Cross-metathesis approach for stereocontrolled synthesis of the C1-C15 fragment of rhizopodin

Article abstract of DOI:10.1055/s-0033-1340154

The C1-C15 fragment of rhizopodin was synthesized through either Suzuki coupling reaction of vinyl iodide and vinyl boronate or cross-metathesis of a terminal olefin and a diene adduct in the presence of Hoveyda-Grubbs II catalyst. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340154

138▌
LETTER
lCettreross-Metathesis Approach for Stereocontrolled Synthesis of the C1–C15
Fragment of Rhizopodin
Synthesis of C1–C15 Fragment of Rhizopodin
Honggang Gui,a Junyang Liu,a,b Liankai Song,a Chunngai Hui,b Junmin Feng,a Zhengshuang Xu,*a Tao Ye*b
a
Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, University Town of Shenzhen, Xili, Nanshan District,
Shenzhen, 518055, P. R. of China
b
Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong,
P. R. of China
Fax +852(2)2641912; E-mail: tao.ye@polyu.edu.hk; E-mail: xuzs@pkusz.edu.cn
Received: 18.08.2013; Accepted after revision: 22.09.2013
ments 2 and 3. Alternatively, a Suzuki cross-coupling of
Abstract: The C1–C15 fragment of rhizopodin was synthesized
vinyl boronate 4 with vinyl iodide 5 was envisioned to de-
through either Suzuki coupling reaction of vinyl iodide and vinyl
liver diene 1 (Scheme 1). Oxazole-containing fragments 2
boronate or cross-metathesis of a terminal olefin and a diene adduct
and 4 were planned to originate from the common
precursor 10, which, in turn, would be prepared from the
known methyl-2-(chloromethyl)oxazole-4-carboxylate
(7; Scheme 2).
in the presence of Hoveyda–Grubbs II catalyst.
Key words: cross-metathesis, cross-coupling, stereocontrolled
synthesis, conjugated diene, rhizopodin
The synthesis of fragments 2 and 4 is outlined in Scheme
2. Oxazole 7 was obtained from commercially available
2,2-dichloronitrile (6) by using a known sequence.7 Reac-
tion of 7 with sodium acetate in the presence of acetic acid
and acetic anhydride and treatment of the resultant acetate
derivative with potassium carbonate and methanol afford-
ed the corresponding alcohol 8 in 61% yield over two
steps. After protection of the primary alcohol as its TBS
ether, the methyl ester was reduced with DIBAL-H in
THF to give alcohol 9 in 84% yield. This route is opera-
tionally convenient and proceeds well on large scale
(>35 g of 9 was obtained). It should be mentioned that al-
cohol 9 could be obtained by a reported procedure;8 how-
ever, in our hands, we were unable to reproduce the
reaction on large scales. Swern oxidation9 of the primary
alcohol of 9, followed by Keck allylation10 of the resulting
aldehyde, provided homoallylic alcohol 10 in 72% yield
with >97% enantiomeric excess, as measured on its
Mosher ester.11 The absolute stereochemistry at the newly
created stereogenic center was also assigned at this point
by synthesis and comparison of the 1H NMR spectra of its
Mosher derivatives.12 Thus, homoallylic alcohol 10 was
reacted with both (S)- and (R)-α-methoxy-α-(trifluoro-
methyl)phenylacetic acid to generate diastereomeric (S)-
or (R)-Mosher esters 12 and 13, respectively (Table 1).
Subtraction of the chemical shifts of the protons of (R)-
Mosher ester 13 from those of (S)-Mosher ester 12 in the
vicinity of the ester-bearing stereocenter then provides
differences (Δδ), the signs of which are used to assign the
configuration of the stereocenter. The signs of the Δδ are
shown in Table 1, and the absolute stereochemistry at C11
was elucidated to be the (S)-configuration.
