldehyde
12 (1.73 mL, 9.06 mmol). The resultant mixture was stirred at room temperature for 20.5 h. The
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mixture was diluted with hexanes, filtered through a pad of Celite (eluted with hexanes), and the
filtrate was concentrated under reduced pressure to give the crude cycloadduct 14 (4.025 g) as a
dark green oil. This material was immediately used in the next reaction without further
purification.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a solution of the above cycloadduct 14 (4.025 g) in MeOH (16.7 mL) at room temperature
2 3
was added K CO (116.1 mg, 0.8401 mmol), and the resultant solution was stirred at room
temperature for 30 min. The mixture was concentrated under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, 0% to 20% EtOAc/hexanes) gave ketone 15a
(1.771 g) and a mixture of 10, 15a, and 15b (1.078 g). To a solution of the mixture of 10, 15a, and
1
5b (1.078 g) in toluene (10 mL) was added DBU (0.5 mL), and the resultant solution was stirred
at room temperature for 18.5 h. The mixture was concentrated under reduced pressure. Purification
of the residue by flash column chromatography (silica gel, 0% to 30% EtOAc/hexanes) gave an
additional ketone 15a (298.5 mg), along with a mixture of 10, 15a, and 15b (674.1 mg). Second
treatment of this mixture (674.1 mg) with DBU (0.3 mL) in toluene (5 mL) gave ketone 15a (73.9
mg) and 10 (541.0 mg, 26%). Totally, 2.143 g (60% from 10) of ketone 15a was obtained as a pale
29
D
yellow oil: [α]
3
−39.4 (c 1.12, CHCl ); IR (film) 2954, 2929, 2857, 1716, 1615, 1513, 1457,
–
1
1
1
6
3
362, 1249, 1097, 1037, 837, 778 cm ; H NMR (600 MHz, CDCl ) δ 7.26–7.22 (m, 2H),
.89–6.85 (m, 2H), 4.44 (d, J = 11.5 Hz, 1H), 4.41 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H), 3.70–3.60 (m,
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2
2
2
2
2
2
2
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5
H), 3.39 (ddd, J = 9.7, 9.2, 2.3 Hz, 1H), 2.46–2.38 (m, 2H), 2.29 (m, 1H), 2.05 (dddd, J = 14.2,
7.3, 7.3, 2.3 Hz, 1H), 1.78 (dddd, J = 14.2, 9.2, 5.5, 5.5 Hz, 1H), 1.00 (d, J = 6.9 Hz, 3H), 0.89 (s,
1
3
9
3
H), 0.053 (s, 3H), 0.051 (s, 3H); C NMR (150 MHz, CDCl ) δ 208.9, 159.1, 130.5, 129.2 (2C),
0
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0
1
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1
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13.7 (2C), 79.5, 77.6, 72.6, 66.2, 65.8, 55.2, 50.1, 44.2, 34.3, 25.8 (3C), 18.3, 9.2, –5.3 (2C);
+
HRMS (ESI) calcd for C23
H
38
O
5
SiNa [(M + Na) ] 445.2381; found 445.2396.
