Highly efficient total synthesis of Δ12-PGJ2, 15-deoxy-Δ12,14-PGJ2, and their analogues

Tetrahedron 62 (2006) 3329–3343

Highly efﬁcient total synthesis of D¹²-PGJ₂,

15-deoxy-D^12,14-PGJ₂, and their analogues

*

Hukum P. Acharya and Yuichi Kobayashi

Department of Biomolecular Engineering, Tokyo Institute of Technology B52, Nagatsuta-cho 4259, Midori-ku,

Yokohama 226-8501, Japan

Received 26 November 2005; accepted 17 January 2006

Available online 13 February 2006

Abstract—Palladium-catalyzed reaction of TBS ether of 4-cyclopentene-1,3-diol monoacetate (O95% ee) with an anion derived from

methyl malonate and a base such as t-BuOK and LDA proceeded highly efﬁciently and reproducibly. The product obtained in O90% isolated

yield was transformed in ﬁve steps into the key cyclopentenone possessing the a-chain at the g position. Aldol reaction of this enone with the

u-chain aldehyde afforded the aldol adduct, and exposure of the derived mesylate to Al₂O₃furnished the cross-conjugated dienone of the full

structure. Finally, functional group manipulation furnished D¹²-PGJ₂efﬁciently. Similarly, 15-deoxy-D^12,14-PGJ₂, 5,6-acetylene analogues,

and a 5,6-dihydro analogue were synthesized.

1. Introduction

HO

In the 1980s, Fitzpatrick and Wyland reported¹albumin-

CO₂H

catalyzed metabolism of PGD₂in vitro to afford D¹²-PGJ₂

and 15-deoxy-D^12,14-PGJ₂(Scheme 1, Fig. 1). Later,

O

OH

PGJ₂(2)

Hayashi et al. extracted D¹²-PGJ₂from normal human

urine to support the existence of albumin-catalyzed

metabolism in vivo.²In contrast with other PGs, which

elicit a biological response through binding to G-protein

coupled receptors, these metabolites interact with other

speciﬁc cellular targets such as signaling molecules and

transcriptional factors directly.^3,4For example, 15-deoxy-

D^12,14-PGJ₂represents the most potent natural ligands

reported to date for PPARg, a receptor that has been linked

to non-insulin dependent diabetes mellitus (NIDDM or type

II diabetes), obesity, hypertension, and atherosclerosis.⁵

Inhibition of the NF-kB-mediated transcription is another

property of 15-deoxy-D^12,14-PGJ₂, and is responsible for

anti-inﬂammatory activity. On the other hand, D¹²-PGJ₂

exhibits strong antitumor effects by incorporating into

tumor cells and transferring into nuclei, activating the

gadd45 promoter independently of p53⁶and inhibiting

topoisomerase.⁷

PGD₂(1)

O

15-Deoxy-∆^12,14-PGJ₂(4)

OH

¹²-PGJ₂(3)

∆

Scheme 1. Biosynthesis of D¹²-PGJ₂and 15-deoxy-D^12,14-PGJ₂.

Although the fundamental proﬁles of these D¹²-PGs 3 and 4

have been thus elucidated, more than 50 publications using

these PGs have emerged every year in the last several years

indicating importance of their property in life science. PGs 3

and 4 in those studies have been purchased from a company

or gifted by another company. According to a recent

review,⁸the former company produces PG 4⁹by base-

catalyzed decomposition of PGD₂(1), while the method for

synthesis of 3 is not disclosed. On the other hand, 3 and 4 are

synthesized from a PGF_2aderivative in the latter

company.¹⁰Consequently, we felt it important to establish

a chemical method for synthesizing not only these PGs but

also analogues thereof for further biological study (Fig. 1).

Keywords: Aldol reaction; Cyclopentenone; Palladium; PPARg; D¹²-PGJ₂;

15-Deoxy-D^12,14-PGJ₂.

*

Corresponding author. Tel./fax: C81 45 924 5789;

e-mail: ykobayas@bio.titech.ac.jp

doi:10.1016/j.tet.2006.01.051

3330

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

The acetylene analogues 5 and 6 would be precursors of

CO₂H

radio labeled 3 and 4. On the other hand, 5–7 would allow

access to the structure–activity relation. In addition, 7 is

formally the metabolite of PGD₁derived from bishomo-g-

linolenic acid (5-dihydro derivative of arachidonic acid)

though isolation of 7 is not yet reported.

12

O

OH

¹²-PGJ₂(3)

15-Deoxy-∆^12,14-PGJ₂(4)

∆

CO₂H

2. Results and discussion

OH

Acetylene analogue of

Acetylene analogue of 15-deoxy-

^12,14-PGJ₂(6)

¹²-PGJ₂(5)

∆

We envisioned that the cross-conjugated dienone structure

of 3–7 will be constructed by aldol condensation between

cyclopentenone possessing the a chain and an aldehyde of

the u chain. For example, aldol reaction between

cyclopentenone 10 and aldehyde 11 would furnish 12 with

the D¹²-PGJ₂structure (Scheme 2). Likewise, simply

changing the aldehyde partner would produce analogue 4.

It should be mentioned at this stage that g-substituted

cyclopentenones such as 10 were compounds for which an

efﬁcient method has not been established. In this investi-

gation, we contemplated a sequence, which consists of

palladium-catalyzed reaction¹⁶of cyclopentene mono-

acetate 8 with malonate anion and subsequent Wittig reaction

of the derived aldehyde 9. On the other hand, we envisaged

that Corey–Fuchs¹⁷reaction of aldehyde 9 followed by

alkylation of the derived acetylene would produce acetylene

13, which would be transformed to 5,6-dehydro derivatives 5

and 6 by the aldol strategy. Concerning a synthesis of 5,6-

dihydro analogue 7, we decided to apply a copper-catalyzed

S_N2 type reaction¹⁸of ent-8 and RMgBr to construct the

necessary enone intermediate (vide infra).

∆

CO₂H

O

5,6-Dihydro-15-deoxy-

^12,14-PGJ₂(7)

∆

Figure 1. D¹²-PGJ₂and related PGs we have synthesized.

Among these targets, 4 was synthesized by Sutton in 2003,

for the ﬁrst time.¹¹Meinwald rearrangement¹²of the

norbornadiene was utilized to construct the core cyclo-

pentenone structure, and was coupled with asymmetric

acetylation using enzyme in two stages to accomplish

resolutions at the stereocenters on the u chain and on the

cyclopentene ring. Later, 4 was again synthesized as a

racemate by Brummond through a silicon-tethered allenic

[2C2C1] cycloaddition.¹³At the same time we reported

another approach to optically active PGs (3 and 4) and the

acetylene analogue 5 as a communication.¹⁴The former two

syntheses by Sutton and Brummond, however, seem to

present little advantage over our method with respect to the

product selectivity, efﬁciency, and, in particular, diastereos-

electivity in the former rearrangement.¹⁵Furthermore, the

reaction conditions would be hardly applicable to synthesis

of 3, the parent compound of this class. These limited

syntheses prompted us to publish a full account of the

synthesis of 3–5 as well as other analogues 6 and 7.

When 0.5–2 g of racemic monoacetate 8a (RZH) was

subjected several times to the reaction with methyl malonate

(14) (2–2.5 equiv), NaH (2 equiv), and Pd(PPh₃)₄(5 mol%) in

THF at room temperatureK50 8C according to the reported

protocol¹⁶(Scheme 3), yields of product 15a observed were

among 50–70% (the best yield is shown in entry 1 of Table 1),

which were lower than that (86%) reported for 100 mg-

scale.¹⁹Since this step was strategically very important, this

CO₂Me

CH

OPMB

OAc

Wittig

CO₂Me

CHO

1

+

C₅H₁₁

Pd cat.

OHC

O

RO

(1R )-isomer

9

8

OTBS

ω-chain (11)

10

for 8 and 9:

a, R = H; b, R = TBS

1) aldol

2) –H₂O

OPMB

TBSO

13

12

O

OTBS

12

∆¹²-PGJ₂(3)

Acetylene analogues 5 and 6

Scheme 2. Our approach to D¹²-PGJ₂and the acetylene analogues through Aldol reaction.

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

3331

Next, these bases were applied to TBS ether of 8a, that is, 8b

(RZTBS). Reaction with LDA proceeded at room tempera-

ture, while t-BuOK required a higher temperature of 50 8C

(entries 7 and 8). Except for the difference in the reaction

temperatures, both entries produced 15b in O90% yields

(entries 7 and 8). Of the two bases, we have routinely used the

latter base for the present investigation because of easy

handling. In several 2–3 g-scale reactions, yields constantly

exceeded 90% (see Section 4).

CH₂(CO₂Me) (14)

OAc

CH(CO₂Me)₂

base

Pd cat.

RO

see Table 1

8a, R = H

8b, R = TBS

15a, R = H

15b, R = TBS

Scheme 3. Palladium-catalyzed reaction of 8a,b with malonate anion.

Table 1. Palladium-catalyzed reaction of 8a,b with 14 (Scheme 3)^a

The above reaction was repeated with 8b derived from 8a²⁰of

O95% ee to obtain optically active 15b. Transformation of

15b to the key enone 10, aldol reaction thereof, and further

transformation to D¹²-PGJ₂(3) are delineated in Scheme 4.

Decarboxylation of 15b with KI in wet DMI proceeded well at

130 8C to afford ester 16 in 89% isolated yield after

chromatography. Ester 16 was also synthesized from alcohol

15a by decarboxylation using KI in wet DMF followed by

silylation with TBSCl. Of the two routes to 16, the former

sequence had the advantage of easily purifying the crude TBS

ether 16 containing DMI, because of the sufﬁciently different

R_fvalues thereof. Aldehyde 9b synthesized in 89% yield

by DIBAL reduction of 16 was subjected to Wittig reaction

with the ylide derived from [Ph₃P(CH₂)₅OPMB]^CBr^K(17)

and NaN(TMS)₂ﬁrst at K70 8C then at room temperature

according to the literature procedure²¹to afford cis oleﬁn 18

exclusively in 84% yield.²²The TBS group was removed and

the resulting alcohol 19 was oxidized to the key intermediate

10 in good yield.

Entry Substrate

Base

Time Temperature (8C)

(h)

Yield

(%)

1

2

3

4

5

6

7

8

8a

8b

NaH

MeONa

LDA

t-BuOK

NaH

MeONa

LDA

t-BuOK

2

rt

69^b,c

71^b

83^b

90

66

87

2

rt

1.5

2

4

3

rt

50^d

rt

91

93

3

50^d

^aReactions were carried out with malonate anions (2.2 equiv) in the

presence of Pd(PPh₃)₄(5 mol%) in THF.

^bAn unidentiﬁed by-product was also produced.

^cThe maximum yield among several runs is given. See the text for more

information.

^dNo reaction at room temperature was monitored by TLC.

reactionwasre-investigatedundervariousconditions. Weﬁrst

focused on the loading of Pd(PPh₃)₄(5–20%) and the PPh₃

ligand (2–6 equiv of Pd), use of polar solvents, etc. These

changes, however, resulted in no improvement. Next,

malonate anion generated from 14 (2.2 equiv) and a base

(2.0 equiv) was subjected to the reaction with 5 mol%

Pd(PPh₃)₄. Among the bases listed in Table 1, LDA and

t-BuOK provided substantially higher yields of 15a than NaH

(entries 3 and 4).

Aldehyde 11, the aldol partner of enone 10, was synthesized

from alcohol 25 through epoxy alcohol 26 in ﬁve steps in

48% overall yield (Scheme 5). Thus, epoxy alcohol 26

([a]²_D⁴K43 (c 0.45, CHCl₃); lit.²³[a]²_D⁵K42.7 (c 4.7,

CHCl₃) for O98% ee), synthesized by the Sharpless

asymmetric epoxidation^23,24of 25, was subjected to

OPMB

[Ph₃P(CH₂)₅OPMB]⁺Br^–(17)

a,b

c

R

8a

15b

e

87%

89%

> 95%

TBSO

84%

RO

f

16, R = CO₂Me

9b, R = CHO

18, R = TBS

19, R = H

d

89%

95%

C₅H₁₁

OHC

OPMB

OTBS

11

g

j

93%

h

H

i

O

OR OTBS

20, R = H

10

21, R = Ms

OR

l

n

R

∆¹²-PGJ₂(3)

94%

92%

O

OTBS

12, R = PMB, 59% from 10

22, R = H

23, R = CHO

24, R = CO₂H

k

m

89%

91%

Scheme 4. Synthesis of D¹²-PGJ₂: (a) TBSCl, imidazole; (b) CH₂(CO₂Me)₂, t-BuOK, Pd(PPh₃)₄(cat.); (c) KI, DMI–H₂O (10:1), 130 8C; (d) DIBAL, CH₂Cl₂,

K78 8C; (e) 17, NaN(TMS)₂, K70 8C to rt; (f) TBAF; (g) PCC; (h) LDA (2.0 equiv), K78 8C, THF then 11 (1.2 equiv), K78 8C; (i) MsCl, Et₃N, 0 8C;

(j) Al₂O₃; (k) DDQ, CH₂Cl₂–H₂O (19:1); (l) PCC; (m) NaClO₂, MeCH]C(Me)₂, t-BuOH, phosphate buffer (pH 3.6); (n) HF–MeCN (1:19).

