Substrate-controlled asymmetric total synthesis and structure revision of (+)-itomanallene a

Article abstract of DOI:10.1002/anie.200905826

Chemical equation presented In control: The first asymmetric total synthesis of (-)-itomanallene A (revised structure) has been accomplished starting from commercially available (S)-glycidol in a substrate-controlled fashion. The approach yields α,α' -cis- or α,α' -transtetrahydrofuran isomers by intramolecular alkylation with either an amide enolate or a nitrile anion, respectively.

Full text of DOI:10.1002/anie.200905826

Communications
DOI: 10.1002/anie.200905826
Natural Products
Substrate-Controlled Asymmetric Total Synthesis and Structure
Revision of (+)-Itomanallene A**
Wonjang Jeong, Mi Jung Kim, Hyoungsu Kim, Sanghee Kim, Deukjoon Kim,* and
Kye Jung Shin
Species of the red algal genus Laurencia (Rhodomelaceae,
Ceramiales) have been a prolific source of diverse halogen-
ated secondary metabolites.[1] Since Kurata et al. reported the
isolation of isolaurallene (1) from the red alga Laurencia
nipponica in 1982,[2] new C15 acetogenins with the 2,10-
and neolaurallene (2) were firmly established on the basis of
X-ray crystallographic studies.[2,3]
Unlike isolaurallene and neolaurallene, itomanallene A
possesses an a,a’-cis-tetrahydrofuran moiety. The relative
stereochemistry of the bicyclic skeleton of itomanallene A
was established by extensive spectroscopic studies. In partic-
ular, nOe interactions between the protons on C6 and C4 and
between the protons on C6 and C7 were supportive of the
assigned cis relative stereochemistry of the tetrahydrofuran
ring. Judging from the strong positive rotation of itomanalle-
ne A, its bromoallene moiety would be assigned as S by
application of Loweꢀs rule.[5] Since the relative stereochem-
istry between the bicyclic skeleton and the bromoallene unit
could not be determined, 3a and 3b were proposed for the
possible structures of itomanallene A.
Among these structurally exquisite dioxabicyclic oxonene
marine natural products, only isolaurallene has succumbed to
total synthesis to date, wherein Crimmins et al. exploited dual
synergistic gauche effects to guide the course of their ring-
closing metathesis (RCM) to form the nine-membered-ring
ether.[6]
Reported herein are the first asymmetric total synthesis of
(+)-itomanallene A and its structure revision. A highly
stereoselective intermolecular a-alkoxy N,N-dimethylamide
enolate alkylation is a key step in our approach. In the course
of this work, we discovered a striking difference in the
stereochemistry of the intramolecular alkylation involving
either an N,N-dimethylamide enolate or a nitrile anion. We
used this advantage to develop complementary routes for
establishing the relative stereochemistry of the tetrahydro-
furan oxymethine unit, and the synthesis of both isomers
allowed us to propose the structure revision. Our substrate-
controlled route should provide a general strategy for the
synthesis of both a,a’-cis- and a,a’-trans-tetrahydrofurans in
such dioxabicylic marine natural products and related struc-
tures.
dioxabicyclo[7.3.0]dodecene skeleton have been isolated.
Examples include (+)-neolaurallene (2), which was isolated
by Kurosawa and co-workers from the red alga Laurencia
okamurai in 1984,[3] and (+)-itomanallene A, which was
subsequently isolated by Suzuki et al. from the red alga
Laurencia intricata collected at Itoman (Japan) in 2002.[4] The
structure and absolute configuration of both isolaurallene (1)
[*] W. Jeong, M. J. Kim, Dr. H. Kim, Prof. Dr. S. Kim, Prof. Dr. D. Kim
The Research Institute of Pharmaceutical Sciences
College of Pharmacy, Seoul National University
San 56-1, Shinrim-Dong, Kwanak-Ku, Seoul 151-742 (Korea)
Fax: (+82)2-888-0649
Our first objective was to determine the relative stereo-
chemistry between the dioxabicyclic core and the bromoal-
lene appendage of itomanallene A. For simplicity, we initially
opted to synthesize ent-3a and 3b instead of the originally
proposed structures 3a and 3b. As it turned out, this decision
was a fortuitous one.
