Asymmetric Total Synthesis of Amphirionin-2

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Asymmetric Total Synthesis of Amphirionin‑2

Dhiman Saha, Gour Hari Mandal, and Rajib Kumar Goswami*

Cite This: J. Org. Chem. 2021, 86, 10006 −10022

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ABSTRACT: A convergent route for the asymmetric total synthesis of potent anticancer polyketide natural product amphirionin-2

has been developed. Our initial synthetic trials revealed that the proposed structures of amphirionin-2 need to be revised consistent

with a recent report of Fuwa et al., where the actual structure of amphirionin-2 was established. The key features of our synthesis

comprised Sharpless asymmetric dihydroxylation, followed by cycloetheriﬁcation, Wittig oleﬁnation, Julia−Kocienski oleﬁnation, and

Crimmins propionate aldol reaction.

structures need to be revised as also observed by Fuwa et al.

Later, this developed strategy was employed to achieve the

total synthesis of the actual structure (1c, Figure 1) of

amphirionin-2. The developed route is quite diﬀerent

compared to the recent report,³where a diﬀerent set of

reactions was adopted to install the diﬀerent functional

moieties and asymmetric centers embedded in the molecule.

INTRODUCTION

■

Amphirionin-2 was isolated by Tsuda and co-workers in 2014

from the KCA09051strain of laboratory-cultured marine

dinoﬂagellates Amphidinium sp.¹It showed promising in

vitro anticancer activities against Caco-2 (human colon

carcinoma) and A549 (human nonsmall cell lung adenocarci-

noma) cell lines as well as in vivo antitumor eﬃcacy against

murine tumor P388 cells.¹The discovery of amphirionin-2

may play a signiﬁcant role in deciphering cancer biology. The

chemical structures (1a and 1b, Figure 1) of amphirionin-2

were proposed initially based on detailed NMR and Mosher’s

ester analysis. Architecturally, it is a linear polyketide

embedded with two unique hexahydrofuro[3,2-b] furan

moieties, 10 stereogenic centers, a conjugated oleﬁn, and two

isolated oleﬁns. The relative stereochemistry of the asymmetric

centers present on left and right halves of the molecule was

speculated based on J values and NOESY correlation, but the

stereochemical correlation between hexahydrofuro[3,2-b]

furan units remained undisclosed during its isolation. Our

continued interest²in chemical synthesis of bioactive natural

products prompted us to embark on the total synthesis of

structurally complex and potential anticancer polyketide

natural product amphirionin-2. During our ongoing synthetic

study, an elegant synthetic route was reported by Fuwa et al.,

where the actual structure³(1c, Figure 1) of amphirionin-2

was established. Herein, we report a convergent and ﬂexible

stereoselective synthetic route for the proposed structures of

amphirionin-2 (1a and 1b, Figure 1). The spectroscopic data

of the synthesized proposed structures of amphirionin-2

indicated discrepancies, which suggested that the proposed

RESULTS AND DISCUSSION

■

Retrosynthetic analysis of the proposed structure (1a) of

amphirionin-2 is delineated in Scheme 1. The target molecule

could be assembled from the two major segments 2 and 3

using Julia−Kocienski oleﬁnation as the key reaction. Left

segment 2 could be constructed from compound 5 via

compound 4 adopting Sharpless asymmetric dihydroxylation,

followed by subsequent in situ cycloetheriﬁcation and

Crimmins propionate aldol and Wittig oleﬁnation as the

pivotal steps, whereas right segment 3 could be synthesized

from ent-5 through ent-4 in a similar way to compound 2

except the use of Julia−Kocienski oleﬁnation in place of the

Wittig oleﬁnation.

Received: March 23, 2021

Published: July 16, 2021

https://doi.org/10.1021/acs.joc.1c00686

J. Org. Chem. 2021, 86, 10006−10022

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Figure 1. Chemical structures of amphirionin-2.

Scheme 1. Retrosynthetic Analysis of the Proposed Structure of Amphirionin-2 (1a)

The synthesis of compound 4 is described in Scheme 2. The

known compound 6, prepared in four steps from ^D-aspartic

acid following a literature procedure,⁴was treated with TESCl/

Et₃N/DMAP to get the corresponding TES ether. Our initial

eﬀort for oxidative cleavage of the oleﬁn moiety using OsO₄/

NaIO₄/NaHCO₃was not eﬀective. The reaction was sluggish,

where in situ deprotection of TES ether took place. Thus, a

two-step protocol was followed. First dihydroxylation was

performed using OsO₄/NMO. The resultant mixture of diol

was then subjected to oxidative cleavage using NaIO₄/

NaHCO₃to get the corresponding aldehyde without having

any TES-deprotected compound, which was further reduced to

alcohol 7 by NaBH₄. Alcohol 7 was then reacted with 1-

phenyl-1H-tetrazole-5-thiol (PTSH) in the presence of Ph₃P/

DIAD following the Mitsunobu protocol⁵to produce the

corresponding sulﬁde, which was further oxidized⁶to sulfone 8

using mCPBA. On the other hand, the known alcohol 9,

obtained from R-glycidyl benzyl ether in one step following the

literature procedure,⁷was treated with TESCl/Et₃N, followed

by OsO₄/NMO and NaIO₄/NaHCO₃to obtain the required

aldehyde 10. The stage was set for Julia−Kocienski oleﬁnation⁸

to couple aldehyde 10 and sulfone 8. Our initial trial with

NaHMDS provided compound 11 with 75% yield with an E/Z

ratio of 4:1. Delightfully, the use of KHMDS resulted the

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Scheme 2. Synthesis of Compound 4

Table 1. Optimization of Dihydroxylation and Cycloetheriﬁcation for Compound 4

entry

reagents

solvent

temperature time (h) yield (%) dr (4:12)

1

2

3

4

5

OsO₄(0.01 equiv)/NMO (2 equiv)/K₂CO₃(3 equiv)

AD-mix-α (1.4 g/mmol)/MeSO₂NH₂(2 equiv)

AD-mix-β (1.4 g/mmol)/MeSO₂NH₂(2 equiv)

AD-mix-β (14 g/mmol)/MeSO₂NH₂(2 equiv)

AD-mix-β (1.4 g/mmol)/OsO₄(0.5 equiv)/MeSO₂NH₂(2 equiv)

THF/^tBuOH: H₂O (4:4:1)

H₂O/^tBuOH (1:1)

0 °C to rt

12

36

28

12

55

50

60

59

65

1.5:2

1:1

3:1

2.9:1

3.5:1

required compound exclusively in E geometry with 70% yield.

Compound 11 was then treated with CSA to get diol 5, which

was mesylated further to access the corresponding dimesylated

compound. Next, dihydroxylation, followed by the cyclo-

etheriﬁcation strategy⁹was adopted to prepare a

hexahydrofuro[3,2-b] furan moiety. A number of conditions

were screened (Table 1). The use of a catalytic amount of

OsO₄(entry 1) or AD-mix-α (entry 2) provided compounds 4

and 12 almost in a 1:1 ratio, whereas AD-mix-β (entry 3)

elevated that ratio to 3:1. A tenfold increase in the amount of

AD-mix-β (entry 4) provided almost similar results compared

to the entry 3 but the reaction time reduced considerably. The

increase of the OsO₄concentration in the AD-mix-β reaction

(entry 5) by addition of an excess amount of it provided a

faster result with a further increase of selectivity to 3.5:1.

However, in our case, the selectivity was still lower compared

to the literature report,^9awhere the substrate for dihydrox-

ylation, followed by cycloetheriﬁcation, bears two benzyl ethers

in the tris-homoallylic position. In contrast, the dimesylated

counterpart of compound 5 possesses one bis-homoallylic

benzyl ether and one tris-homoallylic TBDPS ether. It is most

likely the steric inﬂuence,^10a,bof benzyl ether in the bis-

homoallylic position opposed the Sharpless facial selectivity

model to some extent. It was conceived further from our trial

with the corresponding substrate, where the benzyl ether was

replaced with bulky TBS ether. The reaction in that case was

too sluggish following the condition in entry 5, where the

selectivity reduced to ∼2:1. It is noteworthy that the reaction

functioned better toward a stoichiometric amount of OsO₄in

the presence of chiral amine (entry 5) compared to its catalytic

variation (entry 3), which might be due to the probability

factor. Both the compounds were separated using column

chromatography. Analysis of mass spectrometry as well as

NMR spectroscopy especially NOESY correlation revealed

their structural identities. It is noteworthy that the identi-

ﬁcation of expected NOESY interactions between H-2 and H-7

of compound 4 was diﬃcult in this stage as those protons were

resonating in close proximity as a multiplet.

The synthesis of the left segment 2 is depicted in Scheme 3.

Compound 4 was treated with TBAF to get the corresponding

primary alcohol, which was oxidized to the corresponding

aldehyde using DMP/NaHCO₃and ﬁnally subjected to the

Crimmins propionate aldol reaction,^11a,busing the known

thiazolidinethione 13^11cin the presence of TiCl₄/DIPEA to

achieve compound 14 exclusively. Initially, our exhaustive trials

to install the required terminal allyl group of compound 2 via

opening of oxetane, prepared from compound 14,¹²using vinyl

Grignard did not work. Next, the free hydroxyl of compound

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Scheme 3. Synthesis of Compound 2

14 was protected as TBS ether using TBSOTf/2,6-lutidine and

reduced further to the corresponding primary alcohol, which

was then transformed into the corresponding iodo compound.

It was quite unfortunate to observe that substitution of iodo by

the vinyl group following Gilman’s protocol¹³did not proceed

and the iodo compound remained unreactive. Thus, the TBS

ether obtained from compound 14 was reacted cautiously with

DIBAL-H to generate the corresponding aldehyde, which was

then treated with Ph₃PCH₃Br/^tBuOK to produce compound

15 in good overall yield. It was further subjected to

hydroboration using BH₃-DMS. The resultant alcohol was

oxidized to the corresponding aldehyde using DMP/NaHCO₃

and subsequently exposed to oleﬁnation in the presence of

Ph₃PCH₃Br/^tBuOK to obtain compound 16. Benzyl ether of

compound 16 was removed by Li-naphthalide and the

resultant alcohol was oxidized to the corresponding aldehyde

using DMP/NaHCO₃, which was ﬁnally subjected to Wittig

oleﬁnation¹⁴using Ph₃PC(CH₃)CO₂Et to get the correspond-

ing α, β-unsaturated esters (E/Z = 3:1) as an inseparable

mixture. The ester group was then reduced with DIBAL-H to

get alcohol 2 along with its corresponding Z-counterpart,

which remained inseparable in this stage too.

The synthesis of compound 3 is shown in Scheme 4. The

known compound ent-6, synthesized from ^L-aspartic acid

following the literature procedure,¹⁵was converted to sulfone

ent-8 via the intermediate ent-7 following exactly the same

chemistry of sulfone 8. On the other hand, the known

compound ent-9,¹⁶prepared from S-glycidyl benzyl ether, was

transformed into aldehyde ent-10 mimicking the synthesis of

aldehyde 10. Next, compounds ent-8 and ent-10 were stitched

together following Julia−Kocienski oleﬁnation to produce ent-

11 in good yield. The formation of the corresponding Z-

counterpart was not observed. Compound ent-11 was then

transmuted to its corresponding dimesylated compound in two

steps following the same chemistry described in Scheme 2. The

crucial dihydroxylation followed by cycloetheriﬁcation was

carried out under diﬀerent dihydroxylation conditions (Table

2). AD-mix-α (entry 1) and AD-mix-β (entry 2) produced the

desired compound ent-4 and the undesired compound ent-12

in a ratio of 1:1.2 and 1:2, respectively. However, the reaction

proceeded in a favorable direction with a slight increase of the

ratio to 1.2:1 in the presence of a catalytic amount of OsO₄

(entry 3). The use of excess OsO₄in association with AD-mix-

α (entry 3) improved the required selectivity further to 1.6:1

(entry 4). Both compounds were separated using column

chromatography. Compound ent-4 was then subjected to

debenzylation, followed by oxidation to obtain the correspond-

ing aldehyde, which further reacted with the known sulfone

17⁶in the presence of NaHMDS to get compound 18 (E/Z =

2.5:1). Later KHMDS was tested but the result was similar to

NaHMDS. The minor Z-isomer was inseparable at this stage.

TBDPS ether of compound 18 mixed with its corresponding

Z-counterpart was then removed using TBAF and the resultant

alcohols were converted to their corresponding sulﬁdes. These

were further oxidized¹⁷using H₂O₂/(NH₄)₆MoO₄·6H₂O to

get sulfone 18 and its corresponding Z-counterpart, which

were separated completely by column chromatography.

The completion of total synthesis of one of the proposed

structures (1a) of amphirionin-2 is described in Scheme 5.

Alcohol 2 mixed with its inseparable Z-counterpart was

oxidized to aldehyde 19 mixed with its corresponding minor

isomer and subjected further to Julia−Kocienski oleﬁnation

using sulfone 3 in the presence of NaHMDS. However, the

required product remained inseparable in this stage with the

minor counterpart generated from the Z-isomer of reacting

aldehyde 19. Next, this inseparable mixture was treated with

TBAF. Compound 1a was isolated in the pure form and the

corresponding Z-counterpart originated from inseparable

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Scheme 4. Synthesis of Compound 3

Table 2. Optimization of Dihydroxylation and Cycloetheriﬁcation for Compound ent-4

time

(h)

yield

(%)

dr

entry

reagents

solvent

temperature

(ent-4/ent-12)

1

2

3

4

AD-mix-α (1.4 g/mmol)/MeSO₂NH₂(2 equiv)

AD-mix-β (1.4 g/mmol)/MeSO₂NH₂(2 equiv)

OsO₄(0.01 equiv)/NMO (2 equiv)/K₂CO₃(3 equiv)

AD-mix-α (1.4 g/mmol), OsO₄(0.5 equiv), MeSO₂NH₂(2 equiv)

H₂O/^tBuOH (1:1)

0 °C to rt

48

12

52

55

57

60

1:1.2

1:2

1.2:1

1.6:1

H₂O/^tBuOH (1:1)

THF/^tBuOH: H₂O (4:4:1)

H₂O/^tBuOH (1:1)

minor aldehyde counterpart was discarded during column

puriﬁcation. It is noteworthy that Julia−Kocienski oleﬁnation

proceeded in a complete E-regioselective fashion in this case.

The conﬁguration of the conjugated diene moiety of

compound 1a was conﬁrmed unambiguously as E, E from

the observed NOESY correlation between H₁₃−H₁₅and H₃₂−

H₁₆and also from the large coupling constant values of H-15

and H-16 (J_{H =}15.6 Hz and J_{H =}15.1, 7.2 Hz). The observed

Z-isomer (E/Z = 3:1). Next, ent-18 mixed with its minor

counterpart was treated with TBAF, followed by PTSH under

Mitsunobu conditions and the resultant sulﬁde was oxidized to

achieve sulfone ent-3 in its pure form along with its separable

corresponding Z-isomer. Next, sulfone ent-3 and aldehyde 19

were subjected to Julia−Kocienski oleﬁnation to obtain the

corresponding coupled products with complete E-selectivity,

which was further desilylated to produce compound 1b in

good yield. The minor isomer carried over from aldehyde 19

was discarded at this step during column chromatographic

puriﬁcation.

15

16

NOESY interactions between H-7 and H-12 as well as H-18

and H-23 have conﬁrmed further the stereochemistry of

hexahydrofuro[3,2-b] furan moieties of compound 1a.

The spectroscopic data of both compounds 1a and 1b were

analyzed and compared to the reported data of the isolated

amphirionin-2. It is noteworthy that the ¹³C spectra of both

compounds 1a and 1b were almost identical but a minor

mismatch in the ¹H spectra between them was observed at H-

18 and H-12, which might be due to the diﬀerence in a long-

Completion of the total synthesis of other proposed

structure (1b) of amphirionin-2 is depicted in Scheme 6.

Following the similar chemistry of sulfone 3, compound 4 was

debenzylated and the resultant alcohol was oxidized to the

corresponding aldehyde, which was further reacted with

sulfone 17 to obtain ent-18 along with its inseparable minor

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Scheme 5. Completion of Total Synthesis of the Proposed Structure (1a) of Amphirionin-2

Scheme 6. Completion of Total Synthesis of Compound 1b

20

range interaction between the C-12 and C-18 centers.

However, it was quite unfortunate that considerable mis-

matches were observed in the ¹H NMR data of the synthesized

compounds (1a and 1b) with respect to the reported data¹of

the isolated natural product especially for H-2, H-3, H-4, H-6,

H-7, H-8, H-10, H-11, and H-12 (Table S1). Anomalies in the

¹³C spectra were also observed (Table S2). The chemical shifts

of C-5 to C-10 of both compounds 1a and 1b were recorded at

δ 74.4, 40.1, 81.5, 42.2, 83.0, and 84.6 ppm, respectively,

whereas those signals were observed at δ 71.2, 39.2, 78.3, 41.2,

84.0, and 83.8 ppm, respectively, for the isolated amphirionin-

2. Moreover, the optical rotations of compounds 1a {observed

[α]_D= −26.6 (c 0.3, CHCl₃)} and 1b {observed [α]_D

=

−13.3 (c 0.6, CHCl₃)} diﬀered signiﬁcantly from the data¹of

the isolated natural product {reported [α]_D= +5 (c 0.8,

20

CHCl₃)}. These ﬁndings clearly indicated that the proposed

structures of amphirionin-2 might not be right. At this stage,

we were looking for synthesizing other analogues by changing

the relative stereochemistry of the fused ring system embedded

on the left segment with respect to the stereochemistry of

hexahydrofuro[3,2-b] furan on the right part of isomers 1a and

1b as the absolute stereochemistry of the C-5 center was

established by the isolation group according to Mosher’s ester

analysis. Coincidentally, an elegant synthetic study at this

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Scheme 7. Completion of Total Synthesis of Compound 1c

juncture was disclosed by Fuwa et al.,³where the actual

structure (1c, Figure 1) of amphirionin-2 was established

unambiguously. We were happy to observe that our ongoing

investigations were in good alignment with the reported study.

