Stereocontrolled route to vicinal diamines by [3.3] sigmatropic rearrangement of allyl cyanate: Asymmetric synthesis of anti-(2R,3R)- and syn-(2R,3S)-2,3-diaminobutanoic acids

Article abstract of DOI:10.1021/ol0621102

(Diagram presented) A stereocontrolled route via allyl 1,2-diols to vicinal diamines based on the [3.3] sigmatropic rearrangement of allyl cyanate has been developed. Our approach consists of two consecutive steps: stereoselective construction of allyl an

Full text of DOI:10.1021/ol0621102

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5737-5740
Stereocontrolled Route to Vicinal
Diamines by [3.3] Sigmatropic
Rearrangement of Allyl Cyanate:
Asymmetric Synthesis of anti-(2R,3R)-
and syn-(2R,3S)-2,3-Diaminobutanoic
Acids
Yoshiyasu Ichikawa,*,† Haruka Egawa,† Takashi Ito,‡ Minoru Isobe,‡
Keiji Nakano,† and Hiyoshizo Kotsuki†
Faculty of Science, Kochi UniVersity, Akebono-cho, Kochi 780-8520, Japan, and
Laboratory of Organic Chemistry, School of Bioagricultural Sciences,
Nagoya UniVersity, Chikusa, Nagoya 464-8601, Japan
ichikawa@kochi-u.ac.jp
Received August 27, 2006
ABSTRACT
A stereocontrolled route via allyl 1,2-diols to vicinal diamines based on the [3.3] sigmatropic rearrangement of allyl cyanate has been developed.
Our approach consists of two consecutive steps: stereoselective construction of allyl anti- and syn-1,2-diols followed by [1,3]-chirality transfer
by sigmatropic rearrangement, which allow an access to anti-(2R,3R)- and syn-(2R,3S)-2,3-diaminobutanoic acids.
Over the course of the past decades, chiral 1,2-diamines have
become an increasing targeted functional motif in organic
synthesis owing to their ubiquity in natural products and
medicinal agents.1 For example, it is found in biotin,
penicillins, R,â-diamino acids, and antiinfluenza neuramini-
dase inhibitor Tamiflu. Moreover, chiral vicinal diamines and
their metal complexes have been employed in stereoselective
organic synthesis, in particular, as chiral auxiliaries and
ligands in catalytic asymmetric synthesis. Although a number
of strategies for the synthesis of vicinal diamines have been
developed, there are few synthetic methods that allow one
to obtain 1,2-diamino building blocks with all possible
absolute and relative stereochemical arrangements.
Among many reports for the synthesis of vicinal diamines,
there are two representative approaches based upon the
sigmatropic rearrangement. Weinreb reported stereocon-
trolled synthesis of unsaturated vicinal diamines from Diels-
Alder adducts of sulfur dioxide diimides and 1,3-dienes.2 In
this case, [2.3] sigmatropic rearrangement of allyl sulfin-
imines to allyl sulfenamides followed by desulfurization with
trimethylphosphite afforded the syn- and anti-diamine de-
rivatives. Ernst and Bellus reported a strategy based on the
[3.3] sigmatropic rearrangement of allyl trichloroacetimidate
derived from R-amino acids, which underwent palladium-
catalyzed aza-Claisen rearrangement to afford anti vicinal
diamines with good diastereoselectivity.3
Recent reports from our group have presented a stereo-
selective synthesis of allyl amines based upon allyl cyanate-
† Kochi University.
‡ Nagoya University.
(1) For a review on the synthesis of vicinal diamines, see: (a) Lucet,
D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1988, 37, 2580-
2627. For recent examples on the synthesis of vicinal diamines, see: (b)
Ooi, T.; Kameda, M.; Fuji, J.; Maruoka, K. Org. Lett. 2004, 6, 2397-
2399. (c) Rondot, C.; Zhu, J. Org. Lett. 2005, 7, 1641-1644.
(2) Natsugari, H.; Whittle, R. R.; Weinreb, S. M. J. Am. Chem. Soc.
1984, 106, 7867-7872.
(3) Gonda, J.; Helland, A.-C.; Ernst, B.; Bellus, D. Synthesis 1993, 729-
733.
10.1021/ol0621102 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/09/2006

