A concise formal synthesis of (-)-hamigeran B

Article abstract of DOI:10.1021/ol400030a

A concise and efficient formal synthesis of (-)-hamigeran B is reported. The critical intermediate was synthesized from 3-methoxy-5-methylphenyl trifluoromethanesulfonate with an 11-steps 7.2% total yield route. The chiral quaternary carbon was efficientl

Full text of DOI:10.1021/ol400030a

ORGANIC
LETTERS
2013
Vol. 15, No. 4
871–873
A Concise Formal Synthesis of
(À)-Hamigeran B
Biao Jiang,*,†,‡,§ Ming-ming Li,† Ping Xing,† and Zuo-gang Huang‡
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China, Shanghai Advanced Research Institute, Chinese Academy of Sciences,
99 Haike Road, Shanghai 201210, China, and Shanghai Institute for Advanced
Immunochemical Studies, ShanghaiTech University, 99 Haike Road, Shanghai 201210, China
jiangb@sioc.ac.cn
Received January 5, 2013
ABSTRACT
A concise and efficient formal synthesis of (À)-hamigeran B is reported. The critical intermediate was synthesized from 3-methoxy-5-methylphenyl
trifluoromethanesulfonate with an 11-steps 7.2% total yield route. The chiral quaternary carbon was efficiently and steroselectively constructed through
an intermolecular PausonÀKhand reaction and a Claisen rearrangement reaction with >99% ee; the cyclohexane B was then closed through an aldehyde
FriedelÀCrafts cyclization. Lastly, the isopropenyl group of ring C was introduced through a Suzuki coupling reaction.
Hamigeran B (1) is a member of the hamigerans which
were first isolated from the poecilosclerid sponge Hami-
gera tarangaensis by Bergquist and Fromont.1 Hamigeran
B shows 100% in vitro inhibition against herpes and polio
viruses at a concentration of 132 μg per disk and exhibits
little cytotoxity. It also has strong in vitro antitumor activity
against P-388 (IC50 = 13.5 μM). Because of its unique
tricarbocyclic skeleton and high bioactivity, hamigeran B
has been an attractive target for synthesis.
Since the first total synthesis of hamigeran B by the
Nicolaou group,2 several asymmetric and racemic total
syntheses3 or its core tricarbocyclic skeleton4 have been
reported. The generation of the three continuous chiral
centers in (À)-hamigeranBcouldbeachievedbyasymmetric
hydrogenation controlled by the stereocenter at C(9).3a,d,4b
Our retrosynthetic analysis of hamigeran B (Scheme 1)
focused on constructing the Miesch’s diene intermediate 2
which contains a chiral quaternary carbon center at C(9).
The cyclohexane ring of 2 could be constructed through a
FriedelÀCrafts cyclization, and the isopropenyl group at
C(5) could be introduced through a Suzuki cross-coupling
from aldehyde 3. The aldehyde 3 could be constructed by
† Shanghai Institute of Organic Chemistry.
‡ Shanghai Advanced Research Institute.
§ ShanghaiTech University.
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r
10.1021/ol400030a
2013 American Chemical Society
Published on Web 02/04/2013

the [3,3]-sigmatropic rearrangement from a chiral cyclo-
pentenol 4. Cyclopentenol 4 was synthesized by an inter-
molecular PausonÀKhand reaction of aryl propyne with
ethylene5 and subsequent 1,2-reduction.
increased gradually. This indicated that the steric hindrance
of the cyclopentenone 7 might have prevented the approach
of chiral reagents. Therefore, we seek other accesses to chiral
cyclopentenol 4. Among which, kinetic resolution is a good
choice. Cyclopentone 7 was first converted into the corre-
sponding racemic cyclopentenol in almost quantitative yield
via a Luche reduction (Scheme 2), and then the gross
product was subjected directly to the Pd-catalyzed oxidative
resolution conditions developed by the Stoltz group.9
Nearly optically pure cyclopentenol 4 (>99% ee) was
obtained in 43% yield, and cyclopentenone 7 could be
recovered in 52% yield by this procedure. This reaction
could be applied well to a 15-g scale, and the recovered
cyclopentenone 7 could be recycled.
Scheme 1. Retrosynthetic Analysis of (À)-Hamigeran B
Scheme 2. Kinetic Resolution of Allylic Alcohol 4
We prepared the aryl propyne 6 via Sonogashira coupling
of the readily available triflate 5 and propyne.6 Alkyne 6was
then subjected to different PausonÀKhand conditions with
ethylene to afford the cyclopentenone 7 (Table 1). Only
moderate yields were achieved when NMO, TMANO, or
nBuSMe was used as a promoter because of the relative
bulky 3-methoxy-5-methylphenyl moiety (entries 1À3).7
However, an excellent result was achieved when excessive
Me2S (30 equiv) was applied with the reaction temperature
raised to 130 °C (entry 5). The reaction was very clean; the
cyclopentenone 7was separated by simple filtration through
a Celite pad, and no further purification was needed.
Next, chiral allylic alcohol 4 was subjected to Claisen
rearrangement conditions. However, neither IrelandÀ
Claisen10 nor JohnsonÀClaisen11 conditions could work.
A reductive Claisen rearrangement, reported also by the Stoltz
group, proved to be effective (Scheme 3).12 Cyclopentenol 4
was converted into the corresponding vinyl ester 8 via a Hg-
catalyzed vinylation,13 and 8 was prone to [3,3]-sigmatropic
rearrangement in the presence of DIBAL-H to yield alcohol 9.
The configuration of the chiral quaternary carbon center
contained in 9 was controlled by the substrate 4.
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Reaction of 6 with Ethylene
ꢀ
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entry
promotors
conditionsa
yieldb (%)
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1
2
3
4
5
TMANO (9 equiv)
NMO (6 equiv)
nBuSMe (3.5 equiv)
Me2S (30 equiv)
Me2S (30 equiv)
PhMe, 40 °C
59
56
44
70
89
˚
DCM, 4 A MS, rt
ClCH2CH2Cl, 83 °C
ClCH2CH2Cl, 83 °C
xylene, 130 °C
a The pressure of ethylene used is ∼30 bar. b Yield of isolated product.
ꢀ
M. J.; OBrien, P.; Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47, 6367. (d)
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D. D.; Trend, R. M.; Stoltz, B. M. Chem.;Eur. J. 2009, 15, 12978. For
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We anticipated a direct enantioselective carbonyl reduction
of 7 to produce the key chiral intermediate cyclopentenol 4.
Unfortunately, we were able to obtain only low to moderate
ee values under the conditions of CBS or Midland reduction.8
The reactions normally proceeded slowly, and the byproducts
872
Org. Lett., Vol. 15, No. 4, 2013

