Asymmetric hydrogen transfer protocol for a synthesis of (+)-frontalin and (-)-malyngolide

Article abstract of DOI:10.1016/S0040-4039(00)00430-5

An insect aggregate pheromone (+)-frontalin and a marine antibiotic (-)- malyngolide, both bearing a quaternary stereogenic center in their molecules, have been synthesized in diastereocontrolled manner by employing a catalytic asymmetric hydrogen transfer reaction as the key step. An inversion protocol allowing enantioconvergent use of the other enantiomeric resolved product has also been devised. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00430-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3631–3635
Asymmetric hydrogen transfer protocol for a synthesis of
(
+)-frontalin and (−)-malyngolide
∗
Regina Mikie Kanada, Takahiko Taniguchi and Kunio Ogasawara
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 16 February 2000; revised 9 March 2000; accepted 10 March 2000
Abstract
An insect aggregate pheromone (+)-frontalin and a marine antibiotic (−)-malyngolide, both bearing a quaternary
stereogenic center in their molecules, have been synthesized in diastereocontrolled manner by employing a catalytic
asymmetric hydrogen transfer reaction as the key step. An inversion protocol allowing enantioconvergent use of
the other enantiomeric resolved product has also been devised. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric reaction; epoxides; natural products; radicals and radical compounds; ruthenium and compounds.
We recently found that the racemic tricyclic allyl alcohol (±)-3b and its oxygenated derivatives
R_CH OH, CH OTBS, CH OPiv) are well discriminated in asymmetric hydrogen transfer reaction3
1
,2
(
2 2 2
4
II
in the presence of a ruthenium(II)–chiral amine complex [Ru -(S,S)-or (R,R)-TsDPEN] to give the chiral
enones, leaving the chiral alcohols both in acceptable enantiomeric purity, though the unsubstituted (±)-
2
3
a is not well discriminated. On the contrary, the unsubstituted (±)-3a is well discriminated under the
5
lipase-mediated asymmetric transesterification conditions to give the enantiopure acetate, leaving the
6
enantiopure alcohol 3a, though the substituted (±)-3b does not react under the same conditions (Scheme
1
). We also found that the chiral enones 4a and b may be inverted into the corresponding enantiomers
1,7
in a three-step sequence of reactions involving the Wharton rearrangement in an acceptable overall
yield. On the basis of these findings, we planned enantio- and diastereocontrolled construction of two
natural products bearing a quaternary stereogenic center in their molecules by utilizing an appropriate α-
substituted chiral enone 4 obtained through the resolution by the catalytic asymmetric hydrogen transfer
reaction. In this paper we wish to report a diastereocontrolled route to an insect aggregate pheromone
8
9
(
2
+)-frontalin 12 isolated from the Dendroctonus pine beetle and a marine antibiotic (−)-malyngolide
0 and a new molecular inversion method which enables the enantioconvergent synthesis of the latter.
27
To obtain (+)-frontalin 12, the enone (+)-4b, [α]
+83.8 (c 1.65, CHCl ) (>99% ee), obtained from
D
3
10
the tricyclic 1,2-enediol bis-trimethylsilyl ether 1 via 2b by employing a sequence of ring-expansion
1
,11
reductive elimination, and the asymmetric hydrogen transfer reaction,1–4 was treated with
reaction,
∗
Corresponding author. Fax: +81-22-217-6845; e-mail: konol@mail.cc.tohoku.ac.jp (K. Ogasawara)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00430-5
tetl 16710

