Enantioselective synthesis of benzyl (1S,2R,4R)-4-(tert- butoxycarbonylamino)-2-(hydroxymethyl)-cyclohexylcarbamate using an iodolactamization as the key step

Article abstract of DOI:10.1021/jo9011249

(Chemical Equation Presented) An efficient enantioselective synthesis of benzyl (1S,2R,4R)-4-(tert-butoxycarbonylamino)-2-(hydroxymethyl) cyclohexylcarbamate 2, an essential intermediate for a series of potent CCR2 antagonists, is described. The key step

Full text of DOI:10.1021/jo9011249

pubs.acs.org/joc
(1S,2R,4R)-4-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-
Enantioselective Synthesis of Benzyl (1S,2R,4R)-4-
(tert-Butoxycarbonylamino)-2-(hydroxymethyl)-
cyclohexylcarbamate Using an Iodolactamization As
the Key Step
cyclohexylcarbamate 2. In this paper, we describe the full
details of our synthesis of 2.5 To our knowledge, a synthesis
of 2 has not appeared, although some work has been
published on related diastereomers of 1,4-diamino-2-(car-
boxylate)cyclohexanes that was not suitable for our needs.6
As shown in Scheme 1, we envisioned that 2 would be
available from the cyclic compound 3, which in turn could
be synthesized from an enantiomerically enriched monoacid
4. The enantiomer we needed in 4 was opposite that obtained
via a pig liver esterase cleavage of a diester.7
Hence, we initiated the synthesis of 2 with an asymmetric
methanolysis of the inexpensive 1,2,3,6-tetrahydrophthalic an-
hydride 5, as described by Bolm et al.,8 to give the monoacid 6in
86-92% yield and 93% ee9 (Scheme 2). The free carboxylate of
6 was then transformed via a Curtius reaction to carbamate 7.10
Saponification of the ester gave carboxylate 8,11 which was
converted to amide 9. We were unable to perform a lactamiza-
tion directly13 on amide 9, and so we explored making the
amide NH more acidic to promote lactamization.14 After some
experimentation, we found that treatment of amide 9 in a
NMP/THF mixture with n-BuLi and Boc2O15 gave the acyl
carbamate 10. We were then able to utilize lactamization
Carlton L. Campbell,‡ Carla Hassler,‡ Soo S. Ko,†
Matthew E. Voss,† Michael A. Guaciaro,‡ Percy H. Carter,†
and Robert J. Cherney*,†
†Research and Development, Bristol-Myers Squibb Company,
Princeton, New Jersey 08543-4000, and ‡AMRI, 26
Corporate Circle, P.O. Box 15098, Albany, New York 12212
robert.cherney@bms.com
Received May 27, 2009
(5) Cherney, R. J.; Carter, P. H.; Duncia, J. V.; Gardner, D. S.; Santella,
J. B. WO 2004071460, August 26, 2004; Chem Abstr. 2004, 141, 225304.
(6) (a) Appella, D. H.; LePlae, P. R.; Raguse, T. L.; Gellman, S. H. J.
Org. Chem. 2000, 65, 4766–4769. (b) Kiss, L.; Szatmari, I.; Fulop, F. Lett.
Org. Chem. 2006, 3, 463–467.
An efficient enantioselective synthesis of benzyl (1S,2R,4R)-
4-(tert-butoxycarbonylamino)-2-(hydroxymethyl)cyclohexyl-
carbamate 2, an essential intermediate for a series of po-
tent CCR2 antagonists, is described. The key step in the
sequence is an iodolactamization to yield the highly func-
tionalized (1R,2S,4S,5S)-tert-butyl 2-(benzyloxycarbonyl-
amino)-4-iodo-7-oxo-6-azabicyclo[3.2.1]octane-6-carbox-
ylate 11. An examination of the reaction mechanism within
the 2-step iodolactamization sequence led to the discovery
of a single-pot transformation of increased efficiency.
(7) Masaji, O.; Masami, O. Org. React. 1989, 37, 1–55.
(8) (a) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000,
65, 6984–6991. (b) For a review on anhydride openings, see: Atodiresei, I.;
Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683–5712. (c) For a recent
enzymatic approach to monoacid 6, see: Goswami, A.; Kissick, T. P. Org.
Process Res. Dev. 2009, 13, 483–488.
