Stereoselective total syntheses of insect juvenile hormones JH 0 and JH i

Article abstract of DOI:10.1055/s-0031-1290803

Total syntheses of juvenile hormones JH 0 and JH I have been achieved by a new iterative enol tosylate homologation strategy. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290803

LETTER
▌1213
LSettteerreoselective Total Syntheses of Insect Juvenile Hormones JH 0 and JH I
Stereoselective Total Syntheses of Insect Juvenile Hormones
Atsushi Manabe, Yasufumi Ohfune,* Tetsuro Shinada*
Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Fax +81(6)66053153; E-mail: shinada@sci.osaka-cu.ac.jp; E-mail: ohfune@sci.osaka-cu.ac.jp
Received: 08.12.2011; Accepted after revision: 27.02.2012
reochemically defined steps (2) and (3) under mild
Abstract: Total syntheses of juvenile hormones JH 0 and JH I have
reaction conditions.
been achieved by a new iterative enol tosylate homologation strate-
gy.
O
O
Key words: juvenile hormone, acyclic terpenoid, enol tosylate,
O
O
OMe
Negishi coupling reaction
–
–
Br
OMe
(1)
9
prenyl bromide (8)
(2) stereoselective
synthesis of Z-olefin
Juvenile hormone (JH) is a key hormone that regulates an
insect’s life cycle.1 The presence of JH in insects was first
reported by Wigglesworth.2 Since then, many efforts have
been made for the structure determination of JH. The first
structure determination was achieved by Röller and Trost
in 1967.3 The JH isolated from the robin moth, Hyalo-
phora cecropia, was labeled as JH I. To date, several JH
structures have been elucidated (Figure 1).4 Among them,
JH 0 (1), JH I (2), JH II (3), and 4-Me-JH I (5) are known
to be unusual sesquiterpenoid congeners in which the
methyl group(s) on the acyclic framework are substituted
with ethyl group(s). These unusual structural features as
well as their intriguing biological activities have received
significant interests from the synthetic communities. Ex-
tensive synthetic reports have been documented for the to-
tal syntheses of these natural products focusing on the
stereoselective construction of the unusual ethyl-group-
containing terpene structure5 as well as the chiral trisub-
stituted epoxide5a–e,6 in which the 10R,11S stereocenters
play a crucial role in the juvenilizing effects.7 Although
several total syntheses of 1–3 have been reported, the ef-
ficient total synthesis of the optically active 1–3 still re-
mains a challenging synthetic task. We now report the
total synthesis of JH 0 (1) and JH I (2) in an optically ac-
tive form by the iterative enol tosylate homologation strat-
egy.
(3) cross-
coupling reaction
R
O
OX
O
OMe
OMe
11
(4)
10
X = Tf or P(=O)(OEt)2
R
repeat
R
OH
Br
n
12
13
Scheme 1 Previous homologation sequence for the access to acyclic
terpenoid analogues
R1
R2
R3
O
OMe
O
R4
JH 0 (1): R1, R2, R3 = Et; R4 = H,
JH I (2): R1, R2 = Et; R3 = Me; R4 = H
JH II (3): R1 = Et; R2, R3 = Me; R4 = H
JH III (4): R1, R2, R3 = Me; R4 = H
4-Me-JH I (5): R1, R2 = Et; R3 = Me; R4 = Me..
O
OMe
O
O
O
JHB3 (6)
O
Recently, the stereoselective syntheses of acyclic terpene
derivatives by the vinyl triflate and vinyl phosphate medi-
ated strategies have been reported (Scheme 1).8 These ap-
proaches consisted of a series of the following sequential
transformations: (1) alkylation of acetylacetate with a
commercially available halide such as prenyl bromide (8)
to give the β-keto ester 9, (2) Z-selective conversion into
vinyl triflate or vinyl phosphate 10, (3) cross-coupling re-
action of 10 to install the side chain, and (4) conversion of
the resulting coupling product into an allyl bromide 12.
