Metal-mediated alkynediol cycloisomerization: First and second generation formal total syntheses of didemniserinolipid B

Tetrahedron 69 (2013) 1881e1896

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Tetrahedron

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Metal-mediated alkynediol cycloisomerization: ﬁrst and second

generation formal total syntheses of didemniserinolipid B

*

Shyamsundar Das, Boddeti Induvadana, C.V. Ramana

Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune e 411 008, India

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 3 October 2012

Received in revised form 14 December 2012

Accepted 20 December 2012

Available online 29 December 2012

A formal total synthesis of didemniserinolipid B was developed by employing a regioselective metal-

mediated 6-endo-dig alkynol-cycloisomerization reaction. Two routes for the synthesis of key Burke’s

intermediate have been developed. Our initial approach involved the introduction of a C₁₇-alkynol fol-

lowed by Pd-mediated cycloisomerization and then coupling with the serinol unit prior to the in-

troduction of an

a,b

-unsaturated ester unit through selective oxidation of 1^ꢀ-OH followed by a two-

carbon Wittig homologation. Alternatively, the second generation strategy featuring the serinol cou-

pling with the C₁₇-alkynol followed by alkyne addition to the epoxide and subsequent Au-mediated

cycloisomerization of an acetonide protected alkynediol unit has been executed. This approach has

avoided several late stage protectionedeprotection events.

Keywords:

Alkynol-cycloisomerization

Bicyclic ketal

Palladium catalysis

Gold catalysis

Zipper reaction

1. Introduction

group.^5t,8In case of competitive 5-exo-dig versus 6-endo-dig cy-

clizations these investigations have revealed that the regiose-

Bicyclic ketal, a common structural unit present in many natural

products has received substantial synthetic attention in recent

years, due to the isolation of several new natural products having

a bicyclic ketal unit as an integral part of their structures and the

diverse biological activities reported such as anti-fungal, anti-can-

cer, and anti-HIV.¹An intramolecular acetal formation from a suit-

able keto-diol is a commonly employed method used for the

construction of the bicyclic ketal core.²The synthesis of a bicyclic

lectivity of the cyclization was in line with electronic control.^5t

However, in case of competitive 6-exo-dig versus 7-endo-dig cy-

clizations, a complete 6-exo-dig selectivity without any electronic

interference has been observed.^8bBased on these ﬁndings, we have

recently documented the total synthesis of cephalosporolides E and

F,^6da formal total synthesis of didemniserinolipid B,^6eand the

central 6,8-dioxabicyclo[3,2,1]octane core of cyclodidemniserinol

trisufate^6ffeaturing selective 5-exo-dig, 6-endo-dig, and 6-exo-dig

alkynol cyclization, respectively. In our previous communication,

dealing with the didemniserinolipid B (1), we synthesized the key

Burke’s intermediate 2.^6eThe assembly of the central carbon skel-

eton has been addressed by employing alkyneeepoxide coupling

and the serniol unit has been appended after the construction of

the key bicyclic ketal (via a regioselective Pd-mediated alkynol-

cycloisomerization of an alkyne triol). Herein, we provide the

complete details of our basic investigations related to the acyclic

stereocontrol over the regiochemistry of these cyclizations, which

ultimately led us to arrive at the designing of the key alkyne triol

that has served as the advanced intermediate in our formal total

synthesis of didemniserinolipid B (1) and we also provide details of

two closely related approaches for the formal total syntheses of

didemniseriniolipid B.

ketal through cycloisomerization of u-alkynediols reported initially

using a Pd-complex by Utimoto,³has caught the attention of sev-

eral groups in recent years and various transition metals like pal-

ladium, silver, gold, platinum, iridium, and mercury have been

employed as catalysts for this key transformation.^4,5In recent years,

the metal-mediated alkynediol cycloisomerization has been used

as one of the key skeletal construct in the synthesis of complex

natural products.⁶The key issue in these cycloisomerization re-

actions is the mode of cyclization i.e. exo-dig versus endo-dig.^5t,7,8In

order to address the regioselectivity issues, a systematic in-

vestigation dealing with the inﬂuence of electronic and steric fac-

tors over competitive 5-exo-dig versus 6-endo-dig cyclizations and

over the 6-exo-dig versus 7-endo-dig modes of cyclizations medi-

ated by Pd[CH₃CN]₂Cl₂complex has been carried out by our

Didemniserinolipids AeC (Fig. 1) were isolated in 1999 by

ꢀ

Gonzalez et al. from the methanol extract of didemnum sp., with the

aim of ﬁnding new cytotoxic agents against P388, A549, and HT29

* Corresponding author. Tel.: þ91 20 2590 2577; fax: þ91 20 2590 2629; e-mail

tumor cell lines.⁹Didemniseriniolipids are characterized by their

address: vr.chepuri@ncl.res.in (C.V. Ramana).

http://dx.doi.org/10.1016/j.tet.2012.12.045

1882

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

from the epoxide 15, which, in turn, can be made from the penul-

timate intermediate that has been planned for preparing the orig-

inal epoxide 9. In our earlier communication, we documented the

details about the synthesis of didemniserinolipid B, featuring the

alkynol-cycloisomerization of a free 1,2,3-triol unit. The cyclo-

isomerization is completely selective toward the desired 6-endo

product even if the spectator homopropargylic eOH (of the 1,2,3-

triol) group could possibly participate in a 5-exo-dig fashion.^6e

2. Results and discussion

2.1. Synthesis and cycloisomerization of model substrates

11e14

The synthesis of epoxide 9 started from the known diacetonide

10¹⁸by oxidative diol cleavage using NaIO₄, subsequent Wittig re-

action of the intermediate aldehyde with the ylide generated from

the phosphonium salt A¹⁹by using KO^tBu as the base (Scheme 1).

The optimized reaction conditions involve the addition of ylide

generated in THF to a solution of the aldehyde in ether at 0 ^ꢀC,

which gave the oleﬁn 16 in a Z/E ratio of 9:1. Hydrogenation of the

oleﬁn 16 using Raney-Ni gave the saturated dicetonide 17. Selective

deprotection of the terminal acetonide group using p-TSA in MeOH

afforded the diol 18 in 80% yield. The diol 18 was transformed to the

key epoxide 9 at 83% overall yield following a two-step sequence

involving selective tosylation of the primary hydroxyl group using

tosyl chloride, dibutyltin oxide, and triethylamine and subsequent

treatment of the resulting tosylate 19 with K₂CO₃. The protons at-

tached to the oxirane ring in compound 9 resonated at relatively

Fig. 1. Structures of didemniserinolipid B and cyclodidemniserinol trisulfate.

unusual serinolipid structure, which has been proposed with the

help of extensive NMR analysis. The related macrocycle containing

serinolipid cyclodidemniserinol sulfate was subsequently isolated

from Palauan ascidian Didemnum guttatumas by Faulkner and co-

workers and showed promising HIV-integrase inhibitory activ-

ity,¹⁰thus attracting considerable synthetic interest.^11e14In 2002,

Steven Ley’s group reported the synthesis of didemniserinolipid B

and revised its structure as 1 by amending the stereochemistry of

the serinol fragment and they proposed the position of O-sulfate at

C(31).¹¹Later, Burke and co-workers reported the second total

synthesis of 1 by employing ketalization and ring closing metath-

esis as the key strategy for constructing the central bridged bicyclic

core.¹²

Our interest in this regard was to extend the synthetic potential

of alkynediol cycloisomerization for the construction of the central

bicyclic ketal core unit and apply it in the total synthesis of the

didemniserinolipids. The key features of our retro synthesis are

depicted in Fig. 2. The target molecule has been visualized from 2,

a key protected derivative of 1 that has been synthesized by Burke

and co-workers.¹²The selective oxidation of the 1^ꢀ-OH in diol 3 and

subsequent two-carbon Wittig homologation has been planned as

the ﬁnal event in the synthesis of 2. The next disconnection is the

ether link that combines the central lipid carbon framework 4 and

the serinol unit 5.

The key bicyclic ketal intermediate 4 was planned by the

cycloisomerization of the alkynol 6. Keeping the knowledge that we

acquired with the model cycloisomerization reactions of sugar

alkynols in mind, the alkyne group has been positioned favorably

for 6-endo-dig cyclization. Based upon these key disconnections

compounds 5, 6, and 8 were identiﬁed as important coupling

partners representing the serinol, the central bicyclic core, and

long-chain alcohol portions, respectively. The alkynol 6 can be

obtained from the opening of the epoxide 9 with the alkyne 8.¹⁵

After the stereochemical comparisons, epoxide 9 synthesis was

up-ﬁeld [d

2.63 (dd), 2.80 (dd), 2.94 (ddd)] in the ¹H NMR spectrum,

while a triplet and doublet at 45.1 and 51.5 ppm in the ¹³C NMR

spectrum conﬁrmed the formation of the epoxide. Next, the epi-

meric epoxide 15 was prepared from 18 following a three-step

sequencedi. selective 1^ꢀ-OH benzoylation, ii. mesylation of the 2^ꢀ-

OH, and subsequent iii. LiOH treatment. After having the epoxides 9

and 15 in hand, we next proceeded for their opening and the

preparation of model substrates. Thus, the opening of epoxide 9

with the lithiated 1-heptyne under Yamaguchi conditions¹⁵gave

the alkynol 20, which, upon acetonide deprotection by using 60%

AcOH in water, gave the parent model compound 11. Protection of

the free eOH of 20 as its benzoate 21 followed by acetonide hy-

drolysis gave the model substrate 12. Similarly, the opening of the

epimeric epoxide 15 through the Yamaguchi protocol afforded the

alkynol 24, which, upon acetonide deprotection, gave the model

substrate 13. The model compound 14 was prepared by the ben-

zoylation of 24 and the acetonide hydrolysis of the resulting ben-

zoate 25.

The cycloisomerization of model compounds 11, 12, 13, and 14

was carried out under the optimized conditions. The results are

given in Scheme 2. In all the cases, the reactions proceeded in a 6-

endo-dig mode of cyclization and the corresponding [3,2,1]bicyclic

ketals were obtained in good yields. These results indicate that the

stereochemistry as well as bulkiness of the substituent at the b-

position to the alkyne seems to be not having much inﬂuence over

intended from

D-mannitol. The synthesis of alkynol 8 has been

the regioselectivity of the cycloisomerization. The cyclization of

envisioned from propargyl alcohol via alkylation with the requisite

14-carbon long-chain halide and a subsequent acetylenic Zipper

reaction.¹⁶The synthesis of serinol derivative 5 has been already

acetonides 20 and 24 having the free alcohol b- to the alkyne is

facile and gave the corresponding bicyclic ketals in moderate

yields.²⁰On the other hand, the benzoates 21 and 25 are intact

under similar reaction conditions, which indicate that the aceto-

nide hydrolysis might be facilitated by the presence of an adjacent

free-OH (Table 1).

reported from

D

-serine.¹⁷Considering our observations in the

synthesis of central bicyclic core of cyclodidemniserinol trisulfate,

where we noticed an exclusive 5-exo-dig over the 6-endo-dig

cyclization,^5twe have initially designed the epimeric alkynols 11,

13, and their benzoates 12, 14 as model substrates in the context of

the present total synthesis to learn about the possible acyclic

stereocontrol over the regioselectivity of the alkynol-cyclo-

isomerization. The synthesis of 13 and its benzoate 14 was planned

2.2. Synthesis of C₁₇-alkynol fragment 8

Having completed the model studies and established the con-

struction of the requisite bicyclic ketal core with complete

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

1883

Fig. 2. Retrosynthetic strategy for didemniserinolipid B (1) and the model substrates 11e14 designed for understanding the acyclic stereocontrol over the regioselectivity of the

alkynol cyclization.

regioselectivity, we next proceeded for the synthesis of C₁₇-alkynol

8. The acetylenic Zipper reaction¹⁶that involves the isomerization

of an internal alkyne to the terminal alkyne in the presence of

a base has been selected in this regard. The known THP ether of

propargyl alcohol was alkylated with tetradecyl bromide using n-

butyl lithium as a base to afford the substituted alkyne 30 (Scheme

3). The deprotection of the THP ether 30 was effected by using p-

TSA and methanol to afford the alkylated propargyl alcohol 31. After

exploring a variety of bases and reaction conditions (Table 2) we

concluded that the isomerization of alcohol 31 to the requisite

heptadec-16-yn-1-ol (32) could be conducted successfully by

employing lithium metal in combination with potassium tert-but-

was investigated with the help of spectral data analysis. In the ¹H

NMR spectrum of 36, the three characteristic methine protons of

the ketal are present at

d 3.97, 4.28 and 4.89. The protons of the

CH₂eCH₂unit present in the bicyclic ketal were found to resonate

separately from the rest of the alkane-H as multiplets at downﬁeld.

The presence of the characteristic ketal carbon at 109.4 ppm in the

¹³C NMR spectrum and two CH₂s as triplets separately in the

downﬁeld at 35.1 and 37.8 ppm indicated the presence of a [3.2.1]

bicyclic ketal. Similarly, in the ¹H NMR spectrum of 35, the three

characteristic methine protons of the bicyclic ketal resonated at

d

3.58, 3.86, 4.04 ppm and in the ¹³C NMR spectrum a singlet cor-

responding to the ketal carbon at 109.5 ppm and the two triplets

corresponding to ring CH₂at 35.2 and 37.5 ppm were seen. Selec-

tive protections of the 1^ꢀ-OH in compound 35 as its TBS ether 37

followed by the benzylation of 2^ꢀ-OH and subsequent deprotection

of the silyl group in resulting 38 gave the key bicyclic ketal frag-

ment 4.

Burke’s group has earlier showed that the serinol coupling was

effective with the mesylate of the bicyclic ketal and the serinol 5

using sodium hydride as the base, and importantly with DMSO as

solvent. Accordingly, compound 4 was subjected for mesylation to

obtain the key mesylate 39. The coupling of the mesylate 39 with

the serinol 5 needs a special mention (Scheme 5).¹²The control of

the reaction temperature during the addition has substantial in-

ﬂuence on the outcome of the reaction. When the reaction was

conducted below 0 ^ꢀC, the required ether 40 was obtained in 65%

yield along with an unidentiﬁed mixture of products comprising an

oleﬁn, probably obtained by demesylation. However, when the

temperature was above 0 ^ꢀC, the elimination of mesylate was the

major event.

oxide in 1,3-diaminopropane as the solvent/base.²¹The ¹H and ¹³

C

NMR spectra of 32 evidenced the presence of terminal acetylene.

For example, in the ¹H spectrum of 32, the acetylenic-H resonated

as a triplet at 1.88 and the propargylic protons resonated as dt at

d

2.16 ppm. The acetylenic carbons resonated as a doublet and

a singlet at 68.2 and 84.6 ppm, respectively, in the ¹³C NMR spec-

trum. Subsequently, the free eOH group in compound 32 was

protected as its TBS ether to obtain the key fragment 8.

2.3. First generation formal total synthesis of didemniser-

inolipid B

The coupling of the oxirane 9 with the alkyne 8 resulted in the

formation of homopropargylic alcohol 33, which was protected as

its benzoate 34 (Scheme 4). The hydrolysis of the acetonide group

in compounds 33 and 34 using cat. p-TSA in methanol afforded the

alkynol 6 and its benzoate 7. The intended cycloisomerization of

alkynols 6 and 7 proceeded smoothly with Pd(CH₃CN)₂Cl₂as the

catalyst, and afforded, respectively, the bicyclic ketals 35 and 36 in

good yield. The constitution of the bicyclic ketal unit present in 36

Having executed the key cycloisomerization and serinol cou-

pling events successfully, our next concern was the two-carbon

1884

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

Scheme 1. Reagents and conditions: (a) i. NaIO₄, CH₂Cl₂/H₂O (9:1), 0 ^ꢀC/rt, 4 h; ii. BnOC₄H₈PPh₃I, KOtBu, THF, 0 ^ꢀC, 2 h; (b) Raney-Ni, H₂, EtOH, rt, 30 min; (c) cat. p-TSA, MeOH, 0 ^ꢀC,

20 h; (d) TsCl, Et₃N, cat. Bu₂SnO, cat. DMAP, CH₂Cl₂, 0 ^ꢀC/rt, 4 h; (e) K₂CO₃, MeOH, 0 ^ꢀC, 1 h; (f) hept-1-yne, n-BuLi, THF, BF₃$Et₂O, ꢁ78 ^ꢀC, 1 h; (g) BzCl, Et₃N, CH₂Cl₂, 0 ^ꢀC/rt, 2 h;

(h) 60% AcOH, 85 ^ꢀC, 4 h; (i) MsCl, Et₃N, CH₂Cl₂, 0 ^ꢀC/rt, 4 h; (j) LiOH, MeOH/THF (1:1), rt, 4 h.

homologation. Compound 40 was subjected to debenzylation to

afford the diol 3. The diol 3 was oxidized selectively to the aldehyde

using DMP as the oxidizing agent and the resulting aldehyde was

used as such for the next step without further puriﬁcation.²²The

Wittig oleﬁnation of the intermediate aldehyde using the stable

ylide Ph₃P]CHCO₂Et in reﬂuxing benzene afforded the desired

unsaturated ester 2. The ¹H NMR spectrum revealed the presence of

the oleﬁnic protons at 5.80 (d) and 6.94 (dt) with a coupling

a,b-

d

Scheme 2. Cycloisomerization of model substrates.

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

1885

Table 1

synthesis, we converted compound 44 to the corresponding diac-

etate 45 and subsequently carried out its debenzylation. The oxi-

dation of the resulting alcohol 46 and Wittig homologation gave 47.

However, the deacetylation of compound 47 has turned out to be

a difﬁcult proposition. In this context, the intermediate ketal 44

was subjected for the acetonide protection to obtain compound 48,

which subsequently transformed to 2 following the established

three-step sequenceei. debenzylation, ii. oxidation, and iii. Wittig

homologation.