Rhizopodin was isolated by Höfle and Reichenbach from
the myxobacterium Myxococcus stipitatus and was as-
signed as a monomeric lactone in 1993.1 Its structure and
absolute stereochemistry were recently revised as shown
in Scheme 1.2,3 Rhizopodin exhibits significant biological
properties including potent cytostatic activity in the low
nanomolar range against a range of tumor cell lines.1–3
The distinctive structural features and biological activi-
ties, together with our interest in macrocyclic marine nat-
ural products4 prompted us to undertake studies on the
synthesis of rhizopodin. Recently, various synthetic ap-
proaches toward the synthesis of rhizopodin have been re-
ported.5 The syntheses of monorhizopodin and 16-epi-
monorhizopodin were achieved by Nicolaou and co-
workers in 20115e and, since then, two total syntheses of
rhizopodin have been reported.5g,j
So far, total syntheses of the macrocycle of rhizopodin
have employed either intramolecular Suzuki coupling re-
action or macrolactonization.5g–j An alternative approach
to the macrocyclizations was sought and we opted to close
the macrocyclic core by ene-diene cross-metathesis6 as
shown in our retrosynthetic plan (Scheme 1). To test the
feasibility of the key ene-diene cross-metathesis step of
our designed strategy toward rhizopodin, a model study
based on the construction of the C1–C15 fragment (1) of
rhizopodin was undertaken. Herein we detail two synthet-
ic approaches to fragment 1.
Retrosynthetic analysis of 1 led us to disconnect between
positions C8 and C9, which imposed the construction of
the conjugated diene through cross-metathesis of frag-
O-Methylation of the homoallylic alcohol 10 by using io-
domethane and sodium hydride in THF provided 2 in 84%
yield. Olefin cross-metathesis between 2 and vinyl pinac-
ol boronate 11 under the influence of the Hoveyda–
SYNLETT 2014, 25, 0138–0142
Advanced online publication: 05.11.2013
DOI: 10.1055/s-0033-1340154; Art ID: ST-2013-W0795-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Synthesis of C1–C15 Fragment of Rhizopodin
139
OMe
OMe
OH
OMe OH
O
O
Me
O
O
N
O
N
Suzuki coupling
cross metathesis
HO
OMe
MeO
N
O
O
O
N
MeO
Me
O
OH OMe
OMe
O
rhizopodin
TBS
OMe
OMe
O
O
9
7
N
15
11
5
3
1
OMe
TBSO
13
O
Suzuki coupling
cross metathesis
1
OMe
N
OMe
Bpin
N
TBSO
TBSO
O
O
2
4
+
+
TBS
TBS
OMe
O
O
OMe
O
O
OMe
I
OMe
3
5
Scheme 1 Retrosynthetic analysis
Grubbs II catalyst furnished vinyl boronate 4 in 65% yield
(E/Z = 10:1; Scheme 2).13
OMe
OMe
O
Cl
Cl
N
N
i, ii
O
CN
The preparation of coupling partners 3 and 5 commenced
from methyl ester 14, which was prepared according to
conditions described by Paterson14 (Scheme 3). Methyl
ester 14 was reduced to aldehyde 15 in 94% yield by using
DIBAL-H in dichloromethane. Subsequent treatment of
15 with β-(+)-allyldiisopinocampheylborane according to
Brown et al.15 provided a 10:1 mixture of syn- and anti-
monomethylated diols, favoring the desired isomer,
which was protected as its TBS ether 16 (55% yield over
two steps). Oxidative cleavage of the terminal olefin by
using the Sharpless protocol,16 and esterification of the re-
sultant acid with trimethylsilyldiazomethane17 provided
methyl ester 17 in 63% yield over two steps. Selective re-
moval of the primary TBS group in the presence of the
secondary TBS group under mild acidic conditions pro-
vided alcohol 18 in 88% yield. Oxidation of the primary
alcohol in 18 by using the Dess−Martin periodinane
reagent18 buffered with sodium bicarbonate afforded the
corresponding aldehyde, which served as the precursor
leading to both 3 and 5. Thus, a Horner–Wadsworth–
Emmons olefination between the diethyl allylphospho-
nate and the aldehyde derived from 18 successfully led to
the required diene 3 in 53% yield and good E/Z selectivity
(15:1). In parallel, treatment of the aldehyde with iodo-
HO
Cl
61%
O
8
61%
O
6
7
iii, iv
84%
OH
N
N
v, vi
OH
72%
TBSO
TBSO
O
O
10
9
O
B
vii
84%
O
11
OMe
O
OMe
viii
B
N
N
O
65%
TBSO
TBSO
O
O
2
4 (E/Z = 10:1)
Scheme 2 Preparation of intermediates 2 and 4. Reagents and con-
ditions: (i) NaOAc, HOAc-Ac2O; (ii) K2CO3, MeOH; (iii) TBSCl,
imidazole, CH2Cl2; (iv) DIBAL-H, THF; (v) (COCl)2, DMSO, Et3N,
CH2Cl2, –78 °C; (vi) (S)-BINOL, Ti(Oi-Pr)4, allyltributylstannane,
CH2Cl2, –20 °C, 72 h; (vii) NaH, MeI, THF; (viii) 11, Hoveyda–
Grubbs II catalyst, toluene, 80 °C.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 138–142

