Total synthesis of (+)-awajanomycin

Article abstract of DOI:10.1002/ejoc.201200059

The total synthesis of (+)-awajanomycin has been achieved by asymmetric allylboration of a vicinal tricarbonyl compound as the key step. A substrate-controlled dihydroxylation and subsequent differentiation of diastereotopic ester groups were used to synt

Full text of DOI:10.1002/ejoc.201200059

FULL PAPER
DOI: 10.1002/ejoc.201200059
Total Synthesis of (+)-Awajanomycin
Malte Wohlfahrt,[a] Klaus Harms,[a] and Ulrich Koert*[a]
Keywords: Natural products / Total synthesis / Diastereoselectivity / Boranes / Asymmetric synthesis
The total synthesis of (+)-awajanomycin has been achieved
by asymmetric allylboration of a vicinal tricarbonyl com-
groups were used to synthesize the γ-lactone substructure.
After formation of the δ-lactam, the bicyclic core structure
pound as the key step. A substrate-controlled dihydrox- was established. The synthetic strategy and overall efficacy
ylation and subsequent differentiation of diastereotopic ester
is compared with Huang’s route to awajanomycin.
Introduction
Results and Discussion
The natural product (+)-awajanomycin (1; Figure 1) was
first isolated in 2006 from the marine-derived fungus Acre-
monium sp. AWA16-1.[1] The name refers to its marine
source, sea mud collected from around Awajishima Island
(Japan).
Comparative Retrosynthesis
Both groups planned to introduce the C-8 side-chain at
the end of the synthesis (Scheme 1). Huang and co-workers
used a cross metathesis of the terminal olefin precursor 2,
which has the advantage of tolerating the presence of the
unprotected C-11 hydroxy group. We planned to use an (E)-
selective Wittig reaction of aldehyde 3 with subsequent
stereoselective enone reduction.
Figure 1. Structure of (+)-awajanomycin (1).
(+)-Awajanomycin (1) exhibits cytotoxic activity (IC50
for A549 cells 27.5 μg/mL). It possesses a unique bicyclic
core structure consisting of a γ-lactone and a δ-lactam. A
tertiary OH group is located at C-3 and a side-chain at C-
8. The side-chain contains an allylic alcohol with the stereo-
center at C-11.
Huang and co-workers achieved the total syntheses of
(–)-awajanomycin (ent-1)[2] as well as (+)-awajanomycin
(1)[3] and its C-11 epimer. Syntheses of the bicyclic core
have been reported by Hiroya et al.[4] and Pritchard and
Wilden.[5] We have communicated a total synthesis of (+)-
awajanomycin (1) achieved by asymmetric allylboration of
a vic-tricarbonyl compound as the key step.[6] Herein we
present the development of our synthetic route in detail and
compare this strategy with that of Huang and co-workers.
Scheme 1. Different approaches to the introduction of the C-8 side-
chain.
The strategy of Huang and co-workers for the synthesis
of compound 2 relied on the early generation of the δ-lact-
am and the use of C-5 as directing stereocenter for the
introduction of the remaining stereocenters (Scheme 2).
The γ-lactone was generated late in the synthesis from the
hydroxy ester 4, which is accessible by hydroxylation of the
malonic ester lactam 5. This can be prepared from the α,β-
unsaturated δ-lactam 6 by 1,4-addition of vinyl cuprate and
trapping of the resulting enolate with NCCO2Me. Two
routes lead to lactam 6: One begins with aspartate 8 and
proceeds via imide 7, the other has N-Boc-glycine 9 as the
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Strasse, 35043 Marburg, Germany
Fax: +49-6421-28-25677
E-mail: koert@chemie.uni-marburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200059.
2260
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2260–2265