These synthetic methods are characterized by the stereo-
controlled synthesis of the trisubstituted olefin via the ste-
OMe
O
JHSB3 (7)
Figure 1 Structures of juvenile hormones
We assumed that JH 0 (1) and JH I (2) could be accessed
by the above synthetic strategy starting from the known
allyl bromide A or B (Scheme 2). However, these bro-
mides are known to be volatile compounds and must be
prepared in large quantities via rectification accompany-
ing the separation of the olefin geometric mixture.9 We
postulated that these practical inconveniences could be
solved by the outset of the unprecedented (Z)-1-bromo-3-
tosyloxy-2-buten (15) and its E-isomer 16 as a surrogate
of the allyl bromides. These tosylates would be much less
volatile than A and B. Moreover, it is expected that 15 and
SYNLETT 2012, 23, 1213–1216
Advanced online publication: 20.04.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290803; Art ID: ST-2012-U0755-L
© Georg Thieme Verlag Stuttgart · New York

1214
A. Manabe et al.
LETTER
16 could be a versatile synthon in organic synthesis, while
the syntheses and their synthetic potentials have not yet
been examined. In this context, we planned a new homol-
ogation sequence using the allyl bromides 15 and 16
(Scheme 2). These bromides could be transformed into
the bistosylates 19 and 20, respectively, to test the double
Negishi cross-coupling to access the common intermedi-
ates 21 and 22 of the racemic or optically active JH 0 (1)
and JH I (2), respectively. The simultaneous side-chain in-
stallation to 19 is more efficient than the previous homol-
ogation methods in which the side chain was embedded
one by one.
Table 1 Synthesis of (E)- and (Z)-Enol Tosylates 23 and 24
TsCl (1.5 equiv)
NMI (1.5 equiv), Et3N (1.5 equiv)
O
O
CO2Me
OMe
CH2Cl2, r.t., 17 h, 90%
TsO
(E)-23 (> 95:5)
14
OTs
additive (5.0 equiv), TsCl (1.5 equiv)
NMI (1.5 equiv), Et3N (1.5 equiv)
CO2Me
solvent, r.t., 17 h
(Z)-24
Entry
Additive
Solvent
Scale
Yield
Z/E
(mmol) (%)
1
2
3
4
LiOH
LiOH
LiCl
toluene
toluene
CH2Cl2
CH2Cl2
1
10
84
14
95
93
94:6
O
O
75:25
>95:5
>95:5
OMe
14
10
OTs
LiCl
100
TsO
Br
Br
Br
(Z)-tosylate 15
Br
B
(E)-tosylate 16
A
sylation reaction to provide the (2Z,6Z)-enol tosylate 19
(>95:5).12 In a similar manner, the (2Z,6E)-enol tosylate
20 was prepared from (E)-23 (Scheme 3)11 These results
confirmed that the enol tosylates 19 and 23 were compat-
ible under the homologation reaction sequence.
chain
elongation
O
O
OTs
O
O
O
TsO
selective
construction of
Z-olefins
OMe
OMe
OMe
18
17
OTs
OTs
OTs
O
2
25: X = OH
15: X = Br
b, 90%
c 79%
OTs
OTs
a
6
OMe
TsO
O
O
CO2Me
71%
(2E,6Z)-tosylate 20
(2Z,6Z)-tosylate 19
X
17: X =
d
OMe
simultaneous
installation of
Et groups
(Z)-24
75%
OTs
O
O
OTs
CO2Me
OMe
OMe
22
21
(2Z,6Z)-19 (> 95:5)
rac-JH I
a–d
OTs
ent-JH 0 and JH I
CO2Me
(E)-23
CO2Me
TsO
TsO
33%, 4 steps
Scheme 2 New synthetic strategy for the stereoselective total syn-
theses of JH 0 and JH I
(2E,6Z)-20 (> 95:5)
Scheme 3 Stereoselective synthesis of dienol tosylates 19 and 20.
Reagents and conditions: (a) LiAlH4 (1.0 equiv), Et2O, –40 °C to 0
°C, 2 h; (b) CBr4 (1.3 equiv), Ph3P (1.5 equiv), CH2Cl2, 0 °C, 30 min;
(c) methyl acetylacetate (3.0 equiv), NaH (3.0 equiv), n-BuLi (3.0
equiv), THF, 0 °C, 1 h; (d) LiCl (5.0 equiv), TsCl (1.5 equiv), NMI
(1.5 equiv), Et3N (1.5 equiv), CH2Cl2, r.t., 3 h.
The syntheses of 15 and 16 were initially investigated.