Thus, we decided to explore our developed strategy to achieve

the total synthesis of the actual natural product (Scheme 7).

Compound ent-4 was desilylated, following that it was oxidized

and subsequently subjected to Crimmins propionate aldol to

get compound 20, which was later transformed into compound

22 via intermediate 21. Benzyl ether of compound 22 was

deprotected and the resultant alcohol was oxidized to the

corresponding aldehyde, which was then exposed to Wittig

oleﬁnation, followed by DIBAL-H reduction to obtain major

compound 23 mixed with its inseparable Z-counterpart with an

improved ratio (E/Z = 3.5:1) compared to compound 2. The

mixture of alcohols was then oxidized to the corresponding

aldehydes and subjected to Julia−Kocienski oleﬁnation with

sulfone 3 to get the corresponding coupled products, which

were ﬁnally desilylated. Compound 1c was separated easily

from its minor counterpart. The NMR data of synthesized

compound 1c were in accordance with the reported data

(Table S3) of the isolated natural product. The optical rotation

in line with the results from Fuwa et al., which appeared when

these investigations were underway. Dihydroxylation followed

by the cycloetheriﬁcation approach was used to build the fused

ring system, whereas Julia−Kocienski oleﬁnation was adopted

to stitch the major halves together. The developed synthetic

route is quite ﬂexible, which creates an opportunity to explore

the structure−activity relationship of this potent molecule.

EXPERIMENTAL

■

General Experimental Procedure. All moisture sensitive

reactions were performed in an oven or ﬂame-dried glassware with

a Teﬂon-coated magnetic stirring bar under an argon atmosphere

using dry, freshly distilled solvents, unless otherwise noted. Air- and

moisture-sensitive liquids were transferred via a gastight syringe and a

stainless-steel needle. Reactions were monitored by thin layer

chromatography (TLC, Silica gel 60 F254) plates with UV light,

ethanolic anisaldehyde (with 1% AcOH and 3.3% conc. H₂SO₄) with

heat and aqueous KMnO₄(with K₂CO₃and 10% aqueous NaOH

solution) as developing agents. All workup and puriﬁcation

procedures were carried out with reagent-grade solvents under an

ambient atmosphere unless otherwise stated. Column chromatog-

raphy was performed using silica gel 60−120 mesh, 100−200 mesh,

and 230−400 mesh. Yields were mentioned as chromatographically

and spectroscopically homogeneous materials unless otherwise stated.

Optical rotations were measured only for pure compounds and not for

mixtures using a sodium (589, D line; Anton paar MCP 200 system)

20

of compound 1c {observed [α]_D= +6.65 (c 0.6, CHCl₃)}

was in agreement with the literature value of amphirionin-2,

which clearly demonstrates its total synthesis.

25

lamp and are reported as follows: [α]_D= (c = g/100 mL, solvent).

IR spectra were recorded as neat (for liquids). HRMS were recorded

using a Quadruple-TOF (Q-TOF) micro-MS system using the

electrospray ionization (ESI) technique. ¹H NMR spectra were

recorded on 300 and 600 MHz spectrometers in appropriate solvents

and calibrated using a residual undeuterated solvent as an internal

reference, and the chemical shifts are shown on ppm scales.

Multiplicities of NMR signals are designated as s (singlet), d

(doublet), t (triplet), q (quartet), br (broad), m (multiplet, for

unresolved lines), and so forth. ¹³C and 2D NMR spectra were

CONCLUSIONS

■

In summary, we have achieved the total synthesis of

amphirionin-2 from L-aspartic acid in 30 longest linear steps

with 0.3% overall yield. Our initial eﬀorts resulted in the total

synthesis of the proposed structures of the natural product too,

which eventually revealed that the structural revision of the

reported structure was essential. The conclusions arrived at are

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recorded on a 75 MHz spectrometer. Structural assignments were

made with additional information from gCOSY, gHSQC, gNOESY,

gTOCSY, and gHMBC experiments.

temperature. The reaction mixture was then quenched with saturated

aqueous NaHCO₃(10 mL), extracted with EtOAc (3 × 50 mL),

washed with brine, dried (Na₂SO₄), and concentrated under vacuum.

The residue was puriﬁed by column chromatography (SiO₂, 100−200

mesh, 5% EtOAc in hexane as the eluent) to aﬀord the corresponding

sulﬁde (10.3 g, 88%) as a thick oil. R_f= 0.45 (10% EtOAc/hexane);

[α]_D= −11.4 (c 0.7, CHCl₃); H NMR (300 MHz, CDCl₃): δ

7.69−7.60 (m, 4H), 7.59−7.50 (m, 5H), 7.44−7.31 (m, 6H), 4.10

(qd, J = 6.4, 4.6 Hz, 1H), 3.72 (td, J = 6.2, 1.6 Hz, 2H), 3.51−3.36

(m, 2H), 2.12−1.88 (m, 2H), 1.85−1.67 (m, 2H), 1.02 (s, 9H), 0.93

(t, J = 8.3, 9H), 0.58 (q, J = 7.2, 6H); ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 135.6, 130.1, 129.8, 129.7, 129.7, 127.8, 127.7, 123.9, 68.2,

60.5, 39.9, 36.3, 29.6, 26.9, 19.2, 7.0, 5.1 ppm; IR (neat) ν_max: 2956,

2929, 1500, 1427, 1250, 1111, 836 cm⁻¹; HRMS (ESI) m/z: calcd for

C₃₄H₄₈N₄NaO₂SSi₂, [M + Na]⁺655.2934; found, 655.2936.

(R)-5-((Tert-butyldiphenylsilyl)oxy)-3-((triethylsilyl)oxy)pentan-1-

ol (7). To an ice-cold solution of compound 6 (9.5 g, 26.8 mmol) in

anhydrous CH₂Cl₂(60 mL) under argon, Et₃N (5.6 mL, 40.3 mmol)

was added. After 10 min stirring at 0 °C, TESCl (5.4 mL, 32.2 mmol)

and DMAP (327 mg, 2.7 mmol) were added sequentially and the

reaction mixture was stirred for another 40 min at the same

temperature prior to quenching with a saturated solution of NH₄Cl (5

mL). The resultant mixture was extracted with CH₂Cl₂(3 × 50 mL),

washed with H₂O, brine, dried over Na₂SO₄, and ﬁnally concentrated

in vacuo. Column chromatographic (SiO₂60−120 mesh, 5% EtOAc

in hexane as the eluent) puriﬁcation gave the corresponding TES

ether (12.1 g, 96%) as a colorless oil; R_f= 0.9 (10% EtOAc/hexane);

[α]_D²⁵= −10.4 (c 0.9, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.66

(ddd, J = 6.3, 4.1, 2.0 Hz, 4H), 7.39 (ddt, J = 7.6, 5.2, 2.5 Hz, 6H),

5.81 (ddt, J = 19.2, 9.5, 7.1 Hz, 1H), 5.10−4.94 (m, 2H), 3.96 (p, J =

5.9 Hz, 1H), 3.72 (q, J = 6.4 Hz, 2H), 2.21 (q, J = 6.7 Hz, 2H), 1.69

(p, J = 6.4 Hz, 2H), 1.05 (s, 9H), 0.93 (t, J = 7.8 Hz, 9H), 0.58 (q, J =

8.1 Hz, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 135.7, 135.2, 134.1,

129.6, 127.7, 116.9, 69.0, 60.9, 42.2, 39.8, 29.8, 27.0, 7.0, 5.1 ppm;

IR(neat) ν_max: 2964, 2929, 1428, 1109, 1080,735, 699 cm⁻¹; HRMS

(ESI) m/z: calcd for C₂₈H₄₅O₂Si₂, [M + H]⁺469.2958; found,

469.2956.

25

1

To an ice-cold solution of the above sulﬁde (10.2 g, 16.11 mmol)

and NaHCO₃(8.12 g, 96.68 mmol) in anhydrous CH₂Cl₂(80 mL)

under argon, mCPBA (11.11 g, 64.38 mmol) was added portion wise.

The reaction was stirred for 12 h at room temperature. The reaction

mixture was then quenched with saturated aqueous Na₂S₂O₃solution

(20 mL) at 0 °C and extracted with CH₂Cl₂(3 × 50 mL), washed

with brine, dried over Na₂SO₄, ﬁltered, and concentrated. The crude

material was puriﬁed by column chromatography (SiO₂, 100−200

mesh, 5% EtOAc in hexane as eluant) to yield sulfone 8 (9.1 g, 85%)

25

as a pale-yellow oil. R_f= 0.42 (10% EtOAc/hexane); [α]_D= −10.0

(c 2.0, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.72−7.56 (m, 9H),

7.40 (dtd, J = 8.8, 5.6, 5.0, 2.0 Hz, 6H), 4.16 (qd, J = 6.4, 4.6 Hz, 1H),

3.88−3.68 (m, 4H), 2.27−2.12 (m, 1H), 2.10−1.99 (m, 1H), 1.86−

1.73 (m, 1H), 1.71−1.58 (m, 1H), 1.05 (s, 9H), 0.95 (t, J = 7.9 Hz,

9H), 0.60 (q, J = 7.8 Hz, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ

153.6, 135.6, 133.6, 131.5, 129.8, 129.8, 127.8, 127.8, 125.1, 67.2,

60.3, 52.5, 39.6, 29.1, 26.9, 19.2, 7.0, 5.0 ppm; IR (neat) ν_max: 2955,

2857, 1468, 1428, 1111, 701 cm⁻¹; HRMS (ESI) m/z: calcd for

C₃₄H₄₈N₄NaO₄SSi₂, [M + Na]⁺687.2832; found, 687.2834.

To a stirred solution of the above compound (12 g, 25.6 mmol) in

t

THF (50 mL), BuOH (50 mL) and H₂O (10 mL) at 0 °C, OsO₄

t

(0.2 M solution in BuOH, 0.3 mL), and NMO (6.0 g, 51.2 mmol)

were added, and the reaction mixture was stirred for 12 h at room

temperature. The reaction mixture was then cooled to 0 °C and

quenched with saturated solution of NaHSO₃(10 mL). The resultant

mixture was extracted with EtOAc (3 × 50 mL), washed with water,

and concentrated in vacuo. The corresponding diol was taken for the

next step without further puriﬁcation and characterization.

To a stirred solution of the above diol (25.6 mmol) in THF (40

mL) and H₂O (40 mL) at 0 °C, NaHCO₃(4.3 g, 51.2 mmol) and

NaIO₄(10.9 g, 51.2 mmol) were added. The reaction mixture was

slowly warmed to the room temperature and stirred further for 1 h.

The reaction mixture was then passed through a small bed of Celite,

and the THF solvent was evaporated under reduced pressure and

extracted with EtOAc (4 × 50 mL). The ﬁltrate was washed with

water then brine and dried over Na₂SO₄, and concentrated in vacuo

to obtain the crude aldehyde. It was then passed through a short silica

pad to get the corresponding aldehyde, which was used in the next

reaction without further puriﬁcation or characterization.

To a stirred solution of the above aldehyde (25.6 mmol) in

anhydrous methanol (60 mL) under argon at 0 °C, NaBH₄(1.45 g,

38.4 mmol) was added portion wise. The reaction mixture was stirred

at the same temperature for 1 h and then quenched with saturated

aqueous NH₄Cl (10 mL) solution. The methanol solvent was

evaporated under reduced pressure and the mixture was extracted

with EtOAc (3 × 50 mL), washed with H₂O, brine, dried over

Na₂SO₄, and ﬁnally concentrated in vacuo. Column chromatographic

(SiO₂60−120 mesh, 7% EtOAc in hexane as the eluent) puriﬁcation

resulted alcohol 7 (9.2 g, 76%) as a colorless oil; R_f= 0.35 (10%

EtOAc/hexane); [α]D²⁵= −3.0 (c 2.7, CHCl₃); ¹H NMR (300 MHz,

CDCl₃): δ 7.73−7.62 (m, 4H), 7.44−7.35 (m, 6H), 4.26−4.07 (m,

1H), 3.86−3.62 (m, 4H), 2.55 (t, J = 5.2 Hz, 1H), 1.92−1.71 (m,

3H), 1.67−1.55 (m, 1H), 1.06 (s, 9H), 0.97 (t, J = 4.5 Hz, 9H), 0.62

(q, J = 7.35, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 135.6, 133.8,

129.7, 127.7, 69.4, 60.8, 60.5, 39.7, 37.9, 26.9, 19.2, 6.9, 5.0 ppm; IR

(neat) ν_max: 3440, 2937, 2874, 1465, 1107, 1036, 855 cm⁻¹; HRMS

(ESI) m/z: calcd for C₂₇H₄₅O₃Si₂, [M + H]⁺473.2907; found,

473.2905.

(R)-4-(Benzyloxy)-3-((triethylsilyl)oxy)butanal (10). Following the

same experimental procedure as described in the preparation of

compound 7, compound 9 (4.0 g, 20.8 mmol) was converted to the

corresponding TES ether. Column chromatographic (SiO₂60−120

mesh, 5% EtOAc in hexane as the eluent) puriﬁcation gave the

compound (6.0 g, 95%) as a colorless oil; R_f= 0.8 (10% EtOAc/

25

hexane); [α]_D= −8.9 (c 0.9, CHCl₃); ¹H NMR (300 MHz,

CDCl₃): δ 7.34−7.28 (m, 5H), 5.83 (ddt, J = 17.3, 10.1, 7.2 Hz, 1H),

5.10−4.98 (m, 2H), 4.52 (s, 2H), 3.88 (p, J = 5.6 Hz, 1H), 3.39 (d, J

= 5.5 Hz, 2H), 2.42−2.31 (m, 1H), 2.28−2.18 (m, 1H), 0.94 (q, J =

7.5 Hz, 6H), 0.61 (t, J = 7.8 Hz, 9H); ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 135.0, 128.5, 128.4, 127.7, 127.6, 117.1, 74.3, 73.4, 71.2,

39.5, 6.9, 5.0 ppm; IR (neat) ν_max: 2910, 2876, 1455, 1111, 1004, 731

cm⁻¹; HRMS (ESI) m/z: calcd for C₁₈H₃₀NaO₂Si, [M + Na]⁺

329.1913; found, 329.1914.

Following the same experimental procedure as described in the

preparation of compound 7, the above compound (6.0 g, 19.6 mmol)

was converted to the corresponding diol (6.6 g, quantitative) as a light

yellowish oil using OsO₄(0.2 M solution in t-BuOH, 0.2 mL) and

NMO (4.58 g, 39.1 mmol), which was taken for the next step without

further characterization.

Following the same experimental procedure as described in the

preparation of compound 7, the above diol (19.6 mmol) was

converted to the corresponding aldehyde 10. Puriﬁcation by ﬂash

column chromatography (SiO₂, 60−120 mesh, 10−20% EtOAc in

hexane as the eluent) provided a pure compound (4.68 g, 78% over

two steps) as a colorless liquid, which was taken for the next step

without further characterization.

(5R,10R,E)-5-((Benzyloxy)methyl)-3,3-diethyl-15,15-dimethyl-

14,14-diphenyl-10-((triethylsilyl)oxy)-4,13-dioxa-3,14-disilahexa-

dec-7-ene (11). Sulfone 8 (3.0 g, 4.51 mmol) was dissolved in

anhydrous THF (15 mL) under argon and cooled to −78 °C.

KHMDS (0.5 M in THF, 9.8 mL, 4.88 mmol) solution was added to

it and stirred for 10 min. A solution of aldehyde 10 (1.16 g, 3.76

mmol) in THF (7 mL) was cannulated into the reaction mixture and

stirred for 2 h. The reaction was then quenched with saturated

(S)-5-((5-((Tert-butyldiphenylsilyl)oxy)-3-((triethylsilyl)oxy)-

pentyl)sulfonyl)-1-phenyl-1H-tetrazole (8). To a mixture of alcohol

7 (8.75 g, 18.51 mmol), Ph₃P (9.71 g, 37.0 mmol), and 1-phenyl-1H-

tetrazol-5-thiol (PTSH) (4.95 g, 27.76 mmol) in anhydrous THF (60

mL) at 0 °C under argon, DIAD (7.3 mL, 37.0 mmol) was added in

dropwise and the reaction mixture was stirred for 2 h at ambient

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aqueous NH₄Cl solution (3 mL) at the same temperature. The

resultant mixture was extracted with EtOAc (2 × 30 mL), washed

with water and brine, dried over Na₂SO₄, and ﬁnally concentrated in

vacuo. Puriﬁcation by ﬂash column chromatography (SiO₂, 100−200

mesh, 2% EtOAc in hexane as the eluent) of the resultant crude

residue provided compound 11 (1.96 g, 70%) as a colorless liquid. R_f

= 0.45 (5% EtOAc/hexane); [α]_D²⁵= −2.35 (c 8.5, CHCl₃);¹H NMR

(300 MHz, CDCl₃): δ 7.66 (ddd, J = 7.8, 4.4, 1.8 Hz, 4H), 7.45−7.34

(m, 6H), 7.32 (d, J = 4.5 Hz, 4H), 5.51−5.39 (m, 2H), 4.51 (s, 2H),

3.97−3.80 (m, 2H), 3.71 (td, J = 6.4, 3.8 Hz, 2H), 3.38 (d, J = 5.4 Hz,

2H), 2.37−2.25 (m, 1H), 2.22−2.08 (m, 3H), 1.72−1.59 (m, 2H),

1.04 (s, 9H), 1.00−0.84 (m, 18H), 0.65−0.49 (m, 12H); ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 138.6, 135.7, 134.1, 134.1, 129.6, 129.1,

128.7, 128.4, 127.7, 127.5, 74.4, 73.4, 71.6, 69.3, 61.0, 41.2, 39.8, 38.3,

27.0, 19.3, 7.0, 7.0, 5.1, 5.1 ppm; IR (neat) ν_max: 2930, 2875, 1457,

1110, 1090, 1006, 736, 700 cm⁻¹; HRMS (ESI) m/z: calcd for

C₄₄H₇₀NaO₄Si₃, [M + Na]⁺769.4480; found, 769.4477. The same

reaction was performed batchwise.