Total Synthesis of (+)-Awajanomycin
starting point.[5] According to this plan, (+)-awajanomycin tion of the tertiary alcohol 15 (15 Ǟ 18). The resulting
(1) was synthesized by Huang and co-workers for the first homoallylic TMS ether 18 exhibited a clear conformational
time in an overall yield of 3.8%.[3]
bias that allowed substrate-controlled dihydroxylation of
the (E)-alkene. The product of the dihydroxylation 19
underwent direct cyclization to the γ-lactone 20. Only one
of the diastereotopic ester groups in 19 was attacked by one
hydroxy group of the diol to produce selectively lactone 20.
After removal of the TMS group, the lactone 17 obtained
was identical to the previously prepared sample.
Scheme 2. Comparative retrosynthetic analyses for the bicyclic core
structure of awajanomycin: alkene 2 (Huang’s route), compound
10 (our approach).
The synthesis of aldehyde 3 or the more general com-
pound 10 should be possible by stereocontrolled function-
alization of alkene 11 and subsequent differentiation of the
diastereotopic ester groups. The homoallylic alcohol 11 can
be prepared from the substituted allylboronate 12 and di-
ethyl mesoxalate 13. The stereocontrolled allylboration of
aldehydes and α-oxo esters is an established methodology.[7]
Chiral (Z)-pentenylboronates are among the most efficient
allylborating reagents for aldehydes,[8] and thus compounds
of type 12 should be good candidates for the allylboration
of vic-tricarbonyl compounds.
Scheme 3. Allylboration with boronate 14, subsequent dihydrox-
ylation, and differentiation of the diastereotopic ester groups. The
crystal structure of 17 is provided.
Racemic Synthesis of the Bicyclic Core
The synthesis of a racemic model system for the bicyclic
Thus, in the case of osmylation of alkene 18, introduc-
core in which the C-8 side-chain is replaced by a methyl tion of the TMS group led to stereoselective dihydrox-
group was investigated first (Scheme 3). The allylboration ylation and subsequent differentiation of the diastereotopic
of tricarbonyl compound 13 with racemic boronate 14[9] ester groups. The TMS protecting group contributed ac-
gave, in a solvent-free reaction at room temperature, the tively through its conformative effect to the success of this
homoallylic alcohol 15 in very good yield. Dihydroxylation reaction sequence.
of alkene 15 led to a mixture of products. Chromatographic
The formation of the δ-lactam was examined next
separation gave a fraction containing stereoisomeric γ-lact- (Scheme 4). Conversion of the secondary alcohol 20 into
one 16 and another of γ-lactone 17, the unambiguous the mesylate 21 then led to the azide 22. Attempts to form
structural assignment of which was achieved by X-ray crys- the lactam ring by azide reduction (22 Ǟ 23) failed. The
tal structure analysis. Thus, the lack of differentiation of the bulky TMS group inhibits lactam formation and had to be
diastereotopic ester groups in 15 resulted in a lactone mix- removed. This was possible if the reaction leading to the
ture. This situation was completely avoided by TMS protec- azide was conducted at higher temperatures. The resulting
Eur. J. Org. Chem. 2012, 2260–2265
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2261

