Formal total synthesis of N-methylmaysenine

Article abstract of DOI:10.1021/ol900384u

A novel synthetic approach for the formal total synthesis of N-methylmaysenine (1) has been developed. Key steps Involve the Ti-mediated vlnylogous Mukaiyama aldol reaction of chlral ketene silyl N,O-acetal with β-dithiane-substituted aldehyde, an aldol c

Full text of DOI:10.1021/ol900384u

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1809-1812
Formal Total Synthesis of
N-Methylmaysenine
Lin Wang, Jianxian Gong, Lujiang Deng, Zheng Xiang, Zhixing Chen,
Yuefan Wang, 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, and Laboratory of Chemical Genomics, Shenzhen Graduate School,
Peking UniVersity, Beijing 100871, China
jhchen@pku.edu.cn; zyang@pku.edu.cn
Received February 23, 2009
ABSTRACT
A novel synthetic approach for the formal total synthesis of N-methylmaysenine (1) has been developed. Key steps involve the Ti-mediated
vinylogous Mukaiyama aldol reaction of chiral ketene silyl N,O-acetal with ꢀ-dithiane-substituted aldehyde, an aldol condensation, and a
ring-closing metathesis reaction.
Maytansinoids are 19-membered macrolides (such as 1-3
in Fugure 1), and some are potent antimitotic agents, which
exert exceptional cytotoxicity by disrupting microtubule
assembly.1 The antitumor activity of maytansine has been
extensively evaluated in human clinical trials, but its clinical
advancement was hampered by its poor therapeutic index in
vivo.2 Because of maytansinoids’ distinguished biological
activity, there have been numerous efforts to devise efficient
syntheses of this type of natural product, culminating in total
syntheses by several laboratories.3 Recently, a novel type
of ansamitocinoside P-2 (4 in Figure 1) has been isolated
from Actinosynnema pretiosum spp. as a potent antitumor
agent by Shen and co-workers.4 A striking feature of 4 is
that its ring is decorated with an N-glycosyl amide side chain,
rather than the N-methyl amide found previously in most of
the maytansinoids.
Figure 1. Biologically active maytansinoids.
(1) (a) Kupchan, S. M.; Branfman, A. R.; Sneden, A. T.; Verma, A. K.;
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.
(c) Remillard, S.; Rebhum, L. I.; Howie, G. A.; Kupchan, S. M. Science
1975, 189, 1002. (d) Huang, A. B.; Lin, C. M.; Hamel, E. Biochem. Biophys.
Res. Commun. 1985, 128, 1239.
Stimulated by our interest in the unusual biological
properties of these structurally intriguing architectures and
their natural scarcity, we have initiated a synthetic program
(2) Issell, B. F.; Crooke, S. T. Cancer Treat. ReV. 1978, 5, 199.
10.1021/ol900384u CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society