E-mail: deukjoon@snu.ac.kr
Dr. K. J. Shin
Life Sciences Research Division
Center for Chemoinformatics Research
Korea Institute of Science and Technology, Seoul 130-650 (Korea)
Our retrosynthetic plan for the substrate-controlled syn-
thesis of ent-3a and 3b, as shown in Scheme 1, hinges upon
the versatility of the a-alkoxy N,N-dimethylamide function-
ality. We envisioned that bicyclic bromoaldehyde 4 could be
elaborated to both ent-3a and 3b by installation of the
respective bromoallene units. The requisite bromoaldehyde 4
could be produced from 5 by bromination with inversion of
[**] We thank Prof. M. Suzuki (Hokkaido University) for providing the
spectra of itomanallene A and neolaurallene. We are grateful to Dr.
H. C. Ahn (KIST) for the measurement of 900 MHz 1H NMR spectra
of 3c and ent-2. This work was supported by the SRC/ERC program
of MOST/KOSEF (R11-2007-107-00000-0).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905826.
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11[12] by addressing the C6/C7-syn stereochemistry through a
chelation-controlled nucleophilic addition.
A significant feature of this approach is that it showcases
the versatility of the a-alkoxy amide enolate alkylation in
establishing both sets of a,a’-oxymethine relative configura-
tions without recourse to using additional chiral auxiliaries.
Our synthesis commenced with preparation of the key
intermolecular amide enolate alkylation substrate 10
(Scheme 2). Therefore, one-carbon homologation of (S)-
Scheme 2. Intermolecular amide enolate alkylation: a) (CH3)3SI, nBnLi,
THF, ꢀ108C to RT, 2 h, 98%; b) ClCH2CONMe2, NaH, DMF, 08C to
RT, 3 h, 97%; c) 1. OsO4, NMO, H2O/acetone (2:1), RT, 4 h; 2. NaIO4,
RT, 2 h, 85%; d) allyltributyltin, MgBr2·Et2O, CH2Cl2, ꢀ788C to RT,
18 h, 85%, syn/anti=15:1; e) TIPSOTf, Et3N, CH2Cl2, 08C to RT, 3 h,
93%; f) LiHMDS, EtI, THF, ꢀ78 to ꢀ408C, 2 h, 91%, anti/syn=57:1.
DMF=N,N-dimethylformamide, LiHMDS=lithium hexamethyldisila-
zide, NMO=N-methylmorpholine-N-oxide.
Scheme 1. Retrosynthetic plan for ent-3a and 3b. PMB=para-meth-
oxybenzyl, TIPS=triisopropylsilyl.
the configuration at C12, and reduction of the a-alkoxy N,N-
dimethylamide functionality. Furthermore, we envisioned
that the a,a’-cis-tetrahydrofuran ring in bicyclic a-alkoxy
amide 5 could be constructed in a stereoselective manner
through an intramolecular amide enolate alkylation (IAEA)
of tosylate 6, which in turn could be readily prepared from
oxonene intermediate 7. It is worthwhile mentioning at this
point that carbon–oxygen bond formation at C4 by a 5-exo-
trigonal ring closure leads to an a,a’-trans-tetrahydrofuran.[7]
We reasoned that the nine-membered ether 7 could be
constructed by RCM of bis-alkene 8. However, the efficiency
of the hitherto uninvestigated RCM of bis-alkene 8 (syn-C6/
C7, anti-a,a’, syn-C12/C13) caused some concern since it was
known that the relative stereochemistry of the incipient cyclic
ether oxygen atom with respect to each of the adjacent
oxygen substituents, as well as the a,a’ relative stereochem-
istry, can exert a subtle conformational effect on the rate of
RCM reactions to give oxonenes.[8–10] Specifically, the anti
isomer places one side chain in a pseudo-axial orientation in
the transition state for ring closure, which would be unfav-
orable for the desired outcome.
In this plan, the syn stereochemical relationship between
C12 and C13 in the RCM substrate 8 could be established by
manipulation of the a-alkoxy N,N-dimethylamide group in 9
by using our direct ketone synthesis/l-Selectride reduction
protocol.[11] For the greater challenge of the pivotal a,a’-anti
stereochemistry in 9, we envisaged that this would be
established through a chemoselective chelation-controlled
intermolecular amide enolate alkylation of 10. Furthermore,
analysis suggested that the alkylation substrate 10 would be
readily accessible from known PMB-protected (S)-glycidol
glycidol 11 by treatment with dimethylsulfonium methyl-
ide,[13] and subsequent O-alkylation of the resulting allylic
alcohol 12 with N,N-dimethyl chloroacetamide, produced a-
alkoxy amide 13 in excellent overall yield (95%, two steps).
