Rh(I)-Catalyzed 1,4-Conjugate Addition of Alkenylboronic Acids to a Cyclopentenone Useful for the Synthesis of Prostaglandins

Article abstract of DOI:10.1021/acs.joc.6b01913

An efficient and trans-diastereoselective Rh(I)-catalyzed 1,4-conjugate addition reaction of alkenylboronic acids and a homochiral (R)-4-silyloxycyclopentenone useful for the synthesis of derivatives of prostaglandins E and F is described for the first time. The reaction functions under mild conditions and is particularly rapid (≤6 h) under low power (50 W) microwave irradiation at 30 °C in MeOH in the presence of a catalytic amount of KOH. Under these conditions, 3 mol % of [RhCl(COD)]₂ is typically required to produce high yields. The method also functions without microwave irradiation at 3 °C in the presence of a stoichiometric amount of KOH. Under these conditions, only 1.5 mol % of [RhCl(COD)]₂ is needed, but the reaction is considerably slower. The method accepts a range of aryl- and alkyl-substituted alkenylboronic acids, and its utility has been demonstrated by the synthesis of PGF_2α (dinoprost) and tafluprost.

Full text of DOI:10.1021/acs.joc.6b01913

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Article
Rh(I)-Catalyzed 1,4-Conjugate Addition Of Alkenylboronic Acids
to a Cyclopentenone Useful for the Synthesis of Prostaglandins
Jin-Fong Syu, Yun-Ting Wang, Kung-Cheng Liu, Ping-
Yu Wu, Julian Paul Henschke, and Hsyueh-Liang Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01913 • Publication Date (Web): 07 Oct 2016
Downloaded from http://pubs.acs.org on October 8, 2016
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Rh(I)-Catalyzed 1,4-Conjugate Addition Of Alkenylboronic
Acids to a Cyclopentenone Useful for the Synthesis of
Prostaglandins
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Jin-Fong Syu,† Yun-Ting Wang,† Kung-Cheng Liu,‡ Ping-Yu Wu,‡ Julian P.
Henschke*,‡ and Hsyueh-Liang Wu*,†
†Department of Chemistry and Instrumentation Center, National Taiwan Normal University, No. 88,
Section 4, Tingzhou Road, Taipei 11677, Taiwan, Republic of China
‡ScinoPharm Taiwan, Ltd. No. 1, Nan-Ke 8th Road, Southern Taiwan Science Park, Shan-Hua, Tainan
74144,Taiwan, Republic of China
*E-mail: julian.henschke@scinopharm.com (J. P. Henschke) and hlw@ntnu.edu.tw (H.-L. Wu)
KEYWORDS: rhodium-catalyzed, conjugate addition, PGF2α, dinoprost, tafluprost
TOC:
CO2i-Pr
CO2R4
i-PrO2C
O
O
HO
HO
R2
[RhCl(COD)]2
MeOH, KOH
R2
R1
(HO)2B
+
R1
R3
R1
TBSO
TBSO
R3
R1 = alkyl or aryl
R2 = R3 = H or alkyl
15 examples
up to 98%
isolated yield
2 examples
C5H11
PGF2α: R1 =
, R4 = H
OH
4
tafluprost: R1 =
, R = i-Pr
OPh
• Rh(I)-catalyzed two-component coupling
• High diastereoselectivity (trans) and yields
F
F
• Useful for gram-scale synthesis of PGF2αs (tafluprost and PGF2α
)
ABSTRACT: An efficient and trans-diastereoselective Rh(I)-catalyzed 1,4-conjugate
addition reaction of alkenylboronic acids and homochiral (R)-4-
a
silyloxycyclopentenone useful for the synthesis of prostaglandin E and F derivatives
is described for the first time. The reaction functions under mild conditions and is
particularly rapid (≤6 h) under low power (50 W) microwave irradiation at 30 °C in
MeOH in the presence of a catalytic amount of KOH. Under these conditions, 3 mol
% of [RhCl(COD)]2 is typically required to produce high yields. The method also
functions without microwave irradiation at 3 °C in the presence of a stoichiometric
amount of KOH. Under these conditions, only 1.5 mol % of [RhCl(COD)]2 is needed,
but the reaction is considerably slower. The method accepts a range of aryl- and alkyl-
substituted alkenylboronic acids and its utility has been demonstrated by the synthesis
of PGF2α (dinoprost) and tafluprost.
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INTRODUCTION
Discovered by von Euler in the 1930s, prostaglandins1 (PGs) are naturally
occurring, monocyclic C20-polyunsaturated fatty acids that regulate a host of
physiological functions in animals and are employed in the clinic for the treatment of
human ailments including peptic ulcers, erectile dysfunction and pain, and to induce
childbirth (e.g. 1a) and abortion.2 Additionally, the synthetic PGF2α derivatives
tafluprost (1b)3a, travoprost (1c),3b bimatoprost (1d)3c and latanoprost (1e)3d are used
for the treatment of ocular hypertension and glaucoma (Figure 1). Bimatoprost is also
marketed as the beauty product Latisse®. The 16,16-difluoro-PGE1 derivative,
lubiprostone (1f),3e is used orally for the treatment of constipation.
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CO2i-Pr
CO2i-Pr
CO2H
HO
HO
HO
HO
HO
O
OPh
CF3
HO
HO
F
F
HO
PGF2α
(dinoprost (1a))
travoprost (1c)
(Travatan®)
tafluprost (1b)
(Zioptan®)
CO2i-Pr
CO2H
CONHEt
HO
O
HO
lubiprostone (1f)
Ph
Ph
HO
HO
O
(Amitiza®)
HO
HO
bimatoprost (1d)
(Lumigan® & Latisse®)
latanoprost (1e)
HO
F
(Xalatan®)
F
Figure 1. Clinically Useful Prostaglandins
Given their therapeutic efficacy, the development of efficient and practical
methods for the synthesis and manufacture of prostaglandins and their analogues has
attracted great interest both in academia and in industry since the 1970s (Scheme 1).2,4
Amidst the many synthetic approaches reported,2,4b,5 the industrially useful Corey
lactone route6 and Sih’s two-component 1,4-conjugate addition method,7 and the
elegant but less practical three-component method8 epitomized by Noyori in the
1980s,9 embody the more commonly used strategies.
Scheme 1. Synthetic Strategies for Prostaglandins (Illustrated for Dinoprostone)
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O
O
O
O
6
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8
O
Corey
(late 1960s)
C5H11
9
PgO
PgO
Corey lactone
PgO
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CO2H
PGE2
O
5
9
6
14
(dinoprostone)
Pg = protecting group
12
13
11
C5H11
HO
HO
Sih
(early 1970s)
Noyori
(mid 1980s)
CO2Pg
CO2Pg
O
O
X
Three-component
coupling
Two-component
coupling
[Cu]
C5H11
PgO
[Cu]
C5H11
PgO
PgO
PgO
Previously we disclosed the use10a,b of the homochiral (R)-4-
silyloxycyclopentenone isopropyl ester 210c as a pivotal starting material for the
manufacture of pharmacologically useful PGE1 and PGF2α derivatives. Using the
aforementioned two-component method, 2 was reacted with higher-order
alkenyl(cyano)cuprates 311 at or below −50 °C (Scheme 2). Although viable on
manufacturing scales for the production of clinical-grade 1c,10a 1d10a and 1f,10b
coupling of the electron deficient γ,γ-difluoroalkenylcuprate 4 with 2, requisite for the
synthesis of tafluprost (1b), was unsuccessful; a more lengthy approach was
required.12a Given this, the need for cryogenic temperatures and wanting to avoid the
use of vinyltin11 compounds as precursors to 3, we sought to develop an improved
variant of the conventional two-component method.
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Scheme 2. Synthesis of Prostaglandin Derivatives 1b, 1c, 1d, and 1f Using
Alkenyl(cyano)cuprates in the Two-Component Method10,12a
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7
8
9
CO2i-Pr
n-Bu3Sn
R
Li2Me(CN)Cu
R
O
travoprost (1c)
bimatoprost (1d)
lubiprostone (1f)
3
OPg
OPg
Ref. 10a, 10b
BzO
(Pg: protecting group)
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cryogenic temperatures
R
(−50 to −78 °C)
TBSO
PgO
CO2i-Pr
CO2i-Pr
O
OPh
O
BzO
TBSO
2
Ref. 10c
CO2i-Pr
Ref. 12a
O
1,4-conjugate addition
failed
tafluprost (1b)
n-Bu3Sn
Li2Me(X)Cu
OPh
OPh
OPh
TBSO
F
F
F
F
F F
X = CN or I
4
6q
Although the Hayashi-Miyaura reaction,13 namely the Rh(I) catalyzed 1,4-addition
of aryl- and alkenylboron compounds to activated alkenes, has been applied to the
conjugate addition of alkenyl nucleophiles to cyclopentenone substrates, neither
components possessed the structural complexity required to prepare prostaglandins.14
Csákÿ et al.14c reported the Rh(I)-catalyzed 1,4-addition reaction of arylboronic acids
and 2-aryl-alkenylboronic acids to (S)-2-phenyl-4-hydroxycyclopent-2-enone,
featuring an unprotected hydroxyl group. While the use of arylboronic acids provided
3,4-trans-substituted products, 2-aryl-alkenylboronic acids selectively gave 3,4-cis-
substituted products, or mixtures (0.7:1–1.5:1) of the cis- and trans-substituted
products, unless 3 equiv of CsF was used as an additive using aqueous dioxane as a
solvent. Having experience with variants of the Hayashi-Miyaura reaction,15 we
predicted that its application to prostaglandin synthesis, if feasible,15c would allow
for: milder reaction conditions, circumvention of cryogenic temperatures, and the
trading of the moisture- and air-sensitive alkenylcuprates 3 of the conventional
approach for readily accessible,16 stable and isolable alkenylboronic acids and their
derivatives. Crucially, however, to fit with the established manufacturing
processes,10a,b it was imperative that: cyclopentenone 2 could be used, that 3,4-trans-
substituted products would be exclusively obtained and that the reaction conditions
were amenable to the use of silyl protecting groups and alkenylboronic acids
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substituted with alkyl substituents, including those possessing stereogenic centers,
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suitable for the preparation of prostaglandins such as 1a–1f.
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RESULTS AND DISCUSSION
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Preliminary results. Model studies began with the 1,4-addition of styrylboronic
acid (5a) to enone 2 using [RhCl(COD)]2 as precatalyst (Table 1). While dioxane is
commonly used in Rh(I)-catalyzed reactions,13,14c its toxicity17 rendered it unattractive
and studies were therefore focused on manufacturing-applicable alcohol solvents
instead. Despite prior success using the mild combination of Et3N in MeOH for 1,2-
and 1,4-additions in the presence of Rh(I) catalysts,15a Et3N, piperidine or t-BuNH2 in
MeOH promoted only low to moderate conversion of 2 to PGE2 derivative 6a (entries
1–3). KHF2 in MeOH, EtOH or i-PrOH (entries 4–6), on the other hand, provided
considerably improved yields (73–75%), while reactions in these same solvents
(entries 7–9) in the presence of KOH proved best in MeOH (80%; entry 7). K3PO4 in
MeOH (entry 10) was inferior to KOH (entry 7) and KHF2 (entry 4) in the same
solvent.