exploring efficient strategies toward these natural products
themselves, as well as their structurally related analogs,
which we hope could potentially lead to improve therapeutic
profiles. In this paper we wish to describe the formal total
synthesis of N-methylmaysenine (1), and we choose 5 as
the specific synthetic target because it could act as a pivotal
parent structure allowing access to all other maytansinoids.
Accordingly, compound 1 was expected to be made via Corey’s
method from 5,3c which was expected to be derived from 6 via
RCM.5,6 Fragment 6 could be made from intermediates 7
and 8 via aldol condensation, and 8 in turn could be made
from 9 via a sequential formylation, vinylation, and
methylation.3i We also envisaged that the key intermediate
9 might be prepared from 10 and 11 by using a modified
Kobayashi’s vinylogous Mukaiyama aldol reaction.7
The scaffold of maytansinoids features a conjugated diene,
an N-substituted amide side chain, a 3-hydroxyl-[1,3]oxazi-
nan-2-one moiety, and several stereocenters that are com-
monly found in polyketides. Proven strategies to reach the
final macrolactam are based on amide bond formation by
macrolactamazation.3 However, this method could not apply
to the newly identified maytansinoids, such as 4, with
hindered substituents on the nitrogen.
Scheme 2. Synthesis of Fragment 7
In our previous communication, we reported our progress
on constructing the macrolides via diene-ene based ring-
closing metathesis (RCM),5 and this strategy was later
applied successfully by Kirschning and co-workers to
j 6
synthesize dechloroansamitocin P3.
We then devised a strategy for the synthesis of 1 via the Ti-
mediated vinylogous Mukaiyama aldol reaction of chiral ketene
silyl N,O-acetal with ꢀ-dithiane-substituted aldehyde, an aldol
condensation, and a RCM reaction as key steps (Scheme 1).
Scheme 1. Retrosynthetic Analysis
Our synthesis of fragment 7 therefore began with modifica-
tion of Mayer’s approach to make diene 18.8 To this end, methyl
vanillate 12 first underwent nitration, followed by chlorination
to afford 13 in 73% yield for two steps. Compound 13 was
then subjected to hydrogenation to convert its nitro group into
an amine, followed by its protection to give 14 in 81% overall
yield. When 14 was next treated with DIBAL-H, its ester group
was reduced to its corresponding primary alcohol accompanied
by selective removal of one Boc from substrate 14 to give 15
in 97% yield. Alcohol 15 first underwent Appel reaction9 to
afford its bromide, followed by reaction with methyl dithiane
anion to afford 16 in 47% yield for two steps. To make diene
18, compound 17 first underwent 1,3-dithiane hydrolysis,
followed by Wittig reaction to give diene 18 in 54% overall
(4) Lu, C-H.; Bai, L-Q.; Shen, Y-M. J. Antibiot. 2004, 57, 348.
(5) Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J; Yang, Z. Org. Lett.
2006, 8, 1193. and related references cited therein.
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Soc. 1978, 100, 2916. (b) Meyers, A. I.; Roland, D. M.; Comins, D. L.;
Henning, R.; Fleming, M. P.; Shimizu, K. J. Am. Chem. Soc. 1979, 101,
4732. (c) Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Lipshutz, B. J. Am.
Chem. Soc. 1980, 102, 1439. (d) Corey, E. J; Weigel, L. O.; Chamberlin,
A. C.; Cho, H.; Hua, D. H. J. Am. Chem. Soc. 1980, 102, 6613. (e) Meyers,
A. I.; Reider, P. J.; Campbell, A. L. J. Am. Chem. Soc. 1980, 102, 6597. (f)
Isobe, M.; Kitamura, M.; Goto, T. J. Am. Chem. Soc. 1982, 104, 4997. (g)
Kitamura, Isobe, M.; Ichikawa, Y.; Goto, T. J. Am. Chem. Soc. 1984, 106,
3252. (h) Kitanura, M.; Isobe, M.; Ichikawa, Y.; Goto, T. J. Org. Chem.
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(6) Meyer, A.; Bru¨njes, M.; Taft, F.; Frenzel, T.; Sasse, F.; Kirschning,
A. Org. Lett. 2007, 9, 1489.
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zaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604.
(8) Meyers, A. I.; Babiak, K. A.; Campbell, A. L.; Comins, D. L.;
Fleming, M. P.; Henning, R.; Heuschmann, M.; Hudspeth, J. P.; Kane, J. M.;
Reider, P. J.; Roland, D. M.; Shimizu, K.; Tomioka, K.; Walkup, R. D.
J. Am. Chem. Soc. 1983, 105, 5015.
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(b) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
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Org. Lett., Vol. 11, No. 8, 2009