M. Wohlfahrt, K. Harms, U. Koert
FULL PAPER
azido alcohol 24 could be cleanly reduced to the amino es- methyl)boronate 37 with methyllithium gave the (1-chloro-
ter 25, which spontaneously cyclized to the lactam 26. ethyl)boronate 38, which upon addition of the alkenyl-
Compound 26, the model system for the bicyclic core with lithium reagent 31 led to the chiral α,γ-disubstituted (2S)-
a methyl group as the C-8 side-chain, was accessible in six allylboronate 39. The disubstituted allylboronate 40 was
steps from the vicinal tricarbonyl compound 13 in 47% prepared by using the alkenyllithium reagent 32. The enan-
yield.
tiomerically pure reagents 39 and 40 were purified by silica
gel chromatography.
Scheme 4. Strategy for lactam formation.
Synthesis of the Bicyclic Core with a Protected
C-8 Hydroxymethyl Group
To synthesize aldehyde 3, the corresponding alcohol with
a hydroxymethyl group at C-8 is a suitable precursor. The
allylboration strategy required for this task the preparation
of
an
O-protected
γ-(hydroxymethyl)allylboronate
(Scheme 5). The racemic pinacol-derived substituted allyl-
boronates 35 and 36 were prepared first. Then, the enantio-
merically pure substituted allylboronates 39 and 40 were
synthesized. 1,2-Dicyclohexylethane-1,2-diol was chosen as
chiral director because of its known high stereoselectivity
in reactions of α,γ-disubstituted allylboronates with alde-
hydes.[8,10] Methyl (Z)-β-iodoacrylate (27)[11] was converted
Scheme 5. Preparation of racemic allylboronates 35 and 36 and en-
antiomerically pure allylboronates 39 and 40.
The allylboration of the vic-tricarbonyl compound 13
into the (Z)-alkenyl iodides 29 and 30. Compound 29 is with the different racemic and enantiomerically pure α,γ-
also accessible from the iodoalkyne 28[12] by diimide re- disubstituted allylboronates prepared as described above
duction using o-nitrobenzenesulfonyl hydrazide (NBSH).[13] was the next task (Scheme 6). The reactions of the racemic
The α,γ-disubstituted allylboronates were prepared by allylboronates 35 and 36 proceeded smoothly to deliver the
Matteson’s method starting from (dichloromethyl)- homoallylic alcohols rac-41 and rac-42, respectively. The re-
boronates.[14] The required (Z)-alkenyllithium reagents 31 actions with enantiomerically pure allylboronates 39 and 40
and 32 were prepared by iodine/lithium exchange in the required longer reaction times to obtain the desired prod-
corresponding (Z)-alkenyl iodides 29 and 30, respectively, ucts 41 and 42 in more than 80% yield. The enantio-
and used directly furthering the preparation of the allyl- selectivity of the allylboration reaction (95% ee for 41, 92%
boronates. Treatment of the (dichloromethyl)boronate 33[15] ee for 42) was determined by 19F NMR analysis of the
with methyllithium gave the (1-chloroethyl)boronate 34, Mosher ester derived from the hydroxy lactones 45 and 46.
which upon addition of the alkenyllithium reagent 31 led to The stereochemical outcome of the asymmetric allylbor-
the (racemic) α,γ-disubstituted allylboronate 35, which ation of the vicinal tricarbonyl compound 13 can be ration-
could be purified by silica gel chromatography. The disub- alized by a cyclic Zimmerman–Traxler-type transition state
stituted allylboronate 36 was prepared by using the alkenyl- TS.[8] The α stereocenter of the allylboronate acts as direc-
lithium reagent 32. The enantiomerically pure (S,S)-(di- tor by placing the methyl group in an equatorial position,
chloromethyl)boronate 37 was prepared according to the which leads, by avoidance of 1,3-allylic strain, to differentia-
method of Hoffmann et al.[8] by Sharpless asymmetric di- tion of the prochiral olefin sides and a backside attack of
hydroxylation of (E)-stilbene. Treatment of the (dichloro- the carbonyl group. Thus, tricarbonyl compounds such as
2262
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2260–2265

Total Synthesis of (+)-Awajanomycin
13 behave in asymmetric allylboration reactions in a com-
parable way to aldehydes.
Scheme 7. Formation of lactams rac-49 and 53.
Attachment of the C-8 Side-Chain and Final
Steps
Scheme 6. Stereoselective allylboration reactions with racemic
boronates 35 and 36 and enantiomerically pure boronates 39 and
40, and subsequent dihydroxylation/lactonization.
The final part of the synthesis required the introduction
of the C-8 side-chain. The deprotection of the PMB ether
in compound rac-49 was unexpectedly problematic. Neither
oxidative (DDQ) nor hydrogenolytic (Pd/C) conditions gave
satisfactory or reproducible yields. One cause of the prob-
lem could have been the high polarity and low solubility of
the primary alcohol in organic media. To avoid the isolation
of the free alcohol, the synthetic plan was revised to use the
TES ether instead of the PMB ether. A primary TES ether
can be oxidized directly to the aldehyde by avoiding the
isolation of the alcohol.[17] Oxidation of the primary TES
ether 53 under Swern conditions gave the intermediate alde-
hyde 54, which was directly converted with the ylene 56 into
enone 58 (Scheme 8). The tertiary hydroxy group in com-
pound 53 was converted at the aldehyde stage into the S,O-
acetal, which was cleaved before purification of enone 57.
Enone 58, the product of this Swern/Wittig sequence was
isolated in 76% yield. The ylene 56 was accessible by alkyl-
ation of ylene 55.[18]
Homoallylic alcohols 41 and 42 were both converted into
the corresponding TMS ethers 43 and 44. Stereoselective
dihydroxylation and subsequent differentiation of the dia-
stereotopic ester groups resulted in the formation of the hy-
droxy lactones 45 and 46.
The conversion of hydroxy lactone 45 into the bicyclic
lactam 49 was possible by the route developed for lactam
26. This reaction sequence was performed on the racemic
lactone 45 (Scheme 7) and proceeded via the mesylate rac-
47. The azide rac-48 was obtained, which led upon azide
reduction to the corresponding amino ester. Cyclization to
the lactam rac-49 required activation by isopropylmagne-
sium chloride. The bicyclic structure of compound rac-49
was unambiguously assigned by single-crystal X-ray analy-
sis.[6]
The enantiomerically pure hydroxy lactone 46 was the
The final task in the synthesis required the stereoselective
starting point for the reaction sequence leading to lactam reduction of the ketone. A substrate-controlled reduction of
53 (Scheme 7). Transformation of the secondary alcohol compound 58 with NaBH(OAc)3 showed no diastereoselec-
into the azide under Mitsunobu conditions[16] gave com- tivity. Next, a CBS reduction[19] was examined, which gave
pound 50. After deprotection of the tertiary alcohol (50 Ǟ unsatisfactory diastereoselectivity (2:1) in the presence of
51 Ǟ 52), azide reduction resulted in the spontaneous for- the free tertiary alcohol. An optimal stereoselective CBS
mation of the bicyclic lactam 53.
reduction (Ͼ95:5) was possible when the TMS ether 59 was
Eur. J. Org. Chem. 2012, 2260–2265
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2263

