Comparative approaches toward diamines containing spatially separated homobenzylic and benzylic nitrogen stereocenters

Article abstract of DOI:10.1016/j.tetlet.2007.05.073

Several synthetic strategies to diamines 1-3 are described. The optimum approach via opening of aziridine afforded 1-3 in 29-60% yield over 3-5 steps. A study on formation of the benzylic stereocenter using Toste's rhenium-catalyzed asymmetric reduction of phosphinyl ketimines was also evaluated and afforded 15 in 92% de.

Full text of DOI:10.1016/j.tetlet.2007.05.073

Tetrahedron Letters 48 (2007) 4825–4829
Comparative approaches toward diamines containing
spatially separated homobenzylic and benzylic
nitrogen stereocenters
Michal Achmatowicz,* Johann Chan, Philip Wheeler, Longbin Liu and Margaret M. Faul
Chemistry Process Research and Development, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA
Received 29 March 2007; accepted 11 May 2007
Available online 18 May 2007
Abstract—Several synthetic strategies to diamines 1–3 are described. The optimum approach via opening of aziridine afforded 1–3 in
29–60% yield over 3–5 steps. A study on formation of the benzylic stereocenter using Toste’s rhenium-catalyzed asymmetric reduc-
tion of phosphinyl ketimines was also evaluated and afforded 15 in 92% de.
Ó 2007 Elsevier Ltd. All rights reserved.
Inhibition of the MAP kinase p38 has been implicated in
the treatment of arthritis and other inflammatory dis-
eases.1 Our medicinal chemistry team identified the
homobenzylic–benzylic diamine motifs 1–3 (Fig. 1) as
a key structural feature of several potent p38 inhibitors.2
While benzylic and homobenzylic amines are common
pharmacophores found among active pharmaceutical
ingredients,3 their syntheses remain a challenge. Herein
we disclose our investigations toward an optimal synthe-
sis of chiral diamines 1–3 containing two spatially sepa-
rated nitrogen stereocenters.4
The common feature of diamines 1–3 is the (S)-config-
ured homobenzylic stereogenic center, which we initially
envisaged to arise via diastereoselective alkylation of an
appropriate propionate followed by a Curtius rear-
rangement. We proposed that the secondary benzylic
center would be introduced by enantioselective reduc-
tion of the corresponding ketone or imine. In the case
of 3, a benzylic Ritter-type reaction would afford the
corresponding gem-dimethyl product.
Our original route to diamines 1–3 took advantage of
the readily available amine 4 (Scheme 1) that was
suitable for SAR studies. The chiral N-protected
Homobenzylic amine center
Benzylic amine center
Ph
O
N
O
R
R
Ph
+ LG
O
N
N
O
NH2
CH3
a, b, c
68%
d, e
93%
OH
O
N
iPr
D-valinol (5)
Enantioselective reduction
Mitsunobu inversion
iPr
HO2C
Br
Diastereoselective alkylation
8
iPr
6
CH3
PG
N
f, g, h
67%
NH2
R1 R2
CH3
(S)
H2N
R
H2N
OH
1
2
3
R1 = CH3, R2 = H
R1 = H, R2 = CH3
R1 = CH3, R2 = CH3
OH
CH3
CH3
Enantioselective reduction
Deoxygenation of Metaraminol
NH2
R1 R2
CbzHN
Br
H2N
4
CH3
+
1, 2, 3
R
97% ee
N
XMg
R
PG
Scheme 1. Diastereoselective alkylation approach to setting the
homobenzylic stereocenter. Reagents and conditions: (a) PhNCS,
THF, rt; (b) TsCl, aq NaOH, THF, rt, 91% (2-step yield); (c) KOtBu,
EtCOCl, THF, rt, 75%; (d) LiHMDS, m-bromobenzyl bromide (7),
THF, À78 °C, >99% de, 99%; (e) NaOH, dioxane, 100 °C, 93%; (f)
EtOCOCl, TEA, THF, 0 °C to rt; (g) aq NaN3, 0 °C to rt; (h) BnOH,
dioxane, toluene, 110 °C, 96.7% ee, 67% (3-step yield).
Ritter amination
Aziridine opening
Figure 1. Different approaches to setting the homobenzylic and the
benzylic stereochemistry.