3332

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

reduction with Red-Al to produce 1,3-diol 27 in good yield

with 22:1 regioselection over the 1,2-isomer by H NMR

mesylate was exposed to Al₂O₃at room temperature, which

assisted stereoselective and exclusive formation of dienone

12 in 59% yield from enone 10. The corresponding (Z)-

oleﬁn isomer of 12 (structure not shown) was not detected at

the expected 0.5 ppm up ﬁeld region in the ¹H NMR

spectrum of the crude dienone 12.²⁹The selective formation

of the (E)-oleﬁn by using Al₂O₃is consistent with the

original dehydration of an aldol,³⁰though the reason for the

selectivity is still a matter of conjecture.³¹

1

spectroscopy. Diol 27 was converted to the bis-silyl ether,

and exposed to PPTS (1.2 equiv) in EtOH–CH₂Cl₂(1:1) to

afford, after easy chromatography, mono alcohol 28 and

unwanted diol 27 in 71 and 26% yield, respectively. Diol 27

was recycled. Finally, PCC oxidation of 28 afforded

aldehyde 11 ([a]_D²⁷C6.7 (c 0.21, CHCl₃); lit.²⁵[a]²_D⁴K5.0

(c 1.0, CHCl₃) for the enantiomer of O98% ee).²⁶

The remaining transformation of 12 to D¹²-PGJ₂(3) was

accomplished efﬁciently as presented in Scheme 4. The

PMB group of 12 was removed with DDQ in wet

CH₂Cl₂without affecting the dienone moiety. The

resulting alcohol 22 was converted to acid 24 by two-

step oxidation through aldehyde 23 in 84% yield. Direct

oxidation of 22 with PDC in DMF produced a mixture of

products. Finally, deprotection of the TBS group with HF

O

a

b

HO

C₅H₁₁

HO

C₅H₁₁

82%

88%

25

26

e

R¹O

c,d

C₅H₁₁

OR²

C₅H₁₁

OTBS

11

OHC

94%

1

in MeCN afforded D¹²-PGJ₂(3) in 92% yield.³²The H

27, R¹= R²= H

NMR spectrum of synthetic 3 was identical with that

reported (d 5–8 ppm)¹and that provided by Ono

Pharmaceutical Co., Ltd.

28, R¹= H, R²= TBS

71%

Scheme 5. Preparation of aldehyde 11: (a) t-BuOOH, L-(C)-DIPT

˚

(0.3 equiv), Ti(i-PrO)₄(0.25 equiv), MS 4 A; (b) Red-Al, THF;

(c) TBSCl, imidazole; (d) PPTS, EtOH–CH₂Cl₂(1:1); (e) PCC.

As illustrated in Scheme 6, the above enone 10 was next

converted to 15-deoxy-D^12,14-PGJ₂(4). Thus, aldol reaction

between enone 10 and trans-2-octenal (29) afforded aldol 30

as a 2:1 mixture of the anti and syn isomers.²⁸Without

separation, the mixture was treated with MsCl at 0 8C. In

contrast to the above case, elimination of the mesylate took

place simultaneously to produce dienone 31 and its (Z)-

isomer 34 in a 4:1 ratio.³³Fortunately, this low product

selectivity was improved to 14:1 by simply conducting the

reaction at K15 8C to furnish dienone 31 in 69% from

enone 10 after chromatography. Following the procedure

described above in Scheme 4, the CH₂OPMB group of 31

was converted to the carboxylic acid moiety of 15-deoxy-

D^12,14-PGJ₂(4) in 79% yield from the PMB ether 31.

The structure of 4 thus synthesized was conﬁrmed by

According to the protocol²⁷for aldol reaction of cyclo-

pentenone with aldehyde, the lithium enolate of enone 10

was prepared by using LDA at K78 8C for 20 min, and

subjected to aldol reaction with aldehyde 11. After 30 min at

K78 8C, the reaction was quenched to afford aldol 20 as a

3:1 mixture of the anti and syn isomers by ¹H NMR

spectroscopy.²⁸Without separation, the aldol mixture was

converted to mesylates with MsCl and Et₃N. During the

mesylation, elimination of the derived mesylate to dienone

12 did not take place (cf. Scheme 6 for the aldol 30 derived

from enal 29). After ﬁltration through a silica gel pad, the

comparison of the ¹H NMR (500 MHz, d 5–8 ppm)¹and ¹³

C

NMR (75 MHz, all peaks)¹¹spectra with those reported.

These spectra were also consistent with those reported by

Brummond.¹³

C₅H₁₁

OPMB

(29)

OHC

10

a

H

O

OH

OPMB

30

anti:syn = 2:1

Z

O

OR

d

b

92%

O

34: (Z )-Isomer of 31

31, R = PMB, 69% from 10

32, R = H, 92%

c

Synthesis of acetylene analogue 5 was accomplished

through a sequence delineated in Scheme 7. Initially,

aldehyde 9b was converted to acetylene 36³⁴by the

Corey–Fuchs method.¹⁷Alkylation of 36 with Br(CH₂)₄-

OPMB proceeded in THF–DMPU (4:1), and the silyl group

of 13 thus produced was removed by using TBAF to afford

alcohol 37 in 81% yield from acetylene 36. Oxidation of 37

to the key enone 38 followed by aldol reaction with

aldehyde 11 furnished 39, which upon mesylation and

elimination with Al₂O₃gave dienone 40 exclusively.

Finally, the C(1) carbon was oxidized to the carboxylic

R

O

33, R = CHO

4, R = CO₂H (15-deoxy-∆^12,14-PGJ₂)

e

93%

Scheme 6. Synthesis of 15-deoxy-D^12,14-PGJ₂: (a) LDA (2.0 equiv),

K78 8C, THF then 29 (1.2 equiv), K78 8C; (b) MsCl, Et₃N, K15 8C;

(c) DDQ, CH₂Cl₂–H₂O (19:1); (d) PCC; (e) NaClO₂, MeCH]C(Me)₂,

t-BuOH, phosphate buffer (pH 3.6).

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

3333

OPMB

a

c

e

CHO

R

76%

94%

OTBS

9b

OTBS

35, R = –CH=CBr₂

36, R =

RO

O

38

13, R = TBS

37, R = H

d

b

–C CH

81% from 36

91%

OPMB

OR

g,h

j,k

91%

f

CO₂H

H

O

l

O

i

OR

OH OTBS

OTBS

40, R = PMB, 43% from 38

41, R = H

42, R = TBS

5, R = H

39

anti:syn = 3:1

(5,6-Dehydro-∆¹²-PGJ₂)

91%

95%

Scheme 7. Synthesis of acetylene analogue of D¹²-PGJ₂: (a) PPh₃, CBr₄, 0 8C; (b) n-BuLi, K78 8C; (c) n-BuLi, PMBO(CH₂)₄Br, THF–DMPU (4:1), K78 8C

to rt; (d) TBAF; (e) PCC; (f) LDA then 11, K78 8C; (g) MsCl, Et₃N, 0 8C; (h) Al₂O₃; (i) DDQ; (j) PCC; (k) NaClO₂, MeCH]C(Me)₂, t-BuOH, phosphate

buffer (pH 3.6); (l) HF–MeCN (1:19).

acid moiety, and the protective group of the C(15)–OH was

removed to furnish 5,6-dehydro-D¹²-PGJ₂(5) in good yield.

OAc

(CH₂)₇OPMB

PMBO(CH₂)₇MgBr (45)

a

Synthesis of another acetylene analogue 6 is summarized in

Scheme 8. Aldol 43 was derived from enone 38 and aldehyde

29 with similar efﬁciency. Subsequently, mesylation with

MsCl and Et₃N at K15 8C produced dienone 44 in good yield

with high product selectivity (44:(Z)-isomerZ12:1).

HO

46

81%

ent-8a

> 95% ee

(CH₂)₇OPMB

C₅H₁₁

b

(29)

OHC

91%

c

C₅H₁₁

O

OPMB

47

(29)

OHC

38

(CH₂)₇OPMB

C₅H₁₁

R

a

H

O

d

OH

43

anti:syn = 2:1

H

O

OH

b

R

48

49, R = CH₂OPMB, 51%

from 47

50, R = CH₂OH, 92%

7, R = CO₂H, 84%

e

anti:syn = 3:1

f,g

O

44, R = CH₂OPMB, 71% from 38

6, R = CO₂H

(15-Deoxy-∆^12,14-PGJ₂)

(5,6-Dihydro-15-deoxy-

∆

c,d,e

77%

^12,14-PGJ₂)

Scheme 9. Synthesis of 5,6-dihydro-15-deoxy-D^12,14-PGJ₂: (a) 45

(3 equiv), CuCN (0.3 equiv), LiCl (4.0 equiv), THF, K10 8C; (b) PCC;

(c) LDA, K78 8C, THF then 29, K78 8C; (d) MsCl, Et₃N, K20 8C;

(e) DDQ, CH₂Cl₂–H₂O (19:1); (f) SO₃$pyridine, DMSO, Et₃N;

(g) NaClO₂, MeCH]C(Me)₂, t-BuOH, phosphate buffer (pH 3.6).

Scheme 8. Synthesis of 5,6-dehydro-15-deoxy-D^12,14-PGJ₂: (a) LDA,

K78 8C, THF then 29, K78 8C; (b) MsCl, Et₃N, K15 8C; (c) DDQ,

CH₂Cl₂–H₂O (19:1); (d) PCC; (e) NaClO₂, MeCH]C(Me)₂, t-BuOH,

phosphate buffer (pH 3.6).

(CH₂)₇OPMB

Recently, the S_N2 type reaction of 4-cyclopentene-1,3-diol

monoacetate 8a with RMgBr (RZaryl, alkenyl) was

attained with the CuCN catalyst and the LiCl additive.¹⁸

We envisioned that this reaction with an alkyl Grignard

reagent of the a-chain would afford 46 and that

transformation of 46 along the present strategy would

produce 5,6-dihydro-15-deoxy-D^12,14-PGJ₂(7) (Scheme 9).

To this end, the required ent-8a of O95% ee was prepared

by the literature method³⁵and subjected to the CuCN-

catalyzed reaction with PMBO(CH₂)₇MgBr (3 equiv) in

the presence of LiCl (4 equiv) to afford S_N2 product 46 and

anti S_N2⁰product 51 in a 92:8 ratio. The isomers were

easily separated by chromatography and alcohol 46 thus

isolated in 81% yield was oxidized to the key enone 47

with PCC.

PMBO(CH₂)₇

Z

O

HO

51

C₅H₁₁

52

Aldol reaction between the key enone 47 and trans-2-

octenal (29) furnished aldol 48 as a mixture of anti and syn

isomers in a 3:1 ratio.²⁸Upon treatment with MsCl and Et₃N

at K20 8C, aldol 48 underwent mesylation/elimination

smoothly as in the above cases (see Schemes 6 and 8) to

produce dienone 49 and the (Z)-isomer 52 in 51 and 5%

yields, respectively, from enone 47. Finally, dienone 49 was

3334

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

converted into 5,6-dihydro-15-deoxy-D^12,14-PGJ₂(7) in

good yield.

under reduced pressure to afford an yellow oily residue,

which was puriﬁed by chromatography (hexane/EtOAc) to

furnish 15b (2.98 g, 93% yield): bp 130 8C (1 mmHg); IR

1

(neat) 1738, 1252, 837, 777 cm^K1; H NMR (300 MHz,

3. Conclusion

CDCl₃) d 0.06 (s, 6H), 0.88 (s, 9H), 1.40 (ddd, JZ14, 7,

5 Hz, 1H), 2.44 (dt, JZ14, 7 Hz, 1H), 3.15–3.26 (m, 1H),

3.37 (d, JZ10 Hz, 1H), 3.74 (s, 6H), 4.77–4.84 (m, 1H),

5.80 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) d K4.61, K4.58,

18.2, 25.9, 39.0, 43.5, 52.52, 52.54, 57.3, 76.8, 133.6, 136.3,

168.98, 169.04. Anal. Calcd for C₁₆H₂₈O₅Si: C, 58.50; H,

8.59. Found: C, 58.49; H, 8.49.

In summary, total synthesis of D¹²-PGJ₂(3) was accom-

plished through aldol reaction between cyclopentenone 10

and aldehyde 11 (Schemes 2 and 3). Cyclopentenone 10 was

prepared from monoacetate 8b, and the ﬁrst step, that is, the

palladium-catalyzed reaction of 8a and malonate anion, was

improved with t-BuOK, which was found to generate the

highly reactive malonate anion. The synthesis of 15-deoxy-

4.2.3. Methyl (1S,4S)-4-[(tert-butyldimethylsilyl)oxy]-2-

cyclopenten-1-yl acetate (16). A slurry of 15b (2.80 g,

8.52 mmol), KI (11.32 g, 68.2 mmol), DMI (30 mL), and

water (3 mL) was vigorously stirred at 130 8C for 10 h and

diluted with water and hexane. The organic layer was

separated and the aqueous layer was extracted four times

with hexane. The combined organic layers were dried over

MgSO₄and concentrated to furnish an oily residue, which

was puriﬁed by chromatography (hexane/EtOAc) to afford

16 (2.05 g, 89% yield): [a]³_D¹K19 (c 0.56, CHCl₃); bp

115 8C (1 mmHg); IR (neat) 1742, 1252, 1085, 836,

D

^12,14-PGJ₂(4) and D¹²-PGJ₂analogues 5–7 was carried out

with similar efﬁciency, thus demonstrating ﬂexibility and

reliability of the aldol strategy using g-substituted cyclo-

pentenones for construction of the cross-conjugated cyclo-

pentadienone structures. We believe that the biological

investigation of D¹²-PGJ₂and 15-deoxy-D^12,14-PGJ₂would

be spurred by these analogues.

