Enantiopure hydroxymethylated cycloalkenols as privileged small molecular multifunctional scaffolds for the asymmetric synthesis of carbocycles

Tetrahedron: Asymmetry xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Tetrahedron: Asymmetry

journal homepage: www.elsevier.com/locate/tetasy

Enantiopure hydroxymethylated cycloalkenols as privileged small

molecular multifunctional scaffolds for the asymmetric synthesis of

carbocycles

⇑

Rajan Kumar, Rohan Kalyan Rej, Joydev Halder, Haridas Mandal, Samik Nanda

Department of Chemistry, Indian Institute of Technology, Kharagpur, 721302, India

a r t i c l e i n f o

a b s t r a c t

Article history:

Enantiopure hydroxymethylated cycloalkenols bearing a quaternary stereocenter have been synthesized

by a Pybox mediated enantioselective desymmetrization method. The synthesized cycloalkenols serve as

starting precursors for the construction of several chiral small ring carbocyclic frameworks by a distinct

functional group transformation.

Received 13 April 2016

Accepted 5 May 2016

Available online xxxx

1

. Introduction

Biological space, consists of DNA, RNA, carbohydrates, proteins,

the other is a substrate-based strategy.⁸In the former strategy, a

core scaffold is subjected to different reagents and conditions to

afford diversity in the products while in the latter strategy, a

diverse collection of products is obtained by reacting different sub-

strates to the same sequence of reagents and conditions. In the for-

mer approach, which sometimes can be regarded as scaffold

oriented synthesis, the synthesized libraries are mainly based on

the core scaffold from individual natural products or speciﬁc sub-

structures found across a class of natural products or a new chemo-

type together. The core scaffolds are then synthetically

manipulated to give a new scaffold mainly by a linear or divergent

route. From our recent work in the area of scaffold oriented synthe-

sis, we identiﬁed hydroxymethylated cycloalkenone derivatives as

potential multifunctional scaffolds, which can be successfully

lipids and related molecules seem to be modest in size; the human

4

genome is in the order of 3 ꢀ 10 genes of which only a fraction is

targeted by current therapeutics.¹Meanwhile, chemical space is

60

inﬁnite, and there are an estimated 10 organic compounds with

a molecular weight cutoff of 500 D.²Our limited understanding

of certain areas of chemical space that are best suited to interact

with biological space is a major bottleneck of drug discovery. In

recent years, there have been various attempts at narrowing this

gap by statistical analyses to deﬁne descriptors for small-molecule

3

drug-like space. The ever-increasing demand for the production of

natural products and their analogues for pharmaceutical applica-

tions is the basis of research efforts on the development of conve-

nient synthetic pathways.⁴For this purpose various synthetic

strategies e.g. diversity oriented synthesis, target oriented synthe-

9

applied to the asymmetric synthesis of natural products, designed

10

11

cyclitols and novel carbasugars. In continuation of our earlier

work, we herein report our research ﬁndings based on the scaffold

oriented synthesis of novel chemical entities from two relatively

new hydroxymethylated cycloalkenol based scaffold containing a

quaternary stereocenter (Scheme 1).

5

sis and biology oriented synthesis have been successfully utilized.

Natural products and their analogues provide the inspiration for a

variety of strategies used in the diversity oriented synthesis of

novel small molecule libraries.⁶Diversity oriented synthesis has

emerged as a powerful approach to obtain complex molecules for

biological studies. The utility of diversity oriented synthesis relies

on the development of chemical methodologies for the synthesis

of novel structural types with high levels of skeletal and stereo-

2

. Results and discussion

The initial hurdle was to access both hydroxymethylated

cycloalkenol scaffolds S1 and S2 bearing a quaternary stereocenter

in enantiopure form. The ring closing metathesis reaction was

thought to be explored to construct the internal oleﬁnic unsatura-

tion present in both the scaffolds. The ring closing metathesis

precursor was thought to be accessed from diethyl 2-allyl-2-

methylmalonate as shown in Scheme 2.

7

chemical complexity. There are two main strategies involved in

diversity oriented synthesis; one is a reagent based strategy while

⇑

Corresponding author. Tel.: +91 3222 283328; fax: +91 3222 282252.

E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).

http://dx.doi.org/10.1016/j.tetasy.2016.05.003

0

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2

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

OH

New chemical entities

based on a core scaffold

S1

-(hydroxymethyl)-5-methylcyclopent-2-en-1-ol

S2

6-(hydroxymethyl)-6-methylcyclohex-3-en-1-ol

5

Scheme 1. Hydroxymethylated 2-cycloalkenols bearing a quaternary stereocenter.

OH

PgO

OH

RCM

CO

diethyl 2-allyl-2-methylmalonate

2

Et

OBz

OH

S1

2

Et

(R)

HO

PgO

OH

RCM

OH

S2

Scheme 2. Retrosynthetic analysis for both the scaffolds.

2

.1. Synthesis of all of the stereoisomers of S1 and S2

from enantiopure aldehyde (R)-8. Allylation of aldehyde 8 under

1

8

Barbier conditions afforded an inseparable mixture of diastere-

omers 15 and 16 in 88% yield. The ring closing metathesis reaction

of the mixture of 15 and 16 with G-I catalyst afforded cyclic com-

pounds 17 and 18, which were then separated by column chro-

matography. By applying a similar procedure, ent-17 and ent-18

were also synthesized from aldehyde (S)-8. Hence all of the

stereoisomers of scaffold S2 were also synthesized as shown in

Scheme 3. The absolute conﬁgurations of diols 17 and 18 were

assigned by comparing their spectroscopic data and speciﬁc rota-

In our initial attempt to ﬁx the quaternary stereocenter present

in diethyl 2-allyl-2-methylmalonate 1, PLE (pig liver esterase)

mediated hydrolysis through an enantioselective enzymatic

12

desymmetrization strategy was unsuccessful. The corresponding

half ester 2 was obtained in 90% yield but with low enantioselec-

tivity (ee = 30%) in favor of the (S)-stereoisomer. The lipase

(

Amano-PS) mediated enantioselective enzymatic desymmetriza-

tion through an irreversible transesteriﬁcation of the prochiral diol

(obtained after reducing both the –CO Et groups of compound 1)

1

7a

3

2

tions with those reported in the literature.

also failed to produce any reasonable enantioselection. As a result,

the direct enantioselective desymmetrization using a chemical cat-

alyst was explored as reported by Lee et al.¹³2,2-Disubstituted 1,3-

2.2. Scaffolding of hydroxymethylated cyclopent-2-enol S1

propane diol 3 was treated with a C

2

-symmetric Pybox ligand and

The creation of a diverse set of small molecular compounds was

initiated with 11. Compound 11 was subjected to substrate direc-

ted epoxidation with mCPBA in DCM solvent to afford the epoxide

21 in 90% yield as the sole product. Epoxide opening with 0.2 M

H SO in dioxane:water (1:1) afforded triol 22 as a single product.

2 4

PMB deprotection and subsequent esteriﬁcation of the tetraol fur-

CuCl in the presence of PhCOCl to afford compound (R)-5 in 98%

2

yield and with 90% ee. This desymmetrization method ﬁxed the

quaternary stereocenter of our desired scaffolds. The free alcohol

group in compound 5 was then protected with PMB-imidate to fur-

nish compound 6 in 88% yield. Removal of benzoate group with

methanolic K

2

CO

3

afforded compound 7 in 90% yield. Oxidation

nished tetraacetate 23 in 80% yield. Later on 11 was subjected to

dihydroxylation with OsO /NMO to afford diol 24 and 25 in a 3:2

4

14

of compound 7 under Swern conditions afforded aldehyde (R)-8

in 90% yield. Vinylmagnesium bromide addition on compound 8

at ꢁ78 °C afforded compounds 9 and 10 as an inseparable diastere-

omeric mixture in 82% yield. At this stage we did not assign the

absolute conﬁguration of both diastereomers. The diastereomeric

mixture was subjected to ring closing metathesis reaction with

ratio. The structure and relative stereochemistry for both the diols

were conﬁrmed by X-ray crystallographic analysis. The ORTEP

(Oakridge Thermal Ellipsoid Plot) diagrams for diols 24 and 25

are shown in Figure 1. Next we decided to create an extra ring

fused with the original cyclopentane ring present in 11. For this

purpose, the free hydroxyl group in 11 was protected as its TBS

ether by treatment with imidazole and TBS-Cl to furnish com-

pound 26 in 95% yield. Dihydroxylation of compound 26 with

1

5

G-I catalyst (Grubbs 1st generation metathesis catalyst) to afford

compounds 11 and 12 in 80% yield. Deprotection of the PMB

groups in compounds 11 and 12 was achieved by treatment with

1

6

17

DDQ to afford the known cyclic diols 13 and 14. The absolute

conﬁgurations for compounds 13 and 14 were then assigned

ambiguously. Hence two stereoisomers of scaffold S1 bearing a

quaternary stereocenter was easily synthesized from the (S)-enan-

tiomer of compound 7. Protecting group manipulation was carried

out as shown in Scheme 3, and afforded (S)-8 from (R)-5 in good

yield. Enantiopure (S)-8 was then synthetically manipulated to fur-

nish ent-13 and ent-14 separately by following the same proce-

dure. Hence all of the stereoisomers of scaffold S1 can be easily

accessed. For accessing the stereoisomers of scaffold S2, we started

4

OsO /NMO afforded diols 27 and 28 in 78% yield (3:1). The diol

functionality in compound 27 was protected as its acetonide by

treatment with 2,2-DMP in the presence of a catalytic amount of

CSA to afford acetonide 29 in 92% yield. Treatment of compound

29 with DDQ furnished alcohol 30 after removal of the PMB group

in 88% yield. Oxidation under Swern conditions afforded aldehyde

31 in 90% yield. Aldehyde 31 was then subjected to Wittig oleﬁna-

+

ꢁ

3

tion with Ph P MeI in presence of LHMDS to afford the oleﬁnic

compound 32 in 74% yield. Treatment of compound 32 with TBAF

afforded alcohol 33 in 88% yield. Treatment of compound 33 in the

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R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

3

OH

OAc

4

; yield = 90%; ee = <5

d

CO

2

Et

CO

Et

2

OH

a

c

e

OBz

OH

f

OBz

OPMB

CO

2

1

3

(R)-5; ee = 90%

6

b

g

CO

2

Et

OPMB

H

OH

OPMB

i

h

CO

2

H

+

HO

O

2

9

10

(R)-8

(S)-7

yield = 90%; ee = 30%

(

inseparable diastereomers)

OPMB

PMBO

OH

k

OPMB

HO

OH

HO

j

k

11

9 + 10

+

1

2

13

11

12

14

(

separable by chromatography)

PMBO

OPMB

l

HO

j

(R)-8

+

HO

16

HO

15

18

17

(inseparable diastereomers)

(separable by chromatography)

OBz

OH

m

n

OH

OTBDPS

OPMB

OH

p

OPMB

H

OBz

OTBDPS

o

O

(S)-8

(

R)-5

19

20

(R)-7

OH

HO

OH

HO

(

S)-8

ent-13

ent-14

PMBO

OPMB

l

j

HO

+

(

S)-8

+

HO

ent-16

HO

ent-15

ent-17

ent-18

nBu

O

N

nBu

N

Ph

Pybox ligand

Scheme 3. Reagents and conditions: (a) NaH, allyl bromide, reﬂux, 6 h, 90%; (b) PLE, phosphate buffer (pH = 8.0), 24 h; (c) LAH, THF, 90%; (d) lipase-PS (Amano), vinyl acetate,

i

Pr

0%; (h) (COCl)

bromide, Zn, NH

2

O, MS (4 Å), rt, 20 h; (e) (i) Pybox ligand, CuCl

, Me N, 90%; (i) CH

SO, ꢁ78 °C, Et

Cl, THF, 88% (m) imidazole, TBDPS-Cl, rt, 90%; (n) K

2

, THF, 4 h; (ii) PhCOCl, Et

@CHMgBr, ꢁ78 °C, 2 h, 82%; (j) G-I, DCM, reﬂux, 6 h, 80%; (k) DDQ, DCM:phosphate buffer (19:1), rt, 2 h, 90%; (l) Allyl

CO , MeOH, 6 h, 90%; (o) (i) same as (f), (ii) TBAF, THF, rt, 79%; (p) same as h, 90%.

3

N, THF, ꢁ78 °C, 12 h, 98%; (f) PMBAOA(C@NH)ACCl

3 2 3

, CSA, rt, 6 h, 88%; (g) K CO , MeOH, rt, 6 h,

9

2

3

2

4

2

3

presence of NaH and allylbromide afforded the O-allylated com-

pound 34 in 78% yield. The ring closing metathesis reaction of com-

pound 34 in presence of G-II catalyst (Grubbs 2nd generation

metathesis catalyst, 5 mol %) in reﬂuxing DCM afforded the ring

closing product 35 in 80% yield. Finally dihydroxylation with

the tetraol 37, whose structure and relative conﬁguration were

assigned with the help of single crystal X-ray structure analysis.

Tetraol 37 was subsequently converted into tetraacetate 38 for

1

obtaining sharp resolution in the respective H NMR spectrum

(Scheme 4). Compound 11 was subjected to substrate directed

Simmons-Smith cyclopropanation to afford bicyclic compound 39

as the sole product. The free hydroxyl group in 39 was protected

OsO

4

/NMO afforded diol 36 as the sole product in 82% yield. The

acetonide group in compound 36 was removed with PTSA to afford

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4

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

Compound 24

Compound 25

Compound 37

Figure 1. ORTEP presentation of triols 24 and 25 and tetraol 37.

as its TBS ether by treatment with imidazole and TBS-Cl to furnish

compound 40 in 90% yield. Treatment of compound 40 with DDQ

furnished alcohol 41 in 88% yield after removal of the PMB group.

Oxidation under Swern conditions afforded aldehyde 42 in 90%

yield. Aldehyde 42 was then subjected to Wittig oleﬁnation with

3. Conclusion

In conclusion, all of the stereoisomers of the hydroxymethy-

lated cycloalkenol scaffolds based on cyclopentane and cyclohex-

ane frameworks bearing quaternary stereocenters have been

synthesized. The scaffolds can be further synthetically manipu-

lated by a distinctive transformation based strategy in a linear

way to access several carbocycles via a stereoselective fashion.

We believe that most of the reactions reported herein can be car-

ried out efﬁciently on a multigram scale, and so their use on an

industrial scale can be amended at a later stage. The synthesized

small ring carbocycles might exhibit some biological activity and

could contribute to the chemical space project.

+

ꢁ

3

Ph P MeI in the presence of LHMDS to afford the oleﬁnic com-

pound 43 in 74% yield. Treatment of compound 43 with TBAF

afforded alcohol 44 in 86% yield. Treatment of compound 44 in

presence of NaH and allylbromide afforded the O-allylated com-

pound 45 in 70% yield. The ring closing metathesis reaction of com-

pound 45 in the presence of G-II catalyst (5 mol %) in reﬂuxing

DCM afforded the ring closing product, which upon treatment with

4

OsO /NMO afforded diol 46 as the sole product in 53% overall yield

after two steps. The crystal structures of triol 24, 25 and tetraol 37

were obtained with the help of single crystal X-ray analysis, and

the corresponding ORTEP presentations are shown in Figure 1,

which also establishes the relative stereochemistry of the different

functional groups present in those compounds.

4

. Experimental

.1. General

All oxygen and/or moisture-sensitive reactions were carried out

under an N

2

atmosphere in glassware that had been ﬂame-dried

prior to use.

2

.3. Scaffolding of the hydroxymethylated cyclohex-3-enol S2

under a vacuum (w0.5 mmHg) and purged with N

2

Unless otherwise stated, materials were obtained from commercial

suppliers and used without further puriﬁcation. Lipase (Amano-PS)

was purchased from Sigma Aldrich Co, USA and used as obtained.

THF and diethyl ether were distilled from sodium benzophenone

ketyl. Dichloromethane (DCM) was distilled from calcium hydride.

Reactions were monitored by thin-layer chromatography (TLC) car-

ried out on0.25 mmsilica gel plates with UVlight, ethanolic anisalde-

hyde, and phosphomolybdic acid/heat as developing agents. Silica gel

The creation of a diverse set of small molecular compound

libraries was initiated with 19. Compound 19 was subjected to sub-

strate directed epoxidation with mCPBA in DCM solvent to afford

epoxides 47 and 48 in 80% yield (2:1). Epoxide opening of com-

2 4

pounds 47 and 48 with 0.2 M H SO in dioxane:water (1:1) followed

by removal of the PMB group with DDQ afforded tetraols 49 and 50,

respectively. Compound 19 was next subjected to substrate directed

Simmons-Smith cyclopropanation to afford bicyclic compound 51

as the sole product in 75% yield. Next we decided to create an extra

ring fused with original cyclohexane ring present in 19. For this pur-

pose, the free hydroxyl group in 19 was protected as its TBS ether by

treatment with imidazole and TBS-Cl to furnish compound 52 in

6% yield. Dihydroxylation of compound 52 with OsO /NMO

4

afforded diols 53 and 54 in 81% yield (1:2). The diol functionality

in compound 54 was protected as its acetonide by treatment with

100–200 mesh was used for column chromatography. Yields refer to

chromatographically and spectroscopically homogeneous materials

unless otherwise stated. NMR spectra were recorded on 600, 400

3

and 200 MHz spectrometers at 25 °C in CDCl using TMS as the inter-

1

3

nal standard. Chemical shifts are shown in d. C NMR spectra were

8

recorded with a complete proton decoupling environment. The

1

13

H C

chemical shift value is listed as d and d for H and C, respectively.