*
Corresponding author. E-mail: michala@amgen.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.073

4826
M. Achmatowicz et al. / Tetrahedron Letters 48 (2007) 4825–4829
homobenzylic amine 4 was synthesized via an 8-step
sequence starting from D-valinol (5). Thus enantiomeri-
cally pure 5 was converted, using literature methods,5
into an Evans-type chiral auxilliary6 followed by acyla-
tion with propionyl chloride to afford 6 in 68% yield.
A chelation-controlled diastereoselective alkylation of
the lithium (Z)-enolate of 6, using meta-bromobenzyl
bromide (7) followed by hydrolytic removal and recy-
cling of the chiral auxilliary (98% recovery), produced
enantiomerically pure acid 8.7 Curtius rearrangement
followed by trapping of the intermediary isocyanate
with benzyl alcohol provided enantiomerically enriched
4 (97% ee). This synthetic sequence provided sufficient
quantities of 4 in 42% overall yield (Scheme 1).8
CH3
CH3
(S)
a
c, d, e
43 %
(R)
(S)
CbzHN
(S)
CbzHN
OH
NHBoc
(
S,S)-10
(
S,R)-12
95% de
>99% de
9
no chromatography required
CH3
CH3
b
c, d, e
60 %
(S)
(R)
(S)
(S)
CbzHN
CbzHN
OH
NHBoc
(S,R)-10
(S,S)-12
90% de
98.6% de
Scheme 3. Telescoped sequence from 9 to (S,R)-12 and (S,S)-12.
Reagents and conditions: (a) 5 mol % (S)-CBS, THF, À14 °C, 95% de;
(b) 5 mol % (R)-CBS, THF, À14 °C, 90% de; (c) DIAD, TPP, HN3,
CH2Cl2, À20 °C to rt; (d) Zn, NH4Cl, EtOH, 80 °C; (e) Boc2O,
CH2Cl2, rt, 43–60% 4-step yield.
Our initial attempts to set the benzylic amine center in
compounds 1–3 focused on accessing acetophenone 9
(Scheme 2). The treatment of 4 with 1 mol % Pd(OAc)2,
2.2 mol % dppp, 1.2 equiv K2CO3, and 2.5 equiv n-butyl
vinyl ether in 8.5 vol. DMF/water (5:1)9 at 80 °C affor-
ded ketone 9 in 91% yield after aqueous workup and
recrystallization (0.1 kg scale).10
ketone 9 followed by reaction with chlorodiphenylphos-
phine at low temperature (À40 °C) afforded a reactive
intermediate15 that was subsequently rearranged to
required diphenylphosphinyl ketimine 13 (64% yield)
(Scheme 4). Reduction of 13 was attempted in the
presence of 3 mol % rhenium catalysts (R)-14a or
(S)-14b with phenyldimethylsilane (DPMS-H) as the
stoichiometric reductant (Scheme 4).
To set the benzylic stereogenic center present in 1 or 2,
ketone 9 was diastereoselectively reduced using either
(S)-CBS or (R)-CBS reagents to afford N-Cbz-protected
aminoalcohols (S,S)-10 (95% de) and (S,R)-10 (90% de),
respectively (Scheme 2). Alcohols 10 were separately
carried through the sequence starting with a Mitsunobu
inversion using hydrazoic acid,11 zinc reduction of the
resulting azide 11, followed by protection of the result-
ing amine as the N-Boc derivative 12. Each of the above
sequences from ketone 9 to the orthogonally protected
diastereomeric diamines 12 was optimized, allowing
the 4-steps to be performed with a single isolation
(Scheme 3). Final purification by recrystallization affor-
ded both (S,R)-12 (43% yield,12 >99% de) and (S,S)-12
(60% yield,12 >98.5% de) in excellent yield over 4-steps
on a multigram scale.
In contrast to several similar ketimines studied by Toste
and co-workers,13,16 reduction of 13 with catalyst (R)-
14a suffered poor reactivity (77%, 88% de) leading to a
mixture of N-Dpp-amines 15 after 5 days at room tem-
perature. Interestingly replacing dichloromethane with
1,2-dichloroethane did not improve the reactivity;
however, it resulted in a markedly increased diastereo-
selectivity (95% de). A similar trend was observed with
a less elaborated but more readily available catalyst
(S)-14b. However, the diastereoselectivities were not
synthetically useful (50% de). Ultimately, we found that
increasing the reaction temperature in 1,2-dichloro-
ethane had little effect on diastereoselectivity. Thus
using (R)-14a as catalyst reaction at 70 °C for 3 days
gave 86% conversion to (S,R)-1517 with 92% de.