4. Experimental

1

776 cm^K1; H NMR (300 MHz, CDCl₃) d 0.07 (s, 6H),

4.1. General methods

0.89 (s, 9H), 1.30 (ddd, JZ13, 6, 5 Hz, 1H), 2.38 (dd, JZ

16, 8 Hz, 1H), 2.46 (dt, JZ13, 7.5 Hz, 1H), 2.48 (dd, JZ16,

7 Hz, 1H), 2.86–3.00 (m, 1H), 3.68 (s, 3H), 4.78–4.86 (m,

1H), 5.74 (dt, JZ6, 2 Hz, 1H), 5.80 (dt, JZ6, 2 Hz, 1H);

¹³C NMR (75 MHz, CDCl₃) d K4.6, 18.2, 26.0, 40.4, 40.6,

40.8, 51.5, 77.3, 135.0, 135.7, 173.1. Anal. Calcd for

C₁₄H₂₆O₃Si: C, 62.18; H, 9.69. Found: C, 61.86; H, 9.70.

Infrared (IR) spectra are reported in wave numbers (cm^K1).

The ¹H NMR (300 and 500 MHz) and ¹³C NMR (75 MHz)

spectra were measured in CDCl₃using SiMe₄(dZ0 ppm)

and the center line of CDCl₃triplet (dZ77.1 ppm) as

internal standards, respectively. The following solvents

were distilled before use: THF (from Na/benzophenone),

Et₂O (from Na/benzophenone), and CH₂Cl₂(from CaH₂).

Purity of the title compounds were conﬁrmed by elemental

analysis in most of cases or by the spectral method (¹H and

¹³C NMR) in the case the satisfactory results were not

recorded.

4.2.4. (1S,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-cyclo-

penten-1-yl ethanal (9b). To a stirred solution of 16

(1.80 g, 6.66 mmol) in CH₂Cl₂(26 mL) at K78 8C was

added (i-Bu)₂AlH (7.98 mL, 0.95 M in hexane, 7.59 mmol)

dropwise. After 45 min the solution was poured into a ﬂask

containing water (2.5 mL, 140 mmol) and ether with

vigorous stirring. The mixture was stirred with NaF (2.8 g,

67 mmol) at room temperature for 30 min, and ﬁltered

through a pad of Celite. The ﬁltrate was concentrated and

puriﬁed by chromatography (hexane/EtOAc) to afford

aldehyde 9b (1.42 g, 89% yield) and the corresponding

alcohol (138 mg, 9% yield): [a]³_D⁰K23 (c 0.38, CHCl₃); IR

4.2. Synthesis of the key enone 10

4.2.1. (1R,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-cyclo-

penten-1-yl acetate (8b). According to the literature

method,²⁰a solution of 8a (1.52 g, 10.7 mmol, 96% ee by

¹H NMR spectroscopy of the derived MTPA ester), TBSCl

(2.42 g, 16.1 mmol), and imidazole (1.46 g, 21.4 mmol) in

DMF (22 mL) was stirred at room temperature for 2 h to

afford silyl acetate 8b (2.58 g, 94% yield) after chromato-

graphy (hexane/EtOAc). The ¹H and ¹³C NMR spectra were

identical with those reported.³⁶

1

(neat) 1726, 1251, 836, 775 cm^K1; H NMR (300 MHz,

CDCl₃) d 0.05 (s, 6H), 0.87 (s, 9H), 1.29 (ddd, JZ13, 6,

5 Hz, 1H), 2.41–2.68 (m, 3H), 2.92–3.04 (m, 1H), 4.78–4.85

(m, 1H), 5.71–5.80 (m, 2H), 9.79 (s, 1H); ¹³C NMR

(75 MHz, CDCl₃) d K4.44, K4.42, 18.3, 26.1, 38.1, 40.9,

50.6, 77.2, 135.0, 135.4, 201.6. Anal. Calcd for C₁₃H₂₄O₂Si:

C, 64.95; H, 10.06. Found: C, 64.96; H, 9.80.

4.2.2. Dimethyl (1R,4S)-4-[(tert-Butyldimethylsilyl)oxy]-

2-cyclopenten-1-yl malonate (15b). To an ice-cold slurry

of t-BuOK (2.19 g, 19.5 mmol) in THF (18 mL) was added

methyl malonate (14) (2.46 mL, 21.4 mmol) in a dropwise

manner. After being stirred vigorously at room temperature

for 30 min, Pd(PPh₃)₄(564 mg, 0.49 mmol) and a solution

of 8b (2.50 g, 9.76 mmol) in THF (2 mL) were added into

the mixture. The resulting mixture was stirred vigorously at

50 8C for 3 h. The reaction was quenched by adding

saturated NH₄Cl and hexane with vigorous stirring. The

organic layer was separated and the aqueous layer was

extracted by using hexane three times. The combined

organic layers were dried over MgSO₄and concentrated

4.2.5. (1S,4R,2⁰Z)-1-[(tert-Butyldimethylsilyl)oxy]-4-[7⁰-

(4-methoxybenzyloxy)-2⁰-heptenyl]-2-cyclopentene (18).

To an ice-cold slurry of [PPh₃P(CH₂)₅OPMB]^CBr^K(17)

(2.05 g, 3.73 mmol) in THF (25 mL) was added

NaN(TMS)₂(5.0 mL, 1.0 M in THF, 5.0 mmol) dropwise.

After being stirred for 30 min at room temperature, the

mixture was cooled to K70 8C and aldehyde 9b (0.60 g,

2.50 mmol) was added to it. The temperature was kept at

K70 8C for 1 h, and then allowed to increase gradually to

room temperature over 2 h. The mixture was stirred

overnight at ambient temperature and diluted with saturated

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

3335

NH₄Cl and hexane. The organic layer was separated and the

4.3. Synthesis of aldehyde 11

aqueous layer was extracted with hexane twice. The

combined organic layers were dried over MgSO₄and

concentrated under reduced pressure to obtain an yellow oil,

which was puriﬁed by chromatography (hexane/EtOAc) to

afford 18 (0.90 g, 84% yield): IR (neat) 1612, 1513,

4.3.1. (2S,3S)-2,3-Epoxy-1-octanol (26). (E)-Octen-1-ol

(25) (1.20 g, 9.36 mmol) was subjected to Sharpless

epoxidation by using Ti(i-PrO)₄(0.69 mL, 2.33 mmol),

L-(C)-DIPT (0.59 mL, 2.78 mmol), t-BuOOH (2.3 mL,

1

1249 cm^K1; H NMR (300 MHz, CDCl₃) d 0.07 (s, 6H),

˚

5.71 M in CH₂Cl₂, 13.1 mmol) over activated 4 A molecular

sieves (600 mg) at K20 8C for 9 h. After the reaction, H₂O

(1.7 mL) and NaF (4.0 g, 95 mmol) were added. The

resulting mixture was stirred vigorously for 30 min at

room temperature and ﬁltered through a pad of Celite. The

ﬁltrate was concentrated to obtain an yellow residue, which

was diluted with CH₂Cl₂(10 mL). Brine and 30% NaOH

(4 mL) were added to the solution, and the mixture was

stirred at room temperature for 20 min. The phases were

separated and the aqueous layer was extracted with CH₂Cl₂

two times. The combined organic layers were dried over

MgSO₄and concentrated to afford an oil, which was

puriﬁed by chromatography (hexane/EtOAc) to furnish

epoxy alcohol 26 (1.11 g, 82% yield): [a]²_D⁴K43 (c 0.45,

CHCl₃); lit.²⁴[a]_D²⁵K42.7 (c 4.7, CHCl₃); ¹H NMR

(300 MHz, CDCl₃) d 0.90 (t, JZ7 Hz, 3H), 1.24–1.66 (m,

8H), 1.73 (br t, JZ6 Hz, 1H), 2.90–3.00 (m, 2H), 3.58–3.70

(m, 1H), 3.87–3.97 (m, 1H). Anal. Calcd for C₈H₁₆O₂: C,

66.63; H, 11.18. Found: C, 66.85; H, 11.31.

0.89 (s, 9H), 1.22–1.32 (m, 1H), 1.35–1.48 (m, 2H), 1.54–

1.66 (m, 2H), 1.98–2.25 (m, 4H), 2.36 (dt, JZ13, 7 Hz, 1H),

2.46–2.58 (m, 1H), 3.43 (t, JZ7 Hz, 2H), 3.78 (s, 3H), 4.42

(s, 2H), 4.78–4.86 (m, 1H), 5.33–5.46 (m, 2H), 5.70 (dt, JZ

6, 2 Hz, 1H), 5.78 (dt, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz,

2H), 7.26 (d, JZ9 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) d

K4.34, K4.31, 18.4, 26.2, 26.5, 27.3, 29.6, 34.0, 40.8, 44.5,

55.4, 70.1, 72.6, 77.7, 113.8, 128.1, 129.2, 130.5, 130.8,

134.1, 136.7, 159.0. Anal. Calcd for C₂₆H₄₂O₃Si: C, 72.51;

H, 9.83. Found: C, 72.84; H, 9.86.

4.2.6. (1S,4R,2⁰Z)-4-[7⁰-(4-Methoxybenzyloxy)-2⁰-hep-

tenyl]-2-cyclopenten-1-ol (19). To an ice-cold solution of

silyl ether 18 (1.21 g, 2.81 mmol) in THF (28 mL) was

added TBAF (3.36 mL, 1.0 M in THF, 3.36 mmol). The

solution was stirred at room temperature for 5 h and diluted

with saturated NH₄Cl and EtOAc. The organic layer was

separated and the aqueous layer was extracted with EtOAc

twice. The combined organic layers were dried over MgSO₄

and concentrated under reduced pressure to obtain an oily

residue, which was puriﬁed by chromatography (hexane/

EtOAc) to afford 19 (835 mg, 95% yield): [a]²_D⁶C51

4.3.2. (S)-1,3-Octanediol (27). To an ice-cold solution of

epoxy alcohol 26 (150 mg, 1.04 mmol) in THF (4 mL) was

added Red-Al (0.65 mL, 65% in toluene, 2.09 mmol) in a

dropwise manner. After being stirred at 0 8C for 1 h and then

at room temperature for 10 h, the solution was poured into a

ﬂask containing water (0.4 mL, 22 mmol) and ether (10 mL)

at 0 8C with vigorous stirring. The mixture was stirred

vigorously with NaF (350 mg, 8.3 mmol) for 30 min at

ambient temperature, and ﬁltered through a pad of Celite.

The ﬁltrate was concentrated and the residue was puriﬁed

by chromatography (hexane/EtOAc) to afford 1,3-diol 27

(134 mg, 88% yield): IR (neat) 3350, 1055 cm^K1; ¹H NMR

(300 MHz, CDCl₃) d 0.88 (t, JZ7 Hz, 3H), 1.22–1.54

(m, 8H), 1.58–1.78 (m, 2H), 2.61 (br s, 1H), 2.70 (br s, 1H),

3.76–3.94 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) d 14.1,

22.7, 25.3, 31.9, 37.8, 38.3, 61.9, 72.4. Anal. Calcd for

C₈H₁₈O₂: C, 65.71; H, 12.41. Found: C, 65.95; H, 12.39.

(c 0.51, CHCl₃); IR (neat) 3409, 1613, 1513, 1247 cm^K1

;

¹H NMR (300 MHz, CDCl₃) d 1.27 (dt, JZ14, 5 Hz, 1H),

1.36–1.48 (m, 2H), 1.55–1.68 (m, 2H), 1.93 (br s, 1H), 1.98–

2.25 (m, 4H), 2.43 (dt, JZ14, 8 Hz, 1H), 2.56–2.68 (m, 1H),

3.43 (t, JZ6 Hz, 2H), 3.79 (s, 3H), 4.42 (s, 2H), 4.71–4.82

(m, 1H), 5.30–5.52 (m, 2H), 5.74–5.81 (m, 1H), 5.82–5.88

(m, 1H), 6.87 (d, JZ9 Hz, 2H), 7.26 (d, JZ9 Hz, 2H); ¹³

C

NMR (75 MHz, CDCl₃) d 26.3, 27.2, 29.4, 33.7, 39.8, 44.5,

55.3, 70.0, 72.5, 77.2, 113.7, 127.6, 129.2, 130.6, 131.1,

133.4, 138.1, 159.0. Anal. Calcd for C₂₀H₂₈O₃: C, 75.91; H,

8.92. Found: C, 75.85; H, 9.12.

4.2.7. (4R,2⁰Z)-4-[7⁰-(4-Methoxybenzyloxy)-2⁰-heptenyl]-

2-cyclopenten-1-one (10). A mixture of alcohol 19

(750 mg, 2.37 mmol) and PCC (1.02 g, 4.73 mmol) in

CH₂Cl₂(23 mL) was stirred vigorously at room temperature

for 3 h and diluted with ether. The resulting mixture was

ﬁltered through a short pad of Celite. The ﬁltrate was

concentrated to furnish an yellow residue, which was

puriﬁed by chromatography (hexane/EtOAc) to afford

enone 10 (693 mg, 93% yield): [a]²_D⁹C106 (c 0.39,

4.3.3. (S)-3-[(tert-Butyldimethylsilyl)oxy]-octan-1-ol

(28). A solution of diol 27 (1.70 g, 11.6 mmol), TBSCl

(5.25 g, 34.8 mmol), and imidazole (3.16 g, 46.4 mmol) in

DMF (22 mL) was stirred at room temperature for 3 h, and

diluted with saturated NaHCO₃and hexane with vigorous

stirring. The organic layer was separated and the aqueous

layer was extracted with hexane several times. The

combined organic layers were dried over MgSO₄and

concentrated under reduced pressure to obtained an oily

residue, which was puriﬁed by chromatography (hexane/

EtOAc) to obtain the corresponding disilyl ether (3.64 g,

CHCl₃); IR (neat) 1711, 1612, 1586, 1512, 1247 cm^K1

;

¹H NMR (300 MHz, CDCl₃) d 1.36–1.49 (m, 2H), 1.54–

1.67 (m, 2H), 1.95–2.08 (m, 3H), 2.12–2.34 (m, 2H), 2.50

(dd, JZ19, 6 Hz, 1H), 2.93–3.03 (m, 1H), 3.43 (t, JZ6 Hz,

2H), 3.79 (s, 3H), 4.42 (s, 3H), 5.28–5.40 (m, 1H), 5.43–

5.56 (m, 1H), 6.15 (dd, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz,

1

94% yield): H NMR (300 MHz, CDCl₃) d 0.04 (s, 12H),

0.88 (s, 9H), 0.89 (s, 9H), 0.86–0.90 (m, 3H), 1.20–1.48

(m, 9H), 1.64 (q, JZ6 Hz, 1H), 3.62–3.73 (m, 2H), 3.79

(quintet, JZ6 Hz, 1H).