Scheme 3. Construct of the A/B/C Tricarbocyclic Skeleton
Scheme 4. Synthesis of Key Intermediate 2
protocol by treatment with BF3•Et2O in diluted ether at
0 °C afforded diene 10 in 44% yield (ortho/para = 3:2).14
Hydrogenation of the less substituted double bond using
Adam’s catalyst in EtOH gave a nearly quantitative yield, and
the crude product was treated directly with Py•HBr3 in dry
DCM at 0 °C and afforded the allyl bromide 11 in 85% yield
(Scheme 4).15 A Suzuki coupling of 11 with an isopropenyl
borate gave diene 2 with the desired isopropenyl group,16
which had previously been converted to hamigeran B in five
steps.3b,e,4b Therefore, we completed the formal synthesis of
(À)-hamigeran B.
Table 2. Construct of the A/B/C Tricarbocyclic Skeleton
entry
R
conditions
cyield (%)
In summary, we have developed an efficient and concise
formal synthesis of (À)-hamigeran B in an 11-step, 7.2% total
yield. The key steps involve an intermolecular PausonÀ
Khand reaction and a reductive Claisen rearrangement. The
route is highly enantioselective and essentially free of protect-
ing groups. Besides, minimum or no column chromatography
separations and purifications in most of the steps were needed
because of the generally high conversions as well as excellent
regioslectivity and yields. In fact, we have presented a general
and efficient method to construct a chiral quaternary carbon
center containing a five-membered ring, via a PausonÀ
Khand/asymmetric reduction/[3,3]-sigmatropic process.
1
CH2OH
CH2OTs
COCl
BF3•OEt2, OEt2, rt
TMEDA, nBuLi, THF, À78 °C
DCM, AlCl3, 0 °C
À
2
À
3
À
4
CHO
TiCl4, OEt2, rt
À
5a
6b
CHO
BF3•OEt2, OEt2, rt
BF3•OEt2, OEt2, 0 °C
28
44
CHO
a In a 0.1 M solution, ortho/para = 1:1. b In a 0.008 M solution, ortho/
para = 3:2. c Isolated yield of ortho isomer.
Subsequently, we tried to close the cyclohexane B
through a FriedelÀCrafts reaction (Table 2). FriedelÀ
Crafts cyclization of 9 or its oxidation product carboxylic
acid (R = COX) failed (entries 1, 3). Cyclization of its sulfo-
nates (R = CH2OTs) with the ortho-MeO-directed lithiation
of the benzene ring was also problematic (entry 2). A direct
FriedelÀCrafts cyclization with aldehyde (R = CHO) was
also tried (entries 4À6). Oxidation of 9 with DMP afforded
the aldehyde 3, and cyclization according to the Taber
Acknowledgment. This work was supported by the Na-
tional Basic Research Program of China (973-2010CB833200
and 973-2010CB833300), the National Natural Science
Foundation of China (20832007 and 21102167), the Science
and Technology Commission of Shanghai Municipality
(12DZ1930902), and the Knowledge Innovation Program
of the Chinese Academy of Sciences.
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Supporting Information Available. Full experimental
1
details, spectroscopic data, and copies of H and 13C
NMR for compounds 2À11. This material is available
free of charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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