After fruitless attempts to selectively deprotect the R-
hydroxyaldehyde, we opted for the removal of all the
protecting groups by treatment with 6 N hydrochloric acid
in THF. The reaction mixture was then concentrated and
used directly in the intramolecular Petasis reaction. After
optimization, the best results were obtained with an excess
of diallylamine in a 4:1 mixture of ethanol/water at 80 °C
for 192 h. The cyclization product 9 was obtained as a
unique diastereomer in 72% yield. Using a 4:1 mixture of
CH2Cl2/HFIP at 50 °C, the reaction time could be reduced
Scheme 3. Synthesis of Conduramine C-4
to 96 h leading to the same cyclization adduct 9 in a 50%
3
yield. For this compound, the coupling constant J3,4
=
7.0 Hz points to a trans diaxial orientation between H-3
and H-4. In order to confirm this selectivity, 9 was deal-
lylated using Guibe’s conditions24 to furnish conduramine
ent-A-1 10, [R]D þ19.0 (c 0.1, MeOH).10e This com-
25
pound, having an anti relationship between the amine
and the R-hydroxyl group, is not the expected diastereo-
isomer according to the previous studies on intermolecular
borono-Mannich condensation.2,3,25
Using the same strategy, conduramine C-4 was also
prepared in a short six-step sequence from commercially
available 2,3-O-isopropylidene-β-D-ribofuranoside 11
(Scheme 3).26 Oxidation of the primary alcohol and elon-
gation of the resulting aldehyde with PPh3, CBr4 in the
presenceof activated zinc affordeddibromoolefin12.27 Pd-
catalyzed hydrogenolysis of 12with n-Bu3SnH provided 13
as a 90:10 mixture of (Z):(E) stereoisomers that could be
easily separated by flash chromatography.28 Boronic acid
14 was obtained in a 70% yield after halogenꢀlithium
exchange, intermediate trapping with trimethylborate, for-
mation of the pinacol ester, and deprotection with sodium
metaperiodate.
3
coupling constant J3,4 = 9.0 Hz. This indicates a trans
diaxial orientation between H-3 and H-4 that again implies
an anti relationship between the CꢀN bond at C4 and the
CꢀO bond at C3 of a new amino alcohol motif in 15.
Palladium-catalyzed removal of the allyl protecting group
25
then provided conduramine C-4, [R]D ꢀ170.0 (c 0.3,
MeOH), in 78% yield (Scheme 3).10a
To rationalize the observed stereoselectivity of this
intramolecular reaction leading to the formation of β-
amino alcohols 9 and 15, transition states (TSs) modeling
was undertaken using dimethylamine. Transition struc-
tures based on all possible intramolecular coordinations at
the boron atom by the R-, β-, or γ-oxygen relative to the
aldehyde were built by blocking the C(boron)ꢀC[Nꢀ(Me)2]
distance, forming a tetracoordinated borate intermediate
in a seven-, six-, or five-membered ring.29 For both com-
pounds, 1000 conformations of each possible transition
structure were generated by the Monte Carlo random
search method30 and optimized by PRCG molecular me-
chanics minimization31 using the Macromodel (Version
5.5) program32 with the MM2* force field.33,29Ab initio
gradient optimizations of these structures using the B3LYP/
6-31G(d,p) basis set were, then, performed with the Gaussian
03 program.29
Complete deprotection of 14 was carried out with TFA
for 2 h, and treatment of the crude reaction mixture with
diallylamine in EtOH/water (80 °C, 192 h) or in CH2Cl2/
HFIP(50°C, 64h) afforded15as a uniquediastereoisomer
in 54% and 60% yields respectively. The relative stereo-
chemistry can be deduced unambiguously at this stage
1
from the analysis of the H NMR spectrum, showing a
(18) Treatment of (E)-configurated vinylic boronic acid 14-E
(obtained from 13-E) with TFA and then with diallylamine in EtOH/
water (4:1) failed to yield any cyclization product.
(19) Takami, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2002, 4, 2993–
2995.
(20) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew.
Chem., Int. Ed. 1984, 23, 727–729.
The analysis of the energies and the geometries of these
transition structures (see experimental section, Tables 1ꢀ6
in the Supporting Information) revealed that the most
stable TSs were obtained with the six-membered rings
having the B-atom coordinated with the β-oxygen
(Scheme 4, Figure 1).
(21) Reddy, Y. K.; Falck, J. R. Org. Lett. 2002, 4, 969–971.
(22) (a) Takahashi, K.; Takagi, J.; Ishiyama, T.; Miyaura, N. Chem.
Lett. 2000, 29, 126–127. (b) Takagi, J.; Takahashi, K.; Ishiyama, T.;
Miyaura, N. J. Am. Chem. Soc. 2002, 124, 8001–8006.
(23) Nakamura, M.; Hatakeyama, T.; Hara, K.; Fukudome, H.;
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 14344–14345.
(24) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993,
58, 6109–6113.
(29) For details, see the SI.
(30) Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989,
111, 4379.
(31) Polak, E.; Ribiere, G. Rev. Fr. Inf. Rech. Oper. 1969, 16-R1, 35–
44.
(25) The anti-selectivity reported here in a cyclic system obviously
corresponds to a syn-selectivity in an acyclic system.
(26) 2,3-O-Isopropylidene-β-D-ribofuranoside was also easily synthesized
in one step from D-ribose: Paquette, L. A.; Bailey, S. J. Org. Chem. 1995,
60, 7849–7856.
(27) Kaliappan, K. P.; Subrahmanyam, A. V. Org. Lett. 2007, 9,
1121–1124.
(28) Uenishi, J. i.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org.
Chem. 1998, 63, 8965–8975.
(32) Mohamadi, F.; Richards, N. J. G.; Guida, W. C.; Liskamp, R.;
Lipton, M. C.; Caufield, M.; Chang, G.; Hendrickson, T.; Still, W. C.
J. Comput. Chem. 1990, 11, 440–467.
(33) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127–8134.
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