Substrate-controlled asymmetric total synthesis of (+)-microcladallene B with a bromination strategy based on a nucleophile-assisting leaving group

Article abstract of DOI:10.1002/anie.200700854

(Chemical Equation Presented) The formidable challenge of incorporating a bromine substituent stereoselectively at an sp³ center was met through application of a nucleophile-assisting leaving group (see scheme). A further highlight of the highl

Full text of DOI:10.1002/anie.200700854

Communications
DOI: 10.1002/anie.200700854
Natural Products Synthesis
Substrate-Controlled Asymmetric Total Synthesis of
(+)-Microcladallene B with a Bromination Strategy Based on a
Nucleophile-Assisting Leaving Group**
Janghyun Park, Byungsook Kim, Hyoungsu Kim, Sanghee Kim, and Deukjoon Kim*
(+)-Microcladallene B (1) was isolated by Kennedy et al.
from the red alga Laurencia microcladia collected off the
French coast at Cap Ferrat.[1] The structure and absolute
configuration of the C15 acetogenin were assigned by a
combination of spectroscopic analysis and X-ray crystallog-
raphy.[1] The key structural features of the marine natural
product are 1) a unique cis-fused 2,9-dioxabicyclo-
[6.4.0]dodecane skeleton composed of an a,a’-trans oxocene
and a tetrahydropyran ring, 2) an S bromoallene appendage,
and 3) a secondary bromide functionality.[2] The successful
execution of a synthesis of the halogenated medium-sized
oxacyclic natural product hinges upon the stereoselective
incorporation of the bromine functionality at C12, which is
recognized to be a significant challenge.[3] Herein, we report
the first and completely substrate-controlled asymmetric total
synthesis of (+)-microcladallene B (1). Our synthesis features
a novel dianion alkylation to provide the a,a’-anti substrate
for ring-closing metathesis (RCM), a chemoselective RCM to
form the oxocene, a SmI2-mediated reductive cyclization to
construct the cis-fused dioxabicyclic core, and a novel
application of methodology based on a nucleophile-assisting
leaving group (NALG) for the stereoselective introduction of
the bromine functionality at C12.
We envisaged that (+)-microcladallene B (1) could be
elaborated from the dioxabicyclic compound 2 by an NALG
bromination method (Scheme 1).[4] The cis-fused dioxabicylic
intermediate 2 could be prepared in turn by a SmI2-mediated
reductive cyclization[5] of the b-alkoxy acrylate 3. We further
envisaged that the key a,a’-anti RCM substrate 4 could be
secured stereoselectively by alkylation of the dianion derived
from the hydroxyamide 5 without resorting to the use of a
chiral auxiliary. Further analysis suggested that the hydroxy-
amide 5 should be readily accessible from the known
aldehyde 6 through a Grignard reaction.
Scheme 1. Retrosynthetic analysis of (+)-microcladallene B (1).
PMB=p-methoxybenzyl.
Recently, we reported that the “protecting-group-dependent”
alkylation of the TIPS-protected a-alkoxy amide 5’a (PG =
TIPS) with allyl bromide furnished the corresponding a,a’-
anti bisalkene with 5:1 stereoselectivity by electrophilic attack
from the side of the smaller (ethyl) group in the H,H-eclipsed
conformation shown by the monodentate model
A
(Scheme 2).[6] In an ensuing study, we observed that anti/syn
stereoselectivity diminishes as the R group becomes larger, as
illustrated by the results obtained with the TIPS-protected
amides 5’b and 5’c (PG = TIPS). However, we were delighted
to find that the corresponding unprotected hydroxyamides
5’a–c (PG = H) reacted to furnish the desired a,a’-anti
bisalkenes with high stereoselectivity under similar conditions
(Scheme 2), presumably via a dianion.
Our study commenced with the exploration of a direct
stereoselective route to the a,a’-anti RCM substrate 4.
[*] J. Park, B. Kim, Dr. H. Kim, Prof. S. Kim, Prof. 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
E-mail: deukjoon@snu.ac.kr
[**] This research was supportedby a Korea Research Foundation Grant
(KRF-2004–015-C00272) andthe Brain Korea Project in 2005 and
2006.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Dianion alkylation of hydroxyamides. Bn=benzyl,
HMDS=hexamethyldisilazide, TIPS=triisopropylsilyl.