Table 1. Screening of Solvents and Additivesa
CO2i-Pr
O
[RhCl(COD)]2
(1.5 mol %)
(HO)2B
+
2
Ph
11
solvent, additive
25 °C, 72 h
Ph
R
5a
6a: R = OTBS
7: R = (E)-CH=CHPh
(mixture of diastereomers at C11)
entry
solvent
additive
yield 6a (%)b
yield 7 (%)b
MeOH
MeOH
MeOH
MeOH
EtOH
Et3N
Piperidine
t-BuNH2
KHF2
18
28
50
75
73
74
80
75
70
60
10
0
1
2
0
3
0
4
KHF2
20
9
5
i-PrOH
MeOH
EtOH
KHF2
6
KOH
4
7
KOH
9
8
i-PrOH
MeOH
KOH
3
9
K3PO4
0
10
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aSolutions of 2 (0.15 mmol), 5a (0.225 mmol, 1.5 equiv), [RhCl(COD)]2 (1.5 mol %),
and amines (0.9 mmol), or aq KHF2 (3.0 M, 0.3 mL, 0.9 mmol), aq KOH (3.1 M,
9.5 µL, 30 µmol) or aq K3PO4 (1.5 M, 0.6 mL, 0.9 mmol) in MeOH, or EtOH or i-
PrOH (0.8 mL) were stirred at 25 °C for 72 h. Determined by H NMR analysis
using 3,4,5-(MeO)3C6H2CHO as external standard.
b
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Consistent with organocuprate additions to enone 2,10 the Rh(I)-catalyzed addition
of 5a occurred to the sterically more accessible Re-face of the C8−C12 olefin of 2 at
C12, yielding 6a as a single diastereomer.18 Additionally, the double-addition product
7, isolated as a ca. 8:2 mixture of 7 and 11-epi-7, was formed, presumably via
elimination of the silyl ether of 6a and subsequent Rh(I)-catalyzed addition of 5a to
the resulting α,β-unsaturated ketone. Consistent with this, subjecting 6a to the
conditions in Table 1, entry 7 at 60 °C in the presence of 5a resulted in its conversion
to 7. This side-product initially proved persistent and troublesome, particularly at
higher temperatures such as ≥60 °C and/or in the presence of a large excess of the
boronic acid. In fact, in some tests 7 dominated the product mixtures.
Table 2. Reaction Optimizationa
[RhCl(COD)]2
(x mol %)
X
2
+
6a and 7
Ph
MeOH, KOH
(1.5 equiv)
5a: X = B(OH)2
5b: X = BF3K
5c: X = B[OC(Me)2]2
entry
1c
x
1.5
5
T (°C)
time (h) yield 6a (%)b yield 7 (%)b
5a
5a
5a
5a
5a
5a
5a
5b
5c
50
50
40
30
30
30
30
30
30
8
3
6
5
6
5
6
5
5
60
65
73
84
29
84
96g
48
58
29
9
2d
1.5
3d
1.5
3
4d
1.5
0
5d,e
6d
1.5
0
3.0
0
7d,f
8d,f
9d,f
1.5+1.5
1.5+1.5
1.5+1.5
0
0
0
aSolutions of 2 (0.15 mmol), 5a (0.225 mmol, 1.5 equiv), [RhCl(COD)]2 (1.5 mol %)
and aq KOH (3.1 M, 9.5 µL, 30 µmol) in MeOH (0.8 mL) were stirred at T °C. bNMR
c
yield using 3,4,5-(MeO)3C6H2CHO as external standard. Conventional heating.
dMicrowave irradiation. e[RhOH(COD)]2 was used. fAdditional portions of
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[RhCl(COD)]2 (1.5 mol %) and 5a (0.5 equiv) were added after 5 h; 5b or 5c (0.5
equiv) was added after 3 h. gIsolated yield.
6
7
8
9
While using the conditions identified in Table 1, entry 7 at 50 °C (Table 2, entry 1)
shortened the reaction time, more 7 (29%) was produced at the expense of 6a (60%).
To our surprise, however, while conducting the reaction at 50 °C under microwave
irradiation19 further improved the reaction rate (65% yield of 6a in 3 h), rather than
increasing, the amount of 7 (9%) was significantly reduced (entry 2). Further
improvements occurred under microwave irradiation when the reaction was
conducted at 40 °C (73% 6a) or 30 °C (84% 6a) and little or no 7 was detected
(entries 3 and 4). While a low yield was observed when directly employing the pre-
activated20 RhOH catalyst (entry 5) and doubling the amount of [RhCl(COD)]2 to
3 mol % (entry 6) garnered no improvement, adding the catalyst in two 1.5 mol %-
portions along with additional 6a after 5 h offered 6a in an excellent 96% isolated
yield (entry 7). Notably, no 7 was detected. While it was expected that the addition of
extra boronic acid 5a would effect further conversion of 2 to 6a, it was unexpected
that an additional portion of the Rh(I) catalyst would also be beneficial. This implies
that the Rh(I) catalyst was poisoned. The use of the corresponding trifluoroborate 5b
or boronic ester 5c in place of boronic acid 5a furnished 6a in a 48% or 58% yield,
respectively (entries 8 and 9).
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REACTION SCOPE UNDER MICROWAVE
Using the same double-portion addition protocol of catalyst and boronic acid, 1,4-
addition of 2-aryl-vinylboronic acids bearing electron-releasing (5d and 5e) and alkyl
substituents (5f–5h) to 2 led to PGE2 derivatives 6d–6h in 88% to 98% isolated yields
(Table 3, entries 1–5). Despite their electron deficiency, both fluorine-containing
boronic acids 5i and 5j were sufficiently reactive giving rise to 6i and 6j in 80% and
92% yield (entries 6 and 7), respectively. Although non-branching alkenylboronic
acid 5k provided 6k in 93% yield (entry 8), less satisfactory yields were observed
(38–76%) when using α-branched alkenylboronic acids 5l, 5m, and 5o (entries 9, 10
and 12). Conversely, the less hindered β,β-dialkyl-substituted alkenylboronic acid 5n
afforded 6n in 99% yield (entry 11).
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Table 3. Reaction Scope under microwave irradiationa
5
6
7
8
CO2i-Pr
O
[RhCl(COD)]2
R2
(3 mol %)
R2
(HO)2B
2
+
R1
9
MeOH, KOH
µW, 30 °C
R3
R1
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TBSO
R3
5
6
entry
1
2c
5
time (h)
yield 6 (%)b
93 (6d)
93 (6e)
95 (6f)
R1=4-MeO-Ph, R2=R3=H (5d)
R1=3-MeO-Ph, R2=R3=H (5e)
R1=4-Me-Ph, R2=R3=H (5f)
R1=3-Me-Ph, R2=R3=H (5g)
R1=2-Me-Ph, R2=R3=H (5h)
R1=4-CF3-Ph, R2=R3=H (5i)
R1=4-F-Ph, R2=R3=H (5j)
R1=C6H13, R2=R3=H (5k)
R1-R3=(CH2)4, R2=H (5l)
R1=R3=Me, R2=H (5m)
6
5
6
6
5
5
5
6
5
5
6
5
3
4
5c
6c
7c
98 (6g)
88 (6h)
80 (6i)
92 (6j)
8
9c
10c
11
12c
93 (6k)
38 (6l)
37 (6m)
99 (6n)
76 (6o)
R1=R2=Me, R3=H (5n)
R3=Me, R1=R2=H (5o)
(HO)2B
13d,e
5
98 (6p)f
OTBS
(5p)
(HO)2B
OPh
14e,g
6
67 (6q)h
F
F
(5q)
15c
5
65 (6r)
64 (6s)
(HO)2B
O
CF3
OTBS
(5r)
(HO)2B
Ph
16c
6
OTBS
(5s)
aSolutions of 2 (0.15 mmol), 5 (0.225 mmol, 1.5 equiv), [RhCl(COD)]2 (1.5 mol %)
and aq KOH (3.1 M, 9.5 µL, 30 µmol) in MeOH (0.8 mL) were stirred under
microwave irradiation at 30 °C. Additional portions of [RhCl(COD)]2 (1.5 mol %)
and 5 (0.5 equiv) were added after 5 h and the reaction was irradiated for a further 1 h.
bChromatographically isolated yield. Additional portions of [RhCl(COD)]2 (1.5 mol
c
%) and 5 (0.5 equiv) were added after 3 h instead of after 5 h, and the reaction was
d
e
irradiated for a further 2 h. On a 0.79 mmol scale of 2. Additional portions of
f
[RhCl(COD)]2 (1.5 mol %) and 5p or 5q (1.5 equiv) were added after 3 h. 82%
Isolated yield (2.65 g) on a 5.2 mmol scale of 2. gConducted at 50 °C. hThe potassium
trifluoroborate derivative of 5q gave a 62% isolated yield of 6q (after 13 h).
Demonstrating the utility of the reaction. We next explored the synthetic
usefulness of the method by the syntheses of several of the pharmacologically active
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compounds listed in Figure 1. To this end, boronic acids 5p, 5r and 5s were
synthesized from the corresponding optically active propargylic alcohols.21 PGE2
derivative 6p, prepared by the reaction of 5p with 2, was isolated in 98% yield (entry
13), and in an unoptimized 82% yield (2.65 g) on a 5.2 mmol scale. Reduction of 6p
with L-Selectride® gave protected PGF2 8p in 76% yield as a single diastereomer,
following chromatography (Scheme 3). Hydrolysis with NaOMe in MeOH provided
carboxylic acid 9p in 90% yield that was then desilylated in 3 N aq HCl in THF
offering naturally occurring PGF2α, dinoprost (1a), in 89% yield (0.6 g).
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Scheme 3. Synthesis of PGF2α (Dinoprost (1a))
CO2i-Pr
CO2H
HO
HO
RO
L-Selectride®
NaOMe
6p
THF, –78 °C
76%
MeOH, rt
90%
C5H11
C5H11
(Table 3
entry 13)
TBSO
TBSO
8p
RO
9p R = TBS
3 N HCl
THF
89%
1a R = H
More gratifyingly, coupling of difluoro-substituted boronic acid 5q21 and 2 garnered
tafluprost precursor 6q in 67% yield (entry 14), despite the conventional 1,4-addition
of cuprate 4 with 2 failing to produce 6q (Scheme 1). Reduction of 6q with L-
Selectride® in THF followed by fluoride-mediated removal of the silyl ether provided
tafluprost12b (1b; Scheme 4) in high yield (1.52 g, 90%). To the best of our knowledge,
this is the first report of the two-component coupling approach being used for the
synthesis of 1b. Additionally, the formal syntheses of travoprost (1c) and bimatoprost
(1d) were accomplished by the reaction of boronic acids 5r or 5s with 2 under the
standard conditions giving PGE2 derivatives 6r or 6s in 65% or 64% yield,
respectively (entries 15 and 16). The NMR spectra of these compounds were identical
to the same products previously prepared using the conventional cuprate approach.10a
Scheme 4. Synthesis of Tafluprost (1b)
CO2i-Pr
CO2i-Pr
HO
HO
L-Selectride®
TBAF
6q
THF, –78 °C
94%
THF, rt
90%
(Table 3
entry 14)
OPh
OPh
HO
TBSO
F
F
F
F
8q
1b
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Speculating that the presence of the cis-double bond in the α-side chain of
cyclopentenone 2 or the PGE2 products 6 might be responsible for the putative
poisoning of the catalyst suggested above, the saturated analog 10 of cyclopentenone
2 was synthesized for comparative purposes.22 To our surprise, reaction of
cyclopentenone 10 with styrylboronic acid (5a) under the conditions identified in
Table 2, entry 4 furnished PGE1 derivative 11 in only 35% (Table 4, entry 1),
considerably lower than the expected >80% yield. In a competition experiment
between cyclopentenones 2 and 10, addition product 6a was produced in 80% yield,
whereas 11 was obtained in 38% (entry 2). Thus, contrary to that anticipated, these
tests suggest that the distal double bond present in the α-side chain of 2 actually
enhances the rate of the conjugate addition to the cyclopentenone, perhaps by
intramolecular coordination of Rh(I)-metal center to the two double bonds.