3
632
Scheme 1. Reagents and conditions: (i) for 1b: (a) MeCH (OMe)
NaH, DMF–THF (1:1) (56%). For 1c: (a) Me(CH CH(OMe)
, BF3·OEt
°C (47%). (ii) LAH, Et
acetone, rt [(+)-3b (47%:59% ee) and (+)-4b (30%:>99% ee)]; for 3c: [Ru (η -p-cymene)](1S,2S)-TsDPEN (2 mol%), acetone,
rt [(+)-3c (44%:>99% ee) and (+)-4c (52%:85% ee)]
2
, BF3·OEt
2
, CH
Cl
2
Cl
2
, −78°C, then TFA reflux. (b) Me
2
SO
4
,
2
)
8
2
2
, CH
2
II
2
, −78°C, then TFA rt. (b) (i) CH
2
N
2
, Et O,
2
6
0
2
O, reflux (for 3b: 65%, for 3c: 61%). (iii) For 3b: [Ru (η -mesitylene)](1S,2S)-TsDPEN (1 mol%),
II
6
diisobutylaluminum hydride (DIBAL) and copper(I) iodide, followed by gaseous formaldehyde in the
1
2
same flask to construct the quaternary stereogenic center adjacent to the ketone functionality, giving
2
8
rise to the single hydroxyketone 5 [α]
+205.9 (c 1.15, CHCl ), diastereoselectively. After O-silylation,
D
3
2
9
13
the resulting TBS ether 6, [α]D +144.7 (c 0.90, CHCl ), was heated in diphenyl ether at 280°C to
3
2
8
give the cyclopentenone 7 [α]
+53.1 (c 0.59, CHCl ), by retro-Diels–Alder reaction, which gave the
D
3
2
8
cyclopentanone 8 [α]D +53.8 (c 0.64, CHCl ), on catalytic hydrogenation. Baeyer–Villiger reaction of
3
29
8
with m-chloroperbenzoic acid proceeded regioselectively to give the δ-lactone 9 [α]D +10.7 (c 0.67,
CHCl ), as the single product. Treatment of 9 with N-methylhydroxylamine methyl ether hydrochloride
3
1
4
31
in the presence of trimethylaluminum afforded the methyl hydroxamate 10 [α]
+2.6 (c 0.66,
D
29
CHCl ), which gave the methyl ketone 11 [α]D +1.5 (c 0.94, CHCl ), on reaction with methyllithium.
3
3
27
On exposure to methanolic hydrochloric acid, 11 furnished (+)-frontalin 12 [α]
+53.4 (c 0.37, Et O)
2
D
8
a
22
[
2
lit. : [α]
+53.8 (c 0.8, Et O)], by concurrent desilylation and intramolecular ketalization (Scheme
2
D
).
Scheme 2. Reagents and conditions: (i) DIBAL, CuI, THF–HMPA (4:1), −50°C, 1 h then HCHO (gas) (74%). (ii) TBSCl, Et
DMAP, CH Cl , rt (100%). (iii) PhOPh, 280°C, 30 min (97%). (iv) H ,10% Pd–C, AcOEt, overnight, rt (96%). (v) m-CPBA,
NaHCO , CH Cl Al, 0°C, 3 h (77%). (vii) MeLi, CH Cl , −78°C, 1 h (90%).
, rt, 3 days (75%). (vi) MeONHMe·HCl, Me
viii) concd HCl (cat.), pentane (80%)
3
N,
2
2
2
3
2
2
3
2
2
(
On the other hand, to obtain (−)-malyngolide 20, the asymmetric hydrogen transfer reaction of (±)-3c
having an α-C H substituent was first examined chain as only the substrates having a one-carbon 2-
9
19
substituent were so far examined and as (±)-3c was found to be completely inert under lipase-mediated
resolution conditions. Thus, (±)-3c was stirred with (1S,2S)-TsDPEN (2 mol%) in acetone (1 M) at
room temperature to give the enantioenriched enone (+)-4c [α]D27 +17.0 (c 0.45, CHCl ) (85% ee),
3