An alternative approach to introduction of the chiral
phenethylamine moiety utilized the method of diastereo-
selective imine reduction, recently published by Toste
and co-workers.13 The required diphenylphosphinyl
ketimine was prepared according to literature proce-
dures.14 Quantitative formation of the oxime from
Initial attempts at formation of the gem-dimethyl di-
amine 3 began with the addition of a methyl anion
equivalent to ketone 9 to afford tertiary alcohol 16
followed by a Ritter-type reaction with hydrazoic acid.11,18
However, a low yield was observed upon addition of
CH3
CH3
a
b
or c
4
CbzHN
CbzHN
91%
99%
R
R
O
OH
CH3
O
O
9
10
a, b
O
O
9
N
N
N
N
(S)
CbzHN
d
Cl Cl
Cl Cl
NC
Re
Re
CN
82%
N
13
P(O)Ph2
CH3
OPPh3 Ph3PO
O
O
R
)-14a
R = 4- -Bu-Ph
R
(
c
CH3
CH3
(
R
S
)-14b
R = Ph
i) e, 90%
ii) f, 98%
t
CbzHN
CbzHN
CH3
N3
NHBoc
(R)
(S)
12
11
+
(
S
)
(S)
CbzHN
CbzHN
HN
HN
Scheme 2. Conversion of aryl bromide 4 to orthogonally protected
diamine 12. Reagents and conditions: (a) 1 mol % Pd(OAc)2,
2.2 mol % dppp, K2CO3, n-butyl vinyl ether, DMF/water 5:1, 80 °C,
91%; (b) 5 mol % (S)-CBS, THF, À14 °C, 99% (S,S)-10 (95% de); (c)
5 mol % (R)-CBS, THF, À14 °C, 99% (S,R)-10 (90% de); (d) DIAD,
TPP, HN3, CH2Cl2, À20 °C to rt, 82%; (e) Zn, NH4Cl, EtOH, 60 °C,
90%; (f) Boc2O, CH2Cl2, rt, 98%.
P(O)Ph2
P(O)Ph2
(S,R)-15
(S,S)-15
Scheme 4. Catalytic diastereoselective reduction of N-diphenylphos-
phinyl ketimine using chiral rhenium complexes. Reagents and
conditions: (a) NH2OH, MeOH, rt, 99%; (b) Ph2PCl, TEA, À40 °C
to rt, 64%; (c) 3 mol % (R)-14a or (S)-14b, 2 equiv PhMe2SiH,
chlorinated solvent, rt or 70 °C.

M. Achmatowicz et al. / Tetrahedron Letters 48 (2007) 4825–4829
4827
CH3
6-step sequence (Scheme 7). Carbonylation of metaram-
inol using phosgene followed by treatment with triflic
anhydride afforded 22 in 44% yield over 2 steps. Protec-
tion of the cyclic carbamate (as the N-Bn derivative 23,
89% yield) allowed a clean cross coupling with potas-
sium iso-propenyltrifluoroborate (18) to afford 1,1-
disubstituted olefin 24 in 95% yield. Finally, treatment
of 24 with hydrazoic acid gave the azide that upon
hydrogenation in the presence of Pearlmann’s catalyst
afforded diamine 3 in 60% yield over 2 steps.
CH3
a
40%
b
9
N3
OH
CbzHN
CbzHN
17
16
c
90%
CH3
NH2
H2N
3
Scheme 5. Initial approach to 3. Reagents and conditions: (a)
MeMgBr, THF, À20 °C, 40%; (b) HN3, TFA, toluene, rt; (c) H2,
Pd–C, rt, 90% 2-step yield.