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Table 4. Competition reactiona
CO2Me
( )6
CO2Me
( )6
O
O
[RhCl(COD)]2 (1.5 mol %)
5a, MeOH, KOH, µW, 30 °C, 5 h
6a
+
2
+
Ph
10
TBSO
TBSO
11
entry
2 (mmol)
10 (mmol)
0.15
6a (%)b
11 (%)b
35
1
2
0
0
0.075
0.075
80
38
aSolutions of 2 or 10 with indicated amount, 5a (0.225 mmol, 1.5 equiv),
[RhCl(COD)]2 (1.5 mol %) and aq KOH (3.1 M, 9.5 µL, 30 µmol) in MeOH (0.8 mL)
were stirred at 30 °C under microwave irradiation. bIsolated yield.
REACTION IN THE ABSENCE OF MICROWAVE IRRADIATION.
Despite improvements to the conventional two-component method having been
realized, it was concluded that the need for microwave irradiation and the addition of
extra catalyst and boronic acid was limiting; particularly if the method was to be used
on manufacturing scales. With this in mind, the non-microwave irradiated version of
the reaction was reinvestigated (Table 5). While a respectable 80% yield of 6a had
been achieved (Table 1, entry 7) in the absence of microwave irradiation at 25 °C,
higher temperatures resulted in higher yields of double-addition product 7 at the
expense of 6a. It therefore followed that lowering the reaction temperature might
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improve the yield of 6a further. Although 7 was no longer detected (Table 5, entry 1),
conducting the conjugate addition of 5a and 2 at 3 °C provided no improvement (78%
yield of 6a) upon that at 25 °C. In an attempt to enhance the rate of transfer of the
alkenyl group from boron to rhodium, and to reduce protodeboration, the influence of
the base was examined.23 Pleasingly, when the amount of KOH was increased from
20 mol % to 60 mol % at 3 °C, the chemical yield of 6a was raised to 85% (entry 2).
A further improvement (95% yield; entry 3) was seen when employing 120 mol % of
KOH. While the yield corresponded to that of the microwave irradiated reaction
(Table 2, entry 7), the amounts of both the boronic acid 5a and Rh catalyst were
significantly reduced. Although replacing the boronic acid with the corresponding
trifluoroborate 5b or boronic ester 5c under the same conditions (Table 5, entries 4
and 5) was inferior to using 5a (entry 3), the yields similarly matched those of the
corresponding microwave irradiated reaction (Table 2, entries 8 and 9); again, less
catalyst and alkenyl donor 5 were required.
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We speculated that the enhanced boronic acid 5a and Rh catalyst efficiency was the
-
result of a combination of i) improved boronic acid/boronate (RB(OH)2/[RB(OH)3
]K+) equilibria due to the excess base, ii) the impediment of competitive
protodeboration of the boronic acids by the use of a lower reaction temperature, and
iii) reduced over reaction of 6a to form 7 that results from the lower reaction
temperature.
Table 5. Reaction Optimization without microwave irradationa
[RhCl(COD)]2
(1.5 mol %)
2
+
5
6a
KOH (x mol%)
MeOH, 3 °C
(1.5 equiv)
entry
1
x
5
time (d)
yield 6a (%)b yield 7 (%)b
20
60
5a
5a
5a
5b
5c
3
3
3
3
3
78
85
95
44
50
0
0
0
0
0
2c
3d
120
120
120
4d
5d
aSolutions of 2 (0.15 mmol), 5 (0.225 mmol, 1.5 equiv), [RhCl(COD)]2 (1.5 mol %)
and aq KOH (3.1 M, 9.5 µL, 30 µmol) in MeOH (0.8 mL) were stirred at 3 °C.
c
bChromatographically isolated yield. Aq KOH (3.1 M, 29 µL, 90 µmol) was used.
dAq KOH (6.0 M, 30 µL, 0.18 mmol) was used.
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REACTION SCOPE IN THE ABSENCE OF MICROWAVE.
5
6
7
8
Next, the substrate scope was reexamined (Table 6) using the same library of
boronic acids already tested in the microwave irradiated version of the reaction. While
the reactions were much slower at 3 °C than under microwave irradiation at 30 °C, the
reaction yields were generally slightly better. The only general exception was for the
conjugate addition of α-branched alkenylboronic acids 5l and 5m (entries 8 and 9)
that provided much improved yields (90 and 98%) as compared to the microwave
irradiated reaction (Table 3, entries 9 and 10). Although in some cases additional
boronic acid 5 was added to the reactions to ensure good conversion of 2, no reactions
required supplemental additions of the Rh catalyst.
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Owing to decomposition of boronic acid 5p during the attempted preparation of 6p,
as required for the synthesis of dinoprost (1a) (Scheme 3), the amount of KOH was
reduced back to 20%. This allowed conversion to the desired product 6p in an
acceptable 72% yield on a 0.84 mmol scale without extra boronic acid being added
(entry 11). While addition of 5q to 2 (0.45 mmol) afforded 6q in 78% yield, an
additional portion of boronic acid 5q (1.0 equiv, entry 12) was used. The method was
also applicable to the syntheses of PGE derivatives 6r (>99%) and 6s (95%) which
are precursors to travoprost (1c) and bimatoprost (1d) (entries 13 and 14),
respectively.
Table 6. Reaction Scope without microwave irradationa
[RhCl(COD)]2
(1.5 mol %)
2
+
5
6
KOH, MeOH, 3 °C
entry
1
5
time (d)
yield 6 (%)b
94 (6d)
90 (6e)
R1=4-MeO-Ph, R2=R3=H (5d)
R1=3-MeO-Ph, R2=R3=H (5e)
R1=4-Me-Ph, R2=R3=H (5f)
R1=2-Me-Ph, R2=R3=H (5h)
R1=4-CF3-Ph, R2=R3=H (5i)
R1=4-F-Ph, R2=R3=H (5j)
R1=C6H13, R2=R3=H (5k)
R1-R3=(CH2)4, R2=H (5l)
R1=R3=Me, R2=H (5m)
1.5
2
2
3
1.5
2
>99 (6f)
90 (6h)
92 (6i)
4c
5d
6
5
1
93 (6j)
7
3
69 (6k)
90 (6l)
8c
9e
10f
2
2.5
3
98 (6m)
>99 (6n)
R1=R2=Me, R3=H (5n)
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5
(HO)2B
11g
1
72 (6p)
78 (6q)
OTBS
(5p)
6
7
(HO)2B
12c,h
2
OPh
F
F
(5q)
8
9
13i
1.2
>99 (6r)
(HO)2B
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O
CF3
OTBS
(5r)
(HO)2B
Ph
14i
1.2
95 (6s)
OTBS
(5s)
aSolutions of 2 (0.15 mmol), 5 (0.225 mmol, 1.5 equiv), [RhCl(COD)]2 (1.5 mol %)
and aq KOH (6.0 M, 30 µL, 0.18 mmol) in MeOH (0.8 mL) were stirred at 3 °C.
bChromatographically isolated yield. An additional portion of 5 (1.0 equiv) was
c
d
e
added after 1 d. An additional portion of 5 (1.0 equiv) was added after 3 d. An
additional portion of 5 (1.0 equiv) was added after 1.5 d. An additional portion of 5
f
g
(1.0 equiv) was added after 2 d. On a 0.84 mmol scale of 2 using 20 mol % KOH
(3.1 M, 53 µL, 164 µmol).hOn a 0.45 mmol scale of 2. iAn additional portion of 5 (1.0
equiv) was added after 0.7 d.
CONCLUSION
In conclusion, a novel approach to the synthesis of prostaglandin derivatives and a
natural prostaglandin comprising the 1,4-conjugate addition of variously substituted
alkenylboronic acids to (R)-4-silyloxycyclopentenone 2 catalyzed by a simple Rh(I)-
catalyst has been described. We believe this is a significant advance of the
conventional two-component approach to prostaglandins that hitherto relied upon the
use of organocuprates at cryogenic temperatures. The reaction is highly trans-
diastereoselective, without the need for a fluoride additive, providing the addition
products in good to excellent yields.
While the reaction is rapid (typically ≤6 h) and selective under microwave
irradiation at 30 °C, a total of 3 mol % of [RhCl(COD)]2 added in two 1.5 mol %
portions along with an extra 0.5 equiv of boronic acid 5 were typically required to
produce high yields. Although conducting the reaction at low temperature without
microwave irradiation was considerably slower, the reaction often give higher yields
than the corresponding microwave irradiated reaction, when a greater than
stoichiometric amount of the base was employed. Moreover, the loading of
[RhCl(COD)]2 was halved to 1.5 mol % and the amount of boronic acid 5 was
reduced. In some instances, the non-microwave irradiated reaction also benefited
from the addition of extra boronic acid 5, however. The double-conjugate addition
side product 7 seen in the model studies was eradicated by the use of a low reaction
temperature or by employing microwave irradiation at 30 °C.
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Both alkyl- and aryl-substituted boronic acids were tolerated under both
microwave and non-microwave irradiation conditions, including those containing
stereogenically disposed γ-silyloxy- (5p, 5r, and 5s) or γ,γ-difluoro substituents (5q).
The usefulness of the method was validated by the preparation of the
pharmacologically useful compounds PGF2α (dinoprost (1a)) and tafluprost (1b) on
0.6–1.5 g scales, respectively. Moreover, precursors to access travoprost (1c) and
bimatroprost (1d) were synthesized using this method. 15j Finally, as demonstrated by
the successful coupling of boronic acid 6q and 2, this variant of the conventional
approach may allow access to 1,4-addition products not accessible using
organocuprates.
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EXPERIMENTAL SECTION
Materials and Methods. All commercial chemicals and solvents were reagent grade;
solvents were distilled before use. Boronic acids were either commercially available
or used as supplied or were prepared using methods reported in the literature.
Cyclopentenone 2 was prepared as described by Henschke et al.10 All reactions were
carried out under an atmosphere of argon or nitrogen gas. Reactions were monitored
by TLC using silica gel plates; zones were detected visually under ultraviolet
irradiation (254 nm) or by spraying with KMnO4 solution followed by heating with a
heat gun or on a hot plate. Flash column chromatography was conducted over silica
gel. Reactions carried out under microwave irradiation were conducted with magnetic
stirring in capped microwave vessels (anhydrous conditions were not required) using
a Milestone StartSYNTH microwave reactor equipped with a variable power source
(0–300 W) and an infrared temperature sensor allowing the reaction temperature to be
1
controlled. H NMR spectra were recorded on 400 MHz or 600 MHZ spectrometers;
13C NMR spectra were recorded on 100 MHz or 125 MHz spectrometers. Chemical
shifts δ were recorded in parts per million (ppm) and were reported relative to the
deuterated solvent signal (or the residual 1H-solvent for 1H NMR spectroscopy). First
order spin multiplicities are abbreviated as follows: s (singlet), d (doublet), t (triplet),
q (quadruplet), qui (quintet), and sep (septet); multiplets are abbreviated as m. High-
resolution mass spectra were obtained using ESI, FAB, and APCI ionization methods,
and TOF-Q mass analyzer was used for APCI ionization. Optical rotations were
measured on a polarimeter.