(2S,3R,4S,6S)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(2-((4-methoxybenzyl)oxy)ethyl)-
3-methyltetrahydro-2H-pyran-4-ol (16). To a solution of ketone 15a (1.444 g, 3.416 mmol) and
3 2 4
CeCl ·7H (135.7 mg,
O (1.336 g, 3.586 mmol) in MeOH (68 mL) at −20 °C was added NaBH
3
.586 mmol), and the resultant solution was stirred at –20 °C for 40 min. The reaction was
quenched with saturated aqueous NH Cl solution. The resultant mixture was allowed to warm to
4
room temperature and extracted with EtOAc/hexanes. The organic layer was washed with brine,
2 4
dried over Na SO , filtered, and concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 8% to 20% EtOAc/hexanes) gave alcohol 16 (1.368 g,
9
1
–
1
4
4%, dr >20:1) as a colorless oil. The enantiomer ratio (er 98:2) and the absolute configuration of
1
22
6 were determined by H NMR analysis of the corresponding Mosher esters. Data for 16: [α]D
3
56.1 (c 0.92, CHCl ); IR (film) 3445, 2954, 2928, 2856, 1614, 1513, 1464, 1362, 1302, 1249,
–
1 1
107, 1037, 836, 778 cm ; H NMR (600 MHz, CDCl
3
) δ 7.27–7.23 (m, 2H), 6.89−6.85 (m, 2H),
.44 (d, J = 11.9 Hz, 1H), 4.41 (d, J = 11.9 Hz, 1H), 3.80 (s, 3H), 3.65 (dd, J = 10.5, 5.5 Hz, 1H),
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9
3
.59 (dd, J = 7.7, 5.9 Hz, 2H), 3.50 (dd, J = 10.5, 5.5 Hz, 1H), 3.40 (dddd, J = 11.0, 5.5, 5.5, 1.8
Hz, 1H), 3.34 (ddd, J = 10.6, 10.1, 4.6 Hz, 1H), 3.11 (ddd, J = 9.6, 9.6, 2.8 Hz, 1H), 2.03–1.97 (m,
13
2
H), 1.67–1.60 (m, 2H), 1.27–1.18 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (150 MHz, CDCl ) δ 159.1, 130.7, 129.2 (2C), 113.7 (2C), 77.9, 75.9, 73.5, 72.6, 66.8, 66.3,
3
5
5.2, 44.1, 37.7, 33.2, 25.9 (3C), 18.3, 12.8, −5.3, −5.3; HRMS (ESI) calcd for C23
H O SiNa [(M
40 5
+
+
Na) ] 447.2537; found 447.2535.
tert-Butyl(((2S,4S,5S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-5-methyl-4-((triisopropylsilyl)-
oxy)tetrahydro-2H-pyran-2-yl)methoxy)dimethylsilane (18). To a solution of alcohol 16 (1.976
2 2
g, 4.653 mmol) in CH Cl (23 mL) at 0 °C were added 2,6ꢀlutidine (1.10 mL, 9.30 mmol) and
TIPSOTf (1.20 mL, 4.65 mmol), and the resultant solution was stirred at 0 °C for 65 min. The
4
reaction was quenched with saturated aqueous NH Cl solution. The resultant mixture was extracted
2 4
with hexanes, and the organic layer was washed with brine, dried over Na SO , and concentrated
under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 3%
2
D
1
to 20% to 30% EtOAc/hexanes) gave TIPS ether 18 (2.545 g, 94%) as a colorless oil: [α]
–2.4
3
(c 1.41, CHCl ); IR (film) 2946, 2865, 1613, 1514, 1464, 1361, 1302, 1249, 1090, 1038, 837, 777
–1
1
cm ; H NMR (600 MHz, CDCl ) δ 7.27–7.24 (m, 2H), 6.89–6.85 (m, 2H), 4.44 (d, J = 11.5 Hz,
3
1
H), 4.41 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H), 3.66 (dd, J = 10.1, 5.5 Hz, 1H), 3.58 (dd, J = 7.8, 5.9
Hz, 2H), 3.50 (ddd, J = 10.5, 9.6, 4.6 Hz, 1H), 3.46 (dd, J = 10.1, 5.9 Hz, 1H), 3.36 (dddd, J = 11.4,
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
.9, 5.5, 1.8 Hz, 1H), 3.11 (ddd, J = 9.6, 9.6, 2.3 Hz, 1H), 2.04–1.96 (m, 2H), 1.64 (m, 1H),
1
3
1.32–1.23 (m, 2H), 1.09–1.05 (m, 21H), 0.96 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H);
C
NMR (150 MHz, CDCl ) δ 159.1, 130.8, 129.2 (2C), 113.7 (2C), 78.1, 75.8, 74.6, 72.6, 66.9, 66.3,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
5.3, 44.7, 38.7, 33.3, 25.8 (3C), 18.3 (4C), 18.2 (3C), 13.3, 12.8 (3C), −5.3, −5.4; HRMS (ESI)
+
calcd for C32
H
60
O
5
Si
2
Na [(M + Na) ] 603.3871; found 603.3886.
((2S,4S,5S,6S)-6-(2-((4-Methoxybenzyl)oxy)ethyl)-5-methyl-4-((triisopropylsilyl)oxy)-
tetrahydro-2H-pyran-2-yl)methanol (19). To a solution of TIPS ether 18 (2.528 g, 4.351 mmol)
2 2
in MeOH/CH Cl (1:1, v/v, 44 mL) at 0 °C was added CSA (204.1 mg, 10.88 mmol), and the
resultant solution was stirred at 0 °C for 2 h 25 min. The reaction mixture was neutralized with
Et N, stirred at room temperature for 25 min, and concentrated under reduced pressure.
