Angewandte
Chemie
Compounds generated by exchange of the 2,4-dimethoxy-
benzyl group for all of the common amine protecting groups
also met with extensive decomposition upon treatment with
DIBAL-H. Confronted with these complications, we exam-
ined masking the amine as an azide. Although the use of
azides as protected amines can be found in the carbohydrate
literature, it is rather uncommon in natural products synthesis.
The 2,4-dimethoxybenzyl group was removed by treatment of
13 with a mixture of trifluoroacetic acid, water, and triiso-
propylsilane, leading to 14 in 87% yield (Scheme 4). The
azido group was then introduced through a copper(II)-
catalyzed diazotransfer reaction involving the in situ forma-
Scheme 1. a) (À)-Menthylfumarate, Et2AlCl, toluene, À788C, 92%;
b) Br2, CH2Cl2, RT, 99%; c) AgNO3, MeOH, 708C, 97%. TMS=tri-
methylsilyl.
Scheme 2.
as the dimethyl ketal (10) in 92% yield (Scheme 3). Reduc-
tion of the esters in 10 with LiAlH4 provided a diol that was
subjected to benzylation, leading to 11 (90%).[10] Hydrolysis
of the ketal gave access to norbornenone 12 (98%).
Scheme 4. a) CF3CO2H/H2O/iPr3SiH, RT, 87%; b) NaN3, Tf2O,
CuSO4·5H2O, toluene/H2O/MeOH (ca. 4:1:6), RT, 79%; c) DIBAL-H,
toluene, À788C; d) NaBH4, MeOH, 08C 77% (over 2 steps); e) TBSCl,
imidazole, CH2Cl2, 98%; f) PMe3, CH2Cl2/MeOH (2:1), RT, then CbzCl,
NaHCO3, acetone/H2O (5:1), 93%; g) O3, NaHCO3, CH2Cl2/MeOH
(5:1), À788C, then Ac2O, NEt3, CH2Cl2, 08C, 97%; h) NaClO2,
NaH2PO4, 2-methyl-2-butene, tBuOH, RT, 98%. Tf=trifluoromethane-
sulfonyl; DIBAL-H=diisobutylaluminum hydride; Cbz=benzyloxycar-
bonyl; TBS=tert-butyldimethylsilyl.
Scheme 3. a) (COCl)2, DMSO, NEt3, CH2Cl2, À788C, 89%; b) HC-
(OMe)3, p-TsOH (cat.), MeOH, 508C, 92%; c) LAH, THF, 08C, 95%;
d) KOtBu, BnBr, dioxane, 90%; e) p-TsOH (15 mol%), THF/H2O (4:1),
reflux, 98%; f) DMBNH2, p-TsOH (10 mol%), 4 ꢁ M.S., toluene,
1108C, then Me3SiCN, ZnCl2 (5 mol%), MeOH, RT, 95%; p-TsOH=p-
toluenesulfonic acid; M.S.=molecular sieves; LAH=lithium alumi-
num hydride; Bn=benzyl; DMBNH2 =2,4-(MeO)-C6H4CH2NH2.
tion of TfN3 (79%).[13] Azidonitrile 15 proved compatible
with the DIBAL-H reduction, furnishing desired aldehyde 16
in 92% yield.[14] Reduction of 16 to the corresponding alcohol
and then protection with a TBS group proceeded in a 75%
yield over three steps from 15. Subsequently, the azido moiety
was converted into a benzyl carbamate through a two-step
procedure involving a Staudinger reduction and subsequent
treatment with CbzCl to provide 17 in 93% yield.
At this stage the synthetic route was at a strategically
critical point, because cleavage of the norbornene to reveal a
cyclopentane core would require conditions for distinguishing
between the two sp2-hybridized carbons. In this respect, we
found particularly intriguing the possibility of effecting
ozonolytic opening of 17 accompanied by regioselective
end-group differentiation.[15,16]
The stage was set for a Strecker aminocyanation reaction.
In initial experiments involving ketone 12 reacting with
Me3SiCN and ammonia in the presence of Ti(OiPr)4, the
corresponding cyanohydrin was the only product obtained.
However, upon screening various amines, we found that
benzylamines effectively participated in this transformation.
Hence, the use 2,4-dimethoxybenzylamine led to aminonitrile
13 in 95% yield.[11] The aminocyanation proceeded with
remarkable diastereoselectivity (> 95:5) as determined by
1H NMR spectroscopic analysis. This selectivity most likely
resulted from the efficient shielding of one of the iminium
diastereofaces by the exo-positioned benzyloxymethylene
substituent.[12]
When norbornene 17 was exposed to ozone in the
presence of sodium bicarbonate, ester/aldehyde 21 was
isolated as the only product in 97% yield. This transformation
proved robust, even on a multigram scale. The structure and
relative configuration of 21 were unambiguously established
on the basis of NOE and two-dimensional NMR spectro-
Nitrile reduction proved to be difficult with DIBAL-H at
À788C and led to decomposition of the starting material.
Angew. Chem. Int. Ed. 2008, 47, 8514 –8517
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8515