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Preparation of alkenylboronic acids 5p, 5q, 5r, 5s
(S)-tert-Butyl-(1-ethynyl-hexyloxy)-dimethyl-silane (S1)24
7
8
9
To a solution of (S)-oct-1-yn-3-ol (11.6 mL, 76.1 mmol), imidazole (10.4 g, 153
mmol) and 4-dimethylaminopyridine (0.93 g, 7.60 mmol) in CH2Cl2 (100 mL) at 0–
5 °C was added dropwise a solution of tert-butyldimethylsilyl chloride (17.2 g, 114
mmol) in CH2Cl2 (50 mL). The resulting white suspension was stirred at room
temperature for 20 h. The product mixture was diluted with CH2Cl2 (150 mL) and
mixed with saturated aqueous NH4Cl (300 mL). The organic layer was separated and
the aqueous layer was back-extracted twice with CH2Cl2 (200 mL each). The
combined organic layers were washed with brine (100 mL), dried over anhydrous
MgSO4, and concentrated. Column chromatography (eluting with 1:20 (v/v) EtOAc–
n-heptane) afforded title alkyne S1 as a colorless liquid (18.11 g, 99%). 1H NMR (400
MHz, CDCl3): δ 0.11 (s, 3H), 0.13 (s, 3H), 0.85–0.90 (m, 3H), 0.91 (s, 9H), 1.21–1.35
(m, 4H), 1.38–1.50 (m, 2H), 1.62–1.71 (m, 2H), 2.36 (d, J = 2.0 Hz, 1H), 4.33 (td, J =
2.1, 6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ −5.1 (CH3), −4.6 (CH3), 14.0 (CH3),
18.2 (C), 22.6 (CH2), 24.8 (CH2), 25.8 (CH3), 31.4 (CH2), 38.6 (CH2), 62.8 (CH), 71.8
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(CH), 85.8 (C); FTIR (KBr, neat) ν̃ 3319, 2941, 2962, 1465, 1257, 1090, 837, 790,
656, 635 cm-1; [α]!!" −32.3 (c 1.00 in CHCl3).
(S)-2-[3-(tert-Butyl-dimethylsilanyloxy)-oct-1-enyl]-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (S2)25
A solution of alkyne S1 (2.48 g, 10.3 mmol), 4-dimethylaminobenzoic acid (83 mg,
0.50 mmol, 5 mol %) and pinacolborane (4.5 mL, 30 mmol; as a neat oil) in n-heptane
(10.0 mL) was heated at 100 °C for 5.5 h. After being cooled to room temperature, the
mixture was diluted with EtOAc (30 mL) and was washed with saturated aqueous
NH4Cl solution (40 mL). Following separation of the layers, the aqueous layer was
back-extracted with EtOAc (30 mL) and the combined organic layers were washed
with brine (50 mL), dried over anhydrous MgSO4 (2.5 g), and were filtered and
concentrated under reduced pressure. The resulting residue was purified by column
chromatography (eluting with n-heptane (200 mL) then 1:50 (v/v) MTBE–n-heptane
(750 mL)) to give the title boronic ester S2 as a colorless oil (2.85 g, 7.74 mmol, 75%
yield). 1H NMR (400 MHz, CDCl3): δ 0.01 (s, 3H), 0.03 (s, 3H), 0.85–0.89 (m, 12H),
1.22–1.34 (m, 18H), 1.42–1.50 (m, 2H), 4.10–4.19 (m, 1H), 5.57 (dd, J = 1.5, 18.0
Hz, 1H), 6.56 (dd, J = 4.8, 18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ −4.9 (CH3),
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−4.4 (CH3), 14.0 (C H3), 18.2 (C), 22.6 (CH2), 24.66 (CH2), 24.73 (CH3), 24.8 (CH3),
5
6
25.9 (CH3), 31.9 (CH2), 37.5 (CH2), 74.2 (CH), 83.1 (C), (the C-B signal was not
7
8
9
observed due to quadrupolar relaxation), 156.2 (CH); FTIR (KBr, neat) ν̃ 3424, 2939,
2862, 1640, 1463, 1368, 1260, 1147, 1090, 998 cm-1; HRMS (APCI) m/z calcd for
C20H42BO4Si- [M + HO-] 385.2951, found 385.2970; [α]!!" −1.9 (c 1.00 in CHCl3).
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(S,E)-{3-[(tert-Butyldimethylsilyl)oxy]oct-1-en-1-yl}boronic acid (5p)
A mixture of boronic ester S2 (9.29 g, 25.2 mmol), NaIO4 (15.0 g, 70.13 mmol) and
NH4OAc (5.15 g, 66.80 mmol) in a 2:1 (v/v) mixture of acetone and water (540 mL,)
was stirred at 40 °C for 20 h.26 The acetone was evaporated under reduced pressure an
d the remaining residue was extracted with EtOAc (200 mL). Following separation of
the layers, the aqueous layer was back-extracted with EtOAc (200 mL) and the combi
ned organic layers were washed with brine (200 mL), dried over anhydrous MgSO4 (5.
0 g), filtered, and concentrated under reduced pressure to provide the title boronic aci
1
d 5p as a yellow clear oil (3.86 g, 13.5 mmol, 53.5%). H NMR (400 MHz, d6-DMS
O): δ 0.00 (s, 3H), 0.03 (s, 3H), 0.86 (t, J = 7.0 Hz, 3H), 0.88 (s, 9H), 1.18–1.32 (m, 6
H), 1.36–1.45 (m, 2H), 4.12 (q, J = 5.4 Hz, 1H), 5.44 (dd, J = 1.0, 17.8 Hz, 1H), 6.38
(dd, J = 5.4, 17.8 Hz, 1H), 7.57 (2H, s); 13C NMR (100 MHz, d6-DMSO): δ −4.9 (CH
3), −4.4 (CH3), 13.8 (CH3), 17.9 (C), 22.1 (CH2), 24.2 (CH2), 25.8 (CH3), 31.2 (CH2),
37.2 (CH2), 74.0 (CH), 152.1 (C). (the C-B signal was not observed due to quadrupola
r relaxation); FTIR (KBr, neat) ν̃ 3393, 2938, 2863, 1641, 1463, 1367, 1257, 1087, 10
00, 833 cm-1; HRMS (APCI) m/z calcd for C14H30BO3Si- [M - H+] 285.2063, found 28
5.2076; [α]!!" +25.1 (c 1.00 in CHCl3).
((2,2-Difluorobut-3-yn-1-yl)oxy)benzene (S3)
To a round-bottom flask was sequentially added XtalFluor-E27 (36.0 g, 157.2 mmol,
1.5 eq.), CH2Cl2 (36 mL), Et3N•3HF (34.2 mL, 209.8 mmol, 2.0 eq.) and a solution of
1-phenoxybut-3-yn-2-one28 (16.8 g, 104.9 mmol, 1.0 eq.) in CH2Cl2 (83 mL). The
mixture was stirred until (overnight) TLC analysis indicated that the reaction was
complete. The resulting mixture was extracted with a chilled, (0 °C) solution of
saturated aq. NaHCO3 until bubbling ceased. The aqueous layer was separated and
back-extracted with diethyl ether (450 mL). The combined organic layers were
washed with brine (60 mL), separated, dried over anhydrous Na2SO4, filtered, and
concentrated to give the crude product. The residue was purified by column
chromatography (eluting with 1:100 (v/v) EtOAc/heptane) to give alkyne S3 as a
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colorless oil (12.03 g, 65.9 mmol, 63% yield). 1H NMR (400 MHz, CDCl3): δ 2.82 (t,
J = 5.2 Hz, 1H), 4.27 (t, J = 2.4 Hz, 2H), 6.91–6.97 (m, 2H), 6.98–7.04 (m, 1H),
7.26–7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 70.1 (t, J = 32 Hz; CH2), 74.6 (t,
J = 38 Hz; C), 77.1 (t, J = 7 Hz; CH), 110.8 (t, J = 235.0 Hz; C), 115.1 (CH), 122.2
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(CH), 129.6 (CH), 157.8 (C); FTIR (KBr, neat) ν̃ 3723, 2938, 2857, 2353, 1700,
1498, 1303, 1250, 1167 cm-1; HRMS (EI) m/z calcd for C10H8F2O+• [M !• ] 182.0543,
found 182.0542.
Potassium (E)-(3,3-difluoro-4-phenoxybut-1-en-1-yl)trifluoroborate (S4)
A mixture of 2,5-dimethylhexa-2,4-diene (27 mL, 189.4 mmol) in THF (15 mL) and a
1 M solution of BH3•THF in THF (86 mL, 86.0 mmol) was stirred for 3 h at 0 ˚C.29
To this was then added a solution of alkyne S3 (6.3 g, 34.5 mmol) in THF (37 mL)
while maintaining the temperature at 0 °C. The reaction mixture was stirred at room
temperature for 3 h before being cooled in an ice bath and carefully quenched with
water (13 mL). After being stirred at room temperature for an additional 1.5 h, a 37%
aqueous solution of formaldehyde (31 mL) was added. The mixture was stirred
overnight, quenched with brine (30 mL), and the resulting mixture was extracted three
times with EtOAc (50 mL each). The organic layers were combined, dried over
anhydrous MgSO4, filtered and evaporated to give crude (E)-(3,3-difluoro-4-
phenoxybut-1-en-1-yl)boronic acid (5q).
To a solution of the above prepared boronic acid 5q in MeCN (143 mL) was added a
solution of KF (7.27 g, 125.3 mmol) in water (11 mL). The mixture was stirred until
no solid could be seen30 and then a solution of L-(+)-tartaric acid (9.7 g, 64.6 mmol)
in THF (50 mL) was added over a period of 20 min. The mixture was stirred for 30
min, and was then filtered. The filter cake was washed with MeCN (114 mL) and the
combined organic layers were concentrated and the resulting residue was slurried in
diethyl ether (30 mL) for 1 h. The solids were filtered off and the filtered cake was
dried under reduced pressure to provide trifluoroborate S4 as a white solid (7.6 g, 26.2
mmol, 76% yield). 1H NMR (400 MHz, d6-DMSO): δ 4.28 (t, J = 13.2 Hz, 2H), 5.79
(dt, J = 10.9, 18.3 Hz, 1H), 6.60 (dq, J = 3.1, 18.3 Hz, 1H), 6.98–7.07 (m, 3H), 7.30–
13
7.38 (m, 2H); C NMR (100 MHz, d6-DMSO): δ 69.1 (t, J = 31.0 Hz; CH2), 115.2
(CH), 120.2 (t, J = 236.0 Hz; C), 121.7 (CH), 126.5 (tq, J = 4.0, 24.0 Hz; CH), 130.0
(CH), 158.4 (C), (the C-B signal was not observed due to quadrupolar relaxation);
FTIR (KBr, neat) ν
̃
2927, 1640, 1494, 1445, 1294, 1267, 1169, 1134, 1090, 1033 cm-
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1; HRMS (ESI) m/z calcd for C10H9OF5B- [M-K+] 251.0667 found 251.0669; mp:
>260 °C.
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(E)-(3,3-Difluoro-4-phenoxybut-1-en-1-yl)boronic acid (5q)
A mixture of a solution of trifluoroborate S4 (1.5 g, 5.2 mmol) in water (5 mL) and
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silica gel (0.31 g, 5.2 mmol) was stirred at 30 C for overnight. The mixture was
filtered and evaporated providing the title boronic acid 5q as a white solid (1.0 g, 4.4
mmol, 85% yield). 1H NMR (400 MHz, d6-DMSO): δ 4.40 (t, J = 12.9 Hz, 2H), 6.12
(dt, J = 2.4, 18.4 Hz, 1H), 6.60 (dt, J = 11.1, 18.4 Hz, 1H), 6.95–7.10 (m, 3H), 7.30–
13
7.40 (m, 2H), 8.2 (s, 2H); C NMR (100 MHz, d6-DMSO): δ 68.7 (t, J = 31.5 Hz;
CH2), 115.3 (CH), 119.3 (t, J = 238.5 Hz; C), 122.0 (CH), 130.0 (CH), 131.6 (CH),
138.7 (t, J = 25.0 Hz; CH), 158.1 (C); FTIR (KBr, neat) ν
̃
3398, 3296, 2936, 1594,
1494, 1372, 1294, 1250, 1164, 1088 cm-1; HRMS (EI): m/z calcd for C10H11BF2O3
[M !• ] 228.0769, found 228.0768; mp: decomposed at >150 °C.
