Asymmetric total synthesis and structural elucidation of NFAT-68

Article abstract of DOI:10.1021/ol102574d

Total synthesis of NFAT-68 (7) has been achieved and its relative stereochemistry has been determined. A key step thereof is the utilization of the chelation-controlled vinylogous Mukaiyama aldol reaction (VMAR) to stereoselectively synthesize the syn-ald

Full text of DOI:10.1021/ol102574d

ORGANIC
LETTERS
2011
Vol. 13, No. 1
74-77
Asymmetric Total Synthesis and
Structural Elucidation of NFAT-68
Lin Wang,† Yumeng Xi,† Shouliang Yang,† Rong Zhu,† Yufan Liang,†
Jiahua Chen,*,† and Zhen Yang*,†,‡
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education and Beijing National Laboratory for Molecular Science (BNLMS), College
of Chemistry, Peking UniVersity, Beijing 10087, China, and Laboratory of Chemical
Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School
of Peking UniVersity, Shenzhen 518055, China
jhchen@pku.edu.cn; zyang@pku.edu.cn
Received October 23, 2010
ABSTRACT
Total synthesis of NFAT-68 (7) has been achieved and its relative stereochemistry has been determined. A key step thereof is the utilization
of the chelation-controlled vinylogous Mukaiyama aldol reaction (VMAR) to stereoselectively synthesize the syn-aldol product 8. This developed
chemistry is anticipated to have wider application in total syntheses of many other natural products.
Developing efficient strategies to access optically pure
compounds is at the forefront of synthetic organic chemistry.
The Evans-aldol reaction has been regarded as one of the
premier methods to achieve that goal.1 Many efforts were
observed in designing an extension of the Evans-aldol
reaction.2 Among those, Evans’ chiral auxiliary derived
vinylogous Mukaiyama aldol reaction (VMAR), which was
developed by Kobayashi and co-workers,3 turned out to be
able to stereoselectively construct δ-hydroxyl-R,γ-dimethyl-
R,ꢀ-unsaturated units. The latter are seen as common
substructures in many natural products as well as important
synthetic intermediates.4
Recently, our group has been devoted to undertaking the
diversity-oriented synthesis of maytansinoids, a family of
19-membered macrolides with potent antimitotic activity, by
way of disrupting microtubule assembly.5 We desired to
identify an efficient way to generate structurely diverse
δ-hydroxyl-R,γ-dimethyl-R,ꢀ-unsaturated units via the VMAR.
In this context, our experiments revealed that the stereo-
chemistry of VMAR adducts could be regulated by either
adding additives6 or changing the chelation state of sub-
† College of Chemistry, Peking University.
‡ Shenzhen Graduate School of Peking University.
(3) (a) Shirokawa, S.-I.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
13604. (b) Shinoyama, M.; Shirokawa, S.-i.; Nakazaki, A.; Kobayashi, S.
Org. Lett. 2009, 11, 1277. (c) Nakamura, T.; Shirokawa, S. I.; Hosokawa,
S.; Nakazawk, A.; Kobayashi, S. Org. Lett. 2006, 8, 677. (d) Yamaoka,
M.; Nakazaki, A.; Kobayashi, S. Tetrahedron Lett. 2009, 50, 3849. (e)
Yamaoka, M.; Fukatsu, Y.; Nakazaki, A.; Kobayashi, S. Tetrahedron Lett.
2009, 50, 6764. (f) Yamaoka, M.; Nakazaki, C.; Kobayashi, S. Tetrahedron
Lett. 2010, 51, 287.
(1) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982,
13, 1. (b) Heathcock, C. H. In ComprehensiVe Carbonion Chemistry; Buncel,
E., Durst, T., Eds.; Elsevier: New York, 1984; Vol. 5B, p 177. (c) Kim,
B. M.; Williams, S. F.; Masumune, S. In ComprehensiVe Organic Synthesis;
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1991; Vol. 2, Chapter 1.7, p 239.
(2) Carreira, E. M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Chapter 8B2.
10.1021/ol102574d  2011 American Chemical Society
Published on Web 12/01/2010