Coupling constants (J) are reported in Hertz (Hz) and the resonance

multiplicity abbreviations used are s, singlet; d, doublet; t, triplet; q,

quartet; dt, doublet of triplets; dd, doublet of doublets; ddd, doublet

of doublet of doublets; m, multiplet; comp, overlapping multiplets of

magnetically non-equivalent protons. Mass spectrometric analysis

was performed in the CRF, IIT-Kharagpur (TOF analyzer). Optical rota-

tions were measured on a digital polarimeter.

2

,2-DMP in the presence of a catalytic amount of CSA to afford ace-

tonide 55 in 90% yield. Treatment of compound 55 with DDQ fur-

nished alcohol 56 after removal of the PMB group in 88% yield.

Oxidation under Swern conditions followed by Wittig oleﬁnation

with Ph P MeI in the presence of LHMDS afforded oleﬁnic com-

3

pound 57 in 64% yield (for two step). Treatment of compound 57

with TBAF afforded alcohol 58 in 88% yield. Treatment of compound

+

ꢁ

5

8 in the presence of NaH and allylbromide afforded the O-allylated

4

.2. General procedure for the substrate directed epoxidation

compound 59 in 78% yield. The ring closing metathesis reaction of

compound 59 in the presence of G-II catalyst (5 mol %) in reﬂuxing

DCM afforded the ring closing product 60 in 80% yield. Finally dihy-

with mCPBA

Unsaturated alcohols (0.31 mmol) were dissolved in DCM

droxylation with OsO

2% yield. The acetonide group in compound 61 was removed with

PTSA to afford tetraol 62 in 90% yield (Scheme 5).

4

/NMO afforded diol 61 as the sole product in

(

5 mL) along with NaHCO

3

(52 mg, 0.62 mmol). To a stirred

8

suspension, meta-chloroperoxybenzoic acid (108 mg, 0.62 mmol)

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R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

5

AcO

PMBO

a

AcO

d

HO

c

HO

b

HO

+

OAc

OH

O

11

OH

AcO

HO

23

22

21

24

25

e

PMBO

TBSO

HO

f

+

OH

HO

26

27

28

PMBO

O

CHO

O

g

HO

TBSO

i

j

k

h

O

OH

O

HO

27

29

30

31

32

33

l

HO

O

HO

O

AcO

O

OH

OAc

p

o

m

n

O

OH

O

OAc

HO

AcO

38

37

36

35

34

PMBO

HO

CHO

q

TBSO

r

s

t

HO

TBSO

1

39

40

41

42

u

HO

O

OH

HO

v

TBSO

x

w

O

4

6

45

44

43

, dioxane:water (1:1), 8 h, 88%; (d) (i) DDQ, DCM/

3

N, DMAP (5 mol %), rt, 12 h, 80%; (e) imidazole, TBS-Cl, 95%; (f) same as a, 78%; (g) 2,2-DMP, CSA, DCM, rt, 92%; (h) same as d, 88%; (i)

P MeI , LHMDS, 0 °C, 74%; (k) TBAF, THF, rt, 88%; (l) NaH, allylbromide, rt, 78%; (m) G-II, DCM, reﬂux, 8 h, 80%; (n) same as a, 82%; (o)

Br , Zn–Cu couple, diethylether, 30 h, reﬂux, 75%; (r) same as e, 90%; (s) same as d, 88%; (t) same as i,

Scheme 4. Reagents and conditions: (a) OsO

phosphate buffer (19:1), rt, (ii) Ac O, Et

COCl) N, 90%; (j) Ph

, DMSO, ꢁ78 °C, Et

PTSA, DCM, rt, 90%; (p) Ac O, Et N, DMAP (5 mol %), rt, 12 h, 95%; (q) CH

0%; (u) same as j, 74%; (v) same as k, 86%; (w) same as l, 70%; (x) (i) same as m, (ii) same as a, 53% (in two steps).

4

(0.5 M in toluene), NMO, 75%; (b) mCPBA, DCM, rt, 90%; (c) 0.2 M H

2

SO

4

2

+

ꢁ

(

2

3

2

3

2

9

was added at room temperature. The resulting suspension was

stirred vigorously for 19 h. Next a 20% aqueous solution of sodium

sulﬁte (10 mL) was added and the resulting two-phase mixture

was stirred vigorously for 15 min. The two layers were separated

and the aqueous layer was extracted with DCM (30 mL). The com-

bined organic layers were washed with a 20% aqueous solution of

4.3. General procedure for the acid induced epoxide ring

opening

Epoxide compounds (0.085 mmol) were added to a 1:1 mixture

of 0.2 M sulfuric acid/1,4-dioxane (5 mL) and the reaction mixture

was stirred at room temperature for 8 h. The reaction was then

sodium sulﬁte (10 mL) and saturated aqueous NaHCO

3

(5 mL),

diluted with a saturated solution of NaHCO

with ethyl acetate (30 mL). The organic layers were combined,

dried (Na SO ), and concentrated in vacuo. The residue was puri-

ﬁed by ﬂash column chromatography to afford the diols.

3

(5 mL) and extracted

dried (Na SO ) and evaporated under reduced pressure. The resi-

2

4

due was puriﬁed by ﬂash column chromatography to afford the

epoxide.

2

4

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6

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

OPMB

+

OPMB

HO

c

a

O

b

O

b

1

9

51

47

48

d

OPMB

OH

OPMB

TBSO

HO

e

TBSO

+

OH

50

53

54

52

49

OPMB

OH

OPMB

g

OH

O

TBSO

HO

f

h

i

O

OH

O

5

4

55

56

57

58

OH

j

OH

O

m

O

l

O

k

O

OH

O

OH

O

6

2

61

60

59

Scheme 5. Reagents and conditions: (a) mCPBA, DCM, rt, 80%; (b) (i) 0.2 N H

couple, diethylether, 30 h, reﬂux, 75%; (d) imidazole, TBS-Cl, 86%; (e) OsO (O.5 M in toluene), NMO, 81%; (f) 2,2-DMP, CSA, DCM, rt, 90%; (g) DDQ, DCM/phosphate buffer

P MeI , LHMDS, 0 °C, 64%; (i) TBAF, THF, rt, 88%; (j) NaH, allylbromide, rt, 78%; (k) G-II, DCM, reﬂux, 8 h, 80%; (l) same

2 4 2 2

SO , dioxane:water (1:1), 8 h, (ii) DDQ, DCM/phosphate buffer (19:1), rt; (c) CH Br , Zn–Cu

4

+

ꢁ

(

19:1), 88%; (h) (i) (COCl)

2

, DMSO, ꢁ78 °C, Et

3 3

N, (ii) Ph

as e, 82%; (m) PTSA, DCM, rt, 90%.

4

.4. General procedure for the cyclopropanation reaction

was cooled to 0 °C. Next, DDQ (2.51 g, 11.07 mmol) was added por-

tion wise to the solution and the mixture was stirred at this tem-

perature for 2 h. The reaction mixture was then ﬁltered through

a pad of Celite. The residue was then washed with 25 mL of

DCM. The combined organic solution was washed successively

To a hot, rapidly stirred solution of cupric acetate monohydrate

(

140 mg, 0.7 mmol) in 2 mL of glacial acetic acid was added zinc

dust (790 mg, 12 mmol). After approximately 0.5 min, all of the

copper had deposited on the zinc. The couple was allowed to settle

for 10 min, then the acetic acid was decanted while taking care to

not lose the silt-like couple. The dark reddish gray couple was then

washed with one portion (2 mL) of acetic acid followed by three

portions (10 mL) of ether. The moist couple was thus ready for

use. Methylene bromide (124 mg, 0.72 mmol) and iodine (0.15 g,

with saturated aqueous NaHCO

The organic layer was then dried over anhydrous Na

3

solution, water and brine solution.

SO and evap-

2

4

orated in vacuo. Puriﬁcation by silica gel chromatography afforded

the required alcohol.

4.6. General procedure for the TBS protection

0

.6 mmol) in anhydrous ether (5 mL) were added to a mixture of

the zinc–copper couple. The iodine color disappeared immediately;

the initial gray-colored mixture was then reﬂuxed for 30 min. Dur-

ing this period, the mixture turned darker; the color change was

accompanied by a gentle exothermic reaction. External heating

was discontinued and the compound (60 mg, 0.18 mmol, in anhy-

drous ether 2 mL) was added dropwise over 30 min. During the

addition, the mixture continued to reﬂux. Heating was resumed

and the mixture was reﬂuxed for 30 h. The reaction mixture was

then cooled and ﬁltered. The ether solution was extracted with

hydrochloric acid (3 mL) to remove the dissolved zinc iodide, aque-

ous sodium bicarbonate (5 mL) and saturated aqueous sodium

chloride. The combined ether extract was evaporated. The product

was puriﬁed by ﬂash chromatography to afford the compounds.

To a stirred solution of alcohol (11.80 mmol) in dry DCM

(30.0 ml) were added imidazole (2.0 g, 29.40 mmol) and tert-

butyldimethylsilylchloride (2.1 g, 13.93 mmol) at room tempera-

ture and the mixture was stirred for 3 h. The solvent was removed

and the residue partitioned between ethyl acetate and water. The

organic layer was washed with brine, dried over anhydrous Na

2

-

SO , and evaporated. The residue was puriﬁed by silica gel column

4

chromatography to afford the TBS protected compound.

4.7. General procedure for the TBDMS/TBDPS deprotection

To an ice-cooled solution of the TBS protected compound

(2.66 mmol) in dry THF (10.0 ml) was added a 1 M solution of TBAF

(

3.99 ml, 3.99 mmol) and stirred for 2 h at room temperature. After

4

.5. General procedure for the PMB deprotection

completion of the reaction, water was added to the reaction mix-

ture and THF was removed under vacuum. The aqueous layer

was then extracted with ethyl acetate and washed with saturated

The PMB protected compound (9.23 mmol) was dissolved in

0.0 ml of DCM/phosphate buffer (pH = 7; 19:1) and the solution

4

4 2 4

aqueous NH Cl, and brine, dried over anhydrous Na SO , and

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R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

7

concentrated in vacuum. The residue was puriﬁed by silica gel col-

umn chromatography to afford the alcohol.

4.10.2. (S)-2-(Ethoxycarbonyl)-2-methylpent-4-enoic acid 2

To a suspension of diester 1 (0.025 g, 0.12 mmol) in a pH 8

phosphate buffer (3 mL) was added PLE (15 units), and the reac-

tion mixture was stirred at 30 °C for 24 h. After diester 1 disap-

peared, 2 N HCl was added to the reaction mixture to make a

pH 3 solution. The aqueous layers were extracted with EtOAc

4

.8. General procedure for the Swern oxidation

Oxalyl chloride (1.16 ml, 13.26 mmol) was taken in DCM

(

32.0 ml) and the reaction vessel was kept at ꢁ78 °C. Dimethyl

(1.5 mL ꢀ 3), dried over Na

2 4

SO , ﬁltered and evaporated. The resi-

due was puriﬁed by ﬂash column chromatography (EtOAc/hex-

sulphoxide (DMSO, 1.88 ml, 26.52 mmol) was then added and

the reaction mixture was kept at the same temperature for

ane, 1:2) to afford known compound 2 (0.02 g) in 90% yield.¹⁹

2

5 min. The alcohol (2.02 g, 8.84 mmol) in DCM was then added

and the mixture was kept for a further 45 min at the same temper-

ature, after which triethyl amine (Et N 7.37 ml, 53.00 mmol) was

f

R = 0.1 (EtOAc/hexane, 1:2).

3

4.10.3. 2-Allyl-2-methylpropane-1,3-diol 3

added and the reaction mixture was gradually warmed to the room

temperature for 1 h. The reaction was then quenched by adding

water and extracted with DCM. The organic layer was washed suc-

To a solution of LAH (2.7 g, 71.14 mmol,) in dry ether (150 mL) a

solution of diethyl 2-allyl-2-methylmalonate (10 g, 46.67 mmol) in

dry ether (100 mL) at 0 °C was added via a cannula. The reaction

was then allowed to warm up to rt and stirred for 12 h. TLC anal-

ysis indicated the disappearance of the starting material and the

reaction was quenched by the dropwise addition of a saturated

3

cessively with water, saturated aqueous NaHCO solution and

brine. The organic layer was dried (Na SO ) and evaporated. The

2

4

residue was puriﬁed by silica gel column chromatography to afford

the aldehyde.

2 4

Na SO solution. The precipitated white aluminum salt was ﬁltered

off and the aluminum salt was washed thoroughly with ether

4

.9. General procedure for enzymatic esteriﬁcation

(3 ꢀ 100 mL). The ﬁltrate was washed with satd aq NaCl (50 mL),

2 4

dried over Na SO , and concentrated in vacuo. The crude residue

To a solution of diol (2.5 mmol) in 8 mL of vinyl acetate, 100 mg

was puriﬁed by ﬂash column chromatography (EtOAc/hexane,

1:3) to afford compound 3 (5.46 g) in 90% yield. R = 0.2 (EtOAc/

: 5.92–5.71 (m, 1H),

5.11 (d, 1H, J = 1.4 Hz), 5.09–5.01 (m, 1H), 3.45 (s, 4H), 2.85 (br s,

of lipase were added. The suspension was magnetically stirred at

room temperature and the reaction course was followed by HPLC

analysis. The reaction was interrupted by ﬁltration of the enzyme

and the ﬁltrate was evaporated under reduced pressure. The resi-

due was characterized by HPLC analysis.

f

1

3 H

hexane, 1:3). H NMR (200 MHz, CDCl ), d

1

3

2H), 2.08 (d, 2H, J = 7.6 Hz), 0.81 (s, 3H). C NMR (50 MHz, CDCl

3

),

d

C

: 134.3, 118.0, 69.9, 39.4, 38.8, 18.6. HRMS (ESI) for C Na

7 14 2

H O

+

[

M+Na] , calculated: 153.0892; found: 153.0897.

4

.10. General procedure for the OsO oxidation

4

.10.4. (S)-2-(Hydroxymethyl)-2-methylpent-4-enyl acetate 4

Compound 4 was prepared according to the general procedure

The compound (8.2 mmol) was dissolved in 32 ml of THF/H

3:1) and the solution was cooled to 0 °C. To this solution, NMO

1.4 g, 12.3 mmol) and a 0.05 M solution of OsO in toluene

16 mL, 0.82 mmol) were added consecutively and the reaction

was protected from light by covering the reaction ﬂask with black

paper. The mixture was stirred for 12 h at the same temperature.

The reaction was quenched by the addition of a saturated aq.

2

O

(

for the enzymatic esteriﬁcation starting from compound 3 (0.5 g,

3.84 mmol). Puriﬁcation by silica gel chromatography (EtOAc/hex-

4

ane, 1:5) afforded compound 4 (0.595 g) in 90% yield. R

(EtOAc/hexane, 1:5). H NMR (400 MHz, CDCl ), d

3 H

f

= 0.3

: 5.82–5.75

(m, 1H), 5.08–5.04 (m, 2H), 3.93 (t, 2H, J = 12 Hz), 3.27 (s, 2H),

2.30 (br s, 1H), 2.06 (s, 3H), 2.05–2.03 (m, 2H), 0.86 (s, 3H). ¹³

NMR (50 MHz, CDCl ), d : 171.8, 133.5, 118.2, 68.0, 66.6, 39.1,

1

C

Na

2

SO

3

solution (8 mL) and then stirred for 1 h at room tempera-

3

C

+

ture. Next, 20 mL of water and 40 mL of EtOAc were added to this

mixture and the organic layer was separated. The aqueous part

was washed with EtOAc (2 ꢀ 50 mL). The combined organic layer

was washed with brine solution (40 mL), dried over anhydrous

38.7, 20.8, 18.5. HRMS (ESI) for C

195.0997; found: 195.0999.

9 16 3

H O Na [M+Na] , calculated:

4.10.5. (R)-2-(Hydroxymethyl)-2-methylpent-4-enyl benzoate 5

Na SO

2 4

and concentrated under reduced pressure. The two diastere-

At ﬁrst, DCM (8 mL) was added to a mixture of the Pybox ligand

omeric diols were puriﬁed by ﬂash column chromatography.

2

(0.059 g, 0.1 mmol) and CuCl (0.013 g, 0.1 mmol) at room temper-

ature and then the mixture was stirred at that temperature for 4 h.