+•
(S)-tert-butyldimethyl((1-(3-(trifluoromethyl)phenoxy)but-3-yn-2-yl)oxy)silane
(S5)
Following the method preparing S1, parent alcohol (0.7 g, 3.04 mmol) was used and
S5 was isolated as a colorless oil (1.1 g, >99%). 1H NMR (400 MHz, CDCl3): δ 0.13
(s, 3H), 0.17 (s, 3H), 0.91 (s, 9H), 2.47 (d, J = 2.1 Hz, 1H), 4.10 (d, J = 6.0 Hz, 2H),
4.74 (dt, J = 2.1, 6.0 Hz, 1H), 7.09 (dd, J = 2.2, 8.3 Hz, 1H), 7.14 (s, 1H), 7.21 (d, J =
13
7.8 Hz, 1H), 7.38 (dd, J = 8.0, 8.0 Hz, 1H); C NMR (100 MHz, CDCl3): δ −5.0
(CH3), −4.8 (CH3), 18.2 (C), 25.7 (CH3), 62.1 (CH), 72.3 (CH2), 73.7 (CH), 82.0 (C),
111.6 (q, J = 4.0 Hz, CH), 117.8 (q, J = 4.0 Hz, CH), 118.3 (CH), 123.9 (q, J = 271.0
Hz, C), 130.0 (CH), 131.9 (q, J = 32.0 Hz, C), 158.7 (C); FTIR (KBr, neat) ν̃ 3309,
2942, 2863, 1603, 1455, 1331, 1251, 1170, 1128, 1056, 970 cm-1; HRMS (FAB) m/z
calcd for C17H22F3O2Si- [M - H+] 343.1347, found 343.1339; [α]!!" −26.5 (c 1.00,
CHCl3).
(S,E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-
(trifluoromethyl)phenoxy)but-3-en-2-yl)oxy)silane (S6)
To a solution of catechol (70.0 mg, 0.58 mmol) in THF (1.3 ml) at 0 °C was added
BH3 (1.0 M in THF, 0.58 ml, 0.58 mmol) slowly, and the reaction mixture was stirred
for 1 h at 0 °C and at r.t. for an additional 1 h. To the stirred solution were added S5
(0.2 g, 0.58 mmol) and dicyclohexylborane (0.1 M, 0.3 ml, 0.03 mmol) in THF at 0
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°C. The reaction mixture was warmed to r.t. and after been stirred for another 6 h at
r.t., pinacol (0.1 g, 0.85 mmol) was added to the resultant mixture at 0 °C and the
mixture was allowed to warmed to r.t. and stirred for 48 h. Bubbling air into the
solution for 2 h was carried out at r.t. The resulting mixture was diluted with hexane,
washed with water, and the organic layer was separated and dried over Na2SO4,
filtered and evaporated to give a yellow oil which was purified by column
chromatography (eluting with hexane/EtOAc=40/1) to give boronic ester S6 as a
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colorless oil (0.23 g, 0.5 mmol, 85% yield). H NMR (400 MHz, CDCl3): δ 0.08 (s,
3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.28 (s, 12H), 3.86 (dd, J = 7.5, 9.4 Hz, 1H), 3.95 (J =
4.1, 9.4 Hz, 1H), 4.55–4.65 (m, 1H), 5.86 (dd, J = 1.7, 17.9 Hz, 1H), 6.66 (dd, J = 4.1,
17.9 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.09 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.37
13
(dd, J = 8.0, 8.0 Hz, 1H); C NMR (100 MHz, CDCl3): δ −4.8 (CH3), −4.7 (CH3),
18.3 (C), 24.7 (CH3), 24.8 (CH3), 25.8 (CH3), 72.1 (CH2), 72.5 (CH), 83.3 (C), 111.2
(q, J = 4.0 Hz, CH), 117.4 (q, J = 4.0 Hz, CH), 118.1 (CH), 123.9 (q, J = 271.0 Hz,
C), 129.9 (CH), 131.8 (q, J = 32.0 Hz, C), 151.0 (CH), 158.7 (C); FTIR (KBr, neat) ν
̃
2941, 2863, 1641, 1604, 1455, 1332, 1249, 1136, 1044, 982, 889 cm-1; HRMS (FAB)
m/z calcd for C23H35BF3O4Si- [M - H+] 471.2355, found 471.2342; [α]!!" −1.5 (c 1.00,
CHCl3).
(R,E)-(3-((tert-butyldimethylsilyl)oxy)-5-phenylpent-1-en-1-yl)boronic acid (5r)
To a solution of boronic ester S6 (0.23 g, 0.5 mmol, 1 equiv) in acetone and water (5
mL, 2:1) were added sodium metaperiodate (0.33 g, 1.5 mmol, 3.1 equiv) and
ammonium acetate (0.11 g, 1.5 mmol, 3.0 equiv). The reaction mixture was warmed
to r.t. and after being stirred for 48 h, the volatile was removed under reduced
pressure. The residue was diluted with ethyl acetate and the organic phase was
separated. The aqueous layer was extracted with ethyl acetate and the combined
organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure to provide boronic acid 5r as a colorless oil (0.18 g, 0.46
mmol, 95% yield); 1H NMR (400 MHz, d6-DMSO): δ 0.08 (s, 3H), 0.10 (s, 3H), 0.90
(s, 9H), 3.91 (J = 7.7, 10.1 Hz, 1H), 4.11 (J = 3.5, 10.1 Hz, 1H), 4.54–4.66 (m, 1H),
5.75 (dd, J = 1.3, 17.9 Hz, 1H), 6.54 (dd, J = 4.5, 18.0 Hz, 1H), 7.20–7.35 (m, 3H),
7.55 (dd, J = 8.0 Hz, 1H), 7.71 (s, 2H); 13C NMR (100 MHz, d6-DMSO): δ −3.9
(CH3), −3.8 (CH3), 18.9 (C), 26.6 (CH3), 72.9 (CH2), 73.6 (CH), 111.8 (q, J = 4.0 Hz,
CH), 118.1 (q, J = 4.0 Hz, CH), 119.8 (CH), 124.9 (q, J = 271.0 Hz, C), 129.9 (CH),
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131.1 (q, J = 32 Hz, C), 131.6 (CH), 148.3 (CH), 159.7 (C); FTIR (KBr, neat) ν̃ 3387,
2941, 2864, 1640, 1453, 1332, 1249, 1166, 1130, 1056, 991 cm-1; HRMS (FAB) m/z
calcd for C17H25BF3O4Si- [M - H+] 389.1567, found 389.1563; [α]!!" +19.9 (c 1.00,
CHCl3).
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(R)-tert-butyldimethyl((5-phenylpent-1-yn-3-yl)oxy)silane (S7)
Following the method preparing S1, parent alcohol (1.2 g, 7.49 mmol) was used and
S7 was isolated as a colorless oil (1.8 g, 88%). 1H NMR (400 MHz, CDCl3): δ 0.11 (s,
3H), 0.13 (s, 3H), 0.91 (s, 9H), 1.95–2.05 (m, 2H), 2.42 (d, J = 2.0 Hz, 1H), 2.69–
2.84 (m, 2H), 4.37 (dt, J = 1.7, 6.4 Hz, 1H), 7.15–7.23 (m, 3H), 7.25–7.32 (m, 2H);
13C NMR (100 MHz, CDCl3): δ −5.1 (CH3), −4.5 (CH3), 18.2 (C), 25.8 (CH3), 31.3
(CH2), 40.2 (CH2), 62.1 (CH), 72.4 (CH), 85.3 (C), 125.9 (CH), 128.36 (CH), 128.43
(CH), 141.6 (C); FTIR (KBr, neat) ν̃ 3303, 3031, 2942, 2861, 1597, 1463, 1254, 1097,
973, 841, 778 cm-1; HRMS (FAB) m/z calcd for C17H25OSi- [M - H+] 273.1680, found
273.1679; [α]!!" −11.2 (c 1.00, CHCl3).
(S,E)-tert-butyldimethyl((5-phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)pent-1-en-3-yl)oxy)silane (S8)
Following the method preparing S6, parent alkyne (0.2 g, 0.72 mmol) was used and
S8 was isolated as a colorless oil (0.22 g, 75%). 1H NMR (400 MHz, CDCl3): δ 0.02
(s, 3H), 0.04 (s, 3H), 0.91 (s, 9H), 1.27 (s, 12H), 1.78–1.88 (m, 2H), 2.59–2.72 (m,
2H), 4.20–4.28 (m, 1H), 5.63 (dd, J = 1.4, 18.0 Hz, 1H), 6.61 (dd, J = 4.8, 18.0 Hz,
1H), 7.13–7.22 (m, 3H), 7.23–7.31 (m, 2H); 13C NMR (100 MHz, CDCl3): δ −4.9
(CH3), −4.4 (CH3), 18.2 (C), 24.7 (CH3), 24.8 (CH3), 25.9 (CH3), 31.1 (CH2), 39.1
(CH2), 73.6 (CH), 83.1 (C), 125.6 (CH), 128.3 (CH), 128.4 (CH), 142.4 (C), 155.6
(CH); FTIR (KBr, neat) ν̃ 2941, 2861, 1643, 1463, 1351, 1258, 1148, 1105, 973, 840,
777.4 cm-1; HRMS (FAB) m/z calcd for C23H38BO3Si- [M - H+] 401.2689, found
401.2683; [α]!!" +13.6 (c 1.00, CHCl3).
(R,E)-(3-((tert-butyldimethylsilyl)oxy)-5-phenylpent-1-en-1-yl)boronic acid (5s)
Following the method preparing 5r, parent boronic ester (0.22 g, 0.55 mmol) was
1
used and 5s was isolated as a colorless oil (0.18 g, 98%). H NMR (400 MHz, d6-
DMSO): δ 0.04 (s, 3H), 0.07 (s, 3H), 0.92 (s, 9H), 1.70–1.84 (m, 2H), 2.62 (t, J = 8.0
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Hz, 2H), 4.22 (ddd, J = 5.7, 5.7, 5.7 Hz, 1H), 5.52 (d, J = 18.0 Hz, 1H), 6.48 (dd, J =
5.7, 18.0 Hz, 1H), 7.17–7.24 (m, 3H), 7.26–7.35 (m, 2H), 7.64 (s, 2H); 13C NMR (100
MHz, d6-DMSO): δ −3.9 (CH3), −3.5 (CH3), 18.9 (C), 26.7 (CH3), 31.6 (CH2), 40.1
(CH2), 74.5 (CH), 126.6 (CH), 129.1 (CH), 129.2 (CH), 142.9 (C), 152.4 (CH).(the C-
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B signal was not observed due to quadrupolar relaxation); FTIR (KBr, neat) ν̃ 3028,
2942, 2859, 1637, 1359, 1257, 1093, 998, 834, 777, 701 cm-1; HRMS (FAB) m/z
calcd for C17H28BO3Si- [M - H+] 319.1900, found 319.1896; [α]!!" +19.4 (c 1.00,
CHCl3).
General procedures for the synthesis of PGE2 derivatives 6a–6h:
All of the NMR spectra presented in the supporting information were obtained
from samples produced using method A described below.