Readily available enantiopure aziridines21,22 in principle
offer a convergent way to construct the homobenzylic
amine portion of 1–3 by a ring opening with appropriate
aryl carbanions. However, carbanions generally exhibit
poor reactivities toward ring opening reactions unless
an activating, electron-withdrawing group is present
on the aziridine nitrogen atom.23 The most prevalent
activating group employed has been the N-tosyl,21,24
but this can be difficult to remove. Aziridines with more
easily removable groups, such as N-Boc,21 have seldom
been used due to poor reactivity25 and side-reactions,26
with the notable exception of N-Dpp-aziridines intro-
duced by Sweeney and co-workers.27 In our search for
a convergent route toward 1–3, we decided to investigate
conditions that favor aziridine ring opening over side-
reactions within the N-substituent. Our first choice was
N-Cbz-protected aziridine (26) derived from L-alaninol
(25). The advantages of the Cbz group over other viable
N-substituents such as Dpp were twofold: (i) the reac-
tion would afford the same N-Cbz-protected intermedi-
ates (9 or 20) for which further chemistry had already
been developed (vide infra); (ii) orthogonal protection
would be retained, as compared with N-Dpp-aziridines
which would likely need a re-protection (cf. imine reduc-
tion approach, Scheme 4).
MeMgBr presumably due to enolization of ketone 9
(Scheme 5).19
Therefore, an alternative approach to 3 targeted 1,1-
disubstituted olefin 20. Coupling of aryl bromide 9 with
potassium iso-propenyltrifluoroborate (18)20 afforded
Ritter reaction substrate 20 in 80–84% yield (Scheme 6).
Hydrazoic acid addition to 20, followed directly by
hydrogenation, afforded 3 in 90% overall yield. Having
established several viable routes to the benzylic amine
we focused our attention back to obtain a more concise
synthesis toward the homobenzylic amine.
Beginning with commercially available metaraminol
(21),3 elaboration to diamine 3 was accomplished via a
CH3
CH3
2 steps
40 %
OH
CbzHN
Br
CbzHN
CbzHN
4
16
BF3K
c
a
80%
18
CH3
CH3
+ H+
- H+
CbzHN
The N-Cbz-protected aziridine 26 was prepared using
analogous one-pot procedure developed for N-Boc-azir-
idines22c in 90% yield. The carbon nucleophiles, in this
case functionalized aryl Grignard reagents 28 or 29,
were prepared from commercially available 3-bromo-
acetophenone (27) (Scheme 8). Reaction of aziridine
26 with aryl cuprates, generated in situ from a copper
salt (0.05–1.0 equiv) and arylmagnesium bromides
(1.1–2.0 equiv) at À20 °C, led predominantly to ring
opening with complete regioselectivity toward the less
substituted carbon. All identified side-products were
20
19
a, b
90%
CH3
NH2
H2N
3
Scheme 6. Alternative approach to 3 via olefination strategy. Reagents
and conditions: (a) HN3, TFA, toluene, rt; (b) H2, Pd–C, rt; (c)
1 mol % Pd(dppf)Cl2, 2 mol % diisopropylamine, K2CO3, n-PrOH,
90 °C.
(tartrate salt)
CH3
CH3
CH3
c
a, b
44%
Ph
N
OTf
HN
OTf
89%
H2N
OH
H
H
O
O
OH
21
O
O
23
22
d
95%
CH3
O
CH3
e, f
Ph
N
NH2
(
S)
60%
H
H2N
O
3
24
Scheme 7. Metaraminol deoxygenation-Ritter strategy toward diamine 3. Reagents and conditions: (a) phosgene, aq KOH, toluene; (b) Tf2O,
pyridine, 44% 2-step yield; (c) NaH, BnBr, THF, rt, 89%; (d) 18, 1 mol % Pd(dppf)Cl2, 2 mol % diisopropylamine, K2CO3, n-PrOH, 90 °C, 95%; (e)
HN3, TFA, toluene, rt; (f) 14 bar H2, 5% Pd(OH)2, EtOAc, rt, 60% 2-step yield.

4828
M. Achmatowicz et al. / Tetrahedron Letters 48 (2007) 4825–4829
CH3
L.; Lopez, P.; Siegmund, A. C.; Tadesse, S.; Tamayo, N.
WO 070932A2, 2005, Amgen Inc.
NH2
a, b
OH
N
3. Homobenzylic amines are present in AramineÒ (metar-
aminol, 21) (antihypotensive), CetaprilÒ (antihypertensive),
DofetilideÒ (antiarrythmic), EdeprylÒ (antiparkinsonia),
ForadilÒ (bronchpdilator), OxyContinÒ (analgesic); Benz-
ylamines are found in TaxotereÒ (anticancer), ZoloftÒ
(anxiolytic), LamisilÒ (antibiotic), SensiparÒ (renal
failure).