(9) Bolm and co-workers have reported8a the enantiopurity of 6 to be
93% ee for this process, and we have confirmed that our material meets this
specification, using the 4-bromophenyl ester8a of 6 and HPLC conditions
(AD column, 4.6 ꢀ 250 mm, 93% n-heptane/7% 2-propanol, 1 mL/min,
220 nm, t1=7.8 (major), t2=8.6 min (minor).
(10) (a) Suga, H.; Tanimoto, N.; Sinskey, A. J.; Masamune, S. J. Am.
Chem. Soc. 1994, 116, 11197–11198. (b) Liang, X.; Zhang, J.; Chen, A.
Xiamen Daxue Xuebao, Ziran Kexueban 2006, 45, 792-796. For related work on
the enantiomer of 7, see: (c) Kobayashi, S.; Kamiyama, K.; Iimori, T.; Ohno, M.
Tetrahedron Lett. 1984, 25, 2557–2560. (d) Kurihara, M.; Kamiyama, K.;
Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1985, 26, 5831–5834. (e) Kobayashi,
S.; Kamiyama, K.; Ohno, M. Chem. Pharm. Bull. 1990, 38, 350–354. (f) Bolm,
C.; Schiffers, I.; Dinter, C. L.; Defrere, L.; Gerlach, A.; Raabe, G. Synthesis 2001,
1719–1730.
(11) We did not observe R-epimerization in the saponification of 7 to 8.
This was confirmed by converting carboxylate 8 back to ester 7 (via
TMSCHN2) and then examining the 1H NMR. The anti-diastereomer i has
been previously reported12 to have a methyl ester resonance in the 1H NMR at
3.64 ppm, and wedid notobservethisinoursampleof7(resynthesized from8).
Substituted cyclohexanes are a fundamental building
block in organic chemistry. Many natural products and
medicinally important compounds contain substituted
cyclohexanes, including FK-506,1 wailupemycin A,2 and
Factor Xa inhibitors.3 Recently,4 we discovered that 1,2,
4-trisubstituted cyclohexanes are an essential scaffold for
a series of potent CCR2 antagonists 1. In order to optimize
the properties of these antagonists, we required a scalable,
entantioselective synthesis of the core intermediate, benzyl
(1) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.;
Goto, T.; Hashimoto, M.; Taga, T. J. Am. Chem. Soc. 1987, 109, 5031–5033.
(2) Kirsch, S. F.; Bach, T. Chem.;Eur. J. 2005, 11, 7007–7023.
(3) Qiao, J. X.; Chang, C-H; Cheney, D. L.; Morin, P. E.; Wang, G. Z.;
King, S. R.; Wang, T. C.; Rendina, A. R.; Luettgen, J. M.; Knabb, R. M.;
Wexler, R. R.; Lam, P. Y. S. Bioorg. Med. Chem. Lett. 2007, 17, 4419–4427.
(4) (a) Cherney, R. J.; Mo, R.; Meyer, D. T.; Voss, M. E.; Lo, Y. C.;
Yang, G.; Miller, P. B.; Scherle, P. A.; Tebben, A. J.; Carter, P. H.; Decicco,
C. P. Bioorg. Med. Chem. Lett. 2009, 19, 3418–3422. (b) Cherney, R. J.;
Brogan, J. B.; Mo, R.; Lo, Y. C.; Yang, G.; Miller, P. B.; Scherle, P. A.;
Molino, B. F.; Carter, P. H.; Decicco, C. P. Bioorg. Med. Chem. Lett. 2009,
19, 597–601.
(12) Abell, A. D.; Gardiner, J. Org. Lett. 2002, 4, 3663–3666.
(13) Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006–4014.
(14) (a) Boeckman, R. K.; Connell, B. T. J. Am. Chem. Soc. 1995, 117,
12368–12369. (b) Fujita, M.; Kitagawa, O.; Suzuki, T.; Taguchi, T. J. Org.
Chem. 1997, 62, 7330–7335. (c) Yeung, Y-Y; Corey, E. J. Tetrahedron Lett.
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(15) Macdonald, S. J. F.; Clarke, G. D. E.; Dowle, M. D.; Harrison, L.