Method A – using microwave irradiation (50 W) at 30 °C (exemplified for 6a). A
solution of isopropyl (Z)-7-[(3R)-3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-cyclopent-
1-enyl]-hept-5-enoate (2) (57 mg, 0.15 mmol), (E)-styreneboronic acid (5a) (0.22
mmol), [RhCl(COD)]2 (1.1 mg, 2.2 µmol) and aqueous KOH (9.5 µL, 3.1 M, 30
µmol) in MeOH (1.0 mL) was stirred under microwave irradiation at 30 °C (50 W).
After 5 h, additional (E)-styreneboronic acid (5a) (74 µmol) and [RhCl(COD)]2 (1.1
mg, 2.2 µmol) were added and the reaction mixture was stirred for another hour under
microwave irradiation (30 °C; 50 W). The product mixture was concentrated under
reduced pressure and the resulting residue was purified by column chromatography
(eluting with 1:80 (v/v) acetone–hexanes) affording cyclopentanone 6a as a colorless
oil (70 mg, 96%).
Method B – without microwave irradiation at 3 °C (exemplified for 6a). A
solution of isopropyl (Z)-7-[(3R)-3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-cyclopent-
1-enyl]-hept-5-enoate (2) (57 mg, 0.15 mmol), (E)-styreneboronic acid (5a) (0.22
mmol), [RhCl(COD)]2 (1.1 mg, 2.2 µmol) and aqueous KOH (30 µL, 6.0 M, 0.18
mmol) in MeOH (1.0 mL) was stirred at 3 °C. After stirred for 3 days, the product
mixture was concentrated under reduced pressure and the resulting residue was
purified by column chromatography (eluting with 1:80 (v/v) acetone–hexanes)
affording cyclopentanone 6a (69 mg, 95%).
(Z)-Isopropyl
7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-((E)-
1
styryl)cyclopentyl)hept-5-enoate (6a). H NMR (400 MHz, CDCl3) δ 0.01 (s, 3H),
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0.03 (s, 3H), 0.86 (s, 9H), 1.20 (d, J = 6.2 Hz, 6H), 1.65 (qui, J = 7.5 Hz, 2H), 2.05
(ddd, J = 7.0, 7.0, 7.0 Hz, 2H), 2.12–2.29 (m, 4H), 2.33–2.45 (m, 2H), 2.57–2.74 (m,
2H), 4.13 (ddd, J = 8.1, 8.1, 8.1 Hz, 1H), 4.97 (sep, J = 6.2 Hz, 1H), 5.30–5.47 (m,
2H), 6.05 (dd, J = 8.6, 15.8 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 7.20–7.26 (m, 1H),
7.27–7.38 (m, 4H) (the relative stereochemistry of C8 and C13 was determined from
a 2D-NOESY spectrum of 7a; see supporting information); 13C NMR (100 MHz,
CDCl3) δ −4.7 (CH3), −4.6 (CH3), 18.1 (C), 21.8 (CH3), 24.8 (CH2), 25.1 (CH2), 25.7
(CH), 26.7 (CH2), 34.1 (CH2), 47.6 (CH2), 54.1 (CH), 54.4 (CH), 67.4 (CH), 73.1
(CH), 126.1 (CH), 126.5 (CH), 127.4 (CH), 128.6 (CH), 129.8 (CH), 131.0 (CH),
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132.9 (CH), 137.1 (C), 173.1 (C), 214.7 (C); FTIR (KBr, neat) ν̃ 2935, 2861, 1736,
1593, 1459, 1372, 1250, 1107, 838, 745 cm-1; HRMS (ESI) m/z calcd for C29H45O4Si
[M + H+] 485.3081, found 485.3064; [α] !!" −57.4 (c 1.00, CHCl3).
(Z)-Isopropyl 7-((1R,2S,3RS)-5-oxo-2,3-di((E)-styryl)cyclopentyl)hept-5-enoate (7
and 11-epi-7). In some reactions (see Tables 1 and 2) an inseparable 83:17
diastereomeric mixture of 7 and 11-epi-7 was produced along with 6a; the 7 and 11-
epi-7 mixture was isolated by column chromatography of the crude 6a. 1H NMR (400
MHz, CDCl3) δ 1.20 (d, J = 6.2 Hz, 6H), 1.65 (qui, J = 7.6 Hz, 2H), 1.96–2.12 (m,
2H), 2.13–2.35 (m, 4H), 2.36–2.58 (m, 3H), 2.62–2.85 (m, 2H), 4.97 (sep, J = 6.4 Hz,
1H), 5.31–5.50 (m, 2H), 6.06–6.22 (m, 2H), 6.41 (d, J = 11.5 Hz, 1H), 6.45 (d, J =
13
11.5 Hz, 1H), 7.16–7.38 (m, 10H); C NMR (100 MHz, CDCl3) δ 21.8 (CH3), 24.8
(CH2), 25.0 (CH2), 26.7 (CH2), 30.9 (CH2), 34.1 (CH2), 44.4 (CH), 51.7 (CH), 55.5
(CH), 67.4 (CH), 77.2 (CH), 126.18 (CH), 126.22 (CH), 126.5 (CH), 127.4 (CH),
127.5 (CH), 128.5 (CH), 128.6 (CH), 130.3 (CH), 131.0 (CH), 131.2 (CH), 132.5
(CH), 137.0 (C), 173.1 (C), 216.7 (C); FTIR (KBr, neat) ν
̃
3446, 2975, 1730, 1640,
+
1443, 1375, 1217, 1164, 1102, 963 cm-1; HRMS (ESI) m/z calcd for C31H37O3 [M +
H+] 457.2743, found 457.2738; [α] !!" −149.5 (c 0.46, CHCl3).
(Z)-Isopropyl 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-4-methoxystyryl)-
5-oxocyclopentyl)hept-5-enoate (6d). Following Method A, the title compound was
isolated as a colorless oil (72 mg, 93%). Following Method B the reaction was stirred
for 1.5 d (73 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.02 (s, 3H), 0.85
(s, 9H), 1.20 (d, J = 6.3 Hz, 6H), 1.64 (qui, J = 7.5 Hz, 2H), 2.05 (ddd, J = 7.0, 7.0,
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7.0 Hz, 2H), 2.11–2.26 (m, 4H), 2.35–2.43 (m, 2H), 2.55–2.72 (m, 2H), 3.81 (s, 3H),
4.10 (ddd, J = 8.1, 8.1, 8.1 Hz, 1H), 4.97 (sep, J = 6.3 Hz, 1H), 5.27–5.46 (m, 2H),
5.89 (dd, J = 8.6, 15.7 Hz, 1H), 6.44 (d, J = 15.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H),
7.28 (d, J = 8.7 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ −4.8 (CH3), −4.7 (CH3), 18.0
(C), 21.8 (CH3), 24.8 (CH2), 25.1 (CH2), 25.7 (CH3), 26.6 (CH2), 34.1 (CH2), 47.6
(CH2), 54.1 (CH), 54.4 (CH), 55.2 (CH3), 67.4 (CH), 73.1 (CH), 114.0 (CH), 126.5
(CH), 127.2 (CH), 127.5 (CH), 129.9 (C), 130.9 (CH), 132.3 (CH), 159.0 (C), 173.1
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(C), 214.9 (C); FTIR (KBr, neat) ν̃ 2939, 2863, 1737, 1604, 1512, 1463, 1371, 1246,
1166, 1109 cm-1; HRMS (ESI) m/z calcd for C30H47O5Si [M + H+] 515.3187, found
515.3182; [α] !!! −50.6 (c 1.00, CHCl3).
(Z)-Isopropyl 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-3-methoxystyryl)-
5-oxocyclopentyl)hept-5-enoate (6e). Following Method A, the additional portions of
[RhCl(COD)]2 and 5e were added after 3 h (instead of after 5 h) and the reaction was
irradiated for a further 2 h; the title compound was isolated as a colorless oil (72 mg,
1
93%). Following Method B, the reaction was stirred for 2 d (70 mg, 90%). H NMR
(400 MHz, CDCl3) δ 0.01 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 1.20 (d, J = 6.2 Hz, 6H),
1.64 (qui, J = 7.5 Hz, 2H), 2.05 (ddd, J = 7.1, 7.1, 7.1 Hz, 2H), 2.13–2.27 (m, 4H),
2.32–2.45 (m, 2H), 2.57– 2.73 (m, 2H), 3.81 (s, 3H), 4.12 (ddd, J = 8.1, 8.1, 8.1 Hz,
1H), 4.97 (sep, J = 6.2 Hz, 1H), 5.29–5.46 (m, 2H), 6.04 (dd, J = 8.6, 15.7 Hz, 1H),
6.47 (d, J = 15.7 Hz, 1H), 6.79 (dd, J = 2.0, 8.0 Hz, 1H), 6.89 (dd, J = 2.0, 3.8 Hz,
1H), 6.94 (d, J = 7.6 Hz, 1H), 7.18–7.25 (m, 1H); 13C NMR (100 MHz) δ −4.8
(CH3),−4.7 (CH3), 18.0 (C), 21.8 (CH3), 24.8 (CH2), 25.1 (CH2), 25.7 (CH3), 26.6
(CH2), 34.0 (CH2), 47.5 (CH2), 54.0 (CH), 54.3 (CH), 55.1 (CH3), 67.3 (CH), 73.0
(CH), 111.6 (CH), 112.8 (CH), 118.8 (CH), 126.4 (CH), 129.5 (CH), 130.1 (CH),
131.0 (CH), 132.7 (CH), 138.5 (C), 159.8 (C), 173.0 (C), 214.6 (C); FTIR (KBr, neat)
ν̃
2945, 2862, 1737, 1666, 1590, 1463, 1375, 1257, 1156, 1108 cm-1; HRMS (ESI)
m/z calcd for C30H47O5Si+ [M + H+] 515.3187, found 515.3172;[α] !!"−65.1 (c 1.00,
CHCl3).
(Z)-Isopropyl 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-4-methylstyryl)-5-
oxocyclopentyl)hept-5-enoate (6f). Following Method A, the title compound was
isolated as a colorless oil (71 mg, 95%). Following Method B, the reaction was stirred
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for 1.5 d (74 mg, >99%). H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.02 (s, 3H),
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0.85 (s, 9H), 1.20 (d, J = 6.2 Hz, 6H), 1.64 (qui, J = 7.5 Hz, 2H), 2.04 (ddd, J = 7.1,
7.1, 7.1 Hz, 2H), 2.12–2.28 (m, 4H), 2.34 (s, 3H), 2.35–2.42 (m, 2H), 2.56–2.74 (m,
2H), 4.11 (ddd, J = 8.1, 8.1, 8.1 Hz, 1H), 4.97 (sep, J = 6.2 Hz, 1H), 5.29–5.45 (m,
2H), 5.98 (dd, J = 8.7, 15.7 Hz, 1H), 6.46 (d, J = 15.7 Hz, 1H), 7.13 (d, J = 8.0 Hz,
2H), 7.25 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ −4.8 (CH3), −4.7 (CH3),
18.0 (C), 21.1 (CH3), 21.8 (CH3), 24.8 (CH2), 25.0 (CH2), 25.7 (CH3), 26.6 (CH2),
34.1 (CH2), 47.6 (CH2), 54.1 (CH), 54.4 (CH), 67.3 (CH), 73.0 (CH), 126.0 (CH),
126.5 (CH), 128.7 (CH), 129.3 (C), 130.9 (CH), 132.7 (CH), 134.3 (C), 137.1 (C),
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173.1 (C), 214.8 (C); FTIR (KBr, neat) ν̃ 2938, 2863, 1737, 1509, 1463, 1372, 1250,
1110, 964, 841 cm-1; HRMS (ESI) m/z calcd for C30H47O4Si [M + H+] 499.3238,
found 499.3244; [α] !!"−40.2 (c 1.00, CHCl3).