230−400 mesh, 10% EtOAc in hexane as the eluent) to separate the

two diastereomers with 60% total yield (dr = 3:1). The isolated major

compound 4 (1.28 g, 45%) was obtained as a colorless oil. R_f= 0.8

25

1

(30% EtOAc/hexane); [α]_D= +4.3 (c 0.9, CHCl₃); H NMR (300

MHz, CDCl₃): δ 7.72−7.62 (m, 4H), 7.48−7.26 (m, 11H), 4.72 (t, J

= 4.5 Hz, 1H), 4.66 (t, J = 4.8 Hz, 1H), 4.63−4.51 (m, 2H), 4.34−

4.17 (m, 2H), 3.75 (dd, J = 7.3, 5.8 Hz, 2H), 3.53 (dd, J = 10.2, 3.3

Hz, 1H), 3.42 (dd, J = 10.2, 5.8 Hz, 1H), 2.23 (dd, J = 13.4, 5.0 Hz,

1H), 2.07 (dd, J = 13.4, 5.8 Hz, 1H), 1.88−1.71 (m, 3H), 1.66−1.59

(m, 1H), 1.04 (s, 9H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.3,

135.6, 133.9, 129.6, 128.4, 127.8, 127.7, 127.7, 84.5, 83.2, 79.1, 77.0,

73.5, 72.6, 61.3, 41.4, 38.5, 37.5, 26.9, 19.3 ppm; IR (neat) ν_max: 2962,

2832, 1466, 1235, 1031 cm⁻¹; HRMS (ESI) m/z: calcd for

C₃₂H₄₀NaO₄Si, [M + Na]⁺539.2594; found, 539.2592.

Minor compound 12 (0.43 g, 15%) was obtained as a colorless

liquid. R_f= 0.75 (30% EtOAc/hexane); [α]_D²⁵= −3.1 (c 0.5, CHCl₃);

¹H NMR (300 MHz, CDCl₃): δ 7.70−7.62 (m, 4H), 7.46−7.27 (m,

11H), 4.61−4.50 (m, 3H), 4.41 (ddd, J = 6.5, 4.5, 2.0 Hz, 1H), 4.20

(qd, J = 7.3, 4.4 Hz, 1H), 4.14−4.04 (m, 1H), 3.79−3.66 (m, 2H),

3.61−3.52 (m, 1H), 3.48 (dd, J = 9.9, 4.4 Hz, 1H), 2.28−2.12 (m,

2H), 2.00−1.87 (m, 1H), 1.85−1.70 (m, 3H), 1.04 (s, 9H); ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 138.3, 135.7, 134.0, 129.7, 128.4, 127.9,

127.7, 127.7, 85.4, 84.0, 80.2, 78.6, 73.4, 73.1, 61.4, 39.5, 39.0, 35.9,

27.0, 19.3 ppm; IR (neat) ν_max: 2935, 2823, 1472, 1135, 953 cm⁻¹;

HRMS (ESI) m/z: calcd for C₃₂H₄₀NaO₄Si, [M + Na]⁺539.2594;

found, 539.2597.

(2R,7R,E)-1-(Benzyloxy)-9-((tert-butyldiphenylsilyl)oxy)non-4-

ene-2,7-diol (5). To an ice cold solution of compound 11 (5.9 g, 7.9

mmol) in anhydrous CH₂Cl₂(20 mL) and MeOH (4 mL), CSA (96

mg, 0.43 mmol) was added and stirred for 45 min. The reaction was

then quenched with Et₃N (5 mL) and concentrated in vacuo. The

crude material was puriﬁed by column chromatography (SiO₂, 60−

120 mesh, 20% EtOAc in hexane as the eluent) to obtain diol 5 (3.64

25

g, 89%) as a colorless oil. R_f= 0.4 (30% EtOAc/hexane); [α]_D

=

−16.65 (c 1.2, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.68 (ddt, J

= 6.6, 2.1, 0.8 Hz, 4H), 7.48−7.37 (m, 6H), 7.37−7.27 (m, 5H),

5.62−5.45 (m, 2H), 4.55 (s, 2H), 3.96−3.79 (m, 4H), 3.50 (dd, J =

9.5, 3.4 Hz, 1H), 3.37 (dd, J = 9.5, 7.3 Hz, 1H), 2.30 (d, J = 5.9 Hz,

1H), 2.27−2.18 (m, 3H), 1.69 (dq, J = 9.5, 4.9 Hz, 2H), 1.06 (s, 9H);

¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.1, 135.6, 135.6, 133.2, 133.1,

Improved Procedure for Dihydroxylation Followed by

t

Cycloetheriﬁcation. To a stirred solution of BuOH/H₂O (1:1, 3

mL) at room temperature, AD-mix-β (38 mg, 1.4 g/mmol), OsO₄

t

(0.2 M solution in BuOH, 60 μL), and methanesulfonamide (6 mg,

0.06 mmol) were added. The solution was further stirred well for 15

min and then the above dimesylated compound (18 mg, 0.03 mmol)

t

129.9, 128.7, 128.5, 127.9, 127.8, 74.0, 73.5, 71.0, 70.0, 63.3, 40.9,

38.0, 36.9, 26.9, 19.1 ppm; IR (neat) ν_max: 3421, 3064, 2930, 2857,

1472, 1427, 1106, 822, 737, 700 cm⁻¹; HRMS (ESI) m/z: calcd for

C₃₂H₄₃O₄Si, [M + H]⁺519.2931; found, 519.2923.

in BuOH (1 mL) was cannulated and stirred for 12 h. The mixture

was quenched with a saturated solution of Na₂SO₃and the resultant

mixture was stirred further for 1 h. The aqueous layer was extracted

with EtOAc (4 × 10 mL), washed with water and brine, dried over

Na₂SO₄, and ﬁnally concentrated in vacuo. The crude material was

puriﬁed by column chromatography (SiO₂, 230−400 mesh, 10%

EtOAc in hexane as the eluent) to separate the two diastereomers

with 60% overall yield (dr = 3.5:1). Isolated major compound 4 (8

mg, 46%) and minor compound 12 (2 mg, 14%) were obtained as a

colorless oil.

(2-((2R,3aR,5S,6aR)-5-((Benzyloxy)methyl)hexahydrofuro[3,2-b]-

furan-2-yl)ethoxy)(tert-butyl)diphenylsilane (4). To a stirred

solution of diol 5 (3.5 g, 6.74 mmol) in anhydrous CH₂Cl₂(20

mL), Et₃N (4.7 mL, 33.7 mmol) at 0 °C under argon, MsCl (1.56

mL, 20.22 mmol), followed by DMAP (0.17 g, 1.4 mmol) were

added. The reaction was quenched with saturated aqueous NH₄Cl (5

mL) solution at 0 °C after 1 h and extracted with CH₂Cl₂(3 × 15

mL), washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated. The crude material was puriﬁed by column

chromatography (SiO₂, 60−120 mesh, 30−40% EtOAc in hexane as

(2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-4-

((2R,3aR,5S,6aR)-5-((benzyloxy)methyl) hexahydrofuro[3,2-b]-

furan-2-yl)-3-hydroxy-2-methylbutan-1-one (14). To the solution

of compound 4 (1.0 g, 1.93 mmol) in anhydrous THF (10 mL) at 0

°C under argon, TBAF (1.0 M in THF, 2.9 mL, 2.90 mmol) was

added. The reaction was stirred at room temperature for 6 h and then

quenched with saturated NH₄Cl (5 mL) solution. The aqueous layer

was extracted with EtOAc (3 × 20 mL), the combined organic layer

was washed with water and brine, and then dried over Na₂SO₄and

concentrated in vacuo. Column chromatography (SiO₂, 60−120

mesh, 20% EtOAc in hexane as the eluent) produces the desire

alcohol (0.45 g, 83%) as a colorless oil. R_f= 0.2 (50% EtOAc/

the eluent) to obtain the corresponding mesylated compound (3.86 g,

25

85%) as a pale-yellow oil. R_f= 0.45 (30% EtOAc/hexane); [α]_D

=

−10.67 (c 3.37, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.66 (ddd, J

= 7.5, 5.3, 1.8 Hz, 4H), 7.48−7.38 (m, 6H), 7.37−7.29 (m, 5H),

5.66−5.45 (m, 2H), 4.97 (dq, J = 6.9, 5.4 Hz, 1H), 4.87−4.75 (m,

1H), 4.62−4.49 (m, 2H), 3.84−3.70 (m, 2H), 3.65−3.57 (m, 2H),

3.00 (s, 3H), 2.92 (s, 3H), 2.59−2.35 (m, 4H), 1.94−1.77 (m, 2H),

1.07 (s, 9H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 137.5, 135.6,

133.4, 133.3, 129.9, 128.5, 128.0, 127.8, 127.8, 127.2, 81.3, 79.8, 73.4,

71.0, 59.5, 38.6, 38.3, 38.3, 38.1, 36.6, 35.3, 26.9, 19.2 ppm; IR (neat)

ν_max: 2932, 2858, 1472, 1428, 1352, 1178, 913, 702 cm⁻¹; HRMS

(ESI) m/z: calcd for C₃₄H₄₆NaO₈S₂Si, [M + Na]⁺697.2301; found,

697.2304.

25

hexane); [α]_D= + 40.0 (c 0.1, CHCl₃); ¹H NMR (300 MHz,

CDCl₃): δ 7.38−7.26 (m, 5H), 4.78−4.69 (m, 2H), 4.64−4.51 (m,

2H), 4.35−4.17 (m, 2H), 3.76 (dd, J = 6.4, 5.1 Hz, 2H), 3.52 (dd, J =

10.2, 3.3 Hz, 1H), 3.41 (dd, J = 10.2, 5.8 Hz, 1H), 2.23 (dd, J = 13.3,

5.0 Hz, 1H), 2.14−2.04 (m, 1H), 1.87−1.77 (m, 2H), 1.75−1.69 (m,

1H), 1.68−1.60 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.2,

128.4, 127.7, 127.7, 83.9, 83.8, 79.6, 79.2, 73.5, 72.5, 61.4, 41.3, 37.4,

37.3 ppm; IR (neat) ν_max: 3422, 3032, 2937, 2867, 1453, 1354, 1173,

1072, 1051, 910, 737 cm⁻¹; HRMS (ESI) m/z: calcd for C₁₆H₂₂NaO₄,

[M + Na]⁺301.1416; found, 301.1417.

t

To a stirred solution of BuOH/H₂O (1:1, 50 mL) at room

temperature, AD-mix-β (7.71 g, 1.4 g/mmol) and methanesulfona-

mide (1.05 g, 11 mmol) were added. The solution was further stirred

well for 15 min. A solution of the above mesylated compound (3.7 g,

t

5.51 mmol) in BuOH/H₂O (1:1, 15 mL) was added to the reaction

mixture at 0 °C and then it was warmed to room temperature and

stirred for 36 h. The mixture was quenched with a saturated solution

of Na₂SO₃and the resultant mixture was stirred further for 1 h. The

aqueous layer was extracted with EtOAc (4 × 30 mL), washed with

water and brine, dried over Na₂SO₄, and ﬁnally concentrated in vacuo.

The crude material was puriﬁed by column chromatography (SiO₂,

To an ice-cold solution of the above alcohol (0.44 g, 1.58 mmol) in

anhydrous CH₂Cl₂(15 mL), NaHCO₃(0.53 g, 6.32 mmol) and DMP

(1.34 g, 3.16 mmol) were added sequentially. The reaction mixture

was warmed gradually to room temperature and stirred further for 1 h.

The reaction was then quenched with saturated aqueous solution of

Na₂S₂O₃(5 mL) and NaHCO₃(5 mL) and then diluted with CH₂Cl₂

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(10 mL) and stirred further until the two phases were separated. The

resultant mixture was extracted with CH₂Cl₂(2 × 20 mL), washed

with water, brine, dried over Na₂SO₄, and concentrated in vacuo. The

crude residue was subjected to ﬂash column chromatography (using a

short pad of 60−120 silica and EtOAc as the eluent) to get the

corresponding aldehyde as a colorless liquid, which was taken for the

next reaction without further characterization.

CH₂Cl₂(3 × 10 mL). The organic layer was washed with water and

brine, dried over Na₂SO₄, and concentrated in vacuo. Puriﬁcation by

ﬂash column chromatography (SiO₂, 60−120 mesh, 30% EtOAc in

hexane as the eluent) to obtain the corresponding aldehyde; R_f= 0.3

(30% EtOAc in hexane), which was taken for the next step without

further characterization.

To a suspension of Ph₃PCH₃Br (542 mg, 1.52 mmol) in anhydrous

THF (6 mL) at 0 °C under argon, ^tBuOK (153 mg, 1.36 mmol) was

added and stirred for 30 min at the same temperature. The above

aldehyde (0.76 mmol, dissolved in 5 mL of anhydrous THF) was

cannulated into it at the same temperature. The reaction mixture was

allowed to stir for another 2 h at room temperature and then

quenched with saturated aqueous NH₄Cl solution (2 mL). The

resultant mixture was extracted with EtOAc (3 × 10 mL), washed

with water, brine, dried (Na₂SO₄), and concentrated in vacuo. Flash

column chromatography (SiO₂, 60−120 mesh, 10% EtOAc in hexane

as the eluent) of the crude residue gave compound 15 (235 mg, 70%)

as a yellowish oil. R_f= 0.7 (15% EtOAc/hexane); [α]_D²⁵= +5.0 (c 0.4,

CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.36−7.27 (m, 5H), 5.97−

5.79 (m, 1H), 5.05−4.95 (m, 2H), 4.75−4.66 (m, 2H), 4.63−4.52

(m, 2H), 4.31−4.22 (m, 1H), 4.19−4.10 (m, 1H), 3.68−3.62 (m,

1H), 3.52 (dd, J = 10.3, 3.4 Hz, 1H), 3.42 (dd, J = 10.3, 5.8 Hz, 1H),

2.45−2.29 (m, 1H), 2.23 (dd, J = 13.2, 4.9 Hz, 1H), 2.07 (dd, J =

13.4, 5.8 Hz, 1H), 1.89−1.72 (m, 2H), 1.58−1.46 (m, 2H), 0.95 (d, J

= 6.8 Hz, 3H), 0.89 (s, 9H), 0.05 (d, J = 2.7 Hz, 6H); ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 141.2, 138.3, 128.4, 127.7, 127.7, 114.3, 84.3,

83.1, 79.1, 76.8, 73.6, 73.4, 72.6, 42.5, 41.6, 39.8, 37.5, 26.0, 18.2,

14.4, −4.2, −4.3 ppm; IR (neat) ν_max: 2957, 2929, 2857, 1456, 1472,

1253, 1090, 835 cm⁻¹; HRMS (ESI) m/z: calcd for C₂₆H₄₂NaO₄Si,

[M + Na]⁺469.2750; found, 469.2752.

(((2S,3S)-1-((2S,3aR,5S,6aR)-5-((Benzyloxy)methyl)-

hexahydrofuro[3,2-b]furan-2-yl)-3-methylhex-5-en-2-yl)oxy)(tert-

butyl)dimethylsilane (16). To a stirred solution of alkene 15 (220

mg, 0.49 mmol) in anhydrous THF (5 mL) at 0 °C under argon,

BH₃-DMS (0.73 mL, 1.47 mmol, 2 M in THF) was added and the

reaction was continued for 1 h at the same temperature. The cooling

bath was then removed and the mixture was stirred for another 1 h at

room temperature. The mixture was cooled to 0 °C. Water (0.1 mL)

and K₂CO₃(200 mg) were added slowly. The resultant mixture was

then ﬁltered and concentrated under reduced pressure. Puriﬁcation of

the crude residue by ﬂash column chromatography (SiO₂, 60−120

mesh, 40% EtOAc in hexane as the eluent) resulted the corresponding

alcohol (154 mg, 68%) as a light yellowish oil. R_f= 0.2 (30% EtOAc/

hexane); [α]_D²⁵= +6.9 (c 0.8, CHCl₃); ¹H NMR (300 MHz, CDCl₃):

δ 7.43−7.27 (m, 5H), 4.66−4.55 (m, 2H), 4.51 (tt, J = 4.4, 2.4 Hz,

1H), 4.47−4.35 (m, 1H), 4.20 (tt, J = 7.3, 3.7 Hz, 1H), 4.00 (dt, J =

12.3, 6.4 Hz, 1H), 3.83 (td, J = 7.2, 6.2, 3.7 Hz, 1H), 3.77−3.57 (m,

3H), 3.51 (ddd, J = 9.6, 4.4, 2.0 Hz, 1H), 2.30−2.12 (m, 2H), 1.96−

1.80 (m, 2H), 1.70 (dddd, J = 14.0, 8.7, 5.6, 3.6 Hz, 4H), 1.40−1.27

(m, 1H), 0.87 (s, 9H), 0.04 (dd, J = 7.9, 3.4 Hz, 6H); ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 138.3, 128.4, 127.9, 127.7, 85.2, 84.1, 80.3, 78.8,

73.8, 73.4, 73.2, 61.7, 39.5, 35.8, 35.6, 29.8, 26.0, 18.1, 16.1, −4.2,

−4.4 ppm; IR (neat) ν_max: 3409, 2934, 2843, 1501, 1251, 1086, 763

cm⁻¹; HRMS (ESI) m/z: calcd for C₂₆H₄₄O₅SiNa, [M + Na]⁺

487.2856; found, 487.2854.