to-isocyanate rearrangement.4 We envisioned that an exten-
sion of this sigmatropic reaction to the synthesis of allyl
vicinal diamines would control two stereogenic centers
attached to nitrogens. To realize this plan, we set up the
synthesis of R,â-diaminobutanoic acids (R,â-Dabs) 1 and 2.
allyl anti and syn vicinal diamine derivatives J and K. In
these transformations (EfF and HfI), we would take
advantage of the concerted nature of sigmatropic rearrange-
ment to achieve a high level of [1,3]-chirality transfer of
two stereogenic centers attached to oxygens during the C-O
to C-N bond reorganization.7 Finally, oxidative cleavage
of alkene moieties in J and K would furnish the R,â-diamino
acids. One merit of this strategy is that a variety of R,â-
diamino acids could be synthesized by simply choosing an
appropriate aldehdyde A.
A common intermediate for the synthesis of R,â-Dabs was
an R,â-unsaturated ketone 6, which was readily obtained by
the condensation of chiral phosphonate 5 with acetaldehyde
(Scheme 2). Protection of the hydroxy group in L-lactic acid
The R,â-diamino acid family constitutes a key structural
element found in a variety of antibiotics, antifungal peptides,
and other biologically active compounds.5 In particular, R,â-
Dabs have attracted numerous synthetic efforts because they
are the simplest member of the R,â-diamino acid family yet
form key elements in both peptide antibiotics and toxins.6
In this communication, we show our approach to the
synthesis of allyl vicinal amines based upon allyl cyanate-
to-isocyanate rearrangement, which allowed the stereoselec-
tive synthesis of these R,â-Dabs.
Scheme 2. Synthesis of a Common Intermediate 6
Our strategy starts with aldehyde A, as outlined in Scheme
1. Horner-Emmons reaction of chiral phosphonate B with
Scheme 1. Strategy for the Synthesis of Allyl Vicinal Amines
methyl ester (3) with p-methoxybenzyl (PMB) trichloroace-
timidate in the presence of trifluoromethanesulfonic acid gave
the PMB ether 4 in 85% yield.8 Condensation of 4 with
lithium methyldimethyl phosphonate in THF furnished the
chiral phosphonate 5, which was then subjected with
acetaldehyde under Masamune-Roush conditions (LiCl,
i-Pr2NEt, CH3CN)9 to furnish the R,â-unsaturated ketone 6
predominantly in 77% yield over two steps.
Stereocontrolled reduction of R-oxygenated enone 6 for
the preparation of allyl anti- and syn-1,2-diols (7 and 8) was
examined employing several reducing reagents (Table 1).
In the case of lithium aluminum hydride (entry A), the
modest level of diastereoselection was observed (83:17) to
deliver an inseparable mixture of 7 and 8 in a combined yield
of 98%.10 Although L-selectride reduction in toluene (entry
B) showed good selectivity (99:1),11 appreciable amounts
(29%) of the competitive conjugate reduction product were
formed, resulting in a reduced yield (59%). Chelation-
A would afford enone C, a common intermediate, which
would give access to both allyl anti and syn vicinal diamines.
Allyl anti- and syn-1,2-diols D were envisioned to derive
from stereoselective reduction of enone C. [3.3] Sigmatropic
rearrangement of allyl cyanates E and H would furnish the
(6) (a) Atherton, E.; Meienhofer, J. J. Antibiot. 1972, 25, 539-540. (b)
Atherton, E.; Meienhofer, J. Hoppe-Seyler’s Z. Physiol. Chem. 1973, 354,
689-696. (c) Schmidt, U.; Mundinger, K.; Riedl, B.; Hass, G.; Lau, R.
Synthesis 1992, 1201-1202. (d) Burke, A. J.; Davies, S. G.; Hedgecock,
C. J. R. Synlett 1996, 621-622. (e) Han, H.; Yoon, J.; Janda, K. D. J. Org.
Chem. 1998, 63, 2045-2048.
(7) Ichikawa, Y.; Tsuboi, K.; Isobe, M. J. Chem. Soc., Perkin Trans. 1
1994, 2791-2796.
(4) (a) Ichikawa, Y.; Ito, T.; Nishiyama, T.; Isobe, M. Synlett 2003,
1034-1036. (b) Ichikawa, Y.; Ito, T.; Isobe, M. Chem.-Eur. J. 2005, 11,
1949-1957.
(5) For a comprehensive summary of literature related to the synthesis
of R,â-diamino acids, see: (a) Luo, Y.; Blaskovich, M. A.: Lajoie, G. A.
J. Org. Chem. 1999, 64, 6106-6111. (b) Viso, A.; Fernandez, P.; Garcia,
A.; Flores, A. Chem. ReV. 2005, 105, 3167-3196. For a recent report on
the asymmetric synthesis of R,â-diamino acids, see: (c) Davis, F. A.; Deng,
J. Org. Lett. 2004, 6, 2789-2792.
(8) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139-4142.
(9) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(10) 1,2-Asymmetric induction of a similar R-oxygenated enone using
LAH was reported by Overman: (a) Overman, L. E.; McCready, R. J.
Tetrahedron Lett. 1982, 23, 2355-2358. See also: (b) Ko, K.-Y.; Eliel, E.
L. J. Org. Chem. 1986, 51, 5353-5362.
5738
Org. Lett., Vol. 8, No. 25, 2006