(Z)-Isopropyl 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-3-methylstyryl)-5-
oxocyclopentyl)hept-5-enoate (6g). Following Method A, the title compound was
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isolated as a colorless oil (73 mg, 98%). H NMR (400 MHz, CDCl3) δ 0.01 (s, 3H),
0.03 (s, 3H), 0.86 (s, 9H), 1.20 (d, J = 6.4 Hz, 6H), 1.65 (qui, J = 7.6 Hz, 2H), 2.05
(ddd, J = 7.1, 7.1, 7.1 Hz, 2H), 2.12–2.27 (m, 4H), 2.30–2.41 (m, 2H), 2.35 (s, 3H),
2.57–2.73 (m, 2H), 4.12 (ddd, J = 8.1, 8.1, 8.1 Hz, 1H), 4.97 (sep, J = 6.4 Hz, 1H),
5.28–5.46 (m, 2H), 6.03 (dd, J = 8.6, 15.8 Hz, 1H), 6.47 (d, J = 15.8, 1H), 7.06 (d, J =
13
7.2 Hz, 1H), 7.13–7.23 (m, 3H); C NMR (100 MHz, CDCl3) δ −4.8 (CH3), −4.6
(CH3), 18.0 (C), 21.4 (CH3), 21.8 (CH3), 24.8 (CH2), 25.1 (CH2), 25.7 (CH3), 26.7
(CH2), 34.1 (CH2), 47.6 (CH2), 54.1 (CH), 54.3 (CH), 67.4 (CH), 73.1 (CH), 123.2
(CH), 126.5 (CH), 126.9 (CH), 128.2 (CH), 128.5 (CH), 129.5 (CH), 131.0 (CH),
133.0 (CH), 137.0 (C), 138.1 (C), 173.1 (C), 214.8 (C); FTIR (KBr, neat) ν̃ 2939,
2863, 1737, 1600, 1463, 1375, 1253, 1112, 971, 884 cm-1; HRMS (ESI) m/z calcd for
C30H47O4Si+ [M + H+] 499.3238, found 499.3242; [α] !!" −51.1 (c 1.00, CHCl3).
(Z)-Isopropyl 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-2-methylstyryl)-5-
oxocyclopentyl)hept-5-enoate (6h). Following Method A, the additional portions of
[RhCl(COD)]2 and 5h were added after 3 h (instead of after 5 h) and the reaction was
irradiated for a further 2 h; the title compound was isolated as a colorless oil (66 mg,
88%). Following Method B, boronic acid 5h (1.0 equiv) was added after 1 d, and the
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reaction was stirred for another 1 d (67 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 0.03
(s, 3H), 0.04 (s, 3H), 0.87 (s, 9H), 1.20 (d, J = 6.2 Hz, 6H), 1.65 (qui, J = 7.4 Hz, 2H),
2.07 (ddd, J = 6.9, 6.9, 6.9 Hz, 2H), 2.13–2.28 (m, 4H), 2.34 (s, 3H), 2.37–2.45 (m,
2H), 2.60–2.76 (m, 2H), 4.15 (ddd, J = 8.1, 8.1, 8.1 Hz, 1H), 4.97 (sep, J = 6.2 Hz,
1H), 5.32–5.47 (m, 2H), 5.93 (dd, J = 8.6, 15.6 Hz, 1H), 6.72 (d, J = 15.6 Hz, 1H),
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7.11–7.20 (m, 3H), 7.38–7.44 (m, 1H); C NMR (100 MHz, CDCl3) δ −4.72 (CH3),
−4.65 (CH3), 18.0 (C), 19.7 (CH3), 21.8 (CH3), 24.8 (CH2), 25.1 (CH2), 25.7 (CH3),
26.7 (CH2), 34.0 (CH2), 47.6 (CH2), 54.4 (CH), 54.5 (CH), 67.3 (CH), 73.0 (CH),
125.5 (CH), 126.1 (CH), 126.6 (CH), 127.3 (CH), 130.2 (CH), 130.7 (CH), 130.9
(CH), 131.2 (CH), 135.1 (C), 136.2 (C), 173.0 (C), 214.7 (C); FTIR (KBr, neat) ν
̃
3454, 2948, 1737, 1647, 1462, 1375, 1253, 1107, 969, 880 cm-1; HRMS (ESI) m/z
calcd for C30H47O4Si [M + H+] 499.3238, found 499.3234; [α] !!" −53.4 (c 1.00,
CHCl3).
(Z)-Isopropyl
7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-((E)-4-
(trifluoromethyl)styryl)cyclopentyl)hept-5-enoate (6i). Following Method A, the
additional portions of [RhCl(COD)]2 and 5i were added after 3 h (instead of after 5 h)
and the reaction was irradiated for a further 2 h; the title compound was isolated as a
colorless oil (66 mg, 80%). Following Method B, boronic acid 5i (1.0 equiv) was
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added after 3 d and the reaction was stirred for another 2 d (77 mg, 92%). H NMR
(400 MHz, CDCl3) δ −0.01 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 1.18 (d, J = 6.2 Hz,
6H), 1.64 (qui, J = 7.5 Hz, 2H), 2.04 (ddd, J = 7.2, 7.2, 7.2 Hz, 2H), 2.14–2.29 (m,
4H), 2.35–2.44 (m, 2H), 2.59–2.75 (m, 2H), 4.13 (ddd, J = 8.2, 8.2, 8.2 Hz, 1H), 4.96
(sep, J = 6.2 Hz, 1H), 5.27–5.48 (m, 2H), 6.16 (dd, J = 8.6, 15.8 Hz, 1H), 6.54 (d, J =
15.8 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ −4.7 (CH3), 18.0 (C), 21.8 (CH3), 24.8 (CH2), 25.1 (CH2), 25.6 (CH3), 26.6
(CH2), 34.0 (CH2), 47.5 (CH2), 54.2 (CH), 54.3 (CH), 67.4 (CH), 72.8 (CH), 124.2 (q,
J = 270.2 Hz; C), 125.6 (q, J = 4.0 Hz; CH), 126.2 (CH), 126.4 (CH), 129.2 (q, J =
33.0 Hz; C), 131.1 (CH), 131.7 (CH), 132.6 (CH), 140.4 (C), 173.0 (C), 214.1 (C);
FTIR (KBr, neat) ν̃ 2941, 2866, 1739, 1617, 1464, 1373, 1252, 1163, 1118, 840, 777
cm-1; HRMS (ESI) m/z calcd for C30H44F3O4Si+ [M + H+] 553.2955, found 553.2936;
[α] !!" −40.4 (c 1.00, CHCl3).
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(Z)-Isopropyl 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-4-fluorostyryl)-5-
oxocyclopentyl)hept-5-enoate (6j). Following Method A, the additional portions of
[RhCl(COD)]2 and 5j were added after 3 h (instead of after 5 h) and the reaction was
irradiated for a further 2 h; the title compound was isolated as a colorless oil (69 mg,
92%). Following Method B, the reaction was stirred for another 1 d (70 mg, 93%). 1H
NMR (400 MHz, CDCl3) δ −0.01 (s, 3H), 0.01 (s, 3H), 0.85 (s, 9H), 1.19 (d, J = 6.2
Hz, 6H), 1.64 (qui, J = 7.5 Hz, 2H), 2.04 (ddd, J = 7.1, 7.1, 7.1 Hz, 2H), 2.11–2.27
(m, 4H), 2.32–2.45 (m, 2H), 2.54–2.74 (m, 2H), 4.11 (ddd, J = 8.6, 8.6, 8.6 Hz, 1H),
4.96 (sep, J = 6.2 Hz, 1H), 5.27–5.47 (m, 2H), 5.95 (dd, J = 8.6, 15.7 Hz, 1H), 6.46
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(d, J = 15.7 Hz, 1H), 7.00 (dd, J = 8.6, 8.7 Hz, 2H), 7.27–7.35 (m, 2H); C NMR
(100 MHz, CDCl3) δ −4.8 (CH3), −4.7 (CH3), 18.0 (C), 21.8 (CH3), 24.8 (CH2), 25.1
(CH2), 25.6 (CH3), 26.6 (CH2), 34.1 (CH2), 47.5 (CH2), 54.1 (CH), 54.3 (CH), 67.4
(CH), 72.9 (CH), 115.5 (d, J = 21.0 Hz; CH), 126.5 (CH), 127.5 (d, J = 8.0 Hz; CH),
129.5 (CH), 131.0 (CH), 131.7 (CH), 133.2 (d, J = 3.0 Hz; C), 162.2 (d, J = 245.0 Hz;
C), 173.0 (C), 214.5 (C); FTIR (KBr, neat) ν̃ 2939, 1737, 1603, 1463, 1373, 1232,
1154, 1111, 845, 777 cm-1; HRMS (ESI) m/z calcd for C29H44FO4Si [M + H+]
503.2987, found 503.2970; [α] !!" −44.7 (c 1.00, CHCl3).
(Z)-Isopropyl 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-oct-1-en-1-yl)-5-
oxocyclopentyl)hept-5-enoate (6k). Following Method A, the title compound was
isolated as a colorless oil (69 mg, 93%). Following Method B, the reaction mixture
was stirred for 3 d (51 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3H), 0.03 (s,
3H), 0.86 (s, 9H), 1.21 (d, J = 6.4 Hz, 6H), 1.23–1.42 (m, 10H), 1.58–1.71 (m, 3H),
1.95–2.07 (m, 5H), 2.08–2.18 (m, 1H), 2.20–2.26 (m, 2H), 2.26–2.44 (m, 3H), 2.61
(ddd, J = 1.2, 7.1, 18.3 Hz, 1H), 3.98 (ddd, J = 8.5, 8.5, 8.5 Hz, 1H), 5.00 (sep, J = 6.4
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Hz, 1H), 5.26 (dd, J = 8.4, 15.2 Hz, 1H), 5.30–5.44 (m, 2H), 5.49–5.59 (m, 1H); C
NMR (100 MHz, CDCl3) δ −4.7 (CH3), 14.1 (CH3), 18.1 (C), 21.8 (CH3), 22.6 (CH2),
24.8 (CH2), 24.9 (CH2), 25.7 (CH3), 26.6 (CH2), 28.9 (CH2), 29.3 (CH2), 31.7 (CH2),
32.6 (CH2), 34.1 (CH2), 47.6 (CH2), 53.5 (CH), 54.2 (CH), 67.3 (CH), 73.1 (CH),
126.8 (CH), 129.6 (CH), 130.6 (CH), 134.0 (CH), 173.1 (C), 215.3 (C); FTIR (KBr,
neat) ν̃
2930, 2860, 1739, 1462, 1371, 1250, 1111, 968, 839, 775 cm-1; HRMS (ESI)
m/z calcd for C29H53O4Si+ [M + H+] 493.3708, found 493.3702; [α] !!" −54.5 (c 1.00,
CHCl3).