To a solution of thiazolidinethione 13 (0.5 g, 1.89 mmol) in

anhydrous CH₂Cl₂(10 mL) at 0 °C under argon, freshly distilled

TiCl₄(216 μL, 1.98 mmol) was added dropwise. The orange slurry

was stirred for 10 min at the same temperature, and DIPEA (0.7 mL,

3.95 mmol) was added dropwise. The deep brown solution was

stirred for another 30 min at 0 °C before being cooled to −78 °C, and

the above aldehyde (1.58 mmol dissolved in 5 mL of CH₂Cl₂) was

cannulated. Stirring was continued at −78 °C for 2 h and then

quenched by water (5 mL). The resultant mixture was extracted with

CH₂Cl₂(2 × 25), washed with water, brine and saturated aqueous

NaHCO₃then dried (Na₂SO₄), ﬁltered, and concentrated in vacuo.

Puriﬁcation by column chromatography (SiO₂, 230−400 mesh, 15−

20% EtOAc in hexane) to obtain isomer 14 (0.55 g, 65%) exclusively

as a yellowish liquid; R_f= 0.6 (40% EtOAc in hexane); [α]_D²⁵= +66.6

(c 0.3, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.38−7.26 (m,

10H), 5.46−5.37 (m, 1H), 4.78−4.66 (m, 3H), 4.63−4.52 (m, 2H),

4.34−4.20 (m, 3H), 3.53 (dd, J = 10.2, 3.3 Hz, 1H), 3.44−3.33 (m,

2H), 3.25 (dd, J = 13.2, 3.9 Hz, 1H), 3.09−2.98 (m, 1H), 2.88 (dd, J

= 11.6, 1.0 Hz, 1H), 2.28 (dd, J = 13.2, 4.9 Hz, 1H), 2.10 (dd, J =

13.5, 5.7 Hz, 1H), 1.87−1.78 (m, 1H), 1.72−1.66 (m, 2H), 1.65−

1.59 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 201.4, 177.0, 138.2, 136.6, 129.5, 129.0, 128.5, 127.8,

127.7, 127.3, 84.0, 83.8, 79.2, 77.3, 73.5, 72.5, 71.0, 69.1, 43.6, 41.6,

39.5, 37.4, 37.1, 31.9, 11.4 ppm; IR (neat) ν_max: 3482, 2925, 2857,

1725, 1700, 1495, 1454, 1078, 743 cm⁻¹; HRMS (ESI) m/z: calcd for

C₂₉H₃₅NNaO₅S₂, [M + Na]⁺564.1854; found, 564.1855.

(((2S,3S)-1-((2S,3aR,5S,6aR)-5-((Benzyloxy)methyl)-

hexahydrofuro[3,2-b]furan-2-yl)-3-methylpent-4-en-2-yl)oxy)(tert-

butyl)dimethylsilane (15). To an ice-cold solution of compound 14

(510 mg, 0.94 mmol) in anhydrous CH₂Cl₂(8 mL) under argon, 2,6-

lutidine (0.22 mL, 1.88 mmol) and TBSOTf (0.32 mL, 1.41 mmol)

were added sequentially. The reaction mixture was stirred at 0 °C for

30 min and was then quenched by saturated aqueous NaHCO₃

solution (2 mL). The solvent was evaporated under reduced pressure

and the resulting mixture was extracted with EtOAc (3 × 10 mL).

The organic extracts were washed with aqueous CuSO₄, water, and

brine, dried (Na₂SO₄), ﬁltered, and concentrated in vacuo.

Puriﬁcation by column chromatography (SiO₂, 60−120 mesh, 5−

10% EtOAc in hexane) furnished the corresponding TBS protected

compound (530 mg, 86%) as a yellowish liquid; R_f= 0.85 (30%

EtOAc/hexane); [α]_D²⁵= +79.9 (c 0.1 CHCl₃); ¹H NMR (300 MHz,

CDCl₃): δ 7.39−7.32 (m, 5H), 7.32−7.26 (m, 5H), 5.38 (ddd, J =

10.4, 7.0, 3.3 Hz, 1H), 4.84 (p, J = 7.0 Hz, 1H), 4.63 (dt, J = 13.6, 4.4

Hz, 2H), 4.57 (d, J = 2.0 Hz, 2H), 4.28−4.18 (m, 3H), 3.53 (dd, J =

10.4, 3.1 Hz, 1H), 3.39 (dd, J = 10.4, 5.7 Hz, 1H), 3.36−3.28 (m,

1H), 3.22 (dd, J = 13.2, 3.3 Hz, 1H), 2.98 (dd, J = 13.2, 10.9 Hz, 1H),

2.81 (dd, J = 11.5, 0.9 Hz, 1H), 2.15 (td, J = 13.0, 5.3 Hz, 2H), 1.95

(ddd, J = 14.6, 8.0, 4.0 Hz, 1H), 1.81−1.69 (m, 2H), 1.54−1.45 (m,

1H), 1.24 (d, J = 7.0 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H); ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 200.2, 176.6, 138.4, 137.0, 129.5, 129.0,

128.4, 127.8, 127.6, 127.3, 100.1, 84.0, 83.5, 79.3, 75.2, 73.5, 72.6,

71.5, 69.0, 43.5, 42.1, 41.0, 37.3, 36.8, 31.1, 26.1, 18.2, 15.3, −4.0,

−4.4 ppm; IR (neat) ν_max: 2951, 2856, 1711, 1693, 1455, 1255, 1091,

835 cm⁻¹; HRMS (ESI) m/z: calcd for C₃₅H₄₉NNaO₅S₂Si, [M +

Na]⁺678.2719; found, 678.2718.

Following the same DMP oxidation conditions as described in the

preparation of compound 14, the above alcohol (140 mg, 0.3 mmol)

was transformed into the corresponding aldehyde (puriﬁed by ﬂash

column chromatography using a short pad of 60−120 silica with 10%

EtOAc in hexane as the eluent) as a yellowish liquid, which was taken

for the next step without further characterization.

Following the same experimental procedure as described in the

preparation of compound 15, the above aldehyde (0.3 mmol) was

converted to the corresponding alkene 16 (92 mg, 67%, puriﬁcation

by ﬂash column chromatography, SiO₂, 60−120 mesh, 10% EtOAc in

hexane as the eluent) as a colorless oil. R_f= 0.8 (20% EtOAc/hexane);

To a cold solution (−78 °C) of the above TBS protected

compound (0.5 g, 0.76 mmol) in anhydrous CH₂Cl₂(10 mL) under

argon, DIBAL-H (1.52 mL, 1.52 mmol, 1.0 M in hexane) was added

slowly. The reaction was quenched immediately with MeOH (0.5

mL) at the same temperature when the color of the reaction mixture

was changed from yellow to colorless. A saturated solution of sodium

potassium tartrate (5 mL) was added into it. After 1 h of vigorous

stirring at room temperature, the resultant mixture was extracted with

25

1

[α]_D= +13.3 (c 1.0, CHCl₃); H NMR (300 MHz, CDCl₃): δ

7.37−7.27 (m, 5H), 5.85−5.70 (m, 1H), 5.07−4.94 (m, 2H), 4.72 (p,

J = 4.4 Hz, 2H), 4.63−4.50 (m, 2H), 4.31−4.23 (m, 1H), 4.15−4.05

(m, 1H), 3.68 (td, J = 6.4, 3.1 Hz, 1H), 3.53 (dd, J = 10.2, 3.3 Hz,

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1H), 3.42 (dd, J = 10.2, 5.8 Hz, 1H), 2.33−2.25 (m, 1H), 2.25−2.18

(m, 1H), 2.11−2.03 (m, 1H), 1.89−1.78 (m, 2H), 1.77−1.64 (m,

2H), 1.57−1.47 (m, 2H), 0.89 (s, 9H), 0.81 (d, J = 6.7 Hz, 3H), 0.05

(d, J = 3.4 Hz, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.3,

138.1, 128.4, 127.7, 127.7, 115.6, 84.3, 83.2, 79.1, 73.4, 73.1, 72.6,

41.6, 39.5, 37.7, 37.5, 37.0, 29.8, 26.0, 18.2, 13.8, −4.1, −4.3 ppm; IR

(neat) ν_max: 2957, 2928, 2856, 1472, 1459, 1436, 1102, 1090, 835,

695 cm⁻¹; HRMS (ESI) m/z: calcd for C₂₇H₄₄O₄SiNa, [M + Na]⁺

483.2907; found, 483.2904.

5.86−5.67 (m, 1H), 5.39 (dd, J = 8.3, 1.4 Hz, 1H), 5.07−4.92 (m,

2H), 4.81−4.74 (m, 1H), 4.73 (dd, J = 4.6, 3.3 Hz, 2H), 4.17 (tt, J =

8.6, 4.4 Hz, 1H), 4.06−3.97 (m, 2H), 3.83 (dt, J = 8.8, 3.3 Hz, 1H),

2.43−2.29 (m, 1H), 2.24−2.13 (m, 2H), 1.72 (s, 3H), 1.70−1.62 (m,

4H), 1.49 (td, J = 8.7, 3.7 Hz, 2H), 0.90 (s, 9H), 0.83 (d, J = 6.6 Hz,

3H), 0.12−0.03 (m, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 139.3,

138.1, 126.0, 124.9, 115.6, 83.7, 83.6, 77.8, 75.9, 73.4, 68.0, 42.0, 41.6,

39.2, 38.4, 36.3, 29.8, 26.0, 18.2, 14.4, 14.1, −4.2, −4.2 ppm; IR

(neat)ν_max: 3388, 2925, 2854, 1457, 1440, 1184, 1074, 776 cm⁻¹;

HRMS (ESI) m/z: calcd for C₂₃H₄₃O₄Si, [M + H]⁺411.2931; found,

411.2923.

3-((2S,3aR,5S,6aR)-5-((2S,3S)-2-((Tert-butyldimethylsilyl)oxy)-3-

methylhex-5-en-1-yl)hexa Hydrofuro[3,2-b]furan-2-yl)-2-methyl-

prop-2-en-1-ol (2). To a solution of naphthalene (100 mg, 0.8

mmol) in anhydrous THF (5 mL) under argon, Li was added (7 mg,

1 mmol) as small pieces. After 1 h stirring at room temperature, the

reaction mixture was cooled to −40 °C and subsequently a solution of

compound 16 (90 mg, 0.19 mmol, dissolved in 3 mL of anhydrous

THF) was cannulated into it. The reaction was continued further for

1 h at the same temperature and then quenched with saturated

aqueous solution of NH₄Cl (2 mL). The resultant mixture was

extracted with EtOAc (2 × 15 mL), washed with water and brine,

dried over anhydrous Na₂SO₄, and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash column chromatography

(SiO₂, 60−120 mesh,20% EtOAc in hexane as the eluent) to get the

corresponding alcohol (60 mg, 86%) as a colorless oil; R_f= 0.2 (35%

(S)-5-((Tert-butyldiphenylsilyl)oxy)-3-((triethylsilyl)oxy)pentan-1-

ol (ent-7). Following the same experimental procedure as described in

the preparation of compound 7, alcohol ent-6 (8 g, 22.6 mmol) was

converted to the corresponding TES ether. Puriﬁcation by column

chromatography (SiO₂, 60−120 mesh, 5% EtOAc in hexane as the

eluent) provides a pure compound (9.9 g, 94%) as a colorless oil. R_f=

25

1

0.9 (10% EtOAc/hexane); [α]_D= +15.0 (c 0.8, CHCl₃); H NMR,

¹³C NMR, IR, and HRMS data were exactly the same as those of TES

ether obtained from compound 6.

Following the same experimental procedure as described in the

preparation of compound 7, the above compound (9.8 g, 20.9 mmol)

was converted to the corresponding diol (10.5 g, quantitative) as a

yellowish oil using OsO₄and NMO, which was taken for the next step

without further puriﬁcation.

25

EtOAc/hexane); [α]_D= +39.95 (c 0.1, CHCl₃);¹H NMR (300

MHz, CDCl₃): δ 5.76 (dddd, J = 16.7, 10.1, 7.7, 6.2 Hz, 1H), 5.08−

4.93 (m, 2H), 4.53 (ddd, J = 6.5, 4.1, 2.2 Hz, 1H), 4.37 (ddd, J = 5.8,

4.1, 1.4 Hz, 1H), 4.22 (dtd, J = 8.6, 5.4, 3.1 Hz, 1H), 3.99 (dq, J = 8.2,

6.8 Hz, 1H), 3.72−3.59 (m, 3H), 2.33−2.24 (m, 2H), 2.19 (dd, J =

8.5, 5.8 Hz, 1H), 1.99 (ddd, J = 14.0, 5.3, 1.5 Hz, 1H), 1.91−1.81 (m,

2H), 1.76−1.63 (m, 3H), 0.88 (s, 9H), 0.82 (d, J = 6.8 Hz, 3H), 0.04

(s, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.1, 115.6, 85.2, 84.3,

81.6, 78.9, 73.1, 65.3, 39.8, 37.9, 36.8, 34.1, 29.8, 26.0, 18.2, 14.0,

−4.3 ppm; IR (neat) ν_max: 3418, 2948, 2929, 2857, 1463, 1440, 1081,

836,774 cm⁻¹; HRMS (ESI) m/z: calcd for C₂₀H₃₉O₄Si, [M + H]⁺

371.2618; found, 371.2613.

Following the same DMP oxidation procedure as compound 14,

the above alcohol (55 mg, 0.15 mmol) was converted to the

corresponding aldehyde (puriﬁcation by ﬂash column chromatog-

raphy, SiO₂, 60−120 mesh, 5% EtOAc in hexane as the eluent) as a

colorless oil. It was taken for the next step without further

characterization.

Following the same experimental procedure as that used for

compound 7, the above diol (20.9 mmol) was treated with NaHCO₃

(3.5 g, 41.8 mmol) and NaIO₄(8.9 g, 41.8 mmol) to get the

corresponding aldehyde (puriﬁcation by ﬂash column chromatog-

raphy, SiO₂, 60−120 mesh, 25% EtOAc in hexane as the eluent) as a

light yellowish oil, which was taken for the next step without further

puriﬁcation.

The above aldehyde (20.9 mmol) was reduced to alcohol ent-7

using NaBH₄(1.6 g, 41.8 mmol) in anhydrous MeOH following the

same experimental procedure as compound 7. Puriﬁcation by ﬂash

column chromatography (SiO₂, 60−120 mesh, 8% EtOAc in hexane

as the eluent) provided a pure compound (7.6 g, 77% over three

25

steps) as a colorless liquid. R_f= 0.35 (10% EtOAc/hexane); [α]_D

=

+7.26 (c 1.1, CHCl₃); ¹H NMR, ¹³C NMR, IR, and HRMS data were

exactly the same as those of compound 7.

(R)-5-((5-((Tert-butyldiphenylsilyl)oxy)-3-((triethylsilyl)oxy)-

pentyl)sulfonyl)-1-phenyl-1H-tetrazole (ent-8). Following the same

experimental procedure as described in the preparation of compound

8, compound ent-7 (7.3 g, 15.5 mmol) was converted to

corresponding sulﬁde (8.4 g, 86%, puriﬁcation by column

chromatography, SiO₂, 230−400 mesh, 5% EtOAc in hexane as the

To a solution of the above aldehyde (0.15 mmol) in anhydrous

toluene, ethyl 2-(triphenylphosphoranylidene) propionate (163 mg,

0.45 mmol) was added at 80 °C under argon. The reaction was

continued for 6 h. Then, toluene was evaporated in vacuum and the

resultant residue was puriﬁed by column chromatography (SiO₂,

230−400 mesh, 2% EtOAc in hexane as the eluent) to get the

corresponding α, β-unsaturated ester (46 mg, 68% over two steps, E/

Z = 3:1) as a colorless liquid, which remained inseparable. R_f= 0.6

25

eluent) as a light yellowish oil. R_f= 0.45 (10% EtOAc/hexane); [α]_D

= +15.98 (c 0.5, CHCl₃); the H NMR, ¹³C NMR, IR, and HRMS

1

data were exactly the same as those of sulﬁde compound obtained

from 7.

1

(15% EtOAc/hexane); H NMR (300 MHz, CDCl₃): δ 6.87 (d, J =

The above sulﬁde (8.3 g, 13.1 mmol) was oxidized to sulfone ent-8

(7.37 g, 84%) following the same experimental procedure as

compound. Puriﬁcation by ﬂash column chromatography (SiO₂,

60−120 mesh, 5% EtOAc in hexane as the eluent) provided a pure

compound as a colorless liquid. R_f= 0.42 (10% EtOAc/hexane);

7.9 Hz, 1H), 5.76 (ddt, J = 17.2, 10.5, 7.0 Hz, 1H), 5.05−4.90 (m,

2H), 4.74 (q, J = 7.4 Hz, 1H), 4.56−4.43 (m, 2H), 4.18 (dd, J = 8.0,

6.3 Hz, 2H), 4.03 (q, J = 7.0 Hz, 1H), 3.66 (td, J = 8.4, 7.9, 4.3 Hz,

1H), 2.34 (ddt, J = 30.8, 13.4, 6.8 Hz, 3H), 1.91 (d, J = 6.5 Hz, 1H),

1.85 (s, 3H), 1.75 (dd, J = 12.7, 6.9 Hz, 2H), 1.68 (d, J = 4.6 Hz, 2H),

1.31−1.27 (m, 3H), 0.88 (s, 9H), 0.83 (d, J = 6.8 Hz, 3H), 0.04 (s,

6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 167.8, 141.6, 138.1, 132.3,

128.7, 115.5, 85.3, 84.4, 79.1, 73.3, 60.8, 39.7, 39.5, 39.3, 38.1, 36.7,

26.0, 18.2, 14.4, 14.2, 12.9, −4.2, −4.3 ppm; IR (neat) ν_max: 2948,

2811, 1561, 1421, 1246, 986 cm⁻¹; HRMS (ESI) m/z: calcd for

C₂₅H₄₄NaO₅Si, [M + Na]⁺475.2856; found, 475.2854.