Cleavage of alkene 13 by a modified Lemieux–Johnson
oxidation then afforded aldehyde 14.[14] Chemoselective
chelation-controlled nucleophilic addition of allyltributyl-
stannane to aldehyde 14[15] in the presence of the a-alkoxy
amide and subsequent protection of the resulting syn-diol
derivative 15 as a TIPS ether furnished the requisite substrate
10 (67% for three steps from 13), setting the stage for the
crucial intermolecular amide enolate alkylation. Therefore,
treatment of 10 with LiHMDS in the presence of ethyl iodide
produced the desired a,a’-anti-alkoxy amide 9 in 91% yield as
essentially a single isomer. The stereochemical outcome of
the chemoselective chelation-controlled alkylation can be
rationalized by considering that the alkylating agent
approaches from the less hindered convex face of the cup-
shaped, chelated enolate intermediate A where the bulky
group at C6 prefers to be located.[16] Notably, the PMB-
protected alkoxy group participates in the chelation in
preference to the TIPS-protected alkoxy group, which is
known to be a poor coordinating group.[17]
Having established the pivotal a,a’-anti stereochemistry
in 9, we proceeded to address construction of the dioxabicy-
clic skeleton using the projected RCM/IAEA strategy
(Scheme 3). The C12/C13-syn stereochemistry in the RCM
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overall yield (85%). As anticipated, intramolecular amide
enolate alkylation of 17 afforded the desired a,a’-cis-tetrahy-
drofuran 18 exclusively in 96% yield, probably through the
H-eclipsed transition-state geometry B.
Gratifyingly, subjection of tetrahydrofuranyl diene 18 to
RCM using Grubbsꢀ second-generation catalyst produced a
70% yield of key bicyclic oxonene 5. Removal of the benzyl
group in 5 under the reaction conditions reported by
Yonemitsu and co-workers[20] and subsequent bromination[21]
of the resulting secondary alcohol 19, with inversion of
configuration, furnished a-bromide 20 (59%, two steps).
Finally, reduction of 20 using the ate complex[22] derived from
DIBAL-H and nBuLi gave rise to the key bromoaldehyde 4
(85%).
With the key bromoaldehyde 4 in hand, we turned our
attention to installation of the bromoallene unit on the basis
of the well-established protocol described by Overman and
co-workers.[23] Therefore, addition of titanium TMS-acetylide
to aldehyde 4 with Felkin–Ahn-type stereoselectivity pro-
duced a 4.7:1 mixture of TMS-propargylic alcohols 21a and
21b in 82% total yield. The structure and absolute config-
uration of the major (R)-TMS-propargylic alcohol 21a were
confirmed by X-ray crystallography.[24] Removal of the TMS
groups in 21a and 21b by exposure to TBAF then afforded
22a and 22b, respectively. Finally, trisylation of propargylic
Scheme 3. Intramolecular amide enolate alkylation and RCM:
a) CH2 =CHCH2MgCl, THF, ꢀ788C, 2 h; b) L-Selectride, THF, ꢀ788C,
2 h, 85% (2 steps), syn/anti=17:1; c) NaH, BnBr, DMF, 08C to RT,
3 h, 95%; d) TBAF, THF, RT, 2 h, 99%; e) ClCH2CONMe2, NaH, DMF,
08C to RT, 3 h, 96%; f) DDQ, CH2Cl2/buffer solution (pH 7.4; 9:1),
08C to 158C, 3 h, 94%; g) TsCl, DMAP, Et3N, CH2Cl2, 08C to RT, 8 h,
95%; h) LiHMDS, THF, ꢀ78 to ꢀ408C, 2 h, 96%; i) (H2IMes)-
=
(Cy3P)Cl2Ru CHPh, CH2Cl2, 708C, 5 h, then DMSO, RT, 12 h, 70%;
j) DDQ, CH2Cl2/buffer solution (pH 7.4; 9:1), RT, 12 h, 91%; k) CBr4,
Oct3P, 1-methylcyclohexene, toluene, 708C, 12 h, 65%; l) nBuLi/DIBAL-
H (1:1), THF, 08C, 30 min, 85%. DDQ=2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, DIBAL-H=diisobutylaluminum hydride, DMAP=4-
dimethylaminopyridine, DMSO=dimethyl sulfoxide, TBAF=tetra-n-
butylammonium fluoride, Ts=toluenesulfonyl.