2H), 7.26 (d, JZ9 Hz, 2H), 7.61 (dd, JZ6, 2 Hz, 1H); ¹³

C

NMR (75 MHz, CDCl₃) d 26.3, 27.2, 29.5, 32.0, 40.6, 41.5,

55.3, 69.9, 72.6, 113.7, 125.7, 129.2, 130.6, 132.4, 134.0,

159.0, 167.9, 209.6. Anal. Calcd for C₁₃H₂₆O₃: C, 76.40; H,

8.33. Found: C, 76.12; H, 8.30.

A solution of the above disilyl ether (380 mg, 1.14 mmol)

and PPTS (342 mg, 1.36 mmol) in EtOH (6 mL) and

CH₂Cl₂(6 mL) was stirred for 14 h at room temperature,

3336

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

and diluted with saturated NH₄Cl and EtOAc. The phases

were separated and the aqueous layer was extracted with

EtOAc twice. The combined organic portions were dried

over MgSO₄and concentrated under reduced pressure to

obtained an oily residue, which was puriﬁed by chromato-

graphy (hexane/EtOAc) to afford alcohol 28 (226 mg, 76%

yield) and diol 27 (26 mg, 16% yield). Diol 27 was recycled.

Alcohol 28: [a]²_D⁷C18 (c 0.62, CHCl₃); IR (neat) 3350,

1255, 1058, 836, 774 cm^K1; ¹H NMR (300 MHz, CDCl₃) d

0.07 (s, 3H), 0.08 (s, 3H), 0.89 (br s, 9H), 0.85–0.91 (m,

3H), 1.20–1.36 (m, 6H), 1.45–1.56 (m, 2H), 1.57–1.70 (m,

1H), 1.74–1.87 (m, 1H), 2.55 (br s, 1H), 3.65–3.76 (m, 1H),

3.77–3.95 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) d K4.5,

K4.2, 14.2, 18.2, 22.8, 25.2, 26.0, 32.1, 36.9, 37.8, 60.4,

72.1. Anal. Calcd for C₁₄H₃₂O₂Si: C, 64.55; H, 12.38.

Found: C, 64.40; H, 12.27.

yellow oil. After being passed through a short column of

silica gel (hexane/EtOAc), the crude mesylate was subjected

to the next reaction.

To a slurry of activated alumina (350 mg, ICN, N-Super I,

activated by heating on a heater for 20 min under vacuum)

in CH₂Cl₂(5 mL) was added a solution of the crude

mesylate 21 in CH₂Cl₂(2 mL). The mixture was stirred

vigorously at room temperature for 10 h and ﬁltered through

a pad of Celite with CH₂Cl₂. The ﬁltrate was concentrated

under reduced pressure to furnish an yellow oil, which was

puriﬁed by chromatography (hexane/EtOAc) to afford

dienone 12 (114 mg, 59% yield from enone 10): [a]_D²⁶

C96 (c 0.43, CHCl₃); IR (neat) 1705, 1657, 1513,

1

1249 cm^K1; H NMR (300 MHz, CDCl₃) d 0.04 (s, 3H),

0.05 (s, 3H), 0.80–0.96 (m, 12H), 1.20–1.64 (m, 12H), 2.00

(q, JZ7 Hz, 2H), 2.17 (dt, JZ15, 9 Hz, 1H), 2.39–2.46 (m,

2H), 2.55–2.67 (m, 1H), 3.43 (t, JZ7 Hz, 3H), 3.80 (s, 3H),

3.78–3.88 (m, 1H), 4.42 (s, 2H), 5.28–5.40 (m, 1H),

5.42–5.56 (m, 1H), 6.32 (dd, JZ6, 1.5 Hz, 1H), 6.60 (t,

JZ8 Hz, 1H), 6.87 (d, JZ8 Hz, 2H), 7.25 (d, JZ8 Hz, 2H),

7.49 (dd, JZ6, 2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) d

K4.4, K4.2, 14.2, 18.3, 22.8, 25.1, 26.0, 26.4, 27.3, 29.6,

30.7, 32.1, 37.4, 37.5, 43.6, 55.4, 70.0, 71.6, 72.6, 113.8,

125.1, 129.2, 130.7, 132.45, 132.51, 134.8, 138.7, 159.0,

161.5, 196.2.

4.3.4. (S)-3-[(tert-Butyldimethylsilyl)oxy]octanal (11). A

mixture of alcohol 28 (1.18 g, 4.53 mmol) and PCC (1.95 g,

9.05 mmol) in CH₂Cl₂(45 mL) was stirred vigorously at

room temperature for 3 h and diluted with ether. The

resulting mixture was ﬁltered through a pad of Celite and

the ﬁltrate was concentrated under reduced pressure. An

yellow oil obtained was puriﬁed by chromatography

(hexane/EtOAc) to afford aldehyde 11 (1.10 g, 94%

yield): [a]_D²⁷C6.7 (c 0.21, CHCl₃); lit.²⁶[a]²_D⁴K5.0 (c

1.0, CHCl₃) for the enantiomer of O98% ee; IR (neat) 1713,

1256, 1095, 836, 776 cm^K1; ¹H NMR (300 MHz, CDCl₃) d

0.05 (s, 3H), 0.07 (s, 3H), 0.87 (br s, 9H), 0.84–0.92 (m,

3H), 1.18–1.40 (m, 6H), 1.45–1.60 (m, 2H), 2.51 (dd, JZ6,

2 Hz, 2H), 4.17 (quintet, JZ6 Hz, 1H), 9.81 (t, JZ2 Hz,

1H); ¹³C NMR (75 MHz, CDCl₃) d K4.5, K4.2, 14.2, 18.2,

22.8, 25.0, 31.9, 38.0, 51.0, 68.4, 202.3.

4.4.2. Aldehyde 23. To an ice-cold solution of dienone 12

(108 mg, 0.195 mmol) in CH₂Cl₂(3.8 mL) and water

(0.2 mL) was added DDQ (66 mg, 0.29 mmol). The mixture

was stirred at 0 8C for 45 min and ﬁltered through a pad of

Celite using ether. The ﬁltrate was concentrated, and a

reddish brown residue produced was puriﬁed by chromato-

graphy (hexane/EtOAc) to furnish alcohol 22 (77 mg, 91%

4.4. Synthesis of D¹²-PGJ₂(3)

1

yield): IR (neat) 3441, 1701, 1654, 1075 cm^K1; H NMR

(300 MHz, CDCl₃) d 0.04 (s, 3H), 0.05 (s, 3H), 0.80 (br s,

12H), 1.2–1.7 (m, 12H), 1.95–2.30 (m, 3H), 2.39–2.46 (m,

2H), 2.55–2.67 (m, 1H), 3.43–3.48 (m, 1H), 3.65 (t, JZ

7 Hz, 2H), 3.78–3.90 (m, 1H), 5.28–5.40 (m, 1H), 5.42–5.56

(m, 1H), 6.32 (dd, JZ6, 1.5 Hz, 1H), 6.60 (t, JZ8 Hz, 1H),

7.49 (dd, JZ6, 2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) d

K4.4, K4.2, 14.2, 18.3, 22.8, 25.1, 25.9, 26.0, 27.3, 30.8,

32.1, 32.5, 37.5, 43.6, 62.8, 71.7, 125.3, 132.4, 132.6, 134.8,

138.7, 161.5, 196.2.

4.4.1. Dienone 12. To an ice-cold solution of (i-Pr)₂NH

(0.15 mL, 1.07 mmol) in THF (4 mL) was added n-BuLi

(0.37 mL, 1.90 M in hexane, 0.703 mmol). The solution was

stirred at 0 8C for 20 min to generate LDA and then cooled

to K78 8C. A solution of enone 10 (109 mg, 0.347 mmol) in

THF (2 mL) was added into the LDA solution. After 20 min

of stirring at the same temperature, aldehyde 11 (108 mg,

0.418 mmol) dissolved in THF (1 mL) was added. The

solution was stirred for 30 min at the same temperature, and

poured into a ﬂask containing saturated NH₄Cl and ether

with vigorous stirring. After 15 min, the organic layer was

separated and the aqueous layer was extracted with EtOAc

twice. The combined extracts were dried over MgSO₄and

concentrated to afford aldol 20 as a mixture of anti and syn

A mixture of alcohol 22 (45 mg, 0.104 mmol) and PCC

(45 mg, 0.209 mmol) in CH₂Cl₂(1 mL) was stirred for 2.5 h

at room temperature, diluted with ether, and ﬁltered through

a short pad of Celite. The ﬁltrate was concentrated, and an

yellow residue obtained was puriﬁed by chromatography

(hexane/EtOAc) to afford aldehyde 23 (42 mg, 94% yield):

[a]²_D⁹C57 (c 0.14, CHCl₃); IR (neat) 1709, 1649, 836,

775 cm^K1; ¹H NMR (300 MHz, CDCl₃) d 0.04 (s, 3H), 0.05

(s, 3H), 0.87 (s, 9H), 0.83–0.91 (m, 3H), 1.16–1.52 (m, 8H),

1.60–1.76 (m, 2H), 2.04 (q, JZ7 Hz, 2H), 2.12–2.26 (m,

1H), 2.30–2.54 (m, 4H), 2.56–2.68 (m, 1H), 3.40–3.52 (m,

1H), 3.78–3.90 (m, 1H), 5.30–5.53 (m, 2H), 6.33 (dd, JZ6,

2 Hz, 1H), 6.60 (t, JZ8 Hz, 1H), 7.48 (dd, JZ6, 2.5 Hz,

1H), 9.76 (t, JZ1.5 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) d

K4.4, K4.2, 14.2, 18.3, 22.0, 22.8, 25.1, 26.0, 26.8, 30.7,

32.1, 37.4, 37.5, 43.40, 43.44, 71.6, 126.2, 131.2, 132.7,

135.0, 138.5, 161.2, 196.1, 201.9.

1

isomers. The ratio of the mixture was ca. 3:1 by H NMR

spectroscopy (d 2.78–2.92 (m) and 3.00–3.11 (m) for anti

and syn isomers, respectively) and TLC analysis. After

being passed through a short column of silica gel (hexane/

EtOAc), the crude aldol was used for the next reaction.

To an ice-cold solution of the above aldol 20 dissolved in

CH₂Cl₂(3.5 mL) were added Et₃N (0.24 mL, 1.72 mmol)

and MsCl (0.053 mL, 0.685 mmol). The solution was stirred

for 45 min at the same temperature, and diluted with

saturated NaHCO₃. The product was extracted with EtOAc

repeatedly. The combined organic layers were dried over

MgSO₄and concentrated to furnish mesylate 21 as an

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

3337

4.4.3. Acid 24. To a slurry of aldehyde 23 (42 mg,

0.097 mmol) in t-BuOH (1.3 mL), phosphate buffer of

pH 3.6 (0.61 mL), and 2-methyl-2-butene (0.105 mL,

0.99 mmol) was added NaClO₂(17 mg, 0.15 mmol, purity

80%) in water (0.5 mL) and the resulting mixture was

stirred at room temperature. After 3 h, t-BuOH was removed

by using a vacuum pump and the phosphate buffer (pH 3.6)

was added to the residue. The product was extracted with

EtOAc several times. The combined organic layers were

dried over MgSO₄and concentrated to afford an oily

residue, which was puriﬁed by chromatography (CH₂Cl₂/

EtOH) to furnish acid 24 (39 mg, 89% yield): IR (neat)

anti Isomer: ¹H NMR (300 MHz, CDCl₃) d 0.88 (t, JZ7 Hz,

3H), 1.16–1.48 (m, 8H), 1.52–1.66 (m, 2H), 1.94–2.14 (m,

5H), 2.15–2.37 (m, 2H), 2.64–2.72 (m, 1H), 3.43 (t, JZ7 Hz,

2H), 3.80(s, 3H),3.95(br s, 1H), 4.14(t, JZ8 Hz, 1H), 4.42(s,

2H), 5.26–5.37 (m, 1H), 5.39–5.58 (m, 2H), 5.73 (dt, JZ15,

7 Hz, 1H), 6.14 (dd, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz, 2H),

7.25 (d, JZ9 Hz, 2H), 7.62 (dd, JZ6, 2 Hz, 1H). syn Isomer:

¹H NMR (300 MHz, CDCl₃) d 0.88 (t, JZ7 Hz, 3H), 1.16–

1.50 (m, 7H), 1.53–1.76 (m, 3H), 1.94–2.14 (m, 4H), 2.15–

2.38 (m, 3H), 2.59 (d, JZ6 Hz, 1H), 2.82–2.94 (m, 1H), 3.43

(t, JZ7 Hz, 2H), 3.80 (s, 3H), 4.42 (s, 2H), 4.49–4.59 (m, 1H),

5.28–5.57 (m, 3H), 5.73 (dt, JZ15, 7 Hz, 1H), 6.15 (dd, JZ6,

2 Hz, 1H), 6.87 (d, JZ9 Hz, 2H), 7.25 (d, JZ9 Hz, 2H), 7.63

(dd, JZ6, 2 Hz, 1H).