25

1

[α]_D= +8.07 (c 1.98, CHCl₃); the H NMR, ¹³C NMR, IR, and

HRMS data were exactly the same as those of compound 8.

(S)-4-(Benzyloxy)-3-((triethylsilyl)oxy)butanal (ent-10). Following

the same experimental procedure as described in the preparation of

compound 7, compound ent-9 (4.0 g, 20.8 mmol) was converted to

the corresponding TES ether. Puriﬁcation by ﬂash column

chromatography (SiO₂, 60−120 mesh, 5% EtOAc in hexane as the

eluent) provided a pure compound (5.9 g, 93%) as a colorless liquid.

R_f= 0.8 (10% EtOAc/hexane); [α]_D²⁵= + 6.0 (c 0.6, CHCl₃); the ¹H

NMR, ¹³C NMR, IR, and HRMS data are exactly the same as those of

the TES ether compound obtained from 9.

Following the same experimental procedure as described in the

preparation of compound 15, the above α, β-unsaturated ester (40

mg, 0.09 mmol) was converted to the alcohol 2 along with its Z-

counterpart using DIBAL-H (0.14 mL, 0.23 mmol, 1.6 M in toluene).

Puriﬁcation by ﬂash column chromatography (SiO₂, 60−120 mesh,

20% EtOAc in hexane as the eluent) provided compound 2 along with

its inseparable minor counterpart (32 mg, 87%) as a colorless liquid.

Following the same experimental procedure as described in the

preparation of compound 7, the above compound (5.8 g, 18.9 mmol)

was converted to the corresponding diol as a light yellowish oil using

OsO₄(5% solution in t-BuOH, 0.5 mL), and NMO (4.4 g, 37.8

1

R_f= 0.3 (30% EtOAc in hexane); H NMR (300 MHz, CDCl₃): δ

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mmol), which was taken for the next step without further

characterization.

extracted with EtOAc (4 × 5 mL), washed with water and brine, dried

over Na₂SO₄, and ﬁnally concentrated in vacuo. The crude material

was puriﬁed by column chromatography (SiO₂, 230−400 mesh, 10%

EtOAc in hexane as the eluent) to separate the two diastereomers

with 60% total yield (dr = 1.6:1). Isolated major compound ent-4 (6

mg, 37%) and minor compound ent-12 (4 mg, 23%) were obtained as

a colorless oil.

Following the same experimental procedure as described in the

preparation of compound 7, the above diol (18.9 mmol) was

converted to the aldehyde ent-10 using NaHCO₃(3.2 g, 37.8 mmol)

and NaIO₄(8 g, 37.8 mmol). Puriﬁcation by ﬂash column

chromatography (SiO₂, 60−120 mesh, 20% EtOAc in hexane as the

eluent) provided pure aldehyde (3.8 g, 75%) as a colorless liquid,

which was taken for the next step without further characterization.

(5S,10S,E)-5-((Benzyloxy)methyl)-3,3-diethyl-15,15-dimethyl-

14,14-diphenyl-10-((triethyl Silyl)oxy)-4,13-dioxa-3,14-disilahexa-

dec-7-ene (ent-11). Following the same experimental procedure as

described in the preparation of compound 11, aldehyde ent-10 (3 g,

9.7 mmol) and sulfone ent-8 (7.1 g, 10.7 mmol) were converted to

the corresponding coupled product. Puriﬁcation by ﬂash column

chromatography (SiO₂, 60−120 mesh, 2% EtOAc in hexane as the

eluent) provided a pure compound (5.2 g, 72%) as a colorless liquid.

R_f= 0.45 (5% EtOAc/hexane); [α]_D²⁵= +6.7 (c 1.2, CHCl₃); the ¹H

NMR, ¹³C NMR, IR, and HRMS data were exactly the same as those

of compound 11.

(2S,7S,E)-1-(Benzyloxy)-9-((tert-butyldiphenylsilyl)oxy)non-4-

ene-2,7-diol (ent-5). Following the same experimental procedure as

described in the preparation of compound 5, the TES ether ent-11

(5.0 g, 6.7 mmol)was converted to the corresponding diol by using

CSA (3.1 g, 2.784 mmol). Puriﬁcation by ﬂash column chromatog-

raphy (SiO₂, 60−120 mesh, 15−20% EtOAc in hexane as the eluent)

provided a pure compound (3.12 g, 90%) as a colorless liquid. R_f= 0.4

(30% EtOAc/hexane); [α]_D²⁵= + 14.0 (c 0.6, CHCl₃); the ¹H NMR,

¹³C NMR, IR, and HRMS data were exactly the same as those of

Tert-butyl(2-((2S,3aS,5R,6aS)-5-(hept-1-en-1-yl)hexahydrofuro-

[3,2-b]furan-2-yl)ethoxy) Diphenylsilane (18). Following the same

experimental procedure as described in the preparation of compound

2, compound ent-4 (400 mg, 0.8 mmol) was treated with Li-

naphthalide to get the corresponding benzyl-deprotected alcohol (280

mg, 82%, puriﬁcation by column chromatography, SiO₂, 100−200

mesh, 40% EtOAc in hexane as the eluent) as a colorless oil. R_f= 0.15

(40% EtOAc/hexane); [α]_D²⁵= −12.2 (c 1.0, CHCl₃); ¹H NMR (300

MHz, CDCl₃): δ 7.71−7.64 (m, 4H), 7.44−7.35 (m, 6H), 4.76−4.58

(m, 2H), 4.19 (dddd, J = 14.9, 8.3, 6.0, 3.9 Hz, 2H), 3.80−3.72 (m,

3H), 3.53−3.42 (m, 1H), 2.20 (dd, J = 13.4, 5.0 Hz, 1H), 2.03 (dd, J

= 13.6, 5.5 Hz, 1H), 1.96−1.85 (m, 2H), 1.84−1.72 (m, 2H), 1.05 (s,

9H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 135.6, 133.9, 129.7, 127.7,

84.4, 83.5, 80.4, 64.3, 61.2, 41.4, 38.5, 36.3, 26.9, 19.3 ppm; IR (neat)

ν_max: 3416, 2933, 2857, 1428, 1111, 1041, 702 cm⁻¹; HRMS (ESI) m/

z: calcd for C₂₅H₃₄NaO₄Si, [M + Na]⁺449.2124; found, 449.2126.

Following the same experimental procedure as described in the

preparation of compound 14, the above alcohol (250 mg, 0.6 mmol)

was oxidized using DMP (500 mg, 1.1 mmol) and NaHCO₃(0.1 g,

1.1 mmol) to get the corresponding aldehyde (puriﬁcation by ﬂash

column chromatography, SiO₂, 60−120 mesh, 40% EtOAc in hexane

as the eluent) as a colorless oil, which was taken for the next step

without further characterization.

compound 5.

Following the same experimental procedure as described in the

preparation of compound 11, the above aldehyde (0.6 mmol) and

sulfone 17 (520 mg, 1.8 mmol) were converted to coupled product

18 along with its inseparable minor Z-isomer. Puriﬁcation by ﬂash

column chromatography (SiO₂, 60−120 mesh, 2% EtOAc in hexane

as the eluent) provided an inseparable mixture of E/Z (2.5:1) isomers

(190 mg, 65%) as a colorless liquid. R_f= 0.7 (20% EtOAc/hexane);

¹H NMR (300 MHz, CDCl₃): δ 7.67 (ddd, J = 6.2, 3.3, 1.7 Hz, 4H),

7.39 (dtd, J = 7.4, 5.9, 5.2, 3.6 Hz, 6H), 5.75−5.50 (m, 1H), 5.44−

5.23 (m, 1H), 4.83−4.57 (m, 2H), 4.50−4.35 (m, 1H), 4.35−4.09

(m, 1H), 3.83−3.69 (m, 2H), 2.33−2.15 (m, 2H), 2.07−1.99 (m,

2H), 1.77 (dt, J = 13.4, 6.6 Hz, 2H), 1.67−1.63 (m, 1H), 1.41−1.28

(m, 7H), 1.05 (s, 9H), 0.87 (m, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 135.7, 134.2, 134.0, 134.0, 129.8, 129.7, 127.7, 83.9, 83.6,

81.0, 61.3, 42.0, 41.6, 38.6, 32.3, 31.5, 29.8, 28.8, 27.0, 22.6, 19.3, 14.1

ppm; IR (neat) ν_max: 2926, 2853, 1497, 1409, 1290, 1072, 762 cm⁻¹;

HRMS (ESI) m/z: calcd for C₃₁H₄₄NaO₃Si, [M + Na]⁺515.2957;

found, 515.2954.

(2-((2S,3aS,5R,6aS)-5-((Benzyloxy)methyl)hexahydrofuro[3,2-b]-

furan-2-yl)ethoxy)(tert-butyl)diphenylsilane (ent-4). Following the

same experimental procedure as described in the preparation of

compound 4, the above diol (3.0 g, 5.8 mmol) was converted to the

corresponding dimesylated compound. Puriﬁcation by ﬂash column

chromatography (SiO₂, 60−120 mesh, 30−40% EtOAc in hexane as

the eluent) provided a pure compound (3.3 g, 84%) as a colorless

25

liquid. R_f= 0.45 (30% EtOAc/hexane); [α]_D= +14.7 (c 0.3,

1

CHCl₃); the H NMR, ¹³C NMR, IR, and HRMS data were exactly

the same as those of the mesylated compound obtained from

compound 5.

To a stirred solution of the above compound (3.2 g, 4.7 mmol) in

THF (20 mL), ^tBuOH (20 mL) and H₂O (4 mL) at 0 °C, OsO₄(0.2

t

M solution in BuOH, 0.3 mL), and NMO (1.01 g, 9.4 mmol) were

added, and the reaction mixture was stirred for 12 h at room

temperature. K₂CO₃(1.95 g, 14.1 mmol) was then added and the

reaction mixture was stirred for another 6 h. The reaction mixture was

then cooled to 0 °C and quenched with saturated solution of

NaHSO₃(5 mL). The resultant mixture was extracted with EtOAc (3

× 50 mL), washed with water and brine, and concentrated in vacuo,

and puriﬁcation by ﬂash column chromatography (SiO₂, 230−400

mesh, 5−20% EtOAc in hexane as the eluent) was carried out to

separate the two diastereomers with 57% overall yield (dr = 1.2:1).

Isolated major isomer ent-4 (0.754 g, 31%) was obtained as a

colorless liquid. R_f= 0.8 (30% EtOAc/hexane); [α]_D²⁵= −7.1 (c 0.4,

5-((2-((2R,3aS,5R,6aS)-5-((E)-Hept-1-en-1-yl)hexahydrofuro[3,2-

b]furan-2-yl)ethyl)sulfonyl)-1-Phenyl-1H-tetrazole (3). Following

the same experimental procedure as described in the preparation of

compound 14, compound 18 mixed with its corresponding Z-isomer

(180 mg, 0.37 mmol) was treated with TBAF (0.7 mL, 1 M in THF)

to get the corresponding silyl deprotected alcohols (70 mg, 75%).

Puriﬁcation by column chromatography (SiO₂, 100−200 mesh, 30%

EtOAc in hexane as the eluent) aﬀorded an inseparable E/Z-mixture

1

CHCl₃); the H NMR, ¹³C NMR, IR, and HRMS data were exactly

1

as a colorless oil. R_f= 0.25 (30% EtOAc/hexane); H NMR (300

same as those of compound 4.

MHz, CDCl₃): δ 5.80−5.52 (m, 1H), 5.45−5.22 (m, 1H), 4.73 (tt, J

= 8.4, 4.5 Hz, 2H), 4.56−4.38 (m, 1H), 4.36−4.11 (m, 1H), 3.87−

3.69 (m, 2H), 2.30−2.16 (m, 2H), 2.02 (tdd, J = 8.1, 5.5, 1.5 Hz,

2H), 1.92−1.78 (m, 2H), 1.76−1.65 (m, 2H), 1.44−1.27 (m, 6H),

0.91−0.85 (m, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 134.4,

133.7, 129.5, 119.6, 84.2, 83.3, 81.1, 80.0, 75.6, 61.4, 42.0, 41.8, 41.5,

Minor isomer ent-12 (343 mg, 26%) was obtained as a colorless

25

liquid with R_f= 0.75 (30% EtOAc/hexane). [α]_D= +5.5 (c 0.7,

1

CHCl₃); the H NMR, ¹³C NMR, IR, and HRMS data were exactly

the same as those of compound 12.

Improved Procedure for Dihydroxylation Followed by

t

Cycloetheriﬁcation. To a stirred solution of BuOH/H₂O (1:1, 3

mL) at room temperature, AD-mix-α (42 mg, 1.4 g/mmol), OsO₄

37.4, 37.4, 32.2, 31.4, 29.4, 28.7, 27.8, 22.6, 14.1 ppm; IR (neat) ν_max

:

t

3421, 2927, 2825, 1457, 1079 cm⁻¹; HRMS (ESI) m/z: calcd for

(0.2 M solution in BuOH, 0.07 mL), and methanesulfonamide (6

C₁₅H₂₆NaO₃, [M + Na]⁺277.1780; found, 277.1782.

mg, 0.06 mmol) were added. The solution was further stirred well for

15 min and then the above dimesylated compound (20 mg, 0.03

Following the same experimental procedure as described in the

preparation of compound 8, the above mixture of alcohols (65 mg,

0.26 mmol) was converted to the corresponding sulﬁdes (87 mg,

83%). Puriﬁcation by column chromatography (SiO₂, 60−120 mesh,

t

mmol) in BuOH (1 mL) was cannulated and stirred for 12 h. The

mixture was quenched with a saturated solution of Na₂SO₃and the

resultant mixture was stirred further for 1 h. The aqueous layer was

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The Journal of Organic Chemistry

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Article

20% EtOAc in hexane as the eluent) resulted a mixture of compounds

(E/Z) as a light yellowish oil. R_f= 0.6 (30% EtOAc/hexane); H

4.08 (m, 2H), 3.89−3.79 (m, 1H), 2.36 (tt, J = 14.8, 7.3 Hz, 3H),

2.26−2.08 (m, 5H), 2.01 (q, J = 7.2, 6.8 Hz, 2H), 1.79 (s, 3H), 1.66

(td, J = 10.0, 3.8 Hz, 5H), 1.49 (d, J = 3.8 Hz, 2H), 1.40−1.29 (m,

4H), 1.26 (d, J = 4.0 Hz, 2H), 0.90 (d, J = 2.8 Hz, 12H), 0.82 (s, 3H),

0.09 (d, J = 11.3 Hz, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.4,

136.6, 134.3, 133.5, 130.4, 129.7, 125.3, 115.4, 84.1, 83.9, 83.7, 81.0,

79.8, 77.3, 76.5, 75.5, 73.0, 42.2, 41.9, 40.7, 39.3, 39.0, 35.6, 32.3,

31.5, 29.4, 28.8, 27.8, 26.1, 22.6, 18.3, 14.9, 14.1, 13.1, −4.1, −4.3

ppm; IR (neat) ν_max: 2961, 2928, 2857, 1459, 1252, 1161, 1093 cm⁻¹;

HRMS (ESI) m/z: calcd for C₃₈H₆₄O₅SiNa, [M + Na]⁺651.4421;

found, 651.4422.

1

NMR (300 MHz, CDCl₃): δ 7.56 (tt, J = 4.7, 2.1 Hz, 5H), 5.80−5.49

(m, 1H), 5.42−5.27 (m, 1H), 4.72 (tt, J = 8.8, 4.4 Hz, 2H), 4.53−

4.35 (m, 1H), 4.29−4.10 (m, 1H), 3.54−3.40 (m, 2H), 2.25−1.99

(m, 6H), 1.75−1.67 (m, 1H), 1.41−1.28 (m, 7H), 0.91−0.84 (m,

3H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 154.3, 134.3, 130.2, 129.9,

129.5, 123.9, 83.6, 80.9, 78.5, 78.4, 41.8, 41.0, 35.1, 32.2, 31.5, 30.1,

29.4, 28.8, 22.6, 14.1 ppm; IR (neat) ν_max: 2957, 2857, 1732, 1498,

1343, 1153, 1074, 764 cm⁻¹; HRMS (ESI) m/z: calcd for

C₂₂H₃₁N₄O₂S, [M + H]⁺415.2168; found, 415.2165.