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Having developed a suitable dianion-alkylation protocol,
we began the synthesis of 1 by the addition of commercially
available (1,3-dioxolan-2-ylmethyl)magnesium bromide to
the known aldehyde 6[7] to furnish the desired syn alcohol 7
in 67% yield with 10:1 syn/anti stereoselectivity (Scheme 3).
ble[3] task of introducing the C12 bromine functionality with
retention of configuration (Scheme 4). The chemoselective
reduction of ester 2 with LiBH4[12] and selective protection of
the primary hydroxy group in the resulting diol with
Scheme 4. NALG bromination: a) LiBH4, MeOH, Et2O, 08C!RT, 2 h,
84%; b) TBDPSCl, imidazole, CH2Cl2, RT, 1 h, 99%; c) 2-[CH3-
(OC2H4)2OC(O)]C6H4SO2Cl, DMAP, CH2Cl2, room temperature, 4 h,
92%; d) TiBr4, CH2Cl2, 08C!RT, 2 h, 63%; e) 2-NO2C6H4SeCN,
(n-C8H15)3P, THF, 08C!RT, 2 h, then H2O2, 08C!RT, 10 h, 91%.
DMAP=4-dimethylaminopyridine, TBDPS=tert-butyldiphenylsilyl.
Scheme 3. Construction of the bicyclic core fragment 2: a) (1,3-dioxo-
lan-2-ylmethyl)magnesium bromide, THF, 608C, 1.5 h, 67%; b) NaH,
THF, 08C, 30 min, then ClCH2CONMe2, RT, 30 min, 99%; c) DDQ,
CH2Cl2/pH 7.4 buffer (9:1), 08C!RT, 1 h, 99%; d) LiHMDS, allyl
iodide, THF, ꢀ788C to ꢀ458C, 3 h, 63%; e) ethyl propiolate, NMM,
CH2Cl2, room temperature, 16 h, 99%; f) [Cl2{(c-C6H11)3P}2Ru=CHPh],
CH2Cl2, room temperature, 18 h, then DMSO, room temperature, 10 h,
91%; g) PPTS, acetone, H2O, 1308C, 5 h, 73%; h) SmI2, MeOH, THF,
room temperature, 1.5 h, 85%. DDQ=2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, DMSO=dimethylsulfoxide, NMM=N-methylmorpho-
line, PPTS=pyridinium p-toluenesulfonate.
TBDPSCl led to the secondary alcohol 10 (83%, two steps)
and set the stage for the pivotal bromination. As anticipated,
the stereoselective introduction of the bromine functionality
at C12 proved to be extremely problematic. Our extensive
efforts to brominate the a alcohol 10, which has an equatorial
hydroxy group, and the corresponding b alcohol, in which the
hydroxy group has an axial orientation, under a variety of
conditions led to unsatisfactory results.[13]
O Alkylation of the syn alcohol 7 with N,N-dimethyl-a-
chloroacetamide, followed by oxidative removal of the PMB
group of the resulting a-alkoxy amide with wet DDQ,[8] then
provided the corresponding hydroxyamide 5 in excellent yield
(98%, two steps) to set the stage for the crucial dianion
After considerable experimentation, we were delighted to
find that the treatment of aryl sulfonate 11, which has an
alkylation. To our satisfaction, the treatment of hydroxy- NALG with a chelating polyether unit, with titanium
amide 5 with LiHMDS followed by allyl iodide produced the
desired a,a’-anti isomer 4 in 63% yield with 6:1 anti/syn
stereoselectivity.
tetrabromide by using a modification of the chlorination
protocol of Lepore and co-workers[4] furnished the desired
a bromide, probably through an SNi mechanism, with con-
comitant cleavage of the TBDPS ether to give 12 in 63%
yield. The hydroxyethyl group at C13 of bromoalcohol 12 was
then transformed into the requisite vinyl group in a one-pot
process by the protocol described by Grieco et al. to furnish
alkene 13 in good yield (91%).[14]
Having properly functionalized the tetrahydropyranyl
moiety, we next directed our attention to the stereoselective
assembly of the bromoallene appendage at C4 to complete
the synthesis (Scheme 5). The use of our protocol for direct
ketone synthesis[15] with the a-alkoxy amide 13 and TIPS-
substituted acetylene under Yamaguchi conditions[16]
afforded the ynone 14 in 84% yield. The highly stereoselec-
tive and efficient reduction of ketone 14 with L-selectride[17]
in a Felkin–Ahn sense, followed by removal of the TIPS group
in the resulting alcohol by exposure to TBAF, led exclusively
to the 3R propargylic alcohol 15 (77%, two steps). Alcohol 15
was then converted into the required 3S trisylate 16 in a single
With the key a,a’-anti isomer 4 in hand, we proceeded to
address the construction of the dioxabicyclic core by using an
RCM reaction[9] and the protocol described by Nakata and
co-workers for SmI2-mediated reductive cyclization.[5] We
were pleased to find that triene 8, prepared from the diene
alcohol 4 by treatment with ethyl propiolate,[10] underwent an
efficient chemoselective RCM reaction to deliver the key
oxocene 9 in excellent overall yield (90%, two steps).