H3C
90%
Cbz
L
-alaninol (25)
26
c, d
98%
e, f, d
40%
BrMg
Br
BrMg
O
O
O
28
27
29
g
68%
g
4. Compounds 1 and 2 contain two stereogenic centers,
whereas 3 contains one homobenzylic amine stereocenter
and a benzylic quaternary center.
67%
CH3
CH3
5. Kim, T. H.; Lee, N.; Lee, G.-J.; Kim, J. N. Tetrahedron
2001, 57, 7137–7141.
CbzHN
CbzHN
O
9
20
6. Facile cleavage and recycling are the main advantages of
this chiral auxiliary over the standard Evans’ oxazolidi-
none system.
7. Lee, G.-J.; Kim, T. H.; Kim, J. N.; Lee, U. Tetrahedron:
Asymmetry 2002, 13, 9–12.
8. Average of multiple runs.
9. Vallin, K. S. A.; Larhed, M.; Hallberg, A. J. Org. Chem.
2001, 66, 4340–4343.
Scheme 8. Homobenzylic amines via copper(I) catalyzed aziridine
opening strategy. Reagents and conditions: (a) CbzCl, CH2Cl2, aq
NaHCO3, rt; (b) TsCl, KOH, Et2O, reflux, 90% (2-step yield); (c)
ethylene glycol, cat. PTSA, toluene, reflux, 98%; (d) Mg, cat. 1,2-
dibromoethane, THF, 35–40 °C to rt; (e) MeMgBr, Et2O, THF,
À5 °C; (f) 10 mol % MsOH, neat, 85 °C, 40% (2-step yield); (g)
0.9 equiv 26 (limiting reagent), 10 mol % CuI, 10 mol % P(n-Bu)3,
À20 °C, then aq NH4Cl, 62–68%.
10. 80% of 9 isolated by crystallization. Additional 11% of 9
could be recovered from the mother liquors by column
chromatography (91% yield total).
11. Caution: Hydrazoic acid is a volatile and potentially
explosive compound in a gaseous state. Handle with care.
Avoid contact with heavy metal salts and alloys.
12. First crop. Additional material could be recovered by
chromatography of the mother liquors.
13. Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 12462–12463.
14. Krzyzanowska, B.; Stec, W. J. Synthesis 1982, 270–
273; Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634–
5635.
15. O-Diphenylphosphinyl oxime. Unstable O-phosphinyl
oximes (cf. Lopez, L.; Barrans, J. J. Chem. Soc., Perkin
Trans. 1 1977, 1806–1811) rearrange thermally to N-
phosphinyl imines via the radical mechanism (cf. Brown,
C.; Hudson, R. F.; Maron, A.; Record, K. A. F. J. Chem.
Soc., Chem. Commun. 1976, 663–664).
derived from the attack of the arylmagnesium (28 or 29)
on the carbonyl of the Cbz-group. Surprisingly, cuprates
generated from the respective organolithiums were not
competent in the ring opening reaction. These results
suggest that lithium cations28 are the cause of this dra-
matic change in the reactivity of aziridines. By using
Grignard reagents as cuprate precursors, homobenzylic
amines 9 and 20 were isolated in good yields (68% and
67%, respectively). Homobenzylic amine 9 was elabo-
rated to the desired 1 or 2 using the CBS reduction/azide
displacement/reduction protocol (cf. Scheme 3). Overall,
diamines 1229 were prepared in a respectable 29–41%
yield over 5-steps from readily available aziridine 26.
gem-Dimethyl amine 3 was prepared in 60% yield over
3-steps from 26.
16. Typical reaction time reported in Ref. 13 was 72 h at room
temperature.
In summary, several approaches to diamines 1–3 con-
taining spatially separated stereocenters have been dem-
onstrated. An approach utilizing an aziridine ring
opening with aryl cuprates afforded the desired amines
1–3 in high overall yield. Key to the ring opening of azir-
idines was the exclusion of lithium cations. Further stud-
ies are currently ongoing.
17. The stereochemistry of the major product was not
assigned. However, the stereochemistry shown in Scheme
4 follows the direction of the induction from Ref. 13.
18. (a) Balderman, D.; Kalir, A. Synthesis 1978, 24–26; (b)
Hassner, A.; Fibiger, R.; Andisik, D. J. Org. Chem. 1984,
49, 4237–4244.