Following the same experimental procedure as described in the

preparation of compound 14, the above coupled compound (12 mg,

0.02 mmol) was treated with TBAF (1 M) (0.2 mL) to get

corresponding silyl deprotected alcohol. Puriﬁcation by column

chromatography, SiO₂, 100−200 mesh, 5% EtOAc in hexane as the

eluent, aﬀorded a pure major compound 1a (8 mg, 80%) as a colorless

oil, which was separated from its minor isomer. R_f= 0.35 (30%

To EtOH (5 mL) solution of the above sulﬁdes (70 mg, 0.17

mmol), H₂O₂(0.1 mL) and ammonium molybdate hexahydrate (42

mg, 0.034 mmol) were added at 0 °C. After 12 h, EtOH was

evaporated and the mixture was extracted with EtOAc (3 × 15 mL),

washed with saturated solution of Na₂S₂O₃, brine, dried over Na₂SO₄,

and concentrated. The crude material was puriﬁed by column

chromatography (SiO₂, 230−400 mesh, 5% EtOAc in hexane as the

eluent) to provide two geometric isomers (55 mg, 72%). Major

isomer 3 (39 mg, 51%) was isolated as a colorless oil. R_f= 0.45 (20%

20

EtOAc/hexane); [α]_D= −26.6 (c 0.3, CHCl₃); ¹H NMR (600

MHz, benzene-d₆): δ 6.21 (d, J = 15.6 Hz, 1H), 5.92 (ddt, J = 17.1,

10.0, 7.3 Hz, 1H), 5.78 (dt, J = 15.1, 7.2 Hz, 1H), 5.70 (dt, J = 14.3,

6.8 Hz, 1H), 5.54−5.49 (m, 2H), 5.21−5.15 (m, 1H), 5.14−5.09 (m,

1H), 4.95−4.86 (m, 1H), 4.59 (dd, J = 10.7, 5.6 Hz, 1H), 4.56 (t, J =

4.3 Hz, 1H), 4.53 (t, J = 4.5 Hz, 1H), 4.43 (t, J = 4.5 Hz, 1H), 4.34−

4.30 (m, 1H), 4.18 (dq, J = 11.1, 5.7 Hz, 1H), 4.15−4.07 (m, 1H),

3.83 (d, J = 10.4 Hz, 1H), 2.54 (dd, J = 13.4, 6.5 Hz, 1H), 2.41−2.35

(m, 1H), 2.27−2.22 (m, 1H), 2.21 (dd, J = 13.0, 5.1 Hz, 1H), 2.12

(dd, J = 13.4, 5.3 Hz, 1H), 2.09−2.06 (m, 1H), 2.05−2.02 (m, 1H),

1.99 (p, J = 7.1 Hz, 3H), 1.74 (d, J = 1.2 Hz, 3H), 1.61 (s, 1H), 1.57−

1.52 (m, 1H), 1.44 (d, J = 4.2 Hz, 1H), 1.41−1.39 (m, 2H), 1.33 (d, J

= 7.6 Hz, 3H), 1.27 (d, J = 7.4 Hz, 2H), 1.23 (dd, J = 9.7, 3.8 Hz,

3H), 1.06 (d, J = 6.9 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H); ¹³C{¹H}

NMR (75 MHz, C₆D6): δ 138.3, 136.7, 135.9, 132.5, 131.4, 131.1,

126.0, 115.9, 84.6, 84.1, 83.9, 83.0, 81.5, 80.9, 80.0, 76.6, 74.4, 42.5,

42.4, 42.2, 41.2, 40.1, 39.4, 39.3, 38.1, 32.5, 31.6, 29.2, 28.0, 22.9,

14.2, 14.1, 13.1 ppm; IR (neat) ν_max: 3445, 2925, 2854, 1456, 1372,

970 cm⁻¹; HRMS (ESI) m/z: calcd for C₃₂H₅₀O₅Na, [M + Na]⁺

537.3556; found, 537.3555.

Tert-butyl(2-((2R,3aR,5S,6aR)-5-(hept-1-en-1-yl)hexahydrofuro-

[3,2-b]furan-2-yl)ethoxy) Diphenylsilane (ent-18). Following the

same experimental procedure as described in the preparation of

compound 2, compound 4 (280 g, 0.54 mmol) was reacted with

lithium naphthalide. Puriﬁcation by ﬂash column chromatography

(SiO₂, 100−200 mesh, 40% EtOAc in hexane as the eluent) provided

the corresponding benzyl-deprotected compound (184 mg, 80%). R_f

= 0.15 (40% EtOAc/hexane); [α]_D²⁵= +13.3 (c 0.9, CHCl₃); the ¹H

NMR, ¹³C NMR, IR, and HRMS data were exactly the same as those

of alcohol obtain from compound ent-4.

25

EtOAc/hexane); [α]_D= −27.0 (c 0.3, CHCl₃); ¹H NMR (300

MHz, CDCl₃): δ 7.69 (dd, J = 7.8, 2.1 Hz, 2H), 7.65−7.56 (m, 3H),

5.80−5.67 (m, 1H), 5.36 (ddt, J = 15.3, 7.4, 1.5 Hz, 1H), 4.71 (dt, J =

12.4, 4.3 Hz, 2H), 4.40 (ddd, J = 10.2, 7.4, 5.2 Hz, 1H), 4.18 (td, J =

8.8, 3.9 Hz, 1H), 3.94 (ddd, J = 14.7, 10.5, 5.2 Hz, 1H), 3.80 (ddd, J =

14.8, 10.4, 5.3 Hz, 1H), 2.29−2.10 (m, 3H), 2.10−1.95 (m, 3H), 1.69

(dddd, J = 13.4, 9.7, 8.9, 4.8 Hz, 2H), 1.43−1.31 (m, 3H), 1.27 (dd, J

= 5.0, 1.7 Hz, 3H), 0.90−0.82 (m, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 153.6, 134.5, 133.1, 131.6, 129.8, 129.4, 125.2, 84.3, 83.5,

81.0, 77.3, 53.6, 41.6, 41.0, 32.2, 31.5, 28.8, 28.2, 22.6, 14.1 ppm; IR

(neat) ν_max: 2932, 2860, 1740, 1500, 1327, 1162, 1088 cm⁻¹; HRMS

(ESI) m/z: calcd for C₂₀H₃₀N₄NaO₄S, [M + Na]⁺469.1885; found,

469.1887.

Minor Z isomer of compound 3 (16 mg, 21%) as a colorless oil. R_f

25

1

= 0.42 (20% EtOAc/hexane); [α]_D= −41.3 (c 0.1, CHCl₃); H

NMR (300 MHz, CDCl₃): δ 7.76−7.65 (m, 2H), 7.61 (td, J = 4.5, 2.3

Hz, 3H), 5.62−5.47 (m, 1H), 5.35−5.26 (m, 1H), 4.74 (ddt, J = 13.9,

8.7, 4.7 Hz, 3H), 4.29−4.13 (m, 1H), 3.95 (ddd, J = 14.7, 10.7, 5.2

Hz, 1H), 3.82 (ddd, J = 15.0, 10.5, 5.3 Hz, 1H), 2.30−2.21 (m, 2H),

2.14−2.05 (m, 3H), 1.75−1.63 (m, 2H), 1.34−1.27 (m, 7H), 0.90 (d,

J = 5.5 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 153.5, 133.8,

133.1, 131.6, 129.8, 129.3, 125.2, 84.3, 83.5, 75.5, 53.6, 41.8, 41.0,

31.5, 29.8, 29.4, 28.2, 27.8, 22.6, 14.1 ppm; IR (neat) ν_max: 2927,

2855, 1731, 1492, 1343, 1129, 1088 cm⁻¹; HRMS (ESI) m/z: calcd

for C₂₀H₃₀N₄NaO₄S, [M + Na]⁺469.1885; found, 469.1887.

3-((2S,3aR,5S,6aR)-5-((2S,3S)-2-((Tert-butyldimethylsilyl)oxy)-3-

methylhex-5-en-1-yl)hexa Hydrofuro[3,2-b]furan-2-yl)-2-methyla-

crylaldehyde (19). Following the same experimental procedure as

described in the preparation of compound 14, alcohol 2 mixed with

its inseparable minor Z-isomer (15 mg, 0.04 mmol) was oxidized

using DMP (33 mg, 0.08 mmol) and NaHCO₃(7 mg, 0.08 mmol) to

get aldehyde 19 mixed with its minor counterpart (puriﬁcation by

column ﬂash chromatography, SiO₂, 60−120 mesh, 20% EtOAc in

hexane as the eluent) as a colorless oil, which was taken for the next

step without further characterization.

Following the same experimental procedure as described in the

preparation of compound 14, the above alcohol (180 mg, 0.4 mmol)

was oxidized using DMP (340 mg, 0.8 mmol) and NaHCO₃(67 mg,

0.8 mmol) to get corresponding aldehyde, and puriﬁcation by column

ﬂash chromatography (SiO₂, 60−120 mesh, 40% EtOAc in hexane as

the eluent) aﬀorded a pure compound as a colorless oil, which was

taken for the next step without further characterization.

Following the same experimental procedure as described in the

preparation of compound 11, the above aldehyde (0.4 mmol) and

sulfone 17 (360 mg, 1.2 mmol) were converted to the corresponding

coupled products. Puriﬁcation by ﬂash column chromatography

(SiO₂, 60−120 mesh, 2% EtOAc in hexane as the eluent) provided an

inseparable mixture of E/Z (3:1) isomers (135 mg, 67%) as a

(2S,3S)-1-((2R,3aR,5S,6aR)-5-((1E,3E)-5-((2S,3aS,5R,6aS)-5-((E)-

Hept-1-en-1-yl)hexahydro furo[3,2-b]furan-2-yl)-2-methylpenta-

1,3-dien-1-yl)hexahydrofuro[3,2-b]furan-2-yl)-3-methylhex-5-en-2-

ol (1a). Following the same experimental procedure as described in

the preparation of compound 11, aldehyde 2 mixed with its minor Z-

isomer (0.04 mmol) and sulfone 3 (21 mg, 0.05 mmol) were

converted to the corresponding Julia−Kocienski oleﬁnation products.

Puriﬁcation by ﬂash column chromatography (SiO₂, 60−120 mesh,

10% EtOAc in hexane as the eluent) provided an inseparable mixture

of diastereomers (14 mg, 75%) as a colorless liquid, which was

generated from the regioisomeric mixture of reacting aldehydes. R_f=

0.6 (20% EtOAc/hexane); R_f= 0.6 (20% EtOAc/hexane); δ ¹H NMR

(300 MHz, CDCl₃): δ 6.11 (d, J = 15.7 Hz, 1H), 5.79−5.48 (m, 3H),

5.35 (dd, J = 22.9, 7.7 Hz, 2H), 5.07−4.93 (m, 2H), 4.81 (dd, J = 9.5,

5.2 Hz, 1H), 4.75−4.61 (m, 4H), 4.41 (d, J = 14.4 Hz, 1H), 4.23−

1

colorless liquid. R_f= 0.7 (15% EtOAc/hexane); the H NMR, ¹³C

NMR, IR, and HRMS data were exactly the same as those of

compound 18.

5-((2-((2S,3aR,5S,6aR)-5-((E)-But-1-en-1-yl)hexahydrofuro[3,2-

b]furan-2-yl)ethyl)sulfonyl)-1-Phenyl-1H-tetrazole (ent-3). Follow-

ing the same experimental procedure as described in the preparation

of compound 14, compound ent-18 (120 mg, 0.24 mmol) mixed with

its minor Z-isomer was treated with TBAF (0.75 mL, 0.75 mmol) to

get the corresponding inseparable mixture of alcohols. Puriﬁcation by

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ﬂash column chromatography (SiO₂, 100−200 mesh, 40% EtOAc in

hexane as the eluent) provided the corresponding mixture of E/Z

isomers (45 mg, 74%). R_f= 0.25 (30% EtOAc/hexane); the ¹H NMR,

¹³C NMR, IR, and HRMS data were exactly the same as those of

alcohol obtained from compound 18.

3H); ¹³C{¹H} NMR (75 MHz, C₆D₆): δ 138.3, 136.7, 135.8, 132.5,

131.4, 131.1, 126.0, 115.9, 84.6, 84.1, 83.9, 83.0, 81.5, 80.9, 79.9, 76.6,

74.4, 42.5, 42.4, 42.2, 41.3, 40.2, 39.5, 39.3, 38.1, 32.5, 31.6, 29.2,

22.9, 14.2, 14.1, 13.1 ppm; IR (neat) ν_max: 3446, 2918, 2836, 1442,

1393, 1146, 1063, 923, 841 cm⁻¹; HRMS (ESI) m/z: calcd for

C₃₂H₅₀O₅Na, [M + Na]⁺537.3556; found, 537.3557.

Following the same experimental procedure as described in the

preparation of compound 8, the above mixture of alcohols (42 mg,

0.12 mmol) was converted to the corresponding inseparable sulﬁdes

(37 mg, 77%, puriﬁcation by column chromatography, SiO₂, 230−400

mesh, 5% EtOAc in hexane as the eluent) as a light yellowish oil. R_f=

(2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-4-

((2S,3aS,5R,6aS)-5-((benzyloxy)methyl) hexahydrofuro[3,2-b]-

furan-2-yl)-3-hydroxy-2-methylbutan-1-one (20). Following the

same experimental procedure as described in the preparation of

compound 14, the above compound (350 mg, 0.67 mmol) was

treated with TBAF (1 mL, 1 mmol, 1 M in THF) to get the

corresponding alcohol. Puriﬁcation by ﬂash column chromatography

(SiO₂, 60−120 mesh, 40% EtOAc in hexane as the eluent) provided

the corresponding silyl-deprotected compound (153 mg, 84%). R_f=

1

0.6 (30% EtOAc/hexane); H NMR, ¹³C NMR, IR, and HRMS data

were exactly the same as those of the sulﬁde compound obtained from

compound 18.

Following the same experimental procedure as described in the

preparation of compound 3, the above mixture of sulﬁdes (35 mg,

0.08 mmol) was converted to the corresponding sulfones. The crude

material was puriﬁed by column chromatography (SiO₂, 230−400

mesh, 5% EtOAc in hexane as the eluent) provided two geometric

isomers (24 mg, 69%). Major isomer ent-3 (18 mg, 52%) was isolated

25

1

0.2 (50% EtOAc/hexane); [α]_D= −37.0 (c 0.2, CHCl₃); the H

NMR, ¹³C NMR, IR, and HRMS data are exactly the same as those of

alcohol obtained from compound 6.

Following the same DMP oxidation conditions as described in the

preparation of compound 14, the above alcohol (150 mg, 0.54 mmol)

was transformed into the corresponding aldehyde (146 mg,

quantitative, puriﬁed by ﬂash column chromatography using a short

pad of 60−120 silica, 40% EtOAc in hexane as the eluent) as a

yellowish liquid, which was taken for the next step without further

characterization.

25

as a colorless oil. R_f= 0.45 (20% EtOAc/hexane); [α]_D= +24.2 (c

1

0.5, CHCl₃); the H NMR, ¹³C NMR, IR, and HRMS data were

exactly the same as those of compound 3.

The Z isomer of compound ent-3 (6 mg, 17%) was isolated as a

25

colorless oil. R_f= 0.42 (20% EtOAc/hexane); [α]_D= +38.6 (c 0.2,

1

CHCl₃); the H NMR, ¹³C NMR, IR, and HRMS data were exactly

Following the same aldol conditions as described in the preparation

of compound 14, the above aldehyde (0.54 mmol) was converted to

aldol product 20. Puriﬁcation by column chromatography (SiO₂,

230−400 mesh, 20% EtOAc in hexane as the eluent) provided a pure

compound (195 mg, 67%) as a yellowish oil. R_f= 0.6 (40% EtOAc/

the same as those of the Z isomer of compound 3.

(2S,3S)-1-((2R,3aR,5S,6aR)-5-((1E,3E)-5-((2R,3aR,5S,6aR)-5-((E)-

Hept-1-en-1-yl)hexa Hydrofuro[3,2-b]furan-2-yl)-2-methylpenta-

1,3-dien-1-yl)hexahydrofuro[3,2-b]furan-2-yl)-3-methylhex-5-en-2-

ol (1b). Following the same experimental procedure as described in

the preparation of compound 11, aldehyde 19 mixed with its minor Z-

counterpart (12 mg, 0.03 mmol) and sulfone ent-3 (17 mg, 0.036

mmol) were coupled to get the corresponding coupled products.

Puriﬁcation by ﬂash column chromatography (SiO₂, 230−400 mesh,

20% EtOAc in hexane as the eluent) provided an inseparable mixture

of diastereomers (13 mg, 71%) as a colorless liquid. R_f= 0.6 (20%

25

hexane); [α]_D= +33.5 (c 0.7, CHCl₃); ¹H NMR (300 MHz,

CDCl₃): δ 7.38−7.26 (m, 10H), 5.37 (ddd, J = 10.7, 7.0, 4.0 Hz, 1H),

4.75 (dq, J = 10.8, 3.8 Hz, 3H), 4.58 (d, J = 2.3 Hz, 2H), 4.30 (ddq, J

= 16.0, 9.0, 3.0 Hz, 3H), 3.53 (dd, J = 10.3, 3.4 Hz, 1H), 3.42 (dd, J =

10.3, 5.7 Hz, 1H), 3.36 (ddd, J = 11.5, 7.2, 1.0 Hz, 1H), 3.22 (dd, J =

13.2, 4.1 Hz, 1H), 3.13−3.04 (m, 1H), 2.87 (dd, J = 11.6, 0.8 Hz,

1H), 2.22 (dd, J = 13.4, 5.1 Hz, 1H), 2.11 (dd, J = 13.4, 5.9 Hz, 1H),

1.84 (dddd, J = 14.8, 9.4, 4.8, 1.8 Hz, 2H), 1.74−1.65 (m, 1H), 1.60−

1.53 (m, 1H), 1.23 (d, J = 7.0 Hz, 3H); ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 201.5, 177.9, 138.3, 136.5, 129.5, 129.0, 128.4, 127.7,

127.7, 127.3, 84.2, 83.5, 79.1, 77.3, 73.5, 72.6, 69.1, 69.0, 43.2, 41.2,

38.8, 37.4, 37.1, 31.8, 11.6 ppm; IR (neat) ν_max: 3405, 2943, 2861,

1722, 1682, 1459, 1376, 1237, 1104, 767 cm⁻¹; HRMS (ESI) m/z:

calcd for C₂₉H₃₅NNaO₅S₂, [M + Na]⁺564.1854; found, 564.1856.