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6368 J. Org. Chem. 2009, 74, 6368–6370
Published on Web 07/09/2009
DOI: 10.1021/jo9011249
r
2009 American Chemical Society

Campbell et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis of 2
13 and then quenched with 1 equiv of Boc2O to give 14
(Scheme 3). With the acyl carbamate NH now very acidic, a
proton transfer could give 15 in situ, which when exposed to
iodine should undergo the cyclization to yield 11. As shown
in eq 1, when we attempted the one-pot procedure with
racemic 9,17 we did not observe any of the desired rac-11.
However, we noticed that the iodocyclization had never been
run in the presence of NMP, which was necessary only for the
solubility of amide 9 in the acylation step. To investigate this,
we ran a control reaction using our normal lactamization
conditions of 10, but in the presence of NMP (eq 2).
Surprisingly, the lactamization failed to occur in the presence
of NMP. Hence, we returned to the one-pot concept and
excluded NMP (eq 3). Treatment of 9 (noncrystalline ma-
terial for solubility purposes) with 2 equiv of n-BuLi at low
temperature followed by Boc2O and then iodine gave the
successful iodolactamization to rac-11 in a single pot (eq 3).
The one-pot process was more efficient as it proceeded in
55% yield as compared to a 34% yield for the two-step
procedure.
SCHEME 2. Enantioselective Synthesis of Trisubstituted Cy-
clohexane 2
In summary, we have described an efficient, enantiose-
lective synthesis of benzyl (1S,2R,4R)-4-(tert-butoxycarbo-
nylamino)-2-(hydroxymethyl)cyclohexylcarbamate 2, which
is an essential core for a series of potent CCR2 antagonists.
The key step in the sequence was an iodolactamization to
yield the highly functionalized 11. An examination of the
reaction mechanism within the two-step amide acylation/
iodolactamization sequence led to the discovery of a single-
pot transformation of increased efficiency.
conditions described by Taguchi et al.14b (n-BuLi and I2) to
afford the cyclized 11.16 Dehalogenation occurred smoothly
with n-Bu3SnH and AIBN to give 12. The desired 2 was then
produced by a reductive opening of 12 with NaBH4 in a THF/
H2O (4/1) mixture. The addition of water to this reductive
opening was critical for its success.
As shown in Scheme 2, the synthesis of 2 was accomplished
in eight steps with an overall yield of 10% from 5. However,
when we examined the lactamization sequence, we hypothe-
sized that the acylation of amide 9 and the subsequent
iodocyclization to 11 could be more efficiently performed
as a one-pot procedure. Based on the reaction mechanism,
our hypothesis was that amide 9 could be dilithiated in situ to
Experimental Section
(1R,2S,4S,5S)-tert-Butyl 2-(Benzyloxycarbonylamino)-4-iodo-
7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (11). The acyl car-
bamate 10 (2.6 g, 6.9 mmol) was dissolved in anhydrous THF
(116 mL) and cooled in an ice/brine bath. After 15 min, n-BuLi
(2.39 M, 2.9 mL, 6.9 mmol) was added dropwise. The resulting
solution was stirred an additional 30 minbeforesolid iodine (5.3 g,
(16) The enantiomeric integrity of compound 11 was confirmed to be
93% ee, using HPLC conditions (OJ column, 4.6ꢀ150 mm, 80% n-heptane/
10% EtOH/10% MeOH and 0.1% diethylamine, 1 mL/min, 217 nm, t1=6.9
(major), t2=8.4 min (minor).
(17) All one-pot investigations were performed with racemic material out
of convenience.
J. Org. Chem. Vol. 74, No. 16, 2009 6369

Campbell et al.
JOCNote
SCHEME 3. Proposed One-Pot Synthesis of 9 to 11
C5H8O2 þ H]þ. Anal. Calcd for C20H26N2O5: C, 64.15; H, 7.00; N,
7.48. Found: C, 63.97; H, 6.63; N, 7.37.
Benzyl (1S,2R,4R)-4-(tert-Butoxycarbonylamino)-2-(hydro-
xymethyl)cyclohexylcarbamate (2). To a solution of lactam 12
(10.5 g, 28 mmol) in THF (180 mL) and water (45 mL) was
added sodium borohydride (5.3 g, 140 mmol) portionwise, and
the mixture was stirred for 20 h at room temperature. The
reaction was quenched by slow addition of satd NH4Cl (200 mL),
and the product was extracted with ethyl acetate (3 ꢀ 200 mL).