Pd-mediated cycloisomerization of alkynediols and their acetonides conditions:

5 mol% Pd[CH₃CN]₂, CH₃CN, rt, 2e6 h

Entry

Substrate

Product

Yield (%)

1

2

3

4

5

6

7

8

11

12

13

14

20

21

24

25

26

27

28

29

26

d

67

80

81

73

65

d

28

d

71

d

3. Conclusions

To conclude, a formal total synthesis of didemniserinolipid B

constant of 15.6 Hz indicative of a trans double bond. Also, the

was developed by employing

a highly regioselective metal-

quartet at d 4.17 was suggestive of the methylene group of the ethyl

mediated 6-endo-dig alkynol-cycloisomerization reaction. The Pd-

mediated cycloisomerization of model alkynols revealed that the

regioselectivity of the alkynol-cycloisomerization was not inﬂu-

enced by stereochemistry and the protecting group present on the

homopropargylic eOH. Two routes for the synthesis of the key

Burke’s intermediate have been developed. The ﬁrst approach

features a sequential coupling of epoxide and alkyne followed

by cycloisomerization and then serinol coupling. Whereas in the

second approach, the alkynol and serinol are coupled prior to

the epoxide alkyne coupling and subsequent alkynol-

cycloisomerization. The later approach is characterized by its

modular nature and avoided several protectionedeprotection

events. Thus, the strategy reported here is characterized by ﬂexi-

bility at different stages and has the potential to synthesize

didemniserinolipid analogs by incorporating changes at either end

of the chain.

ester. The ¹³C NMR spectrum showed doublets at 121.5 and

148.9 ppm corresponding to the oleﬁnic carbons and the ester

carbonyl resonated at 166.7 ppm. All other data were in total

agreement with the reported values by the Burke group. The spe-

ciﬁc rotation of the synthetic sample was found to be [

a]

²⁵þ24.6 (c

D

0.5, CHCl₃) [lit.¹²

[a

]

²⁵þ37.6 (c 0.98, CHCl₃)].

D

2.4. Second generation formal total synthesis of didemniser-

inolipid B

Next, to make the synthetic scheme more convergent, to provide

the step-economy, and to demonstrate the substrate ﬂexibility, we

have devised an alternative strategy (Fig. 3) featuring the serinol

coupling with the C₁₇-alkynol followed by alkyne addition to the

epoxide and subsequent cycloisomerization of the resulting ace-

tonide 41. This approach should thus avoid the several intermediate

protectionedeprotection events.

4. Experimental

The execution of the second generation strategy started with the

preparation of mesylate 43 by treatment of alkynol 32 with mesyl

chloride and triethylamine in dichloromethane (Scheme 6). The

coupling of the mesylate 43 and the serinol 5 proceeded smoothly

to provide the key alkyne 42 in 71% yield. The addition of alkyne 42

to epoxide 9 was carried out under established conditions to obtain

the key cycloisomerization substrate 41 in 71% yield. The cyclo-

isomerization of 41 needed substantial catalyst optimization. Under

the standard conditions using the Pd[CH₃CN]₂Cl₂complex, a com-

plex mixture resulting from the formation of requisite bicyclic

ketal, corresponding ketone, along with the deprotection of the

acetonide group present in the serinol unit was noticed. Pd

[PhCN]₂Cl₂was found to be ineffective for this transformation.

Next, various electrophilic [Au]-complexes such as AuCl₃, AuBr₃,

and Au(PPh₃)₃Cl have been screened for the cycloisomerization of

41.²³To this end, the best results were obtained when Au(PPh₃)₃Cl

(5 mol %) was employed in combination with AgSbSF₆(5 mol %) in

CH₂Cl₂. With this catalyst combination, the cycloisomerization of

41 gave compound 44 (in 85% yield) resulting from the requisite

cycloisomerization followed by the deprotection of serinol aceto-

nide.^23cInitially, to provide alternative ﬁnal events in the total

4.1. General methods

All solvents were dried according to the standard methods prior

to use. Commercial reagents were used without puriﬁcation. Col-

umn chromatography was carried out by using spectrochem silica

gel (60e120, 100e200, 230e400 mesh). ¹H and ¹³C NMR spec-

troscopy measurements were carried out on Bruker AC 200 MHz or

Bruker DRX 400 and Bruker DRX 500 MHz spectrometers, and TMS

was used as an internal standard. ¹H and ¹³C NMR chemical shifts

are reported in parts per million (ppm) downﬁeld from chloroform-

d (

(Hz). The following abbreviations are used to designate signal

multiplicity:

d

¼7.25) or TMS and coupling constants (J) are reported in hertz

s¼singlet, d¼doublet,

t¼triplet,

q¼quartet,

m¼multiplet, b¼broad. The multiplicity of ¹³C NMR signals was

assigned with the help of DEPT spectra and the abbreviations used:

s¼singlet, d¼doublet, t¼triplet, q¼quartet, represent C (quater-

nary), CH, CH₂, and CH₃, respectively. The LCMS and HRMS mass

spectra were taken in a Hybrid QuadrupleeTOF LC/MS and MALDI-

TOF, respectively. Elemental analysis data were obtained on

a Thermo Finnigan Flash EA 1112 Series CHNS Analyzer.

Scheme 3. Reagents and conditions: (a) n-BuLi, HMPA, n-C₁₄H₂₉Br, THF, ꢁ10 ^ꢀC, 1 h; (b) cat. p-TSA, MeOH, rt, 1h; (c) Li, KO^tBu, 1,3-diaminopropane, 0 ^ꢀC/rt, 1 h; (d) TBSCl, CH₂Cl₂,

Et₃N, 0 ^ꢀC, 1 h.

1886

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

Table 2

petroleum ether/EtOAc) to procure 17 (2.0 g, 95%) as colorless

25

Conditions explored for the Zipper reaction

syrup: R_f(10% EtOAc/petroleum ether) 0.52; [

CHCl₃); IR (CHCl₃)

: 3018,1496,1372,1216,1064, 758, 668 cm^ꢁ1; ¹H

NMR (CDCl₃, 200 MHz): 1.32 (s, 6H), 1.36 (s, 3H), 1.38 (s, 3H),

a

]

þ18.7 (c 0.6,

D

n

Entry

Reaction conditions

Results obtained

1

2

3

4

5

6

KH, 1,3-diaminopropane, 0 ^ꢀC/rt

KO^tBu, DMSO, rt

<5% Conversion

d

Starting material recovered

Isomerization with 79% yield

1.41e1.72 (m, 8H), 3.45 (t, J¼6.4 Hz, 2H), 3.45 (t, J¼7.7 Hz, 1H),

Na, liq. NH₃, ꢁ78 ^ꢀC

3.82e4.12 (m, 4H), 4.48 (s, 2H), 7.21e7.32 (m, 5H); ¹³C NMR (CDCl₃,

Li, liq. NH₃, ꢁ78 ^ꢀC

50 MHz): d 25.4 (q), 26.0 (t), 26.3 (t), 26.8 (q), 27.1 (q), 27.4 (q), 29.7

KO^tBu, DMSO, 80 ^ꢀC

Li, KO^tBu, 1,3-diaminopropane, rt

(t), 33.7 (t), 67.7 (t), 70.3 (t), 72.8 (t), 77.3 (d), 80.5 (d), 81.2 (d), 108.7

(s), 109.5 (s), 127.4 (d), 127.6 (d, 2C), 128.3 (d, 2C), 138.6 (s) ppm; MS

(ESI) m/z¼401 [MþNa]^þ; HRMS (ESI) calcd for C₂₂H₃₄O₅Na

[MþNa]^þ401.2304, found 401.2271.

4.2. (4S,4⁰R,5R)-5-((Z)-5-(Benzyloxy)pent-1-enyl)-2,2,2⁰,2⁰-tet-

ramethyl-4,4⁰-bi(1,3-dioxolane) (16)

4.4. (R)-1-((4R,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)ethane-1,2-diol (18)

At 0 ^ꢀC, a solution of the aldehyde (4.0 g, 17.4 mmol) in ether

(20 mL) was treated with a solution of the ylide [generated from

BnO(CH₂)₄P^þPh₃I^ꢁ(28.8 g, 52.2 mmol) using KO^tBu (4.9 g,

43.5 mmol) in THF (50 mL) at 0 ^ꢀC] and stirred for 30 min. The

reaction mixture was quenched with saturated NH₄Cl (25 mL). The

organic layer was separated and the aqueous layer was extracted

with ethyl acetate (2ꢂ25 mL). The combined organic layer was

washed with brine, dried (Na₂SO₄), and concentrated. Puriﬁcation

of the crude product by column chromatography (90:10 petroleum

ether/EtOAc) gave 16 (4.4 g, 67%) as colorless syrup: R_f(10% EtOAc/

To a solution of the diacetonide 17 (1.4 g, 3.7 mmol) in MeOH

(10 mL), catalytic p-TSA (5 mg, 0.03 mmol) was added and the re-

action mixture was stirred at 0 ^ꢀC for 20 h. The reaction mixture

was quenched by the addition of few drops of triethylamine and the

solvent was evaporated. The crude residue was puriﬁed by column

chromatography (65:35 petroleum ether/EtOAc) to obtain 18 (1.0 g,

25

80%) as a colorless oil: R_f(50% EtOAc/petroleum ether) 0.3; [

þ30.8 (c 1.0, CHCl₃); IR (CHCl₃)

759, 669 cm^ꢁ^{1 1}H NMR (CDCl₃, 200 MHz):

a]

D

n

: 3433, 2936,1415,1373,1216,1069,

1.35 (s, 3H), 1.37 (s,

petroleum ether) 0.5; [

a

]

D

²⁵þ10.7 (c 1.3, CHCl₃); IR (CHCl₃)

n: 2986,

;

d

1448, 1243, 1048, 847, 634, 467 cm^ꢁ1

;

¹H NMR (CDCl₃, 200 MHz):

3H), 1.40e1.49 (m, 2H), 1.45 (br s, 1H), 1.56e1.69 (m, 5H), 2.16 (br s,

1H), 2.53 (d, J¼4.0 Hz, 1H), 3.45 (t, J¼6.4 Hz, 2H), 3.57e3.78 (m, 4H),

3.92 (dt, J¼3.5, 7.7 Hz, 1H), 4.48 (s, 2H), 7.24e7.33 (m, 5H); ¹³C NMR

d

1.31 (s, 3H), 1.36 (s, 3H),1.38 (s, 3H), 1.41 (s, 3H), 1.67e1.75 (m, 2H),

2.22e2.31 (m, 2H), 3.48 (t, J¼6.4 Hz, 2H), 3.70 (dd, J¼6.4, 7.6 Hz,1H),

3.89e3.95 (m, 1H), 4.01e4.10 (m, 2H), 4.50 (s, 2H), 4.68 (ddd, J¼0.7,

7.6, 8.7 Hz, 1H), 5.42 (tt, J¼1.5, 10.7 Hz, 1H), 5.64 (tt, J¼7.7, 10.9 Hz,

(CDCl₃, 50 MHz):

d 25.9 (t), 26.0 (t), 27.0 (q), 27.3 (q), 29.5 (t), 33.9

(t), 63.8 (t), 70.2 (t), 72.7 (d), 72.7 (t), 79.3 (d), 80.8 (d), 108.6 (s),

127.4 (d), 127.5 (d, 2C), 128.2 (d, 2C), 138.4 (s) ppm; MS (ESI) m/

z¼361 [MþNa]^þ; HRMS (ESI) calcd for C₁₉H₃₀O₅Na [MþNa]^þ

361.1991, found 361.1972.

1H), 7.27e7.35 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz):

d 24.4 (t), 25.2

(q), 26.6 (q), 26.9 (q), 27.2 (q), 29.3 (t), 66.8 (t), 69.5 (t), 72.8 (t), 74.9

(d), 76.3 (d), 81.1 (d), 109.2 (s), 109.4 (s), 127.4 (d, 2C), 127.5 (d, 2C),

128.3 (d, 2C), 134.9 (d), 138.5 (s) ppm; MS (ESI) m/z¼399 [MþNa]^þ;

HRMS (ESI) calcd for C₂₂H₃₂O₅Na [MþNa]^þ399.2147, found

399.2148.

4.5. (R)-2-((4R,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)-2-hydroxyethyl 4-methyl-benzenesulfonate

(19)

4.3. (4S,4⁰R,5R)-5-(5-(Benzyloxy)pentyl)-2,2,2⁰,2⁰-tetramethyl-

To an ice-cooled solution of the diol 18 (500 mg, 1.48 mmol) in

CH₂Cl₂(15 mL), were added Bu₂SnO (10 mg), DMAP (10 mg), and

Et₃N (0.3 mL, 2.22 mmol) and stirred for 0.5 h at rt. The reaction

mixture was cooled to 0 ^ꢀC and treated with p-TsCl (280 mg,

1.48 mmol) and stirring was continued for 4 h at rt. Solvent was

evaporated under reduced pressure, and the residue was puriﬁed

by column chromatography (80:20 petroleum ether/EtOAc) to yield

19 (655 mg, 90%) as colorless syrup: R_f(30% EtOAc/petroleum

4,4⁰-bi(1,3-dioxolane) (17)

A suspension of the diacetonide 16 (2.1 g, 5.6 mmol), Raney-Ni

(50 mg) in ethanol (20 mL) was ﬂushed with hydrogen gas and

stirred under hydrogen (20 psi) atmosphere for 30 min. The re-

action mixture was ﬁltered through Celite, concentrated, and the

crude product was puriﬁed by column chromatography (90:10

Scheme 4. Reagents and conditions: (a) n-BuLi, BF₃$Et₂O, THF, ꢁ78 ^ꢀC, 1 h; (b) BzCl, Et₃N, CH₂Cl₂, 0 ^ꢀC, 2 h; (c) cat. p-TSA, MeOH, rt, 1 h; (d) 5 mol % Pd(CH₃CN)₂Cl₂, CH₃CN, rt, 2 h;

(e) TBSCl, NEt₃, CH₂Cl₂, 0 ^ꢀC, 2 h; (f) BnBr, NaH, THF, 0 ^ꢀC, 1 h (g) cat. p-TSA, MeOH, rt, 30 min.

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

1887

Scheme 5. Reagents and conditions: (a) MsCl, Et₃N, CH₂Cl₂, 0 ^ꢀC, 1 h; (b) 5, NaH, DMSO, 0 ^ꢀC/rt, 16 h; c) cat. 20% Pd(OH)₂, EtOAc, H₂(1 atm), rt, 30 min; (d) i. DMP, CH₂Cl₂, 0 ^ꢀC/rt,

6 h; ii. Ph₃P]CHCO₂Et, benzene, reﬂux, 1 h.

25

ether) 0.46; [

a

]

þ33.0 (c 1.0, CHCl₃); IR (CHCl₃)

n

: 3434, 2984,

¹H NMR (CDCl₃, 200 MHz):

1.28 (s, 3H), 1.32 (s, 3H), 1.35e1.44 (m, 3H), 1.48e1.69 (m, 5H), 2.45

4.7. (R)-2-((4R,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)-2-hydroxyethyl benzoate (22)

D

1560, 1375, 1247, 1047, 757, 668 cm^ꢁ1

;

d

(s, 3H), 2.47 (br s, 1H), 3.45 (t, J¼6.4 Hz, 2H), 3.48 (t, J¼3.4 Hz, 1H),

3.72e3.83 (m, 1H), 3.91 (dd, J¼3.2, 7.4 Hz, 1H), 4.01 (dd, J¼6.9,

10.5 Hz,1H), 4.25 (dd, J¼2.8, 10.5 Hz, 1H), 4.48 (s, 2H), 7.23e7.32 (m,

5H), 7.34 (d, J¼8.2 Hz, 2H), 7.79 (d, J¼8.2 Hz, 2H); ¹³C NMR (CDCl₃,

At 0 ^ꢀC, to a cooled solution of the diol 18 (4 g, 11.8 mmol) in

CH₂Cl₂(50 mL), Bu₂SnO (50 mg), DMAP (50 mg), and Et₃N (5 mL,

35.5 mmol) were added and stirred for 30 min at the same tem-

perature. To this, benzoyl chloride (1.51 mL, 13.0 mmol) was added

dropwise and the reaction mixture was further stirred for 8 h while

warming to rt. Reaction mixture was poured into water (25 mL) and

the aqueous layer was extracted with CH₂Cl₂(2ꢂ25 mL). Combined

organic layer was washed with brine, dried (Na₂SO₄), and con-

centrated under reduce pressure. The residue was puriﬁed by col-

umn chromatography (85:15 petroleum ether/EtOAc) to obtain 22

(4.6 g, 88%) as colorless syrup: R_f(10% EtOAc/petroleum ether) 0.46;

50 MHz):

d 21.7 (q), 25.9 (t), 26.1 (t), 27.0 (q), 27.4 (q), 29.6 (t), 34.0

(t), 70.3 (t), 71.5 (d), 72.1 (t), 72.8 (t), 79.4 (d), 80.1 (d), 109.9 (s),

127.5 (d), 127.6 (d, 2C), 128.1 (d, 2C), 128.3 (d, 2C), 129.9 (d, 2C),

132.7 (s), 138.6 (s), 144.9 (s) ppm; MS (ESI) m/z¼515 [MþNa]^þ. Anal.

calcd for C₂₆H₃₆O₇S: C, 63.39; H, 7.37; S, 6.51%, found C, 63.28; H,

7.20; S, 6.12%.