To the generated catalyst solution, substrate 3 (0.13 g, 1.0 mmol)

was added with DCM (3 mL) through a cannula at room tempera-

ture. After cooling the resulting solution to ꢁ78 °C, benzoyl chlo-

4

.10.1. Diethyl 2-allyl-2-methylmalonate 1

To an ice-cooled solution of NaH (60% dispersion in mineral oil,

.659 g, 16.48 mmol) in dry THF (32 mL), diethyl 2-methyl-

0

malonate (2.8 g, 16.08 mmol) in THF (16 mL) was added and the

reaction mixture was kept at the same temperature for a further

3

ride (174 lL, 1.5 mmol) and Et N (153 lL, 1.1 mmol) were added

in sequence, and the monobenzoylation proceeded at ꢁ78 °C for

4

5 min, after which allyl bromide (1.43 mL, 16.48 mmol) was

12 h. The reaction was then quenched with saturated aqueous

added and the reaction mixture was stirred at reﬂux for 6 h. The

reaction mixture was then cooled to room temperature and water

was added carefully to the reaction mixture to quench any excess

NaH, and the layers were separated and extracted with 400 mL of

ether, washed with brine. It was then dried over anhydrous

NH

The mixture was extracted with DCM and organic layer was

washed with brine and dried over anhydrous MgSO . The organic

layer was concentrated in vacuo to afford the crude residue, which

upon puriﬁcation by silica gel chromatography (EtOAc/hexane,

4

Cl (5 mL) at ꢁ78 °C and then H

2

O (2 mL) at room temperature.

4

Na

due was puriﬁed by ﬂash column chromatography (EtOAc/hexane,

:40) to afford compound 1 (3.1 g) in 90% yield. R = 0.6 (EtOAc/

: 5.70–5.63 (m, 1H),

.14–5.06 (m, 2H), 4.18 (q, 4H, J = 7.1 Hz), 2.61 (d, 2H, J = 7.4 Hz),

.39 (s, 3H), 1.24 (t, 6H, J = 7.1 Hz). ¹³C NMR (50 MHz, CDCl

), d

71.7, 132.5, 118.9, 61.1, 53.3, 39.9, 19.5, 13.9. HRMS (ESI) for

2

SO

4

, and the solvent was removed in vacuum. The crude resi-

1:5) afforded compound 5 (0.23 g) in 98% yield. R

f

= 0.5 (EtOAc/

= +5.2 (c 1.0, MeOH). H NMR (200 MHz, CDCl ),

: 7.91 (d, 2H, J = 8.2 Hz), 7.42–7.25 (m, 3H), 5.79–5.69 (m, 1H),

5.49 (d, 2H, J = 13.2 Hz), 4.07 (m, 2H), 3.34 (s, 2H), 2.03 (d, 2H,

2

8

1

hexane, 1:5). [

a]

D

3

1

f

d

H

1

3 H

hexane, 1:40). H NMR (200 MHz, CDCl ), d

1

3

5

1

C

J = 7.2 Hz), 0.85 (s, 3H). C NMR (50 MHz, CDCl

3 C

), d : 166.9,

3

C

:

133.5, 133.0, 129.9, 129.5, 128.3, 118.2, 68.2, 66.5, 39.3, 38.8,

+

18.6. HRMS (ESI) for C14

found: 257.1159.

18 3

H O Na [M+Na] , calculated: 257.1154;

+

11

18 4

H O Na [M+Na] , calculated: 237.1103; found: 237.1109.

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8

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

4

.10.6. (R)-2-((4-Methoxybenzyloxy)methyl)-2-methylpent-4-

4.10.9. (3S,4R)-4-((4-Methoxybenzyloxy)methyl)-4-methylhepta-

enyl benzoate 6

1,6-dien-3-ol 9 and (3R,4R)-4-((4-methoxybenzyloxy)methyl)-4-

methylhepta-1,6-dien-3-ol 10

A solution of 4-methoxybenzyl alcohol (2.2 g, 16.0 mmol) in

3

2

0 mL of ether was added to a suspension of 60% NaH (0.08 g,

.0 mmol) in 10 mL of ether at room temperature. The resulting mix-

Aldehyde 8 (2.0 g, 8.05 mmol) was taken in 16 ml of anhydrous

THF. Next, a solution of vinylmagnesium bromide (1.0 M in THF,

8.85 mL, 8.85 mmol) was added at ꢁ78 °C. The reaction mixture

was kept at the same temperature for 2 h, after which a saturated

ture was stirred at room temperature for 30 min and cooled to 0 °C.

Trichloroacetonitrile (TCA;1.6 mL, 16.0 mmol) was then added and

the reaction mixture was allowed to warm slowly to room tempera-

ture over 6 h. The solution was concentrated to an orange syrup,

which was dissolved in anhydrous hexane (15 mL) containing a few

drops of MeOH. This suspension was shaken vigorously and ﬁltered

through Celite, and the ﬁltrate was concentrated to afford the crude

imidate. The crude imidate was taken in cyclohexane (50 mL) and a

solution of alcohol 5 (3.74 g, 16 mmol) in 30 mL of DCM was added.

The resulting solution was cooled to 0 °C and CSA (0.37 g, 1.6 mmol)

was added to it. The reaction mixture was stirred overnight at room

temperature, and a white precipitate of trichloroacetamide slowly

developed. The solution was ﬁltered off, and washed with DCM. The

NH

EtOAc, and the organic layer was washed with water and brine.

The organic layer was dried (MgSO ) and evaporated to afford

4

Cl solution was added. The solution was then extracted with

4

the crude alcohol. Puriﬁcation of the crude product by silica gel

chromatography (EtOAc/hexane, 1:8) afforded compound 9 and

10 as an inseparable diastereomeric mixture (1.82 g) in 82% yield.

1

R

f

= 0.3 (EtOAc/hexane, 1:8). H NMR (200 MHz, CDCl

3 H

), d : 7.27 (d,

2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 5.99–5.81 (m, 2H), 5.27–5.11

(m, 4H), 4.45 (s, 2H), 4.03–4.00 (m, 1H), 3.84 (s, 3H), 3.49–3.43 (m,

1H), 3.32–3.28 (m, 1H), 2.26 (d, 1H, J = 7.4 Hz), 2.05–2.01 (m, 1H),

1

3

3 C

0.93 (s, 3H). C NMR (50 MHz, CDCl ), d : 159.4, 137.7, 137.3,

ﬁltrate was washed with saturated aqueous NaHCO

and brine. Puriﬁcation by means of silica gel chromatography (EtOAc/

hexane, 1:5) yielded compound 6 (5.0 g) in 88% yield. R = 0.4 (EtOAc/

= +6.8(c0.8,MeOH). HNMR(200 MHz, CDCl ),d

.05–8.01 (m, 2H), 7.57–7.43 (m, 3H), 7.28 (d, 2H, J = 8.6 Hz), 6.87 (d,

3

solution, water

134.5, 129.9, 129.4, 118.1, 117.9, 116.6, 116.5, 113.9, 79.9, 79.0,

77.2, 76.8, 75.9, 73.4, 73.4, 60.5, 55.4, 41.1, 39.9, 37.1, 31.7, 22.8,

21.1, 19.3, 18.1, 14.3, 14.2.

f

2

8

1

hexane, 1:5). [

a

]

D

3

H

:

8

2

4

3

1

3

4.10.10. (1S,5R)-5-((4-Methoxybenzyloxy)methyl)-5-methylcycl-

opent-2-enol 11 and (1R,5R)-5-((4-methoxybenzyloxy)methyl)-

5-methylcyclopent-2-enol 12

H, J = 8.6 Hz), 5.88–5.77(m, 1H),5.13(d, 2H, J = 11.6 Hz), 4.19 (s, 2H),

.27 (s, 2H), 3.80 (s, 3H), 3.37 (s, 2H), 2.25 (d, 2H, J = 7.4 Hz), 1.06 (s,

1

3

H). C NMR (50 MHz, CDCl

3 C

), d : 166.3, 158.9, 133.6, 132.8, 130.5,

The starting diastereomeric mixture 9 and 10 (1.82 g,

30.3, 129.5, 129.0, 128.8, 128.3, 118.1, 113.6, 73.6, 72.8, 68.6, 55.1,

6.58 mmol) was taken in anhydrous degassed DCM (500 mL). A

small amount of 1st generation Grubbs’ catalyst was then added

and the solution was stirred at reﬂux for 6 h. The reaction mixture

was then cooled to room temperature and the solution was evap-

orated under reduced pressure. The contents of the ﬂask were

loaded directly onto a silica gel column. Two diastereomeric alco-

hols (compound 11 and compound 12 in 1:1 ratio) were puriﬁed

by ﬂash column chromatography (EtOAc/hexane, 1:5) to afford

alcohol 11 (653.55, mg) in 40% yield and alcohol 12 (653.55 mg)

+

9.2, 38.5, 19.3. HRMS (ESI) for C22

26 4

H O Na [M+Na] , calculated:

77.1729; found: 377.1730.

4

.10.7. (S)-2-((4-Methoxybenzyloxy)methyl)-2-methylpent-4-

en-1-ol 7

A solution of compound 6 (0.5 g, 1.41 mmol) in 5 mL of MeOH

at 0 °C was treated with K CO (0.0584 g, 0.42 mmol). The mixture

2

3

was stirred at room temperature for 6 h. The mixture was then

poured into 5 mL of saturated aqueous ammonium chloride solu-

tion and concentrated in vacuo. The mixture was extracted with

ethyl acetate and the organic layer was washed with brine and

dried over anhydrous MgSO . The organic layer was concentrated

4

in vacuo to afford the crude residue, which upon puriﬁcation by sil-

2

8

in 40% yield. R

0.5, MeOH).

f

of 11 = 0.4 (EtOAc/hexane, 1:5). [

a

]

D

= +24.6 (c

1

H NMR (200 MHz, CDCl ), d : 7.24 (d, 2H,

3 H

J = 8.6 Hz), 6.87 (d, 2H, J = 8.6 Hz), 5.87–5.83 (m, 1H), 5.74 (td,

1H, J = 2.0, 4.0 Hz), 4.63 (s, 1H), 4.50 (s, 2H), 3.84 (s, 3H), 3.34 (d,

2H, J = 2.6 Hz), 2.24 (dd, 2H, J = 2.2, 4.0 Hz), 1.12 (s, 3H). ¹³C NMR

ica gel chromatography (EtOAc/hexane, 1:3) afforded compound 7

(50 MHz, CDCl

3

), d

C

: 159.2, 132.6, 132.5, 130.7, 129.2, 113.9, 81.4,

Na [M

of 12 = 0.5

28

(

1

0.317 g) in 90% yield. R

f

= 0.2 (EtOAc/hexane, 1:3). [

a

]

D

= ꢁ4.2 (c

77.8, 73.1, 55.4, 46.6, 42.7, 18.8. HRMS (ESI) for C15H O

20 3

1

+

.0, MeOH).

H

NMR (200 MHz, CDCl ), 7.24 (d, 2H,

3

H

d :

+Na] , calculated: 271.1310; found: 271.1313. R

f

2

8

1

J = 8.6 Hz), 6.88 (d, 2H, J = 8.6 Hz), 5.90–5.69 (m, 1H), 5.05 (d, 2H,

J = 12.6 Hz), 4.43 (s, 2H), 3.80 (s, 3H), 3.48 (s, 2H), 3.32 (s, 2H),

(EtOAc/hexane, 1:5).

(200 MHz, CDCl ), d : 7.24 (d, 2H, J = 8.6 Hz), 6.87 (d, 2H,

J = 8.6 Hz), 5.87–5.71 (m, 2H), 4.45 (s, 2H), 4.37–4.34 (m, 1H),

3.79 (s, 3H), 3.48 (dd, 2H, J = 8.8, 16.4 Hz), 2.43 (dd, 1H, J = 2.1,

16.9 Hz), 1.94 (d, 1H, J = 17.0 Hz), 1.08 (s, 3H). C NMR (50 MHz,

[a

]

D

= +73.2 (c 1.2, MeOH).

H NMR

3

H

2

1

3

2

.13 (d, 2H, J = 7.4 Hz), 0.83 (s, 3H). ¹³C NMR (50 MHz, CDCl

3

C

), d :

59.1, 134.2, 130.0, 129.0, 117.6, 113.7, 77.7, 73.1, 69.9, 55.1,

+

13

8.9, 38.8, 18.8. HRMS (ESI) for C15

73.1467; found: 273.1469.

H

22

O

3

Na [M+Na] , calculated:

CDCl

3.1, 55.2, 44.4, 42.7, 24.7. HRMS (ESI) for C15

calculated: 271.1310; found: 271.1312.

3 C

), d : 159.3, 133.4, 132.1, 130.2, 129.3, 113.9, 84.7, 75.1,

+

7

20 3

H O Na [M+Na] ,

4

.10.8. (R)-2-((4-Methoxybenzyloxy)methyl)-2-methylpent-4-

enal 8 or (S)-2-((4-methoxybenzyloxy)methyl)-2-methylpent-4-

enal 8

Compound 8 was prepared according to the general procedure

for the Swern oxidation from compound 7 (1.26 g, 5.03 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:10)

4.10.11. (1S,5R)-5-(Hydroxymethyl)-5-methylcyclopent-2-enol

13

Compound 13 was prepared according to the general procedure

for the PMB deprotection from compound 11 (0.65 g, 2.61 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:5)

afforded aldehyde 7 (1.13 g) in 90% yield. R

f

= 0.5 (EtOAc/hexane,

: 9.61 (s, 1H), 7.26 (d, 2H,

J = 8.8 Hz), 6.91 (d, 2H, J = 8.8 Hz), 5.83–5.66 (m, 1H), 5.15–5.08

m, 2H), 4.46 (s, 2H), 3.82 (s, 3H), 3.48 (d, 2H, J = 4.4 Hz), 2.35 (d,

1

:10). H NMR (200 MHz, CDCl

), d

3 H

afforded compound 13 (0.301 g) in 90% yield. R

f

= 0.2 (EtOAc/

= +48.8 (c 0.6, MeOH). H NMR (200 MHz,

: 5.86–5.81 (m, 1H), 5.69 (td, 1H, J = 1.8, 3.8 Hz), 4.57–

4.50 (m, 1H), 3.47 (d, 2H, J = 2.2 Hz), 2.90 (br s, 2H), 2.16–2.12

2

8

1

hexane, 1:5). [

a]

D

(

CDCl ), d

3

H

2

1

3

2

H, J = 7.4 Hz), 1.09 (s, 3H). ¹³C NMR (50 MHz, CDCl

59.2, 132.7, 130.1, 129.1, 118.7, 113.8, 73.0, 72.9, 55.2, 50.1,

3 C

), d : 205.1,

1

3

(m, 2H), 1.06 (s, 3H). C NMR (50 MHz, CDCl

3

C

), d : 133.0, 132.5,

+

6.9, 16.4. HRMS (ESI) for

71.1310; found: 271.1315.

C

15

H

20

O

3

Na [M+Na] , calculated:

80.8, 70.4, 47.3, 42.3, 18.1. HRMS (ESI) for C

culated: 151.0735; found: 151.0738.

H O Na [M+Na] , cal-

7 12 2

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R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

9

+

4

1

.10.12. (1R,5R)-5-(Hydroxymethyl)-5-methylcyclopent-2-enol

4

34.7, 31.0, 15.0. HRMS (ESI) for C16

285.1467; found: 285.1470.

22 3

H O Na [M+Na] , calculated:

Compound 14 was prepared according to the general procedure

for the PMB deprotection from compound 12 (0.65 g, 2.61 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:5)

4.10.15. (S)-2-((tert-Butyldiphenylsilyloxy)methyl)-2-methylpent-

4-enyl benzoate 19

afforded compound 14 (0.301 g) in 90% yield. R

f

= 0.3 (EtOAc/hex-

= +42.2 (c 0.8, MeOH). ¹H NMR (200 MHz, CDCl

),

: 5.94–5.90 (m, 1H), 5.70 (dd, 1H, J = 2.2, 5.6 Hz), 4.39–4.30 (m,

H), 3.62 (dd, 2H, J = 11.0, 18.8 Hz), 3.38 (br s, 2H), 2.43 (dd, 1H,

To a stirred solution of alcohol (R)-5 (0.209 g, 0.89 mmol) in

DCM (10 mL) were added imidazole (0.122 g, 1.78 mmol,

2.0 equiv) and TBDPSCl (0.278 mL, 1.07 mmol, 1.2 equiv) succes-

sively at room temperature. After the reaction was completed, sat-

2

8

ane, 1:5). [

a

]

D

3

d

H

1

3

J = 2.2, 17.2 Hz), 2.02–1.89 (m, 1H), 1.11 (s, 3H). C NMR (50 MHz,

CDCl ), d : 134.7, 131.7, 85.2, 68.2, 45.2, 41.9, 24.1. HRMS (ESI) for

Na [M+Na] , calculated: 151.0735; found: 151.0737.