chemical assignment according to the Mosher-Kusumi
analysis was carried out by calculation of the chemical shift
differences (∆δ values: ∆δ ) δS - δR), which proved to
be identical to those predicted on the basis of the chelation-
control and Felkin-Ahn models.
Table 1. Stereocontrolled Reduction of R-Oxygenated Enone 6
With the preparation of both allyl anti- and syn-1,2-diols
established, we undertook the synthesis of vicinal diamines
via sigmatropic rearrangement (Scheme 3). Treatment of 7
entry
reducing agent
7/8a
% yield
A
B
C
D
E
F
LiAIH4, Et2O, -10 °C
83:17
99:1
91:9
12:88
30:70
10:90
98
L-selectride, toluene, -78 °C
Zn(BH4)2, Et2O, -10 °C
L-selectride, THF, -78 °C
DIBAL, CH2Cl2, -78 °C
NaBH4, CeCl3, MeOH, 0 °C
59 (29)b
99
Scheme 3. Construction of Allyl anti-1,2-Diamine
77 (23)b
60 (35)b
82
a Ratio based on 1H NMR analysis. b Number in parentheses is the yield
of 9.
controlled zinc borohydride reduction (entry C) proved to
be our choice for the preparation of allyl anti-1,2-diol 7 with
a 99% yield and 91:9 selection.12
Felkin-Ahn selective reduction of 6 with L-selectride in
THF (entry D) resulted in a 77% yield and 12:88 selectivity,
accompanied by unwanted conjugate reduction product 9
(23%).13 DIBAL reduction (entry E) also resulted in undesir-
able results: modest selectivity (30:70) and more conjugate
addition product 9 (35%). To suppress this conjugate
reduction problem, Luche reduction was examined (entry F)
and proved to be effective, furnishing products with an 82%
yield and 10:90 selection.14
We initially assigned the stereochemistry of the products
7 and 8 on the basis of chelation-control and Felkin-Ahn
models, which was firmly secured by the Mosher-Kusumi
MTPA ester analysis as illustrated in Figure 1.15 Thus,
with trichloroacetyl isocyanate followed by hydrolysis with
potassium carbonate in aqueous methanol provided allyl
carbamate 12. Dehydration of allyl carbamate 12 using
modified Appel’s conditions (PPh3, CBr4, Et3N)16 provided
allyl cyanate 13, which underwent facile [3.3] sigmatropic
rearrangement to afford allyl isocyanate 14. To avoid the
hydrolysis of 14 during aqueous workup, benzyl alcohol and
a substoichiometric amount of tributyltin benzylalkoxide (30
mol %) were added to the reaction mixture. After stirring at
room temperature overnight followed by workup and chro-
matography, the Cbz-carbamate 15 was obtained in 93%
overall yield from 12. It should be noted that the yields of
15 decreased to ca. 60-70% in the absence of tributyltin
benzylalkoxide.17 The next construction of the stereogenic
center attached to nitrogen began with oxidative deprotection
of the PMB ether in 15 with DDQ in 94% yield.18 The allyl
alcohol 16 was transformed into the carbamate 17, which
Figure 1. Mosher-Kusumi MTPA ester analysis: ∆δ values for
the Mosher ester derivatives 10 and 11.
secondary alcohols 7 and 8 were transformed into the cor-
responding (S)- and (R)-MTPA esters 10 and 11. Stereo-
(11) Faucher, A-M.; Brochu, C.; Landry, S. R.; Duchesne, I.; Hantos,
S.; Roy, A.; Myles, A.; Legault, C. Tetrahedron Lett. 1998, 39, 8425-
8428.
(12) (a) Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1983, 24,
2653-2656. (b) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338-344.
(13) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1976, 61-70.
See also refs 10b and 11.
(14) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454-
5459.
(15) Ohtani, I.; Kusumi, K.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(16) (a) Ichikawa, Y. J. Chem. Soc., Perkin Trans. 1 1992, 2135-2139.
(b) O’Neil, I. A. In ComprehensiVe Organic Functional Group Transforma-
tions; Katritzky, A.; Meth-Cohn, O.; Ress, C. W., Eds.; Pergamon: Oxford,
1995; Vol. 3, pp 696.
(17) Addition of tributyltin alkoxide enhanced the efficiency of this in
situ trapping isocyanate. See: Ichikawa, Y.; Osada, M.; Ohtani, I.; Isobe,
M. J. Chem. Soc., Perkin Trans. 1 1997, 1449-1455.
Org. Lett., Vol. 8, No. 25, 2006
5739