140
H. Gui et al.
LETTER
Table 2 Suzuki Coupling for the Synthesis of Diene 1a
Table 1 Stereochemical Assignment of 10a
OH
9
TBS
OMe O O
OMe
O
B
N
15
11
N
O
TBSO
O
I
OMe
13
TBSO
10
O
4
5
ii
i
85% 91%
catalyst (10 mol%)
r.t., 8 h
(S)-MTPA
(R)-MTPA
O
O
N
N
TBS
OMe
OMe
O
O
TBSO
TBSO
O
O
12
13
N
O
OMe
TBSO
Hydrogen δS (S-MTPA ester) δR (R-MTPA ester) δS–δR
1
TBS(t-Bu) 0.910
0.901
0.088
4.701
7.409
6.077
2.790
5.759
+0.009
+0.016
+0.042
+0.165
–
Entry Ratio 4/5 Catalyst/ligand
Solvent
THF
Base
Yield
(%)
TBS(Me)
0.104
4.742
7.574
6.050
2.745
5.634
1
2
3
1.3:1.0
1.3:1.0
1.3:1.0
[Pd(Ph3P)4]/Ph3As
Cs2CO3 35
Cs2CO3 52
15
13
11
10
9
[Pd(dppf)2Cl2]/Ph3As THF
[Pd(Ph3P)4]
THF–H2O TlOEt
73
a Reaction conditions: See table and text for details.
–0.045
–0.125
8
5.082
5.030
5.171
5.133
–0.089
–0.103
with 10 mol% of either Grubbs II catalyst or Hoveyda–
Grubbs II catalyst in dichloromethane at reflux also failed
to provide any detectable quantities of diene 1. Fortunate-
ly, performing this reaction at 60 °C in toluene with
Grubbs II catalyst or Hoveyda–Grubbs II catalyst, afford-
ed 1 in 24% and 40% yield, respectively (entries 4 and 5).
a Reaction conditions: (i) oxallyl chloride, DMF, CH2Cl2, (S)-MTPA;
then Et3N, DMAP, CH2Cl2, 10, 85%; (ii) oxallyl chloride, DMF,
CH2Cl2, (R)-MTPA; then Et3N, DMAP, CH2Cl2, 10, 91%.
form and chromous chloride in THF19 gave vinyl iodide 5
in 63% overall yield with greater than 10:1 E/Z selectivity.
OMe
O
OMe
OMe OTBS
OMe O
i
ii, iii
94%
55%
With the four requisite fragments 2–5 in hand, the stage
was set to test the palladium-catalyzed cross-coupling re-
action (Table 2) and ene-diene cross-metathesis (Table 3).
First, we explored the Suzuki coupling reaction20 of vinyl
boronate 4 and vinyl iodide 5 under various conditions.