M. Wohlfahrt, K. Harms, U. Koert
FULL PAPER
Experimental Section
Representative Allylboration of a vic-Tricarbonyl Compound (40 +
13 Ǟ 42): Boronic ester 40 (2.76 g, 3.65 mmol) was added to diethyl
mesoxolate (13; 1.4 mL, 9.13 mmol), and the mixture was stirred
in a sealed tube at 20 °C for 9 d. The reaction mixture was sub-
jected to chromatographic purification (silica gel, 150 g; pentane/
acetone, 20:1) to yield olefin 42 (2.02 g, 5.40 mmol, 85%) as a col-
orless oil. TLC (pentane/acetone, 20:1): Rf = 0.31. 1H NMR
(300 MHz, CDCl3): δ = 5.64 (dq, J = 15.3, 6.4 Hz, 1 H, 4Ј-CH),
5.35 (ddd, J = 15.4, 9.4, 1.6 Hz, 1 H, 3Ј-CH), 4.36–4.11 (m, 5 H,
2 OCH2CH3, 2-OH), 3.73 (dd, J = 10.0, 7.6 Hz, 1 H, 1Ј-CHaHb),
3.61 (dd, J = 9.9, 5.8 Hz, 1 H, 1Ј-CHaHb), 3.24 (ddd, J = 9.2, 7.5,
5.9 Hz, 1 H, 2Ј-CH), 1.63 (dd, J = 6.4, 1.5 Hz, 3 H, 4Ј-CH3), 1.27
(t, J = 7.2 Hz, 3 H, OCH2CH3), 1.24 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 0.92 [t, J = 7.8 Hz, 9 H, Si(CH2CH3)3], 0.56 [q, J =
7.9 Hz, 6 H, Si(CH2CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ =
170.3 and 170.0 (CO), 130.6 (3Ј-CH), 126.0 (4Ј-CH), 80.8 (2-Cq),
63.2 (1Ј-CH2), 62.3 and 62.3 (2 C, 2 OCH2CH3), 49.7 (2Ј-CH), 18.2
(4Ј-CH3), 14.2 and 14.1 (2 C, 2 OCH2CH3), 6.8 [3 C, Si(CH2-
CH ) ], 4.3 [3 C, Si(CH CH ) ] ppm. FTIR (neat): ν = 3496 (br.
˜
3 3
2
3 3
w), 2955 (w), 2912 (w), 2877 (w), 1738 (s), 1461 (w), 1414 (w), 1368
(w), 1299 (m), 1248 (m), 1213 (s), 1150 (s), 1099 (s), 1007 (m), 968
(m), 923 (m), 863 (w), 818 (m), 794 (m), 725 (s), 668 (w), 448 (w)
cm–1. HRMS (ESI): calcd. for C18H34O6SiNa [M + Na]+ 397.2017;
found 397.2008. Specific rotations (c = 1.02, CHCl3, T = 22 °C):
[α]D = –27.7, [α]578 = –28.8, [α]546 = –32.9, [α]436 = –59.0, [α]365
=
–97.4.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details and spectroscopic characterizations
of all new compounds.
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft
(KO 1349/17-1) and the Stiftung der Deutschen Wirtschaft (fellow-
ship to M. W.) are gratefully acknowledged.
Scheme 8. Attachment of the C-8 side-chain and completion of the
synthesis.
[1] J.-H. Jang, K. Kanoh, K. Adachi, Y. Shizuri, J. Nat. Prod.
2006, 69, 1358–1360.
[2] R. Fu, J. Chen, L. C. Guo, J. L. Ye, Y. P. Ruan, P. Q. Huang,
Org. Lett. 2009, 11, 5242–5245.
[3] R. Fu, J. L. Ye, X.-J. Dai, Y. P. Ruan, P. Q. Huang, J. Org.
Chem. 2010, 75, 4230–4234.
[4] K. Hiroya, K. Kawamoto, K. Inamoto, T. Sakamoto, T. Doi,
Tetrahedron Lett. 2009, 50, 2115–2118.
used as the starting material (Scheme 8). After TMS depro-
tection, the target compound (+)-awajanomycin (1) was ob-