3
633
in 52% yield, leaving the enantiopure alcohol (+)-3c [α] 30 +114.9 (c 0.58, CHCl ) (>99% ee), in 44%
D
3
recovery yield. Although the absolute configuration could not be determined at this stage, the alcohol (+)-
c, supposed to have the same configuration as (+)-3a and b, was oxidized with manganese(IV) oxide
3
2
9
to give the enone (−)-4c [α]D −17.1 (c 1.30, CHCl ) (>99% ee), in 89% yield. The enone (−)-4c,
3
2
7
thus obtained, was transformed into the hydroxyketone 13 [α]D −125.1 (c 0.96, CHCl ), on the same
3
2
7
reductive aldolization as above, which was then transformed into the silyl ether 14 [α]
−103.6 (c
D
2
7
1
.03, CHCl ). Thermolysis of 14 afforded cyclopentenone 15 [α]D −17.9 (c 1.07, CHCl ), which was
3
3
hydrogenated to give the cyclopentanone 16, −10.1 (c 0.98, CHCl ). Methylation of 16 under kinetic
3
conditions gave the monomethylated ketone 17 as a diastereomeric mixture, which was desilylated to
give the hydroxyketone 18 as a mixture of epimers. The mixture, on treatment with LDA followed by
29
exposure to diluted acetic acid, afforded the single hydroxyketone 19 [α]
−19.3 (c 1.13, CHCl ),
D
3
1
5
by kinetic protonation. Finally, 19 was subjected to the Baeyer–Villiger oxidation to give natural (−)-
3
1
9a
28
malyngolide 20 [α]D −13.7 (c 0.69, CHCl ) [lit. : [α]
−13.4 (c 0.3, CHCl )], regioselectively. This
3
D
3
confirmed the stereochemistry of the products (+)-4c and (−)-3c obtained by the catalytic asymmetric
hydrogenation transfer reaction (Scheme 3).
Scheme 3. Reagents and conditions: (i) DIBAL, CuI, THF–HMPA (4:1), −50°C then HCHO (gas) (98%). (ii) TBSCl, Et
DMAP, CH Cl , rt (83%). (iii) PhOPh, 280°C, 40 min (94%). (iv) H , 10% Pd–C, AcOEt, overnight, rt (100%). (v) LDA,
HMPA, −78°C, 1 h, then MeI, −30°C, 1 h (91%). (vi) LDA, −78°C 1 h (76%). (vii) concd HCl, THF, rt, 2 h (100%). (viii)
m-CPBA, NaHCO , rt, 4.5 days (52%)
3
N,
2
2
2
3
In order to allow enantioconvergent utilization of the other enantiomer, we first examined the Wharton
2
7
rearrangement on the epoxide 21 [α]D −105.9 (c 0.61, CHCl ), obtained from the enantiopure enone
3
(
−)-4c, to obtain the exo-allylic alcohol (−)-24 by following the procedure established for the inversion of
16 1
the enones, 4a and b. However, the reaction of 21 did not proceed in the desired way and gave instead
a complex mixture containing a trace of the allyl alcohol 24 under the same conditions. We, therefore,
25
converted the epoxide 21 first into the xanthate 23 [α]
−99.4 (c 0.49, CHCl ), via the endo-alcohol
D
3
2
8
17
2
2 [α]D −1.48 (c 0.74, CHCl ). On reaction with triethylsilane in the presence of AIBN, 23 yielded
3
2
9
the desired exo-alcohol 24 [α]
−15.8 (c 0.30, CHCl ), which afforded the enantiomeric enone (+)-
D
3
2
5
4
c, [α]D +17.0 (c 0.21, CHCl ), on oxidation. Overall yield of (+)-4c from (−)-4c was 45% in five
3
steps. The xanthate-mediated reaction was found to proceed with the exo-alcohol (−)-24. Thus, the exo-
28
xanthate 26, obtained from (−)-24 via the epoxide 25, [α]
+18.6 (c 0.15, CHCl ), furnished, under
3
D
the same conditions, the inverted alcohol (+)-24 which was further transformed into the enone (−)-4 on
oxidation (Scheme 4).

3
634
Scheme 4. Reagents and conditions: (i) 30% H
MeOH, 0°C, 15 min (90%). (iii) NaH, CS2, MeI, THF (for 23: 100%, for 26: 79%). (iv) AIBN (0.6 equiv.), Et
.5 h, evaporation, TBAF, THF, rt, 1 h (for (−)-24: 72%, for (+)-24: 65%). (v) cat. TPAP, NMO, 4 Å sieves, CH
VO(acac) , t-BuOOH, 2,6-lutidine, toluene–benzene (3:2), rt (66%)
2
O
2
, 0.5N NaOH, MeOH, 0°C to ∼rt; 1 h (95%). (ii) CeCl3·7H
SiH, 85–90°C,
Cl (74%). (vi)
2 4
O, NaBH ,
3
1
2
2
2
In summary, we have devised an enantioconvergent utilization of both enantiomeric α-substituted
enones, resolved through asymmetric hydrogen transfer reaction, for an alternative synthesis of two
natural products bearing a quaternary stereogenic center, an insect pheromone (+)-frontalin and a marine
antibiotic (−)-malyngolide. A cyclopentenone inversion method involving radical reaction of a xanthate
intermediate has also been established during the present study.
Acknowledgements
We are grateful to the Ministry of Education, Science, Sports and Culture, Japan for a scholarship (to
R.M.K.).
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