[a

]

²⁵þ36.0 (c 3.1, CHCl₃); IR (CHCl₃)

n

: 3444, 3019, 1719, 1372, 1276,

1.39 (s, 3H),

D

4.6. (4R,5S)-4-(5-(Benzyloxy)pentyl)-2,2-dimethyl-5-((R)-ox-

iran-2-yl)-1,3-dioxolane (9)

1215, 1047, 758, 668 cm^ꢁ1; ¹H NMR (CDCl₃, 200 MHz):

d

1.4 (s, 3H), 1.45e1.79 (m, 8H), 2.93 (br s, 1H), 3.45 (t, J¼6.6 Hz, 2H),

3.69 (t, J¼7 Hz, 1H), 3.91e4.1 (m, 2H), 4.39 (dd, J¼6.6, 11.8 Hz, 1H),

4.48 (s, 2H), 4.58 (dd, J¼3.2, 11.8 Hz, 1H), 7.23e7.32 (m, 5H), 7.34 (d,

J¼8.2 Hz, 2H), 7.57 (tt, J¼1.4, 6.1 Hz, 1H), 7.79 (d, J¼8.2 Hz, 2H); ¹³C

A suspension of the tosylate 19 (500 mg, 1.02 mmol) and K₂CO₃

(210 mg, 1.52 mmol) in MeOH (10 mL) was stirred at 0 ^ꢀC under

argon atmosphere for 1 h. The reaction mixture was ﬁltered, con-

centrated, and the residue was puriﬁed by silica gel chromatogra-

NMR (CDCl₃, 50 MHz):

d 25.9 (t), 26.1 (t), 27.0 (q), 27.4 (q), 29.5 (t),

34.1 (t), 66.8 (t), 70.3 (t), 71.6 (d), 72.8 (t), 79.3 (d), 80.3 (d), 108.9 (s),

127.4 (d), 127.6 (d, 2C), 128.3 (d, 2C), 128.4 (d, 2C), 129.6 (s), 129.7 (d,

2C), 133.2 (d), 138.5 (s), 167.0 (s); MS (ESI) m/z¼465 [MþNa]^þ;

HRMS (ESI) calcd for C₂₆H₃₄O₆Na [MþNa]^þ465.2253, found

465.2258.

phy (80:20 petroleum ether/EtOAc) to obtain 9 (300 mg, 92%) as

25

colorless oil: R_f(30% EtOAc/petroleum ether) 0.5; [

CHCl₃); IR (CHCl₃)

698 cm^ꢁ1; ¹H NMR (CDCl₃, 200 MHz):

a

]

þ4.5 (c 1.2,

D

n

: 2937, 2861, 1455, 1371, 1217, 1099, 876, 756,

1.40 (s, 6H), 1.42e1.53 (m,

d

3H), 1.57e1.71 (m, 5H), 2.64 (dd, J¼2.5, 5.0 Hz, 1H), 2.80 (dd, J¼3.9,

5.0 Hz, 1H), 2.95 (ddd, J¼2.5, 3.9, 6.3 Hz, 1H), 3.28 (dd, J¼6.3, 7.8 Hz,

1H), 3.47 (t, J¼6.5 Hz, 2H), 3.96 (dt, J¼4.7, 7.8 Hz, 1H), 4.49 (s, 2H),

4.8. (R)-2-((4S,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)-2-(methylsulfonyloxy)ethyl benzoate (23)

7.22e7.34 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz):

d

25.6 (t), 26.1 (t),

26.6 (q), 27.1 (q), 29.5 (t), 33.1 (t), 45.1 (t), 51.5 (d), 70.2 (t), 72.7 (t),

79.5 (d), 81.1 (d),109.0 (s),127.4 (d),127.5 (d, 2C),128.2 (d, 2C),138.6

(s) ppm; MS (ESI) m/z¼343 [MþNa]^þ; HRMS (ESI) calcd for

C₁₉H₂₈O₄Na [MþNa]^þ343.1886, found 343.1860.

To an ice-cooled solution of benzoate 22 (1.5 g, 3.4 mmol) in

CH₂Cl₂(15 mL) and Et₃N (1.43 mL, 10.2 mmol) was added MsCl

(0.4 mL, 5.1 mmol) and it was further stirred for 4 h at rt. Reaction

Fig. 3. Alternative retrosynthetic strategy for didemniserinolipid B.

1888

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

Scheme 6. Reagents and conditions: (a) MsCl, Et₃N, CH₂Cl₂, 0 ^ꢀC, 1 h; (b) 5, NaH, DMSO, 0 ^ꢀC/rt, 16 h; (c) n-BuLi, BF₃$Et₂O, THF, ꢁ78 ^ꢀC, 1 h; (d) Au(PPh₃)₃Cl (5 mol %), AgSbSF₆

(5 mol %), CH₂Cl₂, 0/rt, 3 h; (e) AC₂O, Et₃N, cat. DMAP, CH₂Cl₂, 0 ^ꢀC, 2 h; (f) cat. PdeC, EtOAc, rt, 30 min; (g) i. DMP, CH₂Cl₂, 0 ^ꢀC/rt, 6 h; ii. Ph₃P]CHCO₂Et, benzene, reﬂux, 1 h; (h)

2,2-dimethoxypropane, cat. p-TSA, acetone, 0 ^ꢀC/rt, 16 h; (i) cat. 20% Pd(OH)₂, EtOAc, H₂(1 atm), rt, 30 min.

mixture was diluted with CH₂Cl₂(15 mL) and washed with water,

brine, dried (Na₂SO₄), and the solvent was evaporated under re-

duced pressure. The resulting residue was puriﬁed by column

[MþNa]^þ; HRMS (ESI) calcd for C₁₉H₂₈O₄Na [MþNa]^þ343.1886,

found 343.1821.

chromatography (75:25 petroleum ether/EtOAc) to yield 23 (1.6 g,

4.10. General procedure for epoxide opening (A)

25

90%) as colorless solid: R_f(20% EtOAc/petroleum ether) 0.5; [

þ28.4 (c 8.8, CHCl₃); IR (CHCl₃)

925, 758, 667 cm^ꢁ^{1 1}H NMR (CDCl₃, 400 MHz):

a]

D

n

: 2934, 1723, 1560, 1366, 1274, 1177,

1.41 (s, 6H),

At ꢁ78 ^ꢀC, to a solution of 1-alkyne (4 mmol) in THF (15 mL)

were added n-BuLi (4 mmol) and BF₃$Et₂O (4 mmol) followed by

a solution of the epoxide (1 mmol) in THF (8 mL) with a 15 min

interval. The stirring was continued for another 30 min at ꢁ78 ^ꢀC

and then quenched with NH₄Cl (5 mL). The reaction mixture was

allowed to reach rt and partitioned between ethyl acetate (25 mL)

and water (25 mL). The aqueous layer was extracted with ethyl

acetate (2ꢂ25 mL) and the combined organic layer was washed

with brine, dried over Na₂SO₄, and concentrated. Puriﬁcation of the

crude alkynol product was carried out by column chromatography.

;

d

1.45e1.77 (m, 8H), 3.05 (s, 3H), 3.45 (t, J¼7.4 Hz, 2H), 3.89 (t,

J¼6.7 Hz, 1H), 4.12 (ddd, J¼2.9, 8.2, 10.1 Hz, 1H), 4.43 (d, J¼7.1 Hz,

1H), 4.46 (s, 2H), 4.75 (d, J¼12.5 Hz 1H), 5.01 (t, J¼6.6 Hz 1H),

7.23e7.32 (m, 5H), 7.42 (d, J¼8.2 Hz, 2H), 7.54 (d, J¼1.4,6.1 Hz, 1H),

8.06 (d, J¼8.2 Hz, 2H); ¹³C NMR (CDCl₃,100 MHz):

d 25.6 (t), 25.8 (t),

26.6 (q), 27.1 (q), 29.3 (t), 33.6 (t), 38.6 (q), 63.2 (t), 69.9 (t), 72.5 (t),

78.4 (d), 78.5 (d), 78.9 (d), 109.4 (s), 127.2 (d), 127.3 (d, 2C), 128.0 (d,

2C), 128.3 (d, 2C), 129.1 (s), 129.4 (d, 2C), 133.2 (d), 138.4 (s), 165.7

(s) ppm; MS (ESI) m/z¼543 [MþNa]^þ; HRMS (ESI) calcd for

C₂₇H₃₆O₈SNa [MþNa]^þ543.2029, found 543.2015.

4.11. (R)-1-((4R,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)non-3-yn-1-ol (20)

4.9. (4R,5S)-4-(5-(Benzyloxy)pentyl)-2,2-dimethyl-5-((S)-ox-

iran-2-yl)-1,3-dioxolane (15)

1-Heptyne (594 mg, 6.2 mmol), n-BuLi (3.9 mL, 6.2 mmol, 1.6 M

in hexane), BF₃$Et₂O (0.77 mL, 6.2 mmol), and epoxide 9 (0.5 g,

1.6 mmol) were subjected to general procedure A. The crude

product was puriﬁed by silica gel chromatography (85:15 petro-

A solution of the mesylate 23 (2 g, 3.8 mmol), LiOH$H₂O

(483 mg, 11.5 mmol) in MeOH/THF (2:3, 10 mL) was stirred at rt for

4 h. The reaction mixture was concentrated and dissolved in ethyl

acetate (25 mL), washed with brine, dried, and concentrated under

reduce pressure. The crude residue thus obtained was puriﬁed by

silica gel chromatography (85:15 petroleum ether/EtOAc) to obtain

15 (1.1 g, 89%) as colorless oil: R_f(20% EtOAc/petroleum ether) 0.53;

leum ether/EtOAc) to afford 20 (530 mg, 82%) as a colorless syrup:

25

R_f(10% EtOAc/petroleum ether) 0.57; [

(CHCl₃)

668 cm^ꢁ1; ¹H NMR (CDCl₃, 200 MHz):

a

]

þ37.3 (c 2.5, CHCl₃); IR

D

n

: 3546, 2934, 2861, 2401, 1455, 1370, 1217, 1101, 878, 769,

0.90 (t, 3H), 1.27e1.33 (m,

d

4H), 1.35 (s, 3H), 1.38 (s, 3H), 1.40e1.70 (m, 10H), 2.11e2.16 (m, 2H),

2.16 (br s, 1H), 2.45e2.50 (m, 2H), 3.46 (t, J¼6.6 Hz, 2H), 3.60e3.77

(m, 2H), 3.98 (dt, J¼3.5, 7.0 Hz, 1H), 4.49 (s, 2H), 7.24e7.33 (m, 5H);

[

a]

²⁵þ6.2 (c 0.9, CHCl₃); IR (CHCl₃)

n

: 2935, 2859, 1455, 1370, 1216,

D

1101, 878, 737, 698 cm^ꢁ1; ¹H NMR (CDCl₃, 400 MHz):

d

1.38 (s, 6H),

1.42e1.66 (m, 8H), 2.69 (dd, J¼2.6, 5.2 Hz, 1H), 2.79 (dd, J¼4.4,

5.2 Hz, 1H), 2.99 (ddd, J¼2.7, 4.2, 6.8 Hz, 1H), 3.47 (m, 3H), 3.95 (dt,

J¼4.9, 8.2 Hz, 1H), 4.49 (s, 2H), 7.22e7.34 (m, 5H); ¹³C NMR (CDCl₃,

¹³C NMR (CDCl₃, 50 MHz):

d 14.0 (q), 18.7 (t), 22.2 (t), 24.3 (t), 26.1

(t), 26.3 (t), 27.1 (q), 27.5 (q), 28.6 (t), 29.7 (t), 31.1 (t), 34.5 (t), 70.4

(t), 70.9 (d), 72.9 (t), 74.9 (s), 78.9 (d), 81.9 (d), 84.0 (s), 108.6 (s),

127.5 (d), 127.7 (d, 2C), 128.4 (d, 2C), 138.7 (s) ppm; MS (ESI) m/

z¼439 [MþNa]^þ; HRMS (ESI) calcd for C₂₆H₄₀O₄Na [MþNa]^þ

439.2825, found 439.2826.

100 MHz): d 25.8 (t), 26.2 (t), 26.6 (q), 27.2 (q), 29.6 (t), 33.0 (t), 43.9

(t), 51.4 (d), 70.2 (t), 72.9 (t), 77.8 (d), 81.2 (d), 109.2 (s), 127.5 (d),

127.6 (d, 2C), 128.3 (d, 2C), 138.6 (s) ppm; MS (ESI) m/z¼343

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

1889

4.12. (R)-1-((4R,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-

1,3-dioxolan-4-yl)non-3-yn-1-ol (24)

70.3 (t), 70.6 (d), 72.8 (t), 74.8 (s), 77.2 (d), 80.5 (d), 83.0 (s),108.8 (s),

127.5 (d), 127.6 (d, 2C), 128.3 (d, 2C), 128.4 (d, 2C), 129.8 (d, 2C),

129.9 (s), 133.2 (d), 138.7 (s), 165.9 (s) ppm; MS (ESI) m/z¼543

[MþNa]^þ; HRMS (ESI) calcd for C₃₃H₄₄O₅Na [MþNa]^þ543.3086,

found 543.3096.

Epoxide 15 (400 mg, 1.25 mmol), 1-heptyne (480 mg, 5.0 mmol),

BF₃$Et₂O (0.63 mL, 5.0 mmol), and n-BuLi (3.1 mL, 5.0 mmol, 1.6 M

in hexane) were subjected to general procedure A. The crude

product was puriﬁed by silica gel chromatography (85:15 petro-

4.15. General procedure for acetonide deprotection (B)

leum ether/EtOAc) to obtain alkynol 24 (410 mg, 78%) as a colorless

25

syrup: R_f(10% EtOAc/petroleum ether) 0.58; [

CHCl₃); IR (CHCl₃)

714 cm^ꢁ^{1 1}H NMR (CDCl₃, 200 MHz):

a]

þ55.8 (c 1.6,

A solution of acetonide (1 mmol) in 60% AcOH in water (5 mL)

was stirred at 80 ^ꢀC for 2e4 h. The reaction mixture was evapo-

rated. The crude residue was washed with toluene (10 mL) three

times. Then it was puriﬁed by column chromatography.

D

n

: 3431, 2935, 1453, 1380, 1276, 1068, 879,

;

d

0.90 (t, J¼6.9 Hz, 3H),

1.22e1.33 (m, 4H), 1.39 (s, 3H), 1.40 (s, 3H), 1.44e1.70 (m, 10H), 2.14

(tt, J¼2.2, 4.5, 6.9 Hz, 2H), 2.31e2.53 (m, 3H), 3.46 (t, J¼6.6 Hz, 2H),

3.61 (br s 1H), 3.75 (dd, J¼2.8, 8.1 Hz, 1H), 3.96 (dt, J¼3.5, 7.0 Hz,

1H), 4.49 (s, 2H), 7.24e7.33 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz):

4.16. (6R,7S,8R)-1-(Benzyloxy)tetradec-10-yne-6,7,8-triol (11)

d

14.0 (q),18.7 (t), 22.2 (t), 25.3 (t), 25.9 (t), 26.3 (t), 26.9 (q), 27.5 (q),

Acetonide 20 (150 mg, 0.36 mmol) was subjected to general

procedure B and the crude product was puriﬁed by silica gel

chromatography (15:85 petroleum ether/EtOAc) to obtain 11

28.6 (t), 29.6 (t), 31.0 (t), 33.1 (t), 69.0 (d), 70.2 (t), 72.8 (t), 75.5 (s),

77.8 (d), 81.8 (d), 83.0 (s), 108.8 (s), 127.5 (d), 127.6 (d, 2C), 128.3 (d,

2C), 138.6 (s) ppm; MS (ESI) m/z¼439 [MþNa]^þ; HRMS (ESI) calcd

for C₂₆H₄₀O₄Na [MþNa]^þ439.2824, found 439.2810.

(120 mg, 88%) as a white solid: R_f(80% EtOAc/petroleum ether)

31

0.35; mp: 51e52 ^ꢀC; [

a]

þ3.1 (c 2.9, CHCl₃); IR (CHCl₃)

n

: 3400,

D

2933, 2859, 1603, 1495, 1455, 1216, 1098, 756, 697, 666 cm^ꢁ1

NMR (CDCl₃, 400 MHz):

;

¹H

4.13. (R)-1-((4S,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)non-3-ynyl benzoate (21)

d

0.9 (t, J¼7.0, 3H), 1.28e1.35 (m, 5H),

1.37e1.44 (m, 3H), 1.46e1.55 (m, 3H), 1.59e1.65 (m, 3H), 2.14 (tt,

J¼2.3, 7.1 Hz, 2H), 2.48e2.50 (m, 2H), 2.96e3.02 (m, 2H), 3.17 (br s,

1H), 3.47 (t, J¼6.6 Hz, 3H), 3.81 (q, J¼6.6 Hz,1H), 3.98 (br s,1H), 4.49

To an ice-cooled solution of 20 (500 mg, 1.2 mmol), Et₃N (0.5 mL,

3.60 mmol), and DMAP (20 mg) CH₂Cl₂(10 mL) was added benzoyl

chloride (0.21 mL, 1.8 mmol) and stirred for 2 h at rt. The reaction

mixture was poured into water (10 mL) and extracted with CH₂Cl₂

(2ꢂ10 mL). The combined organic layer was washed with brine,

dried (Na₂SO₄), and concentrated under reduced pressure. The

resulting crude product was puriﬁed by column chromatography

(s, 2H), 7.26e7.34 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz):

d 13.9 (q),

18.6 (t), 22.1 (t), 23.9 (t), 25.5 (t), 26.1 (t), 28.6 (t), 29.6 (t), 31.0 (t),

33.5 (t), 70.3 (d), 70.4 (t), 71.8 (d), 72.8 (t), 73.9 (d), 75.4 (s), 83.6 (s),

127.5 (d), 127.6 (d, 2C), 128.3 (d, 2C), 138.5 (s) ppm; MS (ESI) m/

z¼399 [MþNa]^þ; HRMS (ESI) calcd for C₂₃H₃₆O₄Na [MþNa]^þ

399.2513, found 399.2512.