According to the previous reports on the stereoselective
synthesis of the (E)- or (Z)-vinyl tosylate,8a,10 triflate,11
and phosphonate,8b (Z)-2410 was synthesized from 14 on a
1 mmol scale in a stereoselective manner (Table 1, entry
1). On the other hand, the large-scale synthesis under the
same conditions (LiOH, NMI, toluene) failed due to the
provable insolubility of LiOH in toluene (Table 1, entry
2). The practical problem was solved by the adaptation of
the modified reaction conditions using LiCl in CH2Cl2 to
give (Z)-24 with a satisfactory reproducibility and product
yield (Table 1, entries 3 and 4). The geometrical isomer
(E)-23 was prepared in the absence of LiCl.10
The installation of the ethyl groups by the Negishi cross-
coupling reaction of 19 was attempted using 5 mol% of
Pd(PPh3)4 and Et2Zn to provide the monoethyl product 26
as a single stereoisomer. The coupling reactions using
other catalysts and ligands resulted in recovery of the stat-
ing material or predominant formation of 26. These re-
sults indicated that the simple enol tosylate is less reactive
than that of the β-tosyloxy-α,β-unsaturated ester such as
24.13 Skrydstrup et al. showed that the ligand 27 acceler-
ated the Negishi coupling reaction of the simple enol to-
sylate.13a Thus, the double cross-coupling reaction was
attempted under the reported reaction conditions [1 mol%
Pd2(dba)3, 2 mol% ligand 27, THF] to give the desired 29
in 5% yield along with 26 as the major product. To im-
prove the product yield, the solvents and catalyst loading
The reduction of (Z)-24 to 25 followed by the bromination
reaction smoothly proceeded to give the nonvolatile 15 in
90% yield that was purified by silica gel column chroma-
tography. The bromide 15 was subjected to the acyclic
chain-elongation reaction using the corresponding enolate
of 14 to provide 17 in 79% yield. The resulting β-keto es-
ter 17 was iteratively subjected to the stereoselective to-
Synlett 2012, 23, 1213–1216
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Total Syntheses of Insect Juvenile Hormones
1215
[the ratio of Pd2(dba)3/ligand 27] were reinvestigated. As proceeded in a highly regio- and stereoselective manner to
a result, this process was improved under the reaction con- provide the 6,7-diol 3114 that was converted into the chiral
ditions using twice the amount of the ligand 27 (6 mol%) epoxide 32 via the SN2 inversion reaction of the corre-
to the Pd2(dba)3 (3 mol%) in DMF at 50 °C to furnish the sponding secondary mesylate. The chiral epoxide 32 was
double cross-coupling product (2E,6Z)-29 in 84% yield. subjected to the homologation sequence to provide the
Under the same reaction conditions, 20 was converted (2Z)-enol tosylate 36 in four steps. The Negishi cross-cou-
into (2E,6E)-30 in 84% yield (Scheme 4). Compounds pling reaction using Et2Zn or Me2Zn smoothly proceeded
(2E,6Z)-29 and (2E,6E)-30, and the corresponding allyl to give JH 0 (1)15 or JH I (2)16 in their optically active
alcohols are known to be the synthetic precursors of rac- forms. The analytical data of the synthetic JH 0 and JH I
and ent-JH 0 and JH I, respectively.5a–h These results im- were identical to those of the authentic data (Supporting
ply that the total formal syntheses of rac- and ent-JH I Information).5a,d
have been established by the present homologation se-
quence.13
b, c
a
CO2Me
(2E,6E)-30
96%
2 steps
92%
cat. (5 mol%)
Et2Zn (4.0 equiv)
OH
OH
OTs
OTs
OTs
O
31
CO2Me
CO2Me
32
THF, r.t., 3 h,
39–77%
(2Z,6Z)-19
26
Cat : Pd(PPh3)4, PdCl2(PPh3)2, PdCl2[P(o-tol)3]2
OTs
d
g
PdCl2(Amphos)2, NiCl2(PPh3)2
97%
CO2Me
X
75%
O
PtBu2
PtBu2
36: Z/E > 95:5
Cy2P
Fe
33: X = OH
34: X = Br
e, 59%
f, 82%
Me2N
Amphos (28)
O
O
CyPF-t-Bu (27)
Pd2(dba)3 (3 mol%)
35: X =
OMe
CyPF-t-Bu (6 mol%)
Et2Zn (4.0 equiv)
h
CO2Me
36
CO2Me
CO2Me
DMF, 50 °C, 21 h, 84%
80%
O
O
(2E,6Z)-29
JH 0 (1)
OTs
i
CO2Me
CO2Me
79%
TsO
84%
(2E,6Z)-20
(2E,6E)-30
JH I (2)
Scheme 4 Synthesis of key intermediates 29 and 30 for the synthesis
of rac- and ent-JH I
Scheme 5 Total synthesis of ent-JH 0 (1) and JHI (2). Reagents and
conditions: (a) AD-mix α, MeSO2NH2 (1.0 equiv), t-BuOH–H2O
(1:1), 0 °C to r.t., 16 h, 96%; (b) 1) MsCl (7.5 equiv), pyridine (20
equiv), CH2Cl2, 0 °C to r.t., 4 h; 2) K2CO3 (10 equiv), MeOH, r.t., 1.5
h; (c) LiAlH4 (1.0 equiv), Et2O, –40 °C to 0 °C, 2 h; (d) CBr4 (1.3
equiv), polymer-bound Ph3P (1.5 equiv), imidazole (1.3 equiv),
CH2Cl2, 0 °C, 30 min; (f) 14 (3.0 equiv), NaH (3.0 equiv), n-BuLi (3.0
equiv), THF, 0 °C, 1 h; (g) LiCl (5.0 equiv), TsCl (1.5 equiv), NMI
(1.5 equiv), Et3N (1.5 equiv), CH2Cl2, r.t., 3 h; (h) Et2Zn (2 equiv),
PdCl2(PPh3)2 (5 mol%), THF, r.t., 3 h, 80%; (i) Me2Zn (2 equiv),
PdCl2(PPh3)2 (5 mol%), THF, r.t., 3 h, 79%.
