Concise substrate-controlled asymmetric total synthesis of (+)-3-(Z)-dihydrorhodophytin

Article abstract of DOI:10.3987/COM-10-S(E)76

The first asymmetric total synthesis of (+)-3-(Z)-dihydrorhodophytin (1) has been accomplished in 15 steps in 17% overall yield from readily available starting material 6 in a substrate-controlled manner. Key steps in our synthesis are a highly stereosele

Full text of DOI:10.3987/COM-10-S(E)76

HETEROCYCLES, Vol. 82, No. 2, 2011
1113
HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1113 - 1118. © The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2010, Accepted, 16th August, 2010, Published online, 17th August 2010
DOI: 10.3987/COM-10-S(E)76
CONCISE
SUBSTRATE-CONTROLLED
ASYMMETRIC
TOTAL
SYNTHESIS OF (+)-3-(Z)-DIHYDRORHODOPHYTIN
Byungsook Kim,a Te-ik Sohn,a Sanghee Kim,a Deukjoon Kim,*a and
Jongkook Leeb
aThe Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul
National University, San 56-1, Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Korea
bBio-organic Science Division, Korea Research Institute of Chemical Technology,
PO Box 107, Yuseong, Daejeon 305-600, Korea
e-mail: deukjoon@snu.ac.kr
Abstract – The first asymmetric total synthesis of (+)-3-(Z)-dihydrorhodophytin
(1) has been accomplished in 15 steps in 17% overall yield from readily available
starting material 6 in a substrate-controlled manner. Key steps in our synthesis
are a highly stereoselective dianion alkylation for the synthesis of the
,’-anti-RCM substrate and a strategy for the introduction of the chlorine
function.
(+)-3-(Z)-Dihydrorhodophytin (1) was isolated from the sea hare Aplysia braziliana in 1979 and was
shown to possess fish antifeedant activity.1 The structure and absolute stereochemistry of this C15
nonisoprenoid metabolite were elucidated by a combination of spectroscopic analysis and X-ray
crystallography.1 Reported herein is a completely substrate-controlled asymmetric synthesis of this
interesting ,'-trans-oxocene marine natural product based upon a highly stereoselective dianion
alkylation for the synthesis of an ,’-anti-RCM substrate.
As shown in Scheme 1, we envisaged that (+)-3-(Z)-dihydrorhodophytin (1) could be elaborated from key
,’-trans-disubstituted chloro oxocene 2, which in turn could be prepared from chloro diene 3 by a
ring-closing metathesis. It should be emphasized that it is critical to introduce the chlorine atom at C(7)
of diene alcohol 4 prior to the RCM step (vide infra). We further envisioned that key ,’-anti-diene
alcohol 4 could be stereoselectively secured by our dianion alkylation methodology2 using hydroxy amide
5. Further analysis indicated that hydroxy amide 5 should be readily available from known epoxy alcohol
6.

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HETEROCYCLES, Vol. 82, No. 2, 2011
H
H
H
Cl
Cl
Cl
7
RCM
OH
'
3

OBn
OBn
13
N
O
O
N
O
H
H
H
H
H
H
Br
O
O
trans
2
3
1
H
H
H
H
dianion
allylation
OH
OH
chlorination
OBn
OBn
O
N
O
N
O
H
H
6
4
5
O
O
Scheme 1. Retrosynthetic Plan
The synthesis commenced by preparing key alkylation substrate 5 from known alcohol 63 in four steps as
shown in Scheme 2. Thus, protection of alcohol 6 with a PMB group, followed by opening of the
resultant epoxide 7 with (benzyloxy)methyllithium,4 afforded the one-carbon homologated alcohol 8 in
70% yield for the two steps. Williamson etherification of alcohol 8 with N,N-dimethyl -chloroacetamide
and oxidative removal of the PMB group from the resulting -alkoxy amide 9 with wet DDQ5 then
provided the required alkylation precursor 5 in a highly efficient manner (94%, two steps). To our
satisfaction, the crucial dianion alkylation of hydroxy amide 5 by successive treatment with LiHMDS and
then allyl iodide produced the desired ,’-anti-diene 4 as virtually a single stereoisomer in 85% yield.
It is interesting to note that the observed diastereoselectivity in the dianion alkylation of
C(6)/C(7)-anti-isomer 5 is far superior to that of the previously reported syn-isomer 5’ (>50:1 vs. 6:1).2a
H
H
H
H
OPMB
OBn
OPMB
OBn
d
b
c
OP
7
6
HO
N
O
O
H
8
6: P = H
7: P = PMB
O
9
a
H
H
H
H
H
OH
OH
OH
anti
7
syn
e
6
OBn
OBn
OBn
N
O
N
O
N
O
H
H
O
O
5
O
4
5'
Scheme 2. Dianion Alkylation. aReagent and Conditions: a) NaH, PMBCl,TBAI, DMF, 0 oC to rt, 4.5 h,
86%; b) LiCH2OBn, BF3·Et2O, Et2O, -78 oC, 30 min, 81%; c) NaH, ClCH2CONMe2, THF/DMF (3:1), 0
oC to rt, 15 h, 96%; d) DDQ, CH2Cl2/pH 8.0 buffer (9:1), 0 oC, 3 h, 98%; e) LiHMDS, allyl iodide, THF,
-78 to 0 oC, 2 h, 85%.