(90:10 petroleum ether/EtOAc) to afford the benzoate 21 (560 mg,

25

89%) as colorless syrup: R_f(10% EtOAc/petroleum ether) 0.5; [

þ51.2 (c 1.1, CHCl₃); IR (CHCl₃)

669 cm^ꢁ^{1 1}H NMR (CDCl₃, 400 MHz):

a

]

4.17. (6R,7S,8R)-1-(Benzyloxy)-6,7-dihydroxyhexadec-10-yn-

8-yl benzoate (12)

D

n

: 3019, 1717, 1214, 1111, 757, 711,

0.82 (t, J¼7.1 Hz, 3H),

;

d

1.19e1.34 (m, 8H), 1.36 (s, 3H), 1.41 (s, 3H), 1.46e1.70 (m, 6H), 2.09

(tt, J¼2.1, 6.8 Hz, 2H), 2.63e2.75 (m, 2H), 3.39 (t, J¼6.5 Hz, 2H),

3.96e4.07 (m, 2H), 4.45 (s, 2H), 5.23 (dd, J¼5.8,11.6 Hz, 1H),

7.26e7.35 (m, 5H), 7.41e7.45 (m, 2H),7.53e7.57 (m, 1H), 8.04 (d,

Acetonide 21 (200 mg, 0.38 mmol) was subjected to general

procedure B. The crude product was puriﬁed by silica gel chroma-

tography (40:60 petroleum ether/EtOAc) to obtain 12 (152 mg, 82%)

25

as a colorless thick syrup: R_f(50% EtOAc/petroleum ether) 0.5; [

þ20.2 (c 7.1, CHCl₃); IR (CHCl₃)

757, 712, 640, 668 cm^ꢁ^{1 1}H NMR (CDCl₃, 200 MHz):

a]

D

J¼7.3 Hz, 2H); ¹³C NMR (CDCl₃,100 MHz):

d

13.9 (q), 18.6 (t), 21.6 (t),

n

: 3443, 2932, 1721, 1452, 1272, 1113,

0.81 (t,

22.1 (t), 25.9 (t), 26.1 (t), 27.0 (q), 27.5 (q), 28.5 (t), 29.5 (t), 30.9 (t),

34.2 (t), 70.2 (t), 72.8 (t), 72.9 (d), 74.6 (s), 78.8 (d), 80.3 (d), 82.9 (s),

109.2 (s), 127.5 (d), 127.6 (d, 2C), 128.3 (d, 2C), 128.4 (d, 2C), 129.7 (d,

2C), 129.9 (s), 133.1 (d), 138.6 (s), 165.6 (s) ppm; MS (ESI) m/z¼543

[MþNa]^þ; HRMS (ESI) calcd for C₃₃H₄₄O₅Na [MþNa]^þ543.3087,

found 543.3043.

;

d

J¼7.2 Hz, 3H), 1.12e1.67 (m, 14H), 2.03 (m, 2H), 2.55 (br d, J¼8.1 Hz,

1H), 2.74e2.82 (m, 2H), 2.9 (br s, 1H), 3.43 (t, J¼6.5 Hz, 2H),

3.55e3.65 (m, 2H), 4.46 (s, 2H), 5.08 (ddd, J¼4.6, 6.1, 10.7 Hz, 1H),

7.24e7.32 (m, 5H), 7.43 (dd, J¼1.4, 7.2 Hz,1H), 7.46 (dd, J¼1.4, 7.7 Hz,

1H), 7.59 (tt, J¼2.5, 8.7 Hz, 1H), 8.07 (tt, J¼1.6, 7.2 Hz, 2H); ¹³C NMR

(CDCl₃, 50 MHz): d 13.9 (q),18.6 (t), 21.7 (t), 22.1 (t), 25.7 (t), 26.2 (t),

4.14. (S)-1-((4S,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-1,3-

dioxolan-4-yl)non-3-ynyl benzoate (25)

28.5 (t), 29.6 (t), 30.9 (t), 33.0 (t), 69.3 (d), 70.2 (t), 72.8 (t), 73.2 (d),

73.5 (d), 75.1 (s), 82.7 (s), 127.4 (d), 127.6 (d, 2C), 128.3 (d, 2C), 128.4

(d, 2C), 129.5 (s), 129.9 (d, 2C), 133.4 (d), 138.6 (s), 167.1 (s) ppm; MS

(ESI) m/z¼481 [MþH]^þ; HRMS (ESI) calcd for C₃₀H₄₀O₅Na [MþNa]^þ

503.2773, found 503.2799.

To a solution of 24 (600 mg, 1.40 mmol) in CH₂Cl₂(10 mL) at 0 ^ꢀC

was added triethylamine (0.6 mL, 4.3 mmol), DMAP (10 mg) and

stirred for 15 min. Benzoyl chloride (0.25 mL, 2.2 mmol) was added

at 0 ^ꢀC and stirred further for 2 h. Usual workup followed by pu-

riﬁcation of the crude product by column chromatography (90:10

petroleum ether/EtOAc) gave the benzoate 25 (665 mg, 89%) as

4.18. (6R,7S,8S)-1-(Benzyloxy)tetradec-10-yne-6,7,8-triol (13)

Acetonide 24 (140 mg, 0.34 mmol) was subjected to general

procedure B. The crude product was puriﬁed by silica gel chroma-

tography (15:85 petroleum ether/EtOAc) to obtain 13 (105 mg, 83%)

as a white solid: R_f(80% EtOAc/petroleum ether) 0.36; mp:

colorless syrup: R_f(7% EtOAc/petroleum ether) 0.5; [

CHCl₃); IR (CHCl₃) : 3448, 2933, 1717, 1453, 1271, 1111, 877, 758,

666 cm^ꢁ^{1 1}H NMR (CDCl₃, 400 MHz):

0.83 (t, J¼7.1 Hz, 3H),

a]

²⁵50.8 (c 1.2,

D

n

;

d

1.21e1.3 (m, 6H), 1.40 (s, 3H), 1.42 (s, 3H), 1.48e1.7 (m, 8H), 2.09 (tt,

J¼2.4, 6.9 Hz, 2H), 2.67 (ddd, J¼2.3, 6.8, 9.1 Hz, 2H), 3.44 (t, J¼6.6 Hz,

2H), 3.84 (dt, J¼3.8, 8.1,11.9 Hz,1H), 4.01 (dd, J¼2.8, 8.7 Hz,1H), 4.48

(s, 2H), 5.23 (dt, J¼2.7, 6.8, 9.5 Hz, 1H), 7.26e7.33 (m, 5H), 7.43 (tt,

J¼1.5, 7.9 Hz, 2H), 7.56 (tt, J¼2.6, 7.3 Hz, 1H), 8.07 (tt, J¼1.5, 7.2 Hz,

40e42 ^ꢀC; [

a]

³¹þ8.1 (c 2.8, CHCl₃); IR (CHCl₃)

n

: 3422, 2932, 2859,

;

D

1719, 1602, 1453, 1275, 1070, 755, 697 cm^ꢁ1

¹H NMR (CDCl₃,

400 MHz):

d

0.9 (t, J¼7.1 Hz, 3H), 1.27e1.34 (m, 4H), 1.35e1.42 (m,

3H), 1.44e1.49 (m, 3H), 1.51e1.58 (m, 2H), 1.59e1.65 (m, 2H), 2.13

(tt, J¼2.3, 7.1 Hz, 2H), 2.42e2.5 (m, 2H), 2.89 (br s, 2H), 3.4 (br s, 1H),

3.46 (t, J¼6.6 Hz, 3H), 3.69 (br s, 1H), 3.79 (br s, 1H), 4.48 (s, 2H),

2H); ¹³C NMR (CDCl₃, 100 MHz):

d 14.0 (q), 18.6 (t), 22.0 (t), 22.2 (t),

25.9 (t), 26.3 (t), 26.8 (q), 27.5 (q), 28.5 (t), 29.6 (t), 30.9 (t), 33.0 (t),

7.24e7.34 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz):

d 13.9 (q), 18.6 (t),

1890

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

22.1 (t), 24.3 (t), 25.3 (t), 26.1 (t), 28.6 (t), 29.6 (t), 31.0 (t), 33.6 (t),

70.3 (t), 72.4 (d), 72.8 (t), 73.2 (d), 73.4 (d), 75.6 (s), 83.3 (s), 127.5

(d), 127.6 (d, 2C), 128.3 (d, 2C), 138.5 (s) ppm; MS (ESI) m/z¼399

[MþNa]^þ; HRMS (ESI) calcd for C₂₃H₃₆O₄Na [MþNa]^þ399.2512.

found 399.2516.

(m, 2H), 1.8e1.85 (m, 2H), 1.86e1.9 (dd, J¼6.9, 9.7 Hz 2H), 3.42 (t,

J¼6.5 Hz, 2H), 3.76 (d, J¼5.4 Hz, 1H), 4.46 (s, 2H), 4.66 (d, J¼4.6 Hz

1H), 5.08 (ddd, J¼5.5, 7.3, 12.8 Hz, 1H), 7.26e7.33 (m, 5H), 7.42 (dd,

J¼1.6, 7.6 Hz, 2H), 7.53 (tt, J¼1.5, 8.7 Hz, 1H), 8.05 (tt, J¼1.6, 6.9 Hz,

2H); ¹³C NMR (CDCl₃, 125 MHz):

d 14.0 (q), 22.5 (t), 23.8 (t), 25.4 (t),

26.1 (t), 28.8 (t), 29.6 (t), 30.2 (t), 32.0 (t, 2C), 34.5 (t), 70.3 (t), 72.9

(t), 74.3 (d), 77.2 (d), 81.4 (d), 110.7 (s), 127.5 (d), 127.6 (d, 2C), 128.2

(d, 2C), 128.32 (d, 2C), 129.7 (d, 2C), 130.5 (s), 132.7 (d), 138.6 (s),

166.3 (s) ppm; MS (ESI) m/z¼481 [MþH]^þ; HRMS (ESI) calcd for

C₃₀H₄₀O₅Na [MþNa]^þ503.2773, found 503.2774.

4.19. (6R,7S,8S)-1-(Benzyloxy)-6,7-dihydroxyhexadec-10-yn-

8-yl benzoate (14)

Acetonide 25 (200 mg, 0.38 mmol) was subjected to general

procedure B. The crude product was puriﬁed by silica gel chroma-

tography (30:70 petroleum ether/EtOAc) to obtain 14 (155 mg, 84%)

4.23. (1R,2R,5S,7R)-7-(5-(Benzyloxy)pentyl)-5-pentyl-6,8-

dioxabicyclo[3.2.1]octan-2-ol (28)

as a white syrup: R_f(60% EtOAc/petroleum ether) 0.43; [

2.7, CHCl₃); IR (CHCl₃)

668, 617 cm^ꢁ^{1 1}H NMR (CDCl₃, 400 MHz):

a

]

²⁵þ4.7 (c

D

n

: 3448, 2932, 1718, 1451, 1273, 1114, 758,

;

d

0.9 (t, J¼7.1 Hz, 3H),

Triol 13 (150 mg, 0.36 mmol) and Pd (CH₃CN)₂Cl₂(5 mg,

0.02 mmol) were subjected to general procedure C. The crude

product was puriﬁed by silica gel chromatography (80:20 petro-

1.27e1.36 (m, 4H), 1.42e1.49 (m, 6H), 1.59e1.62 (m, 2H), 1.80e1.83

(m, 2H), 2.12 (tt, J¼2.2, 7.1 Hz, 2H), 2.50 (m, 3H), 2.74 (br s, 1H), 3.44

(t, J¼6.6 Hz, 2H), 3.77 (br s, 2H), 4.47 (s, 2H), 5.26 (ddd, J¼4.4, 6.1,

10.4 Hz, 1H), 7.24e7.34 (m, 5H), 7.43 (tt, J¼1.5, 7.1 Hz, 2H), 7.56 (tt,

J¼2.3, 7.3 Hz, 1H), 8.06 (tt, J¼1.5, 7.1 Hz, 2H); ¹³C NMR (CDCl₃,

leum ether/EtOAc) to obtain 28 (125 mg, 81%) as colorless syrup: R_f

28

(15% EtOAc/petroleum ether) 0.42; [

(CHCl₃)

(CDCl₃, 500 MHz):

a

]

D

þ71.8 (c 0. 4, CHCl₃); IR

n

: 3421, 2932, 1602, 1456, 1029, 697, 617 cm^{ꢁ1 1}H NMR

;

100 MHz):

d

13.9 (q), 18.6 (t), 22.1 (t), 24.5 (t), 25.2 (t), 26.0 (t), 28.6

d

0.90 (t, J¼7.0 Hz, 3H), 1.26e1.34 (m, 6H),

(t), 29.5 (t), 30.7 (t), 31.1 (t), 70.0 (d), 70.2 (t), 72.8 (t), 73.6 (d), 75.2

(s), 75.3 (d), 83.7 (s), 127.4 (d), 127.6 (d, 2C), 128.3 (d, 2C), 128.4 (d,

2C), 129.7 (d, 2C), 130.1 (s), 133.1 (d), 138.6 (s), 166.6 (s) ppm; MS

(ESI) m/z¼481 [MþH]^þ; HRMS (ESI) calcd for C₃₀H₄₀O₅Na [MþNa]^þ

503.2773. found 503.2781.

1.37e1.44 (m, 7H), 1.59e1.70 (m, 7H), 1.80e1.92 (m, 1H), 3.46 (t,

J¼6.6 Hz, 2H), 3.90 (m, 1H), 3.94 (dd, J¼4.5, 7.1 Hz, 1H), 4.20 (dd,

J¼5.5, 7.3 Hz, 1H), 4.49 (br s, 2H), 7.25e7.35 (m, 5H); ¹³C NMR

(CDCl₃, 125 MHz):

d 14.0 (q), 22.6 (t), 22.9 (t), 25.4 (t), 26.1 (t), 26.7

(t), 29.7 (t), 32.0 (t), 33.8 (t), 35.2 (t), 36.7 (t), 66.6 (d), 70.4 (t), 72.9

(t), 75.7 (d), 80.8 (d), 108.5 (s), 127.5 (d), 127.6 (d, 2C), 128.3 (d, 2C),

138.7 (s) ppm; MS (ESI) m/z¼399 [MþNa]^þ; HRMS (ESI) calcd for

C₂₃H₃₆O₄Na [MþNa]^þ399.2512, found 399.2498.

4.20. General procedure for cycloisomerization (procedure C)

A

solution of the alkynol (1 equiv) and Pd (CH₃CN)₂Cl₂

(0.05 equiv) in acetonitrile (30 mL/1 mmol substrate) was stirred

at rt under argon atmosphere for 3e6 h. The reaction mixture

was ﬁltered through Celite and the ﬁltrate was concentrated under

reduced pressure and the residue obtained was puriﬁed by silica gel

chromatography.

4.24. (1S,2S,5S,7R)-7-(5-(Benzyloxy)pentyl)-5-pentyl-6,8-

dioxabicyclo[3.2.1]octan-2-yl benzoate (29)

Diol 14 (150 mg, 0.31 mmol) and Pd (CH₃CN)₂Cl₂(4 mg,

0.02 mmol) were subjected to general procedure C. The crude

product puriﬁed by silica gel chromatography (80:20 petroleum

ether/EtOAc) gave 29 (110 mg, 73%) as colorless syrup: R_f(10%

4.21. (1R,2R,5S,7R)-7-(5-(Benzyloxy)pentyl)-5-pentyl-6,8-

dioxabicyclo[3.2.1]octan-2-ol (26)

EtOAc/petroleum ether) 0.45; [

n

a

]

D

²⁵þ36.8 (c 0.6, CHCl₃); IR (CHCl₃)

: 3418, 2930, 1716, 1602, 1274, 1112, 990, 712, 617 cm^ꢁ1

;

¹H NMR

Triol 11 (200 mg, 0.53 mmol) and Pd (CH₃CN)₂Cl₂(7 mg,

0.03 mmol) were subjected to general procedure C. The crude

product was puriﬁed by silica gel chromatography (80:20 petro-

(CDCl₃, 400 MHz):

d

0.85 (t, J¼7.0 Hz, 3H), 1.27e1.30 (m, 4H),

1.35e1.42 (m, 4H), 1.44e1.52 (m, 2H), 1.58e1.71 (m, 6H), 1.79e1.83

(m, 2H), 1.86e1.90 (m, 2H), 3.42 (t, J¼6.5 Hz, 2H), 3.76 (d, J¼5.3, Hz,

1H), 4.46 (br s, 2H), 4.66 (d, J¼4.4 Hz,1H), 5.08 (dt, J¼5.6, 7.1,11.5 Hz,

1H), 7.26e7.34 (m, 5H), 7.42 (tt, J¼1.5, 6.9 Hz, 2H), 7.53 (tt, J¼1.5,

7.1 Hz, 1H), 8.05 (dt, J¼1.6, 6.9 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz):

leum ether/EtOAc) to obtain 26 (134 mg, 67%) as colorless syrup: R_f

25

(15% EtOAc/petroleum ether) 0.4; [

(CHCl₃)

669 cm^ꢁ1

a

]

D

þ25.0 (c 0.9, CHCl₃); IR

n

: 3444, 2930, 2857, 1722, 1455, 1216, 1100, 892, 753,

;

¹H NMR (CDCl₃, 400 MHz):

d

0.87 (t, J¼6.7, 3H),

d 14.0 (q), 22.5 (t), 23.8 (t), 25.4 (t), 26.1 (t), 28.8 (t), 29.6 (t), 30.2 (t),

1.24e1.34 (m, 5H), 1.36e1.44 (m, 6H), 1.61e1.65 (m, 9H), 1.90 (br s,

1H), 3.46 (t, J¼6.5 Hz, 2H), 3.90 (ddd, J¼5.5, 9.6, 18.2 Hz, 1H), 3.93

(m, 1H), 4.19 (dd, J¼5.6, 6.7 Hz, 1H), 4.49 (s, 2H), 7.26e7.34 (m, 5H);

32.1 (t), 34.5 (t, 2C), 70.3 (t), 72.8 (t), 74.3 (d), 77.2 (d), 81.4 (d), 110.7

(s), 127.5 (d), 127.6 (d, 2C), 128.3 (d, 2C), 128.3 (d, 2C), 129.7 (d, 2C),

130.5 (s), 132.8 (d), 138.6 (s), 166.3 (s) ppm; MS (ESI) m/z¼503

[MþNa]^þ; HRMS (ESI) calcd for C₃₀H₄₀O₅Na [MþNa]^þ503.2773,

found 503.2628.

¹³C NMR (CDCl₃, 100 MHz):

d 14.0 (q), 22.6 (t), 22.9 (t), 25.4 (t), 26.0

(t), 26.6 (t), 29.6 (t), 31.9 (t), 33.7 (t), 35.2 (t), 36.7 (t), 66.5 (d), 70.3

(t), 72.8 (t), 75.7 (d), 80.8 (d), 108.5 (s), 127.5 (d), 127.6 (d, 2C), 128.3

(d, 2C), 138.6 (s) ppm; MS (ESI) m/z¼399 [MþNa]^þ; HRMS (ESI)

calcd for C₂₃H₃₆O₄Na [MþNa]^þ399.2513, found 399.2495.