was then dehydrated as before, to afford the rearranged
product 19. To our delight, the resultant isocyanate 19 was
efficiently trapped in situ by intramolecular attack of nitrogen
in the Cbz group providing imidazolidinone 20 in 70-77%
yields.19 Furthermore, 20 was isolated as crystals, and the
minor isomer arising from the reduction step (6f7) was
removed at this stage by recrystallization.
Scheme 5. Synthesis of syn-(2R,3S)-Dab Hydrochloride
The next task for the synthesis of R,â-Dab is the functional
group transformation of the alkene moiety in 20 into the
corresponding carboxylic function (Scheme 4). This oxidative
Scheme 4. Synthesis of anti-(2R,3R)-Dab Hydrochloride
tions similar to those employed in Scheme 3, and the
imidazolidinone 28 was obtained with comparable efficiency
(67% overall yield from 8 to 28). After acetylation of NH
in 28, the resultant 29 was subjected to the ruthenium-
catalyzed oxidative transformation into the corresponding
carboxylic acid. Although esterification with diazomethane
generated 31 along with 30, separation of 30 followed by
acetylation (Ac2O, DMAP, Et3N, CH3CN) then furnished 31;
a total yield of 81% for the methyl ester 31 was obtained.
As before, hydrolysis of 31 with 2 N HCl followed by ion-
exchange chromatography then completed the synthesis of
(2R,3S)-Dab hydrochloride 32.
We have proposed a new route for the stereocontrolled
construction of allyl 1,2-diamines, which was realized in the
synthesis of anti-(2R,3R)- and syn-(2R,3S)-Dabs, 1 and 2,
starting from L-lactic acid methyl ester (3). Because enan-
tiomeric D-lactic acid derivatives are commercially available,
the present method described here also constitutes a formal
synthesis of the enantiomers of both 1 and 2. Further progress
toward the synthesis of other R,â-diamino acids by choosing
appropriate aldehydes is now underway in our laboratory.
cleavage was found to be more difficult than initially
expected: attempts using several oxidizing reagents (OsO4/
NaIO4, O3, RuCl3/NaIO4) proved futile. We finally found
that protection of the NH in imidazolidinone 20 had a
dramatic effect on this oxidative transformation. Thus,
acetylation of 20 (Ac2O, DMAP, CH3CN) followed by
ruthenium-catalyzed oxidation of 21 under Sharpless condi-
tions (RuCl3, H5IO6, CCl4/H2O/CH3CN)20 resulted in the
smooth cleavage of the double bond. Esterification of the
resultant carboxylic acid by treatment with diazomethane
then led to the methyl ester 22 in 72% isolated yield over
two steps. Removal of the Cbz and acetyl groups and
hydrolytic cleavage of the imidazolidinone ring in 22 were
carried out by acid-catalyzed hydrolysis (2 N HCl, 90 °C,
24 h) to afford the (2R,3R)-Dab hydrochloride 23.
The synthesis of (2R,3S)-Dab 2 starting from allyl syn-
1,2-diol 8 was then explored (Scheme 5). The [1,3]-chirality
transfer of two stereogenic centers attached to oxygen in 8
was accomplished (8f25 and 26f28) using reaction condi-
(18) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888. It should be noted that because the prolonged reaction time
of this oxidative deprotection resulted in the formation of enone i, it was
necessary to perform a workup immediately after checking the consumption
of starting material by TLC analysis.
Acknowledgment. We are grateful for the financial
support from a Grant-in-Aid for Scientific Research
(16002007, 18032055, and 18037053) from MEXT. This
work was supported in part by a Special Research Grant for
Green Science from Kochi University.
Supporting Information Available: Full experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) (a) Dunn, P. J.; Haner, R.; Rapoport, H. J. Org. Chem. 1990, 55,
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