Initially the widely used protocol was employed using
[Pd(Ph3P)4]-Ph3As and Cs2CO3 in THF. Unfortunately,
the desired product 1 was obtained in only 35% isolated
yield (Table 2, entry 1). When the catalyst was switched
to [Pd(dppf)2Cl2], diene 1 was isolated in a much im-
proved yield (52%; entry 2). Further optimization of the
catalytic systems led to the identification of a remarkably
simple protocol, in which vinyl boronate 4 and vinyl
iodide 5 were exposed to [Pd(Ph3P)4] and TlOEt in
THF–H2O (v/v 4:1) to furnish 1 in 73% isolated yield
(entry 3).21
OTBS
OTBS
OTBS
15
14
16
iv, v 63%
TBS
TBS
OMe
O
O
OMe
O
O
vi
88%
OMe
OMe
OTBS
OH
18
17
O
vii, viii 53%
vii, ix
63%
TBS
TBS
OMe
O
OMe
O
O
OMe
I
OMe
3 (E/Z = 15:1)
5 (E/Z > 10:1)
Scheme 3 Preparation of intermediates 3 and 5. Reagents and con-
ditions: (i) DIBAL-H, CH2Cl2, –78 °C; (ii) (+)-Ipc2BOMe, allylmag-
nesium bromide, Et2O, 0 to –78 °C; then 15; (iii) TBSCl, Et3N,
We then examined the key ene-diene cross-metathesis re-
action under several conditions by varying the solvent,
catalyst, and temperature. As shown in Table 3, initial
cross-metathesis of alkene 2 and diene 3 at 80 °C in tolu-
ene with Grubbs I catalyst provided no conversion (entry
DMAP,
CH2Cl2;
(iv) RuCl3,
NaIO4,
CCl4–MeCN–H2O;
(v) TMSCHN2, MeOH; (vi) (–)-CSA, CH2Cl2–MeOH; (vii) Dess–
Martin periodinane, NaHCO3, CH2Cl2; (viii) diethyl allylphospho-
nate, nBuLi, HMPA, THF, –78 °C, then aldehyde; (ix) CrCl2, CHI3,
1). Furthermore, attempts to mediate the cross-metathesis THF.
Synlett 2014, 25, 138–142
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of C1–C15 Fragment of Rhizopodin
141
Furthermore, by increasing the reaction temperature to
80 °C in toluene in the presence of Hoveyda–Grubbs II
catalyst, the yield improved considerably, and diene 1
could be isolated in 51% yield21 as the (E,E)-alkene, the
conformation of which was determined by 1H NMR spec-
troscopic analysis. Considering the thermal stability of
both starting material and catalyst, attempts to further im-
prove the yield by the use of elevated temperatures were
not conducted.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
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OMe
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OMe
TBSO
O
2 (3.0 equiv)
3 (1.0 equiv)
OMe
OMe OTBS O
N
O
OMe
TBSO
1
Entry Catalyst (10 mol%)
Solvent Temp (°C) Yield (%)b
1
2
3
4
5
6
Grubbs I
toluene 80
CH2Cl2 40
CH2Cl2 40
toluene 60
toluene 60
toluene 80
–
Grubbs II
–
Hoveyda–Grubbs II
Grubbs II
–
24
40
51
Hoveyda–Grubbs II
Hoveyda–Grubbs II
a Reaction conditions: See table and text for details.
b Yield based on recovered 3.
In summary, the C1–C15 fragment of rhizopodin was syn-
thesized by either Suzuki coupling reaction of vinyl iodide
and vinyl boronate or by cross-metathesis of a terminal
olefin and a diene adduct in the presence of Hoveyda–
Grubbs II catalyst. This study demonstrates the effective-
ness of an ene-diene cross-metathesis approach to diene 1
and served as a model study for the total synthesis of rhi-
zopodin based on ene-diene cross-metathesis strategy.
Further efforts directed toward the asymmetric total syn-
thesis of rhizopodin and its analogues are underway and
will be reported in due course.
Acknowledgment
We acknowledge financial support from the Hong Kong Research
Grants Council (Projects: PolyU 5040/10P; PolyU 5037/11P,
PolyU 5020/12P; PolyU5030/13P), the Fong Shu Fook Tong Foun-
dation, the Joyce M. Kuok Foundation, the NSFC (21072007,
21272011), GDSFC (10151805704000005), and The Shenzhen Bu-
reau of Science, Technology and Information (JC200903160367A,
JC201005260220A, JC201005260102A, ZYC201105170351A).