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(Z)-Isopropyl 7-((1R,2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclohex-1-en-1-yl)-5-
oxocyclopentyl)hept-5-enoate (6l). Following Method A, the additional portions of
[RhCl(COD)]2 and 5l were added after 3 h (instead of after 5 h) and the reaction was
irradiated for a further 2 h; the title compound was isolated as a colorless oil (26 mg,
38%). Following Method B, boronic acid 5l (1.0 equiv) was added after 1 d and the
reaction was stirred for another 1 d (63 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 0.01
(s, 3H), 0.02 (s, 3H), 0.86 (s, 9H), 1.22 (d, J = 6.3 Hz, 6H), 1.56–1.68 (m, 6H), 1.82–
1.98 (m, 2H), 1.99–2.08 (m, 4H), 2.09–2.16 (m, 1H), 2.17–2.31 (m, 5H), 2.37 (dd, J =
8.5, 12.3 Hz, 1H), 2.63 (dd, J = 7.3, 18.5 Hz, 1H), 4.11 (ddd, J = 8.1, 8.1, 8.1 Hz, 1H),
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4.99 (sep, J = 6.3 Hz, 1H), 5.28–5.43 (m, 2H), 5.54–5.60 (m, 1H); C NMR (100
MHz, CDCl3) δ −4.9 (CH3), −4.8 (CH3), 18.0 (C), 21.8 (CH3), 22.6 (CH2), 22.9
(CH2), 24.9 (CH2), 25.2 (CH2), 25.3 (CH2), 25.4 (CH2), 25.7 (CH3), 26.6 (CH2), 34.2
(CH2), 47.7 (CH2), 51.7 (CH), 58.4 (CH), 67.4 (CH), 70.9 (CH), 125.9 (CH), 126.8
(CH), 130.5 (CH), 134.1 (C), 173.1 (C), 215.7 (C); FTIR (KBr, neat) ν̃ 3450, 2935,
2862, 1738, 1634, 1463, 1375, 1249, 1111, 884 cm-1; HRMS (ESI) m/z calcd for
C27H47O4Si+ [M + H+] 463.3238, found 463.3240; [α] !!" −53.5 (c 1.00, CHCl3).
(Z)-Isopropyl 7-((1R,2S,3R)-2-((E)-but-2-en-2-yl)-3-((tert-butyldimethylsilyl)oxy)-5-
oxocyclopentyl)hept-5-enoate (6m). Following Method A, the additional portions of
[RhCl(COD)]2 and 5m were added after 3 h (instead of after 5 h) and the reaction was
irradiated for a further 2 h; the title compound was isolated as a colorless oil (24 mg,
37%). Following Method B, boronic acid 5m (1.0 equiv) was added after 1.5 d and
the reaction was stirred for another 1 d (64 mg, 98%). 1H NMR (400 MHz, CDCl3) δ
−0.01 (s, 3H), 0.01 (s, 3H), 0.85 (s, 9H), 1.22 (d, J = 6.3 Hz, 6H), 1.54–1.69 (m, 8H),
1.95–2.08 (m, 2H), 2.10–2.32 (m, 6H), 2.58–2.72 (m, 1H), 3.04 (dd, J = 9.0, 12.2 Hz,
1H), 4.16 (ddd, J = 8.8 Hz, 1H), 4.99 (sep, J = 6.0 Hz, 1H), 5.28–5.44 (m, 2H), 5.46–
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5.55 (m, 1H); C NMR (100 MHz, CDCl3) δ −5.0 (CH3), −4.9 (CH3), 13.4 (CH3),
17.9 (C), 18.7 (CH3), 21.8 (CH3), 24.8 (CH2), 24.9 (CH2), 25.7 (CH3), 26.4 (CH2),
34.1 (CH2), 47.7 (CH2), 50.7 (CH), 51.7 (CH), 67.4 (CH), 70.0 (CH), 125.0 (CH),
126.6 (CH), 130.6 (CH), 131.4 (C), 173.1 (C), 215.4 (C); FTIR (KBr, neat) ν̃ 3452,
2938, 1736, 1667, 1461, 1373, 1250, 1108, 972, 838 cm-1; HRMS (ESI) m/z calcd for
C25H45O4Si [M + H+] 437.3081, found 437.3087; [α] !!" −43.6 (c 1.00, CHCl3).
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(Z)-Isopropyl 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(2-methylprop-1-en-1-
yl)-5-oxocyclopentyl)hept-5-enoate (6n). Following Method A, the title compound
was isolated as a colorless oil (65 mg, 99%). Following Method B, boronic acid 5n
(1.0 equiv) was added after 2 d and the reaction was stirred for another 1 d (66 mg,
>99%). 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.02 (s, 3H), 0.86 (s, 9H), 1.22 (d,
J = 6.4 Hz, 6H), 1.60–1.70 (m, 2H), 1.66 (s, 3H), 1.74 (s, 3H), 1.92–1.99 (m, 1H),
2.01–2.08 (m, 2H), 2.12–2.34 (m, 5H), 2.58–2.66 (m, 1H), 2.67–2.77 (m, 1H), 3.95
(ddd, J = 8.1, 8.1, 8.1 Hz, 1H), 4.92 (d, J = 9.6 Hz, 1H), 5.00 (sep, J = 6.4 Hz, 1H),
5.27–5.44 (m, 2H); 13C NMR (100 MHz, CDCl3) δ −5.0 (CH3), 18.0 (C), 18.7 (CH3),
21.8 (CH3), 24.8 (CH2), 25.0 (CH2), 25.6 (CH3), 25.8 (CH3), 26.5 (CH2), 34.1 (CH2),
47.6 (CH2), 49.4 (CH), 55.2 (CH), 67.4 (CH), 73.6 (CH), 125.4 (CH), 127.0 (CH),
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130.4 (CH), 135.4 (C), 173.1 (C), 215.6 (C); FTIR (KBr, neat) ν̃ 2937, 2855, 1738,
1463, 1373, 1248, 1150, 1108, 880, 834 cm-1; HRMS (ESI) m/z calcd for C25H45O4Si+
[M + H+] 437.3082, found 437.3096; [α] !!" −68.2 (c 1.00, CHCl3).
(Z)-Isopropyl
7-((1R,2S,3R)-3-((tert-butyldimethylsilyl)oxy)-5-oxo-2-(prop-1-en-2-
yl)cyclopentyl)hept-5-enoate (6o). Following Method A, the additional portions of
[RhCl(COD)]2 and 5o were added after 3 h (instead of after 5 h) and the reaction was
irradiated for a further 2 h; the title compound was isolated as a colorless oil (48 mg,
1
76%). H NMR (400 MHz, CDCl3) δ 0.016 (s, 3H), 0.024 (s, 3H), 0.86 (s, 9H), 1.22
(d, J = 6.2 Hz, 6H), 1.58–1.69 (m, 3H), 1.73 (s, 3H), 2.04 (ddd, J = 6.9, 6.9, 6.9 Hz,
2H), 2.10–2.35 (m, 5H), 2.50 (dd, J = 8.3, 12.0 Hz, 1H), 2.66 (dd, J = 7.1, 18.4 Hz,
1H), 4.13 (ddd, J = 8.2, 8.2, 8.2 Hz, 1H), 4.85 (s, 1H), 4.93 (s, 1H), 4.99 (sep, J = 6.2
Hz, 1H), 5.28–5.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δ −4.9 (CH3), −4.8 (CH3),
18.0 (C), 19.6 (CH3), 21.8 (CH3), 24.8 (CH2), 25.3 (CH2), 25.7 (CH3), 26.6 (CH2),
34.1 (CH2), 47.7 (CH2), 52.2 (CH), 57.7 (CH), 67.4 (CH), 71.3 (CH), 114.2 (CH2),
126.5 (CH), 130.8 (CH), 142.4 (C), 173.1 (C), 215.2 (C); FTIR (KBr, neat) ν̃ 3421,
2950, 2862, 1738, 1636, 1376, 1253, 1107, 888, 837, 786 cm-1; HRMS (ESI) m/z
calcd for C24H43O4Si [M + H+] 423.2925, found 423.2927; [α] !!" −85.4 (c 1.00,
CHCl3).
(Z)-Isopropyl
7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((S,E)-3-((tert-
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The Journal of Organic Chemistry
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butyldimethylsilyl)oxy)oct-1-en-1-yl)-5-oxocyclopentyl)hept-5-enoate (6p). Following
Method A, a solution of 2 (0.30 g, 0.79 mmol), boronic acid (5p) (1.2 mmol),
[RhCl(COD)]2 (5.8 mg, 11.6 µmol) and aqueous KOH (50 µL, 3.1 M, 155 µmol) in
MeOH (5.3 mL) was stirred under microwave irradiation at 30 °C (50 W). After 3 h,
additional boronic acid 5p (1.2 mmol) and [RhCl(COD)]2 (5.8 mg, 11.6 µmol) were
added and the reaction mixture was stirred for 2 h under microwave irradiation (30
°C; 50 W). The mixture was concentrated under reduced pressure and the resulting
residue was purified by column chromatography (eluting with 1:80 (v/v) acetone–
hexanes) affording cyclopentanone 6p as a colorless oil (0.48 g, 98%). On an
unoptimized 5.2 mmol scale of 2, this reaction provided compound 6p in 82% yield
(2.65 g). Using Method B, a mixture of 2 (0.32 g, 0.84 mmol), boronic acid 5p (1.26
mmol), [RhCl(COD)]2 (6.2 mg, 12.5 µmol) and aqueous KOH (53 µL, 3.1 M, 164
µmol) in MeOH (5.6 mL) was stirred at 3 °C. After stirring for 1 d, the product
mixture was concentrated under reduced pressure and the resulting residue was
purified by column chromatography (eluting with 1:80 (v/v) acetone–hexanes)
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affording cyclopentanone 6p (0.38 g, 72%). H NMR (400 MHz, CDCl3) δ 0.02 (s,
3H), 0.04 (s, 3H), 0.049 (s, 3H), 0.052 (s, 3H), 0.83–0.90 (m, 3H), 0.87 (s, 9H), 0.89
(s, 9H), 1.22 (d, J = 6.4 Hz, 6H), 1.23–1.38 (m, 6H), 1.38–1.48 (m, 2H), 1.64 (qui, J =
7.5 Hz, 2H), 1.98–2.10 (m, 3H), 2.15 (dd, J = 8.4, 18.2 Hz, 1H), 2.21–2.33 (m, 3H),
2.34–2.52 (m, 2H), 2.63 (ddd, J = 1.1, 7.0, 18.2 Hz, 1H), 3.98–4.13 (m, 2H), 4.99
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(sep, J = 6.4 Hz, 1H), 5.27–5.44 (m, 2H), 5.45–5.63 (m, 2H); C NMR (100 MHz,
CDCl3) δ −4.72 (CH3), −4.66 (CH3), −4.61 (CH3), −4.3 (CH3), 14.0 (CH3), 18.0 (C),
18.2 (C), 21.8 (CH3), 22.6 (CH2), 24.8 (CH2), 25.1 (CH2), 25.2 (CH2), 25.8 (CH3),
25.9 (CH3), 26.7 (CH2), 31.9 (CH2), 34.1 (CH2), 38.6 (CH2), 47.7 (CH2), 52.7 (CH),
53.9 (CH), 67.4 (CH), 72.6 (CH), 73.3 (CH), 126.6 (CH), 128.6 (CH), 130.8 (CH),
136.5 (CH), 173.1 (C), 215.4 (C); FTIR (KBr, neat) ν
̃
2937, 2861, 1738, 1577, 1467,
+
1371, 1250, 1107, 835, 774 cm-1; HRMS (ESI) m/z calcd for C35H70O5NSi2 [M +
+
NH4 ] 640.4787, found 640.4775; [α] !!" −29.6 (c 1.00, CHCl3).
(Z)-Isopropyl
7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-3,3-difluoro-4-
phenoxybut-1-en-1-yl)-5-oxocyclopentyl)hept-5-enoate (6q). Following Method A, a
solution of 2 (57 mg, 0.15 mmol), boronic acid 5q (0.22 mmol), [RhCl(COD)]2 (1.1
mg, 2.2 µmol) and aqueous KOH (9.5 µL, 3.1 M, 30 µmol) in MeOH (1.0 mL) was
stirred under microwave irradiation at 30 °C (50 W). After 3 h, additional boronic
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