3
Purification of the residue by flash column chromatography (silica gel, 10% to 20%
21
D
EtOAc/hexanes) gave primary alcohol 19 (2.040 g, quantitative) as a colorless oil: [α]
+5.2 (c
3
1.22, CHCl ); IR (film) 3446, 2943, 2866, 1613, 1514, 1464, 1372, 1302, 1248, 1092, 883, 810
–1 1
cm ; H NMR (600 MHz, CDCl ) δ 7.27–7.24 (m, 2H), 6.89–6.86 (m, 2H), 4.46 (d, J = 11.5 Hz,
3
1
9
1
H), 4.41 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H), 3.61–3.48 (m, 5H), 3.43 (m, 1H), 3.17 (ddd, J = 9.6,
.6, 1.9 Hz, 1H), 2.03 (m, 1H), 1.91 (dd, J = 8.3, 4.2 Hz, 1H), 1.79 (ddd, J = 12.4, 4.6, 1.9 Hz, 1H),
.65 (m, 1H), 1.37 (ddd, J = 12.4, 11.9, 9.6 Hz, 1H), 1.30 (m, 1H), 1.08–1.05 (m, 21H), 0.98 (d, J
1
3
= 6.9 Hz, 3H); C NMR (150 MHz, CDCl
3
) δ 159.1, 130.6, 129.2 (2C), 113.7 (2C), 78.1, 75.5,
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7
4.3, 72.7, 66.6, 66.1, 55.2, 44.5, 37.5, 33.3, 18.24 (3C), 18.17 (3C), 13.3, 12.8 (3C); HRMS (ESI)
+
calcd for C26
H
46
O
5
SiNa [(M + Na) ] 489.3007; found 489.3007.
(((2S,3S,4S,6S)-6-(Iodomethyl)-2-(2-((4-methoxybenzyl)oxy)ethyl)-3-methyltetrahydro-2H-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pyran-4-yl)oxy)triisopropylsilane (20). To a solution of alcohol 19 (510.2 mg, 1.093 mmol) in
3
THF (7.4 mL) at room temperature were added imidazole (50.1 mg, 2.20 mmol), Ph P (431.3 mg,
1
.644 mmol), and iodine (388.7 mg, 1.531 mmol), and the resultant solution was stirred at room
temperature for 3 h 45 min. The reaction was quenched with saturated aqueous Na SO solution.
2
3
The resultant mixture was extracted with EtOAc, and the organic layer was washed with brine,
2 4
dried over Na SO , filtered, and concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 0% to 1% EtOAc/hexanes) gave iodide 20 (620.3 mg,
22
9
9%) as a pale yellow oil: [α]D +17.0 (c 1.24, CHCl ); IR (film) 2943, 2865, 1513, 1464, 1247,
3
–1 1
1
6 6
092, 1038, 882, 809 cm ; H NMR (600 MHz, C D ) δ 7.32–7.29 (m, 2H), 6.85–6.81 (m, 2H),
4.47 (s, 2H), 3.84 (ddd, J = 9.2, 9.2, 5.5 Hz, 1H), 3.65 (ddd, J = 9.2, 6.4, 4.1 Hz, 1H), 3.34 (ddd, J
=
=
10.5, 9.6, 4.6 Hz, 1H), 3.31 (s, 3H), 3.09 (ddd, J = 9.6, 9.6, 2.3 Hz, 1H), 3.05 (m, 1H), 2.83 (dd, J
10.1, 7.3 Hz, 1H), 2.72 (dd, J = 10.1, 4.6 Hz, 1H), 2.03 (m, 1H), 1.93 (ddd, J = 12.0, 4.6, 1.9 Hz,
1
H), 1.62 (m, 1H), 1.31 (m, 1H), 1.23 (ddd, J = 12.0, 11.5, 10.5 Hz, 1H), 1.13–0.99 (m, 21H), 0.92
13
(
6 6
d, J = 6.4 Hz, 3H); C NMR (150 MHz, C D ) δ 159.7, 131.6, 129.5 (2C), 114.0 (2C), 78.1,
7
4.65, 74.61, 73.0, 66.8, 54.7, 44.6, 41.8, 33.9, 18.5 (3C), 18.4 (3C), 13.3, 13.1 (3C), 9.3; HRMS
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