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LETTER
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(17) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475.
(18) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(19) Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987,
109, 951.
(20) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; and
references cited therein.
(21) Procedures for the synthesis of diene 1:
Suzuki Cross-Coupling; General Procedure: Vinyl iodide
5 (1.0 equiv), pinacol boronate 4 (1.2 equiv), base (2.0
equiv) and ligand (0.5 equiv) were dissolved in degassed
THF (2.0 mL) and palladium catalyst (0.1 equiv) dissolved
in degassed THF (1.0 mL) was added by using a cannula.
The reaction mixture was stirred at ambient temperature and
monitored by TLC. Upon completion of the reaction, it was
quenched by addition of sat. aq NH4Cl (10 mL) and filtered
through a pad of Celite, eluted with CH2Cl2 (10 mL). The
filtrate was concentrated to remove volatiles and the aqueous
residue was extracted with CH2Cl2 (3 × 30 mL). The
combined organic layers were dried over Na2SO4 and
concentrated under vacuum. The residue was purified by
flash column chromatography (EtOAc–hexane, 1:4; Rf =
0.4) to give diene 1 as a colorless oil.
Cross-Metathesis; General Procedure: To a solution of
alkene 2 (3.0 equiv) and 1,3-diene 3 (1.0 equiv) in degassed
solvent (1.5 mL), ruthenium catalyst (0.1 equiv; pre-
dissolved in 1.0 mL degassed solvent) was added by using a
cannula, and the reaction mixture was stirred at different
temperatures and monitored by TLC. When the reaction
reached completion, volatiles were removed under vacuum,
and compound 1 was obtained after purification by flash
column chromatography (EtOAc–hexane, 1:4; Rf = 0.4) as a
colorless oil. The analytical data of the product were
identical those of the main product of the Suzuki coupling
reaction.
(7) Hermitage, S. A.; Cardwell, K. S.; Chapman, T.; Cooke, J.
W. B.; Newton, R. Org. Process Res. Dev. 2001, 5, 37.
(8) Panek, J. S.; Beresis, R. T. J. Org. Chem. 1996, 61, 6496.
(9) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(b) Tidwell, T. T. Synthesis 1990, 857; and references cited
therein.
(10) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem.
Soc. 1993, 115, 8467. (b) Keck, G. E.; Krishnamurthy, D.;
Grier, M. C. J. Org. Chem. 1993, 58, 6543.
(11) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(12) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H.
J. Am. Chem. Soc. 1991, 113, 4092. (b) Mosher, H. S.
J. Org. Chem. 1973, 38, 2143.
(13) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031.
(14) Paterson, I.; Findlay, A. D.; Noti, C. Chem. Commun. 2008,
6408.
Analytical Data of 1: [α]D25 +8.4 (c 1.1, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.54 (s, 1 H), 6.24–5.97 (m, 2 H),
5.77–5.56 (m, 1 H), 5.50–5.31 (m, 1 H), 4.75 (s, 2 H), 4.33–
4.14 (m, 2 H), 3.70–3.67 (m, 1 H), 3.66 (s, 3 H), 3.32 (s,
3 H), 3.21 (s, 3 H), 2.72–2.59 (m, 2 H), 2.58–2.45 (m, 2 H),
1.85 (ddd, J = 13.3, 7.9, 5.2 Hz, 1 H), 1.66–1.57 (m, 1 H),
0.91 (s, 9 H), 0.87 (d, J = 8.7 Hz, 9 H), 0.10 (s, 6 H), 0.05 (s,
3 H), 0.03 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 172.19,
162.85, 140.52, 136.03, 132.70, 131.98, 131.81, 129.99,
78.71, 76.08, 66.78, 58.42, 56.86, 55.96, 51.40, 43.40,
42.42, 37.79, 25.76, 18.37, 17.93, –4.49, –4.80, –5.39.
HRMS (ESI): m/z [M + Na]+ calcd for C30H55NO7Si2Na+:
620.3410; found: 620.3406.
(15) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105,
2092. (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986,
Synlett 2014, 25, 138–142
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