4

urated aqueous NH Cl (10 mL) was added to the reaction mixture,

3

C

and the aqueous layers were extracted with DCM (8 mL ꢀ 3). The

+

C

7 12 2

H O

combined organic layers were washed with brine (5 mL ꢀ 1), dried

(

2 4

Na SO ), ﬁltered and concentrated under reduced pressure, which

4

1

.10.13. (4S,5R)-5-((4-methoxybenzyloxy)methyl)-5-methylocta-

,7-dien-4-ol 15 and (4R,5R)-5-((4-methoxybenzyloxy)methyl)-5-

upon puriﬁcation by silica gel chromatography (EtOAc/hexane,

1:20) afforded compound 19 (379.47 mg) in 90% yield. R

f

= 0.4

NMR

2

8

1

methylocta-1,7-dien-4-ol 16

(EtOAc/hexane, 1:20).

(400 MHz, CDCl ), d

[a

]

D

= +10.2 (c 0.5, MeOH).

H

Zn-dust (1.79 g, 27.4 mmol) followed by allyl bromide (2.2 ml,

3

H

: 7.96 (d, 2H, J = 7.6 Hz), 7.65–7.59 (m, 4H),

2

6 mmol) were added to a cold (0 °C) and well-stirred solution of

aldehyde 8 (3.4 g, 13.7 mmol), in tetrahydrofuran (5 ml) and then

a saturated aqueous solution of NH Cl (3.0 ml) was added dropwise

7.58–7.56 (m, 1H), 7.45–7.39 (m, 4H), 7.31–7.26 (m, 4H), 5.86–

7.75 (m, 1H), 5.07 (d, 2H, J = 13.2 Hz), 4.25 (s, 2H), 3.54 (s, 2H),

13

4

2.20 (d, 2H, J = 7.2 Hz), 1.05 (s, 9H), 0.99 (s, 3H).

(50 MHz, CDCl ), d : 166.6, 135.8, 135.8, 133.7, 133.5, 133.0,

130.5, 129.7, 128.5, 127.8, 118.4, 68.2, 67.4, 39.7, 39.1, 27.0, 19.5,

C NMR

over a period of 30 min. The reaction mixture was then stirred at

ambient temperature for 12 h until the aldehyde was totally con-

sumed. The mixture was then ﬁltered and the precipitate was

washed thoroughly with ether. The combined ﬁltrate was then

diluted with water (10 ml) and extracted with ether (200 ml). The

combined organic layer was washed successively with HCl (5%,

3

C

+

19.0. HRMS (ESI) for

495.2332; found: 495.2336.

30 36 3

C H O SiNa [M+Na] , calculated:

4.10.16. (S)-2-((tert-Butyldiphenylsilyloxy)methyl)-2-methylpent-

4-en-1-ol 20

A solution of compound 19 (0.666 g, 1.41 mmol) in 6 mL of

2 3

MeOH at 0 °C was treated with K CO (0.116 g, 0.84 mmol). The

mixture was stirred at room temperature for 6 h. The mixture

was then poured into 6 mL of saturated aqueous ammonium chlo-

ride solution and concentrated in vacuo. The mixture was

extracted with ethyl acetate and the organic layer was washed

1

0 ml), water (20 ml) and brine (10 ml). The organic layer was dried

MgSO ) and evaporated to afford the crude alcohol. Puriﬁcation of

the crude product by silica gel chromatography (EtOAc/hexane,

:10) afforded compound 15 and 16 as an inseparable diastere-

omeric mixture (3.5 g) in 88% yield. R = 0.3 (EtOAc/hexane, 1:10).

: 7.23 (d, 2H, J = 8.4 Hz), 6.87 (d, 2H,

J = 8.4 Hz), 5.99–5.75 (m, 2H), 5.13–5.02 (m, 4H), 4.41 (s, 2H), 3.78

(

4

1

f

1

3 H

H NMR (200 MHz, CDCl ), d

(

s, 3H), 3.54–3.40 (m, 2H), 3.38–3.21 (m, 1H), 2.37–2.03 (m, 4H),

4

with brine and dried over anhydrous MgSO . The organic layer

was concentrated in vacuo to afford the crude residue, which upon

puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:20)

1

3

0

1

7

.87 (s, 3H). C NMR (50 MHz, CDCl

3

C

), d : 159.2, 136.8, 134.5,

34.4, 130.0, 129.2, 117.7, 117.6, 116.4, 113.8, 77.8, 77.5, 76.4,

5.8, 73.2, 55.1, 41.1, 40.0, 37.0, 36.5, 36.3, 19.1, 17.9.

afforded compound 20 (467.72 mg) in 90% yield. R

f

= 0.3 (EtOAc/

= +6.8 (c 0.3, MeOH). H NMR (200 MHz,

: 7.73–7.69 (m, 4H), 7.45–7.43 (m, 6H), 5.91–5.70 (m,

1H), 5.12–5.04 (m, 2H), 3.55–3.50 (m, 4H), 2.46 (br s, 1H), 2.26–

2

8

1

hexane, 1:20). [

a]

D

4

.10.14. (1S,6R)-6-((4-Methoxybenzyloxy)methyl)-6-methylcycl-

CDCl ), d

3

H

ohex-3-enol 17 and (1R,6R)-6-((4-methoxybenzyloxy)methyl)-6-

methylcyclohex-3-enol 18

1

3

2.06 (m, 2H), 1.12 (s, 9H), 0.85 (s, 3H). C NMR (50 MHz, CDCl

3

),

The starting diastereomeric mixture 15 and 16 (1.82 g,

.26 mmol) was taken in anhydrous degassed DCM (500 mL). A

d

C

: 135.9, 135.8, 134.4, 133.2, 130.0, 127.9, 117.8, 70.5, 69.5,

+

6

40.0, 38.7, 27.1, 19.4, 18.6. HRMS (ESI) for C23

calculated: 391.2070; found: 391.2074.

32 2

H O SiNa [M+Na] ,

small amount of 1st generation Grubbs’ catalyst was then added

to it and the solution was stirred at reﬂux for 8 h. The reaction mix-

ture was then cooled to room temperature and the solution was

evaporated under reduced pressure. The contents of the ﬂask were

directly loaded onto a silica gel column. Two diastereomeric alco-

hols (compound 17 and compound 18 in 1:1 ratio) were puriﬁed

by ﬂash column chromatography (EtOAc/hexane, 1:8) to afford

alcohol 17 (0.656 g) in 40% yield and alcohol 18 (0.656 g) in 40%

4.10.17. (R)-2-((4-Methoxybenzyloxy)methyl)-2-methylpent-4-

en-1-ol 7

PMB protection of compound 20 (0.52 g, 1.41 mmol) according

to the experimental procedure of compound 6 afforded a crude

material (0.606 g, 1.24 mmol). The crude compound was used for

the next step without further puriﬁcation. Compound (R)-6 was

prepared according to the general procedure for the TBDPS depro-

tection starting from crude compound (0.606 g, 1.24 mmol). Puriﬁ-

cation by silica gel chromatography (EtOAc/hexane, 1:3) afforded

2

8

yield. R

f

of 17 = 0.4 (EtOAc/hexane, 1:8). [

a

]

D

= +22.8 (c 0.8,

: 7.22 (d, 2H, J = 8.2 Hz),

.85 (d, 2H, J = 8.2 Hz), 5.65–5.54 (m, 2H), 4.42 (s, 2H), 3.77 (s,

H), 3.69–3.60 (m, 1H), 3.53 (d, 1H, J = 8.8 Hz), 3.27 (d, 1H,

1

3 H

MeOH). H NMR (200 MHz, CDCl ), d

6

3

f

(R)-7 (0.28 g) in 79% yield for two steps. R = 0.2 (EtOAc/hexane,

1:3). [a] = +4.6 (c 1.0, MeOH). H NMR, C NMR and HRMS

D

1

3

28

1

13

J = 9.0 Hz), 2.33–2.02 (m, 3H), 1.72–1.64 (m, 1H), 0.89 (s, 3H).

C

3 C

NMR (50 MHz, CDCl ), d : 159.2, 129.8, 129.1, 125.0, 123.5,

(ESI) for (R)-6 were identical as for (S)-7.

1

C

13.8, 77.6, 73.3 (2C), 55.1, 36.9, 32.5, 31.7, 21.5. HRMS (ESI) for

+

16

H

22

O

3

Na [M+Na] , calculated: 285.1467; found: 285.1471. R

f

4.10.18. (1R,2R,3R,5S)-3-((4-Methoxybenzyloxy)methyl)-3-methyl-

6-oxabicyclo[3.1.0]hexan-2-ol 21

28

1

of 18 = 0.5 (EtOAc/hexane, 1:8). [

NMR (600 MHz, CDCl ), d

J = 9.0 Hz), 5.58 (td, 1H, J = 0.8, 2.2 Hz), 5.57–5.51 (m, 1H), 4.49

q, 2H, J = 12.8 Hz), 3.90–3.87 (m, 1H), 3.83 (s, 3H), 3.35 (s, 2H),

a]

D

= +58.8 (c 1.1, MeOH).

H

3

H

: 7.26 (d, 2H, J = 9.0 Hz), 6.95 (d, 2H,

Compound 21 was prepared according to the general procedure

for the substrate directed epoxidation with mCPBA from com-

pound 11 (0.4 g, 1.61 mmol). Puriﬁcation by silica gel chromatog-

raphy (EtOAc/hexane, 1:3) afforded epoxide 21 (0.382 g) in 90%

(

2

1

.32 (dd, 1H, J = 1.2, 16.8 Hz), 2.30–2.06 (m, 1H), 1.93–1.90 (m,

H), 1.74–1.70 (m, 1H), 0.99 (s, 3H). C NMR (50 MHz, CDCl

13

28

1

3

),

yield. R

NMR (200 MHz, CDCl

f

= 0.3 (EtOAc/hexane, 1:3). [

), d

a]

D

= ꢁ23.9 (c 0.5, MeOH). H

d

C

: 159.2, 130.0, 129.1, 124.2, 113.8, 79.6, 73.2, 72.5, 55.2, 37.5,

3

H

: 7.27 (d, 2H, J = 8.6 Hz), 6.91 (d, 2H,

Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.003

1

0

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

J = 8.6 Hz), 4.47 (s, 2H), 4.24–4.21 (m, 1H), 3.85 (s, 3H), 3.58–3.52

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:20)

afforded 26 (0.554 g) in 95% yield. R = 0.5 (EtOAc/hexane, 1:20).

= +55.4 (c 0.8, MeOH). H NMR (200 MHz, CDCl ), d : 7.28

(

m, 1H), 3.48–3.40 (m, 1H), 3.24 (d, 1H, J = 8.6, Hz), 3.13 (d, 1H,

f

13

28

1

J = 8.6, Hz), 1.91 (d, 2H, J = 5.2 Hz), 1.05 (s, 3H).

C NMR

[a]

D

3

H

(

6

50 MHz, CDCl

3

), d

C

: 159.2, 130.4, 129.2, 113.8, 77.1, 76.7, 72.9,

Na

(d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 5.79–5.76 (m, 1H),

5.95–5.57 (m, 1H), 4.63 (s, 1H), 4.47 (s, 2H), 3.82 (s, 3H), 3.25

(dd, 2H, J = 8.8, 12.8 Hz), 2.40–2.05 (m, 2H), 1.02 (s, 3H), 0.91 (s,

0.8, 55.3, 55.1, 41.2, 36.7, 21.1. HRMS (ESI) for C15H O

20 4

+

[

M+Na] , calculated: 287.1260; found: 287.1265.

1

3

9

3 C

H), 0.06 (s, 6H). C NMR (50 MHz, CDCl ), d : 159.2, 133.1,

4

.10.19. (1S,2R,3R,4R)-4-((4-Methoxybenzyloxy)methyl)-4-methyl-

131.6, 131.0, 129.2, 113.8, 80.2, 76.7, 73.0, 55.4, 46.9, 42.4, 26.1,

+

cyclopentane-1,2,3-triol 22

Compound 22 was prepared according to the general procedure

for the acid induced epoxide ring opening from compound 21

19.4, 18.4, ꢁ4.3, ꢁ4.6. HRMS (ESI) for C21

34 3

H O SiNa [M+Na] , cal-

culated: 385.2175; found: 385.2179.

(

0.382 g, 1.45 mmol). Puriﬁcation by silica gel chromatography

4.10.23. (1R,2R,3R,4R)-3-(tert-Butyldimethylsilyloxy)-4-((4-

methoxybenzyloxy)methyl)-4-methylcyclopentane-1,2-diol 27

and (1S,2S,3R,4R)-3-(tert-butyldimethylsilyloxy)-4-((4-methoxy-

benzyloxy)methyl)-4-methylcyclopentane-1,2-diol 28

Compounds 27 and 28 were prepared according to the general

4

procedure for the OsO oxidation from compound 26 (0.8 g,

2.20 mmol). Two diastereomeric diols (compound 24 and com-

pound 25 in 3:1 ratio) were puriﬁed by ﬂash column chromatogra-

phy (EtOAc/hexane, 1:5) to afford diol 27 (0.509 g) in 58.5% yield

EtOAc/hexane, 1:1) afforded triol 22 (0.360 g) in 88% yield.

a]

D

= +16.8 (c 1.0, MeOH). ¹H NMR

2

8

R

f

= 0.3 (EtOAc/hexane, 1:1). [

), 7.27 (d, 2H, J = 8.6 Hz), 6.91 (d, 2H,

J = 8.6 Hz), 4.51 (s, 2H), 4.20–4.14 (m, 1H), 4.00 (dd, 2H, J = 2.1,

.1 Hz), 3.84 (s, 3H), 3.36 (d, 1H, J = 8.4 Hz) 3.21 (d, 1H,

J = 8.4 Hz), 2.48 (br s, 3H), 2.10–2.03 (m, 1H), 1.72–1.63 (m, 1H),

(

200 MHz, CDCl

3

H

d :

5

1

3

1

.03 (s, 3H). C NMR (50 MHz, CDCl

3 C

), d : 159.3, 129.8, 129.4,

13.9, 79.4, 77.6, 75.2, 74.9, 73.2, 55.3, 43.3, 41.4, 20.2. HRMS

+

(

ESI) for

C

15

H

22

O

5

Na [M+Na] , calculated: 305.1365; found:

and diol 28 (0.170 g) 19.5% yield. R

f

of 27 = 0.2 (EtOAc/hexane,

= +10.8 (c 1.1, MeOH). H NMR of 27 (200 MHz, CDCl ),

: 7.22 (d, 2H, J = 8.6 Hz), 6.88 (d, 2H, J = 8.6 Hz), 4.52 (s, 2H),

.02–4.00 (m, 2H), 3.95–3.88 (m, 1H), 3.81 (s, 3H), 3.12 (dd, 2H,

J = 8.6, 14.5 Hz), 2.73 (d, 1H, J = 5.0 Hz), 2.50 (d, 1H, J = 9.6 Hz),

2

8

1

3

05.1369.

1:5). [

a

]

D

3

d

H

4

1

.10.20. (1S,2R,3R,4R)-4-(Acetoxymethyl)-4-methylcyclopentane-

,2,3-triyl triacetate 23

Compound 23 (0.280 g) was prepared from compound 22

1

3

1

.03 (s, 3H), 0.92 (s, 9H), 0.06 (s, 6H). C NMR of 27 (50 MHz,

CDCl ), d : 159.3, 130.5, 129.2, 113.9, 77.4, 76.6, 74.2, 73.0, 72.8,

5.4, 44.6, 42.9, 26.0, 21.6, 18.3, ꢁ4.6. HRMS (ESI) for C21 SiNa

of 28 = 0.3

= +38.8 (c 1.2, MeOH). H NMR of 28

7.25 (d, 2H, J = 8.6 Hz), 6.89 (d, 2H,

3

C

(

0.300 g, 1.06 mmol) in 80% yield, according to the general proce-

5

36 5

H O

dure for the PMB deprotection followed by esteriﬁcation of crude

+

1

[M+Na] , calculated: 419.2230; found: 419.2235. R

f

material as described in experimental part of compound 38.

NMR (200 MHz, CDCl ), d : 5.37–5.22 (m, 3H), 4.14 (d, 1H,

J = 10.8 Hz), 3.97 (d, 1H, J = 10.8 Hz), 2.14 (s, 12H), 1.96 (d, 2H,

H

2

8

1

(

EtOAc/hexane, 1:5). [

a]

D

3

H

200 MHz, CDCl ), d :

3

H

_J₌₄_.₆_H_z₎_,₁_.₀₆₍_s_,₃_H₎_.1 C NMR (50 MHz, CDCl

3

J = 8.6 Hz), 4.50 (s, 2H), 3.93–3.88 (m, 2H), 3.81 (s, 3H), 3.27–3.20

m, 2H), 3.19 (d, 1H, J = 8.4 Hz), 1.85–1.81 (m, 2H), 0.88 (s, 9H),

3

), d

C

: 171.1,

(

1

2

3

70.4, 170.3, 170.2, 77.1, 75.6, 70.2, 69.6, 40.4, 38.6, 21.1, 21.0,

1

3

+

0.86 (s, 3H), 0.09 (s, 6H). C NMR of 28 (50 MHz, CDCl

1

4

3

), d

59.7, 129.8, 129.4, 114.1, 80.7, 79.8, 76.8, 73.4, 70.5, 55.4, 42.5,

1.4, 26.0, 21.0, 18.3, ꢁ4.0, ꢁ4.7. HRMS (ESI) for C21 SiNa

C

:

0.8, 20.4. HRMS (ESI) for

53.1213; found: 353.1218.

