Our retrosynthetic analysis of integramycin (1) is out-
lined in Figure 1. We envisioned that the natural product
should be accessible by coupling of tetramic acid inter-
mediate 2, cis-octahydronaphthalene carboxaldehyde 3,
and Wittig reagent 4. Retrosynthetic disconnection of the
C(22)ÀC(23) bond in 4 gives aldehyde 5 and vinyliodide 6,
substrates for a NozakiÀHiyamaÀKishi coupling
reaction.
Scheme 2. Synthesis of the C(18)ÀC(35) Fragment 4
Our synthesis commenced with the HornerÀ
WadsworthÀEmmons reaction5 of the known β-keto
phosphonate 86 and aldehyde 9,7 followed by Pd-catalyzed
hydrogenation of the resulting olefin to give imide 10
(Scheme 1). Diastereoselective R-methylation of 10 was
performed by using LiHMDS as the base under Evans’
asymmetric alkylation conditions.8 Reductive removal of
the oxazolidinone unit by treatment of the alkylated
product with NaBH4 afforded primary alcohol 11. Finally,
protection of the primary hydroxyl group of 11 by
treatment with p-methoxybenzyl tricholoroacetimidate,
followed by removal of the TBDPS group with TBAF
and oxidation of the resulting primary alcohol under
ParihkÀDoering reaction conditions,9 provided aldehyde
5 in excellent overall yield.
Scheme 1. Synthesis of Aldehyde 5
This afforded γ-stannyl homoallylic alcohol 15 in 81%
yield and 89% ee with a 9:1 anti/syn ratio (Scheme 2).
Protection of the newly formed hydroxyl group as a
TES ether and subsequent treatment with I2 to effect
iodineÀtin exchange gave vinyliodide 6. Coupling of 5
and 6 by using the NozakiÀHiyamaÀKishi reaction12
provided an inseparable mixture of the allylic alcohols
and unreacted aldehyde 5. Treatment of this mixture with
TESOTf enabled 16 (as a mixture of diastereomers) to be
isolated in 83% yield over the two steps. Removal of the
PMB ether with DDQ generated 17, which was subse-
quently converted into the primary iodide by treatment
with I2 and PPh3. Finally, treatment of the iodide with an
excess of PPh3 in benzene at reflux furnished the phospho-
nium salt 4.
We next turned to the task of forming the spiroketal unit
stereoselectively. Cyclohexanecarboxaldehyde was used as
a model substrate in the Wittig reaction with 4, which
provided the (Z)-olefinic product in 86% yield (Scheme 3).
Removal of both TES protecting groups by treatment with
PPTS in MeOH then afforded diol 18. A ruthenium-
mediated olefin isomerization13 selectively converted the
allylic alcohol 18 to the saturated ketone 19a without
scrambling the Z olefin in the substrate. Ketone 19a was
obtained as a 1:1.3 mixture with the corresponding hemi-
acetal isomer 19b, along with 10À20% of unidentified
The enantioconvergent, enantioselective stannyl-crotyl-
boration reaction4 recently developed in our laboratory
can be used to synthesize a variety of highly enantiomeri-
cally enriched γ-stannyl homoallylic alcohols by treating
racemic allenylstannane 1210 (Scheme 2) with (Ipc)2BH
followed by addition of an aldehyde. For the present
synthesis, we employed TIPS-protected 3,5-dihydroxyben-
zaldehyde 14 (1.0 equiv) in the reaction with the highly
enantiomerically enriched crotylborane 13, formed in situ by
treating 12 (2.0 equiv) with (dIpc)2BH (1.9 equiv) at À20 °C.11
(5) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
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(6) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2162.
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79, 59.
(8) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(9) Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L.
Angew. Chem., Int. Ed. 1999, 38, 3175.
(11) Brown, H. C.; Singaram, B. J. Org. Chem. 1984, 49, 945.
(12) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.;
Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.
(13) Uma, R.; Davies, M. K.; Crevisy, C.; Gree, R. Eur. J. Org. Chem.
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(10) Marshall, J. A.; Chobanion, H. Org. Synth. 2005, 82, 43.
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