(((2S,3S)-1-((2R,3aS,5R,6aS)-5-((Benzyloxy)methyl)-

hexahydrofuro[3,2-b]furan-2-yl)-3-methylpent-4-en-2-yl)oxy)

(Tert-butyl)dimethylsilane (21). Following the same experimental

procedure as described in the preparation of compound 15,

compound 20 (180 mg, 0.33 mmol) was converted to the

corresponding TBS-ether. Puriﬁcation by ﬂash column chromatog-

raphy (SiO₂, 60−120 mesh, 15% EtOAc in hexane as the eluent)

provided a pure compound (190 mg, 88%). R_f= 0.8 (30% EtOAc/

1

EtOAc/hexane); H NMR (300 MHz, CDCl₃): δ 6.11 (d, J = 15.6

Hz, 1H), 5.84−5.58 (m, 3H), 5.35 (dd, J = 22.5, 7.1 Hz, 2H), 5.06−

4.94 (m, 2H), 4.86−4.79 (m, 1H), 4.74 (dt, J = 16.3, 5.8 Hz, 4H),

4.47−4.38 (m, 1H), 4.12 (h, J = 6.1 Hz, 2H), 3.66 (t, J = 4.1 Hz, 1H),

2.34 (dq, J = 12.9, 7.2, 6.6 Hz, 3H), 2.17 (ddd, J = 18.4, 9.1, 4.9 Hz,

4H), 2.06−1.97 (m, 3H), 1.79 (d, J = 1.1 Hz, 3H), 1.68−1.61 (m,

3H), 1.52−1.44 (m 3H), 1.34−1.27 (m, 8H), 0.89 (d, J = 2.4 Hz,

9H), 0.87−0.79 (m, 7H), 0.11−0.03 (m, 6H); ¹³C{¹H} NMR (75

MHz, CDCl₃): δ 138.4, 138.2, 136.6, 134.3, 132.4, 129.7, 125.5,

115.4, 84.1, 83.9, 83.7, 83.6, 81.0, 79.8, 77.3, 76.3, 73.0, 42.2, 42.0,

40.8, 39.2, 39.0, 32.3, 31.5, 29.8, 29.5, 28.8, 26.0, 22.8, 22.6, 18.2,

14.4, 14.1, 13.1, −4.2, −4.2 ppm; IR (neat) ν_max: 2935, 2844, 1475,

1352, 1237, 1104, 956, 742 cm⁻¹; HRMS (ESI) m/z: calcd for

+

C₃₈H₆₄O₅SiNa, [M + Na] 651.4421; found, 651.4423.

Following the same experimental procedure as described in the

preparation of compound 14, the mixture of the above coupled

products (10 mg, 0.015 mmol) was treated with TBAF (40 μL, 1 M in

THF) to get the corresponding silyl-deprotected alcohol. Puriﬁcation

by column chromatography (SiO₂, 100−200 mesh, 5% EtOAc in

hexane as the eluent) aﬀorded pure major compound 1b (6 mg, 78%)

as a colorless oil, which was separated from its minor isomer. R_f= 0.35

(30% EtOAc/hexane); [α]_D²⁰= −13.3 (c 0.6, CHCl₃); ¹H NMR (600

MHz, C₆D₆): δ 6.21 (d, J = 15.6 Hz, 1H), 5.97−5.87 (m, 1H), 5.76

(dt, J = 15.1, 7.2 Hz, 1H), 5.70 (dt, J = 14.2, 6.8 Hz, 1H), 5.51 (dd, J

= 15.4, 7.2 Hz, 2H), 5.17 (d, J = 17.0 Hz, 1H), 5.11 (d, J = 10.0 Hz,

1H), 4.91 (td, J = 9.1, 5.6 Hz, 1H), 4.60−4.57 (m, 1H), 4.57−4.54

(m, 1H), 4.54−4.51 (m, 1H), 4.43 (t, J = 4.6 Hz, 1H), 4.34−4.32 (m,

1H), 4.17 (dd, J = 10.4, 5.4 Hz, 1H), 4.16−4.09 (m, 1H), 3.83 (d, J =

9.7 Hz, 1H), 2.54 (dt, J = 13.0, 6.0 Hz, 1H), 2.37 (dt, J = 13.7, 6.9 Hz,

1H), 2.27−2.22 (m, 1H), 2.20 (dd, J = 13.3, 5.4 Hz, 1H), 2.13−2.10

(m, 1H), 2.09−2.07 (m, 1H), 2.07−2.04 (m, 1H), 2.02−1.97 (m,

3H), 1.74 (s, 3H), 1.62−1.60 (m, 1H), 1.55 (dd, J = 8.6, 4.7 Hz, 1H),

1.45−1.43 (m, 1H), 1.43−1.40 (d, J = 4.3 Hz, 2H), 1.36−1.34 (m,

3H), 1.27−1.23 (m, 5H), 1.06 (d, J = 6.9 Hz, 3H), 0.90 (t, J = 7.0 Hz,

25

hexane); [α]_D= +51.5 (c 0.4, CHCl₃); ¹H NMR (300 MHz,

CDCl₃): δ 7.38−7.26 (m, 10H), 5.29 (dddd, J = 10.8, 7.1, 3.7, 2.0 Hz,

1H), 4.72 (t, J = 5.8 Hz, 3H), 4.56 (d, J = 1.3 Hz, 2H), 4.28 (dddd, J

= 8.9, 7.1, 4.9, 2.4 Hz, 2H), 4.22−4.13 (m, 1H), 3.51 (dd, J = 10.3,

3.4 Hz, 1H), 3.41 (dd, J = 10.3, 5.6 Hz, 1H), 3.34−3.24 (m, 2H),

3.06−2.96 (m, 1H), 2.86 (dd, J = 11.5, 2.0 Hz, 1H), 2.21 (dd, J =

13.3, 5.1 Hz, 1H), 2.14−2.04 (m, 1H), 1.92−1.78 (m, 2H), 1.75−

1.66 (m, 1H), 1.58 (dd, J = 9.1, 4.0 Hz, 1H), 1.20 (d, J = 7.0 Hz, 3H),

0.92 (s, 9H), 0.12 (d, J = 6.9 Hz, 6H); ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 201.1, 176.8, 138.4, 136.8, 129.5, 129.0, 128.4, 127.7,

127.6, 127.3, 84.4, 83.4, 79.0, 75.7, 73.4, 72.6, 71.3, 69.4, 44.9, 41.8,

41.5, 37.4, 37.3, 31.9, 26.2, 18.3, 14.0, −4.0, −4.1 ppm; IR (neat)

ν_max: 2968, 2860, 1718, 1684, 1435, 1285, 1121, 925 cm⁻¹;HRMS

(ESI) m/z: calcd for C₃₅H₄₉NNaO₅S₂Si, [M + Na]⁺678.2719; found,

678.2718.

Following the same DIBAL oxidation conditions as described in

the preparation of compound 15, the above compound (170 mg, 0.26

mmol) was transformed into the corresponding aldehyde (puriﬁed by

10019

https://doi.org/10.1021/acs.joc.1c00686

J. Org. Chem. 2021, 86, 10006−10022

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

ﬂash column chromatography using a short pad of 60−120 silica and

20% EtOAc in hexane as the eluent) as a liquid oil, which was taken

for the next step without further characterization.

Following the same experimental procedure as described in the

preparation of compound 15, the above aldehyde (0.26 mmol) was

converted to alkene 21 (80 mg, 68%, puriﬁcation by ﬂash column

0.08 mmol) was reacted with lithium naphthalide. Puriﬁcation by ﬂash

column chromatography (SiO₂, 60−120 mesh, 25% EtOAc in hexane

as the eluent) provided the corresponding benzyl-deprotected

25

compound (24 mg, 84%). R_f= 0.15 (30% EtOAc/hexane); [α]_D

= +29.6 (c 0.6, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 5.77 (dddd,

J = 19.3, 10.2, 7.5, 6.3 Hz, 1H), 5.05−4.92 (m, 2H), 4.71 (t, J = 3.4

Hz, 2H), 4.18 (ddt, J = 12.4, 5.1, 2.9 Hz, 1H), 3.85−3.79 (m, 1H),

3.78−3.71 (m, 1H), 3.68 (dt, J = 6.3, 3.2 Hz, 1H), 3.46 (dd, J = 11.8,

5.0 Hz, 1H), 2.43−2.28 (m, 2H), 2.16 (dd, J = 13.3, 5.0 Hz, 1H), 2.03

(d, J = 7.0 Hz, 1H), 1.93−1.79 (m, 2H), 1.74−1.61 (m, 3H), 0.90 (s,

9H), 0.83 (d, J = 6.6 Hz, 3H), 0.07 (d, J = 4.3 Hz, 6H); ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 138.4, 115.5, 84.4, 83.6, 80.5, 76.4, 73.0,

64.3, 41.9, 39.2, 38.8, 36.4, 35.8, 26.0, 18.2, 14.7, −4.2, −4.3 ppm; IR

(neat) ν_max: 3512, 2927, 2869, 1435, 1319, 1154, 1031, 906 cm⁻¹;

HRMS (ESI) m/z: calcd for C₂₀H₃₉O₄Si, [M + H]⁺371.2618; found,

371.2615.

chromatography, SiO₂, 60−120 mesh, 5% EtOAc in hexane as the

25

eluent) as a colorless liquid. R_f= 0.7 (15% EtOAc/hexane); [α]_D

=

12.7 (c 0.9, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 7.38−7.27 (m,

5H), 5.93 (ddd, J = 17.1, 10.7, 6.3 Hz, 1H), 5.11−4.94 (m, 2H), 4.70

(p, J = 4.5 Hz, 2H), 4.58 (t, J = 2.7 Hz, 2H), 4.29 (dtd, J = 9.3, 5.8,

3.5 Hz, 1H), 4.15 (ddd, J = 10.1, 8.0, 5.0 Hz, 1H), 3.81 (dt, J = 8.3,

4.3 Hz, 1H), 3.52 (dd, J = 10.3, 3.4 Hz, 1H), 3.42 (dd, J = 10.3, 5.6

Hz, 1H), 2.41−2.29 (m, 1H), 2.18 (dd, J = 13.3, 5.0 Hz, 1H), 2.12−

2.05 (m, 1H), 1.89−1.76 (m, 1H), 1.62−1.52 (m, 1H), 1.51−1.43

(m, 2H), 0.97 (d, J = 7.0 Hz, 3H), 0.91 (s, 9H), 0.08 (d, J = 5.2 Hz,

6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 140.6, 138.3, 128.4, 127.7,

127.6, 114.3, 84.4, 83.4, 79.1, 75.9, 73.4, 73.2, 72.6, 43.2, 41.8, 39.3,

37.5, 26.1, 18.2, 14.5, −4.1, −4.4 ppm; IR (neat) ν_max: 2958, 2927,

1462, 1253, 1102, 1055, 775 cm⁻¹; HRMS (ESI) m/z: calcd for

C₂₆H₄₂NaO₄Si, [M + Na]⁺469.2750; found, 469.2751.

Following the same DMP oxidation conditions as described in the

preparation of compound 14, the above alcohol (22 mg, 0.06 mmol)

was transformed into the corresponding aldehyde (puriﬁed by ﬂash

column chromatography using a short pad of 60−120 silica, 10%

EtOAc in hexane as the eluent) as a yellowish liquid, which was taken

for the next step without further characterization.

(((2S,3S)-1-((2R,3aS,5R,6aS)-5-((Benzyloxy)methyl)-

hexahydrofuro[3,2-b]furan-2-yl)-3-methylhex-5-en-2-yl)oxy) (Tert-

butyl)dimethylsilane (22). Following the same experimental

procedure as described in the preparation of compound 16, the

above oleﬁn (80 mg, 0.18 mmol) was reduced using BH₃-DMS (0.5

mL, 0.5 mmol) to the corresponding terminal alcohol (59 mg, 71%,

puriﬁed by ﬂash column chromatography using a short pad of 60−120

silica, 50% EtOAc in hexane as the eluent) as a colorless liquid. R_f=

Following the same experimental procedure as described in the

preparation of compound 2, the above aldehyde (0.06 mmol) was

converted to the α, β-unsaturated ester using ethyl 2-(triphenylphos-

phoranylidene) propionate (65 mg, 0.18 mmol) in dry toluene.

Puriﬁcation by ﬂash column chromatography (SiO₂, 60−120 mesh,

10% EtOAc in hexane as the eluent) provided a pure compound (18

mg, 73%, E/Z = 3.5:1) as a colorless liquid. R_f= 0.4 (20% EtOAc/

25

1

0.2 (30% EtOAc/hexane); [α]_D= +4.8 (c 0.4, CHCl₃); H NMR

(300 MHz, CDCl₃): δ 7.37−7.24 (m, 5H), 4.71 (h, J = 4.4, 3.6 Hz,

2H), 4.57 (t, J = 2.7 Hz, 2H), 4.28 (dddd, J = 14.9, 9.3, 5.4, 2.8 Hz,

1H), 4.20−4.07 (m, 1H), 3.89−3.72 (m, 2H), 3.69−3.59 (m, 1H),

3.51 (dd, J = 10.3, 3.4 Hz, 1H), 3.46−3.37 (m, 1H), 2.18 (dt, J = 13.2,

5.6 Hz, 1H), 2.08−2.02 (m, 1H), 1.91−1.72 (m, 3H), 1.55 (dq, J =

14.1, 5.5, 4.7 Hz, 4H), 0.92−0.84 (m, 12H), 0.05 (d, J = 6.3 Hz, 6H);

¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.3, 128.4, 127.7, 127.6, 84.4,

83.4, 79.1, 76.3, 73.4, 72.5, 41.7, 37.5, 34.1, 32.0, 29.7, 26.0, 22.7,

18.1, 15.5, 14.2, −4.2, −4.6 ppm; IR (neat) ν_max: 3463, 2981, 2869,

1475, 1220, 1088, 932, 750 cm⁻¹; HRMS (ESI) m/z: calcd for

C₂₆H₄₄O₅SiNa, [M + Na]⁺487.2856; found, 487.2853.

hexane); H NMR (300 MHz, CDCl₃): δ 6.63 (dq, J = 7.9, 1.5 Hz,

1H), 5.75 (dtd, J = 17.3, 7.6, 3.8 Hz, 1H), 5.07−4.94 (m, 2H), 4.87−

4.70 (m, 3H), 4.19 (qd, J = 7.1, 6.6, 1.5 Hz, 3H), 3.83 (dd, J = 8.7, 3.4

Hz, 1H), 2.37 (dtd, J = 7.6, 4.2, 1.9 Hz, 1H), 2.31−2.24 (m, 1H), 2.19

(dd, J = 13.5, 5.0 Hz, 1H), 1.87 (s, 3H), 1.79−1.72 (m, 1H), 1.67

(ddd, J = 12.0, 6.0, 3.3 Hz, 3H), 1.51 (dd, J = 8.7, 4.0 Hz, 2H), 1.28

(s, 3H), 0.90 (s, 9H), 0.83 (d, J = 6.6 Hz, 3H), 0.12−0.05 (m, 6H);

¹³C{¹H} NMR (75 MHz, CDCl₃): δ 167.7, 140.8, 138.4, 129.4, 115.5,

84.4, 83.6, 76.7, 76.5, 73.0, 60.8, 42.0, 41.3, 39.3, 38.9, 35.6, 26.1,

18.2, 14.9, 14.3, 13.0, −4.2, −4.2 ppm; IR (neat) ν_max2960, 2852,

1698, 1459, 1360, 1245.1104, 1037 cm⁻¹; HRMS (ESI) m/z: calcd

+

for C₂₅H₄₄NaO₅Si, [M + Na] 475.2856; found, 475.2854.

Following the same DMP oxidation conditions as described in the

preparation of compound 14, the above alcohol (58 mg, 0.13 mmol)

was transformed into the corresponding aldehyde (55 mg,

quantitative, puriﬁed by ﬂash column chromatography using a short

pad of 60−120 silica, 20% EtOAc in hexane as the eluent) as a

yellowish liquid, which was taken for the next step without further

characterization.

Following the same experimental procedure as described in the

preparation of compound 2, the above α, β-unsaturated ester (18 mg,

0.04 mmol) was converted to the alcohol 23 using DIBAL-H (80 μL,

0.12 mmol, 1.6 M in hexane). Puriﬁcation by ﬂash column

chromatography (SiO₂, 60−120 mesh, 30% EtOAc in hexane as the

eluent) provided a pure compound (14 mg, 88%) as a colorless liquid.