15 22 8

C H O Na [M+Na] , calculated:

36 5

H O

+

[

M+Na] , calculated: 419.2230; found: 419.2234.

4

.10.21. (1R,2R,3R,4R)-4-((4-Methoxybenzyloxy)methyl)-4-methyl-

cyclopentane-1,2,3-triol 24 and (1S,2S,3R,4R)-4-((4-methoxy-

benzyloxy)methyl)-4-methylcyclopentane-1,2,3-triol 25

Compound 24 and 25 were prepared according to the general

4

.10.24. tert-Butyl((3aR,4R,5R,6aR)-5-((4-methoxybenzyloxy)

methyl)-2,2,5-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-

4-yloxy)dimethylsilane 29

procedure for the OsO

4

oxidation from compound 11 (0.5 g,

Compound 27 (1.96 g, 4.94 mmol) was taken in 24 mL of dry

2

.01 mmol). Two diastereomeric diols (compound 24 and com-

DCM. 2,2-Dimethoxypropane (DMP, 1.85 mL, 14.82 mmol) was

then added to it followed by addition of a catalytic amount of

CSA (0.151 g, 0.5 mmol,). The reaction mixture was then stirred

at room temperature for 6 h. After completion of the reaction,

water was added to the reaction mixture, after which it was

extracted with DCM and washed with brine. The organic layer

pound 25 in 3:2 ratio) were puriﬁed by ﬂash column chromatogra-

phy (EtOAc/hexane, 2:1) to afford diol 24 (0.255 g) in 45% yield and

diol 25 (0.170 g) in 30% yield. R

f

of 24 = 0.2 (EtOAc/hexane, 2:1).

2

8

= +38.8 (c 1.2, MeOH). ¹H NMR of 21 (200 MHz, CDCl

[a

]

D

3 H

), d :

7

3

.24 (d, 2H, J = 8.4 Hz), 6.88 (d, 2H, J = 8.4 Hz), 4.48 (s, 2H), 4.02–

.90 (m, 2H), 3.81 (s, 4H), 3.35 (d, 1H, J = 8.4 Hz), 3.19 (d, 1H,

was dried over Na

was puriﬁed by silica gel column chromatography (EtOAc/hexane,

2 4

SO and evaporated to dryness. The product

1

3

J = 8.4 Hz), 2.57 (br s, 3H), 1.80–1.78 (m, 2H), 0.96 (s, 3H).

C

NMR of 24 (50 MHz, CDCl

3

C

), d : 159.2, 129.9, 129.3, 113.8, 79.1,

1

:20) to afford compound 29 (1.98 g) in 92% yield. R

f

= 0.4 (EtOAc/

= +22.6 (c 0.8, MeOH). H NMR (200 MHz,

7

O

8.5, 78.0, 73.1, 69.1, 55.2, 41.0, 40.8, 20.0. HRMS (ESI) for C15

H

22

-

28

1

hexane, 1:20). [

CDCl

a]

D

+

5 f

Na [M+Na] , calculated: 305.1365; found: 305.1368. R of

3 H

), d : 7.21 (d, 2H, J = 6.4 Hz), 6.87 (d, 2H, J = 6.4 Hz), 4.66

2

8

1

2

5 = 0.3 (EtOAc/hexane, 2:1). [

NMR of 25 (200 MHz, CDCl ), d

H, J = 8.6 Hz), 4.41 (s, 2H), 4.14–4.01 (m, 2H), 3.80 (s, 4H), 3.13

d, 1H, J = 8.8, Hz), 3.08 (d, 1H, J = 8.8 Hz), 2.93 (br s, 3H), 2.06–

.91 (m, 1H), 1.58 (dd, 1H, J = 3.5, 14.3 Hz), 1.10 (s, 3H). ¹³C NMR

of 25 (50 MHz, CDCl ), d : 159.3, 130.5, 129.2, 113.9, 78.2, 77.8,

4.7, 73.5, 73.1, 55.4, 44.3, 41.9, 20.8. HRMS (ESI) for C15 Na

a

H

]

D

= ꢁ12.8 (c 0.5, MeOH).

H

(

td, 1H, J = 4.4, 6.8 Hz), 4.48 (s, 2H), 4.36 (dd, 1H, J = 3.9, 7.1 Hz),

3

: 7.21 (d, 2H, J = 8.6 Hz), 6.87 (d,

3

.98 (d, 1H, 4 Hz), 3.81 (s, 3H), 3.24 (s, 2H), 1.88 (d, 2H,

2

(

1

J = 4.4 Hz), 1.45 (s, 3H), 1.28 (s, 3H), 0.94 (s, 3H), 0.89 (s, 9H),

13

0

1

3

C

3 C

.11 (s, 3H), 0.05 (s, 3H). C NMR (50 MHz, CDCl ), d : 159.1,

31.1, 129.1, 113.8, 111.6, 87.7, 79.8, 78.1, 74.9, 72.9, 55.4, 48.5,

9.4, 27.1, 26.0, 24.7, 19.1, 18.2, ꢁ4.2, ꢁ4.9. HRMS (ESI) for

3

C

7

22

H O

5

+

H

24 40

O

5

SiNa [M+Na] , calculated: 459.2543; found: 459.2548.

+

[

M+Na] , calculated: 305.1365; found: 305.1370.

4

.10.25. ((3aR,4R,5R,6aR)-4-(tert-Butyldimethylsilyloxy)-2,2,5-

4

.10.22. tert-Butyl((1S,5R)-5-((4-methoxybenzyloxy)methyl)-5-

trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-5-yl)methanol

30

methylcyclopent-2-enyloxy)dimethylsilane 26

Compound 26 was prepared according to the general procedure

for the TBS protection from compound 11 (0.4 g, 1.61 mmol).

Compound 30 was prepared according to the general procedure

for the PMB deprotection from compound 29 (1.98 g, 4.54 mmol).

Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.003

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

11

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:10)

4.10.29. (3aR,4R,5R,6aR)-4-(Allyloxy)-2,2,5-trimethyl-5-vinylte-

trahydro-3aH-cyclopenta[d][1,3]dioxole 34

afforded compound 30 (1.26 g) in 88% yield as a colorless oil.

2

8

1

R

f

= 0.2 (EtOAc/ hexane, 1:10). [

NMR (200 MHz, CDCl ), d : 4.69–4.61 (m, 1H), 4.34 (dd, 1H,

J = 3.6, 7.0 Hz), 3.87 (d, 1H, J = 3.6 Hz), 3.45 (s, 2H), 2.14 (br s,

a

]

D

= +44.2 (c 0.8, MeOH).

H

To an ice-cooled solution of NaH (60% dispersion in mineral oil,

0.16 g, 4.02 mmol) in dry THF (8 mL), alcohol 33 (0.4 g, 2.01 mmol)

in THF (2 mL) was added and the reaction mixture was kept for a

further 45 min at the same temperature, after which allyl bromide

(0.35 mL, 4.02 mmol) was added and the reaction mixture was stir-

red at room temperature for further 8 h. Water was then added

carefully to the reaction mixture to quench any excess NaH. The

layers were separated and extracted with 50 mL of ether, and then

3

H

1

0

H), 1.79–1.75 (m, 2H), 1.46 (s, 3H), 1.26 (s, 3H), 0.92 (s, 3H),

.88 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H). ¹³C NMR (50 MHz, CDCl

),

: 111.6, 87.6, 80.4, 78.2, 68.4, 49.2, 38.8, 26.9, 25.9, 24.5, 18.8,

3

d

C

+

1

3

8.1, ꢁ4.2, ꢁ5.0. HRMS (ESI) for C16

32 4

H O SiNa [M+Na] , calculated:

39.1968; found: 339.1966.

4

washed with brine. It was then dried over anhydrous MgSO , and

the solvent was removed in vacuum. The crude residue was puri-

ﬁed by ﬂash column chromatography (EtOAc/hexane, 1:40) to

4

.10.26. (3aR,4R,5S,6aR)-4-(tert-Butyldimethylsilyloxy)-2,2,5-

trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-5-carbal-

dehyde 31

Compound 31 was prepared according to the general procedure

for the Swern oxidation from compound 30 (1.26 g, 3.99 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:20)

afford compound 34 (0.373 g) in 78% yield. R

f

= 0.4 (EtOAc/hexane,

= ꢁ12.6 (c 1.1, MeOH). H NMR (200 MHz, CDCl ), d

.94–5.80 (m, 2H), 5.29–5.14 (m, 2H), 4.98–4.92 (m, 2H), 4.67

2

8

1

:40). [

a]

D

3

H

:

5

(

dd, 1H, J = 7.1, 12.9 Hz), 4.48 (dd, 1H, J = 4.4, 7.1 Hz), 4.18–4.11

m, 1H), 4.10–4.00 (m, 1H), 3.59 (d, 1H, J = 4.4 Hz), 1.94 (dd, 1H,

afforded aldehyde 31 (1.13 g) in 90% yield. R

f

= 0.5 (EtOAc/hexane,

: 9.62 (s, 1H), 4.69 (t, 1H,

J = 5.7 Hz), 4.32–4.30 (m, 2H), 2.30 (d, 1H, J = 14.4 Hz), 1.86 (dd,

H, J = 5.6, 14.4 Hz), 1.34 (s, 3H), 1.24 (s, 3H), 1.04 (s, 3H), 1.03

1

J = 7.0, 13.2 Hz), 1.80 (dd, 1H, J = 7.0, 13.0 Hz), 1.46 (s, 3H), 1.27

1

3 H

:20). H NMR (200 MHz, CDCl ), d

1

3

(

s, 3H), 1.03 (s, 3H). C NMR (50 MHz, CDCl

3 C

), d : 145.5, 134.8,

1

16.6, 112.6, 112.0, 89.7, 85.2, 77.6, 70.9, 49.3, 42.9, 27.0, 24.7,

1

(

+

_s_,₉_H₎_,₀_.₁₃₍_s_,₃_H₎_,₀_.₀₉₍_s_,₃_H₎_.1 C NMR (50 MHz, CDCl

3

20.0. HRMS (ESI) for C₁₄H₂₂O Na [M+Na] , calculated: 261.1467;

3

C

), d :

found: 261.1471.

2

1

3

03.8, 110.7, 87.3, 79.5, 79.2, 58.3, 38.8, 25.9, 25.4, 23.9, 18.2,

+

6.5, ꢁ4.4, ꢁ4.8. HRMS (ESI) for C16

30 4

H O SiNa [M+Na] , calculated:

4

.10.30. (3aR,3bR,7aR,8aR)-2,2,7a-Trimethyl-3a,3b,5,7a,8,8a-

37.1811; found: 337.1815.

0

hexahydro-[1,3]dioxolo[4 ,5 :4,5]cyclopenta[1,2-b]pyran 35

Starting compound 34 (0.050 g, 0.21 mmol) was taken in anhy-

drous degassed DCM (30 mL). Grubbs second generation metathe-

sis catalyst (G-II, 7 mg, 0.008 mmol) was then added and the

solution was stirred at reﬂux for 8 h. The reaction mixture was

then cooled to room temperature and the solution was evaporated

under reduced pressure, after which the contents of the ﬂask were

directly loaded onto a silica gel column. The crude material was

then puriﬁed by silica gel column chromatography (EtOAc/hexane,

4

.10.27. tert-Butyldimethyl((3aR,4R,5R,6aR)-2,2,5-trimethyl-5-

vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)silane 32

To suspension of methyltriphenylphosphonium iodide

a

(

0.646 g, 1.60 mmol) in dry THF (5 mL) was added LiHMDS

1.0 M solution in THF, 1.60 mL) at 0 °C. The yellow mixture was

stirred at 0 °C for 15 min. A solution of aldehyde 31 (0.251 g,

.80 mmol) in 2 mL of THF was added to the reaction mixture.

0

The yellow suspension was stirred at room temperature for a fur-

ther 4 h. The reaction was then quenched by the addition of water,

and the layers were separated and extracted with 25 mL of ether,

and washed with brine. It was then dried over anhydrous Na SO ,

2 4

and concentrated under vacuum. The crude residue was puriﬁed

by ﬂash column chromatography (EtOAc/hexane, 1:35) to afford

1

:20) to afford product 35 (0.035 g) in 80% yield as a liquid. R

f

= 0.3

: 5.92 (dt, 1H,

J = 2.2, 10.0 Hz), 5.44 (dt, 1H, J = 2.4, 10.0 Hz), 4.74 (td, 1H, J = 5.6,

.2 Hz), 4.41 (t, 1H, J = 7.8 Hz), 4.34 (dd, 2H, J = 2.4, 4.8 Hz), 3.56

d, 1H, J = 8.0 Hz), 2.06 (dd, 1H, J = 7.4, 12.6 Hz), 1.54–1.53 (m,

1

(

3 H

EtOAc/hexane, 1:20). H NMR (400 MHz, CDCl ), d

7

(

1

13

H), 1.51 (s, 3H), 1.31 (s, 3H), 0.95 (s, 3H). C NMR (50 MHz,

compound 32 (0.185 g) in 74% yield. R

f

= 0.5 (EtOAc/hexane,

= +8.7 (c 0.4, MeOH). ¹H NMR (200 MHz, CDCl

), d

.89 (dd, 1H, J = 10.6, 17.6 Hz), 5.01–4.93 (m, 2H), 4.67 (td, 1H,

CDCl ), d : 134.6, 124.8, 113.7, 86.5, 80.3, 77.7, 68.2, 41.8, 38.2,

3

C

2

8

1

5

:35). [

a]

D

3

H

:

+

2

7.4, 24.7, 21.8. HRMS (ESI) for C12

33.1154; found: 233.1152.

18 3

H O Na [M+Na] , calculated:

J = 4.8, 7.0 Hz), 4.35 (dd, 1H, J = 4.3, 7.0 Hz), 3.86 (d, 1H,

J = 4.3 Hz), 2.00–1.90 (m, 1H), 1.84–1.77 (m, 1H), 1.47 (s, 3H),

4

.10.31. (3aR,3bR,6R,7S,7aR,8aR)-2,2,7a-Trimethyloctahydro-[1,3]

1

.27 (s, 3H), 0.99 (s, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H).

0

dioxolo[4 ,5 :4,5]cyclopenta[1,2-b]pyran-6,7-diol 36

1

3

3 C

C NMR (50 MHz, CDCl ), d : 145.7, 112.1, 112.1, 87.2, 83.9,

Compound 36 was prepared according to the general procedure

for the OsO oxidation from compound 35 (0.140 g, 0.66 mmol).

4

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:1)

7

7.9, 49.9, 42.2, 27.1, 26.0, 24.8, 20.0, 18.2, ꢁ4.2, ꢁ4.7. HRMS

+

(

32 3

ESI) for C17H O SiNa [M+Na] , calculated: 335.2019; found:

3

35.2023.

afforded diol 36 (0.132 g) as the sole product in 82% yield.

1

R

f

= 0.2 (EtOAc/hexane, 1:1). H NMR (400 MHz, CDCl

3 H

), d : 4.78

4

.10.28. (3aS,4R,5R,6aR)-2,2,5-Trimethyl-5-vinyltetrahydro-3aH-

(

dd, 1H, J = 7.4, 13.0 Hz), 4.41 (t, 1H, J = 7.4 Hz), 4.14 (dd, 1H,

J = 7.2, 14.4 Hz), 4.00–3.86 (m, 1H), 3.87 (dd, 1H, J = 6.0, 10.8 Hz),

.77–3.71 (m, 1H), 3.46 (t, 1H, J = 10.8 Hz), 2.48 (br s, 1H), 2.21

br s, 1H), 1.93–1.90 (m, 2H), 1.53 (s, 3H), 1.30 (s, 3H), 0.97 (s,

cyclopenta[d][1,3]dioxol-4-ol 33

Compound 33 was prepared according to the general procedure

for the TBS deprotection from compound 32 (0.185 g, 0.59 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:20)

3

(

3

6

1

3

H). C NMR (50 MHz, CDCl

3

), d

C

: 114.0, 81.9, 80.2, 78.0, 73.0,

Na

afforded alcohol 33 (0.102 g) in 88% yield. R

f

= 0.3 (EtOAc/hexane,

= +20.2 (c 0.9, MeOH). ¹H NMR (200 MHz, CDCl

), d

.88 (dd, 1H, J = 10.5, 17.7 Hz), 5.02–4.97 (m, 2H), 4.68 (td, 1H,

8.3, 64.1, 46.8, 35.5, 27.4, 24.9, 18.7. HRMS (ESI) for C12

20 5

H O

2

8

+

1

5

:20). [

a]

D

3

H

:

[

M+Na] , calculated: 267.1209; found: 267.1212.