4.25. 2-(Heptadec-2-ynyloxy)tetrahydro-2H-pyran (30)

At ꢁ10 ^ꢀC, a solution of the THP ether of the propargyl alcohol

(1 g, 7.1 mmol) in THF (10 mL) was treated with n-BuLi (3.66 mL,

8.6 mmol) (2.34 M in hexane) and stirred for 30 min. HMPA

(1.53 mL, 8.6 mmol) was added and the reaction mixture was

stirred at ꢁ10 ^ꢀC for another 30 min. Myristyl bromide (2.37 g,

8.6 mmol) was dissolved in THF (20 mL) and stirred at ꢁ10 ^ꢀC to

which the solution of alkynyl lithium in THF was added and stirred

for further 30 min. The reaction mixture was quenched with sat-

urated NH₄Cl. The organic layer was separated and the aqueous

layer was washed with ethyl acetate, the combined organic layers

were washed with ethyl acetate, brine, dried, and concentrated.

Puriﬁcation of the crude product by column chromatography

4.22. (1R,2R,5S,7R)-7-(5-(Benzyloxy)pentyl)-5-pentyl-6,8-

dioxabicyclo[3.2.1]octan-2-ol (27)

Diol 12 (200 mg, 0.42 mmol) and Pd(CH₃CN)₂Cl₂(5 mg,

0.02 mmol) were subjected to general procedure C. The crude

product was puriﬁed by silica gel chromatography (78:22 petro-

leum ether/EtOAc) to procure 27 (161 mg, 80%) as colorless syrup:

25

R_f(15% EtOAc/petroleum ether) 0.43; [

(CHCl₃)

(CDCl₃, 500 MHz):

1.35e1.43 (m, 4H), 1.45e1.5 (m, 2H), 1.56e1.65 (m, 3H), 1.67e1.71

a

]

þ32.9 (c 1.7, CHCl₃); IR

D

n

: 3448, 2929,1717,1274,1273,1113, 712, 617 cm^ꢁ1; ¹H NMR

0.86 (t, J¼6.7 Hz, 3H), 1.26e1.32 (m, 5H),

d

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

1891

(90:10 petroleum ether/EtOAc) afforded 30 (2.1 g, 87%) as colorless

oil: R_f(7% EtOAc/petroleum ether) 0.6; IR (CHCl₃) : 2926, 1466,

1345, 1216, 1118, 1022, 903, 759, 668 cm^ꢁ^{1 1}H NMR (CDCl₃,

200 MHz):

6.9 Hz, 2H), 3.58 (t, J¼6.6 Hz, 2H); ¹³C NMR (CDCl₃, 50 MHz):

d

ꢁ5.3

n

(q, 2C), 18.4 (t), 18.7 (s), 25.8 (t), 26.0 (q, 3C), 28.5 (t), 28.8 (t), 29.1

(t), 29.5 (t), 29.5 (t), 29.6 (t, 3C), 29.7 (t, 3C), 32.9 (t), 63.3 (t), 68.0

(d), 84.7 (s); MS (ESI) m/z¼389 [MþNa]^þ; HRMS (ESI) calcd for

C₂₃H₄₆OSiNa [MþNa]^þ389.3216, found 389.3222.

;

d

0.88 (t, J¼6.7 Hz, 3H), 1.24e1.34 (m, 24H), 1.46e1.88

(m, 6H), 2.11e2.23 (m, 2H), 3.44e3.55 (m, 1H), 3.81 (ddd, J¼3.3, 8.5,

11.7 Hz, 1H), 4.14 (dt, J¼2.1, 15.3 Hz, 1H), 4.25 (dt, J¼2.1, 15.3 Hz, 1H),

4.79 (t, J¼2.9 Hz, 1H); ¹³C NMR (CDCl₃, 50 MHz):

d

14.2 (q), 18.4 (t),

4.29. (R)-1-((4R,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-

1,3-dioxolan-4-yl)-19-(tert-butyldimethylsilyloxy)nonadec-3-

yn-1-ol (33)

18.9 (t), 19.1 (t), 22.7 (t), 25.5 (t), 28.5 (t), 28.6 (t), 28.8 (t), 28.9 (t),

29.2 (t), 29.4 (t), 29.6 (t), 29.7 (t), 29.7 (t), 30.3 (t), 32.0 (t), 54.5 (t),

61.8 (t), 75.8 (s), 86.6 (s), 96.4 (d) ppm; MS (ESI) m/z¼359 [MþNa]^þ.

Anal. calcd for C₂₂H₄₀O₂: C, 78.51; H, 11.98%, found C, 78.40; H,

12.13%.

Alkyne 8 (2.97 g, 8.12 mmol), n-BuLi (3.47 mL, 8.12 mmol, 2.34 M

in hexane), BF₃$Et₂O (1.1 mL, 8.12 mmol), epoxide 9 (650 mg,

2.03 mmol) were subjected to general procedure C. The crude

product was puriﬁed by silica gel chromatography (85:15 petro-

leum ether/EtOAc) to obtain 33 (1.0 g, 82%) as a colorless syrup: R_f

4.26. Heptadec-2-yn-1-ol (31)

To a solution of 30 (400 mg, 1.1 mmol) in MeOH (10 mL), p-TSA

(7 mg) was added and the reaction mixture was stirred at rt for

30 min. The reaction mixture was quenched by the addition of few

drops of triethylamine and the solvent was evaporated. The crude

residue was puriﬁed by column chromatography (80:20 petroleum

ether/EtOAc) to obtain 31 (275 mg, 91%) as a white solid: R_f(10%

(10% EtOAc/petroleum ether) 0.52; [

3439, 2929, 1463, 1370, 1254, 1101, 836, 697 cm^ꢁ1; ¹H NMR (CDCl₃,

200 MHz): 0.03 (s, 6H), 0.88 (s, 9H), 1.22e1.29 (m, 24H), 1.34 (s,

a]25D _{þ9.5 (c 0.6, MeOH); IR (CHCl}) n:

3

d

3H), 1.37 (s, 3H), 1.40e1.53 (m, 10H), 2.11e2.19 (m, 2H), 2.16 (br s,

1H), 2.43e2.49 (m, 2H), 3.45 (t, J¼6.6 Hz, 2H), 3.58 (t, J¼6.6 Hz, 2H),

3.59 (t, J¼6.7 Hz, 1H), 3.63e3.75 (m, 1H), 3.96 (dt, J¼3.5, 7.0 Hz, 1H),

EtOAc/petroleum ether) 0.4; mp: 48e49 ^ꢀC; IR (CHCl₃)

n

: 3539,

4.48 (s, 2H), 7.24e7.33 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz):

d

ꢁ5.3 (q,

2944, 2254, 1631, 1444, 1376, 1040, 918, 759 cm^ꢁ1; ¹H NMR (CDCl₃,

2C), 18.3 (s), 18.7 (t), 23.3 (t), 24.3 (t), 25.8 (t), 26.0 (q, 3C), 26.0 (t),

26.0 (t), 26.1 (t), 26.2 (t), 27.1 (q), 27.4 (q), 28.9 (t, 2C), 29.1 (t), 29.4

(t), 29.5 (t), 29.6 (t, 4C), 32.9 (t), 34.4 (t), 63.3 (t), 70.3 (t), 70.8 (d),

72.8 (t), 74.9 (s), 78.8 (d), 81.9 (d), 84.0 (s), 108.6 (s), 127.4 (d), 127.6

(d, 2C), 128.3 (d, 2C), 138.6 (s) ppm; MS (ESI) m/z¼709 [MþNa]^þ.

Anal. calcd for C₄₂H₇₄O₅Si: C, 73.42; H, 10.86%, found C, 73.38; H,

10.92%.

200 MHz):

d

0.87 (t, J¼6.7 Hz, 3H), 1.25e1.42 (m, 24H), 2.18 (tt,

J¼2.1, 6.9 Hz, 2H), 4.22 (t, J¼2.1 Hz, 2H); ¹³C NMR (CDCl₃, 50 MHz):

d

14.2 (q), 18.8 (t), 22.7 (t), 28.6 (t), 28.9 (t), 29.2 (t), 29.4 (t), 29.6 (t),

29.7 (t, 5C), 32.0 (t), 51.3 (t), 78.4 (s), 86.5 (s) ppm; MS (ESI) m/

z¼275 [MþNa]^þ. Anal. calcd for C₁₇H₃₂O: C, 80.88; H, 12.78%, found

C, 80.60; H, 12.73%.

4.27. Heptadec-16-yn-1-ol (32)

4.30. (R)-1-((4S,5R)-5-(5-(Benzyloxy)pentyl)-2,2-dimethyl-

1,3-dioxolan-4-yl)-19-(tert-butyldimethylsilyloxy) nonadec-3-

ynyl benzoate (34)

Lithium (3.3 g, 475.4 mmol) was added to freshly distilled 1,3-

diaminopropane (250 mL) and stirred at rt till the reaction mix-

ture turns into a deep purple suspension. The suspension was

heated at 80 ^ꢀC till the blue color disappeared. The reaction mixture

was cooled to rt and KO^tBu (35.6 g, 316.9 mmol) was added and

stirred for 30 min. Alkynol 31 (20 g, 79.2 mmol) was added to the

reaction mixture and stirred at rt for 1 h. The reaction mixture was

poured slowly on ice and partitioned between CH₂Cl₂and water.

The aqueous layer was extracted with CH₂Cl₂and combined CH₂Cl₂

layer was washed with brine, dried (Na₂SO₄), and concentrated.

Puriﬁcation of the residue by column chromatography (80:20 pe-

troleum ether/EtOAc) afforded 32 (15.8 g, 79%) as white solid: R_f

To a solution of 33 (700 mg, 1.02 mmol) in CH₂Cl₂(10 mL) at 0 ^ꢀC

were added Et₃N (0.21 mL,1.5 mmol), DMAP (10 mg) and stirred for

15 min. To this, benzoyl chloride (0.18 mL, 1.5 mmol) was added at

0

^ꢀC and stirred further for 2 h. The reaction mixture was diluted

with CH₂Cl₂(25 mL) and washed with brine, dried (Na₂SO₄), and

concentrated. The resulting crude product was puriﬁed by column

chromatography (90:10 petroleum ether/EtOAc) to afford the

benzoate 34 (741 mg, 92%) as colorless syrup: R_f(10% EtOAc/pe-

troleum ether) 0.6; [

1495, 1369, 1268, 1100, 836, 710 cm^ꢁ1; ¹H NMR (CDCl₃, 200 MHz):

0.04 (s, 6H), 0.89 (s, 9H), 1.15e1.30 (m, 26H), 1.36 (s, 3H), 1.41 (s,

a]25D _{ꢁ4.1 (c 1.0, CHCl3}); IR (CHCl₃) n: 2928, 1725,

(10% EtOAc/petroleum ether) 0.45; mp: 50e51 ^ꢀC; IR (CHCl₃)

n

:

d

3308, 2928, 1603, 1466, 1216, 1049, 758, 669 cm^ꢁ1; ¹H NMR (CDCl₃,

3H), 1.46e1.80 (m, 8H), 2.04e2.11 (m, 2H), 2.67e2.70 (m, 2H), 3.39

(t, J¼6.4 Hz, 2H), 3.59 (t, J¼6.6 Hz, 2H), 3.95e4.09 (m, 2H), 4.45 (s,

2H), 5.23 (q, J¼5.7 Hz, 1H), 7.27e7.34 (m, 5H), 7.38e7.46 (m, 2H),

7.55 (tt, J¼1.4, 7.3 Hz, 1H), 8.04 (dt, J¼1.3, 6.9 Hz, 2H); ¹³C NMR

200 MHz):

d

1.25e1.41 (m, 22H),1.48e1.58 (m, 4H),1.88 (t, J¼2.5 Hz,

1H), 2.15 (dt, J¼2.5, 6.8 Hz, 2H), 3.61 (t, J¼6.7 Hz, 2H); ¹³C NMR

(CDCl₃, 50 MHz): d 18.4 (t), 25.8 (t), 28.5 (t), 28.8 (t), 29.1 (t), 29.4 (t),

29.5 (t), 29.6 (t, 3C), 29.6 (t, 3C), 32.8 (t), 62.9 (t), 68.2 (d), 84.6

(s) ppm; HRMS (ESI) calcd for C₁₇H₃₂ONa [MþNa]^þ275.2350, found

275.2305.

(CDCl₃, 50 MHz):

d

ꢁ5.3 (q, 2C), 18.4 (s), 18.7 (t), 21.6 (t), 25.8 (t),

25.9 (t), 26.0 (q, 3C), 26.1 (t), 27.0 (q), 27.5 (q), 28.8 (t), 29.2 (t), 29.4

(t), 29.5 (t), 29.5 (t), 29.7 (t, 7C), 32.9 (t), 34.2 (t), 63.3 (t), 70.2 (t),

72.8 (t), 72.8 (d), 74.6 (s), 78.8 (d), 80.3 (d), 82.9 (s), 109.2 (s), 127.4

(d), 127.6 (d, 2C), 128.3 (d, 2C), 128.4 (d, 2C), 129.7 (d, 2C), 129.9 (s),

133.1 (d),138.6 (s),165.6 (s) ppm; MS (ESI) m/z¼813 [MþNa]^þ. Anal.

calcd for C₄₉H₇₈O₆Si: C, 74.38; H, 9.94%, found C, 74.10; H, 9.78%.

4.28. tert-Butyl(heptadec-16-ynyloxy)dimethylsilane (8)

To a solution of 32 (1 g, 3.9 mmol) in CH₂Cl₂(5 mL) at 0 ^ꢀC was

added Et₃N (0.83 mL, 5.9 mmol), DMAP (10 mg) and stirred for

15 min. TBSCl (890 mg, 5.9 mmol) was added at 0 ^ꢀC and stirred

further for 1 h. The reaction mixture was diluted with CH₂Cl₂

(15 mL) and washed with brine, dried (Na₂SO₄), and concentrated.

The resulting crude product was puriﬁed by column chromatog-

raphy (95:5 petroleum ether/EtOAc) to afford silyl ether 8 (1.3 g,

90%) as colorless oil: R_f(5% EtOAc/petroleum ether) 0.4; IR (CHCl₃)

4.31. (19R,20S,21R)-26-(Benzyloxy)hexacos-16-yne-1,19,20,21-

tetraol (6)

To a solution of the acetonide 33 (200 mg, 0.29 mmol) in MeOH

(5 mL), p-TSA (5 mg, 0.03 mmol) was added and the reaction

mixture was stirred at rt for 2 h. The reaction mixture was

quenched by the addition of few drops of triethylamine and the

solvent was evaporated. The crude residue was puriﬁed by column

n

: 2944, 2253, 1444, 1376, 1040, 918, 751, 648 cm^ꢁ1; ¹H NMR (CDCl₃,

200 MHz): 0.03 (s, 6H), 0.88 (s, 9H), 1.25 (m, 20H), 1.46e1.55 (m,

5H), 1.77 (t, J¼2.5 Hz, 1H), 1.92 (t, J¼2.7 Hz, 1H), 2.16 (dt, J¼2.7,

d

chromatography (40:60 petroleum ether/EtOAc) to obtain

6

1892

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

25

(130 mg, 82%) as a white syrup: R_f(40% EtOAc/petroleum ether)

(30% EtOAc/petroleum ether) 0.42; [

(CHCl₃)

: 3406, 2928, 1711, 1277, 1216, 758, 669 cm^ꢁ1

(CDCl₃, 200 MHz): 1.25 (m, 22H), 1.37e1.72 (m, 14H), 1.80e1.96

a

]

þ15.0 (c 2.5, CHCl₃); IR

D

0.42; [

a]

²⁵ꢁ3.2 (c 0.5, MeOH); IR (Nujol)

n

: 3438, 2923, 1462, 1377,

1.22

n

;

¹H NMR

D

1111, 1058, 737, 648 cm^ꢁ1; ¹H NMR (methanol-d₄, 200 MHz):

d

(m, 18H), 1.35e1.59 (m, 16H), 2.10e2.16 (m, 2H), 2.38 (ddt, J¼2.5,

5.8, 16.8 Hz, 1H), 2.54 (ddt, J¼2.5, 4.7, 16.9 Hz, 1H), 3.32 (dt, J¼1.6,

7.1 Hz, 1H), 3.48 (t, J¼6.6 Hz, 2H), 3.52 (t, J¼6.4 Hz, 2H), 3.70 (ddd,

J¼4.7, 6.3, 10.5 Hz, 1H), 3.74e3.80 (m, 1H), 4.43 (s, 2H), 7.22e7.28

(m, 2H), 2.06e2.21 (m, 2H), 3.45 (t, J¼6.4 Hz, 2H), 3.62 (t, J¼6.6 Hz,

2H), 3.97 (dd, J¼4.5, 7.1 Hz, 1H), 4.28 (br s, 1H), 4.48 (s, 2H), 4.89 (br

s, 1H), 7.25e7.32 (m, 5H), 7.43 (tt, J¼1.5, 6.9 Hz, 2H), 7.55 (tt, J¼1.5,

7.1 Hz, 1H), 8.08 (dt, J¼1.6, 6.9 Hz, 2H); ¹³C NMR (CDCl₃, 50 MHz):

d

(m, 5H); ¹³C NMR (methanol-d₄, 50 MHz):

d

19.1 (t), 21.5 (t), 24.3 (t),

22.7 (t), 22.8 (t), 25.4 (t), 25.8 (t), 26.1 (t), 29.5 (t), 29.7 (t), 29.7 (t),

29.7 (t, 7C), 29.8 (t), 30.8 (t), 32.8 (t), 35.1 (t), 37.5 (t), 63.0 (t), 68.9

(d), 70.2 (t), 72.9 (t), 77.8 (d), 79.7 (d), 109.4 (s), 127.5 (d), 127.6 (d),

128.3 (d, 3C), 128.4 (d), 129.8 (d), 130.2 (d), 130.4 (s), 133.0 (d), 133.5

(d),138.6 (s), 166.1 (s) ppm; MS (ESI) m/z¼659 [MþNa]^þ. Anal. calcd

for C₄₀H₆₀O₆: C, 75.43; H, 9.50%, found C, 75.14; H, 9.42%.