19. Addition of CuI salts or anhydrous CeCl3 to mitigate these
issues was not investigated.
20. (a) Molander, G. A.; Rivera, M. R. Org. Lett. 2002, 4,
107–109; (b) Molander, G. A.; Bernardi, C. R. J. Org.
Chem. 2002, 67, 8424–8429.
Acknowledgments
21. For recent reviews on aziridine chemistry, see: (a) Hu, X.
E. Tetrahedron 2004, 60, 2701–2743; (b) McCoull, W.;
Davis, F. A. Synthesis 2000, 1347–1365.
We are indebted to Professor Dean Toste for providing
samples of the rhenium complexes (R)-14a and (S)-14b.
We would like to thank Aaron Siegmund, Patricia Lo-
pez, Mike Frohn, and Gilbert Rishton for their early-
stage contributions to this work.
22. (a) Giles, P. R.; Roger-Evans, M.; Soukup, M.; Knight, J.
Org. Process Res. Dev. 2003, 7, 22–24; (b) Travins, J. M.;
Etzkorn, F. A. Tetrahedron Lett. 1998, 39, 9389–9392; (c)
Wessig, P.; Schwarz, J. Synlett 1997, 893–894; (d) Bald-
win, J. E.; Farthing, C. N.; Rusell, A. T.; Schofield, C. J.;
Spivey, A. C. Tetrahedron Lett. 1996, 37, 3761–3764.
23. Aziridines are preferentially ring-opened by soft, hetero-
atom-based nucleophiles (Ref. 21). For the most recent
examples, see: (a) Wu, J.; Sun, X.; Sun, W. Org. Biomol.
Chem. 2006, 4, 4231–4235; (b) Wu, J.; Sun, X.; Sun, W.;
Ye, S. Synlett 2006, 2489–2491; (c) Liu, P.; Forbeck, E.
References and notes
1. For a review, see: Schieven, G. L. Curr. Top. Med. Chem.
2005, 5, 921.
2. (a) Lopez, P.; Siegmund, A.; Frohn, M.; Liu, L. Rishton,
G. unpublished results; (b) Frohn, M. J.; Hong, F.-T.; Liu,

M. Achmatowicz et al. / Tetrahedron Letters 48 (2007) 4825–4829
4829
´
M.; Evans, C. D.; Joullie, M. M. Org. Lett. 2006, 8, 5105–
3 equiv). These methods are economically viable only if a
carbon nucleophile is inexpensive and readily available.
26. Attack of the nucleophile on the carbamate carbonyl (N-
Boc or N-Cbz) or phosphorus atom in the N-diphenyl-
phosphinyl group (N-Dpp) (Ref. 27a).
27. (a) Cantril, A. A.; Osborn, H. M. I.; Sweeney, J.
Tetrahedron 1998, 54, 2181–2208; (b) Osborn, H. M. I.;
Sweeney, J. B. Tetrahedron Lett. 1994, 35, 2739–2742; (c)
Osborn, H. M. I.; Sweeney, J. B. Synlett 1994, 145–147.
28. Solubilization of copper salts effected by anhydrous
lithium salts (LiCl or LiBr) also led to inactive copper
species.
5107; (d) Minakata, S.; Okada, Y.; Oderaotoshi, Y.;
Komatsu, M. Org. Lett. 2005, 7, 3509–3512; (e) Reddy, M.
S.; Rao, K. R. Synlett 2005, 489–490.
24. (a) Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Tetrahedron 2005,
61, 9586–9593; (b) Cox, P.; Craig, D.; Ioannidis, S.; Rahn,
V. S. Tetrahedron Lett. 2005, 46, 4687–4690; (c) Cunha, R.
L. O. R.; Diego, D. G.; Simonelli, F.; Comasseto, J. V.
Tetrahedron Lett. 2005, 46, 2539–2542; (d) Ding, C.-H.;
Dai, L.-X.; Hou, X.-L. Synlett 2004, 1691–1694, For the
earlier examples, see: Ref. 21.
25. Large excess of Grignard reagents were required: Ref. 22b
(2.5–5.0 equiv), Ref. 22d (3.5–10.1 equiv), Osowska-
Pacewicka, K.; Zwierzak, A. Synthesis 1996, 333–335 (2–
29. Compounds (S,S)-12 and (S,R)-12 are orthogonally pro-
tected diamines 1 and 2, respectively.