J = 5.4, 7.1 Hz), 4.45 (dd, 1H, J = 4.8, 7.1 Hz), 3.85 (d, 1H,

J = 4.8 Hz), 2.71 (br s, 1H), 2.04–1.97 (m, 1H), 1.93–1.80 (m, 1H),

4

.10.32. (3R,4S,4aR,6R,7R,7aR)-4a-Methyloctahydrocyclopenta

[

b]pyran-3,4,6,7-tetraol 37

1

.47 (s, 3H), 1.27 (s, 3H), 1.01 (s, 3H). ¹³C NMR (50 MHz, CDCl

3

),

To a stirred solution of alcohol 36 (0.22 g, 0.09 mmol) in anhy-

d

1

C

: 145.1, 112.8, 112.7, 86.4, 83.1, 77.4, 49.5, 42.5, 27.0, 24.6,

9.1. HRMS (ESI) for C11H O Na [M+Na] , calculated: 221.1154;

18 3

drous DCM (2 mL) was added p-toluenesulfonic acid monohydrate

0.034 g, 0.18 mmol) at room temperature and stirred for 6 h. After

completion of the reaction, 20 mg of solid NaHCO were added to

+

(

found: 221.1159.

3

Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.003

1

2

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

the reaction mixture and the solvent was evaporated in vacuo to

3 H

NMR (200 MHz, CDCl ), d : 4.23 (d, 1H, J = 5.4 Hz), 3.34–3.33 (m,

afford compound 37 (0.016 g) in 90% yield, which was used for

the next step without further puriﬁcation. R = 0.3 (MeOH/CHCl ,

f 3

2H), 1.81 (dd, 1H, J = 6.2, 13.4 Hz), 1.56–1.50 (m, 2H), 1.20 (dd,

1H, J = 4.2, 6.2 Hz), 0.90 (s, 9H), 0.87 (s, 3H), 0.70 (dd, 1H, J = 4.1,

13

1

:3).

8.5 Hz), 0.53 (dd, 1H, J = 4.7, 8.1 Hz), 0.09 (s, 6H).

C NMR

(

50 MHz, CDCl ), d : 77.2, 71.4, 50.3, 37.8, 26.2, 26.0, 20.1, 18.3,

3

C

+

4

.10.33. (3R,4S,4aS,6R,7R,7aR)-4a-Methyloctahydrocyclopenta[b]

17.2, 11.6, ꢁ4.1, ꢁ4.8. HRMS (ESI) for C14

28 2

H O SiNa [M+Na] , cal-

pyran-3,4,6,7-tetrayl tetraacetate 38

culated: 279.1757; found: 279.1760.

A solution of tetraol 37 (0.050 g, 0.24 mmol) in triethylamine

(

0.33 mL, 2.4 mmol), at 0 °C was treated with 4-dimethylaminopy-

4.10.37. (1S,2S,3S,5S)-2-(tert-Butyldimethylsilyloxy)-3-methyl-

bicyclo[3.1.0]hexane-3-carbaldehyde 42

ridine (0.013 g, 0.11 mmol), and acetic anhydride (0.12 mL,

1

.3 mmol). The mixture was stirred at room temperature for

2 h, and then treated with saturated aqueous NaHCO solution

Compound 42 was prepared according to the general procedure

for the Swern oxidation from compound 41 (0.65 g, 2.53 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:20)

3

(

2 mL), and extracted with DCM (2 ꢀ 10 mL). The combined

organic phases were washed with brine (2 mL), dried (Na SO ),

2

4

afforded aldehyde 42 (0.579 g) in 90% yield. R

f

= 0.6 (EtOAc/hexane,

1

and concentrated. The crude residue was puriﬁed by ﬂash column

1:20). H NMR (200 MHz, CDCl ), d : 9.36 (s, 1H), 4.62 (d, 1H,

3 H

chromatography (EtOAc/hexane, 1:5) to afford compound 38

J = 5.2 Hz), 2.27 (dd, 1H, J = 5.9, 13.7 Hz), 1.58–1.52 (m, 2H),

28

(

0.084 g) in 95% yield. R

f

= 0.3 (EtOAc/hexane, 1:5). [

a]

D

= +78.2

1.27–1.22 (m, 1H), 0.99 (s, 3H), 0.86 (s, 9H), 0.73–0.69 (m, 1H),

1

13

(

c 1.2, MeOH). H NMR (400 MHz, CDCl ), d : 5.37 (dd, 1H,

3

H

3

0.51 (dd, 1H, J = 5.2, 8.2 Hz) 0.06 (s, 6H). C NMR (50 MHz, CDCl ),

J = 8.0, 14.4 Hz), 5.29–5.22 (m, 2H), 5.06 (dd, 1H, J = 8.0, 10.4 Hz),

d

C

: 203.3, 75.0, 58.6, 36.1, 26.7, 25.9, 18.3, 17.5, 17.0, 10.8, ꢁ4.3,

+

3

1

2

.95 (dd, 2H, J = 5.6, 10.4 Hz), 3.60 (t, 1H, J = 10.8 Hz), 2.17 (s,

ꢁ4.9. HRMS (ESI) for

14 26 2

C H O SiNa [M+Na] , calculated:

H), 2.09 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 1.59–1.50 (m, 1H),

277.1600; found: 277.1608.

.48–1.46 (m, 1H), 1.16 (s, 3H). ¹³C NMR (50 MHz, CDCl

), d

70.2, 169.9, 169.7, 79.2, 71.6, 71.4, 67.8, 65.7, 64.9, 39.5, 35.9,

3

C

:

4.10.38. tert-Butyldimethyl((1S,2S,3R,5S)-3-methyl-3-vinylbicyclo

[3.1.0]hexan-2-yloxy)silane 43

+

0.9, 20.8, 20.6, 18.7. HRMS (ESI) for C17

H

24

O

9

Na [M+Na] , calcu-

lated: 395.1318; found: 395.1320.

To

a suspension of methyltriphenylphosphonium iodide

(

0.646 g, 1.60 mmol) in dry THF (5 mL) was added LiHMDS

4

.10.34. (1S,2S,3R,5S)-3-((4-Methoxybenzyloxy)methyl)-3-methyl-

(1.0 M solution in THF, 1.60 mL) at 0 °C. The yellow mixture was

stirred at 0 °C for 15 min. A solution of aldehyde 42 (0.203 g,

0.80 mmol) in 2 mL of THF was added to the reaction mixture.

The yellow suspension was stirred at room temperature for 4 h.

The reaction was then quenched with the addition of water, and

the layers were separated and extracted with 25 mL of ether, and

washed with brine. It was then dried over anhydrous Na SO ,

2 4

and concentrated under vacuum. The crude residue was puriﬁed

by ﬂash column chromatography (EtOAc/hexane, 1:40) to afford

bicyclo[3.1.0]hexan-2-ol 39

Compound 39 was prepared according to the general procedure

for the cyclopropanation reaction from compound 11 (0.450 g,

1

.8 mmol). Puriﬁcation by silica gel chromatography (EtOAc/hex-

ane, 1:5) afforded 39 (0.354 g) in 75% yield. R = 0.4 (EtOAc/hexane,

= ꢁ23.8 (c 0.4, MeOH). H NMR (400 MHz, CDCl ), d

.24 (d, 2H, J = 8.8 Hz), 6.88 (d, 2H, J = 8.4 Hz), 4.44 (s, 2H), 4.38

f

2

8

1

7

:5). [

a]

D

3

H

:

(

1

d, 1H, J = 5.2 Hz), 3.80 (s, 3H), 3.11 (d, 2H, J = 4.4 Hz), 1.86 (dd,

H, J = 5.8, 13.4 Hz), 1.58–1.50 (m, 2H), 1.25–1.23 (m, 1H), 1.08

compound 43 (0.149 g) in 74% yield. R

f

= 0.8 (EtOAc/hexane,

H

), d :

13

28

1

(

5

s, 3H). 0.65 (t, 1H, J = 4.2 Hz), 0.49–0.47 (m, 1H).

50 MHz, CDCl ), d : 158.7, 130.3, 128.8, 113.4, 78.9, 77.8, 72.5,

4.8, 45.5, 38.2, 24.9, 21.0, 15.4, 9.4. HRMS (ESI) for C16 Na

C NMR

1:40). [

a

]

D

= ꢁ17.8 (c 1.2, MeOH). H NMR (200 MHz, CDCl

3

C

5.91 (dd, 1H, J = 10.6, 17.4 Hz), 4.98–4.85 (m, 2H), 4.08 (d, 1H,

J = 5.2 Hz), 1.93 (dd, 1H, J = 6.3, 13.1 Hz), 1.57–1.52 (m, 2H),

1.29–1.25 (m, 1H), 0.92 (s, 3H), 0.91 (s, 9H), 0.61–0.60 (m, 1H),

22 3

H O

+

[

M+Na] , calculated: 285.1467; found: 285.1470.

1

3

0

.54 (dd, 1H, J = 3.4, 8.2 Hz), 0.06 (s, 6H). C NMR (50 MHz, CDCl

3

),

4

3

.10.35. tert-Butyl((1S,2S,3R,5S)-3-((4-methoxybenzyloxy)methyl)-

-methylbicyclo[3.1.0]hexan-2-yloxy)dimethylsilane 40

Compound 40 was prepared according to the general procedure

d

C

: 148.6, 109.7, 79.8, 54.0, 40.6, 26.5, 26.2, 21.4, 18.5, 18.4, 13.2,

+

ꢁ4.2, ꢁ4.7. HRMS (ESI) for C15

H28OSiNa [M+Na] , calculated:

275.1807; found: 275.1809.

for the TBS protection from compound 39 (0.9 g, 3.43 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:40)

4.10.39. (1S,2S,3R,5S)-3-Methyl-3-vinylbicyclo[3.1.0]hexan-2-ol

44

Compound 44 was prepared according to the general procedure

for the TBS deprotection from compound 43 (0.15 g, 0.59 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:30)

afforded 40 (1.16 g) in 90% yield. R

f

= 0.4 (EtOAc/hexane, 1:40).

= ꢁ32.6 (c 1.0, MeOH). H NMR (200 MHz, CDCl ), d : 7.25

d, 2H, J = 8.8 Hz), 6.87 (d, 2H, J = 8.6 Hz), 4.44 (s, 2H), 4.27 (d,

2

8

1

[a

]

D

3

H

(

1

H, J = 5.4 Hz), 3.80 (s, 3H), 3.17 (s, 2H), 1.94 (dd, 1H, J = 6.2,

3.2 Hz), 1.49–1.40 (m, 2H), 1.29–1.23 (m, 1H), .097 (s, 9H), 0.90

afforded alcohol 44 (0.07 g) in 86% yield. R

f

= 0.4 (EtOAc/hexane,

H

), d :

2

8

1

(

s, 3H), 0.66 (dd, 1H, J = 4.1, 8.3 Hz), 0.48 (td, 1H, J = 4.6, 8.4 Hz),

1:30). [

a

]

D

= ꢁ12.2 (c 1.0, MeOH). H NMR (200 MHz, CDCl

3

1

3

0

1

.06 (s, 6H). C NMR (50 MHz, CDCl

), d

3 C

: 159.1, 131.1, 129.1,

5.89 (dd, 1H, J = 10.6, 17.4 Hz), 4.95 (dd, 1H, J = 1.0, 17.4 Hz), 4.88

(dd, 1H, J = 1.0, 10.6 Hz), 4.26 (d, 1H, J = 5.4 Hz), 2.04 (dd, 1H,

J = 6.1, 13.5 Hz), 1.53 (dd, 2H, J = 1.6, 13.6 Hz), 1.42 (dd, 1H,

J = 1.9, 4.1 Hz), 0.99 (s, 3H), 0.77 (dd, 1H, J = 4.0, 8.8 Hz), 0.55 (td,

13.8, 77.9, 76.5, 73.0, 55.3, 49.6, 38.2, 26.2, 26.1, 21.0, 18.4,

+

7.2, 11.4, ꢁ4.2, ꢁ4.8. HRMS (ESI) for C22

36 3

H O SiNa [M+Na] , cal-

culated: 399.2332; found: 399.2338.

1

3

1

3 C

H, J = 5.2, 8.4 Hz). C NMR (50 MHz, CDCl ), d : 148.4, 109.6,

4

.10.36. ((1S,2S,3R,5S)-2-(tert-Butyldimethylsilyloxy)-3-methyl-

79.5, 50.2, 40.5, 25.7, 21.4, 16.8, 11.1. HRMS (ESI) for C

[M+Na] , calculated: 161.0943; found: 161.0948.

9

H14ONa

+

bicyclo[3.1.0]hexan-3-yl)methanol 41

Compound 41 was prepared according to the general procedure

for the PMB deprotection from compound 40 (1.16 g, 3.08 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:20)

afforded compound 41 (695.1 mg) in 88% yield as a colorless oil.

4.10.40. (1S,2S,3R,5S)-2-(Allyloxy)-3-methyl-3-vinylbicyclo[3.1.0]

hexane 45

To an ice-cooled solution of NaH (60% dispersion in mineral oil,

0.16 g, 4.02 mmol) in dry THF (8 mL), alcohol 44 (0.277 g,

28

1

R

f

= 0.3 (EtOAc/hexane, 1:20). [

a

]

D

= ꢁ22.8 (c 0.5, MeOH).

H

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13

2

.01 mmol) in THF (2 mL) was added and the reaction mixture was

C

d : 159.4, 129.9, 129.3, 114.0, 79.0, 73.3, 69.9, 55.4, 53.8, 50.0,

+

kept for a further 45 min at the same temperature, after which allyl

bromide (0.35 mL, 4.02 mmol) was added and the reaction mixture

was stirred at room temperature for 8 h. Water was added care-

fully to the reaction mixture to quench any excess NaH, and the

layers were separated and extracted with 50 mL of ether, and

36.8, 33.9, 29.6, 16.1. HRMS (ESI) for C16

calculated: 301.1416; found: 301.1421.

22 4

H O Na [M+Na] ,

4.10.43. (1R,2R,4S,5R)-5-(Hydroxymethyl)-5-methylcyclohexane-

1,2,4-triol 49

washed with brine. It was then dried over anhydrous MgSO

the solvent was removed in vacuum. The crude residue was puri-

ﬁed by ﬂash column chromatography (EtOAc/hexane, 1:40) to

4

, and

According to the general procedure for the acid induced epox-

ide ring opening, compound 47 (0.028 g, 0.10 mmol) afforded a

triol which was used for the next step without further puriﬁca-

tion. PMB deprotection of the crude triol (0.026 g, 0.08 mmol)

according to the general procedure for the PMB deprotection

and then puriﬁcation by silica gel chromatography (EtOAc/hex-

afford compound 45 (0.25 g) in 70% yield. R

f

= 0.8 (EtOAc/hexane,

= ꢁ29.8 (c 1.0, MeOH). H NMR (400 MHz, CDCl ), d

.97–5.87 (m, 2H), 5.28 (dd, 1H, J = 2.0, 17.2 Hz), 5.13 (dd, 1H,

2

8

1

:40). [

a

]

D

3

H

:

5

J = 1.2, 10.4 Hz), 4.98–4.88 (m, 2H), 4.07–4.03 (m, 1H), 3.86–3.82

m, 2H), 1.96 (dd, 1H, J = 6.0, 13.2 Hz), 1.57–1.55 (m, 2H), 1.29–

ane, 2:1) afforded tetraol 49 (0.010 g) in 60% yield (for two step).

1

(

R

f

= 0.2 (EtOAc/hexane, 2:1). H NMR (600 MHz, CDCl

3 H

), d : 4.32–

1

.23 (m, 1H), 1.01 (s, 3H), 0.74 (dd, 1H, J = 4.2, 8.2 Hz), 0.64 (dd,

4.30 (m, 1H), 3.95–3.93 (m, 1H), 3.66–3.662 (m, 2H), 3.52 (d, 1H,

H, J = 4.6, 8.2 Hz). ¹C NMR (50 MHz, CDCl

3

), d

C

: 148.7, 135.6,

J = 9.0 Hz), 2.55 (d, 1H, J = 12.0 Hz), 2.12–2.10 (m, 1H), 1.80 (d,

3

13

15.9, 109.7, 85.7, 69.5, 53.1, 41.1, 23.1, 21.0, 18.4, 13.0. HRMS

1H, J = 15.6 Hz), 1.44–1.41 (m, 1H), 1.14 (s, 3H).

C NMR

+

(

ESI) for

C

12

H

18ONa [M+Na] , calculated: 201.1256; found:

(50 MHz, CDCl ), d : 79.0, 75.7, 74.1, 68.8, 45.1, 34.7, 31.5,

3

C

+

2

01.1259.