We next attempted the total syntheses of the optically ac-
tive JH 0 (1) and JH I (2) from (2E,6E)-30 (Scheme 5).
The key to these asymmetric syntheses relied on the con-
struction of the chiral epoxide moiety. To this end, the
Sharpless catalytic dihydroxylation reaction,5a the diaste-
reoselective alkylation and carbonyl reduction of an opti-
cally pure β-keto sulfoxide,5b and the enantioselective
reduction of 2-ethyl-2-methyl-1,3-cyclohexanedione by
yeast as the key steps have been developed.5c–e Among
them, we selected the Sharpless dihydroxylation reaction
as the key reaction in this study.5a,c–e In the previous syn-
thetic routes, the Sharpless dihydroxylation reaction was
performed after the construction of the sesquiterpenoid
skeletons of JH I and JH 0. In these cases, the dihydroxyl-
ation reaction competitively took place at both the C6,7
and C10,11 olefins to give a mixture of the corresponding
diols.4a,5a We expected that this drawback could be over-
come by taking advantage of the present homologation
approach (Scheme 5). The chiral epoxide moiety was ini-
tially installed into (2E,6E)-30 prior to the next homolo-
gation step. In this substrate, the high regioselectivity at
C6,7 was expected due to its electronically richer property
than that of the C2,3 olefin. In fact, the dihydroxylation
In this study, we have established an efficient and conver-
gent synthetic route to access JH 0 and JH I. The new ho-
mologation reaction sequence is advantageous for not
only the synthesis of natural JH but also for their ana-
logues. Further applications of the new homologation
strategy for the synthesis of various acyclic terpene deriv-
atives are now in progress.
Acknowledgment
This study was supported by Grants-in-Aid (No. 20380038 and
23108523) for Scientific Research from the Japan Society for the
Promotion of Science (JSPS) and the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1213–1216

1216
A. Manabe et al.
LETTER
(6) Crispino, G. A.; Sharpless, K. B. Synthesis 1993, 777.
(7) (a) Sakurai, S.; Ohtaki, T.; Mori, H.; Fujiwhara, M.; Mori,
K. Experientia 1990, 46, 220. (b) Kindle, H.; Winistörfer,
M.; Lanzrein, B.; Mori, K. Experientia 1989, 45, 356.
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(b) Jin, Y.; Roberts, F. G.; Coates, R. M. Org. Synth. 2007,
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(9) (Z)-24 was transformed into the corresponding bromide A
by a series of sequential transformations: i) the Negishi
cross-coupling reaction of with Et2Zn in the presence of 10
mol% of Pd(PPh3)4, ii) reduction to the corresponding allylic
alcohol, and iii) bromination to the allyl borimide A.
However, it was found to be volatile and easily evaporated
under the reduced pressure to lower the product yield (ca.
30%).
(10) (a) Nishikado, H.; Nakatsuji, H.; Ueno, K.; Nagase, R.;
Tanabe, Y. Synlett 2010, 2087. (b) Nakatsuji, H.; Ueno, K.;
Misaki, T.; Tanabe, Y. Org. Lett. 2008, 10, 2131.
(c) Nishikado, H.; Nakatsuji, H.; Ueno, K.; Nagase, R.;
Tanabe, Y. Synlett 2010, 2087.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmorinftIangoimnuSpinorttfoIangiStupor
References and Notes
(1) (a) Riddiford, L. M. J. Insect Phys. 2008, 54, 895.
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(2) Wigglesworth, V. B. Comprehensive Insect Physiology,
Biochemistry and Pharmacology, Vol. 7; Kerkut, G. A.;
Gilbert, L. I., Eds.; Pergamon Press: Oxford, 1985, 1–24.