3100, 1710, 1652, 1252, 836, 775 cm^K^{1 1}H NMR

;

(300 MHz, CDCl₃) d 0.05 (s, 6H), 0.84–0.92 (m, 12H),

1.18–1.52 (m, 8H), 1.69 (quintet, JZ7 Hz, 2H), 2.00–2.22

(m, 3H), 2.34 (t, JZ7 Hz, 2H), 2.40–2.48 (m, 2H), 2.60–

2.70 (m, 1H), 3.41–3.50 (m, 1H), 3.78–3.90 (m, 1H), 5.32–

5.56 (m, 2H), 6.33 (dd, JZ6, 1 Hz, 1H), 6.60 (t, JZ8 Hz,

1H), 7.50 (dd, JZ6, 2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃)

d K4.4, K4.2, 14.2, 18.3, 22.8, 24.6, 25.1, 26.0, 26.8, 30.7,

32.0, 33.3, 37.4, 37.5, 43.6, 71.8, 126.2, 131.3, 132.7, 134.9,

138.6, 161.5, 178.1, 196.3.

To a solution of the above aldol 30 in CH₂Cl₂(6 mL) and

Et₃N (0.88 mL, 6.31 mmol) at K15 8C was added MsCl

(0.20 mL, 2.58 mmol) dropwise. After 45 min at the same

temperature, the reaction was quenched by addition of

saturated NaHCO₃. The organic layer was separated and the

aqueous layer was extracted with EtOAc. The combined

organic layers were dried over MgSO₄and concentrated to

furnish an yellow residue, which was subjected to

chromatography (hexane/EtOAc) to afford dienone 31

(185 mg, 69% yield from enone 10) and its (Z)-isomer 34

(14 mg, 5%). Dienone 31: IR (neat) 1685, 1631, 1512,

4.4.4. D¹²-PGJ₂(3). To an ice-cold ﬂask containing acid 24

(9 mg, 0.020 mmol) was added a solution of HF in MeCN

(0.2 mL), which had been prepared by mixing 55% HF and

MeCN in a 1:19 ratio. The solution was stirred at 0 8C for

15 min and poured into brine. The product was extracted

with EtOAc several times. The combined extracts were

dried over MgSO₄and concentrated to leave an oil, which

was puriﬁed by chromatography (CH₂Cl₂/EtOH) to furnish

D¹²-PGJ₂(3) (6.2 mg, 92% yield): IR (neat) 3409, 1699,

1653 cm^K1; ¹H NMR (300 MHz, CDCl₃) d 0.88 (t JZ7 Hz,

3H), 1.20–1.80 (m, 10H), 2.06–2.18 (m, 3H), 2.26–2.63 (m,

4H), 2.66–2.78 (m, 1H), 3.42–3.54 (m, 1H), 3.78–3.92 (m,

1H), 5.1–5.9 (br s, 4H), 6.35 (dd, JZ6, 2 Hz, 1H), 6.59 (t,

1

1248 cm^K1; H NMR (300 MHz, CDCl₃) d 0.89 (t, JZ

7 Hz, 3H), 1.1–1.6 (m, 10H), 2.01 (q, JZ7 Hz, 2H), 2.16–

2.35 (m, 3H), 2.58 (dt, JZ14, 6 Hz, 1H), 3.42 (t, JZ6 Hz,

2H), 3.51–3.60 (m, 1H), 3.80 (s, 3H), 4.42 (s, 2H), 5.27–

5.39 (m, 1H), 5.41–5.53 (m, 1H), 6.15–6.39 (m, 3H), 6.87

(d, JZ8 Hz, 2H), 6.94 (d, JZ11 Hz, 1H), 7.25 (d, JZ8 Hz,

2H), 7.46 (dd, JZ6, 2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃)

d 14.2, 22.6, 26.4, 27.3, 28.6, 29.6, 31.0, 31.5, 33.6, 43.7,

55.4, 70.0, 72.6, 113.8, 125.1, 125.7, 129.2, 130.6, 131.6,

132.5, 135.1, 135.2, 146.7, 159.0, 160.7, 197.2. (Z)-Isomer

34: IR (neat) 1684, 1634, 1512, 1248 cm^K^{1 1}H NMR

;

1

JZ8 Hz, 1H), 7.56 (dd, JZ6, 2 Hz, 1H). The H NMR

spectrum was identical with that provided by Ono

Pharmaceutical Co., Ltd.

(300 MHz, CDCl₃) d 0.88 (t, JZ7 Hz, 3H), 1.20–1.66 (m,

10H), 2.01 (q, JZ7 Hz, 2H), 2.16–2.36 (m, 3H), 2.44 (dt,

JZ14, 7 Hz, 1H), 3.29–3.38 (m, 1H), 3.42 (t, JZ6 Hz, 2H),

3.80 (s, 3H), 4.42 (s, 2H), 5.28–5.56 (m, 2H), 6.06 (dt, JZ

15, 7 Hz, 1H), 6.28 (dd, JZ6, 2 Hz, 1H), 6.43 (d, JZ11 Hz,

1H), 6.87 (d, JZ9 Hz, 2H), 7.25 (d, JZ9 Hz, 2H), 7.37 (dd,

JZ6, 2 Hz, 1H), 7.66 (ddt, JZ15, 11, 2 Hz, 1H).

4.5. Synthesis of 15-deoxy-D^12,14-PGJ₂(4)

4.5.1. Dienone 31 through aldol 30. To a solution of i-Pr₂NH

(0.22 mL, 1.57 mmol) in THF (10 mL) at 0 8C was added

n-BuLi(0.58 mL, 2.20 Minhexane, 1.28 mmol).Thesolution

was stirred at the same temperature for 20 min to prepare

LDA, and cooled to K78 8C. A solution of enone 10 (200 mg,

0.636 mmol) in THF (3 mL) was added into the LDA solution

dropwise, and the solution was stirred for 20 min. (E)-2-

Octenal (29) (0.115 mL, 0.771 mmol) was added to the

solution. After 20 min at the same temperature, the solution

was poured into a ﬂask containing saturated NH₄Cl and ether

with vigorousstirring. The organic layerwasseparated and the

aqueous layer was extracted with EtOAc. The combined

organic extracts were dried over MgSO₄and concentrated to

afford aldol 30 as a mixture of the anti and syn isomers in a 2:1

4.5.2. Aldehyde 33 through alcohol 32. To an ice-cold

solution of PMB ether 31 (53 mg, 0.125 mmol) in CH₂Cl₂

(1.2 mL) and water (0.1 mL) was added DDQ (43 mg,

0.19 mmol). After 45 min, the reaction was quenched by

addition of saturated NaHCO₃and ether. The organic layer

was separated and the aqueous layer was extracted with

ether twice. The combined organic fractions were dried over

MgSO₄and concentrated to obtained an yellow residue,

which was puriﬁed by chromatography (hexane/EtOAc) to

furnish alcohol 32 (35 mg, 92% yield): IR (neat) 3421,

1

1685, 1629 cm^K1; H NMR (300 MHz, CDCl₃) d 0.90 (t,

1

ratio by H NMR spectroscopy (anti isomer, d 4.14 (t, JZ

JZ7 Hz, 3H), 1.1–1.7 (m, 11H), 2.02 (q, JZ7 Hz, 2H),

2.16–2.38 (m, 3H), 2.54–2.66 (m, 1H), 3.50–3.70 (m, 3H),

5.25–5.60 (m, 2H), 6.16–6.31 (m, 2H), 6.32–6.40 (m, 1H),

6.95 (d, JZ11 Hz, 1H), 7.48 (dd, JZ6, 2 Hz, 1H).

8 Hz); syn isomer, d 4.49–4.58 (m)). The aldol product 30 was

subjected to the next reaction after ﬁltration through a short

column of silica gel (hexane/EtOAc).

The aldol reaction was repeated, and the stereoisomers were

separated by chromatography on silica gel (hexane/EtOAc).

To an ice-cold solution of alcohol 32 (35 mg, 0.116 mmol)

in CH₂Cl₂(1.2 mL) was added PCC (37 mg, 0.17 mmol).

3338

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

The mixture was stirred vigorously at room temperature for

2.5 h, and diluted with Et₂O. The resulting mixture was

ﬁltered through a short pad of Celite. The ﬁltrate was

concentrated, and the residue was puriﬁed by chromato-

graphy (hexane/EtOAc) to afford aldehyde 33 (32 mg, 92%

was puriﬁed by chromatography (hexane) to afford

dibromide 35 (125 mg, 76% yield): IR (neat) 3058, 1256,

1

1086, 836, 775 cm^K1; H NMR (300 MHz, CDCl₃) d 0.08

(s, 6H), 0.89 (s, 9H), 1.31 (dt, JZ13, 5 Hz, 1H), 2.08–2.32

(m, 2H), 2.39 (dt, JZ13, 8 Hz, 1H), 2.66 (quintet, JZ7 Hz,

1H), 4.78–4.85 (m, 1H), 5.75 (s, 2H), 6.45 (t, JZ7 Hz, 1H);

¹³C NMR (75 MHz, CDCl₃) d K4.3, 18.4, 26.1, 39.2, 40.3,

42.8, 77.3, 89.3, 135.1, 135.5, 137.0. Anal. Calcd for

C₁₄H₂₄Br₂OSi: C, 42.44; H, 6.11. Found: C, 42.93; H, 6.52.

1

yield): IR (neat) 1727, 1695, 1632, 1206 cm^K1; H NMR

(300 MHz, CDCl₃) d 0.89 (t, JZ7 Hz, 3H), 1.20–1.72 (m,

8H), 2.02 (q, JZ7 Hz, 2H), 2.16–2.44 (m, 5H), 2.58 (dt, JZ

15, 5 Hz, 1H), 3.54–3.62 (m, 1H), 5.28–5.52 (m, 2H), 6.14–

6.40 (m, 3H), 6.94 (d, JZ11 Hz, 1H), 7.45 (dd, JZ6, 3 Hz,

1H), 9.75 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) d 14.2, 22.0,

22.7, 26.8, 28.7, 30.9, 31.6, 33.6, 43.4, 43.6, 125.6, 126.1,

131.3, 131.6, 135.0, 135.3, 146.9, 160.4, 197.1, 202.0.

4.6.2. (1S,4R)-1-[(tert-Butyldimethylsilyl)oxy]-4-(2⁰-pro-

pynyl)-2-cyclopentene (36). To a solution of 35 (115 mg,

0.290 mmol) in THF (3 mL) at K78 8C was added n-BuLi

(0.32 mL, 2.25 M in hexane, 0.72 mmol) dropwise. After

being stirred at K78 8C for 30 min, the reaction ﬂask was

immersed into an ice-water bath (0 8C). The reaction was

continued for 30 min and quenched by addition of saturated

NH₄Cl and hexane. The phases were separated and the

aqueous layer was extracted with hexane. The combined

organic layers were dried over MgSO₄and concentrated

under reduced pressure to leave an oil, which was puriﬁed

by chromatography (hexane/EtOAc) to furnish acetylene 36

(62 mg, 91% yield): IR (neat) 3313, 1256, 1079, 836,

775 cm^K1; ¹H NMR (300 MHz, CDCl₃) d 0.08 (s, 6H), 0.90

(s, 9H), 1.37 (ddd, JZ13, 6, 5 Hz, 1H), 1.96 (t, JZ2.5 Hz,

1H), 2.26 (d, JZ2.5 Hz, 1H), 2.28 (d, JZ2.5 Hz, 1H), 2.44

(dt, JZ13, 8 Hz, 1H), 2.66–2.78 (m, 1H), 4.79–4.87 (m,

1H), 5.76 (dt, JZ6, 2 Hz, 1H), 5.87 (dt, JZ6, 2 Hz); ¹³C

NMR (75 MHz, CDCl₃) d K4.5, 18.3, 25.3, 26.0, 40.4,

43.4, 68.8, 77.4, 83.3, 135.2, 135.5. Anal. Calcd for

C₁₄H₂₄OSi: C, 71.12; H, 10.23. Found: C, 71.22; H, 10.51.

4.5.3. 15-Deoxy-D^12,14-PGJ₂(4). To a slurry of aldehyde

33 (32 mg, 0.106 mmol) in t-BuOH (1.4 mL), phosphate

buffer of pH 3.6 (0.66 mL), and 2-methyl-2-butene

(0.11 mL, 1.04 mmol) was added NaClO₂(18 mg,

0.16 mmol, 80% purity) in water (0.53 mL). The mixture

was stirred at ambient temperature for 3 h, and concentrated

by using a vacuum pump. Phosphate buffer of pH 3.6 was

added to the residue, and the mixture was extracted with

EtOAc several times. The combined organic layers were

dried over MgSO₄and concentrated to afford an oily

residue, which was puriﬁed by chromatography (CH₂Cl₂/

EtOH) to furnish 15-deoxy-D^12,14-PGJ₂(4) (31 mg, 93%

yield): [a]²_D⁶C193 (c 0.17, CHCl₃) (lit.¹³[a]_DC194.3 (c

1

0.7, CHCl₃)); IR (neat) 3303, 1707, 1628, 1209 cm^K1; H

NMR (300 MHz, CDCl₃) d 0.89 (t, JZ7 Hz, 3H), 1.15–1.54

(m, 6H), 1.67 (quintet, JZ7 Hz, 2H), 2.05 (q, JZ7 Hz, 2H),

2.16–2.40 (m, 5H), 2.54–2.66 (m, 1H), 3.54–3.62 (m, 1H),

3.6–5.0 (br s, 2H), 5.28–5.56 (m, 2H), 6.16–6.42 (m, 3H),

6.96 (d, JZ11 Hz, 1H), 7.47 (dd, JZ6, 2 Hz, 1H); ¹³C

NMR (75 MHz, CDCl₃) d 14.2, 22.6, 24.6, 26.7, 28.6, 30.9,

31.6, 33.4, 33.6, 43.6, 125.6, 126.1, 131.3, 131.9, 135.0,

135.3, 147.0, 160.7, 178.5, 197.5.