19.2. HRMS (ESI) for C

8 16 4

H O Na [M+Na] , calculated: 199.0947;

found: 199.0950.

4

.10.41. (3S,4R,4aR,5aS,6aS,6bS)-4a-Methyloctahydro-2H-cyclo-

propa[4,5]cyclopenta[1,2-b]pyran-3,4-diol 46

4.10.44. (1S,2S,4S,5R)-5-(Hydroxymethyl)-5-methylcyclohexane-

1,2,4-triol 50

Compound 45 (0.037 g, 0.21 mmol) was taken in anhydrous

degassed DCM (30 mL). Grubbs second generation metathesis cat-

alyst (G-II, 0.007 g, 0.008 mmol) was added and the solution was

stirred at reﬂux for 8 h. The reaction mixture was then cooled to

room temperature and the solution was evaporated under reduced

pressure. The crude material was used for the next step without

further puriﬁcation. Compound 46 was prepared according to the

According to the experimental procedure of compound 49,

compound 48 (0.028 g, 0.10) afforded tetraol 50 (0.012 g) in 70%

2

8

yield (for two step). R

1.1, MeOH). H NMR (600 MHz, C N), d

f

= 0.4 (MeOH/CHCl

3

, 1:3). [

D

a] = +33.5 (c

1

5

D

5

H

: 4.34–4.30 (m, 1H),

4.22–4.21 (m, 1H), 3.94 (d, 1H, J = 10.8 Hz), 3.74 (d, 1H,

J = 10.2 Hz), 3.58–3.50 (m, 1H), 2.61–2.60 (m, 1H), 2.28–2.26 (m,

1H), 2.16–2.10 (m, 1H), 1.98–1.96 (m, 1H), 1.62 (s, 3H). ¹³C NMR

4

general procedure for the OsO oxidation starting from the crude

material (23.34 mg, 0.16 mmol). Puriﬁcation by silica gel chro-

matography (EtOAc/hexane, 1:1) afforded exclusively compound

5 5 C

(150 MHz, C D N), d : 71.4, 71.0, 69.4, 49.4, 40.9, 36.1, 34.8, 29.7.

+

8 16 4

HRMS (ESI) for C H O Na [M+Na] , calculated: 199.0947; found:

4

6 (0.020 g) in 53% overall yield for two steps. R

f

= 0.3 (EtOAc/hex-

: 4.26 (d, 1H, J = 4.8 Hz),

.96–3.91 (m, 1H), 3.89–3.87 (m, 1H), 3.65–3.60 (m, 1H), 3.42 (t,

199.0955.

1

3 H

ane, 1:1). H NMR (400 MHz, CDCl ), d

3

1

0

4.10.45. (1R,3S,4R,6S)-4-((4-Methoxybenzyloxy)methyl)-4-methyl-

bicyclo[4.1.0]heptan-3-ol 51

Compound 51 was prepared according to the general procedure

for the cyclopropanation reaction from compound 19 (0.028 g,

0.11 mmol). Puriﬁcation by silica gel chromatography (EtOAc/

H, J = 10.6 Hz), 2.06 (dd, 2H, J = 4.6, 12.6 Hz), 1.64 (br s, 2H),

.50 (d, 1H, J = 12.8 Hz), 1.48–1.41 (m, 1H), 1.04–1.03 (m, 1H),

.93 (s, 3H), 0.39 (dd, 1H, J = 7.6, 14.8 Hz). ¹³C NMR (50 MHz,

CDCl

HRMS (ESI) for C10

2

3 C

), d : 79.9, 75.4, 69.3, 64.2, 39.1, 31.2, 22.6, 16.8, 12.8, 9.1.

+

H

16

O

3

Na [M+Na] , calculated: 207.0997; found:

hexane, 1:5) afforded 51 (0.022 g) in 75% yield. R

f

= 0.3 (EtOAc/

= ꢁ28.0 (c 1.1, MeOH). H NMR (600 MHz,

H

: 7.25 (d, 2H, J = 7.8 Hz), 6.89 (d, 2H, J = 7.8 Hz), 4.45

2

8

1

07.0999.

hexane, 1:5). [

a]

D

CDCl ), d

3

4

7

.10.42. (1S,3S,4R,6R)-4-((4-Methoxybenzyloxy)methyl)-4-methyl-

-oxabicyclo[4.1.0]heptan-3-ol 47 and (1R,3S,4R,6S)-4-((4-

(dd, 2H, J = 12.0, 16.8 Hz), 3.82 (s, 3H), 3.68–3.66 (m, 1H), 3.34 (d,

1H, J = 9.0 Hz), 3.21 (d, 1H, J = 8.4 Hz), 2.18–2.06 (m, 1H), 1.65–

1.62 (m, 2H), 1.30–1.27 (m, 3H), 0.90 (s, 3H), 0.74–0.72 (m, 1H),

methoxybenzyloxy)methyl)-4-methyl-7-oxabicyclo[4.1.0]heptan-

-ol 48

Compounds 47 and 48 were prepared according to the general

1

3

3 C

0.58–0.57 (m, 1H). C NMR (150 MHz, CDCl ), d : 159.1, 130.3,

129.1, 113.8, 79.3, 73.2, 73.1, 55.2, 37.0, 30.9, 28.2, 19.3, 13.2,

+

procedure for the substrate directed epoxidation with mCPBA from

compound 19 (0.1 g, 0.38 mmol). The two diastereomeric epoxides

8.1, 7.7. HRMS (ESI) for

299.1623; found: 299.1628.

17 24 3

C H O Na [M+Na] , calculated:

(

compound 47 and compound 48 in a 2: 1 ratio) were puriﬁed by

ﬂash column chromatography (EtOAc/hexane, 1:2) to afford epox-

ide 47 (0.056 g) in 53.5% yield and epoxide 48 (0.028 g) in 26.50%

4.10.46. tert-Butyl((1S,6R)-6-((4-methoxybenzyloxy)methyl)-6-

methylcyclohex-3-enyloxy)dimethylsilane 52

2

8

yield. R

f

of 47 = 0.4 (EtOAc/hexane, 1:2). [

a

]

D

= +13.8 (c 0.3,

: 7.24 (d, 2H, J = 8.4 Hz),

.89 (d, 2H, J = 8.4 Hz), 4.37 (dd, 2H, J = 11.7, 17.1 Hz), 3.82 (s,

Compound 52 was prepared according to the general procedure

for the TBS protection from compound 19 (2.5 g, 9.5 mmol).).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:30)

1

3 H

MeOH). H NMR (600 MHz, CDCl ), d

6

3

2

1

2

8

H), 3.59–3.55 (m, 1H), 3.24–3.20 (m, 1H), 3.19–3.14 (m, 2H),

.99–2.90 (m, 1H), 2.20–2.11 (m, 1H), 2.10–2.07 (m, 1H), 1.89 (d,

H, J = 16.2 Hz), 1.73 (dd, 1H, J = 4.8, 16.2 Hz), 1.15 (s, 3H).

), d : 159.1, 130.1, 129.0, 113.7, 77.0, 73.0,

0.9, 55.2, 52.9, 52.0, 36.8, 30.4, 28.3, 21.2. HRMS (ESI) for

afforded compound 52 (3.10 g) in 86% yield. [

a

]

D

= +38.8 (c 0.9,

= 0.5 (EtOAc/hexane, 1:30). H NMR (600 MHz, CDCl ),

H

d : 7.26 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 5.56–5.48 (m,

1

MeOH). R

f

3

1

3

C

NMR (50 MHz, CDCl

3

C

2H), 4.49 (d, 1H, J = 11.4 Hz), 4.35 (d, 1H, J = 11.4 Hz), 3.91 (dd,

1H, J = 6.0, 8.4 Hz), 3.82 (s, 3H), 3.38 (d, 1H, J = 8.4 Hz), 3.12 (d,

1H, J = 8.4 Hz), 2.29 (d, 1H, J = 17.4 Hz), 2.21–2.18 (m, 1H), 2.03–

2.01 (m, 1H), 1.83–1.80 (m, 1H), 0.98 (s, 9H), 0.90 (s, 3H), 0.04 (s,

7

C

+

16

H

22

O

4

Na [M+Na] , calculated: 301.1416; found: 301.1419. R

f

2

8

1

of 48 = 0.3 (EtOAc/hexane, 1:2). [

NMR (600 MHz, CDCl ), d

J = 8.4 Hz), 4.47 (d, 1H, J = 11.4 Hz), 4.41 (d, 1H, J = 12.0 Hz), 3.80

s, 4H), 3.26–3.22 (m, 3H), 3.09 (t, 1H, J = 4.5 Hz), 2.36–2.33 (m,

H), 1.76–1.70 (m, 3H), 0.96 (s, 3H). ¹³C NMR (50 MHz, CDCl

),

a

]

D

= ꢁ18.2 (c 1.1, MeOH).

H

1

3

H

: 7.23 (d, 2H, J = 8.4 Hz), 6.88 (d, 2H,

6H). C NMR (50 MHz, CDCl

3 C

), d : 159.1, 131.2, 129.1, 125.9,

123.8, 113.8, 76.3, 73.0, 69.7, 55.4, 38.8, 34.7, 32.5, 26.0, 18.2,

+

(

1

15.8, ꢁ3.8, ꢁ4.8. HRMS (ESI) for C22

36 3

H O SiNa [M+Na] , calculated:

3

399.2332; found: 399.2336.

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1

4

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

4

.10.47. (1R,2S,4R,5S)-5-(tert-Butyldimethylsilyloxy)-4-((4-meth-

oxybenzyloxy)methyl)-4-methylcyclohexane-1,2-diol 53 and

1S,2R,4R,5S)-5-(tert-butyldimethylsilyloxy)-4-((4-methoxy-

35.1, 33.0, 28.1, 25.9, 18.1, 16.9, ꢁ3.9, ꢁ4.8. HRMS (ESI) for

+

17 34 4

C H O SiNa [M+Na] , calculated: 353.2124; found: 353.2127.

(

benzyloxy)methyl)-4-methylcyclohexane-1,2-diol 54

4.10.50. tert-Butyldimethyl((3aS,5S,6R,7aR)-2,2,6-trimethyl-6-

vinylhexahydrobenzo[d][1,3]dioxol-5-yloxy)silane 57

Compound 53 and 54 were prepared according to the general

procedure for the OsO

4

oxidation starting from compound 52

Oxalyl chloride (1.16 ml, 13.26 mmol) was taken in DCM

(32.0 ml) and the reaction vessel was kept at ꢁ78 °C. Dimethyl

sulphoxide (DMSO, 1.88 ml, 26.52 mmol) was then added and

the reaction mixture was kept at the same temperature for

25 min. Alcohol 56 (2.92 g, 8.84 mmol) in DCM was then added

to it and the mixture was kept for a further 45 min at the same

temperature, after which triethyl amine (7.37 ml, 53.00 mmol)

was added and the reaction mixture was gradually warmed to

the room temperature for 1 h. The reaction was then quenched

by adding water and extracted with DCM. The organic layer was

(

1.5 g, 3.98 mmol). Two diastereomeric diols 53 and compound

5

4 in a 1:2 ratio were puriﬁed by ﬂash column chromatography

(

EtOAc/hexane, 1:5) to afford diol 53 (0.441 g) in 27% yield and diol

2

8

5

+

4 (0.882 g) in 54% yield. R

f

of 53 = 0.3 (EtOAc/hexane, 1:5). [

), d : 7.22 (d, 2H,

J = 8.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 4.43 (d, 1H, J = 12.0 Hz), 4.37

d, 1H, J = 12.0 Hz), 3.87–3.81 (m, 1H), 3.65 (s, 5H), 3.19 (t, 2H,

J = 9.0 Hz), 2.05–2.01 (m, 1H), 1.74–1.72 (m, 1H), 1.64–1.57 (m,

H), 1.02 (s, 3H), 0.93 (s, 9H), 0.15 (s, 3H), 0.10 (s, 3H). ¹³C NMR¹³

NMR (150 MHz, CDCl ), d : 159.1, 130.4, 128.9, 113.7, 75.1, 72.9,

9.9, 68.1, 55.2, 34.6, 33.2, 25.9, 25.8, 17.9, ꢁ4.3, ꢁ4.9. HRMS

D

a] =

32.8 (c 0.6, MeOH). ¹H NMR (600 MHz, CDCl

3

H

(

2

C

3

C

washed successively with water, saturated aqueous NaHCO

3

solu-

6

tion and brine. The organic layer was dried (MgSO ) and evapo-

4

+

(

ESI) for C22

H

38

O

5

SiNa [M+Na] , calculated: 433.2387; found:

rated. The residue was used for next step without further

puriﬁcation. To a suspension of methyltriphenylphosphonium

iodide (5.7 g, 14.19 mmol) in dry THF (40 mL) was added LiHMDS

(1.0 M solution in THF, 14.2 mL) at 0 °C. The yellow mixture was

stirred at 0 °C for 30 min. A solution of the crude aldehyde

(2.32 g, 7.1 mmol) in 16 mL of THF was added to the reaction mix-

ture. The yellow suspension was stirred at room temperature for a

further 4 h. Next, the reaction was quenched by the addition of

water, and the layers were separated and extracted with 200 mL

of ether, and washed with brine. It was then dried over anhydrous

28

4

33.2388. R

f

of 54 = 0.2 (EtOAc/hexane, 1:5). [

), d : 7.24 (d, 2H, J = 8.6 Hz),

.89 (d, 2H, J = 8.6 Hz), 4.49 (d, 1H, J = 12.0 Hz), 4.36 (d, 1H,

J = 12.0 Hz), 4.13 (d, 1H, J = 6.6 Hz), 3.99–3.93 (m, 1H), 3.81 (s,

D

a] = +44.2 (c 1.0,

1

MeOH). H NMR (600 MHz, CDCl

6

3

H

4

2

3

1

3

H), 3.29 (d, 1H, J = 9.0 Hz), 3.11 (d, 1H, J = 9.0 Hz), 1.95–1.91 (m,

H), 1.68–1.64 (m, 1H), 1.57–1.54 (m, 1H), 0.93 (s, 9H), 0.85 (s,

H), 0.07 (s, 3H), 0.06 (s, 3H). ¹³C NMR (50 MHz, CDCl

), d

59.2, 130.6, 129.3, 113.9, 77.2, 73.1, 69.4, 68.5, 55.4, 40.3, 36.2,

5.6, 26.0, 18.2, 16.9, ꢁ3.9, ꢁ4.8. HRMS (ESI) for C22 SiNa

3

C

:

38 5

H O

+

[

M+Na] , calculated: 433.2387; found: 433.2389.

2 4

Na SO , and concentrated under vacuum. The crude residue was

puriﬁed by ﬂash column chromatography (EtOAc/hexane, 1:10)

4

.10.48. tert-Butyl((3aS,5S,6R,7aR)-6-((4-methoxybenzyloxy)

to afford compound 57 (1.85 g) in 64% yield (for two step).

2

8

1

methyl)-2,2,6-trimethylhexahydrobenzo[d][1,3]dioxol-5-yloxy)

dimethylsilane 55

R

f

= 0.6 (EtOAc/hexane, 1:10). [

a

]

D

= +12.4 (c 0.8, MeOH).

H

NMR (200 MHz, CDCl ), d : 5.98 (dd, 1H, J = 10.7, 17.7 Hz), 5.00–

3

H

Compound 54 (2.02 g, 4.91 mmol) was taken in 24 mL of dry

DCM. 2,2-Dimethoxypropane (DMP, 1.85 mL, 14.82 mmol) was

then added followed by a catalytic amount of CSA (0.13 g, 0.

4.92 (m, 2H), 4.27–4.22 (m, 2H), 3.70–3.64 (m, 1H), 2.05 (dd, 1H,

J = 3.8, 10.8 Hz), 1.98–1.68 (m, 3H), 1.46 (s, 3H), 1.30 (s, 3H), 0.99

1

3

(s, 3H), 0.85 (s, 9H), 0.04 (s, 6H). C NMR (50 MHz, CDCl

3 C

), d :

5

6 mmol). The reaction mixture was then stirred at room temper-

146.8, 111.6, 107.7, 73.5, 72.7, 72.6, 41.1, 36.7, 32.8, 28.5, 26.1,

ature for 6 h. After completion of the reaction water was added to

the reaction mixture, which was then extracted with DCM and

25.8, 18.1, 18.0, ꢁ4.2, ꢁ4.8. HRMS (ESI) for C18

34 3

H O SiNa [M

+

+Na] , calculated: 349.2175; found: 349.2177.