26.0 (t), 26.1 (t), 26.5 (t), 29.3 (t), 29.4 (t), 29.5 (t), 29.8 (t), 29.9 (t),

30.0 (t, 6C), 32.7 (t), 33.7 (t), 62.8 (t), 70.5 (d), 70.8 (t), 71.6 (d), 73.3

(t), 74.3 (s), 76.4 (d), 83.0 (s), 128.0 (d), 128.1 (d, 2C), 128.7 (d, 2C),

138.6 (s) ppm; MS (ESI) m/z¼555 [MþNa]^þ. Anal. calcd for

C₃₃H₅₆O₅: C, 74.39; H, 10.59%. Found: C, 74.17; H, 10.44%.

4.32. (6R,7S,8R)-1-(Benzyloxy)-6,7,26-trihydroxyhexacos-10-

yn-8-yl benzoate (7)

4.35. (1R,2R,5S,7R)-7-(5-(Benzyloxy)pentyl)-5-(15-(tert-bu-

tyldimethylsilyloxy)pentadecyl)-6,8-dioxabicyclo[3.2.1]octan-

2-ol (37)

To a solution of the acetonide 34 (400 mg, 0.51 mmol) in MeOH

(10 mL), p-TSA (5 mg, 0.03 mmol) was added and the reaction

mixture was stirred at rt for 2 h. The reaction mixture was

quenched by the addition of few drops of triethylamine and the

solvent was evaporated. The crude residue was puriﬁed by column

To a solution of 35 (500 mg, 0.94 mmol) in CH₂Cl₂(5 mL) at 0 ^ꢀC

were added imidazole (130 mg, 1.9 mmol), DMAP (10 mg) and

stirred for 15 min. To this, TBSCl (210 mg, 1.41 mmol) was added at

0

^ꢀC and stirred further for 1 h. The reaction mixture was diluted

chromatography (50:50 petroleum ether/EtOAc) to obtain

7

with CH₂Cl₂(25 mL) and washed with brine, dried (Na₂SO₄), and

concentrated. The resulting crude product was puriﬁed by column

chromatography (90:10, 75:25 petroleum ether/EtOAc) to afford 37

(550 mg, 91%) and the disilyl ether 37-OTBS (50 mg, 7%) as colorless

syrups.

(280 mg, 86%) as colorless syrup: R_f(30% EtOAc/petroleum ether)

25

0.4; [

a]

ꢁ3.9 (c 0.8, CHCl₃); IR (CHCl₃)

n

: 3427, 2929, 1706, 1453,

D

1276, 1116, 757, 668 cm^ꢁ1

;

¹H NMR (CDCl₃, 200 MHz):

d

1.24e1.40

(m, 26H), 1.45e1.67 (m, 8H), 2.08 (tt, J¼2.0, 6.7 Hz, 2H), 2.54 (br d,

J¼8.3 Hz, 1H), 2.65e2.81 (m, 2H), 2.92 (br s, 1H), 3.42 (t, J¼6.6 Hz,

2H), 3.55e3.65 (m, 2H), 3.62 (t, J¼6.6 Hz, 2H), 4.46 (s, 2H), 5.06

(ddd, J¼4.4, 6.3, 10.3 Hz, 1H), 7.23e7.31 (m, 5H), 7.44 (tt, J¼1.5,

7.1 Hz, 2H), 7.59 (tt, J¼2.3, 7.3 Hz, 1H), 8.06 (tt, J¼1.5, 7.1 Hz, 2H); ¹³C

4.35.1. Characterization data of 37. R_f(30% EtOAc/petroleum ether)

0.42; [

a

]

²⁵þ21.4 (c 0.9, CHCl₃); IR (CHCl₃)

n

: 3428, 3019, 2929, 1464,

0.03 (s, 6H),

D

1216,1097, 758, 669 cm^ꢁ1; ¹H NMR (CDCl₃, 400 MHz):

d

NMR (CDCl₃, 50 MHz):

d

18.6 (t), 21.7 (t), 25.7 (t), 25.8 (t), 26.2 (t),

0.88 (s, 9H), 1.24e1.32 (m, 24H), 1.36e1.44 (m, 6H), 1.46e1.56 (m,

3H), 1.58e1.69 (m, 4H), 1.64 (br s, 1H), 1.77 (dt, J¼5.8, 12.3 Hz, 1H),

1.92e2.03 (m, 1H), 2.39 (br s, 1H), 3.46 (t, J¼6.5 Hz, 2H), 3.58 (t,

J¼6.8 Hz, 2H), 3.58 (s, 1H), 3.87 (dd, J¼5.8, 7.5 Hz, 1H), 4.04 (br s,

1H), 4.49 (s, 2H), 7.24e7.28 (m, 1H), 7.29e7.35 (m, 4H); ¹³C NMR

28.8 (t), 28.8 (t), 29.1 (t), 29.4 (t), 29.5 (t), 29.6 (t, 6C), 29.6 (t), 32.7

(t), 33.0 (t), 63.0 (t), 69.2 (d), 70.2 (t), 72.8 (t), 73.2 (d), 73.6 (d), 75.1

(s), 82.7 (s), 127.4 (d), 127.6 (d, 2C), 128.3 (d, 2C), 128.4 (d, 2C), 129.5

(s), 129.9 (d, 2C), 133.5 (d), 138.6 (s), 167.1 (s) ppm; MS (ESI) m/

z¼659 [MþNa]^þ. Anal. calcd for C₄₀H₆₀O₆: C, 75.43; H, 9.50%, found

C, 75.70; H, 9.63%.

(CDCl₃, 100 MHz):

d

ꢁ5.3 (q, 2C), 18.4 (s), 23.0 (t), 25.1 (t), 25.4 (t),

25.8 (t), 26.0 (q, 3C), 26.0 (t), 29.4 (t), 29.6 (t), 29.6 (t), 29.7 (t, 7C),

29.8 (t), 30.1 (t), 32.9 (t), 35.2 (t), 37.5 (t), 63.3 (t), 66.3 (d), 70.3 (t),

72.9 (t), 77.9 (d), 82.4 (d), 109.5 (s), 127.5 (d), 127.6 (d, 2C), 128.3 (d,

2C), 138.6 (s) ppm; MS (ESI) m/z¼669 [MþNa]^þ. Anal. calcd for

C₃₉H₇₀O₅Si: C, 72.39; H, 10.90%, found: C, 71.95; H, 10.75%.

4.33. (1S,2R,5S,7R)-7-(5-(Benzyloxy)pentyl)-5-(15-

hydroxypentadecyl)-6,8-dioxabicyclo[3.2.1]octan-2-ol (35)

Tetrol 6 (500 mg, 0.94 mmol) and Pd(CH₃CN)₂Cl₂(12 mg,

0.05 mmol) were subjected to general procedure C. The crude

product was puriﬁed by silica gel chromatography (50:50 petro-

4.35.2. Characterization data of 37-TBS. R_f(10% EtOAc/petroleum

ether) 0.6; [

a

]

D

²⁵þ14.6 (c 1.2, CHCl₃); IR (CHCl₃)

n

: 2929, 1471, 1216,

0.03 (s, 6H),

leum ether/EtOAc) to obtain 35 (350 mg, 70%) as colorless syrup: R_f

1098, 836, 759, 668 cm^ꢁ1; ¹H NMR (CDCl₃, 400 MHz):

d

25

(40% EtOAc/petroleum ether) 0.4; [

(CHCl₃)

NMR (CDCl₃, 400 MHz):

a]

þ14.4 (c 1.0, CHCl₃); IR

0.06 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 0.90 (s, 9H), 1.24e1.32 (m,

28H), 1.40e1.43 (m, 4H), 1.48e1.54 (m, 2H), 1.60e1.69 (m, 4H), 1.83

(dt, J¼5.5, 12.3 Hz, 1H), 1.90e2.00 (m, 1H), 3.46 (t, J¼6.5 Hz, 2H),

3.58 (t, J¼6.8 Hz, 2H), 3.58 (br s, 1H), 3.78 (dd, J¼5.2, 7.3 Hz, 1H),

3.92 (br s, 1H), 4.49 (s, 2H), 7.27e7.33 (m, 5H); ¹³C NMR (CDCl₃,

D

n

: 3437, 2929, 1639, 1560, 1416, 1216, 757, 668 cm^ꢁ1

;

¹H

d

1.24e1.32 (m, 23H), 1.35e1.44 (m, 5H),

1.49e1.58 (m, 4H), 1.60e1.69 (m, 6H), 1.77 (dt, J¼5.5, 12.3 Hz, 1H),

1.92e2.01 (m, 1H), 3.45 (t, J¼6.5 Hz, 2H), 3.58 (t, J¼1.5 Hz, 1H), 3.62

(t, J¼6.8 Hz, 2H), 3.86 (dd, J¼5.5, 7.4 Hz, 1H), 4.04 (br s, 1H), 4.48 (s,

100 MHz):

d

ꢁ5.3 (q, 2C), ꢁ4.7 (q), 18.3 (s), 18.4 (s), 22.9 (t), 25.5 (t),

2H), 7.26e7.35 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz):

d

22.9 (t), 25.0

25.8 (t), 25.9 (q, 3C), 26.0 (q, 3C), 26.1 (t), 29.4 (t), 29.6 (t, 5C), 29.7 (t,

5C), 29.8 (t), 30.3 (t), 32.9 (t), 35.2 (t), 37.6 (t), 63.3 (t), 66.9 (d), 70.3

(t), 72.9 (t), 77.7 (d), 83.0 (d), 109.2 (s), 127.5 (d), 127.6 (d, 2C), 128.3

(d, 2C), 138.6 (s) ppm; MS (ESI) m/z¼783 [MþNa]^þ. Anal. calcd for

C₄₅H₈₄O₅Si₂: C, 70.99; H, 11.12%, found C, 70.75; H, 10.95%.

(t), 25.3 (t), 25.7 (t), 26.0 (t), 29.4 (t), 29.5 (t), 29.6 (t), 29.6 (t, 6C),

29.7 (t), 29.8 (t), 30.1 (t), 32.8 (t), 35.2 (t), 37.5 (t), 63.0 (t), 66.3 (d),

70.3 (t), 72.9 (t), 77.8 (d), 82.3 (d), 109.5 (s), 127.5 (d), 127.6 (d, 2C),

128.3 (d, 2C), 138.6 (s) ppm; MS (ESI) m/z¼555 [MþNa]^þ. Anal.

calcd for C₃₃H₅₆O₅: C, 74.39; H, 10.59%, found C, 74.20; H, 10.46%.

4.36. (15-((1R,2R,5S,7R)-2-(Benzyloxy)-7-(5-(benzyloxy)pen-

tyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl)pentadecyloxy)(tert-bu-

tyl)dimethylsilane (38)

4.34. (1S,2R,5S,7R)-7-(5-(Benzyloxy)pentyl)-5-(15-hydrox-

ypentadecyl)-6,8-dioxabicyclo[3.2.1]octan-2-yl benzoate (36)

Triol 7 (500 mg, 0.79 mmol) and Pd (CH₃CN)₂Cl₂(11 mg,

0.04 mmol) were subjected to general procedure C. The crude

product was puriﬁed by silica gel chromatography (60:40 petro-

leum ether/EtOAc) to obtain 36 (355 mg, 71%) as colorless syrup: R_f

To an ice-cooled solution (0 ^ꢀC) of alcohol 37 (0.2 g, 0.31 mmol)

in DMF (10 mL) was added NaH (11 mg, 0.46 mmol) and stirred for

30 min. Benzyl bromide (0.06 mL, 0.46 mmol) was added to the

reaction mixture at 0 ^ꢀC and the reaction mixture was stirred for

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

1893

1 h. The reaction mixture was quenched with ice, partitioned be-

3017, 2928, 1690, 1454, 1393, 1216, 1092, 757, 669 cm^ꢁ1

;

¹H NMR

tween ethyl acetate, water and the organic layer was separated,

washed with ethyl acetate, brine, dried (Na₂SO₄), and concentrated.

Puriﬁcation of the residue by column chromatography (90:10 pe-

(CDCl₃, 400 MHz): d 1.23e1.28 (m, 28H), 1.38 (s, 3H), 1.40 (s, 3H),

1.46 (m, 9H), 1.51e1.71 (m, 10H), 1.79e1.89 (m, 2H), 3.28 (br s, 1H),

3.28e3.30 (br s, 1H), 3.37 (t, J¼6.5 Hz, 1H), 3.45 (t, J¼6.5 Hz, 2H),

3.78 (dd, J¼4.8, 7.5 Hz, 1H), 3.89e3.92 (m, 1H), 3.97e4.00 (m, 2H),

4.03e4.07 (m, 1H), 4.16 (br s, 1H), 4.48 (s, 2H), 4.58 (d, J¼12.5 Hz,

1H), 4.62 (d, J¼12.5 Hz, 1H), 7.25e7.28 (m, 3H), 7.32e7.37 (m, 7H);

troleum ether/EtOAc) afforded 38 (0.21 g, 92%) as colorless syrup: R_f

25

(7% EtOAc/petroleum ether) 0.6; [

(CHCl₃)

NMR (CDCl₃, 400 MHz):

a

]

þ20.2 (c 1.8, CHCl₃); IR

D

n

: 2926,1455,1361,1347,1254,1099, 836, 758, 697 cm^ꢁ1; ¹H

0.04 (s, 6H), 0.89 (s, 9H), 1.24e1.25 (m,

d

¹³C NMR (CDCl₃,100 MHz):

d 21.9 (t), 22.7 (t), 22.7 (t), 24.4, 24.7 (2q,

28H), 1.34e1.44 (m, 4H), 1.49e1.53 (m, 4H), 1.63e1.67 (m, 2H),

1.79e1.87 (m, 2H), 3.28 (br s, 1H), 3.45 (t, J¼6.5 Hz, 2H), 3.59 (d,

J¼6.5 Hz, 2H), 3.78 (dd, J¼4.8, 7.3 Hz,1H), 4.17 (br s,1H), 4.49 (s, 2H),

4.58 (d, J¼12.8 Hz, 1H), 4.62 (d, J¼12.5 Hz, 1H), 7.27e7.36 (m, 10H);

1C), 25.4 (t), 26.0 (t), 26.1 (t), 26.2 (t), 26.7, 27.4 (2q, 1C), 28.4, 28.4

(2q, 3C), 29.3 (t), 29.5 (t), 29.6 (t, 2C), 29.7 (t, 4C), 29.8 (t), 30.7 (t),

31.9 (t), 35.2 (t), 37.4 (t), 56.3, 56.5 (2d, 1C), 65.4, 65.7 (2t, 1C), 69.2,

70.0 (2t, 1C), 70.3 (t, 2C), 71.4 (t), 72.3 (d), 72.9 (t), 77.7 (d), 79.7, 80.2

(2s, 1C), 80.0 (d), 93.2, 93.7 (2s, 1C), 109.3 (s), 127.5 (d), 127.6 (d, 3C),

127.6 (d, 2C), 128.3 (d, 2C), 128.4 (d, 2C), 138.5 (s), 138.6 (s), 151.7,

152.2 (2s, 1C) ppm; MS (ESI) m/z¼858 [MþNa]^þ. Anal. calcd for

C₅₁H₈₁NO₈: C, 73.25; H, 9.76; N, 1.68%, found C, 72.80; H, 9.83; N,

1.42%.

¹³C NMR (CDCl₃, 100 MHz):

d

ꢁ5.3 (q, 2C), 18.4 (s), 21.9 (t), 22.7 (t),

25.4 (t), 25.8 (t), 26.0 (q, 3C), 29.4 (t), 29.6 (t), 29.7 (t, 8C), 29.8 (t),

30.7 (t), 31.9 (t), 32.9 (t), 35.2 (t), 37.4 (t), 63.3 (t), 70.3 (t, 2C), 72.3

(d), 72.9 (t), 77.7 (d), 80.0 (d), 109.3 (s), 127.5 (d, 2C), 127.6 (d, 2C),

127.6 (d, 2C), 128.3 (d, 2C), 128.4 (d, 2C), 138.5 (s), 138.6 (s) ppm; MS

(ESI) m/z¼760 [MþNa]^þ. Anal. calcd for C₄₆H₇₆O₅Si: C, 74.95; H,

10.39%, found C, 74.80; H, 10.43%.