4.6.3. (1S,4R)-4-[7⁰-(4-Methoxybenzyloxy)-2⁰-heptynyl]-

2-cyclopenten-1-ol (37). To a solution of acetylene 36

(180 mg, 0.761 mmol) in THF (6 mL) at K78 8C was added

n-BuLi (0.76 mL, 1.90 M in hexane, 1.44 mmol) dropwise.

After 20 min of stirring at the same temperature, DMPU

(1.5 mL) and PMBO(CH₂)₄Br (250 mg, 0.915 mmol) were

added. The reaction was conducted at K78 8C for 1 h, and

then gradually warmed to room temperature over 10 h. The

mixture was diluted with saturated NH₄Cl and hexane. The

organic layer was separated and the aqueous layer was

extracted with hexane twice. The combined organic layers

were dried over MgSO₄and concentrated under reduced

pressure to obtain an oil containing acetylene 13 and

PMBO(CH₂)₄Br. This residue was passed through a short

1

The following H NMR spectrum, measured at 500 MHz,

unambiguously indicated the trans oleﬁn geometry at

1

C(14)–C(15): H NMR (500 MHz, CDCl₃) d 0.89 (t, JZ

7 Hz, 3H), 1.22–1.36 (m, 4H), 1.39–1.49 (m, 2H), 1.62–1.72

(m, 2H), 2.04 (q, JZ7 Hz, 2H), 2.22 (q, JZ7 Hz, 2H), 2.26–

2.37 (m, 3H), 2.56–2.62 (m, 1H), 3.56–3.61 (m, 1H), 5.33–

5.40 (m, 1H), 5.42–5.49 (m, 1H), 6.23 (dt, JZ15, 7 Hz, 1H),

6.31 (ddt, JZ15, 11, 1 Hz, 1H), 6.36 (dd, JZ6, 2 Hz, 1H),

6.95 (d, JZ11 Hz, 1H), 7.47 (ddd, JZ6, 2.5, 1 Hz, 1H).

1

pad of silica gel for the next reaction: H NMR (300 MHz,

These spectra were in good agreement with the reported

IR,^{13 1}H NMR (600 MHz),¹³and ¹³C NMR (150, 75 MHz)

spectra.^11,13

CDCl₃) (characteristic peaks only) d 3.40–3.52 (m, 2H),

3.80 (s, 3H), 4.42 (s, 2H), 4.78–4.87 (m, 1H), 5.73 (dt, JZ6,

2 Hz, 1H), 5.86 (dt, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz, 2H),

7.26 (d, JZ9 Hz, 2H).

4.6. Synthesis of 5,6-dehydro-D¹²-PGJ₂(5)

To an ice-cold solution of the above product dissolved in

THF (8 mL) was added n-Bu₄NF (1.14 mL, 1.0 M in THF,

1.14 mmol). The solution was stirred at room temperature

for 3 h and diluted with saturated NH₄Cl and EtOAc. The

organic layer was separated, and the aqueous layer was

extracted with EtOAc three times. The combined organic

extracts were dried over MgSO₄and concentrated under

reduced pressure to leave an oil, which was puriﬁed by

chromatography (hexane/EtOAc) to afford alcohol 37

(193 mg, 81% yield in two steps): [a]²_D⁸C50 (c 0.31,

CHCl₃); IR (neat) 3420, 1612, 1513, 1248 cm^K1; ¹H NMR

4.6.1. (1S,4R)-1-[(tert-Butyldimethylsilyl)oxy]-4-[3⁰,3⁰-

dibromo-2⁰-propenyl]-2-cyclopentene (35). To an ice-

cold solution of PPh₃(436 mg, 1.66 mmol) in CH₂Cl₂

(3 mL) was added CBr₄(276 mg, 0.832 mmol) portionwise.

After vigorous stirring for 10 min, aldehyde 9b (100 mg,

0.416 mmol) dissolved in CH₂Cl₂(1.5 mL) was added

slowly. The solution was stirred at 0 8C for 30 min and

diluted with hexane. The resulting mixture was ﬁltered

through a pad of Celite with hexane and the ﬁltrate was

concentrated under reduced pressure to leave an oil, which

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

3339

(300 MHz, CDCl₃) d 1.42 (dt, JZ14, 4 Hz, 1H), 1.50–1.75

(m, 4H), 1.89–1.97 (m, 1H), 2.12–2.22 (m, 2H), 2.28–2.36

(m, 2H), 2.45 (dt, JZ14, 8 Hz, 1H), 2.74–2.84 (m, 1H), 3.44

(t, JZ6 Hz, 2H), 3.80 (s, 3H), 4.42 (s, 2H), 4.73 (br s, 1H),

5.83 (dd, JZ6, 2 Hz, 1H), 5.88 (dt, JZ6, 2 Hz, 1H), 6.87 (d,

JZ9 Hz, 2H), 7.26 (d, JZ9 Hz, 2H); ¹³C NMR (75 MHz,

CDCl₃) d 18.6, 25.1, 25.9, 29.0, 39.1, 43.5, 55.3, 69.6, 72.6,

76.9, 79.2, 81.7, 113.7, 129.2, 130.6, 134.3, 137.0, 159.0.

Anal. Calcd for C₂₀H₂₆O₃: C, 76.40; H, 8.33. Found: C,

76.25; H, 8.12.

1.5 Hz, 1H), 6.61 (t, JZ8 Hz, 1H), 6.87 (d, JZ8 Hz, 2H),

7.26 (d, JZ8 Hz, 2H), 7.65 (dd, JZ6, 2 Hz, 1H); ¹³C NMR

(75 MHz, CDCl₃) d K4.4, K4.1, 14.2, 18.3, 18.7, 22.8,

23.2, 25.1, 25.8, 26.0, 29.1, 32.1, 37.4, 37.5, 43.0, 55.4,

69.7, 71.6, 72.7, 76.5, 82.8, 113.8, 129.2, 130.6, 133.0,

135.3, 137.9, 159.0, 161.0, 195.8.

4.6.6. Alcohol 41. A solution of dienone 40 (102 mg,

0.184 mmol) in CH₂Cl₂(2 mL) and water (0.1 mL) was

treated with DDQ (63 mg, 0.278 mmol) at 0 8C for 45 min,

and diluted with saturated NaHCO₃and ether to obtain an

yellow residue, which was puriﬁed by chromatography

(hexane/EtOAc) to furnish alcohol 41 (73 mg, 91% yield):

[a]²_D⁹C158 (c 0.61, CHCl₃); IR (neat) 3441, 1703,

4.6.4. (R)-4-[7⁰-(4-Methoxybenzyloxy)-2⁰-heptynyl]-2-

cyclopenten-1-one (38). A mixture of alcohol 37

(190 mg, 0.604 mmol) and PCC (195 mg, 0.905 mmol) in

CH₂Cl₂(6 mL) was stirred for 1 h, diluted with ether, and

ﬁltered through a pad of Celite. The ﬁltrate was

concentrated to obtain an yellow residue, which was

puriﬁed by chromatography (hexane/EtOAc) to furnish

enone 38 (177 mg, 94% yield): [a]²_D⁸C107 (c 0.62, CHCl₃);

1

1653 cm^K1; H NMR (300 MHz, CDCl₃) d 0.03 (s, 3H),

0.04 (s, 3H), 0.87 (s, 9H), 0.82–0.90 (m, 3H), 1.1–1.7 (m,

12H), 1.87 (br s, 1H), 2.10–2.20 (m, 2H), 2.28–2.48 (m,

3H), 2.72 (ddt, JZ17, 4, 2 Hz, 1H), 3.50–3.59 (m, 1H), 3.61

(t, JZ6 Hz, 2H), 3.82 (quintet, JZ6 Hz, 1H), 6.39 (dd, JZ

6, 2 Hz, 1H), 6.61 (t, JZ8 Hz, 1H), 6.59 (dd, JZ6, 2 Hz,

1H); ¹³C NMR (75 MHz, CDCl₃) d K4.4, K4.2, 14.2, 18.2,

18.6, 22.8, 22.9, 25.1, 25.2, 26.0, 31.9, 32.0, 37.3, 37.4,

42.8, 62.5, 71.5, 76.3, 82.9, 133.1, 135.4, 137.8, 160.9,

196.2.

IR (neat) 1714, 1612, 1512, 1247 cm^K1

;

¹H NMR

(300 MHz, CDCl₃) d 1.50–1.72 (m, 4H), 2.08–2.21 (m,

3H), 2.34–2.44 (m, 2H), 2.52 (dd, JZ19, 7 Hz, 1H), 3.06–

3.16 (m, 1H), 3.45 (t, JZ6 Hz, 2H), 3.80 (s, 3H), 4.43 (s,

2H), 6.20 (dd, JZ6, 2 Hz, 1H), 6.87 (d, JZ8 Hz, 2H), 7.26

(d, JZ8 Hz, 2H), 7.63 (dd, JZ6, 3 Hz, 1H); ¹³C NMR

(75 MHz, CDCl₃) d 18.6, 24.0, 25.8, 29.0, 40.2, 40.6, 55.4,

69.6, 72.6, 76.4, 82.4, 113.7, 129.2, 130.6, 134.6, 159.0,

166.7, 209.2. Anal. Calcd for C₂₀H₂₄O₃: C, 76.89; H, 7.74.

Found: C, 76.52; H, 8.99.

4.6.7. Acid 42. A mixture of alcohol 41 (20 mg,

0.046 mmol) and PCC (15 mg, 0.069 mmol) in CH₂Cl₂

(1 mL) was stirred vigorously at room temperature for 2 h,

and diluted with ether to afford the corresponding aldehyde

(18 mg, 90% yield) after chromatography (hexane/EtOAc):

¹H NMR (300 MHz, CDCl₃) d 0.04 (s, 3H), 0.05 (s, 3H),

0.88 (s, 9H), 0.84–0.92 (m, 3H), 1.16–1.50 (m, 8H), 1.72–

1.84 (m, 2H), 2.16–2.50 (m, 5H), 2.53 (dt, JZ1.5, 7 Hz,

2H), 2.75 (ddt, JZ17, 4.5, 3 Hz, 1H), 2.68–2.82 (m, 1H),

3.50–3.60 (m, 1H), 3.83 (quintet, JZ6 Hz, 1H), 6.39 (dd,

JZ6, 1.5 Hz, 1H), 6.61 (t, JZ8 Hz, 1H), 7.60 (dd, JZ6,

2 Hz, 1H), 9.79 (t, JZ1.5 Hz); ¹³C NMR (75 MHz, CDCl₃)

d K4.4, K4.1, 14.2, 18.26, 18.32, 21.5, 22.8, 23.0, 25.1,

26.0, 32.1, 37.4, 37.5, 42.7, 42.9, 71.6, 77.4, 81.8, 133.1,

135.4, 137.8, 160.6, 195.7, 201.7.

4.6.5. Dienone 40. According to the aldol reaction of enone

10 and aldehyde 11, a solution of LDA was prepared (0 8C,

20 min) from i-Pr₂NH (0.23 mL, 1.64 mmol) and n-BuLi

(0.67 mL, 1.90 M in hexane, 1.27 mmol) in THF (9 mL) and

used for preparation of the anion from enone 38 (200 mg,

0.64 mmol) in THF (2 mL) at K78 8C for 20 min. Aldehyde

11 (199 mg, 0.77 mmol) in THF (2 mL) was added to the

solution, and, after 20 min, the solution was poured into a

ﬂask containing saturated NH₄Cl and ether with vigorous

stirring. Aldol 39, thus synthesized as a mixture of the anti

and syn isomers (ca. 3:1 by TLC), was subjected to the next

reaction after ﬁltration through a short column of silica gel

(hexane/EtOAc).