Hydrolysis of the acetal functionality in 9 under carefully
controlled acidic conditions, followed by SmI2-mediated
pyranoannulation of the resultant aldehydo b-alkoxy acrylate
3, gave the key dioxabicycle 2 in 62% yield for the two steps
in a 13:1 a/b-OH ratio at C12. The preferred geometry of the
transition state for this cyclization is probably described by
B.[11]
Following the construction of the dioxabicyclic core of
(+)-microcladallene B (1), we set out to tackle the formida-
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Communications
Cohn, C. Lefkowitz, J. Org. Chem. 2006, 71, 3285 – 3286, and
references therein.
[5] a) N. Hori, H. Matsukura, G. Matsuo, T. Nakata, Tetrahedron
Lett. 1999, 40, 2811 – 2814; b) G. Matsuo, H. Kadohama, T.
Nakata, Chem. Lett. 2002, 148 – 149.
[6] a) H. Lee, H. Kim, T. Yoon, B. Kim, S. Kim, H. Kim, D. Kim, J.
Org. Chem. 2005, 70, 8723 – 8729; b) in the case of 5’a, the
enantiomer of the compound actually prepared is shown for
comparison purposes.
[7] I. Kadota, H. Uyehara, Y. Yamamoto, Tetrahedron 2004, 60,
7361 – 7365.
Scheme 5. Completion of the synthesis of (+)-microcladallene B (1):
[8] Y. Oikawa, T. Yoshioka, O. Yonemitsu, Tetrahedron Lett. 1982,
23, 885 – 888.
[9] a) G. C. Fu, R. H. Grubbs, J. Am. Chem. Soc. 1992, 114, 5426 –
5427; b) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc. Chem. Res.
1995, 28, 446 – 452; c) for the synthesis of a,a’-trans-oxocene
natural products by RCM, see ref. [2a,b].
[10] a) E. Winterfeldt, Chem. Ber. 1964, 97, 1952 – 1958; b) E.
Winterfeldt, H. Preuss, Chem. Ber. 1966, 99, 450 – 458.
[11] To the best of our knowledge, this pyranoannulation constitutes
the first example of the use of the protocol of Nakata and co-
workers for the synthesis of a cis-fused bicyclic structure.
[12] a) K. Soai, A. Ookawa, J. Org. Chem. 1986, 51, 4000 – 4005;
b) the free hydroxy group at C12 in 2 was found to be necessary
for the efficient chemoselective reduction of the ester function-
ality in the presence of the a-alkoxy amide group, possibly by
internal delivery of the hydride.
ꢀ ꢁ
a) BF3·Et2O, TIPS C CH, nBuLi, THF, ꢀ788C, 2 h, 84%; b) L-selec-
tride, THF, ꢀ788C, 1 h, 91%; c) TBAF, THF, 08C!RT, 1 h, 85%;
d) 2,4,6-iPr3C6H2SO3H, DIAD, Ph3P, Et3N, THF, 608C, 2 h, 56%;
e) LiBr, CuBr, THF, 608C, 8 h, 73%. DIAD=diisopropylazodicarboxy-
late, TBAF=tetrabutylammonium fluoride, Tris=2,4,6-triisopropylben-
zenesulfonyl.
step by using the modification by Anderson et al. of the
procedure described by Galynker and Still.[18] Finally, SN2’
displacement of the trisylate group upon the exposure of 16 to
LiCuBr2 delivered (+)-microcladallene B (1) in 73% yield
along with a small amount of the corresponding product of
SN2 substitution.[19] The optical-rotation data for synthetic
(+)-microcladallene B were in close agreement with those of
the natural product: [a]2D0 = + 93.2 (c = 0.14, Me2CO; lit.[1]:
[a]2D0 = + 96.0 (c = 0.50, Me2CO)).[20,21]
In conclusion, we have completed an asymmetric total
synthesis of (+)-microcladallene B (1) in 18 steps and 3%
overall yield from the readily available aldehyde 6 in a
substrate-controlled fashion. Highlights of the synthesis
include a novel dianion alkylation for the synthesis of the
a,a’-anti substrate for RCM and a novel application of NALG
methodology for the demanding stereoselective introduction
of the bromine substituent at C12. The application of the
NALG halogenation to the synthesis of other natural
products is under investigation in our laboratories.