The combined extracts were washed with brine, dried over
sodium sulfate, and evaporated to give the desired alcohol 2 as
a white solid (10.6 g, 100% yield). The material was pure enough
for various transformations.
An analytical sample was obtained by recrystallization of the
above solid with ethyl acetate and hexane: 1H NMR (400 MHz,
DMSO-d6) δ ppm 7.29-7.39 (m, 5H), 7.00 (d, J=7.47 Hz, 1H),
6.53 (d, J=7.03 Hz, 1 H), 5.02 (s, 2H), 4.38 (t, J=5.27 Hz, 1H),
3.78 (d, J=3.52 Hz, 1 H), 3.26-3.36 (m, 1H), 3.09-3.22 (m, 2H),
1.76 (d, J=10.11 Hz, 1H), 1.60 (d, J=10.55 Hz, 2H), 1.52 (d,
J=6.15 Hz, 1H), 1.43-1.32 (m, 1H), 1.37 (s, 9H), 1.06-1.23 (m,
1H); 13C NMR (100 MHz, DMSO-d6) δ 156.0, 154.7, 137.1,
128.3, 127.8, 77.3, 65.2, 62.6, 49.0, 46.0, 41.8, 29.8, 29.5, 28.3,
20.8 mmol) was added in a single portion. The cooling bath
was removed, and the reaction mixture was allowed to warm to
room temperature and stir for 24 h. The iodine was quenched
with 2 M aqueous Na2S2O3 5H2O solution (16 mL) to yield a
3
pale yellow solution. A majority of the THF was removed by
rotary evaporation prior to the addition of ethyl acetate (100 mL).
The layers were separated, and the aqueous phase was extracted
with ethyl acetate. The combined organic layers were washed with
water (2ꢀ45 mL) and brine (2ꢀ50 mL), dried (Na2SO4), filtered,
and concentrated to a pale yellow solid. This solid was diluted with
ether to make a slurry, and the solid material was collected by
vacuum filtration. The product was repeatedly rinsed with cold
ether and dried to give 11 (1.79 g, 3.6 mmol, 52%) as a white solid:
mp 183.9, 194 °C, DSC; 1H NMR (300 MHz, CDCl3) δ 7.35 (m,
5H), 5.20-5.03 (m, 3H), 4.62 (br m, 1H), 4.43 (br t, J=4.3 Hz, 1H),
4.18 (m, 1H), 2.73 (br m, 1H), 2.62 (d, J=12.5 Hz, 1H), 2.51 (dd, J=
16.0, 5.5 Hz, 1H), 2.34-2.25 (m, 1H), 2.14-2.02 (m, 1H), 1.53 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 173.2, 155.6, 149.3, 136.4,
128.7, 128.4, 128.2, 84.2, 67.2, 60.5, 47.6, 46.0, 36.8, 31.5, 28.2, 21.2;
26.7; [R]25 þ43.12 (c 0.517, MeOH); IR (KBr) 3374, 3265,
D
2942, 1705, 1666, 1562, 1454, 1389, 1271, 1177, 1113 cm-1; high
res MS calcd for (M þ Na)þ 401.20603, found 401.20540. Anal.
Calcd for C20H30N2O5: C, 63.47; H, 7.99; N, 7.40. Found: C,
63.26; H, 7.95; N, 7.33.
One-Pot Procedure: (1R*,2S*,4S*,5S*)-tert-Butyl 2-(benzy-
loxycarbonylamino)-4-iodo-7-oxo-6-azabicyclo[3.2.1]octane-6-
carboxylate (rac-11). Racemic amide 9 (500 mg, 1.82 mmol) in
THF (36 mL) was cooled to -70 °C (internal temperature) and
stirred as n-BuLi (2 equiv, 3.64 mmol) was slowly added to keep
the temperature e-65 °C. The resulting mixture was stirred at
-70 °C for 30 min after which time a solution of di-tert-butyl
dicarbonate (398 mg, 1.82 mmol) in tetrahydrofuran (1.5 mL)
was slowly added to keep the temperature e-60 °C. After the
mixture was stirred for 30 min at -70 °C, the flask was
transferred to an ice-water bath and allowed to warm to 0 °C
with stirring (15 min). Solid iodine (1.39 g, 5.47 mmol) was then
added in a single portion. After 15 min, the bath was removed,
and the resulting mixture was allowed to warm to room tem-
perature and stirred for 14 h. Iodine was quenched with aqueous
sodium thiosulfate (9.1 mmol in 15 mL water), and the mixture
was extracted with ethyl acetate (2ꢀ50 mL). The extracts were
combined, washed with water (2ꢀ30 mL) and brine (2ꢀ30 mL),
dried (Na2SO4), filtered, and concentrated to a pale yellow solid.