substrate 8 was introduced as follows: addition of allylmag-
nesium chloride to 9, and subsequent l-Selectride reduction
of the resulting ketone 16 (in the crude reaction mixture)
according to Felkin–Ahn control;[18] then protection as a
benzyl ether yielded the desired RCM substrate 8 in good
overall yield (81%, three steps) with 17:1 syn/anti selectivity.
Our initial concerns regarding the RCM of 8 were borne
out, as only a low yield of the desired oxonene (ca. 20%) was
obtained despite a considerable amount of effort. The ration-
ale that a cyclic constraint might facilitate the RCM prompted
us to construct the five-membered ring first.[19] To this end, 8
was transformed into the key intramolecular alkylation
Scheme 4. Completion of the synthesis of ent-3a and 3b: a) TMS-
acetylene, nBuLi, ClTi(OiPr)3, Et2O, ꢀ788C to RT, 12 h, 82%, R/S=
4.7:1; b) TBAF, THF, RT, 2 h, 96%; c) TrisCl, DMAP, CH2Cl2, 08C to RT,
12 h, 99%; d) LiCuBr2, THF, reflux, 14 h, 80%; e) TBAF, THF, RT, 3 h,
89%; f) TrisCl, DMAP, CH2Cl2, 08C to RT, 16 h, 83%; g) LiCuBr2, THF,
reflux, 48 h, 73%. TMS=trimethylsilyl, Tris=2,4,6-triisopropyl ben-
zenesulfonyl.
substrate 17 by
a straightforward four-step sequence
[1) removal of TIPS group; 2) O-alkylation with N,N-
dimethyl chloroacetamide; 3) chemoselective removal of the
PMB group with wet DDQ;[20] 4) tosylation] in excellent
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alcohols 22a and 22b, and then the copper-catalyzed
anti-SN2’ reaction of the corresponding trisylates gave
rise to ent-3a and 3b, respectively. Unfortunately, the
1H NMR spectra of both compounds differ from that
of natural itomanallene A. In particular, the chemical
shift values of the C4 protons were significantly
different as indicated in Scheme 4.
Careful examination of NMR data of structurally
related natural products that possess a bromoallene
led to the conclusion that itomanallene A might
possess an a,a’-trans-tetrahydrofuran despite the
aforementioned reported observation of an nOe
interaction between the protons on C4 and C6. On
the basis of this assumption, we set out to synthesize
the C4 epimers of ent-3a and 3b. Incidentally, the C4
epimer of ent-3a corresponds to the enantiomeric
form of neolaurallene (ent-2; Scheme 5).
For this purpose, we were intrigued by the
possibility that the requisite a,a’-trans-tetrahydrofur-
anyl aldehyde 4ꢀ might be secured by intramolecular
nitrile anion alkylation methodology based on the
pioneering work by Stork et al.[25] and ensuing
investigations by Fleming et al.[26,27] To this end, the
key intramolecular nitrile anion cyclization substrate
23 was synthesized uneventfully in four steps starting
from 8 [1) removal of TIPS group (99%); 2) O-
alkylation with bromoacetonitrile (69%, 91% brsm);
3) removal of the PMB group with DDQ (92%);
4) tosylation (97%)].[28] We were delighted to find
that upon exposure to LiHMDS in benzene, nitrile
tosylate 23 gave rise to the desired a,a’-trans isomer
24 as the major isomer (87% total yield; trans/cis =
4.5:1).