A mixture of the above aldehyde (18 mg, 0.042 mmol) in

t-BuOH (0.55 mL), phosphate buffer of pH 3.6 (0.26 mL),

and 2-methyl-2-butene (0.045 mL, 0.42 mmol) was treated

with NaClO₂(8 mg, 0.071 mmol, 80% purity) in water

(0.21 mL) at ambient temperature for 3 h to afford acid 42

(17.5 mg, 91% yield) after chromatography (CH₂Cl₂/

According to the conversion of aldol 20 to dienone 12, the

above aldol 39 in CH₂Cl₂(6.5 mL) was converted into the

mesylate with MsCl (0.10 mL, 1.29 mmol) and Et₃N

(0.45 mL, 3.23 mmol) at 0 8C for 45 min. This mesylate,

after being passed through a short column of silica gel

(hexane/EtOAc), was dissolved in CH₂Cl₂(2 mL) and the

solution was added to a slurry of alumina (496 mg, ICN

Alumina N-Super I, activated by heating on a heater for

20 min under vacuum) in CH₂Cl₂(7 mL). After 13 h at

room temperature, the mixture was ﬁltered through a pad of

Celite, and the ﬁltrate was concentrated to furnish an yellow

residue, which was puriﬁed by chromatography (hexane/

EtOAc) to afford dienone 40 (151 mg, 43% yield from

enone 38): [a]²_D⁸C98 (c 0.38, CHCl₃); IR (neat) 1708, 1662,

1

EtOH): IR (neat) 3100, 1707, 1653, 813, 775 cm^K1; H

NMR (300 MHz, CDCl₃) d 0.04 (s, 3H), 0.05 (s, 3H), 0.88

(s, 9H), 0.84–0.92 (m, 3H), 1.16–1.54 (m, 8H), 1.79

(quintet, JZ7 Hz, 2H), 2.12–2.60 (m, 7H), 2.76 (dm, JZ

17 Hz, 1H), 3.52–3.62 (m, 1H), 3.84 (quintet, JZ6 Hz, 1H),

4.4–5.6 (br s, 1H), 6.41 (dd, JZ6, 2 Hz, 1H), 6.62 (t, JZ

8 Hz, 1H), 7.63 (dd, JZ6, 2 Hz, 1H).

4.6.8. 5,6-Dehydro-D¹²-PGJ₂(5). To a ﬂask containing

acid 42 (17 mg, 0.039 mmol) was added a solution

(0.39 mL) of 55% HF and MeCN in a ratio of 1:19. The

solution was stirred at 0 8C for 15 min and diluted with brine

to furnish 5-dehydro-D¹²-PGJ₂(5) (12 mg, 95% yield) after

chromatography (CH₂Cl₂/EtOH): [a]²_D⁶C199 (c 0.14,

1

1515, 1246 cm^K1; H NMR (300 MHz, CDCl₃) d 0.04 (s,

3H), 0.05 (s, 3H), 0.88 (s, 9H), 0.84–0.92 (m, 3H), 1.16–

1.74 (m, 12H), 2.10–2.28 (m, 3H), 2.35–2.44 (m, 2H), 2.70–

2.82 (m, 1H), 3.45 (t, JZ6 Hz, 2H), 3.48–3.58 (m, 1H), 3.80

(s, 3H), 3.70–3.92 (m, 1H), 4.42 (s, 2H), 6.37 (dd, JZ6,

CHCl₃); IR (neat) 3417, 1699, 1652 cm^K1

;

¹H NMR

(300 MHz, CDCl₃) d 0.89 (t, JZ7 Hz, 3H), 1.20–1.60

3340

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

(m, 8 H), 1.77 (quintet, JZ7 Hz, 2H), 2.16–2.28 (m, 2H),

2.38–2.56 (m, 5H), 2.68–2.82 (m, 1H), 3.56–3.64 (m, 1H),

3.83 (quintet, JZ6 Hz, 1H), 3.2–4.2 (br s, 2H), 6.43 (dd, JZ

6, 2 Hz, 1H), 6.66 (t, JZ8 Hz, 1H), 7.59 (dd, JZ6, 2 Hz,

1H).

(d, JZ11 Hz, 1H), 7.49 (dd, JZ6, 2 Hz, 1H), 7.26–7.68 (m,

1H).

4.7.2. 5,6-Dehydro-15-deoxy-D^12,14-PGJ₂(6). To an ice-

cold solution of dienone 44 (55 mg, 0.13 mmol) in CH₂Cl₂

(1.2 mL) and water (0.1 mL) was added DDQ (45 mg,

0.198 mmol). After 45 min, the reaction was quenched by

addition of saturated NaHCO₃and ether. The organic layer

was separated and the aqueous layer was extracted with

ether twice. The combined organic fractions were dried over

MgSO₄and concentrated to obtained an yellow residue,

which was puriﬁed by chromatography (hexane/EtOAc) to

4.7. Synthesis of 5,6-dehydro-15-deoxy-D^12,14-PGJ₂(6)

4.7.1. Dienone 44 through aldol 43. To a solution of

i-Pr₂NH (0.17 mL, 1.21 mmol) in THF (8 mL) at 0 8C was

added n-BuLi (0.44 mL, 2.20 M in hexane, 0.97 mmol). The

solution was stirred at the same temperature for 20 min to

prepare LDA, and cooled to K78 8C. Enone 38 (150 mg,

0.48 mmol) dissolved in THF (2 mL) was added into the

LDA solution dropwise, and the solution was stirred for

20 min. (E)-2-Octenal (29) (0.086 mL, 0.58 mmol) was

added to the solution. After being stirred for further 20 min

at the same temperature, the solution was poured into a ﬂask

containing saturated NH₄Cl and ether with vigorous stirring.

The organic layer was separated and the aqueous layer was

extracted with EtOAc. The combined organic extracts were

dried over MgSO₄and concentrated to afford aldol 43 as the

anti and syn isomers in a 2:1 ratio by ¹H NMR spectroscopy

(anti isomer, d 4.19 (q, JZ8 Hz); syn isomer, d 4.55–4.62

(m)). The aldol 43 was subjected to the next reaction after

being passed through a short column of silica gel. The aldol

reaction was repeated, and the stereoisomers were separated

by chromatography (hexane/EtOAc). anti Isomer: ¹H NMR

(300 MHz, CDCl₃) d 0.88 (t, JZ7 Hz, 3H), 1.1–1.8 (m,

11H), 1.96–2.56 (m, 7H), 2.72–2.80 (m, 1H), 3.44 (t, JZ

7 Hz, 2H), 3.80 (s, 3H), 4.19 (q, JZ8 Hz, 1H), 4.42 (s, 2H),

5.44 (ddt, JZ16, 8, 1 Hz, 1H), 5.74 (dt, JZ16, 8 Hz, 1H),

6.18 (dd, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz, 2H), 7.25 (d,

1

furnish the corresponding alcohol (36 mg, 92% yield): H

NMR (300 MHz, CDCl₃) d 0.90 (t, JZ7 Hz, 3H), 1.20–1.83

(m, 11H), 2.10–2.30 (m, 5H), 2.37 (ddt, JZ16, 9, 2 Hz, 1H),

2.74 (ddt, JZ16, 4, 3 Hz, 1H), 3.64, (t, JZ7 Hz, 2H), 3.58–

3.72 (m, 1H), 6.22–6.32 (m, 2H), 6.42 (dd, JZ6, 1.5 Hz,

1H), 6.72 (d, JZ11 Hz, 1H), 7.59 (dd, JZ6, 3 Hz, 1H).

To an ice-cold solution of the above alcohol (35 mg,

0.116 mmol) in CH₂Cl₂(1 mL) was added PCC (38 mg,

0.176 mmol). The mixture was stirred vigorously at room

temperature for 2 h and diluted with ether. The resulting

mixture was ﬁltered through a short pad of Celite. The

ﬁltrate was concentrated, and the residue was puriﬁed by

chromatography (hexane/EtOAc) to afford the corresponding

aldehyde (32 mg, 92% yield): ¹H NMR (300 MHz, CDCl₃)

d 0.90 (t, JZ7 Hz, 3H), 1.16–1.52 (m, 6H), 1.80 (quintet,

JZ7 Hz, 2H), 2.10–2.40 (m, 5H), 2.53 (t, JZ7 Hz, 2H),

2.75 (ddt, JZ17, 4.5, 2 Hz, 1H), 3.60–3.69 (m, 1H), 6.17–

6.34 (m, 2H), 6.41 (dd, JZ6, 1.5 Hz, 1H), 6.96 (d, JZ

11 Hz, 1H), 7.59 (dd, JZ6, 3 Hz, 1H), 9.79 (t, JZ2 Hz,

1H); ¹³C NMR (75 MHz, CDCl₃) d 14.2, 18.3, 21.5, 22.6,

23.4, 28.6, 31.6, 33.6, 42.8, 42.9, 77.3, 81.8, 125.3, 132.0,

134.2, 135.8, 147.4, 159.8, 196.7, 201.8.

1

JZ9 Hz, 2H), 7.66 (dd, JZ6, 2 Hz, 1H). syn Isomer: H

NMR (300 MHz, CDCl₃) d 0.88 (t, JZ7 Hz, 3H), 1.1–1.8

(m, 11H), 2.03 (q, JZ7 Hz, 2H), 2.08–2.22 (m, 2H), 2.28–

2.40 (m, 2H), 2.44–2.52 (m, 1H), 2.95–3.04 (m, 1H), 3.44 (t,

JZ7 Hz, 2H), 3.80 (s, 3H), 4.42 (s, 2H), 4.55–4.62 (m, 1H),

5.46 (ddt, JZ16, 7, 1.5 Hz, 1H), 5.74 (dt, JZ16, 7 Hz, 1H),

6.19 (dd, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz, 2H), 7.25 (d,

JZ9 Hz, 2H), 7.66 (dd, JZ6, 2 Hz, 1H).

To a slurry of the above aldehyde (25 mg, 0.084 mmol) in

t-BuOH (1.1 mL), phosphate buffer of pH 3.6 (0.53 mL),

and 2-methyl-2-butene (0.09 mL, 0.85 mmol) was added

NaClO₂(14 mg, 0.12 mmol, 80% purity) in water

(0.42 mL). The mixture was stirred at ambient temperature

for 3 h, and concentrated by using a vacuum pump.

Phosphate buffer of pH 3.6 was added to the residue, and

the mixture was extracted with EtOAc several times. The

combined organic layers were dried over MgSO₄and

concentrated to afford an oily residue, which was puriﬁed by

chromatography (CH₂Cl₂/EtOH) to furnish the title acid 6

(24 mg, 91% yield): [a]_D²⁷C157 (c 0.22, CHCl₃); IR (neat)

3100, 1699, 1630, 1209 cm^K1; ¹H NMR (300 MHz, CDCl₃)

d 0.90 (t, JZ7 Hz, 3H), 1.20–1.56 (m, 6H), 1.79 (quintet,

JZ7 Hz, 2H), 2.14–2.38 (m, 5H), 2.45 (t, JZ7 Hz, 2H),

2.70–2.84 (m, 1H), 3.60–3.70 (m, 1H), 6.15–6.36 (m, 2H),

6.42 (dd, JZ6, 2 Hz, 1H), 6.96 (d, JZ11 Hz, 1H), 7.61 (dd,

JZ6, 2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) d 14.2, 18.3,

22.6, 23.4, 23.9, 28.6, 31.6, 32.8, 33.7, 43.0, 77.4, 81.7,

125.3, 132.3, 134.2, 135.7, 147.6, 160.2, 178.1, 197.1.

To a solution of the crude aldol 43 in CH₂Cl₂(5 mL) and

Et₃N (0.67 mL, 4.8 mmol) at K15 8C was added MsCl

(0.15 mL, 1.94 mmol) dropwise. After 45 min at the same

temperature, the reaction was quenched by addition of

saturated NaHCO₃. The mixture was extracted with EtOAc

three times. The combined organic layers were dried over

MgSO₄and concentrated to furnish an yellow residue,

which was puriﬁed by chromatography (hexane/EtOAc) to

afford dienone 44 (143 mg, 71% yield from enone 38) and

(Z)-isomer (12 mg, 6% yield). Dienone 44: ¹H NMR

(300 MHz, CDCl₃) d 0.90 (t, JZ7 Hz, 3H), 1.22–1.75 (m,

10H), 2.10–2. 28 (m, 5H), 2.70–2.82 (m, 1H), 3.46 (t, JZ

6 Hz, 2H), 3.58–3.67 (m, 1H), 3.80 (s, 3H), 4.43 (s, 2H),

6.16–6.35 (m, 2H), 6.40 (dd, JZ7, 2 Hz, 1H), 6.88 (d, JZ

8 Hz, 2H), 6.95 (d, JZ11 Hz, 1H), 7.26 (d, JZ8 Hz, 2H),

7.64 (dd, JZ6, 2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) d

14.2, 18.7, 22.6, 23.6, 25.8, 28.7, 29.1, 31.6, 33.6, 43.2,

55.4, 69.7, 72.7, 77.2, 82.9, 113.8, 125.4, 129.2, 130.7,

132.0, 134.3, 135.6, 147.3, 159.1, 160.2, 196.8. (Z)-Isomer

of 44: ¹H NMR (300 MHz, CDCl₃) (characteristic signals) d

6.06 (dt, JZ15, 8 Hz, 1H), 6.33 (dd, JZ6. 2 Hz, 1H), 6.49

4.8. Synthesis of 5,6-dihydro-15-deoxy-D^12,14-PGJ₂(7)

4.8.1. (1R,4R)-4-[7⁰-(4-Methoxybenzyloxy)heptyl]-2-

cyclopenten-1-ol (46). To an ice-cold slurry of LiCl

(180 mg, 4.25 mmol) and PMBO(CH₂)₇MgBr (45)

(9.10 mL, 0.35 M in THF, 3.19 mmol) was added CuCN

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

3341

(29 mg, 0.323 mmol). After 30 min at K10 8C, monoacetate

ent-8a (150 mg, 1.06 mmol, O95% ee) in THF (2 mL) was

added.Themixturewasstirredatthesametemperaturefor3 h,

and the solution was diluted with saturated NH₄Cl, few drops

of 28% NH₃, and EtOAc. The organic layer was separated and

the aqueous layer was extracted with EtOAc twice. The

combined organic fractions were dried over MgSO₄and

concentrated to obtain an yellow oil, which was a mixture of

1,4-isomer 46 and 1,2-isomer 51 in a 92:8 ratio by ¹H NMR

spectroscopy. The mixture was separated by chromatography

(hexane/EtOAc). Alcohol 46 (272 mg, 81% yield): IR (neat)

3398, 1613, 1513, 1248 cm^K1; ¹H NMR (300 MHz, CDCl₃) d

1.16–1.48 (m, 8H), 1.52–1.70 (m, 5H), 1.75 (ddd, JZ14, 7,

5 Hz, 1H), 1.89 (ddd, JZ14, 7, 3 Hz, 1H), 2.78–2.90 (m, 1H),

3.43 (t, JZ7 Hz, 2H), 3.79 (s, 3H), 4.42 (s, 2H), 4.79–4.87 (m,

1H), 5.80 (dt, JZ5, 2 Hz, 1H), 5.93 (dd, JZ5, 2 Hz, 1H), 6.87

(d, JZ9 Hz, 2H), 7.26 (d, JZ9 Hz, 2H); ¹³C NMR (75 MHz,

CDCl₃) d 26.2, 27.9, 29.4, 29.70, 29.75, 35.9, 40.6, 44.1, 55.3,

70.2, 72.5, 77.1, 113.7, 129.2, 130.8, 132.4, 140.2, 159.1.