strates.7 We further found that by incorporating a chelation
element at the ortho-position of benzaldehydes, the syn-aldol
adduct 3 could be obtained as the major product through
transition state A (Scheme 1). In constrast, according to the
In this paper, we report our recent progress about the
asymmetric total synthesis and structure elucidation of NFAT-
68 (7 in Figure 1) via the chelation-controlled VMAR as a key
step.
Scheme 1. Vinylogous Mukaiyama Aldol Reaction
Figure 1. Retrosynthetic analysis.
NFAT-68 (7 in Figure 1), a polyketide from the fermenta-
tion broth and mycelia of two Streptomyces sp. was
discovered with NFAT-/lacZ ꢀ-galactosidase reporter gene
construct assay.8
The primary screening indicates that NFAT-68 is a potent
immunosuppressant with the IC50 concentrations less than 1
µg/mL, and that no apparent toxicity is observed at this
concentration. Therefore, NFAT-68 may become a useful
probe for studying signaling pathways of early T cell
activation.
report by Kobayashi and co-workers,3a when benzaldehyde
was employed as the substrate, the anti-aldol adduct 6 would
be formed predominantly through transition state B (Scheme
1).
The structure of NFAT-68 (7) was assigned based on
analyzing its NMR spectra. However, neither its stereochem-
istry nor optical rotation was reported in the original article.8
Hence in the meantime of pursuing the total synthesis of
NFAT-68 (7), our other mission is to validate its structure.
To resolve the structural issue of NFAT-68, we initially
assumed that the stereochemistry at C6 and C7 in NFAT-68
is a syn-relationship. We therefore expected that our recently
developed chelation-controlled VMAR could potentially be
applied to the synthesis of the δ-hydroxyl-R,γ-dimethyl-R,ꢀ-
unsaturated unite in natural product NFAT-68. Our retrosyn-
thetic analysis of NFAT-68 is outlined in Figure 1. We
envisaged that NFAT-68 could be derived from intermediate
8, which in turn could be generated from 1 and 9 via the
chelation-controlled VMAR (Figure 1).
Our synthesis began with investigating the chelation effect
of substrate on the diastereoselectivity of the aldol adducts
of VMARs. To this end, vinylketene silyl N,O-acetal 17 was
reacted with 2-methoxybenzaldehyde 2 under the conditions
listed in Scheme 2. Delightfully, adducts 10 and 11 were
obtained in 91% combined yield, and the ratio of 10/11 is
1/20 (Scheme 2).
(4) (a) O’Hagan, D. The Polyketide Metabolites; Ellis Horwood:
Chichester, U.K., 1991. (b) O’Hagan, D. Nat. Prod. Rep. 1995, 12, 1. (c)
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E.; Asai, M.; Ootsu, K.; Tanida, S.; Kozai, Y.; Hasegawa, T.; Kishi, T.;
Sugino, Y.; Yoneda, M. Nature (London) 1977, 270, 721. (e) Tanaka, H.;
Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Hoto, T.; Hashimoto,
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Naganawa, H.; Nakae, K.; Imoto, M.; Shiro, M.; Matsumura, K.; Watanabe,
H.; Kitahara, T. J. Antibiot. 2002, 55, 442. (h) Hong, Y.-S.; Lee, D.; Kim,
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J. J. J. Am. Chem. Soc. 2004, 126, 11142. (i) Aldrich, C. C.; Venkatraman,
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Hosokawa, S.; Ogura, T.; Togashi, H.; Tatsuta, K. Tetrahedron Lett. 2005,
46, 333. (k) Hosokawa, S.; Yokota, S.; Imamura, K.; Suzuki, Y.;
Kawarasaki, M.; Tatsuta, K. Tetrahedron Lett. 2006, 47, 5415. (l) Hosokawa,
S.; Kuroda, S.; Imamura, K.; Tatsuta, K. Tetrahedron Lett. 2006, 47, 6183.
(m) Andrus, M. B.; Wong, Y.; Liu, J.; Beebe, K.; Neckers, L. M.
Tetrahedron Lett. 2009, 50, 6701. (n) Hosokawa, S.; Matsushita, K.;
Tokimatsu, S.; Toriumi, T.; Suzuki, Y.; Tatsuta, K. Tetrahedron Lett. 2010,
51, 5532.
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Dailey, R. G., Jr.; Komoda, Y.; Nagao, Y. J. Am. Chem. Soc. 1975, 97,
5294. (b) Sneden, A. T.; Beemsterboer, G. L. J. Nat. Prod. 1982, 45, 624.
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The stereochemistry for 11 was established by both NMR
and X-ray single crystal analysis. These studies demonstrate
(6) Liang, Y.; Wang, L.; Zhu, R.; Deng, L.; Yang, Y.; Quan, J.; Chen,
J.; Yang, Z. AdV. Synth. Catal. 2010, 352, 2387.
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Org. Lett., Vol. 13, No. 1, 2011
75