tained. The spectral properties and optical rotation of syn-
thetic (+)-awajanomycin (1) were identical to those reported
for the natural product.[1]
[5] D. R. Pritchard, J. D. Wilden, Tetrahedron Lett. 2010, 51,
1819–1821.
[6] a) M. Wohlfahrt, K. Harms, U. Koert, Angew. Chem. 2011,
123, 8554–8556; Angew. Chem. Int. Ed. 2011, 50, 8404–8406;
b) M. Wohlfahrt, K. Harms, U. Koert, Angew. Chem. 2011,
123, 10945; Angew. Chem. Int. Ed. 2011, 50, 10742.
[7] H. Lachance, D. G. Hall, Org. React. 2008, 73, 1–608.
Conclusions
An efficient, versatile, and enantioselective route to the
natural product (+)-awajanomycin (1) has been developed. [8] R. W. Hoffmann, K. Ditrich, G. Köster, R. Stürmer, Chem.
[22.5% over 10 steps (from 13) compared with 3.8% over
Ber. 1989, 122, 1783–1789.
[9] M. W. Andersen, B. Hildebrandt, G. Köster, R. W. Hoffmann,
13 steps in ref.[3]]. The key steps in this procedure are the
Chem. Ber. 1989, 122, 1777–1782.
asymmetric allylboration of a vic-tricarbonyl compound, a
[10] W. C. Hiscox, D. S. Matteson, J. Org. Chem. 1996, 61, 8315–
substrate-controlled alkene dihydroxylation with subse-
quent differentiation of the diastereotopic ester groups, and
a catalyst-controlled reduction of an enone. The crucial role
of the silyl protecting group on the tertiary alcohol in
achieving the introduction of three out of the five stereocen-
ters is noteworthy.
8316.
[11] a) Z. Li, X. Lu, S. Ma, J. Org. Chem. 1992, 57, 709–713; b) E.
Piers, T. Wong, P. D. Coish, C. Rogers, Can. J. Chem. 1994, 72,
1816–1819.
[12] K.-S. Masters, B. L. Flynn, J. Org. Chem. 2008, 73, 8081–8084.
[13] A. G. Myers, B. Zheng, M. Movassaghi, J. Org. Chem. 1997,
62, 7507.
2264
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2260–2265

Total Synthesis of (+)-Awajanomycin
[14] D. S. Matteson, Acc. Chem. Res. 1988, 21, 294–300.
[15] P. G. M. Wuts, P. A. Thompson, J. Organomet. Chem. 1982,
234, 137–141.
[16] a) P.-O. Johansson, Y. Chen, A. K. Belfrage, M. J. Blackman,
I. Kvarnström, K. Jansson, L. Vrang, E. Hamelink, A.
Hallberg, A. Rosenquist, B. Samuelsson, J. Med. Chem. 2004,
47, 3353–3366; b) K. Ninomiya, T. Shioiri, S. Yamada, Tetrahe-
dron 1974, 30, 2151–2157.
[17]
[18]
A. Rodriguez, M. Nomen, B. W. Spur, J. J. Godfroid, Tetrahe-
dron Lett. 1999, 40, 5161–5164.
M. P. Cooke Jr., J. Org. Chem. 1973, 38, 4082–4084.
[19] E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem. Soc. 1987,
109, 5551–5553.
Received: January 17, 2012
Published Online: February 29, 2012
Eur. J. Org. Chem. 2012, 2260–2265
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2265