4.39. (S)-tert-Butyl-4-((15-((1R,2R,5S,7R)-2-hydroxy-7-(5-

hydroxypentyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl)pentadecy-

loxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (3)

4.37. 15-((1R,2R,5S,7R)-2-(Benzyloxy)-7-(5-(benzyloxy)pen-

tyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl)pentadecan-1-ol (4)

A suspension of 40 (50 mg, 0.06 mmol), Pd(OH)₂(5 mg) in ethyl

acetate (5 mL) was ﬂushed with hydrogen gas and stirred under

hydrogen (20 psi) atmosphere for 30 min. The reaction mixture was

ﬁltered through Celite, concentrated and the crude product was

puriﬁed by column chromatography (60:40 petroleum ether/

To a solution of 38 (200 mg, 0.27 mmol) in MeOH (10 mL), p-TSA

(5 mg, 0.03 mmol) was added and the reaction mixture was stirred

at rt for 30 min. The reaction mixture was quenched by the addition

of few drops of triethylamine and the solvent was evaporated. The

crude residue was puriﬁed by column chromatography (60:40 pe-

EtOAc) to yield 3 (35 mg, 90%) as colorless oil: R_f(40% EtOAc/pe-

25

troleum ether/EtOAc) to obtain 4 (152 mg, 88%) as a colorless oil: R_f

troleum ether) 0.4; [

a

]

þ36.3 (c 0.2, CHCl₃); IR (CHCl₃)

n

: 3436,

¹H NMR (CDCl₃,

d 1.24e1.35 (m, 24H), 1.40e1.46 (m, 6H), 1.46 (s, 9H),

D

25

(20% EtOAc/petroleum ether) 0.4; [

(CHCl₃)

NMR (CDCl₃, 200 MHz):

a]

þ23.8 (c 1.4, CHCl₃); IR

2928, 1690, 1406, 1394, 1216, 758, 668 cm^ꢁ1

400 MHz):

;

D

n

: 3437, 2927, 1596, 1384, 1217, 1027, 759, 698 cm^ꢁ1

;

¹H

d

1.24 (m, 26H), 1.35e1.46 (m, 4H),

1.51e1.70 (m, 14H), 1.77 (dt, J¼5.5, 12.3 Hz, 1H), 1.92e2.04 (m, 1H),

3.23e3.50 (m, 2H), 3.39 (dd, J¼2.7, 8.1 Hz, 1H), 3.46 (dd, J¼2.9,

8.1 Hz, 1H), 3.60e3.66 (m, 1H), 3.63 (t, J¼6.44 Hz, 2H), 3.85e4.00

(m, 3H), 3.97e4.05 (m, 1H), 4.05 (br s, 1H); ¹³C NMR (CDCl₃,

1.49e1.70 (m, 8H), 1.79e1.87 (m, 2H), 3.28 (s, 1H), 3.45 (t, J¼6.5 Hz,

2H), 3.61 (d, J¼6.5 Hz, 2H), 3.78 (dd, J¼4.8, 7.3 Hz, 1H), 4.17 (br s,

1H), 4.49 (s, 2H), 4.59 (d, J¼12.5 Hz, 1H), 4.62 (d, J¼12.5 Hz, 1H),

7.25e7.28 (m, 2H), 7.32e7.37 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz):

100 MHz):

d 22.7 (t), 22.9 (t), 23.1, 24.4 (2q, 1C), 25.0 (t), 25.3 (t),

d

21.9 (t), 22.7 (t), 22.7 (t), 25.4 (t), 25.7 (t), 26.0 (t), 29.3 (t), 29.4 (t),

25.6 (t), 26.1 (t), 26.7, 27.5 (2q, 1C), 28.4, 28.5 (2q, 3C), 29.1 (t), 29.3

(t), 29.4 (t), 29.6 (t, 2C), 29.6 (t, 3C), 29.8 (t), 30.1 (t), 31.9 (t), 32.6 (t),

35.2 (t), 37.5 (t), 56.3, 56.5 (2d, 1C), 62.8 (t), 65.4, 65.7 (2t, 1C), 66.3

(d), 69.3, 70.0 (2t, 1C), 71.4 (t), 77.8 (d), 79.7, 80.2 (2s, 1C), 82.4 (d),

93.3, 93.7 (2s, 1C), 109.6 (s), 151.7, 152.2 (2s, 1C) ppm; MS (ESI) m/

z¼678 [MþNa]^þ. Anal. calcd for C₃₇H₆₉NO₈: C, 67.75; H, 10.60; N,

2.14%, found C, 67.60; H, 10.43; N, 2.02%.

29.5 (t), 29.6 (t, 4C), 29.7 (t), 29.8 (t), 30.7 (t), 31.9 (t), 32.8 (t), 35.2

(t), 37.4 (t), 63.0 (t), 70.3 (t, 2C), 72.2 (d), 72.8 (t), 77.7 (d), 80.0 (d),

109.3 (s), 127.4 (d, 2C),127.5 (d, 2C), 127.6 (d, 2C),128.3 (d, 2C),128.3

(d, 2C), 138.5 (s), 138.6 (s) ppm; MS (ESI) m/z¼645 [MþNa]^þ. Anal.

calcd for C₄₀H₆₂O₅: C, 77.13; H, 10.03%, found C, 77.01; H, 9.86%.

4.38. tert-Butyl-4-((15-((1R,2R,5S,7R)-2-(benzyloxy)-7-(5-

(benzyloxy)pentyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl)pentade-

cyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (40)

4.40. (S)-tert-Butyl-4-((15-((1R,2R,5S,7R)-7-((E)-7-ethoxy-7-

oxohept-5-enyl)-2-hydroxy-6,8-dioxabicyclo[3.2.1]octan-5-yl)

pentadecyloxy)methyl)-2,2-dimethyloxazolidine-3-

carboxylate (2)

At 0 ^ꢀC, triethylamine (0.06 mL, 0.48 mmol) was added to a so-

lution of 4 (0.2 g, 0.32 mmol) in CH₂Cl₂and stirred for 30 min. MsCl

(0.03 mL, 0.38 mmol) was added at 0 ^ꢀC and stirred for 30 min. The

reaction mixture was extracted with CH₂Cl₂. The combined organic

extracts were washed with brine, dried (Na₂SO₄), concentrated and

the resulting crude mesylate 39 (208 mg, 93%) was used as such for

the next step without puriﬁcation.

To an ice-cooled solution of the diol 3 (35 mg, 0.05 mmol) in

CH₂Cl₂(2 mL), DMP (22 mg, 0.06 mmol) was added in small por-

tions and stirred for 6 h. The reaction mixture was quenched with

ice, partitioned between CH₂Cl₂, water and the organic layer was

separated, washed with CH₂Cl₂, brine, dried (Na₂SO₄), and con-

centrated to afford the aldehyde (29 mg, 85%) as colorless syrup.

The crude aldehyde was used for the next step without puriﬁcation.

To a solution of the aldehyde (29 mg, 0.04 mmol) in benzene

(2 mL), the ylide [(carbethoxymethylene) triphenyl phosphorane]

(42 mg, 0.12 mmol) was added and reﬂuxed for 1 h. The solvent was

evaporated under reduced pressure and the crude residue was

puriﬁed by column chromatography (80:20 petroleum ether/

Serinol derivative 5 (65 mg, 0.28 mmol) was dissolved in dry

DMSO (3 mL) and treated with NaH (5 mg, 60% dispersion in

mineral oil, 0.21 mmol) and mesylate 39 (100 mg, 0.14 mmol) was

added sequentially. The reaction immediately changed color from

nearly colorless to orange red. The reaction was stirred at room

temperature for 16 h, and was then quenched by the ice and diluted

with ethyl acetate. The two layers were separated and the aqueous

layer extracted with ethyl acetate (5ꢂ15 mL). The combined organic

layers were dried (Na₂SO₄) and concentrated in vacuo. Puriﬁcation

by ﬂash column chromatography (70:30 petroleum ether/EtOAc)

yielded the serinol ether 40 (105 mg, 65%) as colorless oil: R_f(30%

EtOAc) to yield 2 (25 mg, 78%) as colorless oil: R_f(15% EtOAc/pe-

25

troleum ether) 0.45; [

a

]

þ24.6 (c 0.5, CHCl₃); IR (CHCl₃)

n

: 3451,

¹H NMR

1.24e1.34 (m, 24H), 1.39e1.42 (m, 6H), 1.46 (s,

9H), 1.51e1.59 (m, 10H), 1.63e1.70 (m, 4H), 1.77 (dt, J¼5.5, 12.5 Hz,

D

2928, 1732, 1693, 1465, 1393, 1247, 1046, 758, 667 cm^ꢁ1

(CDCl₃, 400 MHz):

;

d

EtOAc/petroleum ether) 0.4; [

a

]

D

²⁵þ12.6 (c 0.2, CHCl₃); IR (CHCl₃)

n:

1894

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

1H), 1.92e2.05 (m, 1H), 2.20 (q, J¼6.5 Hz, 2H), 2.30e2.44 (m, 1H),

3.26e3.32 (m, 1H), 3.37e3.49 (m, 3H), 3.54e3.60 (m, 1H), 3.60 (br s,

1H), 3.66e3.92 (m, 3H), 3.97e3.99 (m, 1H), 4.05 (br s, 1H), 4.17 (q,

J¼7.0 Hz, 2H), 5.80 (br d, J¼15.6 Hz,1H), 6.94 (dt, J¼7.0, 15.6 Hz,1H);

74.9 (s), 78.8 (d), 79.7, 80.2 (2s, 1C), 81.8 (d), 83.9 (s), 93.2, 93.6 (2s,

1C), 108.6 (s), 127.4 (d), 127.6 (d, 2C), 128.3 (d, 2C), 138.6 (s), 151.7,

152.2 (2s, 1C) ppm; MS (ESI) m/z¼808 [MþNa]^þ; HRMS (ESI) calcd

for C₄₇H₇₉NO₈Na [MþNa]^þ808.5704, found 808.5649.

¹³C NMR (CDCl₃,100 MHz):

d 14.3 (q), 22.7 (t), 23.0 (t), 23.1, 24.4 (2q,

1C), 25.0 (t), 25.1 (t), 26.1 (t), 26.7, 27.5 (2q, 1C), 27.8 (t), 28.4, 28.5

(2q, 3C), 29.3 (t), 29.5 (t), 29.7 (t, 7C), 29.8 (t), 30.1 (t), 31.9 (t), 35.0

(t), 37.5 (t), 56.5, 56.3 (2d, 1C), 60.2 (t), 65.4, 65.7 (2t, 1C), 66.2 (d),

69.3, 70.0 (2t, 1C), 71.4 (t), 77.7 (d), 79.7, 80.2 (2s, 1C), 82.4 (d), 93.2,

93.7 (2s, 1C), 109.6 (s), 121.5 (d), 148.9 (d), 166.7 (s) ppm; MS (ESI)

m/z¼746 [MþNa]^þ. Anal. calcd for C₄₁H₇₃NO₉: C, 68.01; H, 10.16; N,

1.93%, found C, 67.90; H, 10.03; N, 1.72%.

4.43. tert-Butyl (R)-1-(15-((1R,2R,5S,7R)-7-(5-(benzyloxy)pen-

tyl)-2-hydroxy-6,8-dioxabicyclo[3.2.1]octan-5-yl)pentadecy-

loxy)-3-hydroxypropan-2-ylcarbamate (44)

A solution of the acetonide 41 (120 mg, 0.15 mmol) in dry CH₂Cl₂

was degassed properly. Then (C₆H₅)₃PAuCl (4 mg, 0.008 mmol)

followed by AgSbF₆(3 mg, 0.008 mmol) were added at 0 ^ꢀC and

stirred at rt under argon atmosphere for 3 h. The reaction mixture

was concentrated under reduce pressure and the obtained residue

was puriﬁed by silica gel chromatography (40:60 petroleum ether/

EtOAc) to obtain 44 (92 mg, 85%) as colorless syrup: R_f(40% EtOAc/

4.41. (S)-tert-Butyl 4-((heptadec-16-ynyloxy)methyl)-2,2-

dimethyloxazolidine-3-carboxylate (42)

At 0 ^ꢀC, triethylamine (6.7 mL, 47.5 mmol) was added to a so-

lution of 32 (4 g, 15.8 mmol) in CH₂Cl₂and stirred for 30 min. MsCl

(1.9 mL, 23.8 mmol) was added at 0 ^ꢀC and stirred for 30 min. The

reaction mixture was extracted with CH₂Cl₂. The combined organic

extracts were washed with brine, dried (Na₂SO₄), concentrated and

the resulting crude mesylate 43 (4.8 g, 92%) was used as such for

the next step without puriﬁcation.

petroleum ether) 0.4; [

a]

²⁵þ20.8 (c 3.6, CHCl₃); IR (CHCl₃)

n

: 3444,

D

2927, 2856, 1695, 1455, 1366, 1246, 1172, 1092, 755, 697 cm^ꢁ1

;

¹H

NMR (CDCl₃, 400 MHz):

d 1.23 (s, 24H), 1.35e1.41 (m, 4H), 1.43 (s,

9H), 1.48e1.55 (m, 4H), 1.60e1.67 (m, 6H), 3.53 (dt, J¼5.6, 18.7 Hz,

1H), 1.91e2.00 (m, 1H), 2.59 (br s, 1H), 3.40 (t, J¼6.7 Hz, 2H), 3.44 (t,

J¼6.5 Hz, 2H), 3.53 (dd, J¼3.9, 9.5 Hz, 1H), 3.57 (dd, J¼3.6, 9.3 Hz,

2H), 3.65 (dd, J¼3.7, 10.2 Hz, 1H), 3.75e3.78 (m, 2H), 3.85 (dd, J¼5.4,

7.1 Hz, 1H), 4.03 (br s, 1H), 3.92 (br s, 1H), 4.47 (s, 2H), 5.19 (d,

Serinol derivative 5 (2.8 g, 12.1 mmol) was dissolved in dry

DMSO (30 mL) and treated with NaH (582 mg, 60% dispersion in

mineral oil, 14.5 mmol) and mesylate 43 (4.8 g, 14.5 mmol) was

added sequentially. The reaction immediately changed color from

nearly colorless to orange red. The reaction was stirred at room

temperature for 16 h, and was then quenched by the ice and diluted

with ethyl acetate. The two layers were separated and the aqueous

layer extracted with ethyl acetate (5ꢂ15 mL). The combined organic

layers were dried (Na₂SO₄) and concentrated in vacuo. Puriﬁcation

by ﬂash column chromatography (85:15 petroleum ether/EtOAc)

yielded the serinol ether 42 (4.01 g, 71%) as colorless oil: R_f(10%

J¼5.5 Hz, 1H), 7.24e7.33 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz):

d 22.9

(t), 25.0 (t), 25.3 (t), 26.0 (t), 28.3 (q, 3C), 29.4 (t), 29.5 (t), 29.5 (t,

3C), 29.6 (t, 7C), 29.7 (t), 30.1 (t), 35.2 (t), 37.5 (t), 51.4 (d), 64.2 (t),

66.2 (d), 70.2 (t), 71.4 (t), 71.7 (t), 72.8 (t), 77.8 (d), 79.6 (s), 82.3 (d),

109.5 (s), 127.4 (d), 127.6 (d, 2C), 128.3 (d, 2C), 138.5 (s), 156.0

(s) ppm; MS (ESI) m/z¼728 [MþNa]^þ; HRMS (ESI) calcd for

C₄₁H₇₁NO₈Na [MþNa]^þ728.5078, found 728.5030.

4.44. (1S,2R,5S,7R)-5-(15-((S)-3-Acetoxy-2-(tert-butox-

ycarbonylamino)propoxy)pentadecyl)-7-(5-(benzyloxy)pen-

tyl)-6,8-dioxabicyclo[3.2.1]octan-2-yl acetate (45)

EtOAc/petroleum ether) 0.4; [

a

]

²⁵þ20.9 (c 1.1, CHCl₃); IR (CHCl₃)

n

:

;

D

3311, 2928, 2856, 1694, 1466, 1392, 1260, 1090, 847, 758, 629 cm^ꢁ1

¹H NMR (CDCl₃, 200 MHz):

d

1.23 (s, 24H),1.45 (s, 9H),1.43e1.49 (m,

To a solution of 44 (80 mg, 0.11mmol)inCH₂Cl₂(10 mL)at0 ^ꢀC was

addedEt₃N(0.1mL,0.7mmol), DMAP(2mg)andstirredfor15min. To

this, acetic anhydride (0.032 mL, 0.34 mmol) was added at 0 ^ꢀC and

stirred further for 2 h. The reaction mixture was diluted with CH₂Cl₂

(10 mL) and washed with brine, dried (Na₂SO₄), and concentrated

under reduced pressure. The resulting crude product was puriﬁed by

column chromatography (60:40 petroleum ether/EtOAc) to afford the

diacetate 45 (87 mg, 97%) as colorless syrup: R_f(30% EtOAc/petroleum

2H), 1.50 (s, 3H), 1.55 (s, 3H), 1.92 (t, J¼2.7 Hz, 1H), 2.15 (dt, J¼2.6,

6.8 Hz, 2H), 3.22e3.36 (m, 1H), 3.42 (dd, J¼6.4, 12.1 Hz, 2H),

3.48e3.60 (m, 1H), 3.86e4.07 (m, 3H); ¹³C NMR (CDCl₃, 50 MHz):

d

18.4 (t), 23.1, 24.4 (2q,1C), 26.1 (t), 26.8, 27.5 (2q,1C), 28.5 (2q, 3C),

28.5 (t), 28.8 (t), 29.1 (t), 29.5 (t), 29.5 (t), 29.6 (t, 4C), 29.7 (t, 3C),

56.3, 56.5 (2d,1C), 65.4, 65.7 (2t,1C), 68.1 (d), 69.3, 70.1 (2t,1C), 71.4

(t), 79.7, 80.2 (2s, 1C), 84.8 (s), 93.3, 93.7 (2s, 1C), 151.7, 152.2 (2s,

1C) ppm; MS (ESI) m/z¼488 [MþNa]^þ; HRMS (ESI) calcd for

C₂₈H₅₁NO₄Na [MþNa]^þ488.3716, found 488.3706.

ether) 0.43; [

1739, 1497, 1366, 1244, 1114, 925, 756, 666 cm^ꢁ1

400 MHz): 1.23(s, 24H),1.35e1.41 (m, 4H),1.42 (s, 9H),1.48e1.54(m,

a]

D

²⁵19.6 (c 5.5, CHCl₃); IR (CHCl₃)

n

: 3447, 2928, 2855,

;

¹H NMR (CDCl₃,

d

4.42. (S)-tert-Butyl 4-(((R)-19-((4R,5R)-5-(5-(benzyloxy)pen-

tyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-19-hydroxynonadec-16-

ynyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (41)

4H),1.57e1.62 (m, 3H),1.64e1.71 (m, 3H),1.77 (dt, J¼5.6,18.7 Hz, 2H),

2.03 (s, 3H), 2.09 (s, 3H), 3.38 (t, J¼6.7 Hz, 2H), 3.44 (t, J¼6.6 Hz, 2H),

3.38e3.49 (m, 2H), 3.88(dd, J¼4.8, 7.3 Hz,1H), 3.97 (br s,1H), 4.09(dd,

J¼5.5, 10.8 Hz, 1H), 4.15 (dd, J¼6.2, 11.0 Hz, 2H), 4.47 (s, 2H), 4.66 (t,

J¼2.3 Hz, 1H), 4.89 (d, J¼8.1 Hz, 1H), 7.24e7.33 (m, 5H); ¹³C NMR

Alkyne 43 (3.2 g, 6.9 mmol), n-BuLi (4.6 mL, 6.9 mmol, 1.6 M in

hexane), BF₃$Et₂O (0.9 mL, 6.9 mmol), epoxide 9 (550 mg, 1.7 mmol)

were subjected to general procedure A. The crude product was pu-

riﬁed by silica gel chromatography (80:20 petroleum ether/EtOAc) to

obtain 41 (960 mg, 71%) as a colorless syrup: R_f(15% EtOAc/petro-

(CDCl₃,100 MHz): d 20.8 (q), 21.3 (q), 22.5 (t), 22.7 (t), 25.3 (t), 26.0 (t),

26.0 (t), 28.3 (2q, 3C), 29.4 (t), 29.5 (t), 29.6 (t, 3C), 29.6 (t, 2C), 29.6 (t,