To the best of our knowledge, this constitutes the first
example of the construction of a tetrahydrofuran through an
intramolecular alkylation of an a-alkoxy nitrile.[29] It is also
highly significant that in this tetrahydrofuran construction,
the a-alkoxy nitrile affords stereoselection that is comple-
mentary to that obtained with the corresponding a-alkoxy
N,N-dimethylamide. The origin of this stereodifferentiation is
unclear at the present time; although not unprecedented,[25–27]
it is not clear that comparable parameters determine the
outcome. The exact nature of the nitrile anion involved is
elusive factor, and the underlying reasons for this selectivity
along with its use in synthesis are the subject of further
investigation.[30]
Scheme 5. Intramolecular nitrile anion alkylation and structure revision: a) TBAF,
THF, RT, 2 h, 99%; b) NaH, BrCH2CN, MeCN, RT, 20 min, then ꢀ208C, 72 h,
69% (brsm 91%); c) DDQ, CH2Cl2/buffer solution (pH 7.4; 9:1), 158C, 4 h,
92%; d) TsCl, DMAP, Et3N, CH2Cl2, 08C to RT, 5 h, 97%; e) LiHMDS, benzene,
=
78C, 30 min, 87%, trans/cis=4.5:1; f) (H2IMes)(Cy3P)Cl2Ru CHPh, CH2Cl2, 708C,
4 h, then DMSO, RT, 12 h, 57%; g) DDQ, CH2Cl2/buffer solution (pH 7.4; 9:1),
RT to 408C, 27 h, 87%; h) CBr4, Oct3P, 1-methylcyclohexene, toluene, 708C, 4 h,
60%; i) DIBAL-H, toluene, ꢀ788C, 1 h. brsm=based on recovered starting
material.
½aꢁ2D2 = + 99 degcm3 gꢀ1 dmꢀ1 (c = 0.44 gcmꢀ3, CHCl3)]. On
the basis of the synthesis, the structure of itomanallene A
should be revised to that shown in Scheme 5. In addition, the
spectral and optical rotation data of our synthetic ent-2 were
in close agreement with those of the natural product except
for the sign of the optical rotation.[32] It is worth mentioning
that we were unable to observe nOe interactions between the
protons on C4 and C6 in 3c as well as ent-2.
In summary, the first asymmetric total synthesis, and
consequent structure revision of (+)-itomanallene A, has
been achieved starting from the readily available PMB-
protected (S)-glycidol 11. Our substrate-controlled synthesis
provides a versatile strategy for the synthesis of both a,a’-cis-
and a,a’-trans-tetrahydrofurans in such dioxabicylic marine
natural products and related structures through the judicious
choice of an amide enolate versus nitrile anion, respectively,
for the intramolecular alkylation. Problems with an inefficient
ring-closing metathesis reaction were overcome by modifying
the synthetic route to incorporate the tetrahydrofuran ring
earlier and benefit from its conformational bias. An asym-
metric synthesis of ent-neolaurallene has also been achieved.
To complete the synthesis, tetrahydrofuranyl nitrile 24 was
converted into the desired a,a’-trans-bicyclic nitrile 25 by a
three-step sequence analogous to that employed for synthesis
of 20 [1) RCM; 2) removal of benzyl group; 3) bromination
with inversion of configuration]. The a,a’-trans-aldehyde 4’,
prepared by DIBAL-H reduction of nitrile 25, was converted
into 3c and ent-2 by a four-step sequence identical to that
employed for syntheses of ent-3a and 3b.[31] The spectral
characteristics and optical rotation of our synthetic material
3c, which corresponds to the C4 epimer of one of the
proposed structures (3b), were in good agreement with those
22
reported for the natural itomanallene A: ½aꢁD
=
Received: October 16, 2009
Published online: December 22, 2009
+ 122.1 degcm3 gꢀ1 dmꢀ1 (c = 0.25 gcmꢀ3
,
CHCl3) [Ref. [3]
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Communications
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[20] Y. Oikawa, T. Yoshioka, O. Yonemitsu, Tetrahedron Lett. 1982,
23, 885 – 888.
[21] R. Matsumura, T. Suzuki, H. Hagiwara, T. Hoshi, M. Ando,
Tetrahedron Lett. 2001, 42, 1543 – 1546.
[22] S. Kim, K. H. Ahn, J. Org. Chem. 1984, 49, 1717 – 1724.
[23] T. A. Grese, K. D. Hutchinson, L. E. Overman, J. Org. Chem.
1993, 58, 2468 – 2477.
[24] CCDC 74799 (for 21a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Keywords: alkylation · natural products · structure elucidation ·
total synthesis
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