Regioisomer 51: ¹H NMR (300 MHz, CDCl₃) d 1.10–1.46 (m,

8H), 1.50–1.65 (m, 5H), 2.25 (dm, JZ18 Hz, 1H), 2.46–2.56

(m, 1H), 2.70 (dd, JZ18, 7 Hz, 1H), 3.43 (t, JZ7 Hz, 2H),

3.79 (s, 3H), 4.04–4.12 (m, 1H), 4.42 (s, 2H), 5.61–5.73 (m,

2H), 6.87 (d, JZ9 Hz, 2H), 7.26 (d, JZ9 Hz, 2H).

saturated NaHCO₃. The mixture was extracted with EtOAc

three times. The combined organic layers were dried over

MgSO₄and concentrated to furnish an yellow residue,

which was subjected to chromatography (hexane/EtOAc) to

afford dienone 49 (136 mg, 51% yield from enone 47) and

(Z)-isomer 52 (14 mg, 5% yield). Dienone 49: IR (neat)

1

1694, 1633, 1513, 1248, 1099 cm^K1; H NMR (300 MHz,

CDCl₃) d 0.89 (t, JZ7 Hz, 3H), 1.2–1.7 (m, 17H), 1.75–

1.95 (m, 1H), 2.22 (q, JZ7 Hz, 2H), 3.41 (t, JZ7 Hz, 2H),

3.49–3.56 (m, 1H), 3.79 (s, 3H), 4.42 (s, 2H), 6.14–6.30 (m,

2H), 6.34 (dd, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz, 2H), 6.92

(d, JZ10 Hz, 1H), 7.25 (d, JZ9 Hz, 2H), 7.51 (dd, JZ6,

2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) d 14.1, 22.5, 26.0,

26.2, 28.5, 29.4, 29.76, 29.78, 31.4, 33.0, 33.5, 43.6, 55.3,

70.2, 72.6, 113.8, 125.7, 129.3, 130.8, 131.3, 135.2, 135.7,

146.6, 159.1, 161.2, 197.7. (Z)-Isomer 52: ¹H NMR

(300 MHz, CDCl₃) (characteristic signals) d 6.07 (dt, JZ

15, 8 Hz, 1H), 6.28 (dd, JZ6, 2 Hz, 1H), 6.38 (d, JZ11 Hz,

1H), 7.42 (dd, JZ6, 2 Hz, 1H), 7.60–7.74 (m, 1H).

4.8.4. Alcohol 50. To an ice-cold solution of dienone 49

(135 mg, 0.317 mmol) in CH₂Cl₂(3 mL) and water (0.2 mL)

was added DDQ (108 mg, 0.476 mmol). After 45 min, the

reaction was quenched by addition of saturated NaHCO₃and

ether. The organic layer was separated and the aqueous layer

was extracted with ether twice. The combined organic

fractions weredried overMgSO₄and concentrated toobtained

an yellow residue, which was puriﬁed by chromatography

(hexane/EtOAc) to furnish alcohol 50 as an oil (90 mg, 92%

4.8.2. (R)-4-[7⁰-(4-Methoxybenzyloxy)heptyl]-2-cyclo-

penten-1-one (47). To a solution of alcohol 46 (250 mg,

0.79 mmol) in CH₂Cl₂(8 mL) was added PCC (254 mg,

1.18 mmol). After being stirred vigorously for 1 h, the

mixture was diluted with ether and ﬁltered through a pad of

Celite. The ﬁltrate was concentrated to obtain an yellow

residue, which was puriﬁed by chromatography (hexane/

EtOAc) to furnish enone 47 (226 mg, 91% yield) as an oil:

¹H NMR (300 MHz, CDCl₃) d 1.1–1.7 (m, 12H), 1.99 (dd,

JZ19, 2 Hz, 1H), 2.52 (dd, JZ19, 7 Hz, 1H), 2.84–2.96 (m,

1H), 3.42 (t, JZ7 Hz, 2H), 3.79 (s, 3H), 4.42 (s, 2H), 6.13

(dd, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz, 2H), 7.25 (d, JZ

9 Hz, 2H), 7.62 (dd, JZ6, 2 Hz, 1H).

1

yield): IR (neat) 3417, 1695, 1630, 1213 cm^K1; H NMR

(300 MHz, CDCl₃) d 0.90 (t, JZ7 Hz, 3H), 1.1–1.7 (m, 18H),

1.80–1.94 (m, 1H), 2.22 (q, JZ7 Hz, 2H), 3.50–3.59 (m, 1H),

3.63(t, JZ7 Hz, 2H), 6.15–6.31(m, 2H), 6.35(dd,JZ6,2 Hz,

1H), 6.92 (d, JZ11 Hz, 1H), 7.51 (dd, JZ6, 2 Hz, 1H); ¹³C

NMR (75 MHz, CDCl₃) d 14.1, 22.6, 25.7, 26.0, 28.5, 29.4,

29.8, 31.5, 32.8, 33.0, 33.5, 43.6, 63.1, 125.7, 131.4, 135.2,

135.7, 146.7, 161.2, 197.8.

4.8.5. 5,6-Dihydro-15-deoxy-D^12,14-PGJ₂(7). To an ice-

cold solution of alcohol 50 (90 mg, 0.296 mmol) in CH₂Cl₂

(5 mL), DMSO (1.5 mL), and Et₃N (0.29 mL, 2.1 mmol) was

added SO₃$pyridine (141 mg, 0.89 mmol). The solution was

stirred vigorously at the same temperature for 1.5 h, and

diluted with ether and cold water. The resulting mixture was

stirred vigorously at room temperature for 20 min. The phases

were separated and the aqueous layer was extracted with ether

twice. The combined organic layers were dried over MgSO₄

and concentrated to obtain an yellow residue, which was

puriﬁed bycolumn chromatography(hexane/EtOAc) to afford

the corresponding aldehyde (83 mg, 93% yield): IR (neat)

1725, 1694, 1634, 1205 cm^K1; ¹H NMR (300 MHz, CDCl₃) d

0.90 (t, JZ7 Hz, 3H), 1.1–1.7 (m, 17H), 1.78–1.92 (m, 1H),

2.22 (q, JZ7 Hz, 2H), 2.41 (dt, JZ1.5, 7 Hz, 2H), 3.50–3.58

(m, 1H), 6.14–6.30 (m, 2H), 6.35 (dd, JZ6, 2 Hz, 1H), 6.92(d,

JZ10 Hz, 1H), 7.51 (dd, JZ6, 2 Hz, 1H), 9.76 (t, JZ1.5 Hz,

1H);¹³CNMR(75 MHz,CDCl₃)d14.1, 22.0, 22.5, 25.8, 28.5,

29.0, 29.6, 31.4, 32.9, 33.5, 43.5, 43.9, 125.7, 131.4, 135.3,

135.6, 146.7, 161.1, 197.8, 202.7.

4.8.3. Dienone 49. To an ice-cold solution of i-Pr₂NH

(0.27 mL, 1.93 mmol) in THF (9 mL) was added n-BuLi

(0.67 mL, 1.90 M in hexane, 1.27 mmol). The solution was

stirred at the same temperature for 20 min to prepare LDA

and cooled to K78 8C. To this solution were added enone 47

(200 mg, 0.63 mmol) dissolved in THF (3 mL) and, after

20 min, trans-2-octenal (29) (0.14 mL, 0.94 mmol). The

solution was stirred for further 30 min at the same

temperature, and poured into a ﬂask containing saturated

NH₄Cl and ether with vigorous stirring. After 30 min, the

organic layer was separated and the aqueous layer was

extracted with EtOAc twice. The combined organic extracts

were dried over MgSO₄and concentrated to afford aldol 48

as the anti and syn isomers in a 3:1 ratio by TLC analysis,

which was used for the next reaction after ﬁltration through

1

a short column of silica gel: H NMR (300 MHz, CDCl₃)

(characteristic peaks only) d 5.38–5.50 (m, 1H), 5.64–5.78

(m, 1H), 6.12 (dd, JZ6, 2 Hz, 1H), 6.87 (d, JZ9 Hz, 2H),

7.25 (d, JZ9 Hz, 2H), 7.65–7.72 (m, 1H).

To a solution of the above aldol 48 in CH₂Cl₂(6 mL) and

Et₃N (0.88 mL, 6.31 mmol) at K20 8C was added MsCl

(0.195 mL, 2.52 mmol) dropwise. After 45 min at the same

temperature, the reaction was quenched by addition of

To a slurry of the above aldehyde (80 mg, 0.264 mmol) in

t-BuOH (3.5 mL), phosphate buffer of pH 3.6 (1.7 mL), and

2-methyl-2-butene (0.26 mL, 2.45 mmol) was added

NaClO₂(45 mg, 0.398 mmol, purity 80%) in water

3342

H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

9. The cis geometry at C(14) of this compound from the company

is recently claimed to be trans.¹³

(1.3 mL). The resulting mixture was stirred at room

temperature for 1 h, and connected to a vacuum pump to

remove volatile compounds (t-BuOH). The phosphate

buffer of pH 3.6 was added to the residue, and the mixture

was extracted with EtOAc several times. The combined

organic layers were dried over MgSO₄and concentrated to

afford an oily residue, which was puriﬁed by chromato-

graphy (CH₂Cl₂/EtOH) to furnish acid 7 (76 mg, 90%

10. Wakatsuki, H,; Yamoto, T.; Hashimoto, S. Eur. Pat. Appl.,

EP97023, 1983; Chem. Abstr. 1984, 100, 174519.

11. Bickley, J. F.; Jadhav, V.; Roberts, S. M.; Santoro, M. G.;

Steiner, A.; Sutton, P. W. Synlett 2003, 1170–1174.

12. Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc.

1963, 85, 582–585.

1

yield): IR (neat) 3000, 1708, 1697, 1206 cm^K1; H NMR

13. Brummond, K. M.; Sill, P. C.; Chen, H. Org. Lett. 2004, 6,

149–152.

(300 MHz, CDCl₃) d 0.89 (t, JZ7 Hz, 3H), 1.1–1.7 (m,

17H), 1.78–1.94 (m, 1H), 2.22 (q, JZ7 Hz, 2H), 2.33 (t, JZ

7.5 Hz, 2H), 3.50–3.58 (m, 1H), 6.15–6.34 (m, 2H), 6.35

(dd, JZ6, 2 Hz, 1H), 6.93 (d, JZ11 Hz, 1H), 7.51 (dd, JZ

6, 2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) d 14.1, 22.6, 24.6,

25.8, 28.5, 29.0, 29.5. 31.4, 32.9, 33.5, 33.9, 43.6, 125.7,

131.5, 135.3, 135.6, 146.8, 161.2, 179.1, 197.8.

14. Acharya, H. P.; Kobayashi, Y. Tetrahedron Lett. 2004, 45,

1199–1202.

15. Meinwald rearrangement of the optically enriched intermedi-

ate produces a 1:1 mixture of diastereomers at the newly

created stereocenter.¹¹

16. (a) Deardorff, D. R.; Linde, R. G., II; Martin, A. M.; Shulman,

M. J. J. Org. Chem. 1989, 54, 2759–2762. (b) Montforts, F.-P.;

Gesing-Zibulak, I.; Grammenos, W.; Schneider, M.; Laumen,

K. Helv. Chim. Acta 1989, 72, 1852–1859.

Acknowledgements

This work was supported by a Grant-in-Aid for Scientiﬁc

Research from the Ministry of Education, Science, Sports,

and Culture, Japan. We thank Ono Pharmaceutical Co., Ltd

17. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–3772.

18. (a) Kobayashi, Y.; Nakata, K.; Ainai, T. Org. Lett. 2005, 7,

183–186. (b) Ainai, T.; Ito, M.; Kobayashi, Y. Tetrahedron

Lett. 2003, 44, 3983–3986.

1

for providing us H NMR spectrum of D¹²-PGJ₂.

19. b-Hydride elimination is probably the reason, though we did

not obtain any evidence for the production of 3-cyclopentenon.

20. (a) Sugai, T.; Mori, K. Synthesis 1988, 19–22. (b) Laumen, K.;

Schneider, M. P. J. Chem. Soc., Chem. Commun. 1986,

1298–1299.

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1

comparison of R_fvalues and H NMR chemical shifts with

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hydrogen at C(12), the steric congestion between the carbonyl

oxygen and the C(14) methylene (shown as R) changes A less

favorably than B, and that (2) the participation of Al₂O₃in the

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H. P. Acharya, Y. Kobayashi / Tetrahedron 62 (2006) 3329–3343

3343

32. Deprotection of the TBS group with TBAF in THF and with

NBS in wet DMSO was unsuccessful.

OMs

33. The stereochemistry of the newly formed oleﬁn at C(13) was

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H

O

R

H

O

O Al

(Z )-Isomer

anti elimination A

of 12

anti-21

R

H

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O

H O

O

S

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Me

12

Al

O

syn elimination B

Article Doi

Highly efficient total synthesis of Δ12-PGJ2, 15-deoxy-Δ12,14-PGJ2, and their analogues

DOI: 10.1016/j.tet.2006.01.051

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Full text of DOI:10.1016/j.tet.2006.01.051

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