Total synthesis of (+)-tubelactomicin A. 2. Synthesis of the upper-half segment and completion of the total synthesis

Article abstract of DOI:10.1021/ol050763x

(Chemical Equation Presented) We have completed the total synthesis of natural (+)-tubelactomicin A (1), a 16-membered macrolide antibiotic. This Letter presents a highly efficient synthesis of the upper-half segment (C14-C24) and the completion of the to

Full text of DOI:10.1021/ol050763x

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2265-2267
Total Synthesis of (+)-Tubelactomicin
A. 2. Synthesis of the Upper-Half
Segment and Completion of the Total
Synthesis
Toru Motozaki, Kiyoto Sawamura, Akari Suzuki, Keigo Yoshida, Tatsuo Ueki,
Aiko Ohara, Ryosuke Munakata, Ken-ichi Takao, and Kin-ichi Tadano*
Department of Applied Chemistry, Keio UniVersity, Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
tadano@applc.keio.ac.jp
Received April 8, 2005
ABSTRACT
We have completed the total synthesis of natural (
efficient synthesis of the upper-half segment (C14
+
)-tubelactomicin A (1), a 16-membered macrolide antibiotic. This Letter presents a highly
−C24) and the completion of the total synthesis featuring a high-yielding Stille coupling for
the connection of the upper-half and lower-half segments and Mukaiyama macrolactonization for the construction of the entire structure of 1.
The biological properties1a and structural uniqueness1b of (+)-
tubelactomicin A (1) (Scheme 1), isolated recently from the
Scheme 1. Retrosynthetic Analysis of 1
culture broth of an actinomycete strain designated MK703-
102F1, prompted us to attempt its total synthesis. Along the
retrosynthetic analysis shown in Scheme 1, we describe in
the preceding paper2 the stereoselective synthesis of the
lower-half segment (C1-C13), a highly functionalized trans-
fused octahydronaphthalene carboxylic acid 3, based on the
intramolecular Diels-Alder strategy. In this Letter, we
describe a synthesis of the upper-half (C14-C24) segment
2, an (E)-vinylstannane including an R,â-disubstituted (Z)-
acrylic acid part, and the connenction of the upper-half
segment 2 and lower-half segment 3. These two segments
(1) (a) Igarashi, M.; Hayashi, C.; Homma, Y.; Hattori, S.; Kinoshita,
N.; Hamada, M.; Takeuchi, T. J. Antibiot. 2000, 53, 1096-1101. (b)
Igarashi, M.; Nakamura H.; Naganawa, H.; Takeuchi, T. J. Antibiot. 2000,
53, 1102-1107.
(2) Motozaki, T.; Sawamura, K.; Suzuki, A.; Yoshida, K.; Ueki, T.;
Ohara, A.; Munakata, R.; Takao, K.-i.; Tadano, K.-i. Org. Lett. 2005, 7,
2261-2264.
10.1021/ol050763x CCC: $30.25
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could be connected sequentially by sp2-sp2 Stille coupling
to form a single bond between C13 and C14 and then by
intramolecular esterification at the carboxylic acid (C1) and
a hydroxyl group at C23 to form the 16-membered macro-
lactone structure, providing a ptotected form of tubelacto-
micin A. Deprotection would complete the total synthesis.
Scheme 3. Synthesis of the Upper-Half Segment (Part 2)
The synthesis of the upper-half segment 2 is outlined in
Schemes 2 and 3. Methyl (R)-lactate (4) was converted into
Scheme 2. Synthesis of the Upper-Half Segment (Part 1)
in the presence of MeOH.5,6 The resulting R-substituted
acrylic acid ester 9 was obtained as a 1:1 diastereomeric
mixture (1H NMR analysis). Treatment of the mixture 9 with
NBS and Me2S provided the (Z)-acryloyl ester 10 stereose-
lectively, which bears a bromomethyl group at the R-position,
as a result of an SN2′ substitution of a bromide ion.7 The
allylic bromide 10 was converted into the allylic alcohol 11
by hydrolysis in aqueous 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone (DMPU) under buffered conditions.8 A
two-step reduction/oxidation applied to the ester functionality
in 12, the tert-butyldimethylsilyl (TBS) ether of 11, provided
the unsaturated aldehyde 13.9
ethyl (2E,4R)-4-(tert-butyldiphenylsilyloxy)-2-pentenoate (5)
using the Roush-Masamune variant3 of Horner-Emmons
elongation. The unsaturated ester part in 5 was reduced,
providing a partially protected 1,4-pentanediol 6 by hydro-
genation, followed by diisobutylaluminum hydride (Dibal-
H) reduction. The hydroxyl group in 6 was replaced by a
cyano group via the iodo derivative, providing a hexanenitrile
derivative 7. Dibal-H reduction of 7 gave aldehyde 8, which
was subjected to a Morita-Baylis-Hillman reaction4 with
methyl acrylate and 1,4-diazabicyclo[2.2.2]octane (DABCO)
Next, the contiguous stereogenic centers at C16 and C17
were introduced by a boron-mediated syn-stereoselective
(5) Although a higher yield (92%) was realized when this reaction was
carried out in neat DABCO, the reaction was completed after 30 days at
room temperature. The coexistence of MeOH remarkably reduced the
reaction time. We confirmed that 3-hydroxyquinuclidine (neat) also
accelerates the reaction without a loss of the yield of 9.
(6) For the acceleration of the Baylis-Hillman reaction in the presence
of MeOH, see: Aggarwal, V. K.; Mereu, G. T.; Tarver, R.; McCague, R.
J. Org. Chem. 1998, 63, 7183-7189 and references therein.
(7) Hoffmann, H. M. R.; Rabe, J. J. Org. Chem. 1985, 50, 3849-3859.
(8) In place of DMPU, HMPA was also effective, although the yield of
11 was somewhat reduced. The phosphate-buffered solution was crucial to
sustain the silyl protecting group. For the effect of the polar aprotic solvents,
see: Hutchins, R. O.; Taffer, I. M. J. Org. Chem. 1983, 48, 1360-1362.
(9) In the NOE experiment of 13, a remarkable (22%) signal enhancement
of the CHO proton was observed when the â-vinyl proton was irradiated.
Thus, the geometrical structures of 11-13 were ascertained.
(3) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(4) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968,
41, 1, 2815. (b) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113,
1972; Chem. Abstr. 1972, 77, 34174q. For a recent review on this subject,
see: Basavaiah, D.; Rao, A. J.: Satyanarayana, T. Chem. ReV. 2003, 103,
811-891.
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Org. Lett., Vol. 7, No. 11, 2005