5C), 29.7 (t), 30.6 (t), 35.0 (t), 37.3 (t), 49.0 (d), 63.7 (t), 68.3 (d), 69.3(t),

70.2 (t), 71.5 (t), 72.8 (t), 77.8 (d), 79.5 (s), 79.6 (d),109.2 (s), 127.4 (d),

127.6 (d, 2C), 128.3 (d, 2C),138.6 (s),155.3 (s),170.8 (s) ppm; MS (ESI)

m/z¼812 [MþNa]^þ; HRMS (ESI) calcd for C₄₅H₇₅NO₁₀Na [MþNa]^þ

812.5289, found 812.5244.

leum ether) 0.46; [

a

]

²⁵þ91.7 (c 0.9, CHCl₃); IR (CHCl₃)

n: 3019, 2930,

D

1691, 1456, 1393, 1216, 1173, 759, 668 cm^ꢁ1

;

¹H NMR (CDCl₃,

200 MHz): d 1.23 (s, 24H),1.34 (s, 3H),1.38 (s, 3H),1.40e1.44 (m, 6H),

1.46 (s, 9H), 1.51 (s, 3H),1.55 (s, 3H), 1.58e1.62 (m, 4H), 2.14 (tt, J¼2.7,

6.8 Hz, 2H), 2.23 (d J¼4.2 Hz, 1H), 2.43e2.48 (m, 2H), 3.25e3.38 (m,

1H), 3.41e3.48 (m, 4H), 3.54e3.76 (m, 3H), 3.86e4.03 (m, 4H), 4.48

4.45. (1S,2R,5S,7R)-5-(15-((S)-3-Acetoxy-2-(tert-butox-

ycarbonylamino)propoxy)pentadecyl)-7-(5-hydroxypentyl)-

6,8-dioxabicyclo[3.2.1]octan-2-yl acetate (46)

(s, 2H), 7.24e7.34 (m, 5H); ¹³C NMR (CDCl₃, 50 MHz):

d 18.7 (t), 23.0,

24.3 (q, 2C), 24.3 (t), 26.0 (t, 3C), 26.2 (t), 27.1, 27.4 (q, 2C), 28.4 (q, 3C),

28.9 (t, 3C), 29.1 (t), 29.4 (t), 29.6 (t, 7C), 34.4 (t), 56.3, 56.4 (2d, 1C),

65.4, 65.6 (2t,1C), 69.2, 70.0 (2t,1C), 70.3 (t), 70.8 (d), 71.3 (t), 72.8 (t),

A suspension of 45 (200 mg, 0.3 mmol), Pd/C (5 mg) in ethyl ac-

etate (5 mL) was ﬂushed with hydrogen gas and stirred under

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

1895

hydrogen (20 psi) atmosphere for 30 min. The reaction mixture was

ﬁltered through Celite, concentrated and the crude product was pu-

riﬁed by column chromatography (50:50 petroleum ether/EtOAc) to

yield46(175mg, 88%)ascolorlessoil: R_f(30%EtOAc/petroleumether)

1.38e1.44 (m, 6H), 1.46 (s, 9H), 1.51 (s, 3H), 1.55 (s, 3H), 1.53e1.54 (m,

2H), 1.60e1.69 (m, 6H), 1.76 (dt, J¼5.6, 18.4 Hz, 1H), 1.93e2.00 (m,

1H), 2.37 (d, J¼6.3 Hz, 1H), 3.29 (dd, J¼9.5, 21.4 Hz, 1H), 3.41 (t,

J¼6.7 Hz, 2H), 3.45 (t, J¼6.4 Hz, 2H), 3.37e3.49 (m, 1H), 3.59 (br s,

1H), 3.85e3.92 (m, 3H), 3.98 (br s, 1H), 4.04 (br s, 1H), 4.49 (s, 2H),

0.4; [

a

]

²⁵ꢁ47.4 (c 1.3, CHCl₃); IR (CHCl₃)

n: 3448, 2928, 2855, 1735,

D

1

1499, 1366, 1244, 1043, 756, 665 cm^ꢁ1; H NMR (CDCl₃, 400 MHz):

7.24e7.35 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz):

d 23.0 (t), 23.1, 24.4

d

1.23 (s, 22H), 1.35e1.41 (m, 6H), 1.43 (s, 9H), 1.51e1.58 (m, 6H),

(2q,1C), 25.1 (t), 25.4 (t), 26.0 (t), 26.1 (t), 26.7, 27.5 (2q,1C), 28.4, 28.5

(2q, 3C), 29.5 (t), 29.6 (t, 5C), 29.7 (t, 4C), 29.8 (t), 30.1 (t), 35.2 (t), 37.5

(t), 56.3, 56.5 (2q, 1C), 65.4, 65.7 (2t, 1C), 66.3 (d), 69.3, 70.0 (2t, 1C),

70.3 (t), 71.4 (t), 72.9 (t), 77.9 (d), 79.7, 80.2 (2s, 1C), 82.3 (d), 93.2,

93.7 (2s, 1C), 109.5 (s), 127.5 (d), 127.6 (d, 2C), 128.3 (d, 2C), 138.6 (s),

151.7, 152.2 (2s, 1C) ppm; MS (ESI) m/z¼768 [MþNa]^þ; HRMS (ESI)

calcd for C₄₄H₇₅NO₈Na [MþNa]^þ768.5391, found 768.5352.

1.61e1.72 (m, 5H),1.78 (dt, J¼5.6,18.4 Hz,1H), 2.04 (s, 3H), 2.10 (s, 3H),

3.38 (t, J¼6.4 Hz, 2H), 3.41e3.49 (m, 2H), 3.63 (t, J¼6.4 Hz, 2H), 3.91 (t,

J¼5.5Hz,1H), 3.97 (brs,1H), 4.10 (dd, J¼5.3,10.1 Hz,1H), 4.13e4.18 (m,

2H), 4.67 (br s,1H), 4.88 (d, J¼7.1 Hz,1H); ¹³C NMR (CDCl₃,100 MHz):

d

20.8 (q), 21.3 (q), 22.5 (t), 22.7 (t), 25.3 (t), 25.5 (t), 26.0 (t), 28.3 (q,

3C), 29.4 (t), 29.5 (t), 29.6 (t, 3C), 29.6 (t, 2C), 29.7 (t, 5C), 29.7 (t), 30.6

(t), 32.6 (t), 35.0 (t), 37.3 (t), 49.0 (d), 62.8 (t), 63.7 (t), 68.4 (d), 69.3 (t),

71.6 (t), 77.8 (d), 79.6 (d),109.3 (s),155.4(s),170.9 (s) ppm; MS (ESI) m/

z¼722 [MþNa]^þ; HRMS (ESI) calcd for C₃₈H₆₉NO₁₀Na [MþNa]^þ

722.4819, found 722.4765.

4.48. (4S)-tert-Butyl-4-((15-((1R,2R,5S)-2-hydroxy-7-(5-

hydroxypentyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl)pentadecy-

loxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (3)

4.46. (E)-Ethyl 7-((1S,2R,5S,7R)-2-acetoxy-5-(15-((S)-3-

acetoxy-2-(tert-butoxycarbonylamino)propoxy)pentadecyl)-

6,8-dioxabicyclo[3.2.1]octan-7-yl)hept-2-enoate (47)

A suspension of 48 (50 mg, 0.07 mmol), 20% Pd(OH)₂/C (5 mg) in

ethyl acetate (5 mL) was ﬂushed with hydrogen gas and stirred

under hydrogen (20 psi) atmosphere for 30 min. The reaction

mixture was ﬁltered through Celite, concentrated and the crude

product was puriﬁed by column chromatography (60:40 petroleum

ether/EtOAc) to yield 3 (40 mg, 91%) as colorless oil: R_f(40% EtOAc/

To an ice-cooled solution of the alcohol 46 (50 mg, 0.07 mmol) in

CH₂Cl₂(2 mL), DMP (36 mg, 0.08 mmol) was added in small por-

tions and stirred for 6 h. The reaction mixture was quenched with

ice, partitioned between CH₂Cl₂, water and the organic layer was

separated, washed with CH₂Cl₂, brine, dried (Na₂SO₄), and con-

centrated to afford the aldehyde (40 mg, 80%) as colorless syrup.

The crude aldehyde was used for the next step without puriﬁcation.

To a solution of the aldehyde (35 mg, 0.05 mmol) in benzene

(2 mL), the ylide [(carbethoxymethylene) triphenyl phosphorane]

(52 mg, 0.15 mmol) was added and reﬂuxed for 1 h. The solvent was

evaporated under reduced pressure and the crude residue was

puriﬁed by column chromatography (80:20 petroleum ether/

petroleum ether) 0.4; [

a]

²⁵þ36.3 (c 0.2, CHCl₃); IR (CHCl₃)

n: 3436,

D

2928, 1690, 1406, 1394, 1216, 758, 668 cm^ꢁ1

;

¹H NMR (CDCl₃,

500 MHz):

d 1.24e1.35 (m, 24H), 1.37e1.44 (m, 6H), 1.46 (s, 9H),

1.51e1.59 (m, 11H), 1.62e1.71 (m, 3H), 1.77 (dt, J¼5.5, 12.3 Hz, 1H),

1.92e2.01 (m, 1H), 2.37 (d, J¼9.2 Hz, 1H), 3.26e3.50 (m, 2H), 3.39

(dd, J¼2.7, 8.1 Hz, 1H), 3.46 (dd, J¼2.9, 8.1 Hz, 1H), 3.60e3.66 (m,

1H), 3.63 (t, J¼6.4 Hz, 2H), 3.85e4.00 (m, 3H), 3.97e4.05 (m, 1H),

4.05 (br s, 1H); ¹³C NMR (CDCl₃, 125 MHz):

d 22.7 (t), 22.9 (t), 23.1,

24.4 (2q, 1C), 25.0 (t), 25.3 (t), 25.6 (t), 26.1 (t), 26.7, 27.5 (2q, 1C),

28.4, 28.5 (2q, 3C), 29.1 (t), 29.3 (t), 29.4 (t), 29.6 (t, 2C), 29.6 (t, 3C),

29.8 (t), 30.1 (t), 31.9 (t), 32.6 (t), 35.2 (t), 37.5 (t), 56.3, 56.5 (2d, 1C),

62.8 (t), 65.4, 65.7 (2t, 1C), 66.3 (d), 69.3, 70.0 (2t, 1C), 71.4 (t), 77.8

(d), 79.7, 80.2 (2s, 1C), 82.4 (d), 93.3, 93.7 (2s, 1C), 109.6 (s), 151.7,

152.2 (2s, 1C) ppm; MS (ESI) m/z¼678 [MþNa]^þ; HRMS (ESI) calcd

for C₃₇H₆₉NO₈Na [MþNa]^þ678.4921, found 678.4874.

EtOAc) to yield 47 (29 mg, 75%) as colorless oil: R_f(10% EtOAc/pe-

25

troleum ether) 0.4; [

a

]

ꢁ83.4 (c 0.98, CHCl₃); IR (CHCl₃)

n

: 3367,

¹H NMR

1.23 (s, 24H), 1.27 (t, J¼7.2 Hz, 3H), 1.36e1.41

D

2927, 2854, 1720, 1500, 1465, 1244, 1042, 971, 775 cm^ꢁ1

(CDCl₃, 400 MHz):

;

d

(m, 4H), 1.43 (s, 9H), 1.47e1.56 (m, 6H), 1.65e1.72 (m, 3H), 1.79 (dt,

J¼5.8, 8.2 Hz, 1H), 2.05 (s, 3H), 2.10 (s, 3H), 2.19 (dd, J¼6.8, 13.6 Hz,

2H), 3.39 (t, J¼6.7 Hz, 2H), 3.42e3.50 (m, 2H), 3.89 (dd, J¼5.1, 7.8 Hz,

1H), 3.97 (br s, 1H), 4.09 (dd, J¼5.6, 11.1 Hz, 1H), 4.14e4.18 (m, 2H),

4.17 (q, J¼7.3 Hz, 2H), 4.67 (t, J¼2.0 Hz, 1H), 4.87 (d, J¼7.4 Hz, 1H),

5.80 (d, J¼15.6 Hz, 1H), 6.93 (dt, J¼7.0, 15.6 Hz,1H); ¹³C NMR (CDCl₃,

4.49. (4S)-tert-Butyl 4-((15-((1R,2R,5S)-7-((E)-7-ethoxy-7-

oxohept-5-enyl)-2-hydroxy-6,8-dioxabicyclo[3.2.1]octan-5-yl)

pentadecyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxyl-

ate (2)

100 MHz): d 14.3 (q), 20.9 (q), 21.3 (q), 22.5 (t), 22.8 (t), 25.1 (t), 26.1

(t), 27.8 (t), 28.3 (q, 3C), 29.5 (t), 29.5 (t), 29.6 (t, 3C), 29.6 (t, 2C),

29.7 (t, 5C), 29.7 (t), 30.6 (t), 32.1 (t), 34.9 (t), 37.4 (t), 60.1 (t), 63.7

(t), 68.3 (d), 69.3 (t), 71.6 (t), 77.7 (d), 79.7 (d), 109.4 (s), 121.5 (d),

148.9 (d), 152.7 (s), 166.7 (s), 170.9 (s, 2C) ppm; MS (ESI) m/z¼790

[MþNa]^þ; HRMS (ESI) calcd for C₄₂H₇₃NO₁₁Na [MþNa]^þ790.5082,

found 790.5037.

To an ice-cooled solution of the diol 3 (35 mg, 0.05 mmol) in

CH₂Cl₂(2 mL), DMP (27 mg, 0.6 mmol) was added in small portions

and stirred for 6 h. The reaction mixture was quenched with ice,

partitioned between CH₂Cl₂, water and the organic layer was sep-

arated, washed with CH₂Cl₂, brine, dried (Na₂SO₄), and concen-

trated to afford the aldehyde (30 mg, 85%) as colorless syrup. The

crude aldehyde was used for the next step without puriﬁcation.

To a solution of the aldehyde (30 mg, 0.05 mmol) in benzene

(2 mL), the ylide ((carbethoxymethylene) triphenyl phosphorane)

(56 mg, 0.16 mmol) was added and reﬂuxed for 1 h. The solvent was

evaporated under reduced pressure and the crude residue was

puriﬁed by column chromatography (80:20 petroleum ether/

4.47. (4S)-tert-Butyl 4-((15-((1R,2R,5S)-7-(5-(benzyloxy)pen-

tyl)-2-hydroxy-6,8-dioxabicyclo[3.2.1]octan-5-yl)pentadecy-

loxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (48)

To a solution of diol 44 (100 mg, 0.14 mmol) in acetone, were

added DMP (0.07 mL, 0.6 mmol) and p-TSA (5 mg) at 0 ^ꢀC. The re-

action mixture was stirred at rt for 2.5 h when TLC analysis indicates

the reaction was complete then was treated with few drops of trie-

thylamine and the solvent was removed under reduced pressure and

the resulting crude product was puriﬁed by column chromatography

(70:30 petroleum ether/EtOAc) to obtain 48 (87 mg, 82%) as a col-

EtOAc) to yield 2 (26 mg, 78%) as colorless oil: R_f(15% EtOAc/pe-

25

troleum ether) 0.45; [

a

]

þ26.6 (c 0.4, CHCl₃); MS (ESI) m/z¼746

D

[MþNa]^þ; HRMS (ESI) calcd for C₄₁H₇₃NO₉Na [MþNa]^þ746.5183.

found 746.5129.

Acknowledgements

orless thick syrup: R_f(35% EtOAc/petroleum ether) 0.4; [

1.0, CHCl₃); IR (CHCl₃)

847, 770, 732, 697 cm^ꢁ1; ¹H NMR (CDCl₃, 400 MHz):

a

]

²⁵þ28.7 (c

D

n

: 3404, 2925, 2854, 1702, 1459, 1388, 1103,

We thank the Ministry of Science and Technology for funding

through the Department of Science and Technology under the

d

1.24 (s, 24H),

1896

S. Das et al. / Tetrahedron 69 (2013) 1881e1896

6. (a) Trost, B. M.; Horne, D. B.; Woltering, M. J. Angew. Chem., Int. Ed. 2003, 42,

5987e5990; (b) Miyakoshi, N.; Aburano, D.; Mukai, C. J. Org. Chem. 2005, 70,

6045e6052; (c) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46,

7664e7666; (d) Zhang, Y.; Xue, J.; Xin, Z.; Xie, Z.; Li, Y. Synlett 2008, 940e944;

(e) Ramana, C. V.; Induvadana, B. Tetrahedron Lett. 2009, 50, 271e273; (f)

Ramana, C. V.; Mallik, R.; Sahoo, G. Tetrahedron Lett. 2009, 50, 4844e4847; (g)

Liu, J.; De Brabander, J. K. J. Am. Chem. Soc. 2009, 131, 12562e12563; (h)

Ramana, C. V.; Suryawanshi, S. B.; Gonnade, R. G. J. Org. Chem. 2009, 74,

2842e2845; (i) Trost, B. M.; O’Boyle, B. M.; Hund, D. J. Am. Chem. Soc. 2009,

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2009, 30, 771e772; (k) fortner, K. C.; Kato, D.; Tanaka, Y.; Shair, M. D. J. Am.

Chem. Soc. 2009, 132, 275e280; (l) Ravindar, K.; Reddy, M. S.; Lindqvist, L.;

Pelletier, J.; Deslongchamps, P. Org. Lett. 2010, 12, 4420e4423; (m) Fang, C.;

Pang, Y.; Forsyth, C. J. Org. Lett. 2010, 12, 4528e4531; (n) Tlais, S. F.; Dudley, G.

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SD and BI is gratefully acknowledged.

Supplementary data

NMR spectra. Supplementary data associated with this article

can be found in the online version, at http://dx.doi.org/10.1016/

j.tet.2012.12.045.

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Article Doi

Metal-mediated alkynediol cycloisomerization: First and second generation formal total syntheses of didemniserinolipid B

DOI: 10.1016/j.tet.2012.12.045

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