yield. Finally, diene 18 was sequentially treated with TBSOTf
and TBAF10 to afford its primary amine 19, which subsequently
underwent acetylation11 and methylation to afford the key
intermediate 7 in 63% overall yield.
could be best performed with 1.0 equiv of TiCl4 at 25 °C,
and products 9 and 9a (in a ratio of 3.5/1) were obtained in
79%, albeit in moderate syn-selectivity (Table 1, entry 6).
With 7 in hand, we next started to explore the synthesis of
intermediate 8. Since the conversion of 9 to 8 could be achieved
easily by the known procedure,3i we therefore aimed to make
intermediate 9. Among those potential approaches surveyed,
we found that enantioselective vinylogous aldol reactions
seemed to be most efficient in providing a rapid access to our
target. We envisaged that by using aldehyde with a dithane at
its ꢀ-postion, such as 11, the Ti-chelation transition state A
should be favored, whereas the nonchelated Ti-complex B may
be preferred when excess Lewis acid was used (Figure 2); as a
result, we might switch the facial selectivity of the vinylogous
Mukayama aldol reaction.7,12
Table 1. Vinylougous Aldol Reaction between Vinylketene Silyl
N,O-Acetal 10 and Aldehyde 11
With an efficient asymmetric synthesis of fragment 9 in
hand, we next set out to advance it into fragment 8. The full
sequence of reactions leading to aldehyde 8 is shown in
Scheme 3. To make intermediate 20, substrate 9 was
subjected to a sequential treatment by first reaction with
LiBH4, followed by protection with TPS for the primary
Figure 2. Rationale for vinylogous Mukaiyama aldol reaction.
Scheme 3. Synthesis of Fragment 8
To test this scenario, we prepared vinylketene silyl N,O-
acetal 10 from commercially available (E)-2-methyl-2-
pentenoic acid and (S)-4-benzyloxazolidin-2-one and then
studied its TiCl4-mediated vinylogous Mukaiyama aldol
reaction. In the event, silyl acetal 10 was reacted with
aldehyde 11 to give its corresponding aldol adducts 9 and
9a in 40% yield with 4:5 diastereoselectivity when the
reaction was carried out at -65 °C in the presence of 2 equiv
of TiCl4. The relative as well as absolute stereochemistries
for C6(S) and C7(R) in 9 was confirmed by comparasion
with the compounds independently prepared through Evans’
classical approach (see Supporting Information for details).
The observation of product 9 in the aldol reaction
suggested that our proposed chelation complex (A in Figure
2) could have been formed. We therefore started to profile
the conditions to imporve its diastereoselectivity. After
substantial experimentation, we found that this aldol reaction
(11) (a) Bald, E.; Saigo, K.; Mukayama, T. Chem. Lett. 1975, 1163. (b)
Bai, D. L.; Bo, Y.; Zhou, Q. Tetrahedron Lett. 1990, 31, 2161
.
(12) Kobayashi and co-workers recently published in Organic Letters
their result of a switch of facial selectivity using R-heteroatom-substituted
aldehydes in the vinylogous Mukaiyama Aldol reaction, which prompts us
to disclose our research. Shinoyama, M.; Shirokawa, S.-i.; Nakazaki, A.;
Kobayashi, S. Org. Lett. 2009, 11, 1277–1280
.
Org. Lett., Vol. 11, No. 8, 2009
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alcohol and MEM for the secondary alcohol, for 64% yield
for three steps.
Scheme 4. Formal Synthesis of N-Methylmaysenine (1)
Compound 20 was first treated with n-BuLi at -78 °C
followed by formylation with DMF, and the formed aldehyde
was then reacted with vinyl Grinard reagent to give a pair
of diastereoisomers 21a and 21b in 76% overall yield. The
stereochemistries of 21a and 21b were established after 21a
was transferred to its target 5 (Scheme 4). Compound 21a
then underwent the methylation to give 22 in 90%. Thus,
upon treatment with TBAF, compound 22 was converted to
its free alcohol, which was then oxidized to its aldehyde 8
in 88% overall yield.
We now advanced to the stage for the completion of the
formal total synthesis of N-methylmaysenine (1). To this end,
amide 7 was first converted to enolide and then reacted with
aldehyde 8 to give their coupling product 6 in 85% yield
(Scheme 4). The subsequent RCM reaction13 proceeded with
almost complete trans-double bond geometry control, giving
the macrolide 23 in 85% yield as a pair of diastereoisomers.
Nevertheless, the diastereoisomers 23 could be converted to 5
as a single isomer by dehydration with Martine sulfurane,14 and
compound 5 was utilized as a key intermediate in the first total
synthesis of N-methylmaysenine (1) by Corey and co-workers
in 1980.3d
In summary, we have established herein an efficient route
to construct the core of maytansinoids, and the developed
synthetic strategy could allow us to access other maytansi-
noids as well. Our strategy features a switch of facial
selectivities of the vinylogous Mukaiyama aldol reaction by
using ꢀ-dithiane-substituted aldehyde that yielded a novel
stereochemical profile matching that found in maytansinoids
and other natural products.15 To the best of our knowledge,
this is the first example of direct construction of the adjacent
methyl-hydroxyl syn-stereochemical motif by using the
vinylogous Mukaiyama aldol reaction. Further studies di-
rected toward the total synthesis of ansamitocinoside P-2 are
in progress and will be reported in due course.
Acknowledgment. Financial support by the National
Science Foundation of China (Grants 20272003, 20325208,
20832003), and the Ministry of Education of China (985 and
211 programs, and Grant 20010001027) is gratefully ac-
knowledged. We thank Professors David Zhigang Wang,
Junmin Quan, and Chuangchuang Li (The Laboratory of
Chemical Genomics of Shenzhen Graduate School of Peking
University) for fruitful discussion.
Supporting Information Available: Experimental pro-
cedure and NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900384U
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