Synthetic study of aquayamycin. Part 2: Synthesis of the AB ring fragment

Article abstract of DOI:10.1016/S0040-4039(00)01479-9

A highly oxygen-functionalized cyclohexenone 2, the AB ring fragment for the aquayamycin synthesis, was efficiently synthesized via stereoselective addition of allylzinc bromide to ketone 3a which, in turn, was available from the optically pure cyclohexane 1,2,3-triol derivative 5. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01479-9

TETRAHEDRON
LETTERS
8389
Pergamon
Tetrahedron Letters 41 (2000) 8389–8392
Synthetic study of aquayamycin. Part 2: Synthesis of
the AB ring fragment
Hiroki Yamaguchi, Tadayoshi Konegawa, Mitsujiro Tanabe, Takeshi Nakamura,
Takashi Matsumoto and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST,
Japan Science and Technology Corporation (JST), O-okayama, Tokyo 152-8551, Japan
Received 3 August 2000; accepted 28 August 2000
Abstract
A highly oxygen-functionalized cyclohexenone 2, the AB ring fragment for the aquayamycin synthesis,
was efficiently synthesized via stereoselective addition of allylzinc bromide to ketone 3a which, in turn,
was available from the optically pure cyclohexane 1,2,3-triol derivative 5. © 2000 Elsevier Science Ltd. All
rights reserved.
In the preceding paper,1a we described an access to the left-half fragment for the synthesis of
aquayamycin (1).2 The present paper describes the synthesis of the corresponding right-half (AB
ring) fragment, i.e. the cyclohexenone 2 with many oxygen functions.
1
O
OH
R1O
OR
O
O
–
Me
OR2
HO
A
12b
12
OTBDPS
12b
1
OH
D
C
B
O
O
O
HO
HO
OBn
O
5
9
5
O
7
R3
HO
O
2
3
left half
right half
the right-half (AB ring)
Aquayamycin (1)
R4O
OH
4: R4 = R5 = Ac
Candida
antarctica
lipase
5: R4 = Ac, R5 = H
OR5
(94%, >99% e.e.)
(ref. 3)
Figure 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01479-9

8390
The key to the synthesis of 2 was the stereocontrolled construction of the chiral tertiary
alcohols. As shown retrosynthetically in Fig. 1, we envisioned the ketone 3 as the precursor to
2. We hoped that a suitable choice of the protecting groups (R1–R3) would allow the
stereoselective addition of a b-alkoxyethyl anion equivalent. Furthermore, the ketone 3 could be
easily obtained from the diol 5, which is available in an optically pure form by the enzymatic
hydrolysis of the meso-acetate 4.3
Along these lines, the methyl ketones 3a–f were synthesized from the diol 5.3 Scheme 1 shows
the synthesis of the p-methoxybenzyl (MPM) ether 3a.4
OMPM
AcO
OR
OR
3b: R = Bn
3c: R = TBS
3d: R = Bz
3e: R = BOM
3f : R = H
d,e
a,b
OH
OH
O
O
O
O
O
O
O
O
5
6: R = H
7: R = MPM
3a
c
Scheme 1. (a) CH2ꢀC(OMe)Me, TsOH, benzene, 30 min. (b) K2CO3, MeOH, 45 min (97%, two steps). (c) MPMCl,
NaH, DMF, 0°C, 2 h (92%). (d) H2, quinoline, Lindlar’s catalyst, hexane, 70 min (97%). (e) Hg(OAc)2, MeOH, 1 h;
then PdCl2, LiCl, CuCl2, 30 min (80%)
Protection of the vicinal diol in 5 (>99% ee) as an acetonide followed by deacetylation gave
the alcohol 6, which was then protected as a p-methoxybenzyl ether. The stereochemical
integrity of this three-step conversion was proven by the HPLC analysis (no decrease in the ee).5
After semi-hydrogenation of the triple bond with Lindlar’s catalyst, oxidation of the resulting
olefin to the methyl ketone was examined. Unfortunately, under the conventional conditions of
Wacker-type oxidation (PdCl2, CuCl, O2/DMF, H2O, 25°C), the positional selectivity of the
carbonyl formation was not satisfactory to give a 5.7/1-mixture of the ketone 3a and the
corresponding aldehyde (92% combined yield). After considerable experimentation, the desired
ketone 3a was selectively obtained by the Hg2+-mediated procedure.6 The other ketones 3b–e
with different protecting groups (R) were similarly synthesized from the alcohol 6. The ketone
3f was synthesized by the hydrogenolysis of 3b.4
With these ketones in hand, their reaction with several allylmetal reagents was examined.
Among them, allylmagnesium chloride (Et2O, −78°C) or allylzinc bromide (THF, −78°C) turned
out to react in high yields and to give uniformly the (S)-alcohol 8 as the major isomer (Table
1).4,7 Further optimization of the reaction of allylzinc bromide with 3a, 3b and 3d, revealed that
Et2O was the solvent of choice. The highest selectivity (24:1) was achieved in the reaction of 3a
in Et2O (Table 2).
A possible rationale for the high stereoselectivity is the involvement of the six-membered zinc
chelate as A, where a methyl on the acetal hinders the top-face approach of the nucleophile as
shown. Indeed, much poorer selectivities (2.1:1 in Et2O, 1.6:1 in THF) resulted for the same
reaction with the ketone 3g without two methyl groups on the acetal center.
OMPM
H
O
CH3
O
O
O
O
O
Zn2+
MPMO
3g
A