Evans aldol reaction10 using (4R)-4-benzyl-3-propionyl-2-
oxazolidinone 14.11 Protection of the hydroxyl group in the
aldol adduct 15, which was followed by the reductive
removal of the chiral auxiliary in the resulting MOM ether
16, provided 17. The synthesis of the upper-half segment 2
from 17 was achieved uneventfully by the following reaction
sequence: (1) conversion of 17 into R,R-dibromoalkene 18
via Dess-Martin oxidation12 and Corey-Fuchs dibromoole-
fination13 of the resulting aldehyde, followed by Bu4NF-
mediated simultaneous desilylation of the TBS ether and
dehydrobromination; (2) two-step oxidation of the resulting
primary hydroxyl group in the bromoalkyne 19 to the
carboxylic acid and successive esterification; (3) desilylation
of the TBDPS group in the resluting 20, which regenerates
the secondary hydroxyl group; and (4) regioselective hy-
drostannylation of 21 according to Pattenden’s proce-
dure.14
Scheme 4. Completion of the Total Synthesis
With the upper-half segment 2 in hand, we explored the
assembly of 2 and 3, taking advantage of a Stille coupling
protocol15 for the formation of the (E,E)-conjugate diene part
in 1 (Scheme 4). Treatment of 2 and 3 in the presence of
Pd2(dba)3 (5% molar equiv), AsPh3 (40% molar equiv), and
CuI (20% molar equiv) at 60 °C in DMF16 provided the
coupling product 22 in 74% yield. The HF‚pyridine-mediated
deprotection of the SEM ester, followed by the macrolac-
tonization of the resulting seco-acid 23 under Mukaiyama
conditions,17 using 2-chloro-1-methyl-pyridinium iodide 24
and Et3N in refluxing MeCN, provided 25 in excellent yield.
Finally, acidic removal of the MOM group in 25, followed
by alkaline hydrolysis, provided 1. A comparison of the
spectral data of synthetic 1 (1H, 13C NMR, IR, and TLC
behaviors in two solvent systems) with those of a natural
specimen revealed that they were identical. The optical
In conclusion, we have completed the first total synthesis
of natural (+)-tubelactomicin A (1). The total synthesis of
1 was achieved with 54 total steps and 30 or 29 linear steps
from methyl (R)-lactate (4) or from diethyl (R)-malate in
6.2% or 4.1% overall yields, respectively.
rotation of synthetic 1 [[R]20.5 +101 (c 0.63, MeOH)]
D
coincided with that of the natural product [[R]25 +103 (c
D
Acknowledgment. We thank Dr. Masayuki Igarashi
(Institute of Microbial Chemistry) for providing us with a
sample of natural 1 and copies of its spectral data (1H and
13C NMR and IR). This work was supported by Grants-in-
Aid for the 21st Century COE program “Keio LCC” from
the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
0.64, MeOH)].
(10) Evans, D. A.; Bartroli, J.; Shih, T. L J. Am. Chem. Soc. 1981, 103,
2127-2129.
(11) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77-82; 83-91.
(12) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (c) Frigerio,
M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538.
(13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
(14) Boden, C. D. J.; Pattenden, G.; Ye. T. J. Chem. Soc., Perkin Trans.
1 1996, 2417-2419.
Supporting Information Available: Experimental pro-
cedures and characterization data, including 1H and 13C NMR
spectra for all new synthetic compounds and natural tubelac-
tomicin A. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) For some reviews on Stille coupling, see: (a) Stille, J. K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508-524. (b) Espinet, P.; Echavarren, A.
E. Angew. Chem., Int. Ed. 2004, 43, 4704-4734.
(16) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J. Org. Chem. 1994, 59, 5905-5911.
(17) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49-50.
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