[13] The treatment of the mesylate derived from alcohol 10 with
nBu4NBr in xylene at reflux according to the double-inversion
protocol of Masamune and co-workers produced the corre-
sponding bromide in only moderate (20%) yield as a 2:1 mixture
of
a and b isomers, along with a significant amount of
elimination products: a) A. Fukuzawa, H. Sato, T. Masamune,
Tetrahedron Lett. 1987, 28, 4303 – 4306; b) D. Kim, I. H. Kim,
Tetrahedron Lett. 1997, 38, 415 – 416.
[14] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41,
1485 – 1486.
[15] H. Kim, W. J. Choi, J. Jung, S. Kim, D. Kim, J. Am. Chem. Soc.
2003, 125, 10238 – 10240.
[16] M. Yamaguchi, I. Hirao, Tetrahedron Lett. 1983, 24, 391 – 394.
[17] a) J. S. Clark, A. B. Holmes, Tetrahedron Lett. 1988, 29, 4333 –
4336; b) K. Tsushima, A. Murai, Tetrahedron Lett. 1992, 33,
4345 – 4348.
[18] a) N. G. Anderson, D. A. Lust, K. A. Colapret, J. H. Simpson,
M. F. Malley, J. Z. Gougoutas, J. Org. Chem. 1996, 61, 7955 –
7958; b) I. Galynker, W. C. Still, Tetrahedron Lett. 1982, 23,
4461 – 4464; c) to the best of our knowledge, this reaction is the
first example of trisylation under Mitsunobu conditions.
[19] a) C. J. Elsevier, P. Vermeer, A. Gedanken, W. Runge, J. Org.
Chem. 1985, 50, 364 – 367; b) H. H. Mooiweer, C. J. Elsevier, P.
Wijkens, P. Vermeer, Tetrahedron Lett. 1985, 26, 65 – 66; c) T . A.
Grese, K. D. Hutchinson, L. E. Overman, J. Org. Chem. 1993, 58,
2468 – 2477.
Received: February 26, 2007
Published online: May 11, 2007
Keywords: bromination · dianion alkylation · natural products ·
.
nucleophile-assisting leaving groups · total synthesis
[1] D. J. Kennedy, I. A. Selby, H. J. Cowe, P. J. Cox, R. H. Thomson,
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5473 – 5476; b) K. Fujiwara, S.-I. Souma, H. Mishima, A. Murai,
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H. Hagiwara, T. Hoshi, Tetrahedron Lett. 2003, 44, 3175 – 3178;
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[20] We were unable to obtain the spectra of the natural product from
Dr. D. J. Kennedy as a result of his retirement.
[21] Characterization of synthetic 1: Rf = 0.21 (hexane/ethyl acetate,
10:1); m.p. 84–888C; 1H NMR (500 MHz, CDCl3): d = 6.11 (1H,
dd, J = 5.9, 2.8 Hz, 1H), 5.85–6.00 (m, 2H), 5.81 (ddd, J = 17.2,
10.3, 10.3 Hz, 1H), 5.41–5.45 (m, 2H), 5.32 (d, J = 10.5 Hz, 1H),
4.83 (ddd, J = 7.2, 3.5, 3.5 Hz, 1H), 4.08 (ddd, J = 12.4, 10.1,
4.3 Hz, 1H), 3.89 (dd, J = 10.2, 6.8 Hz, 1H), 3.83 (bs, 1H), 3.69
(dd, J = 9.8, 4.6 Hz, 1H), 2.65–2.67 (m, 1H), 2.60 (ddd, J = 12.8,
9.8, 3.0 Hz, 1H), 2.52 (ddd, J = 7.8, 3.8, 3.8 Hz, 1H), 2.27–2.33
(m, 2H), 2.17 ppm (ddd, J = 12.7, 11.5, 3.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d = 202.6, 135.4, 129.3, 128.7, 119.4, 100.0,
83.3, 80.6, 74.9, 74.4, 69.9, 48.0, 43.2, 31.7, 30.2 ppm.
[4] a) S. D. Lepore, A. K. Bhunia, P. Cohn, J. Org. Chem. 2005, 70,
8117 – 8121; b) S. D. Lepore, A. K. Bhunia, D. Mondal, P. C.
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