8391
Table 1
conditions A
MgCl
OR
OR
OR
S
R
/Et2O, –78 °C
O
O
O
O
O
O
O
OH
OH
conditions B
ZnBr
/THF, –78 °C
9a–f
8a–f
3a–f
(a: MPM, b: Bn, c: TBDMS, d: Bz, e: BOM, f: H)
Ketone 3
Conditions A
Conditions B
8:9 (yield%)a
8:9 (yield%)a
R=MPM (3a)
R=Bn (3b)
R=TBS (3c)
R=Bz (3d)
R=BOM (3e)
R=H (3f)
3.9:1 (77)
3.8:1 (81)
1.5:1 (85)
3.2:1 (89)
2.4:1 (85)
1.3:1 (68)
8.0:1 (89)
8.5:1 (77)
5.3:1 (77)
9.6:1 (91)
3.6:1 (87)
3.8:1 (87)
1
a The stereoselectivities were determined by H NMR analyses (400 MHz).
Table 2
OR
OR
OR
ZnBr
O
O
O
O
O
O
O
OH
OH
solvent, –78 °C
9a,b,d
8a,b,d
3a,b,d
(a: MPM, b: Bn, d: Bz)
Solvent
R=MPM (3a)
R=Bn (3b)
R=Bz (3d)
8a:9aa (yield%)
8b:9ba (yield%)
8d:9da (yield%)
THF
8.0:1 (89)
4.0:1 (97)
10:1 (95)
24:1 (89)
8.5:1 (77)
4.5:1 (86)
7.7:1 (87)
17:1 (84)
9.6:1 (91)
5.2:1 (97)
6.3:1 (95)
15:1 (91)
CH2Cl2
Toluene
Et2O
1
a The stereoselectivities were determined by H NMR analyses (400 MHz).
The alcohol 8a was converted to the compound 10 in four steps: (1) protection of the tertiary
alcohol, (2) ozonolysis of the olefin followed by reduction with NaBH4,8 (3) silylation and (4)
selective removal of the MPM group. Oxidation of 10 followed by dehydrogenation of the
resulting ketone via the enol allyl carbonate under the palladium-promoted conditions furnished
the enone 29 (Scheme 2).

8392
OH
O
OTBDPS
OTBDPS
e–g
a–d
8a
O
O
O
O
OBn
OBn
2
10
Scheme 2. (a) BnBr, KH, cat. (n-Bu)4NI, DMF, 0°C, 1.5 h (98%). (b) O3, MeOH, −78°C; then NaBH4, 0°C, 1 h
(78%). (c) TBDPSCl, imidazole, DMF, 25 min (98%). (d) DDQ, CH2Cl2, H2O, 0°C, 30 min (98%). (e) (COCl)2,
DMSO, Et3N, CH2Cl2, −78“0°C, 50 min (94%). (f) KHMDS, THF, −78“−40°C, 30 min; then
CH2ꢀCHCH2OCOCl, −78°C (quant.). (g) Pd(OAc)2, MeCN, 15 h (82%)
In summary, the cyclohexenone 2, the key intermediate of the aquayamycin synthesis, was
efficiently synthesized from the optically pure diol 5 in a stereoselective manner. The total
synthesis of aquayamycin (1) will be described in the following paper.1b
Acknowledgements
Financial support from the Nissan Science Foundation is gratefully acknowledged.
References
1. (a) Matsumoto, T.; Yamaguchi, H.; Hamura, T.; Tanabe, M.; Kuriyama, Y.; Suzuki, K. Tetrahedron Lett. 2000,
41, 8383. (b) Matsumoto, T.; Yamaguchi, H.; Tanabe, M.; Yasui, Y.; Suzuki, K. Tetrahedron Lett. 2000, 41, 8393.
2. (a) Sezaki, M.; Hara, T.; Ayukawa, S.; Takeuchi, T.; Okami, Y.; Hamada, M.; Nagatsu, T.; Umezawa, H. J.
Antibiot. 1968, 21, 91. Nagatsu, T.; Ayukawa, S.; Umezawa, H. J. Antibiot. 1968, 21, 91. (b) Sezaki, M.; Kondo,
S.; Maeda, K.; Umezawa, H.; Ohno, M. Tetrahedron 1970, 26, 5171. Also see, (c) Imamura, N.; Kakinuma, K.;
Ikekawa, N.; Tanaka, H.; Omura, S. Chem. Pharm. Bull. 1981, 29, 1788.
3. Matsumoto, T.; Konegawa, T.; Yamaguchi, H.; Nakamura, T.; Sugai, T.; Suzuki, K., submitted for publication.
4. The syntheses of ketones 3b–f, and the reactions of ketones 3a–f with other allylmetal reagents will be detailed in
the full paper.
5. Column: CHIRALCEL OD-H (Daicel, Co), 4.6×250 mm; Eluent: hexane-2-propanol (97:3), 0.35 mL/min;
retention time: 14.9 min for 7, 15.5 min for ent-7.
6. Rodeheaver, G. T.; Hunt, D. F. J. Chem. Soc., Chem. Commun. 1971, 818.
7. The configuration of the newly formed chiral center was eventually confirmed by applying each diastereomer to
the synthesis of aquayamycin (1) (Ref. 1b). The stereostructures of the adducts from 3b–3f were determined by
correlation to the compound 8a.
8. The diastereomers were easily separated by silica-gel chromatography at this stage.
9. Shimizu, I.; Tsuji, J. J. Am. Chem. Soc. 1982, 104, 5844.
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.