HETEROCYCLES, Vol. 82, No. 2, 2011
1115
With ,’-anti-diene alcohol 4 available in multigram quantities, we directed our attention to synthesis of
key chloro oxocene 2. Chlorination of the acyclic secondary homoallylic alcohol 4 with inversion of
configuration by the Hooz protocol,6 followed by RCM7 of the resultant chloro diene 3 with the
first-generation Grubbs’ Ru catalyst, afforded key oxocene 2 in 79% overall yield for the two steps
(Scheme 3). Our extensive experience in this field suggested that ,’-trans, C(6)/C(7)-anti system
such as 10 represents the worst substrate for halogenation with inversion of configuration among the four
possible diastereomeric oxocene alcohols. This result is probably due to steric hindrance to backside
approach of the incoming chloride in the preferred syn-conformation A of 10.8-10 In fact, chlorination of
,’-trans-alcohol 10, prepared by RCM of diene alcohol 4, led to complete elimination, even under the
improved chlorination conditions of Boeckman,9a to give diene 11 as the sole product (83%).
a
Scheme 3. Chlorination and Ring-Closing Metathesis. Reagent and Conditions: a) CCl4, Oct3P,
o
o
1-methylcyclohexene, toluene, 0 C to 70 C, 3 h, 81%; b) Cl2(Cy3P)2Ru=CHPh, CH2Cl2, rt, 2 h, then
DMSO, rt, 12 h, 97%; c) (H2IMes)(Cy3P)Cl2Ru=CHPh, Ti(OiPr)4, CH2Cl2, 40 oC, 3.5 h, then DMSO, rt,
12 h, 67%; d) CCl4, Oct3P, 1-methylcyclohexene, toluene, rt to 70 oC, 2 h, 83%.
Conversion of key chloro oxocene intermediate 2 to (+)-3-(Z)-dihydrorhodophytin (1) was accomplished
in an uneventful sequence similar to that employed for our synthesis of (+)-3-(Z)-pinnatifidenyne,9b as
summarized in Scheme 4. Our direct ketone synthesis protocol9b on -alkyloxy amide 2 with
ethylmagnesium bromide, followed by L-Selectride reduction6b,11 of the resulting ethyl ketone in a
Felkin-Ahn sense, provided secondary alcohol 12 as a single isomer in 88% yield for the two steps.
Introduction of the bromine functionality at C(13) with inversion of configuration in the presence of the
chlorine atom under the Hooz conditions completed elaboration of the C(12) side chain to give bromide
13 in 93% yield.

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HETEROCYCLES, Vol. 82, No. 2, 2011
Next, we turned our attention to incorporation of the (Z)-enyne side chain to complete the synthesis. For
this purpose, removal of the benzyl group in bromide 13 by exposure to wet DDQ afforded alcohol 14 in
67% yield. Dess-Martin periodinane oxidation12 of primary alcohol 14 and subsequent Stork-Zhao
olefination13 of the resulting aldehyde produced (Z)-vinyl iodide 15 as a single isomer in 84% yield from
alchohol 14. Sonogashira coupling reaction14 of (Z)-vinyl iodide 15 with (trimethylsilyl)acetylene in the
presence of (Ph3P)4Pd/CuI provided the desired (Z)-enyne 16 (98%). Finally, removal of the
trimethylsilyl protecting group with TBAF delivered (+)-3-(Z)-dihydrorhodophytin (1) in 84% yield.
Spectral data and specific rotation of the synthetic material were in good agreement with those of the
natural product.15
H
H
H
H
H
Cl
Cl
Cl
a,b
c
OBn
OBn
OP
N
O
O
O
H
H
H
H
2
12
O
HO
Br
13: P = Bn
d
14: P = H
H
Cl
H
Cl
e,f
g
16:
P = TMS
1: P = H
O
h
H
O
H
H
I
Br
H
Br
15
P
Scheme 4. Completion of the Synthesis. aReagent and Conditions: a) EtMgBr, THF, 0 oC to rt, 30 min, 89%;
b) L-Selectride, THF, -78 oC, 1 h, 99%; c) CBr4, Oct3P, pyridine, toluene, 0 oC to 70 oC, 1 h, 93%; d)
DDQ, CH2Cl2/pH 8.0 buffer (9/1), 0 oC, 5 h, 67%; e) Dess-Martin periodinane, CH2Cl2, 0 oC, 4 h, 93%; f)
[Ph3PCH2I]I, NaHMDS, THF, -78 oC to rt, 30 min, 90%; g) TMS-acetylene, (Ph3P)4Pd, CuI, Et2NH, rt, 1
h, 98%; h) TBAF, THF, -40 oC, 30 min, 84%.
In summary,
a
concise and highly stereoselective asymmetric total synthesis of
(+)-3-(Z)-dihydrorhodophytin (1) has been accomplished in 15 steps in 17% overall yield from readily
available starting material 6 in a completely substrate-controlled manner. Our synthesis features a
highly stereoselective dianion alkylation, a strategy for the demanding introduction of the chlorine
function into the oxocene skeleton, and an RCM as key steps.
ACKNOWLEDGEMENTS
Dedicated to Professor Dr. Albert Eschenmoser on the occasion of his 85th birthday. This research was
supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea Government
(MEST) (No. 20100001710).

HETEROCYCLES, Vol. 82, No. 2, 2011
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1
D
D
(500 MHz, CDCl3)  6.03 (ddd, J = 8.0, 8.0, 11.0 Hz, 1 H), 5.79-5.90 (m, 2 H), 5.58 (ddd, J = 1.0,
1.0, 11.0 Hz, 1 H), 4.21 (dd, J = 6.5, 8.0 Hz, 1 H), 4.06-4.10 (m, 2 H), 3.90 (ddd, J = 2.5, 7.5, 11.0
Hz, 1 H), 3.16 (d, J = 2.0 Hz, 1 H), 2.55-2.70 (m, 5 H), 2.46 (ddd, J = 7.5, 11.0, 14.5 Hz, 1 H), 2.19
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