Scheme 2
.
Syntheses of Compounds 10, 11, and 13
Table 1. Profile of VMAR
that the chelation-controlled VMAR is an effective method
to enable the diastereoselective synthesis of syn-aldol adducts.
To profile the scope of the chelation-controlled VMAR,
several ortho-substituted aryl aldehydes were reacted with
vinylketene silyl N,O-acetal 1, and their coupling results are
listed in Table 1. The stereochemistry of the coupling
products was first analyzed by modified Mosher method,9
then those compounds were converted to their cooresponding
acetonides to further verify their sterochemistry by way of
1D-NOE study (Scheme 2).
We derive the following observations from Table 1: (1)
both benzyloxy and methoxy groups are effective chelation
elements in this chelation-controlled VMARs to give the syn-
aldol adducts; (2) adding both electron-donating and electron-
withdrawing groups to the aromatic ring of the R-substituted
aryl aldehyde affords the syn-aldol adducts in high yield and
good diastereoselectivity; (3) benzo[d][1,3]dioxane-4-car-
baldehyde (entry 4) does not give the expected high syn-
selectivity aldol adduct, presumbly because its rigid 1,3-
dioxane ring prevents formation of the chelation complex A
(Scheme 1); (4) the ester, nitro group, and halogens (entries
5-8) are not chelation elements in this chelation-controlled
VMAR, and no significant diaselectivity is observed in their
VMARs; and (5) phenol cannot be utilized as a chelation
element, as 2-hydroxybenzaldehyde (entry 9) does not give
any aldol adduct under the conditions listed in Table 1. It is
a Reactions were conducted with silylketene (60 mg, 1.0 equiv), aldehyde
(2.0 equiv), and TiCl4 (1.0 equiv). b Diastereo selectivity was detemined
by H NMR (300 or 400 MHz).
1
worthwhile mentioning that in the event of replacing MeO
or BnO with other protecting groups, such as AcO, MOMO,
and BOMO, the desired VMAR adducts could not form at
low temperature, and the starting materials were decomposed
when the reactions were carried out at room temperature,
presumably because of the existence of TiCl4.
Upon completion of the development of a method for
stereoselective synthesis of syn-aldol adducts via VMAR,
we then applied this methodology to the total synthesis of
NFAT-68 (7). To this end, aldehyde 9 (Scheme 3) was
reacted with chiral vinylketene silyl N,O-acetal 1 to give aldol
(9) For review of the Mosher method, see: Seco, J. M.; Quin˜oa´, E.;
Riguera, R. Tetrahedron: Asymmetry 2001, 12, 2915.
76
Org. Lett., Vol. 13, No. 1, 2011

1
obtained in 50% yield. The data of H NMR and 13C NMR
were identical with the published data,8 indicating that the
relative stereochemistry of natural product NFAT-68 (7) is the
syn-relationship at C6 and C7. The optical rotation of the
Scheme 3. Total Synthesis of NFAT-68
synthesized NFAT-68 is -65.5 ([R]20 0.5, CHCl3).
D
To elucidate the absolute stereochemistry of NFAT-68 (7),
the enantiomer of NFAT-68 (7) was made following the
same chemistry shown in Scheme 3, the synthetic details of
which are provided in the Supporting Information. To further
determine the absolute stereochemistry of NFAT-68, we will
conduct biological testing of the both synthesized enanti-
omers of NFAT-68. We wish such an effort might help us
to decide the absolute stereochemistry of the naturally
occurring NFAT-68.
In summary, our group has developed a concise synthetic
strategy to construct the scaffold of NFAT-68 (7). Both
enantiomers were asymmetrically synthesized via the che-
lation-controlled VMAR as a key step. This developed
chemistry is anticipated to have wider application in the total
synthesis of many other natural products.
Acknowledgment. We thank Dr. Jill Hochlowski and Dr.
James McAlpine for their help in providing the original
spectra of NFAT-68. We also thank Dr. N. D. Wang (PKU)
and Dr. W. X. Zhang (PKU) for X-ray crystallographic
assistance. This work has been supported by the National
Science and Technology Major Project “Development of
Novel Vaccines, Antibodies and Therapeutic Agents against
Influenza Infection” (2009ZX10004-016), the National
Science and Technology Major Project “Development of
key technology for the combinatorial synthesis of privi-
leged scaffolds” (2009ZX09501-012), the National Science
Foundation of China (20821062, 20832003, and 20902007),
and the Shenzhen Basic Research Program (No.
JC200903160352A).
adducts 17 and 8 in 85% combined yield, and the ratio of 17/8
was ca. 1:20. 8 was then subjected to the action of protection-
reduction protocols, as shown in Scheme 3, which resulted in
aldehyde 18 in 73% yield in two steps. Aldehyde 18 was further
reacted with Ph3PdCHCOOMe in toluene at 100 °C,10 afford-
ing ester 19 in 95% yield. To complete the total synthesis, a
sequential reduction11-acetylation event on 19 delivered 20 in
74% yield in two steps. Thus, after global deprotection by
treatment of 20 with AlCl3/t-BuSH, the proposed NFAT-68 was
Supporting Information Available: Details of experi-
mental procedures and results. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL102574D
(11) (a) Lalancette, J. M., Jr.; Freche, A.; Birndle, J. R.; Laliberte, M.
Synthesis 1972, 527. (b) Lalancette, J. M., Jr.; Freche, A.; Monteux, R.
Can. J. Chem. 1968, 46, 2754.
(10) House, H. O.; Jones, V. K.; Frank, G. A. J. Org. Chem. 1964, 29,
3327.
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