The crude product was suspended in 3:1 diethyl ether-hexanes
(10 mL), stirred 45 min, collected by vacuum filtration, and dried to
afford racemic iodolactam rac-11 (503 mg, 1.0 mmol, 55%) as a
cream-colored solid: mp 180-182 °C; 1H NMR (300 MHz,
CDCl3) δ 7.35 (m, 5H), 5.20-5.03 (m, 3H), 4.62 (br m, 1H), 4.43
(br t, J=4.3 Hz, 1H), 4.18 (m, 1H), 2.73 (br m, 1H), 2.62 (d, J=
12.5 Hz, 1H), 2.51 (dd, J=16.0, 5.5 Hz, 1H), 2.34-2.25 (m, 1H),
2.14-2.02 (m, 1H), 1.53 (s, 9H); ESI MS m/z 401 [C20H25IN2O5 -
C5H8O2 þ H]þ.
[R]25 -69.6 (c 1.0, MeOH); IR (ATR) 3291, 2981, 1732, 1701,
D
1541, 1454, 1363, 1308, 1224, 1198 cm-1; ESI MS m/z 401
[C20H25IN2O5 - C5H8O2 þ H]þ. Anal. Calcd for C20H25IN2O5:
C, 48.01; H, 5.04; N, 5.60; I, 25.36. Found: C, 48.03; H, 4.79; N,
5.38; I, 25.27.
(1R,2S,5R)-tert-Butyl 2-(Benzyloxycarbonylamino)-7-oxo-6-
azabicyclo[3.2.1]octane-6-carboxylate (12). A mixture of iodo-
lactam 11 (38.2 g, 76.4 mmol) and 2,20-azobisisobutyronitrile
(626 mg, 3.8 mmol) in deoxygenated benzene (510 mL) was
stirred under nitrogen as tri-n-butyltin hydride (24.4 g, 0.084
mol) was added in a single portion. The resulting mixture was
slowly warmed to a gentle reflux, and this was stirred for 0.66 h.
TLC atthistime indicated the reactionwas complete. Solvent was
removed by rotary evaporation, and the residue was dried briefly
under vacuum to yield a pasty solid. The solid was broken up,
suspended in hexanes (450 mL), and stirred vigorously for 2 h.
After being cooled in an ice-water bath for 0.25 h, the solid
material was collected by vacuum filtration, rinsed with cold
hexanes (3 ꢀ 150 mL), and dried under vacuum to afford 12 (26.2 g,
70.0 mmol, 91%) as a white solid. Recrystallization of a 200 mg
sample from 10% ethyl acetate/hexanes afforded an analytical
sample (168 mg, mp 96.9 °C, DSC): 1H NMR (300 MHz, CDCl3)
δ 7.33 (s, 5H), 5.19 (d, J=8.9 Hz, 1H) 5.14-4.95 (m, 2H), 4.30 (br
t, J=4.4 Hz, 1H), 3.97-3.81 (m, 1H), 2.68 (br d, J=2.7 Hz, 1H),
2.33-1.99 (m, 3H), 1.52 (s, 9H), 1.71-1.10 (m, 3H); 13C NMR
(75 MHz, CDCl3) δ 173.9, 155.5, 149.5, 136.3, 128.5, 128.0, 127.9,
Acknowledgment. We thank Dr. Joel C. Barrish for a
critical review of the manuscript.
Supporting Information Available: Experimental proce-
dures for the preparation of compounds 6-10 and copies of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
83.0, 77.2, 66.7, 55.0, 48.5, 47.2, 33.8, 28.0, 26.7, 26.2; [R]25
-
113.6 (c 1.03, MeOH); IR (ATR) 3320, 2978, 1736, 1698, 1530,
D
1450, 1367, 1315, 1237, 1216 cm-1; ESI MSm/z 275 [C20H26N2O5 -
6370 J. Org. Chem. Vol. 74, No. 16, 2009