(3) (a) Röller, H.; Dahm, K. H.; Sweely, C. C.; Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1967, 6, 179. (b) Trost, B. M.
Acc. Chem. Res. 1970, 3, 120.
(4) (a) Morgan, E. D.; Wilson, I. D. Mori K. Comprehensive
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Products Including Marine Natural Products, Pheromones,
Plant Hormones, and Aspects of Ecology, Vol. 8; Barton, D.
H. R.; Nakanishi, K., Eds.; Pergamon Press: Oxford, 1999,
263–369. (b) Kotaki, T.; Shinada, T.; Kaihara, K.; Ohfune,
Y.; Numata, H. Org. Lett. 2009, 11, 5234.
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(b) Kosugi, H.; Kanno, O.; Uda, H. Tetrahedron: Asymmetry
1994, 5, 1139. (c) Mori, K.; Fujiwhara, M. Liebigs Ann.
Chem. 1990, 369. (d) Mori, K.; Fujiwhara, M. Liebigs Ann.
Chem. 1989, 41. (e) Mori, K.; Fujiwhara, M. Tetrahedron
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2901.
(12) The olefin geometry was confirmed by NOE experiments of
the synthetic JH 0 and JH I (see Supporting Information).
(13) The use of the unactivated enol tosylate in the cross-coupling
reaction has been discussed, see: (a) Lindhardt, A. T.;
Gøgsig, T. M.; Skrydstrup, T. J. Org. Chem. 2009, 74, 135.
(b) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem.
2005, 70, 9364. (c) Gelman, D.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2003, 115, 6175.
(14) The optical purity was confirmed by the total synthesis of JH
0 and JH I, and comparison of the optical rotations of the
synthetic natural products with those of authentic data
shown in below.
Cotterrell, G.; Cox, G. R.; Henrick, C. A.; Schaub, F.;
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(15) Analytical Data of JH 0 (1): [α]D18 +13.4 (c 0.8, MeOH)
[lit. 5d [α]D + 13.8 (c 0.92, MeOH)]. 1H NMR (400 MHz,
CDCl3): δ = 5.61 (s, 1 H), 5.10 (br, 1 H), 3.68 (s, 3 H), 2.71
(dd, J = 6.6, 5.6 Hz, 1 H), 2.18–2.03 (m, 10 H), 1.63–1.48
(m, 4 H), 1.27 (s, 3 H), 1.07 (t, J = 7.6 Hz, 3 H), 1.00 (t, J =
7.6 Hz, 3 H), 0.96 (t, J = 7.6 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 166.8, 165.7, 141.2, 123.1, 114.5, 64.6, 61.8,
50.7, 38.1, 33.3, 27.2, 25.8, 25.7, 25.3, 23.2, 21.6, 13.1, 12.9,
9.6. IR (neat): 2970, 2353, 1720, 1644, 1461, 1209, 1149,
761 cm–1. HRMS–FAB: m/z calcd for C19H33O3 [M + H]+:
309.2430; found: 309.2421.
(16) Analytical Data of JH I (2): [α]D18 +14.4 (c 0.98, MeOH)
[lit.5a,e [α]D22.5 +14.5 (c 0.78, MeOH)]. 1H NMR (400 MHz,
CDCl3): δ = 5.66 (d, J = 0.6 Hz 1 H), 5.08 (t, J = 6.3 Hz, 1
H), 3.68 (s, 3 H), 2.71 (dd, J = 7.2, 6.0 Hz, 1 H), 2.18–2.03
(m, 8 H), 2.16 (d, J = 0.6 Hz, 3 H), 1.63–1.48 (m, 4 H), 1.27
(s, 3 H), 0.99 (t, J = 7.2 Hz 3 H), 0.97 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.2, 159.9, 141.3, 122.9,
115.3, 64.6, 61.8, 50.8, 41.1, 33.3, 27.2, 25.8, 25.6, 23.1,
21.6, 18.8, 13.1, 9.7. IR (neat): 2968, 2360, 1720, 1650,
1457, 1125, 1149, 770 cm–1. HRMS–FAB: m/z calcd for
C18H31O3 [M + H]+: 295.2273; found: 295.2270.
(w) Zurflueh, R.; Wall, E. N.; Siddall, J. B.; Edwards, J. A.
J. Am. Chem. Soc. 1968, 90, 6224. (x) Dahm, K. H.; Roeller,
H.; Trost, B. M. Life Sci. 1968, 7, 129. (y) Dahm, K. H.;
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Synlett 2012, 23, 1213–1216
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