4

washed with brine. The organic layer was dried over MgSO and

evaporated to dryness. The product was puriﬁed by silica gel col-

umn chromatography (EtOAc/hexane, 1:20) to afford compound

4.10.51. (3aS,5S,6R,7aR)-2,2,6-Trimethyl-6-vinylhexahydrobenzo

[d][1,3]dioxol-5-ol 58

Compound 58 was prepared according to the general procedure

for the TBS deprotection from compound 57 (1.85 g, 5.66 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:10)

28

5

5 (2.0 g) in 90% yield. R

f

= 0.3 (EtOAc/hexane, 1:20). [

c 1.0, MeOH). H NMR (600 MHz, CDCl ), d : 7.28 (d, 2H,

J = 8.6 Hz), 6.87 (d, 2H, J = 8.6 Hz), 4.50 (d, 1H, J = 12.0 Hz), 4.34

a

]

D

= +23.8

1

(

3

H

(

d, 1H, J = 11.4 Hz), 4.27–4.26 (m, 1H), 4.18–4.17 (m, 1H), 3.98

dd, 1H, J = 4.5, 9.3 Hz), 3.82 (s, 3H), 3.24 (s, 2H), 1.99–1.96 (m,

afforded alcohol 58 (1.06 g) in 88% yield. R

f

= 0.2 (EtOAc/hexane,

2

8

1

1:0). [a]

D

= +8.6 (c 0.6, MeOH). H NMR (600 MHz, CDCl ), d :

3

H

1

3

H), 1.86–1.83 (m, 1H), 1.72–1.70 (m, 2H), 1.44 (s, 3H), 1.32 (s,

5.79 (dd, 1H, J = 10.8, 17.4 Hz), 5.17–5.10 (m, 2H), 4.35–4.30 (m,

1H), 4.21–4.18 (m, 1H), 3.80 (dd, 1H, J = 2.1, 11.1 Hz), 2.33 (dd,

1H, J = 2.4, 15.0 Hz), 1.86–1.81 (m, 1H), 1.74 (dd, 1H, J = 6.3,

13

H), 0.99 (s, 9H), 0.86 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H). C NMR

), d : 159.0, 130.9, 128.6, 113.6, 107.6, 76.4,

3.7, 72.7, 68.8, 55.0, 39.6, 35.0, 32.5, 28.5, 26.2, 25.8, 18.0, 16.5,

C

NMR (50 MHz, CDCl

7

3

C

13.5 Hz), 1.57–1.53 (m, 1H), 1.51 (s, 3H), 1.34 (s, 3H), 0.99 (s,

+

13

ꢁ

4.1, ꢁ5.0. HRMS (ESI) for C25

H

42

O

5

SiNa [M+Na] , calculated:

3H). C NMR (50 MHz, CDCl

), d

3 C

: 145.9, 113.7, 107.9, 73.9, 72.0,

4

73.2700; found: 473.2704.

69.9, 41.8, 38.9, 30.8, 28.5, 26.2, 14.1. HRMS (ESI) for C12H O Na

20 3

+

[

M+Na] , calculated: 235.1310; found: 235.1315.

4

.10.49. ((3aR,5R,6S,7aS)-6-(tert-Butyldimethylsilyloxy)-2,2,5-

trimethylhexahydrobenzo[d][1,3]dioxol-5-yl)methanol 56

Compound 56 was prepared according to the general procedure

for the PMB deprotection from compound 55 (2.0 g, 4.43 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:5)

afforded compound 56 (1.29 g) in 88% yield as a colorless oil.

4.10.52. (3aR,5R,6S,7aS)-6-(Allyloxy)-2,2,5-trimethyl-5-vinylhex-

ahydrobenzo[d][1,3]dioxole 59

To an ice-cooled solution of NaH (60% dispersion in mineral oil,

0.16 g, 4.02 mmol) in dry THF (8 mL), alcohol 58 (0.426 g,

2.01 mmol) in THF (2 mL) was added and the reaction mixture

was kept for further 45 min at the same temperature, after which

allyl bromide (0.35 mL, 4.02 mmol) was added and the reaction

mixture was stirred at room temperature for a further 8 h. Water

was then added carefully to the reaction mixture to quench any

excess NaH, and the layers were separated and extracted with

50 mL of ether, and washed with brine. It was then dried over

a]

D

= +22.8 (c 1.0, MeOH). ¹H NMR

2

8

R

(

f

= 0.3 (EtOAc/hexane, 1:5). [

600 MHz, CDCl ), d : 4.31 (dd, 1H, J = 4.8, 9.0 Hz), 4.24 (dd, 1H,

J = 6.3, 12.3 Hz), 4.01–4.00 (m, 1H), 3.45–3.40 (m, 1H), 3.38–3.37

m, 1H), 2.39 (br, s 1H), 1.84–1.83 (m, 1H), 1.68–1.62 (m, 3H),

.50 (s, 3H), 1.33 (s, 3H), 0.90 (s, 9H), 0.88 (s, 3H), 0.11 (s, 6H).

3

H

(

1

3

3 C

C NMR (50 MHz, CDCl ), d : 108.0, 73.8, 72.5, 70.5, 69.4, 40.0,

Please cite this article in press as: Kumar, R.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.003

R. Kumar et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx

15

anhydrous MgSO

crude residue was puriﬁed by ﬂash column chromatography

4

, and the solvent was removed in vacuum. The

(MeOH/CHCl

= 0.4 (MeOH/CHCl , 1:3). [

H

(600 MHz, C N), d : 5.47 (br s 4H), 4.72–4.70 (m, 1H), 4.41 (s,

3

, 1:3) to afford compound 62 (0.07 g) in 90% yield.

a]

D

= +69.2 (c 1.0, MeOH). ¹H NMR

2

8

R

f

3

(

EtOAc/hexane, 1:20) to afford compound 59 (0.395 g) in 78% yield.

5

D

5

2

8

1

R

f

= 0.4 (EtOAc/hexane, 1:20). [

), d : 6.04–6.01 (m, 1H), 5.99–5.87 (m, 1H), 5.26

d, 1H, J = 16.8 Hz), 5.14 (d, 1H, J = 10.2 Hz), 5.04–5.00 (m, 2H),

a]

D

= +25.4 (c 1.0, MeOH). H NMR

1H), 4.38–4.36 (m, 1H), 4.27–4.25 (m, 1H), 4.11 (dd, 1H, J = 5.7,

9.9 Hz), 3.98–3.96 (m, 1H), 3.87 (s, 1H), 3.04 (t, 1H, J = 12.3 Hz),

2.36 (d, 1H, J = 12.6 Hz), 1.91 (t, 1H, J = 12.3 Hz), 1.68 (dd, 1H,

(

600 MHz, CDCl

3

H

1

3

4.32–4.31 (m, 1H), 4.22–4.20 (m, 1H), 4.06 (dd, 1H, J = 5.1,

12.9 Hz), 3.94 (dd, 1H, J = 5.1, 12.9 Hz), 3.43 (dd, 1H, J = 3.6,

9.6 Hz), 2.25 (d, 1H, J = 11.4 Hz), 1.89–1.84 (m, 1H), 1.73 (dd, 1H,

J = 4.2, 12.6 Hz), 1.13 (s, 3H). C NMR (150 MHz, C

5 5 C

D N), d :75.4,

70.5, 70.2, 68.6, 68.1, 64.8, 40.1, 35.8, 33.5, 16.0. HRMS (ESI) for

+

10 18 5

C H O Na [M+Na] , calculated: 241.1052; found: 241.1055.

J = 5.7, 14.1 Hz), 1.65 (dd, 1H, J = 8.4, 13.8 Hz), 1.50 (s, 3H), 1.34

s, 3H), 1.02 (s, 3H). ¹³C NMR (50 MHz, CDCl

), d : 146.8, 135.4,

16.3, 111.7, 108.0, 79.0, 73.7, 72.7, 71.0, 40.9, 38.0, 29.0, 28.6,

(

3

C

Acknowledgements

1

2

+

6.3, 17.7. HRMS (ESI) for

75.1623; found: 275.1625.

C

H

15 24

O

3

Na [M+Na] , calculated:

Institutional support from IIT Kharagpur (SGIRG grant) is thank-

fully acknowledged. DST-India is thanked for the NMR machine

(

IRPHA scheme). Two of the authors R.K. and J.H. are thankful to

4

.10.53. (3aS,4aS,8aR,9aR)-2,2,8a-Trimethyl-4,4a,6,8a,9,9a-hex-

UGC, India for research fellowship.

ahydro-3aH-[1,3]dioxolo[4,5-g]chromene 60

The starting compound 59 (0.211 g, 0.84 mmol) was taken in

anhydrous degassed DCM (120 mL). Grubbs second generation

metathesis catalyst (G-II, 0.028 g, 0.032 mmol) was added and

the solution was stirred at reﬂux for 8 h. The reaction mixture

was then cooled to room temperature and the solution was evap-

orated under reduced pressure. The contents of the ﬂask were

directly loaded onto a silica gel column. The crude material was

then puriﬁed by silica gel column chromatography (EtOAc/hexane,

Supplementary data

Supplementary data associated with this article can be found, in

the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.05.

0

03.

References

1

:20) to afford product 60 (0.15 g) in 80% yield as a liquid. R

f

= 0.2

NMR

1. Mander, L.; Liu, H. In Comprehensive Natural Products II: Chemistry and Biology In

28

1

; Newnes, 2010; Vol. 1,. ISBN: 0080453821 .

(

EtOAc/hexane, 1:20).

200 MHz, CDCl ), d

.22–4.15 (m, 3H), 3.61 (dd, 1H, J = 4.6, 12.4 Hz), 2.19 (dd, 1H,

J = 3.6, 14.6 Hz), 1.92–1.71 (m, 3H), 1.46 (s, 3H), 1.31 (s, 3H), 0.92

[a]

D

= +38.2 (c 1.0, MeOH).

H

2

.

(a) Kirkpatrick, P.; Ellis, C. Nature 2004 , 432 , 823–865 ; (b) Reymond, J. L.;

Awale, M. ACS Chem. Neuorosci. 2012 , 3 , 649–657 ; (c) Ruddigkeit, L.; Van

Deursen, R.; Blum, L. C.; Reymond, J. L. J. Chem. Inf. Model. 2012 , 52 , 2864–2875 .

(a) Reymond, J. L. Acc. Chem. Res. 2015 , 48 , 722–730 ; (b) Reymond, J. L.; Van

Deursen, R.; Blum, L. C.; Ruddigkeit, L. MedChemComm 2010 , 1 , 30–38 .

(a) Harvey, A. L.; Edrada-Ebel, R.; Quinn, R. J. Nat. Rev. (Drug Discovery) 2015 , 14 ,

111–129 ; (b) Huigens, R. W.; Morrison, K. C.; Hicklin, R. W.; Flood, T. A., Jr;

Richter, M. F.; Hergenrother, P. J. Nat. Chem. 2015 , 5 , 195–202 ; (c) Morrison, K.

C.; Hergenrother, P. J. Nat. Prod. Rep. 2014 , 31 , 6–14; (d) Wilson, R. M.;

Danishefsky, S. J. J. Org. Chem. 2006 , 71 , 8329–8351 .

(

4

3

H

: 5.55–5.50 (m, 2H), 4.36–4.32 (m, 1H),

3

.

1

3

(

s, 3H). C NMR (50 MHz, CDCl

3 C

), d : 135.6, 124.1, 107.8, 74.7,

4

7

C

4.2, 72.4, 66.8, 39.1, 34.7, 29.0, 28.4, 26.2, 17.0. HRMS (ESI) for

+

13

H

20

O

3

Na [M+Na] , calculated: 247.1310; found: 247.1317.

4

.10.54. (3aS,4aS,7R,8S,8aR,9aR)-2,2,8a-Trimethyloctahydro-3aH-

5. (a) Schreiber, S. L. Science 2000 , 287 , 1964–1969 ; (b) Bon, R. S.; Waldmann, H.

Acc. Chem. Res. 2010 , 43 , 1103–1114; (c) Kumar, K.; Waldmann, H. Angew.

Chem., Int. Ed. 2009 , 48 , 3224–3242 .

[

1,3]dioxolo[4,5-g]chromene-7,8-diol 61

Compound 61 was prepared according to the general procedure

6.

(a) Welsch, M. E.; Snyder, S. A.; Stockwel, B. R. Curr. Opin. Chem. Biol. 2010 , 14 ,

347–361 ; (b) Kluge, A. F.; Petter, R. C. Curr. Opin. Chem. Biol. 2010 , 14 , 421–427 ;

4

for the OsO oxidation from compound 60 (0.4 g, 1.78 mmol).

Puriﬁcation by silica gel chromatography (EtOAc/hexane, 1:1)

afforded diol 61 (0.377 g) as the sole product in 82% yield.

(

c) Jenkins, I. D.; Lacrampe, F.; Ripper, J.; Alcaraz, L.; Le, P. V.; Nikolakopoulos,

G.; Leone, P. A.; White, R. H.; Quinn, R. J. J. Org. Chem. 2009 , 74 , 1304–1313 .

Galloway, W. R. J. D.; Bender, A.; Welch, M.; Spring, D. R. Chem. Commun. 2009 ,

2446–2462 .

7.

2

8

R

+

(

f

= 0.2 (EtOAc/hexane, 1:1). R

f

= 0.3 (EtOAc/hexane, 2:1). [

44.2 (c 0.8, MeOH). H NMR (600 MHz, CDCl ), d : 4.33–4.21

m, 1H), 4.20–4.19 (m, 1H), 4.10–4.08 (m, 1H), 3.82–3.70 (m, 1H),

D

a] =

1

8. (a) Serba, C.; Winssinger, N. Eur. J. Org. Chem. 2013 , 4195–4214 ; (b) Burke, M.

D.; Berger, E. M.; Schreiber, S. L. Science 2003 , 302 , 613–618 .

3

H

9.

(a) Mahapatra, T.; Nanda, S. Tetrahedron: Asymmetry 2009 , 20 , 610–615 ; (b)

Mahapatra, T.; Bhunya, R.; Nanda, S. Tetrahedron Lett. 2009 , 50 , 5392–5394 .

3

2

1

.69–3.67 (m, 1H), 3.36–3.34 (m, 1H), 3.31–3.30 (m, 1H),

.31–2.30 (m, 1H), 2.28 (d, 1H, J = 4.8 Hz), 2.19–2.09 (m, 1H),

.97–1.92 (m, 1H), 1.53 (s, 3H), 1.34 (s, 3H), 0.91 (s, 3H).

), d : 107.9, 76.8, 76.1, 73.8, 71.9, 71.7, 69.4,

9.6, 38.2, 28.5, 26.2, 10.9. HRMS (ESI) for C13

calculated: 281.1365; found: 281.1369.

10. (a) Mahapatra, T.; Nanda, S. Tetrahedron: Asymmetry 2010 , 21 , 2199–2205 ; (b)

Mahapatra, S.; Nanda, S. Tetrahedron: Asymmetry 2011 , 22 , 406–412 ; (c)

Mahapatra, T.; Jana, N.; Nanda, S. Adv. Synth. Catal. 2011 , 353 , 2152–2168 ; (d)

Bhuniya, R.; Nanda, S. Org. Biomol. Chem. 2012 , 10 , 536–547 .

1

3

C

NMR (50 MHz, CDCl

3

C

+

22

H O

5

Na [M+Na] ,

11. Rej, R.; Jana, N.; Kar, S.; Nanda, S. Tetrahedron: Asymmetry 2012 , 23 , 364–372.

12. Tsuna, K.; Noguchi, N.; Nakada, M. Chem. Eur. J. 2013 , 19 , 5476–5486 .

13. Lee, J. Y.; You, Y. S.; Kang, S. H. J. Am. Chem. Soc. 2011 , 133 , 1772–1774 .

14. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1979 , 44 , 4148–4150 .

4

.10.55. (3R,4S,4aR,6R,7S,8aS)-4a-Methyloctahydro-2H-chromene-

15. Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed. 1995 ,

4 , 2039–2041 .

6. Horita, K.; Yoshioka, T.; Tanaka, Y.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986 ,

2 , 3021 .

3

3,4,6,7-tetraol 62

1

To a stirred solution of alcohol 61 (0.093 g, 0.36 mmol) in anhy-

4

drous DCM (8 mL) was added p-toluenesulfonic acid monohydrate

0.136 g, 0.72 mmol) at room temperature and stirred for 6 h. After

completion of the reaction, 80 mg of solid NaHCO were added to

the reaction mixture and the solvent was evaporated in vacuo.

The residue was then puriﬁed by ﬂash column chromatography

17. (a) Kozawa, I.; Akashi, Y.; Takiguchi, K.; Sasaki, D.; Sawamoto, D.; Takao, K.;

Tadano, K. Synlett 2007 , 399–402 ; (b) Kato, K.; Tanaka, H.; Miyasaka, T.; Baba,

M.; Yamaguchi, K.; Akita, H. Chem. Pharm. Bull. 1999 , 47 , 1256–1264.

(

3

18. Jogi, A.; Maeorg, U. Molecules 2001 , 6 , 964–968 .

19. Tellitu, I.; Beitia, I.; Diaz, M.; Alonso, A.; Moreno, I.; Dominguez, E. Tetrahedron

2015 , 71 , 8251–8255.

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Enantiopure hydroxymethylated cycloalkenols as privileged small molecular multifunctional scaffolds for the asymmetric synthesis of carbocycles

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