1

R_f= 0.3 (40% EtOAc in hexane); H NMR (300 MHz, CDCl₃): δ

Following the same experimental procedure as described in the

preparation of compound 15, the above aldehyde of 21 (55 mg, 0.12

mmol) was converted to the corresponding alkene 22 (38 mg, 69%,

puriﬁcation by ﬂash column chromatography, SiO₂, 60−120 mesh,

10% EtOAc in hexane as the eluent) as a colorless oil. R_f= 0.8 (20%

EtOAc/hexane); [α]_D²⁵= +11.2 (c 0.9, CHCl₃); ¹H NMR (300 MHz,

CDCl₃): δ 7.37−7.26 (m, 5H), 5.85−5.69 (m, 1H), 5.07−4.93 (m,

2H), 4.71 (p, J = 4.4 Hz, 2H), 4.64−4.51 (m, 2H), 4.35−4.24 (m,

1H), 4.13 (dq, J = 12.6, 5.6 Hz, 1H), 3.79 (ddd, J = 7.5, 5.2, 3.0 Hz,

1H), 3.52 (dd, J = 10.3, 3.4 Hz, 1H), 3.41 (dd, J = 10.3, 5.7 Hz, 1H),

2.40−2.27 (m, 1H), 2.18 (dd, J = 13.3, 4.9 Hz, 1H), 2.11−2.03 (m,

1H), 1.82 (ddd, J = 14.2, 9.4, 5.2 Hz, 2H), 1.75−1.57 (m, 3H), 1.58−

1.53 (m, 1H), 0.90 (s, 9H), 0.83 (d, J = 6.7 Hz, 3H), 0.06 (d, J = 5.6

Hz, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.4, 128.4, 127.8,

127.7, 127.7, 115.4, 84.4, 83.3, 79.1, 76.2, 73.4, 73.0, 72.6, 41.8, 39.1,

5.86−5.67 (m, 1H), 5.39 (dt, J = 8.3, 1.4 Hz, 1H), 5.05−4.93 (m,

2H), 4.83−4.66 (m, 3H), 4.25−4.11 (m, 1H), 4.01 (d, J = 1.4 Hz,

2H), 3.83 (dd, J = 8.8, 3.4 Hz, 1H), 2.42−2.29 (m, 1H), 2.25−2.11

(m, 2H), 2.10−1.99 (m, 1H), 1.72 (s, 3H), 1.66 (dq, J = 3.6, 2.4 Hz,

2H), 1.60−1.55 (m, 1H), 1.49 (td, J = 8.5, 3.7 Hz, 2H), 0.90 (s, 9H),

0.83 (d, J = 6.6 Hz, 3H), 0.09 (d, J = 10.9 Hz, 6H); ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 139.0, 138.4, 125.3, 115.4, 83.9, 76.1, 73.0, 68.1,

42.2, 42.0, 39.3, 38.9, 35.6, 29.8, 26.1, 22.8, 18.3, 14.9, 14.1, −4.2,

−4.2 ppm; IR (neat) ν_max: 3479, 2968, 2852, 1451, 1376, 1237, 1088,

1047, 767 cm⁻¹; HRMS (ESI) m/z: calcd for C₂₃H₄₂O₄SiNa, [M +

Na]⁺433.2750; found, 433.2752.

(2S,3S)-1-((3aS,6aS)-5-((1E,3E)-5-((2S,3aS,5R,6aS)-5-((E)-Hept-1-

en-1-yl)hexahydrofuro [3,2-b]furan-2-yl)-2-methylpenta-1,3-dien-

1-yl)hexahydrofuro[3,2-b]furan-2-yl)-3-methyl Hex-5-en-2-ol (1c).

Following the same DMP oxidation conditions as described in the

preparation of compound 14, the above alcohol 23 (12 mg, 0.03

mmol) was transformed into the corresponding aldehyde (puriﬁed by

ﬂash column chromatography using a short pad of 60−120 mesh silica

gel, 20% EtOAc in hexane as the eluent) as a yellowish liquid, which

was taken for the next step without further characterization.

38.9, 37.5, 36.0, 26.1, 18.2, 14.6, −4.2, −4.3 ppm; IR (neat) ν_max

:

2927, 2869, 1451, 1385, 1253, 1096, 824, 758 cm⁻¹; HRMS (ESI) m/

z: calcd for C₂₇H₄₄O₄SiNa, [M + Na]⁺483.2907; found, 483.2906.

3-((2R,3aS,5R,6aS)-5-((2S,3S)-2-((Tert-butyldimethylsilyl)oxy)-3-

methylhex-5-en-1-yl)hexa Hydrofuro[3,2-b]furan-2-yl)-2-methyl-

prop-2-en-1-ol (23). Following the same experimental procedure as

described in the preparation of compound 2, compound 22 (36 mg,

Following the same experimental procedure as described in the

preparation of compound 11, the above aldehyde (0.03 mmol) and

10020

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J. Org. Chem. 2021, 86, 10006−10022

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

sulfone 3 (15 mg, 0.036 mmol) were coupled to get the

corresponding product. Puriﬁcation by ﬂash column chromatography

(SiO₂, 230−400 mesh, 20% EtOAc in hexane as the eluent) provided

an inseparable mixture of diastereomers (13 mg, 72%) as a colorless

liquid. R_f= 0.6 (20% EtOAc/hexane); ¹H NMR (300 MHz, CDCl₃):

δ 6.11 (d, J = 15.7 Hz, 1H), 5.84−5.57 (m, 3H), 5.44−5.27 (m, 2H),

5.07−4.94 (m, 2H), 4.88−4.77 (m, 1H), 4.76−4.65 (m, 4H), 4.42

(dt, J = 11.9, 6.4 Hz, 1H), 4.15 (ddd, J = 15.3, 11.4, 4.8 Hz, 2H),

3.90−3.78 (m, 1H), 2.43−2.28 (m, 3H), 2.24−2.12 (m, 4H), 2.01 (q,

J = 7.0 Hz, 2H), 1.79 (d, J = 1.2 Hz, 3H), 1.75−1.59 (m, 6H), 1.49

(td, J = 8.1, 3.8 Hz, 2H), 1.38 (q, J = 6.2 Hz, 2H), 1.33−1.27 (m,

4H), 0.92−0.87 (m, 12H), 0.83 (d, J = 6.5 Hz, 3H), 0.09 (d, J = 11.2

Hz, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 138.4, 136.6, 136.3,

134.2, 130.4, 129.7, 125.4, 115.4, 84.1, 83.9, 83.7, 81.0, 79.8, 78.6,

77.3, 76.5, 73.0, 42.2, 42.0, 40.8, 39.3, 39.0, 35.7, 32.3, 31.5, 29.8,

28.8, 26.1, 26.0, 22.6, 18.3, 14.9, 14.1, 13.1, −4.1, −4.2 ppm; IR

(neat) ν_max: 2943, 2869, 1475, 1369, 1237, 1121, 981, 725 cm⁻¹;

HRMS (ESI) m/z: calcd for C₃₈H₆₄O₅SiNa, [M + Na]⁺651.4421;

found, 651.4423.

Gour Hari Mandal − School of Chemical Sciences, Indian

Association for the Cultivation of Science, Kolkata 700032,

India

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00686

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

D.S. and G.H.M. thank the Council of Scientiﬁc and Industrial

Research, New Delhi and Indian Association for the

Cultivation of Science, respectively, for their research fellow-

ship. The ﬁnancial support from Science and Engineering

Research Board (project no. CRG/2019/001664) India, to

carry out this work is gratefully acknowledged.

Following the same experimental procedure as described in the

preparation of compound 14, the above coupled compound (10 mg,

0.02 mmol) was treated with TBAF (1 M) (40 μL) to get

corresponding silyl deprotected alcohol. Puriﬁcation by column

chromatography, SiO₂, 100−200 mesh, 5% EtOAc in hexane as the

eluent, aﬀorded pure major compound 1c (8 mg, 82%) as a colorless

oil, which was separated from its minor isomer. R_f= 0.35 (30%

EtOAc/hexane); [α]_D²⁵= +6.65 (c 0.6, CHCl₃); ¹H NMR (600 MHz,

C₆D₆): δ 6.22 (d, J = 15.5 Hz, 1H), 5.85−5.79 (m, 1H), 5.79−5.74

(m, 1H), 5.74−5.67 (m, 1H), 5.56 (d, J = 8.3 Hz, 1H), 5.54−5.49 (m,

1H), 5.08 (d, J = 17.2 Hz, 1H), 5.06 (d, J = 11.0 Hz, 1H), 5.00 (ddd, J

= 10.1, 8.0, 5.3 Hz, 1H), 4.59 (dd, J = 10.6, 5.6 Hz, 1H), 4.56−4.51

(m, 3H), 4.42 (d, J = 4.6 Hz, 1H), 4.40 (d, J = 7.6 Hz, 1H), 4.18 (dq,

J = 11.2, 5.8 Hz, 1H), 3.83 (d, J = 9.7 Hz, 1H), 2.38 (dt, J = 13.8, 6.7

Hz, 1H), 2.29 (dt, J = 13.9, 6.0 Hz, 1H), 2.22 (dd, J = 8.8, 6.0 Hz,

1H), 2.20−2.17 (m, 1H), 2.17−2.14 (m, 1H), 2.12 (dd, J = 13.3, 5.1

Hz, 1H), 2.09−2.06 (m, 1H), 1.99 (q, J = 7.4 Hz, 2H), 1.93 (dt, J =

14.8, 8.0 Hz, 1H), 1.74 (s, 3H), 1.70−1.67 (m, 1H), 1.57−1.51 (m,

2H), 1.48 (ddd, J = 10.1, 8.6, 5.0 Hz, 2H), 1.43−1.41 (m, 1H), 1.39−

1.38 (m, 1H), 1.34 (d, J = 7.4 Hz, 2H), 1.28−1.22 (m, 4H), 0.98 (d, J

= 6.9 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H); ¹³C{¹H} NMR (75 MHz,

C₆D₆): δ 137.9, 136.8, 135.7, 132.5, 131.6, 131.1, 125.8, 115.9, 84.1,

84.0, 83.9, 83.8, 80.9, 79.9, 78.3, 76.8, 71.2, 42.5, 42.4, 41.3, 41.1,

39.5, 39.1, 39.1, 38.2, 32.5, 31.6, 29.2, 22.9, 14.2, 14.0, 13.1 ppm; IR

(neat) ν_max: 3459, 2924, 2855, 1457, 1436, 1375, 1155, 1078, 1031,

915 cm⁻¹; HRMS (ESI) m/z: calcd for C₃₂H₅₀O₅Na, [M + Na]⁺

537.3556; found, 537.3555.

REFERENCES

■

(1) Kumagai, K.; Minamida, M.; Akakabe, M.; Tsuda, M.; Konishi,

Y.; Tominaga, A.; Tsuda, M.; Fukushi, E.; Kawabata, J. Amphirionin-

2, a Novel Linear Polyketide with Potent Cytotoxic Activity from a

Marine Dinoflagellate Amphidinium Species. Bioorg. Med. Chem. Lett

2015, 25, 635−638.

(2) (a) Paul, D.; Saha, S.; Goswami, R. K. Total Synthesis of

Pestalotioprolide e and Structural Revision of Pestalotioprolide F.

Org. Lett. 2018, 20, 4606−4609. (b) Saha, D.; Guchhait, S.; Goswami,

R. K. Total Synthesis and Stereochemical Assignment of Penicitide A.

Org. Lett. 2020, 22, 745−749. (c) Paul, D.; Kundu, A.; Saha, S.;

Goswami, R. K. Total Synthesis : The Structural Confirmation of

Natural Products. ChemComm 2021, 57, 3307−3322. (d) Mondal, J.;

Sarkar, R.; Sen, P.; Goswami, R. K. Total Synthesis and Stereo-

chemical Assignment of Sunshinamide and Its Anticancer Activity.

Org. Lett. 2020, 22, 1188−1192.

(3) Kato, S.; Mizukami, D.; Sugai, T.; Tsuda, M.; Fuwa, H. Total

Synthesis and Complete Configurational Assignment of Amphirionin-

2. Chem. Sci. 2021, 12, 872−879.

(4) Zurwerra, D.; Gertsch, J.; Altmann, K.-H. Synthesis of

(-)-Dactylolide and 13-Desmethylene-(-)-Dactylolide and Their

Effects on Tubulin. Org. Lett. 2010, 12, 2302−2305.

(5) (a) Candy, M.; Audran, G.; Bienaymé, H.; Bressy, C.; Pons, J.-M.

Total Synthesis of (+)-Crocacin C Using Hidden Symmetry. J. Org.

Chem. 2010, 75, 1354−1359. (b) Das, S.; Kuilya, T. K.; Goswami, R.

K. Asymmetric Total Synthesis of Bioactive Natural Lipid Mycalol. J.

Org. Chem. 2015, 80, 6467−6489.

(6) Nakayama, A.; Sato, H.; Karanjit, S.; Hayashi, N.; Oda, M.;

Namba, K. Asymmetric Total Syntheses and Structure Revisions of

Eurotiumide A and Eurotiumide B, and Their Evaluation as Natural

Fluorescent Probes. Eur. J. Org Chem. 2018, 2018, 4013−4017.

(7) Taylor, C. A.; Zhang, Y.-A.; Snyder, S. A. The Enantioselective

Total Synthesis of Laurendecumallene B. Chem. Sci. 2020, 11, 3036−

3041.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00686.

■

sı

Copies of NMR (¹H and ¹³C{¹H}), HRMS, and 2D

NMR (COSY, NOESY, HSQC, HMBC, and TOCSY)

of some representative compounds and comparison of

the NMR data (PDF)

(8) (a) Julia, M.; Paris, J.-M. Syntheses a l ’aide de Sulfones v(+)-

Methode de Synthese Generale de Doubles Liaisons. Tetrahedron Lett.

́

1973, 14, 4833−4836. (b) Blakemore, P. R.; Cole, W. J.; Kocienski, P.

AUTHOR INFORMATION

Corresponding Author

Rajib Kumar Goswami − School of Chemical Sciences, Indian

Association for the Cultivation of Science, Kolkata 700032,

India; orcid.org/0000-0001-7486-0618; Email: ocrkg@

iacs.res.in

J.; Morley, A. A Stereoselective Synthesis of Trans-1,2-Disubstituted

Alkenes Based on the Condensation of Aldehydes with Metallated 1-

Phenyl-1H-Tetrazol-5-Yl Sulfones. Synlett 1998, 1998, 26−28.

(c) Mandal, G. H.; Saha, D.; Goswami, R. K. Total Synthesis of

Nafuredin B. Org. Biomol. Chem. 2020, 18, 2346−2359.

■

(9) (a) Marshall, J. A.; Sabatini, J. J. Synthesis of Cis- and Trans-2,5-

Disubstituted Tetrahydrofurans by a Tandem Dihydroxylation-SN2

Cyclization Sequence. Org. Lett. 2005, 7, 4819−4822. (b) Srinivas, B.;

Reddy, D. S.; Mallampudi, N. A.; Mohapatra, D. K. A General

Diastereoselective Strategy for Both Cis- and Trans-2,6-Disubstituted

Tetrahydropyrans: Formal Total Synthesis of (+)-Muconin. Org. Lett.

2018, 20, 6910−6914.

Authors

Dhiman Saha − School of Chemical Sciences, Indian

Association for the Cultivation of Science, Kolkata 700032,

India

10021

https://doi.org/10.1021/acs.joc.1c00686

J. Org. Chem. 2021, 86, 10006−10022

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(10) (a) Gill, D. M.; Male, L.; Jones, A. M. A Structure-Reactivity

Relationship of the Tandem Asymmetric Dihydroxylation on a

Biologically Relevant Diene: Influence of Remote Stereocenters on

Diastereofacial Selectivity. Eur. J. Org Chem. 2019, 2019, 7568−7577.

(b) Hale, K. J.; Manaviazar, S.; Peak, S. A. Anomalous

Enantioselectivity in the Sharpless Catalytic Asymmetric Dihydrox-

ylation Reaction of 1,1-Disubstituted Allyl Alcohol Derivatives.

Tetrahedron Lett. 1994, 35, 425−428.

(11) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.

Asymmetric Aldol Additions: Use of Titanium Tetrachloride and

(-)-Sparteine for the Soft Enolization of N-Acyl Oxazolidinones,

Oxazolidinethiones, and Thiazolidinethiones. J. Org. Chem. 2001, 66,

894−902. (b) Saha, S.; Paul, D.; Goswami, R. K. Cyclodepsipeptide

Alveolaride C: Total Synthesis and Structural Assignment. Chem. Sci.

2020, 11, 11259−11265. (c) Venkatesham, A.; Nagaiah, K.

Stereoselective Total Synthesis of Stagonolide-C. Tetrahedron:

Asymmetry 2012, 23, 1186−1197.

(12) (a) Trost, B. M.; Wrobleski, S. T.; Chisholm, J. D.; Harrington,

P. E.; Jung, M. Total Synthesis of (+)-Amphidinolide A. Assembly of

the Fragments. J. Am. Chem. Soc. 2005, 127, 13589−13597.

(b) Sharma, G. V. M.; Venkateshwarlu, G.; Katukuri, S.;

Ramakrishna, K. V. S.; Sarma, A. V. S. Design and Synthesis of

Novel Oxetane Β 3-Amino Acids and α , β -Peptides. Tetrahedron 2015,

71, 2158−2167.

(13) (a) Karabiyikoglu, S.; Boon, B. A.; Merlic, C. A. Cycloaddition

Reactions of Cobalt-Complexed Macrocyclic Alkynes: The Trans-

annular Pauson-Khand Reaction. J. Org. Chem. 2017, 82, 7732−7744.

(b) Ma, R.; White, M. C. C-H to C-N Cross-Coupling of

Sulfonamides with Olefins. J. Am. Chem. Soc. 2018, 140, 3202−3205.

(14) Das, S.; Paul, D.; Goswami, R. K. Stereoselective Total

Synthesis of Bioactive Marine Natural Product Biselyngbyolide B.

Org. Lett. 2016, 18, 1908−1911.

(15) Grove, C. I.; Fettinger, J. C.; Shaw, J. T. Second-Generation

Synthesis of (-)-Viriditoxin. Synthesis 2012, 2012, 362−371.

(16) Chen, W.; Xiong, F.; Liu, Q.; Xu, L.; Wua, Y.; Chen, F.

Substrate stereocontrol in bromine-induced intermolecular cycliza-

tion: asymmetric synthesis of pitavastatin calcium. Tetrahedron 2015,

71, 4730−4737.

(17) Cichowicz, N. R.; Nagorny, P. Synthesis of Conjugated

Polyenes via Sequential Condensation of Sulfonylphosphonates and

Aldehydes. Org. Lett. 2012, 14, 1058−1061.

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Asymmetric Total Synthesis of Amphirionin-2

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